Book of Abstracts - MEG Studies Magnetoencephalography 2008–2019 Forewords

Dear reader, We were astounded by the number of patients involved in research on schizophrenia, autism, and many We are delighted about the number and high quality of other disorders. The below chart indicates the number magnetoencephalography (MEG) research published of patients involved in research into some of the most every year by MEGIN customers as well as by users of studied of these disorders and conditions. other MEG devices. While not a comprehensive bibliog- Abstracts included on the following pages represent raphy of magnetoencephalography research, this book what we believe are the most influential studies in each presents you with a selection of abstracts we believe disorder or condition. reflect some of the more exciting and influential clinical While in no way complete, we hope this collection is research using this technology. useful to you who may want to learn about how MEG is When selecting abstracts for this book, we reviewed currently used in clinical research or are perhaps inter- 851 studies published during the past 12 years. These ested in studies pertaining to particular disorder. papers involved a total of 20,435 patients, spanning Enjoy! diseases such as epilepsy, dementias, autism spectrum disorders, and many more. The majority of the articles we reviewed were published in prestigious peer- reviewed journals, which makes us believe that the overall quality of the research is outstanding and worth sharing with the user community as well as profession- als aspring to become familiar with MEG.

Number of patients 0 500 1,000 1,500 2,000 2,500 3,000

Epilepsy 2,728

Schizophrenia 2,546

Autism Spectrum Disorders 2,400

Alzheimer's Disease 1,258

Post-traumatic Stress Disorder 961

Pain 684

Stroke 613

Parkinson's Disease 539

Parkinson's disease 539

Bipolar Disorder 474

Tinnitus 457

Dementia 441

Migraine 434

Depression 419

Dysl exi a 397

Multiple Sclerosis 373

i ii Contents

i Forewords p. 7 Oscillations, networks, and their development: MEG connectivity changes with age iii Contents p. 7 Spectral changes in spontaneous MEG activity 1 Aging across the lifespan p. 1 The impact of age and sex on the oscillatory p. 8 Hippocampal lateralization and memory in chil- dynamics of visuospatial processing dren and adults p. 1 Anticipatory neural dynamics of spatial-tempo- p. 8 Spatiotemporal dependency of age-related ral orienting of attention in younger and older changes in brain signal variability adults p. 8 Visual dominance and multisensory integration p. 2 Maturation trajectories of cortical resting-state changes with age networks depend on the mediating frequency band p. 9 Brain oscillatory complexity across the life span p. 2 Aging Affects Adaptation to Sound-Level Statis- p. 9 Functional and structural correlates of the aging tics in Human Auditory Cortex brain: relating visual cortex (V1) gamma band responses to age-related structural change p. 3 Is an absolute level of cortical beta suppression required for proper movement? Magnetoen- 11 Alzheimer's Disease cephalographic evidence from healthy aging p. 11 Functional Connectivity Disruption in Subjective p. 3 40-Hz oscillations underlying perceptual binding Cognitive Decline and Mild Cognitive Impair- in young and older adults ment: A Common Pattern of Alterations p. 4 Behavioral and Neural Markers of Flexible Atten- p. 11 Dispersion entropy for the analysis of resting- tion over Working Memory in Aging state MEG regularity in Alzheimer's disease p. 4 Age-related changes to oscillatory dynamics in p. 11 Incidence and impact of subclinical epileptiform hippocampal and neocortical networks activity in Alzheimer's disease p. 5 The effect of ageing on fMRI: Correction for the p. 12 Evaluation of resting-state magnetoencepha- confounding effects of vascular reactivity evalu- logram complexity in Alzheimer's disease with ated by joint fMRI and MEG in 335 adults multivariate multiscale permutation and sample entropies p. 6 Effects of aging on the neuromagnetic mismatch detection to speech sounds p. 12 Multiscale entropy analysis of resting-state magnetoencephalogram with tensor factorisations in p. 6 High-gamma activity in an attention network Alzheimer's disease predicts individual differences in elderly adults' behavioral performance

iii p. 13 Analysis of magnetoencephalography record- p. 18 Exercise, APOE, and working memory: MEG and ings from Alzheimer's disease patients using behavioral evidence for benefit of exercise in embedding entropies epsilon4 carriers p. 13 Regional functional connectivity predicts p. 19 Assessment of classification improvement in distinct cognitive impairments in Alzheimer's patients with Alzheimer's disease based on mag- disease spectrum netoencephalogram blind source separation p. 14 Analysis of neural dynamics in mild cognitive im- p. 19 Evaluation of spectral ratio measures from pairment and Alzheimer's disease using wavelet spontaneous MEG recordings in patients with turbulence Alzheimer's disease p. 14 MEG delta mapping along the healthy aging- p. 20 Regional analysis of spontaneous MEG rhythms Alzheimer's disease continuum: diagnostic in patients with Alzheimer's disease using spec- implications tral entropies p. 15 Synchrony analysis of spontaneous MEG activity p. 20 Analysis of the magnetoencephalogram back- in Alzheimer's disease patients ground activity in Alzheimer's disease patients with auto-mutual information p. 15 Disruption of functional brain networks in Alz- heimer's disease: what can we learn from graph p. 21 Phase lag index: assessment of functional con- spectral analysis of resting-state magnetoen- nectivity from multi channel EEG and MEG with cephalography? diminished bias from common sources p. 16 Evaluation and tracking of Alzheimer's disease p. 21 Extraction of spectral based measures from MEG severity using resting-state magnetoencepha- background oscillations in Alzheimer's disease lography 23 Attention Deficit and Hyperactivity p. 16 Complexity analysis of spontaneous brain Disorder activity in Alzheimer disease and mild cognitive impairment: an MEG study p. 23 MEG Analysis of Neural Interactions in Attention- Deficit/Hyperactivity Disorder p. 17 Study of the MEG background activity in Alz- heimer's disease patients with scaling analysis p. 23 Pharmaco-MEG evidence for attention related methods hyper-connectivity between auditory and prefrontal cortices in ADHD p. 17 Blind source separation to enhance spectral and non-linear features of magnetoencephalogram p. 24 Atypical coupling between posterior regions of recordings. Application to Alzheimer's disease the default mode network in attention-deficit/ hyperactivity disorder: a pharmaco-magnetoen- p. 17 Analysis of MEG background activity in Alzhei- cephalography study mer's disease using nonlinear methods and ANFIS p. 24 Behavioral consequences of aberrant alpha lateralization in attention-deficit/hyperactivity p. 18 Resting-state oscillatory brain dynamics in Alz- disorder heimer disease p. 25 Amphetamines modulate prefrontal γ oscillations during attention processing iv p. 25 Regularity analysis of spontaneous MEG activity p. 32 Patterns of altered neural synchrony in the de- in Attention-Deficit/Hyperactivity Disorder fault mode network in autism spectrum disorder revealed with magnetoencephalography (MEG): p. 25 Gamma-frequency neuronal activity is dimin- Relationship to clinical symptomatology ished in adults with attention-deficit/hyperactivity disorder: a pharmaco-MEG study p. 33 Frontal evoked γ activity modulates behavioural performance in Autism Spectrum Disorders in a p. 26 Broadband neurophysiological abnormalities perceptual simultaneity task in the medial prefrontal region of the default- mode network in adults with ADHD p. 33 Magnetoencephalography reveals an increased non-target P3a, but not target P3b, that is associ- p. 26 Abnormal neural reactivity to unpredictable ated with high non-clinical psychosocial deficits sensory events in attention-deficit/hyperactivity disorder p. 34 Diminished neural resources allocation to time processing in Autism Spectrum Disorders p. 27 Community participatory research: student nurses collaborate to reduce lead exposure by p. 34 Disconnection from others in autism is more educating paint retailers than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional 29 Autism Spectrum Disorders faces p. 29 Abnormal auditory mismatch fields in adults p. 35 Mismatch field latency, but not power, may mark with autism spectrum disorder a shared autistic and schizotypal trait phenotype p. 29 Abnormal cortical activation during silent p. 35 Developmental changes in neuromagnetic reading in adolescents with autism spectrum rhythms and network synchrony in autism disorder p. 36 Hypoxia facilitates epithelial-mesenchymal p. 30 Do you know what I'm thinking? Temporal and transition-mediated rectal cancer progress spatial brain activity during a theory-of-mind task in children with autism p. 36 A combined study of MEG and pico-Tesla TMS on children with autism disorder p. 30 Enhanced Early Visual Responses During Implicit Emotional Faces Processing in Autism Spectrum p. 37 Synchrony of auditory brain responses predicts Disorder behavioral ability to keep still in children with autism spectrum disorder: Auditory-evoked p. 31 Altered Gamma Oscillations during Motor Con- response in children with autism spectrum disor- trol in Children with Autism Spectrum Disorder der p. 31 Maturational trajectories of local and long-range p. 37 Maturation of auditory neural processes in functional connectivity in autism during face autism spectrum disorder - A longitudinal MEG processing study p. 32 Predictable information in neural signals dur- p. 38 Atypical Bilateral Brain Synchronization in the ing resting state is reduced in autism spectrum Early Stage of Human Voice Auditory Processing disorder in Young Children with Autism

v p. 38 Multimodal Diffusion-MRI and MEG Assessment p. 46 Reduced Theta Connectivity during Set-Shifting of Auditory and Language System Development in Children with Autism in Autism Spectrum Disorder p. 47 Altered oscillation patterns and connectivity p. 39 Enhanced brain signal variability in children with during picture naming in autism autism spectrum disorder during early childhood p. 47 Maturational differences in thalamocortical white matter microstructure and auditory p. 40 Perceptual Integration Deficits in Autism Spec- evoked response latencies in autism spectrum trum Disorders Are Associated with Reduced disorders Interhemispheric Gamma-Band Coherence p. 48 Neuromagnetic oscillations predict evoked-re- p. 40 Desynchronization of fronto-temporal networks sponse latency delays and core language deficits during working memory processing in autism in autism spectrum disorders p. 41 Stronger Neural Modulation by Visual Motion p. 48 Brain routes for reading in adults with and with- Intensity in Autism Spectrum Disorders out autism: EMEG evidence p. 41 Deficits in auditory processing contribute to im- p. 49 Chest wall reconstruction with methacrylate pairments in vocal affect recognition in autism prosthesis in Poland syndrome spectrum disorders: A MEG study p. 49 A custom magnetoencephalography device p. 42 Somatosensory cortex functional connectivity reveals brain connectivity and high reading/de- abnormalities in autism show opposite trends, coding ability in children with autism depending on direction and spatial scale p. 49 Using multiparametric data with missing fea- p. 43 Reduced beta connectivity during emotional tures for learning patterns of pathology face processing in adolescents with autism p. 50 Autism traits in individuals with agenesis of the p. 43 Progressively increased M50 responses to re- corpus callosum peated sounds in autism spectrum disorder with auditory hypersensitivity: a magnetoencephalo- p. 50 Resting-state oscillatory activity in autism spec- graphic study trum disorders p. 44 Missing and delayed auditory responses in p. 51 Transient and steady-state auditory gamma- young and older children with autism spectrum band responses in first-degree relatives of disorders people with autism spectrum disorder p. 44 Reduced long-range functional connectivity in p. 51 Auditory magnetic mismatch field latency: a young children with autism spectrum disorder biomarker for language impairment in autism p. 45 Reduced predictable information in brain signals p. 52 Validating γ oscillations and delayed auditory in autism spectrum disorder responses as translational biomarkers of autism p. 46 Is inhibitory control a 'no-go' in adolescents with p. 52 Decreased brain coordinated activity in autism autism spectrum disorder? spectrum disorders during executive tasks: reduced long-range synchronization in the frontoparietal networks vi p. 53 How somatic cortical maps differ in autistic and p. 60 Complexity analysis of spontaneous brain activ- typical brains ity: effects of depression and antidepressant treatment p. 53 Magnetoencephalographic pattern of epileptiform activity in children with early-onset autism p. 60 Anterior cingulate desynchronization and func- spectrum disorders tional connectivity with the amygdala during a working memory task predict rapid antidepres- 55 Depression sant response to ketamine p. 55 Dynamic community structure in major depres- p. 61 Preattentive dysfunction in major depression: a sive disorder: A resting-state MEG study magnetoencephalography study using auditory mismatch negativity p. 55 Complexity analysis of spontaneous brain activity in mood disorders: A magnetoencephalogra- p. 61 Increased anterior cingulate cortical activity in phy study of bipolar disorder and major depres- response to fearful faces: a neurophysiological sion biomarker that predicts rapid antidepressant response to ketamine p. 56 A supplementary functional connectivity microstate attached to the default mode network in 63 Dyslexia depression revealed by resting-state magnetoencephalography p. 63 Increased variability of stimulus-driven cortical responses is associated with genetic variability p. 56 Predictability of depression severity based on in children with and without dyslexia posterior alpha oscillations p. 63 Aberrant resting-state functional brain networks p. 57 Magnetoencephalographic Correlates of Emo- in dyslexia: Symbolic mutual information analy- tional Processing in Major Depression Before sis of neuromagnetic signals and After Pharmacological Treatment p. 64 Spatiotemporal reorganization of the reading p. 57 Group differences in MEG-ICA derived resting network in adult dyslexia state networks: Application to major depressive disorder p. 64 Greater Repertoire and Temporal Variability of Cross-Frequency Coupling (CFC) Modes in Rest- p. 58 Baseline working memory activation deficits in ing-State Neuromagnetic Recordings among dimensional anxious depression as detected by Children with Reading Difficulties magnetoencephalography p. 65 Out-of-synchrony speech entrainment in devel- p. 59 Impaired prefrontal-amygdala effective con- opmental dyslexia nectivity is responsible for the dysfunction of emotion process in major depressive disorder: a p. 65 Low frequency overactivation in dyslexia: Evi- dynamic causal modeling study on MEG dence from resting state Magnetoencephalogra- phy p. 59 Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment- p. 66 Changes in cerebellar activity and inter- resistant major depression hemispheric coherence accompany improved reading performance following Quadrato Motor Training

vii p. 66 Lateralized auditory brain function in children p. 74 The clinical impact of integration of magnetoen- with normal reading ability and in children with cephalography in the presurgical workup for dyslexia refractory nonlesional epilepsy p. 67 Gamma phase locking modulated by phonologi- p. 74 Magnetoencephalographic imaging of ictal cal contrast during auditory comprehension in high-frequency oscillations (80-200 Hz) in phar- reading disability macologically resistant focal epilepsy p. 67 Altered low-γ sampling in auditory cortex ac- p. 75 Correlating magnetoencephalography to stereo- counts for the three main facets of dyslexia electroencephalography in patients undergoing epilepsy surgery p. 67 Engagement of temporal lobe regions predicts response to educational interventions in adoles- p. 75 Resective surgery for medically refractory epi- cent struggling readers lepsy using intraoperative MRI and functional neuronavigation: the Erlangen experience of 415 p. 68 Temporo-parietal brain activity as a longitudinal patients predictor of response to educational interventions among middle school struggling readers p. 76 The presence of short and sharp MEG spikes implies focal cortical dysplasia p. 68 The timing and strength of regional brain activation associated with word recognition in p. 77 Epileptogenic zone localization using magne- children with reading difficulties toencephalography predicts seizure freedom in epilepsy surgery p. 69 Dynamic task-specific brain network connectivity in children with severe reading difficulties p. 77 Magnetic source imaging in posterior cortex epilepsies p. 69 Auditory word perception in sentence context in reading-disabled children p. 78 The correlation of magnetoencephalography to intracranial EEG in localizing the epileptogenic 71 Epilepsy zone: a study of the surgical resection outcome p. 71 Magnetoencephalography for epileptic focus p. 78 Clinical relevance of source location in frontal localization in a series of 1000 cases lobe epilepsy and prediction of postoperative long-term outcome p. 71 Magnetoencephalography and ictal SPECT in patients with failed epilepsy surgery p. 79 Magnetic source imaging and ictal SPECT in MRI- negative neocortical epilepsies: additional value p. 72 Assessment of the Utility of Ictal Magnetoen- and comparison with intracranial EEG cephalography in the Localization of the Epilep- tic Seizure Onset Zone p. 80 Magnetic source imaging in non-lesional neocortical epilepsy: additional value and compari- p. 73 Increased Functional MEG Connectivity as a son with ICEEG Hallmark of MRI-Negative Focal and Generalized Epilepsy p. 80 Inverse modeling in magnetic source imaging: Comparison of MUSIC, SAM(g2), and sLORETA to p. 73 Magnetoencephalographic Spike Analysis in interictal intracranial EEG Patients With Focal Cortical Dysplasia: What Defines a "Dipole Cluster"? viii p. 81 Clinical added value of magnetic source imaging p. 88 Neuromagnetic abnormality of motor cortical in the presurgical evaluation of refractory focal activation and phases of headache attacks in epilepsy childhood migraine p. 81 Evaluation of postoperative sharp waveforms p. 88 Aberrant neuromagnetic activation in the motor through EEG and magnetoencephalography cortex in children with acute migraine: a magnetoencephalography study p. 82 Lateralizing language with magnetic source imaging: validation based on the Wada test p. 89 Visual cortex excitability and plasticity associated with remission from chronic to episodic p. 82 Magnetic source imaging for the surgical evalu- migraine ation of electroencephalography-confirmed secondary bilateral synchrony in intractable p. 89 Identification of abnormal neuromagnetic signa- epilepsy tures in the motor cortex of adolescent migraine p. 83 Influence of magnetic source imaging for plan- p. 91 Peri-ictal normalization of visual cortex excitabil- ning intracranial EEG in epilepsy ity in migraine: an MEG study p. 83 Magnetoencephalography is more successful for 93 Multiple Sclerosis screening and localizing frontal lobe epilepsy than electroencephalography p. 93 Neurovascular Coupling During Visual Stimula- tion in Multiple Sclerosis: A MEG-fMRI Study 85 Migraine p. 93 A reduced somatosensory gating response in p. 85 Abnormality of visual neuromagnetic activation individuals with multiple sclerosis is related to in female migraineurs without aura between walking impairment attacks p. 94 Disruption of structural and functional networks p. 85 Abnormal functional connectivity under so- in long-standing multiple sclerosis matosensory stimulation in migraine: a multi- frequency magnetoencephalography study p. 94 Cognitive and clinical dysfunction, altered MEG resting-state networks and thalamic atrophy in p. 86 Somatosensory gating is altered and associated multiple sclerosis with migraine chronification: A magnetoencephalographic study p. 95 Cognitive dysfunction in early multiple sclerosis: altered centrality derived from resting-state p. 86 Quantitative neuromagnetic signatures of functional connectivity using magneto-enceph- aberrant cortical excitability in pediatric chronic alography migraine p. 95 Thalamocortical sensorimotor circuit in multiple p. 87 Resting state brain activity in patients with mi- sclerosis: an integrated structural and electro- graine: a magnetoencephalography study physiological assessment p. 87 Abnormal cortical activation in females with p. 96 Intra-cortical connectivity in multiple sclerosis: a acute migraine: a magnetoencephalography neurophysiological approach study

ix 97 Neoplasms p. 103 Synchronized brain activity and neurocognitive function in patients with low-grade glioma: a p. 97 Histopathologic and Clinical Correlation of Aber- magnetoencephalography study rant Neuromagnetic Activities with Low to High Frequency of Gliomas 105 Pain p. 97 Cognitive functioning and functional brain p. 105 Brain responses to other people's pain in fibro- networks in postoperative WHO grade I menin- myalgia: a magnetoencephalography study gioma patients p. 105 Expectation violation and attention to pain p. 98 Oscillatory brain activity associates with neuroli- jointly modulate neural gain in somatosensory gin-3 expression and predicts progression free cortex survival in patients with diffuse glioma p. 106 Maternal Depression Across the First Years of Life p. 98 Localized N20 Component of Somatosensory Impacts the Neural Basis of Empathy in Preado- Evoked Magnetic Fields in Frontoparietal Brain lescence Tumor Patients Using Noise-Normalized Ap- proaches p. 106 Adolescents growing up amidst intractable conflict attenuate brain response to pain of p. 99 Gamma deficits as a neural signature of cogni- outgroup tive impairment in children treated for brain tumors p. 107 Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI) p. 99 Local MEG networks: the missing link between protein expression and epilepsy in glioma pa- p. 107 Decoding the perception of endogenous pain tients? from resting-state MEG p. 100 MEG network differences between low- and p. 108 Prior exposure to extreme pain alters neural high-grade glioma related to epilepsy and cog- response to pain in others nition p. 108 Cortical reorganization after macroreplantation p. 100 Neural correlates of delayed visual-motor perfor- at the upper extremity: a magnetoencephalo- mance in children treated for brain tumours graphic study p. 101 Long-term effects of cranial irradiation and p. 109 Gamma oscillatory amplitude encodes stimulus intrathecal chemotherapy in treatment of child- intensity in primary somatosensory cortex hood leukemia: a MEG study of power spectrum and correlated cognitive dysfunction p. 109 Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school- p. 102 Epilepsy is related to theta band brain con- age children born at extremely low gestational nectivity and network topology in brain tumor age patients p. 110 The influence of music and music therapy on p. 102 Disturbed functional brain networks and neuro- pain-induced neuronal oscillations measured by cognitive function in low-grade glioma patients: magnetencephalography a graph theoretical analysis of resting-state MEG

x p. 110 Acupuncture induces divergent alterations of p. 116 The perception of pain in others suppresses functional connectivity within conventional somatosensory oscillations: a magnetoencepha- frequency bands: evidence from MEG recordings lography study p. 111 Pre- and post-stimulus alpha activity shows p. 116 Noxious counterirritation in patients with ad- differential modulation with spatial attention vanced osteoarthritis of the knee reduces MCC during the processing of pain but not SII pain generators: A combined use of MEG and EEG p. 111 Sensorimotor Alpha Activity is Modulated in Response to the Observation of Pain in Others p. 117 Attention to painful stimulation enhances gamma-band activity and synchronization in p. 112 Emotional facial expressions modulate pain- human sensorimotor cortex induced beta and gamma oscillations in sensorimotor cortex 119 Parkinson's Disease p. 112 Anesthetic block of pain-related cortical activity p. 119 Distinct cortical responses evoked by electrical in patients with peripheral nerve injury meas- stimulation of the thalamic ventral intermediate ured by magnetoencephalography nucleus and of the subthalamic nucleus p. 113 Cortical activation changes during repeated p. 119 The significance of brain oscillations in motor laser stimulation: a magnetoencephalographic sequence learning: Insights from Parkinson's study disease p. 113 World Health Day 2011--antimicrobial resistance: p. 120 Spontaneous sensorimotor cortical activity is no action today, no cure tomorrow suppressed by deep brain stimulation in patients with advanced Parkinson's disease p. 113 fMRI and MEG analysis of visceral pain in healthy volunteers p. 120 Changes in resting-state directed connectivity in cortico-subcortical networks correlate with p. 114 Abnormal thalamocortical activity in patients cognitive function in Parkinson's disease with Complex Regional Pain Syndrome (CRPS) type I p. 121 Combined MEG and pT-TMS study in Parkinson's disease p. 114 Functional integration within the human pain system as revealed by Granger causality p. 121 Deep brain stimulation modulates synchrony within spatially and spectrally distinct resting p. 115 Quality discrimination for noxious stimuli in state networks in Parkinson's disease secondary somatosensory cortex: a MEG-study p. 122 Subthalamic nucleus phase-amplitude coupling p. 115 Gender differences in the mu rhythm during correlates with motor impairment in Parkinson's empathy for pain: an electroencephalographic disease study p. 122 Effects of rhythmic stimulus presentation on os- p. 116 Evoked magnetic fields following noxious laser cillatory brain activity: the physiology of cueing stimulation of the thigh in humans in Parkinson's disease

p. 123 Resting state cortical oscillations of patients with Parkinson disease and with and without sub-

xi thalamic deep brain stimulation: a magnetoen- p. 129 Dopaminergic modulation of cortico-cortical cephalography study functional connectivity in Parkinson's disease: an MEG study p. 123 Cortico-muscular coherence in advanced Parkin- son's disease with deep brain stimulation p. 130 Increased cortico-cortical functional connectivity in early-stage Parkinson's disease: an MEG p. 124 Predicting dementia in Parkinson disease by study combining neurophysiologic and cognitive markers 131 Post-traumatic Stress Disorder p. 124 Neuromagnetic evidence of abnormal move- p. 131 Post-traumatic stress disorder and chronic hy- ment-related beta desynchronization in Parkin- perconnectivity in emotional processing son's disease p. 131 Increased Small-World Network Topology Fol- p. 125 Movement related dynamics of subthalmo-corti- lowing Deployment-Acquired Traumatic Brain cal alpha connectivity in Parkinson's disease Injury Associated with the Development of Post- Traumatic Stress Disorder p. 125 Differential modulation of STN-cortical and cortico-muscular coherence by movement and p. 132 Veterans with PTSD demonstrate amygdala levodopa in Parkinson's disease hyperactivity while viewing threatening faces: A MEG study p. 126 Movement-related changes in local and long- range synchronization in Parkinson's disease p. 132 Attention training modulates resting-state neu- revealed by simultaneous magnetoencephalog- rophysiological abnormalities in posttraumatic raphy and intracranial recordings stress disorder p. 126 Motor-cortical oscillations in early stages of p. 133 Oscillatory magnetic brain activity is related to Parkinson's disease dissociative symptoms and childhood adversities - A study in women with multiple trauma p. 127 Cognitive decline in Parkinson's disease is associated with slowing of resting-state brain activity: p. 133 Resilience and cross-network connectivity: A a longitudinal study neural model for post-trauma survival p. 127 Complexity analysis of resting-state MEG activity p. 134 Neural correlates of attention bias in posttrau- in early-stage Parkinson's disease patients matic stress disorder p. 128 Distinct oscillatory STN-cortical loops revealed p. 134 Post-Traumatic Stress Constrains the Dynamic by simultaneous MEG and local field potential Repertoire of Neural Activity recordings in patients with Parkinson's disease p. 135 Decreased somatosensory activity to non-threat- p. 128 Slowing of M1 activity in Parkinson's disease ening touch in combat veterans with posttrau- during rest and movement--an MEG study matic stress disorder p. 129 Effects of DBS on auditory and somatosensory p. 135 Soldiers With Posttraumatic Stress Disorder See a processing in Parkinson's disease World Full of Threat: Magnetoencephalography Reveals Enhanced Tuning to Combat-Related Cues

xii p. 136 Diagnosis of posttraumatic stress disorder p. 144 Magnetoencephalographic study of hand and (PTSD) based on correlations of prewhitened foot sensorimotor organization in 325 consecu- fMRI data: outcomes and areas involved tive patients evaluated for tumor or epilepsy surgery p. 136 Neural communication in posttraumatic growth p. 144 Reliability for non-invasive somatosensory p. 136 Development and application of a diagnostic cortex localization: Implications for pre-surgical algorithm for posttraumatic stress disorder mapping p. 137 Voxel-wise resting-state MEG source magnitude p. 145 Magnetoencephalography-guided resection of imaging study reveals neurocircuitry abnormal- epileptogenic foci in children ity in active-duty service members and veterans with PTSD p. 146 Magnetoencephalography helps delineate the extent of the epileptogenic zone for surgical p. 138 Resting-state hippocampal connectivity cor- planning in children with intractable epilepsy relates with symptom severity in post-traumatic due to porencephalic cyst/encephalomalacia stress disorder p. 146 Clinical relevance of source location in frontal p. 138 Colour or shape: examination of neural process- lobe epilepsy and prediction of postoperative es underlying mental flexibility in posttraumatic long-term outcome stress disorder p. 147 Frameless stereotactic functional neuronaviga- p. 139 Neural network modulation by trauma as tion combined with intraoperative magnetic a marker of resilience: differences between resonance imaging as a strategy in highly elo- veterans with posttraumatic stress disorder and quent located tumors causing epilepsy resilient controls p. 147 The utility of magnetoencephalography in the p. 139 Early processing of threat cues in posttraumatic presurgical evaluation of refractory insular epi- stress disorder-evidence for a cortical vigilance- lepsy avoidance reaction p. 148 Preoperative magnetoencephalographic sensory p. 140 Pattern of cortical activation during processing cortex mapping of aversive stimuli in traumatized survivors of war and torture p. 148 Correlation between magnetoencephalography- based "clusterectomy" and postoperative seizure p. 140 Altered oscillatory brain dynamics after repeated freedom traumatic stress p. 149 Magnetic source imaging (MSI) in children with 143 Presurgical Functional Mapping neocortical epilepsy: surgical outcome association with 3D post-resection analysis p. 143 Timing and type of hemispherectomy for Ras- mussen's encephalitis: Analysis of 45 patients p. 149 Interictal MEG reveals focal cortical dysplasias: special focus on patients with no visible MRI le- p. 143 Change in presurgical diagnostic imaging sions evaluation affects subsequent pediatric epilepsy surgery outcome p. 150 FDG-PET and magnetoencephalography in presurgical workup of children with localization- related nonlesional epilepsy

xiii p. 150 Localization value of magnetoencephalography p. 156 Resting functional connectivity in patients with interictal spikes in adult nonlesional neocortical brain tumors in eloquent areas epilepsy p. 157 An assessment of MEG coherence imaging in the p. 151 Magnetic source imaging and ictal SPECT in MRI- study of temporal lobe epilepsy negative neocortical epilepsies: additional value and comparison with intracranial EEG p. 157 Refined analysis of complex language representations by non-invasive neuroimaging tech- p. 151 Magnetoencephalographic imaging of resting- niques state functional connectivity predicts postsurgical neurological outcome in brain gliomas p. 158 Interictal MEG/MSI in intractable mesial temporal lobe epilepsy: spike yield and characteriza- p. 152 Preoperative multimodal motor mapping: a tion comparison of magnetoencephalography imaging, navigated transcranial magnetic stimulation, p. 158 Neurosurgical management of intractable and direct cortical stimulation rolandic epilepsy in children: role of resection in eloquent cortex. Clinical article p. 152 Magnetoencephalography in pediatric lesional epilepsy surgery p. 159 Lateralizing language with magnetic source imaging: validation based on the Wada test p. 153 Magnetic source imaging in non-lesional neocortical epilepsy: additional value and compari- p. 160 Effect of epilepsy magnetic source imaging on son with ICEEG intracranial electrode placement p. 153 Dynamics of hemispheric dominance for lan- p. 160 Temporo-parietal theta activity correlates with guage assessed by magnetoencephalographic misery perfusion in arterial occlusive disease imaging p. 161 Presurgical localization of primary motor cortex p. 154 Potential role for magnetoencephalography in in pediatric patients with brain lesions by the distinguishing low- and high-grade gliomas: a use of spatially filtered magnetoencephalogra- preliminary study with histopathological confir- phy mation p. 161 Changing ictal-onset EEG patterns in children p. 154 Clinical added value of magnetic source imaging with cortical dysplasia in the presurgical evaluation of refractory focal epilepsy p. 162 Characteristics of MEG and MRI between Taylor's focal cortical dysplasia (type II) and other corti- p. 155 Connectivity in MEG resting-state networks cal dysplasia: surgical outcome after complete increases after resective surgery for low-grade resection of MEG spike source and MR lesion in glioma and correlates with improved cognitive pediatric cortical dysplasia performance p. 162 Preoperative localization of hand motor cortex p. 155 MEG in frontal lobe epilepsies: localization and by adaptive spatial filtering of magnetoencepha- postoperative outcome lography data p. 156 Interictal magnetoencephalographic findings p. 162 Treatment-related changes in functional con- related with surgical outcomes in lesional and nectivity in brain tumor patients: a magnetoen- nonlesional neocortical epilepsy cephalography study xiv p. 163 Fast oscillations associated with interictal spikes p. 171 Magnetoencephalographic and functional MRI localize the epileptogenic zone in patients with connectomics in schizophrenia via intra- and partial epilepsy inter-network connectivity p. 163 Mapping functional connectivity in patients with p. 171 Magnetoencephalographic recording of audi- brain lesions tory mismatch negativity in response to duration and frequency deviants in a single session p. 164 Predicting the location of mouth motor cortex in in patients with schizophrenia patients with brain tumors by using somatosensory evoked field measurements p. 172 Abnormal Neural Oscillations in Schizophrenia Assessed by Spectral Power Ratio of MEG During p. 164 Neuromagnetic localization of spike sources in Word Processing perilesional, contralateral mirror, and ipsilateral remote areas in patients with cavernoma p. 172 Frequency-specific disruptions of neuronal oscillations reveal aberrant auditory processing in 167 Schizophrenia schizophrenia p. 167 MEG resting-state oscillations and their relation- p. 173 A multi-layer network approach to MEG connec- ship to clinical symptoms in schizophrenia tivity analysis p. 167 Changes in electrophysiological markers of p. 173 Deficient attention modulation of lateralized cognitive control after administration of galan- alpha power in schizophrenia tamine p. 174 Multimodal based classification of schizophrenia p. 168 Neuroimaging investigations of dorsal stream patients processing and effects of stimulus synchrony in schizophrenia p. 174 Abnormal visuomotor processing in schizophrenia p. 168 Identifying auditory cortex encoding abnormalities in schizophrenia: The utility of low-frequen- p. 175 Frontal slow-wave activity as a predictor of nega- cy versus 40 Hz steady-state measures tive symptoms, cognition and functional capacity in schizophrenia p. 169 Abnormal cortical neural synchrony during working memory in schizophrenia p. 175 Auditory Cortical Plasticity Drives Training- Induced Cognitive Changes in Schizophrenia p. 169 Magnetoencephalography reveals an increased non-target P3a, but not target P3b, that is associ- p. 176 Same clock, different time read-out: Spontane- ated with high non-clinical psychosocial deficits ous brain oscillations and their relationship to deficient coding of cognitive content p. 170 Dissociable auditory mismatch response and connectivity patterns in adolescents with schizo- p. 176 Targeted training modifies oscillatory brain phrenia and adolescents with bipolar disorder activity in schizophrenia patients with psychosis: A magnetoencephalography study p. 177 Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations p. 170 The 40-Hz Auditory Steady-State Response in in Cortical-Subcortical Networks in Humans: Patients With Schizophrenia: A Meta-analysis Evidence From Resting-State Magnetoencepha- lography-Recordings

xv p. 177 Complexity measures in magnetoencephalogra- p. 186 Deficits in high- (>60 Hz) gamma-band oscilla- phy: measuring "disorder" in schizophrenia tions during visual processing in schizophrenia p. 178 Modulation of hippocampal theta and hip- p. 186 Multidimensional analysis of the abnormal neu- pocampal-prefrontal cortex function by a schizo- ral oscillations associated with lexical processing phrenia risk gene in schizophrenia p. 179 Ultra-slow frequency bands reflecting potential p. 187 Adjusting brain dynamics in schizophrenia by coherence between neocortical brain regions means of perceptual and cognitive training p. 179 Intraindividual neurophysiological variability in p. 187 Temporal and frontal cortical thickness associa- ultra-high-risk for psychosis and schizophrenia tions with M100 auditory activity and attention patients: single-trial analysis in healthy controls and individuals with schizophrenia p. 180 Multisensory stimuli elicit altered oscillatory brain responses at gamma frequencies in pa- p. 188 Neuromagnetic auditory response and its rela- tients with schizophrenia tion to cortical thickness in ultra-high-risk for psychosis p. 180 Power spectral aspects of the default mode network in schizophrenia: an MEG study p. 188 Magnetoencephalography study of right parietal lobe dysfunction of the evoked mirror neuron p. 181 Increased visual gamma power in schizoaffective system in antipsychotic-free schizophrenia bipolar disorder p. 189 Effects of metabotropic glutamate receptor 3 p. 181 Functional cognitive and cortical abnormalities genotype on phonetic mismatch negativity in chronic and first-admission schizophrenia p. 189 Aberrant auditory processing in schizophrenia p. 182 Source-reconstruction of event-related fields and in subjects at ultra-high-risk for psychosis reveals hyperfunction and hypofunction of cortical circuits in antipsychotic-naive, first-episode p. 190 Auditory cortex responsiveness during talking schizophrenia patients during Mooney face and listening: early illness schizophrenia and processing patients at clinical high-risk for psychosis p. 182 Cortical thickness as a contributor to abnormal p. 190 Imaging of thalamocortical dysrhythmia in neu- oscillations in schizophrenia? ropsychiatry p. 183 Evidence for dysregulated high-frequency oscil- p. 191 Clinical symptoms and alpha band resting-state lations during sensory processing in medication- functional connectivity imaging in patients with naïve, first episode schizophrenia schizophrenia: implications for novel approaches to treatment p. 184 Intra- and inter-frequency brain network structure in health and schizophrenia p. 191 Reduced high and low frequency gamma synchronization in patients with chronic schizo- p. 184 Dynamics of alpha oscillations elucidate facial phrenia affect recognition in schizophrenia p. 192 Decreased α event-related synchronization in p. 185 Using joint ICA to link function and structure us- the left posterior temporal cortex in schizophre- ing MEG and DTI in schizophrenia xvi nia: a magnetoencephalography-beamformer p. 198 Abnormal neural oscillatory activity to speech study sounds in schizophrenia: a magnetoencephalography study p. 192 Neural basis of semantic priming in schizophrenia during a lexical decision task: a magneto- p. 198 Optimized mismatch negativity paradigm encephalography study reflects deficits in schizophrenia patients. A combined EEG and MEG study p. 193 Reduced mismatch negativity and increased variability of brain activity in schizophrenia p. 199 The perception of emotion-free faces in schizophrenia: a magneto-encephalography study p. 193 Evoked and induced oscillatory activity contributes to abnormal auditory sensory gating in p. 199 Abnormal oscillatory brain dynamics in schizo- schizophrenia phrenia: a sign of deviant communication in neural network? p. 193 Specific cognitive training normalizes auditory sensory gating in schizophrenia: a randomized p. 200 Manifest disease and motor cortex reactivity in trial twins discordant for schizophrenia p. 194 An MEG study of alpha modulation in patients 201 Sclerosis with schizophrenia and in subjects at high risk of developing psychosis p. 201 Magnetoencephalography spike sources interrelate the extensive epileptogenic zone of tuber- p. 194 MEG does not reveal impaired sensory gating in ous sclerosis complex first-episode schizophrenia p. 201 Functional substrate for memory function dif- p. 195 Somatosensory system deficits in schizophrenia ferences between patients with left and right revealed by MEG during a median-nerve oddball mesial temporal lobe epilepsy associated with task hippocampal sclerosis p. 195 Timing is everything: neural response dynam- p. 202 Diffuse cerebral language representation in ics during syllable processing and its relation tuberous sclerosis complex to higher-order cognition in schizophrenia and healthy comparison subjects 203 Stroke p. 196 Classification of schizophrenia with spectro-tem- p. 203 Deep brain stimulation of the ventral striatal poro-spatial MEG patterns in working memory area for poststroke pain syndrome: a magnetoencephalography study p. 196 Pre-attentive auditory processing in ultra-high- risk for schizophrenia with magnetoencephalog- p. 203 Randomized trial of transcranial direct current raphy stimulation for poststroke dysphagia p. 197 Selection of spectro-temporal patterns in multi- p. 204 Strength of ~20-Hz Rebound and Motor Recov- channel MEG with support vector machines for ery After Stroke schizophrenia classification p. 204 Cortical Excitability Measured with nTMS and p. 197 Schizophrenia diagnosis and anterior hippocam- MEG during Stroke Recovery pal volume make separate contributions to sensory gating

xvii p. 205 MEG-based detection and localization of perile- p. 211 Reorganization of the primary somatosensory sional dysfunction in chronic stroke cortex during stroke recovery p. 205 Cortical mechanisms of mirror therapy after p. 212 Music and speech listening enhance the recov- stroke ery of early sensory processing after stroke p. 206 Do movement-related beta oscillations change p. 212 Neuronal functionality assessed by magnetoen- after stroke? cephalography is related to oxidative stress system in acute ischemic stroke p. 206 Laterality of brain activity during motor imagery is modulated by the provision of source level p. 213 Ipsilateral motor-related hyperactivity in pa- neurofeedback tients with cerebral occlusive vascular disease p. 207 Anterobasal temporal lobe lesions alter recur- p. 213 Aberrant cortical functionality and somatosen- rent functional connectivity within the ventral sory deficits after stroke pathway during naming p. 214 Interhemispheric asymmetry of primary hand p. 207 Alterations in spontaneous brain oscillations representation and recovery after stroke: a MEG during stroke recovery study p. 208 Changes of auditory evoked magnetic fields in 215 Tinnitus patients after acute cerebral infarction using magnetoencephalography p. 215 Source-Space Cross-Frequency Amplitude-Am- plitude Coupling in Tinnitus p. 208 Resting state α-band functional connectivity and recovery after stroke p. 215 Impact of Spectral Notch Width on Neurophysi- ological Plasticity and Clinical Effectiveness of p. 208 Effect of afferent input on motor cortex excitabil- the Tailor-Made Notched Music Training ity during stroke recovery p. 216 Enhancing inhibition-induced plasticity in p. 209 Characterization of motor and somatosensory tinnitus--spectral energy contrasts in tailor-made function for stroke patients notched music matter p. 209 Activation in parietal operculum parallels motor p. 216 Source space estimation of oscillatory power recovery in stroke and brain connectivity in tinnitus p. 210 Cortical swallowing processing in early subacute p. 217 Playing and listening to tailor-made notched stroke music: cortical plasticity induced by unimodal and multimodal training in tinnitus patients p. 210 Auditory and cognitive deficits associated with acquired amusia after stroke: a magnetoenceph- p. 217 Modulatory effects of spectral energy contrasts alography and neuropsychological follow-up on lateral inhibition in the human auditory cor- study tex: an MEG study p. 211 Oscillatory MEG motor activity reflects therapy- p. 218 Auditory evoked magnetic fields in individuals related plasticity in stroke patients with tinnitus

xviii p. 218 rTMS induced tinnitus relief is related to an p. 226 Detecting Mild Traumatic Brain Injury Using increase in auditory cortical alpha activity Resting State Magnetoencephalographic Con- nectivity p. 219 Female sex workers in Africa: epidemiology overview, data gaps, ways forward p. 226 Reduced prefrontal MEG alpha-band power in mild traumatic brain injury with associated post- p. 219 Neuromagnetic indicators of tinnitus and tin- traumatic stress disorder symptoms nitus masking in patients with and without hearing loss p. 227 Functional connectivity changes detected with magnetoencephalography after mild traumatic p. 219 Music-induced cortical plasticity and lateral inhi- brain injury bition in the human auditory cortex as foundations for tonal tinnitus treatment p. 227 Low-frequency connectivity is associated with mild traumatic brain injury p. 220 Assessment of non-motor hearing symptoms in hemifacial spasm using magnetoencephalogra- p. 228 Magnetoencephalography Slow-Wave Detection phy in Patients with Mild Traumatic Brain Injury and Ongoing Symptoms Correlated with Long-Term p. 220 Short and intense tailor-made notched music Neuropsychological Outcome training against tinnitus: the tinnitus frequency matters p. 228 Delayed and disorganised brain activation detected with magnetoencephalography after p. 221 Rapid increases of gamma power in the auditory mild traumatic brain injury cortex following noise trauma in humans p. 229 Single-subject-based whole-brain MEG slow- p. 221 Mapping cortical hubs in tinnitus wave imaging approach for detecting abnormality in patients with mild traumatic brain injury p. 222 Abnormal resting-state cortical coupling in chronic tinnitus p. 229 Complexity analysis of resting state magnetoencephalography activity in traumatic brain injury p. 222 Using auditory steady state responses to outline patients the functional connectivity in the tinnitus brain p. 230 Resting state magnetoencephalography func- p. 223 Transient reduction of tinnitus intensity is tional connectivity in traumatic brain injury marked by concomitant reductions of delta band power p. 231 An automatic MEG low-frequency source imaging approach for detecting injuries in mild and 225 Traumatic Brain Injuries moderate TBI patients with blast and non-blast causes p. 225 Theta-Band Oscillations as an Indicator of Mild Traumatic Brain Injury p. 231 Brain signal variability relates to stability of behavior after recovery from diffuse brain injury p. 225 Attentional dysfunction and recovery in concussion: effects on the P300m and contingent p. 232 Principles of recovery from traumatic brain magnetic variation injury: reorganization of functional networks

xix p. 232 Reorganization of functional connectivity as a correlate of cognitive recovery in acquired brain injury p. 233 Integrated imaging approach with MEG and DTI to detect mild traumatic brain injury in military and civilian patients p. 233 Magnetoencephalographic study of posterior tibial nerve stimulation in patients with intracranial lesions around the central sulcus

xx xxi xxii Aging

The impact of age and sex on the oscillatory stronger correlations between age and neural oscilla- dynamics of visuospatial processing tory responses during task performance than women in lateral occipital and superior temporal regions in the Wiesman, AI; Wilson, TW alpha band and in dorsolateral prefrontal cortex in the gamma band, while women exhibited more robust co- Department of Neurological Sciences, University of Nebraska variance between age and neural responses than men Medical Center, Omaha, NE, USA; Center for Magnetoenceph- in inferior temporal and medial prefrontal cortex in the alography, UNMC, Omaha, NE, USA. theta range. (30321644)

ABSTRACT: The ability to dynamically allocate neural Keywords: Aging; Attention; Neural oscillations; Sex differ- resources within the visual space is supported by a ences number of spectrally-specific oscillatory responses, and such visuospatial processing has been found to decline Neuroimage (2019), Vol. 185, pp. 513-520 moderately with age and differ by sex. However, the direct effects of age and sex on these oscillatory dynamics remains poorly understood. Using magnetoen- Anticipatory neural dynamics of spatial-temporal cephalography (MEG), structural magnetic resonance orienting of attention in younger and older adults imaging, and advanced source reconstruction and statistical methods, we investigated the impact of aging Heideman, SG; Rohenkohl, G; Chauvin, JJ; and sex on behavioral performance and the underlying Palmer, CE; van Ede, F; Nobre, AC neural dynamics during visuospatial processing. In a large sample spanning a broad age range, we find that Oxford Centre for Human Brain Activity, Wellcome Centre for a number of prototypical attention and perception Integrative Neuroimaging, Department of Psychiatry, Univer- network components, both spectrally- and spatially- sity of Oxford, UK; Brain and Cognition Lab, Department of defined, exhibit complex and uniquely informative Experimental Psychology, University of Oxford, UK. relationships with age and sex. Specifically, neural responses in the theta range (4-10 Hz) were found to ABSTRACT: Spatial and temporal expectations act covary with chronological age in prefrontal and motor synergistically to facilitate visual perception. In the cortices, signifying a possible relationship between current study, we sought to investigate the anticipatory age and cognitive control. Further, we found that beta oscillatory markers of combined spatial-temporal ori- (18-24 Hz) activity covaried with age across a large enting and to test whether these decline with ageing. swath of the somato-motor strip, supporting previous We examined anticipatory neural dynamics associated findings of motor planning and execution deficits with with joint spatial-temporal orienting of attention using increasing age. Finally, gamma-frequency (48-70 Hz) magnetoencephalography (MEG) in both younger and oscillations were found to exhibit robust covariance older adults. Participants performed a cued covert with age in superior parietal and temporo-parietal spatial-temporal orienting task requiring the discrimi- areas, indicating that the mapping of saliency in visual nation of a visual target. Cues indicated both where space is modulated by the normal aging process. In- and when targets would appear. In both age groups, terestingly, behavioral performance and some of these valid spatial-temporal cues significantly enhanced oscillatory neural responses also exhibited interactions perceptual sensitivity and reduced reaction times. In between age and sex, indicating sex differences in the the MEG data, the main effect of spatial orienting was evolution of the neural coding of visual perception as the lateralised anticipatory modulation of posterior age increases. In particular, men were found to have alpha and beta oscillations. In contrast to previous

1 reports, this modulation was not attenuated in older conditions, mediate maturation differentially, remains adults; instead it was even more pronounced. The main unknown. Using magnetoencephalography (MEG) to effect of temporal orienting was a bilateral suppression map frequency band specific maturation of resting of posterior alpha and beta oscillations. This effect was state networks from age 7 to 29 in 162 participants (31 restricted to younger adults. Our results also revealed independent), we found significant changes with age in a striking interaction between anticipatory spatial and networks mediated by the beta (13-30 Hz) and gamma temporal orienting in the gamma-band (60-75 Hz). (31-80 Hz) bands. More specifically, gamma band When considering both age groups separately, this mediated networks followed an expected asymptotic effect was only clearly evident and only survived sta- trajectory, but beta band mediated networks followed tistical evaluation in the older adults. Together, these a linear trajectory. Network integration increased with observations provide several new insights into the neu- age in gamma band mediated networks, while local ral dynamics supporting separate as well as combined segregation increased with age in beta band mediated effects of spatial and temporal orienting of attention, networks. Spatially, the hubs that changed in impor- and suggest that different neural dynamics associated tance with age in the beta band mediated networks with attentional orienting appear differentially sensitive had relatively little overlap with those that showed the to ageing. (29733953) greatest changes in the gamma band mediated networks. These findings are relevant for our understand- Keywords: Ageing; Anticipatory attention; MEG; Oscilla- ing of the neural mechanisms of cortical maturation, in tions; Spatial orienting; Temporal orienting both typical and atypical development. (29462724)

Neuroimage (2019), Vol. 178, pp. 46-56 Keywords: Brain connectivity; Development; Graph theory; Magnetoencephalography; Rhythms

Maturation trajectories of cortical resting-state Neuroimage (2019), Vol. 174, pp. 57-68 networks depend on the mediating frequency band

Khan, S; Hashmi, JA; Mamashli, F; Michmizos, K; Kitz- Aging Affects Adaptation to Sound-Level Statistics bichler, MG; Bharadwaj, H; Bekhti, Y; Ganesan, S; Garel, in Human Auditory Cortex KA; Whitfield-Gabrieli, S; Gollub, RL; Kong, J; Vaina, LM; Rana, KD; Stufflebeam, SM; Hämäläinen, MS; Kenet, T Herrmann, B; Maess, B; Johnsrude, IS

Department of Neurology, MGH, Harvard Medical School, The Brain and Mind Institute, The University of Western Boston, USA; Department of Radiology, MGH, Harvard Medi- Ontario, London, Ontario N6A 3K7, Canada, herrmann.b@ cal School, Boston, USA; Athinoula A. Martinos Center for gmail.com. Biomedical Imaging, MGH/HST, Charlestown, USA; McGovern Institute for Brain Research, Massachusetts Institute of Tech- ABSTRACT: Optimal perception requires efficient and nology, Cambridge, USA. Electronic address: sheraz@nmr. adaptive neural processing of sensory input. Neurons in mgh.harvard.edu. nonhuman mammals adapt to the statistical properties of acoustic feature distributions such that they become ABSTRACT: The functional significance of resting sensitive to sounds that are most likely to occur in state networks and their abnormal manifestations the environment. However, whether human auditory in psychiatric disorders are firmly established, as is responses adapt to stimulus statistical distributions the importance of the cortical rhythms in mediating and how aging affects adaptation to stimulus statistics these networks. Resting state networks are known to is unknown. We used MEG to study how exposure to undergo substantial reorganization from childhood different distributions of sound levels affects adapta- to adulthood, but whether distinct cortical rhythms, tion in auditory cortex of younger (mean: 25 years; which are generated by separable neural mechanisms (29358362) and are often manifested abnormally in psychiatric

2 Keywords: aging; auditory cortex; magnetoencephalogra- and beyond the effects of age. A similar link was found phy; neural adaptation; stimulus statistics between beta ERD magnitude and movement duration. These findings suggest a direct linkage between beta J Neurosci (2019), Vol. 38, No. 8, pp. 1989-1999 reduction during movement and spontaneous activity in the motor cortex, such that as spontaneous beta power increases, a greater reduction in beta activity is Is an absolute level of cortical beta required to execute movement. We propose that, on suppression required for proper movement? an individual level, the primary motor cortices have an Magnetoencephalographic evidence from healthy absolute threshold of beta power that must be reached aging in order to move, and that an inability to suppress beta power to this threshold results in an increase in move- Heinrichs-Graham, E; Wilson, TW ment duration. (27090351)

Department of Pharmacology and Experimental Neuro- Keywords: MEG; Motor control; Motor network; Oscilla- science, University of Nebraska, Medical Center (UNMC), tions; Precentral gyrus Omaha, NE, USA,; Center for Magnetoencephalography, UNMC, Omaha, NE, USA. Neuroimage (2018), Vol. 134, pp. 514-521

ABSTRACT: Previous research has connected a specific pattern of beta oscillatory activity to proper motor exe- 40-Hz oscillations underlying perceptual binding in cution, but no study to date has directly examined how young and older adults resting beta levels affect motor-related beta oscillatory activity in the motor cortex. Understanding this rela- Ross, B; Fujioka, T tionship is imperative to determining the basic mechanisms of motor control, as well as the impact of patho- Rotman Research Institute, Baycrest Centre, Toronto, Ontario, logical beta oscillations on movement execution. In Canada. the current study, we used magnetoencephalography (MEG) and a complex movement paradigm to quan- ABSTRACT: Auditory object perception requires tify resting beta activity and movement-related beta binding of elementary features of complex stimuli. oscillations in the context of healthy aging. We chose Synchronization of high-frequency oscillation in neural healthy aging as a model because preliminary evidence networks has been proposed as an effective alternative suggests that beta activity is elevated in older adults, to binding via hard-wired connections because binding and thus by examining older and younger adults we in an oscillatory network can be dynamically adjusted were able to naturally vary resting beta levels. To this to the ever-changing sensory environment. Previously, end, healthy younger and older participants were we demonstrated in young adults that gamma oscil- recorded during motor performance and at rest. Using lations are critical for sensory integration and found beamforming, we imaged the peri-movement beta that they were affected by concurrent noise. Here, we event-related desynchronization (ERD) and extracted aimed to support the hypothesis that stimulus evoked virtual sensors from the peak voxels, which enabled ab- auditory 40-Hz responses are a component of thalamo- solute and relative beta power to be assessed. Interest- cortical gamma oscillations and examined whether this ingly, absolute beta power during the pre-movement oscillatory system may become less effective in aging. baseline was much stronger in older relative to younger In young and older adults, we recorded neuromagnetic adults, and older adults also exhibited proportionally 40-Hz oscillations, elicited by monaural amplitude- large beta desynchronization (ERD) responses during modulated sound. Comparing responses in quiet and motor planning and execution compared to younger under contralateral masking with multitalker babble adults. Crucially, we found a significant relationship noise revealed two functionally distinct components between spontaneous (resting) beta power and beta of auditory 40-Hz responses. The first component fol- ERD magnitude in both primary motor cortices, above lowed changes in the auditory input with high fidel-

3 ity and was of similar amplitude in young and older that retro-cues induced a transient lateralization of adults. The second, significantly smaller in older adults, alpha (8-14 Hz) and beta (15-30 Hz) oscillatory power. showed a 200-ms interval of amplitude and phase Interestingly, shorter durations of alpha/beta lateral- rebound and was strongly attenuated by contralateral ization following retro-cues predicted larger cueing noise. The amplitude of the second component was benefits, reinforcing recent ideas about the dynamic correlated with behavioral speech-in-noise perfor- nature of access to WM representations. Our results mance. Concurrent noise also reduced the P2 wave of suggest that older adults retain flexible control over auditory evoked responses at 200-ms latency, but not WM, but individual differences in control correspond the earlier N1 wave. P2 modulation was reduced in to differences in neural dynamics, possibly reflecting older adults. The results support the model of sensory the degree of preservation of control in healthy aging. binding through thalamocortical gamma oscillations. (26865653) Limitation of neural resources for this process in older adults may contribute to their speech-in-noise under- Keywords: alpha; healthy aging; magnetoencephalogra- standing deficits. (27080577) phy; oscillations; working memory

Keywords: Aging; Central auditory processing; Gamma os- Cereb Cortex (2016), Vol. 26, No. 4, pp. 1831-42 cillation; Magnetoencephalography; Perceptual binding; Thalamocortical network Age-related changes to oscillatory dynamics in Psychophysiology (2017), Vol. 53, No. 7, pp. 974-90 hippocampal and neocortical networks

Rondina, R; Olsen, RK; McQuiggan, DA; Fati- Behavioral and Neural Markers of Flexible Attention ma, Z; Li, L; Oziel, E; Meltzer, JA; Ryan, JD over Working Memory in Aging Rotman Research Institute, Baycrest, Toronto, ON, Canada; Mok, RM; Myers, NE; Wallis, G; Nobre, AC Department of Psychology, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected]. Department of Experimental Psychology and Oxford Centre org. for Human Brain Activity, University of Oxford, Oxford OX3 7JX, UK. ABSTRACT: Recent models of hippocampal function have emphasized its role in relational binding - the ABSTRACT: Working memory (WM) declines as we age ability to form lasting representations regarding the and, because of its fundamental role in higher order relations among distinct elements or items which can cognition, this can have highly deleterious effects in support memory performance, even over brief delays daily life. We investigated whether older individuals (e.g., several seconds). The present study examined the benefit from flexible orienting of attention within WM extent to which aging is associated with changes in the to mitigate cognitive decline. We measured magneto- recruitment of oscillatory activity within hippocampal encephalography (MEG) in older adults performing a and neocortical regions to support relational binding WM precision task with cues during the maintenance performance on a short delay visuospatial memory period that retroactively predicted the location of the task. Structural magnetic resonance imaging and relevant items for performance (retro-cues). WM per- MEG were used to characterize potential age-related formance of older adults significantly benefitted from changes in hippocampal volume, oscillatory activ- retro-cues. Whereas WM maintenance declined with ity, and subsequent memory performance, and the age, retro-cues conferred strong attentional benefits. A relationships among them. Participants were required model-based analysis revealed an increase in the prob- to bind the relative visuospatial positions of objects ability of recalling the target, a lowered probability of that were presented singly across time. Subsequently, retrieving incorrect items or guessing, and an improve- the objects were re-presented simultaneously, and ment in memory precision. MEG recordings showed participants were required to indicate whether the

4 relative spatial positions among the objects had been has been proposed as an index of vascular reactivity. maintained. Older and younger adults demonstrated The RSFA compares favourably with other techniques similar task accuracy, and older adults had preserved such as breath-hold and hypercapnia, but the latter are hippocampal volumes relative to younger adults. Age- more difficult to perform in some populations, such group differences were found in pre-stimulus theta as older adults. The RSFA is therefore a candidate for (∼5Hz) and beta (∼20Hz) oscillations, and this pre- use in adjusting for age-related changes in vascular stimulus activity was related to hippocampal volumes reactivity in fMRI studies. The use of RSFA is predicated in younger adults. Age-group differences were also on its sensitivity to vascular rather than neural factors; found in the recruitment of oscillatory activity from the however, the extent to which each of these factors pre-stimulus period to the task. Only younger adults contributes to RSFA remains to be characterized. The showed a task-related change in theta power that was present work addressed these issues by comparing predictive of memory performance. In contrast, older RSFA (i.e., rsfMRI variability) to proxy measures of (i) adults demonstrated task-related alpha (∼10Hz) oscilla- cardiovascular function in terms of heart rate (HR) tory power changes that were not observed in younger and heart rate variability (HRV) and (ii) neural activity adults. These findings provide novel evidence for the in terms of resting state magnetoencephalography role of the hippocampus and functionally connected (rsMEG). We derived summary scores of RSFA, a senso- regions in relational binding that is disrupted in aging. rimotor task BOLD activation, cardiovascular function The present findings are discussed in the context of and rsMEG variability for 335 healthy older adults in the current models regarding the cognitive neuroscience population-based Cambridge Centre for Ageing and of aging. (26688110) Neuroscience cohort (Cam-CAN; www.cam-can.com). Mediation analysis revealed that the effects of ageing Keywords: Aging; Cortical networks; Hippocampus; on RSFA were significantly mediated by vascular fac- Magnetic resonance imaging; Magnetoencephalography; tors, but importantly not by the variability in neuronal Relational memory activity. Furthermore, the converse effects of ageing on the rsMEG variability were not mediated by vascular Neurobiol Learn Mem (2018), Vol. 134 Pt A, pp. 15-30 factors. We then examined the effect of RSFA scaling of task-based BOLD in the sensorimotor task. The scaling analysis revealed that much of the effects of age on The effect of ageing on fMRI: Correction for the task-based activation studies with fMRI do not survive confounding effects of vascular reactivity evaluated correction for changes in vascular reactivity, and are by joint fMRI and MEG in 335 adults likely to have been overestimated in previous fMRI studies of ageing. The results from the mediation analy- Tsvetanov, KA; Henson, RN; Tyler, LK; Davis, SW; Shafto, sis demonstrate that RSFA is modulated by measures of MA; Taylor, JR; Williams, N; Cam-Can, ; Rowe, JB vascular function and is not driven solely by changes in the variance of neural activity. Based on these findings Centre for Speech, Language and the Brain, Department of we propose that the RSFA scaling method is articularly Psychology, University of Cambridge, Cambridge, United useful in large scale and longitudinal neuroimaging Kingdom. studies of ageing, or with frail participants, where alternative measures of vascular reactivity are impractical. ABSTRACT: In functional magnetic resonance imag- (25727740) ing (fMRI) research one is typically interested in neural activity. However, the blood-oxygenation level-dependent (BOLD) signal is a composite of both neural and vascular activity. As factors such as age or medication may alter vascular function, it is essential to account for changes in neurovascular coupling when investigating neurocognitive functioning with fMRI. The resting-state fluctuation amplitude (RSFA) in the fMRI signal (rsfMRI)

5 Keywords: aging; cerebral vascular reactivity; fluctuation Keywords: Aging; Magnetic mismatch negativity amplitude; resting state; scaling; signal variability (MMNm); Magnetoencephalography (MEG); Phonetic processing; Speech sound Hum Brain Mapp (2016), Vol. 36, No. 6, pp. 2248-69 Biol Psychol (2015), Vol. 104, pp. 48-55

Effects of aging on the neuromagnetic mismatch detection to speech sounds High-gamma activity in an attention network predicts individual differences in elderly adults' Cheng, CH; Baillet, S; Hsiao, FJ; Lin, YY behavioral performance

Institute of Brain Science, National Yang-Ming University, Tai- Akimoto, Y; Nozawa, T; Kanno, A; Ihara, M; Goto, T; Ogawa, pei, Taiwan; Laboratory of Neurophysiology, Taipei Veterans T; Kambara, T; Sugiura, M; Okumura, E; Kawashima, R General Hospital, Taipei, Taiwan; Department of Occupa- tional Therapy and Graduate Institute of Behavioral Sciences, Department of Functional Brain Imaging, Institute of Devel- Chang Gung University, Taoyuan, Taiwan; McConnell Brain opment, Aging and Cancer, Tohoku University, Sendai, Japan. Imaging Center, Montreal Neurological Institute, McGill Electronic address: [email protected]. University, Montreal, Canada. ABSTRACT: The current study used a magnetoen- ABSTRACT: The ability to discriminate speech sounds cephalogram to investigate the relationship between is crucial for higher language functions in humans. high-gamma (52-100 Hz) activity within an atten- However, it remains unclear whether physiological tion network and individual differences in behavioral aging affects the functional integrity of pre-attentive performance among healthy elderly adults. We ana- phonological discrimination. The neuromagnetic corti- lyzed brain activity in 41 elderly subjects performing cal responses during automatic change detection of a 3-stimulus visual oddball task. In addition to the speech sounds (/ba/versus/da/) were recorded in 24 average amplitude of event-related fields in the left young and 21 aged male adults. We used minimum intraparietal sulcus (IPS), high-gamma power in the norm estimate of source reconstruction to characterize left middle frontal gyrus (MFG), the strength of high- the spatiotemporal dynamics of magnetic mismatch gamma imaginary coherence between the right MFG responses (MMNm). Distributed activations to phonetic and the left MFG, and those between the right MFG changes were identified in the temporal, frontal and and the left thalamus predicted individual differences parietal regions. Compared to younger participants, in reaction time. In addition, high-gamma power in the elderly volunteers exhibited a significant reduction of left MFG was correlated with task accuracy, whereas cortical responses to phonetic-MMNm, except for the high-gamma power in the left thalamus and left IPS left orbitofrontal cortex and anterior inferior tempo- was correlated with individual processing speed. The ral gyrus. However, among the identified regions of direction of correlations indicated that higher high- interest, we did not observe significant between-group gamma power or coherence in an attention network differences in the hemispheric asymmetry of phonetic- was associated with better task performance and, pre- MMNm. Conclusively, our results suggest an altered sumably, higher cognitive function. Thus, high-gamma phonetic processing at the perceptual level during activity in different regions of this attention network physiological aging. (25451380) differentially contributed to attentional processing, and such activity could be a fundamental process associated with individual differences in cognitive aging. (24960420)

6 Keywords: Aging; Attention; High-gamma activities; Individual differences; Reaction time Neuroimage (2015), Vol. 100, pp. 290-300 ing; magnetoencephalography; neural network; neural oscillations; neural synchrony; resting-state networks

Oscillations, networks, and their development: MEG Hum Brain Mapp (2015), Vol. 35, No. 10, pp. 5249-61 connectivity changes with age

Schäfer, CB; Morgan, BR; Ye, AX; Taylor, MJ; Doesburg, SM Spectral changes in spontaneous MEG activity across the lifespan Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada; Institute of Anatomy and Cell Gómez, C; Pérez-Macías, JM; Poza, J; Biology, University of Heidelberg, Germany. Fernández, A; Hornero, R

ABSTRACT: Magnetoencephalographic (MEG) in- Biomedical Engineering Group, E.T.S. Ingenieros de Telecomu- vestigations of inter-regional amplitude correlations nicación, University of Valladolid, Valladolid, Spain. have yielded new insights into the organization and neurophysiology of resting-state networks (RSNs) first OBJECTIVE: The aim of this study is to explore the identified using fMRI. Inter-regional MEG amplitude spectral patterns of spontaneous magnetoencephalog- correlations in adult RSNs have been shown to be most raphy (MEG) activity across the lifespan. APPROACH: prominent in alpha and beta frequency ranges and to Relative power (RP) in six frequency bands (delta, theta, express strong congruence with RSN topologies found alpha, beta-1, beta-2 and gamma) was calculated in using fMRI. Despite such advances, little is known a sample of 220 healthy subjects with ages ranging about how oscillatory connectivity in RSNs develops from 7 to 84 years. MAIN RESULTS: A significant RP throughout childhood and adolescence. This study decrease in low-frequency bands (i.e. delta and theta) used a novel fMRI-guided MEG approach to investigate and a significant increase in high bands (mainly beta-1 the maturation of resting-state amplitude correlations and beta-2) were found from childhood to adolescence. in physiologically relevant frequency ranges within and This trend was observed until the sixth decade of life, among six RSNs in 59 participants, aged 6-34 years. We though only slight changes were found. Additionally, report age-related increases in inter-regional ampli- healthy aging was characterized by a power increase tude correlations that were largest in alpha and beta in low-frequency bands. Our results show that spectral frequency bands. In contrast to fMRI reports, these changes across the lifespan may follow a quadratic changes were observed both within and between the relationship in delta, theta, alpha, beta-2 and gamma various RSNs analyzed. Our results provide the first bands with peak ages being reached around the fifth evidence of developmental changes in spontaneous or sixth decade of life. SIGNIFICANCE: Our findings neurophysiological connectivity in source-resolved provide original insights into the definition of the RSNs, which indicate increasing integration within and 'normal' behavior of age-related MEG spectral patterns. among intrinsic functional brain networks through- Furthermore, our study can be useful for the forthcom- out childhood, adolescence, and early adulthood. ing MEG research focused on the description of the (24861830) abnormalities of different brain diseases in comparison to cognitive decline in normal aging. (24100075) Keywords: alpha-band; beta-band; development; functional connectivity; functional magnetic resonance imag-

7 J Neural Eng (2014), Vol. 10, No. 6, pp. 066006 Rotman Research Institute of Baycrest, Canada.

ABSTRACT: Recent theoretical and empirical work has Hippocampal lateralization and memory in children focused on the variability of network dynamics in mat- and adults uration. Such variability seems to reflect the spontaneous formation and dissolution of different functional Hopf, L; Quraan, MA; Cheung, MJ; Tay- networks. We sought to extend these observations into lor, MJ; Ryan, JD; Moses, SN healthy aging. Two different data sets, one EEG (total n = 48, ages 18-72) and one magnetoencephalography 1 Rotman Research Institute, Baycrest, Toronto, Ontario. (n = 31, ages 20-75) were analyzed for such spatiotemporal dependency using multiscale entropy (MSE) from ABSTRACT: The neural organization of cognitive pro- regional brain sources. In both data sets, the changes in cesses, particularly hemispheric lateralization, changes MSE were timescale dependent, with higher entropy at throughout childhood and adolescence. Differences in fine scales and lower at more coarse scales with greater the neural basis of relational memory between children age. The signals were parsed further into local entropy, and adults are not well characterized. In this study related to information processed within a regional we used magnetoencephalography to observe the source, and distributed entropy (information shared lateralization differences of hippocampal activation in between two sources, i.e., functional connectivity). children and adults during performance of a relational Local entropy increased for most regions, whereas the memory task, transverse patterning (TP). The TP task dominant change in distributed entropy was age-relat- was paired with an elemental control task, which does ed reductions across hemispheres. These data further not depend upon the hippocampus. We contrasted the understanding of changes in brain signal variability two hypotheses; the compensation hypothesis would across the lifespan, suggesting an inverted U-shaped suggest that more bilateral activation in children would curve, but with an important qualifier. Unlike earlier in lead to better TP performance, whereas the maturation maturation, where the changes are more widespread, hypothesis would predict that a more adult-like right- changes in adulthood show strong spatiotemporal lateralized pattern of hippocampal activation would dependence. (23395850) lead to better performance. Mean-centered partial least squares analysis was used to determine unique pat- Keywords: electroencephalograpy; functional connec- terns of brain activation specific to each task per group, tivity; magnetoencephalography; multiscale entropy; while diminishing activation that is consistent across nonlinear dynamics tasks. Our findings support the maturation hypothesis that a more adult-like pattern of increased right hip- Cereb Cortex (2015), Vol. 24, No. 7, pp. 1806-17 pocampal lateralization in children leads to superior performance on the TP task. We also found dynamic changes of lateralization throughout the time course Visual dominance and multisensory integration for all three groups, suggesting that caution is needed changes with age when interpreting conclusions about brain lateralization. (23920115) Diaconescu, AO; Hasher, L; McIntosh, AR

J Int Neuropsychol Soc (2014), Vol. 19, No. 10, pp. 1042-52 Translational Neuromodeling Unit, Institute for Biomedical Engineering, University of Zürich/ETH Zürich, Switzerland. [email protected] Spatiotemporal dependency of age-related changes in brain signal variability ABSTRACT: Objects comprise of visual and auditory signatures that arrive through distinct sensory chan- McIntosh, AR; Vakorin, V; Kovacevic, N; nels. Exposure to cross-modal events sets up expecta- Wang, H; Diaconescu, A; Protzner, AB tions about what a given object most likely "sounds"

8 like, and vice versa, thereby facilitating detection and OBJECTIVE: Considering the increasing use of com- recognition. Whereas episodic and working mem- plexity estimates in neuropsychiatric populations, ory functions decline with age, the extent to which a normative study is critical to define the 'normal' multisensory integration processes change with age behaviour of brain oscillatory complexity across the remains an open question. In the present study, we life span. METHOD: This study examines changes in examined whether multisensory integration processes resting-state magnetoencephalogram (MEG) complex- play a compensatory role in normal aging. Magneto- ity - quantified with the Lempel-Ziv complexity (LZC) encephalography recordings of semantically-related algorithm - due to age and gender in a large sample of cross-modal and unimodal auditory and visual stimuli 222 (100 males/122 females) healthy participants with captured the spatiotemporal dynamics of multisensory ages ranging from 7 to 84 years. RESULTS: A significant responses in young and older adults. Whereas sensory- quadratic (curvilinear) relationship (p<0.05) between specific regions showed increased activity in response age and complexity was found, with LZC maxima being to cross-modal compared to unimodal stimuli 100 ms reached by the sixth decade of life. Once that peak after stimulus onset in both age groups, posterior pari- was crossed, complexity values slowly decreased until etal and medial prefrontal regions responded preferen- late senescence. Females exhibited higher LZC values tially to cross-modal stimuli between 150 and 300 ms than males, with significant differences in the anterior, in the older group only. Additionally, faster detection of central and posterior regions (p<0.05). CONCLUSIONS: cross-modal stimuli correlated with increased activity These results suggest that the evolution of brain in inferior parietal and medial prefrontal regions 100 oscillatory complexity across the life span might be ms after stimulus onset in older compared to younger considered a new illustration of a 'normal' physiologi- adults. Age-related differences in visual dominance cal rhythm. SIGNIFICANCE: Previous and forthcom- were also observed with older adults exhibiting signifi- ing clinical studies using complexity estimates might cantly larger multisensory facilitation effects relative be interpreted from a more complete and dynamical to the auditory modality. Using structural equation perspective. Pathologies not only cause an 'abnormal' modeling, we showed that age-related increases in increase or decrease of complexity values but they parietal and medial prefrontal source activity predicted actually 'break' the 'normal' pattern of oscillatory com- faster detection of cross-modal stimuli. Furthermore, plexity evolution as a function of age. (22647457) the relationship between performance and source activity was mediated by age-related reductions in gray Clin Neurophysiol (2013), Vol. 123, No. 11, pp. 2154-62 matter volume in those regions. Thus, we propose that multisensory integration processes change with age such that posterior parietal and medial prefrontal activ- Functional and structural correlates of the aging ity underlies the integrated response in older adults. brain: relating visual cortex (V1) gamma band (23036447) responses to age-related structural change

Neuroimage (2013), Vol. 65, pp. 152-66 Gaetz, W; Roberts, TP; Singh, KD; Muthukumaraswamy, SD

Lurie Family Foundations MEG Imaging Center, Department Brain oscillatory complexity across the life span of Radiology, Children's Hospital of Philadelphia, Philadel- phia, PA 19104, USA. [email protected] Fernández, A; Zuluaga, P; Abásolo, D; Gó- mez, C; Serra, A; Méndez, MA; Hornero, R ABSTRACT: The gamma band response is thought to be a key neural signature of information processing in Departamento de Psiquiatría y Psicología Médica, Universi- the mammalian brain, yet little is known about how dad Complutense de Madrid, Madrid, Spain. aferlucas@med. age-related maturation influences the γ-band response. ucm.es Recent MRI-based studies have shown that brain maturation is accompanied by clear structural changes in both gray and white matter, yet the correspondence

9 of these changes to brain function is unclear. The objective of this study was to relate visual cortex (V1) γ-band responses to age-related structural change. We evaluated MEG measured γ-band responses to contrast gratings stimuli and structural MRIs from participants observed from two separate research centers (MEG lab at CUBRIC, Cardiff University, UK, and the Lurie Fam- ily Foundations MEG Imaging Center, (CHOP) at the Children's Hospital of Philadelphia). Pooled participant data (N = 59) ranged in age from 8.7 to 45.3 years. We assessed linear associations between age and MEG γ-band frequency and amplitude, as well as between age and MRI volumetric parameters of the occipital lobe. Our MEG findings revealed a significant negative correlation for gamma band frequency versus age. Volumetric brain analysis from the occipital lobe also revealed significant negative correlations between age and the cortical thickness of pericalcarine and cuneus areas. Our functional MEG and structural MRI findings shows regionally specific changes due to maturation and may thus be informative for understanding physiological processes of neural development, maturation, and age-related decline. In addition, this study represents (to our knowledge), the first published demonstration of multicenter data sharing across MEG centers. (21769992)

Hum Brain Mapp (2012), Vol. 33, No. 9, pp. 2035-46

10 Alzheimer's Disease Keywords: Alzheimer disease; Functional connectivity; Subjective Cognitive Decline; magnetoencephalography; mild cognitive impairment Functional Connectivity Disruption in Subjective Cognitive Decline and Mild Cognitive Impairment: A Front Aging Neurosci (2018), Vol. 9, pp. 109 Common Pattern of Alterations

López-Sanz, D; Bruña, R; Garcés, P; Martín-Bu- Dispersion entropy for the analysis of resting-state ro, MC; Walter, S; Delgado, ML; Montenegro, MEG regularity in Alzheimer's disease M; López Higes, R; Marcos, A; Maestú, F Azami, H; Rostaghi, M; Fernandez, A; Escudero, J Laboratory of Cognitive and Computational Neuroscience, Center for Biomedical Technology, Complutense University ABSTRACT: Alzheimer's disease (AD) is a progressive of Madrid and Technical University of MadridPozuelo de degenerative brain disorder affecting memory, think- Alarcón, Spain. ing, behaviour and emotion. It is the most common form of dementia and a big social problem in western ABSTRACT: Functional connectivity (FC) alterations societies. The analysis of brain activity may help to represent a key feature in Alzheimer's Disease (AD) diagnose this disease. Changes in entropy methods and provide a useful tool to characterize and predict have been reported useful in research studies to the course of the disease. Those alterations have been characterize AD. We have recently proposed disper- also described in Mild Cognitive Impairment (MCI), a sion entropy (DisEn) as a very fast and powerful tool to prodromal stage of AD. There is a growing interest in quantify the irregularity of time series. The aim of this detecting AD pathology in the brain in the very early paper is to evaluate the ability of DisEn, in comparison stages of the disorder. Subjective Cognitive Decline with fuzzy entropy (FuzEn), sample entropy (SampEn), (SCD) could represent a preclinical asymptomatic stage and permutation entropy (PerEn), to discriminate 36 of AD but very little is known about this population. In AD patients from 26 elderly control subjects using the present work we assessed whether FC disruptions resting-state magnetoencephalogram (MEG) signals. are already present in this stage, and if they share any The results obtained by DisEn, FuzEn, and SampEn, spatial distribution properties with MCI alterations (a unlike PerEn, show that the AD patients' signals are condition known to be highly related to AD). To this more regular than controls' time series. The p-values end, we measured electromagnetic spontaneous activ- obtained by DisEn, FuzEn, SampEn, and PerEn based ity with MEG in 39 healthy control elders, 41 elders with methods demonstrate the superiority of DisEn over SCD and 51 MCI patients. The results showed FC altera- PerEn, SampEn, and PerEn. Moreover, the computation tions in both SCD and MCI compared to the healthy time for the newly proposed DisEn-based method is control group. Interestingly, both groups exhibited a noticeably less than for the FuzEn, SampEn, and PerEn very similar spatial pattern of altered links: a hyper- based approaches. (28269715) synchronized anterior network and a posterior network characterized by a decrease in FC. This decrease was Conf Proc IEEE Eng Med Biol Soc (2017), Vol. 2016, pp. more pronounced in the MCI group. These results high- 6417-6420 light that elders with SCD present FC alterations. More importantly, those disruptions affected AD typically related areas and showed great overlap with the altera- Incidence and impact of subclinical epileptiform tions exhibited by MCI patients. These results support activity in Alzheimer's disease the consideration of SCD as a preclinical stage of AD and may indicate that FC alterations appear very early Vossel, KA; Ranasinghe, KG; Beagle, AJ; Mizuiri, D; Honma, in the course of the disease. (28484387) SM; Dowling, AF; Darwish, SM; Van Berlo, V; Barnes, DE; Mantle, M; Karydas, AM; Coppola, G; Roberson, ED; Miller, BL; Garcia, PA; Kirsch, HE; Mucke, L; Nagarajan, SS

11 Memory and Aging Center, Department of Neurology, Univer- ABSTRACT: Alzheimer's disease (AD) is one of the sity of California, San Francisco, San Francisco, CA. fastest growing neurological diseases in the world. We evaluate multivariate multiscale sample entropy OBJECTIVE: Seizures are more frequent in patients (mvMSE) and multivariate multiscale permutation en- with Alzheimer's disease (AD) and can hasten cogni- tropy (mvMPE) approaches to distinguish resting-state tive decline. However, the incidence of subclinical magnetoencephalogram (MEG) signals of 36 AD pa- epileptiform activity in AD and its consequences are tients from those of 26 normal controls. We also discuss unknown. Motivated by results from animal studies, we about choosing the appropriate embedding dimension hypothesized higher than expected rates of subclinical value as an effective parameter for mvMPE and MPE epileptiform activity in AD with deleterious effects on for the first time. The results illustrate that both the cognition. METHODS: We prospectively enrolled 33 mvMPE and mvMSE can be useful in the diagnosis of patients (mean age, 62 years) who met criteria for AD, AD, although with different running times and abilities. but had no history of seizures, and 19 age-matched, In addition, our findings show that the MEG complexity cognitively normal controls. Subclinical epileptiform ac- analysis performed on deeper time scales by mvMPE tivity was assessed, blinded to diagnosis, by overnight and mvMSE may be a useful tool to characterize AD. long-term video-electroencephalography (EEG) and a In most scale factors, the average of the mvMPE and 1-hour resting magnetoencephalography exam with mvMSE values of AD patients are lower than those of simultaneous EEG. Patients also had comprehensive controls. (26738007) clinical and cognitive evaluations, assessed longitudinally over an average period of 3.3 years. RESULTS: Conf Proc IEEE Eng Med Biol Soc (2016), Vol. 2015, pp. Subclinical epileptiform activity was detected in 42.4% 7422-5 of AD patients and 10.5% of controls (p = 0.02). At the time of monitoring, AD patients with epileptiform activity did not differ clinically from those without such Multiscale entropy analysis of resting-state activity. However, patients with subclinical epileptiform magnetoencephalogram with tensor factorisations activity showed faster declines in global cognition, in Alzheimer's disease determined by the Mini-Mental State Examination (3.9 points/year in patients with epileptiform activity Escudero, J; Acar, E; Fernández, A; Bro, R vs 1.6 points/year in patients without; p = 0.006), and in executive function (p = 0.01). INTERPRETATION: Institute for Digital Communications, School of Engineering, Extended monitoring detects subclinical epileptiform The University of Edinburgh, King's Buildings, Thomas Bayes activity in a substantial proportion of patients with AD. Road, EH9 3FG Edinburgh, UK. Electronic address: javier. Patients with this indicator of network hyperexcitability [email protected]. are at risk for accelerated cognitive decline and might benefit from antiepileptic therapies. These data call for ABSTRACT: Tensor factorisations have proven useful more sensitive and comprehensive neurophysiological to model amplitude and spectral information of brain assessments in AD patient evaluations and impending recordings. Here, we assess the usefulness of tensor fac- clinical trials. Ann Neurol 2016;80:858-870. (27696483) torisations in the multiway analysis of other brain signal features in the context of complexity measures recently Ann Neurol (2017), Vol. 80, No. 6, pp. 858-870 proposed to inspect multiscale dynamics. We consider the "refined composite multiscale entropy" (rcMSE), which computes entropy "profiles" showing levels of Evaluation of resting-state magnetoencephalogram physiological complexity over temporal scales for indi- complexity in Alzheimer's disease with multivariate vidual signals. We compute the rcMSE of resting-state multiscale permutation and sample entropies magnetoencephalogram (MEG) recordings from 36 patients with Alzheimer's disease and 26 control subjects. Azami, H; Smith, K; Fernandez, A; Escudero, J Instead of traditional simple visual examinations, we organise the entropy profiles as a three-way tensor to

12 inspect relationships across temporal and spatial scales and subjects with multiway data analysis techniques based on PARAFAC and PARAFAC2 factorisations. A PARAFAC2 Conf Proc IEEE Eng Med Biol Soc (2016), Vol. 2014, pp. model with two factors was appropriate to account for 702-5 the interactions in the entropy tensor between temporal scales and MEG channels for all subjects. Moreover, the PARAFAC2 factors had information related to the Regional functional connectivity predicts distinct subjects' diagnosis, achieving a cross-validated area un- cognitive impairments in Alzheimer's disease der the ROC curve of 0.77. This confirms the suitability spectrum of tensor factorisations to represent electrophysiological brain data efficiently despite the unsupervised na- Ranasinghe, KG; Hinkley, LB; Beagle, AJ; Mizuiri, D; ture of these techniques. This article is part of a Special Dowling, AF; Honma, SM; Finucane, MM; Scher- Issue entitled 'Neural data analysis'. (25982737) ling, C; Miller, BL; Nagarajan, SS; Vossel, KA

Keywords: Alzheimer's disease; Brain activity; Complexity; Memory and Aging Center, Department of Neurology, Univer- Multiway analysis; PARAFAC; PARAFAC2 sity of California San Francisco, San Francisco, CA 94158, USA.

Brain Res Bull (2016), Vol. 119, No. Pt B, pp. 136-44 ABSTRACT: Understanding neural network dysfunction in neurodegenerative disease is imperative to effectively develop network-modulating therapies. In Analysis of magnetoencephalography recordings Alzheimer's disease (AD), cognitive decline associates from Alzheimer's disease patients using embedding with deficits in resting-state functional connectivity of entropies diffuse brain networks. The goal of the current study was to test whether specific cognitive impairments in Gómez, C; Poza, J; Monge, J; Fernández, A; Hornero, R AD spectrum correlate with reduced functional connectivity of distinct brain regions. We recorded resting- ABSTRACT: The aim of this study was to examine the state functional connectivity of alpha-band activity magnetoencephalography (MEG) background activ- in 27 patients with AD spectrum--22 patients with ity in Alzheimer's disease (AD) using three embed- probable AD (5 logopenic variant primary progressive ding entropies: approximate entropy (ApEn), sample aphasia, 7 posterior cortical atrophy, and 10 early-onset entropy (SampEn), and fuzzy entropy (FuzzyEn). These amnestic/dysexecutive AD) and 5 patients with mild three methods measure the time series regularity. Five cognitive impairment due to AD. We used magnetoen- minutes of recording were acquired with a 148-chan- cephalographic imaging (MEGI) to perform an unbi- nel whole-head magnetometer from 36 AD patients ased search for regions where patterns of functional and 24 elderly control subjects. Our results showed connectivity correlated with disease severity and cogni- that MEG activity was more regular in AD patients than tive performance. Functional connectivity measured in controls. Additionally, FuzzyEn revealed statistically the strength of coherence between a given region and significant differences between the two groups (p <; the rest of the brain. Decreased neural connectivity 0.01, Bonferroni-corrected Mann-Whitney U-test), while of multiple brain regions including the right posterior ApEn and SampEn did not. The better discriminating perisylvian region and left middle frontal cortex cor- results of FuzzyEn in comparison with the other en- related with a higher degree of disease severity. Deficits tropy algorithms suggest that it is more efficient for the in executive control and episodic memory correlated characterization of MEG activity in AD. (25570055) with reduced functional connectivity of the left frontal cortex, whereas visuospatial impairments correlated with reduced functional connectivity of the left inferior

13 parietal cortex. Our findings indicate that reductions of abnormalities in the neural activity (p < 0.05), includ- in region-specific alpha-band resting-state functional ing a progressive loss of irregularity, variability, symme- connectivity are strongly correlated with, and might try and Gaussianity. Furthermore, the highest accura- contribute to, specific cognitive deficits in AD spec- cies to discriminate AD and MCI subjects from controls trum. In the future, MEGI functional connectivity could were 79.4% and 68.9%, whereas, in the three-class be an important biomarker to map and follow defective setting, the accuracy reached 67.9%. SIGNIFICANCE: networks in the early stages of AD. (25180158) Our findings provide an original description of several dynamical properties of neural activity in early AD and Keywords: Alzheimer’s disease spectrum; CDR-SOB, Clini- offer preliminary evidence that the proposed method- cal Dementia Rating Sum of Boxes; CVLT, California Verbal ology is a promising tool for assessing brain changes at Learning Test; Logopenic variant PPA; MCI, mild cognitive different stages of dementia. (24608272) impairment; MEGI, magnetoencephalographic imaging; MMSE, Mini-Mental State Exam; Magnetoencephalogra- J Neural Eng (2014), Vol. 11, No. 2, pp. 026010 phy (MEG); Network dysfunction; PCA, posterior cortical atrophy; Posterior cortical atrophy; Resting-state functional connectivity; VOSP, Visual Object and Space Percep- MEG delta mapping along the healthy aging- tion; fMRI, functional magnetic resonance imaging; lvPPA, Alzheimer's disease continuum: diagnostic logopenic variant primary progressive aphasia implications

Neuroimage Clin (2015), Vol. 5, pp. 385-95 Fernández, A; Turrero, A; Zuluaga, P; Gil-Gre- gorio, P; del Pozo, F; Maestu, F; Moratti, S

Analysis of neural dynamics in mild cognitive Departamento de Psiquiatría, Facultad de Medicina, Uni- impairment and Alzheimer's disease using wavelet versidad Complutense de Madrid, Madrid, Spain. aferlucas@ turbulence med.ucm.es

Poza, J; Gómez, C; García, M; Corrale- ABSTRACT: New diagnostic criteria for Alzheimer's jo, R; Fernández, A; Hornero, R disease (AD) stress the role of in vivo biomarkers. Neu- rophysiological markers are usually not considered as Biomedical Engineering Group, Department TSCIT, ETS. such criteria, although theoretical and practical reasons Ingenieros de Telecomunicación, University of Valladolid, Vall- would justify them. In order to assess the value of neu- adolid, Spain. IMUVA, Instituto de Investigación en Matemáti- rophysiology as an AD biomarker, whole-head mag- cas, University of Valladolid, Valladolid, Spain. INCYL, Instituto netoencephalographic (MEG) resting state recordings de Neurociencias de Castilla y León, Salamanca, Spain. were obtained from 35 AD patients, 23 mild cognitive impairment (MCI) patients, and 24 healthy controls. The OBJECTIVE: Current diagnostic guidelines encourage AD group was further split into two groups differing in further research for the development of novel Alzheim- severity according to the GDS/FAST criteria. A Minimum er's disease (AD) biomarkers, especially in its prodromal Norm Estimation procedure was utilized to estimate form (i.e. mild cognitive impairment, MCI). Magnetoen- the cortical origin of slow brain oscillatory activity in cephalography (MEG) can provide essential information the delta band (2-4 Hz). Eight regions of interest (ROIs) about AD brain dynamics; however, only a few studies discriminated between AD patients and controls. Delta have addressed the characterization of MEG in incipient current density (DCD) in all ROIs showed a significant AD. APPROACH: We analyzed MEG rhythms from 36 negative correlation with cognitive status (p < 0.001). AD patients, 18 MCI subjects and 27 controls, introduc- DCD values in posterior parietal, occipital, prerolandic, ing a new wavelet-based parameter to quantify their and precuneus cortices distinguished reliably between dynamical properties: the wavelet turbulence. MAIN MCI patients, AD patients with different severity scores, RESULTS: Our results suggest that AD progression elic- and controls. Importantly, an increase of DCD in right its statistically significant regional-dependent patterns parietal cortex and precuneus indexed the transition

14 from MCI to mild dementia and from mild to more Conf Proc IEEE Eng Med Biol Soc (2013), Vol. 2012, pp. severe dementia. MEG delta mapping might be a 6188-91 serious candidate for a "neural degeneration" marker of AD reflecting dysfunctional synaptic transmission. More importantly, the localization of DCD values is in Disruption of functional brain networks line with functional imaging markers of AD. However, in Alzheimer's disease: what can we learn MEG delta mapping is a totally non-invasive technique from graph spectral analysis of resting-state that directly measures neural activity. We propose that magnetoencephalography? individuals with enhanced DCD in posterior parietal and precuneus cortices are at risk of progression to full de Haan, W; van der Flier, WM; Wang, H; Van dementia. (23478303) Mieghem, PF; Scheltens, P; Stam, CJ

J Alzheimers Dis (2013), Vol. 35, No. 3, pp. 495-507 Department of Clinical Neurophysiology and Magnetoen- cephalography, VU University Medical Center, Amsterdam, The Netherlands. [email protected] Synchrony analysis of spontaneous MEG activity in Alzheimer's disease patients ABSTRACT: In Alzheimer's disease (AD), structural and functional brain network organization is disturbed. Gómez, C; Martínez-Zarzuela, M; Poza, J; Díaz- However, many of the present network analysis mea- Pernas, FJ; Fernández, A; Hornero, R sures require a priori assumptions and methodological choices that influence outcomes and interpretations. Department of Signal Theory and Communications, E.T.S. Graph spectral analysis (GSA) is a more direct algebraic Ingenieros de Telecomunicación, University of Valladolid, method that describes network properties, which Campus Miguel Delibes, 47011 – Valladolid, Spain. cargom@ might lead to more reliable results. In this study, GSA tel.uva.es was applied to magnetoencephalography (MEG) data to explore functional network integrity in AD. Sensor- ABSTRACT: The aim of this study was to analyze the level resting-state MEG was performed in 18 Alzheimer magnetoencephalography (MEG) background activity patients (age 67 ± 9, 6 women) and 18 healthy controls in Alzheimer's disease (AD) patients using cross-approx- (age 66 ± 9, 11 women). Weighted, undirected graphs imate entropy (Cross-ApEn). Cross-ApEn is a nonlinear were constructed based on functional connectivity measure of asynchrony between time series. Five analysis using the Synchronization likelihood, and GSA minutes of recording were acquired with a 148-chan- was performed with a focus on network connectiv- nel whole-head magnetometer in 12 AD patients and ity, synchronizability, and node centrality. The main 12 age-matched control subjects. We found signifi- outcomes were a global loss of network connectivity cantly higher synchrony between MEG signals from AD and altered synchronizability in most frequency bands. patients compared with control subjects. Additionally, Eigenvector centrality mapping confirmed the hub we evaluated the ability of Cross-ApEn to discriminate status of the parietal areas, and demonstrated a low these two groups using receiver operating characteris- centrality of the left temporal region in the theta band tic (ROC) curves with a leave-one-out cross-validation in AD patients that was strongly related to the mini procedure. We obtained an accuracy of 70.83% (66.67% mental state examination (global cognitive function sensitivity, 75% specificity) and a value of area under test) score (r=0.67, p=0.001). Summarizing, GSA is a the ROC curve of 0.83. These results provide evidence theoretically solid approach that is able to detect the of disconnection problems in AD. Our findings show disruption of functional network topology in AD. In the usefulness of Cross-ApEn to detect the brain dys- addition to the previously reported overall connectivity function in AD. (23367342) losses and parietal area hub status, impaired network synchronizability and a clinically relevant left temporal centrality loss were found in AD patients. Our findings imply that GSA is valuable for the purpose of studying

15 altered brain network topology and dynamics in AD. state tests based on MEG. The non-invasive, rapid and (22480296) convenient nature of these scans offers a new tool for translational AD research and early phase development Brain Connect (2012), Vol. 2, No. 2, pp. 45-55 of novel treatments for AD. (21971464)

J Alzheimers Dis (2012), Vol. 26 Suppl 3, pp. 239-55 Evaluation and tracking of Alzheimer's disease severity using resting-state magnetoencephalography Complexity analysis of spontaneous brain activity in Alzheimer disease and mild cognitive impairment: Verdoorn, TA; McCarten, JR; Arciniegas, DB; an MEG study Golden, R; Moldauer, L; Georgopoulos, A; Lewis, S; Cassano, M; Hemmy, L; Orr, W; Rojas, DC Fernández, A; Hornero, R; Gómez, C; Turrero, A; Gil-Gregorio, P; Matías-Santos, J; Ortiz, T Orasi Medical, Inc., Minneapolis, MN 55426, USA. todd.ver- [email protected] Centro de Magnetoencefalografía Dr. Pérez-Modrego, Fac- ultad de Medicina, Pabellón, Universidad Complutense de ABSTRACT: We have conducted multicenter clinical Madrid, Madrid, Spain. [email protected] studies in which brain function was evaluated with brief, resting-state magnetoencephalography (MEG) ABSTRACT: Nonlinear analyses have shown that Al- scans. A study cohort of 117 AD patients and 123 el- zheimer disease (AD) patients' brain activity is charac- derly cognitively normal volunteers was recruited from terized by a reduced complexity and connectivity. The community neurology clinics in Denver, Colorado and aim of this study is to define complexity patterns of Minneapolis, Minnesota. Each subject was evaluated mild cognitive impairment (MCI) patients. Whole-head through neurological examination, medical history, and magnetoencephalography recordings were obtained a modest battery of standard neuropsychological tests. from 18 diagnosed AD patients, 18 MCI patients, and 18 Brain function was measured by a one-minute, resting- healthy controls during resting conditions. Lempel-Ziv state, eyes-open MEG scan. Cross-sectional analysis complexity (LZC) values were calculated. MCI patients of MEG scans revealed global changes in the distribu- exhibited intermediary LZC scores between AD pa- tion of relative spectral power (centroid frequency of tients and controls. A combination of age and posterior healthy subjects = 8.24 ± 0.2 Hz and AD patients = 6.78 LZC scores allowed ADs-MCIs discrimination with 94.4% ± 0.25 Hz) indicative of generalized slowing of brain sensitivity and specificity, whereas no LZC score al- signaling. Functional connectivity patterns were mea- lowed MCIs---controls discrimination. AD patients and sured using the synchronous neural interactions (SNI) controls showed a parallel tendency to diminished LZC test, which showed a global increase in the strength of scores as a function of age, but MCI patients did not functional connectivity (cO2 value of healthy subjects exhibit such "normal" tendency. Accordingly, anterior = 0.059 ± 0.0007 versus AD patients = 0.066 ± 0.001) as- LZC scores allowed MCIs-controls discrimination for sociated with AD. The largest magnitude disease-asso- subjects below 75 years. MCIs exhibited a qualitatively ciated changes were localized to sensors near posterior distinct relationship between aging and complexity and lateral cortical regions. Part of the cohort (31 AD reduction, with scores higher than controls in older and 46 cognitively normal) was evaluated in an identi- individuals. This fact might be considered a new ex- cal fashion approximately 10 months after the first ample of compensatory mechanism in MCI before fully assessments. Follow-up scans revealed multiple MEG established dementia. (20505435) scan features that correlated significantly with changes in neuropsychological test scores. Linear combinations of these MEG scan features generated an accurate multivariate model of disease progression over 10 months. Our results demonstrate the utility of brief resting-

16 Alzheimer Dis Assoc Disord (2010), Vol. 24, No. 2, pp. 182-9 Study of the MEG background activity in Biomedical Engineering Group, E.T.S. Ingenieros de Telecomu- Alzheimer's disease patients with scaling analysis nicación, University of Valladolid, Camino del Cementerio s/n, methods 47011 Valladolid, Spain. [email protected]

Gomez, C; Hornero, R; Abasolo, D; Fernandez, A; Poza, J ABSTRACT: This work studied whether a blind source separation (BSS) and component selection procedure Biomedical Engineering Group at Department of Signal could increase the differences between Alzheimer's Theory and Communications, E.T.S. Ingenieros de Telecomu- disease (AD) patients and control subjects' spectral and nicación, University of Valladolid, Campus Miguel Delibes, non-linear features of magnetoencephalogram (MEG) 47011 - Valladolid, Spain. [email protected] recordings. MEGs were acquired with a 148-channel whole-head magnetometer from 62 subjects (36 AD ABSTRACT: Alzheimer's disease (AD) is one of the most patients and 26 controls), who were divided randomly prominent neurodegenerative disorders. The aim of into training and test sets. MEGs were decomposed us- this research work is to study the magnetoencephalo- ing the algorithm for multiple unknown signals extrac- gram (MEG) background activity in AD patients using tion (AMUSE). The extracted AMUSE components were two scaling analysis methods: detrended fluctua- characterised with two spectral--median frequency and tion analysis (DFA) and backward detrended moving spectral entropy (SpecEn)--and two non-linear features: average (BDMA). Both measures have been designed Lempel-Ziv complexity (LZC) and sample entropy to quantify correlations in noisy and non-stationary (SampEn). One-way analysis of variance with age as signals. Five minutes of recording were acquired with a a covariate was applied to the training set to decide 148-channel whole-head magnetometer in 15 patients which components had the most significant differences with probable AD and 15 control subjects. Both DFA between groups. Then, partial reconstructions of the and BDMA exhibited two scaling regions with dif- MEGs were computed with these significant compo- ferent slopes. Significant differences between both nents. In the test set, the accuracy and area under the groups were found in the second region of DFA and ROC curve (AUC) associated with each partial recon- in the first region of BDMA (p < 0.01, Student's t-test). struction of the MEGs were compared with the case Using receiver operating characteristic curves, accura- where no BSS-preprocessing was applied. This prepro- cies of 83.33% with DFA and of 80% with BDMA were cessing increased the AUCs between 0.013 and 0.227, reached. Our findings show the usefulness of these while the accuracy for SpecEn, LZC and SampEn rose scaling analysis methods to increase our insight into between 6.4% and 22.6%, improving the separation AD. (19964992) between AD patients and control subjects. (19482539)

Conf Proc IEEE Eng Med Biol Soc (2010), Vol. 2009, pp. Med Eng Phys (2009), Vol. 31, No. 7, pp. 872-9 3485-8

Analysis of MEG background activity in Alzheimer's Blind source separation to enhance spectral and disease using nonlinear methods and ANFIS non-linear features of magnetoencephalogram recordings. Application to Alzheimer's disease Gómez, C; Hornero, R; Abásolo, D; Fernández, A; Escudero, J Escudero, J; Hornero, R; Abásolo, D; Fernández, A Biomedical Engineering Group, Department of Signal Theory and Communications, E.T.S. Ingenieros de Telecomunicación,

17 University of Valladolid, Campus Miguel Delibes, Camino del nel magnetoencephalography was recorded during an Cementerio s/n, 47011 Valladolid, Spain. [email protected] eyes-closed resting state. Magnetoencephalography channels were grouped in 10 cortical regions, and both ABSTRACT: This study was designed to analyze the global and regional relative power was analyzed for the magnetoencephalogram (MEG) background activity commonly used frequency bands. Eighteen AD patients from 20 patients with probable Alzheimer's disease [mean age 72.1 years +/- 5.6 (SD); 7 women; mean Mini (AD) and 21 control subjects by using two nonlinear Mental State Examination score 19.2, range: 13-25] methods: sample entropy (SampEn), and Lempel-Ziv and 18 healthy controls [mean age 69.1 +/- 6.8 (SD), complexity (LZC). The former quantifies the signal 11 women; mean Mini Mental State Examination score regularity, and the latter is a complexity measure. The 29, range: 27-30] were recruited, controls being mainly signals were acquired with a 148-channel whole-head spouses of patients. Relative power analysis showed magnetometer placed in a magnetically shielded room. significant differences in most frequency bands, par- Our results show that MEG recordings are less complex ticularly in the temporo-parietal regions, with some and more regular in patients with AD than in control relation to Mini Mental State Examination scores. Great- subjects. Significant differences between both groups est diagnostic accuracy was found in the beta band, were found in 16 MEG channels with SampEn and in especially in the right occipital area (sensitivity 94%, 134 with LZC (p < 0.01, Student's t test with Bonferro- specificity 78%). Quantitative relative power analysis of ni's correction). Using receiver operating characteristic magnetoencephalography recordings is able to show curves with a leave-one-out cross-validation proce- widespread abnormalities in oscillatory brain dynamics dure, accuracies of 70.73 and 78.05% were reached in AD patients. By analyzing distinct cortical regions, with SampEn and LZC, respectively. Additionally, we this study provides a more detailed topographical view wanted to assess whether both nonlinear methods and of abnormal brain activity in AD. (18677182) an adaptive-network-based fuzzy interference system (ANFIS) could improve AD diagnosis. With this classifier, J Clin Neurophysiol (2008), Vol. 25, No. 4, pp. 187-93 an accuracy of 85.37% was achieved. Our findings suggest the usefulness of our methodology to increase our insight into AD. (19130227) Exercise, APOE, and working memory: MEG and behavioral evidence for benefit of exercise in Ann Biomed Eng (2009), Vol. 37, No. 3, pp. 586-94 epsilon4 carriers

Deeny, SP; Poeppel, D; Zimmerman, JB; Roth, SM; Resting-state oscillatory brain dynamics in Brandauer, J; Witkowski, S; Hearn, JW; Ludlow, Alzheimer disease AT; Contreras-Vidal, JL; Brandt, J; Hatfield, BD de Haan, W; Stam, CJ; Jones, BF; Zuider- Department of Kinesiology, School of Public Health, Uni- wijk, IM; van Dijk, BW; Scheltens, P versity of Maryland, College Park, MD 20742, United States. [email protected] Department of Clinical Neurophysiology and MEG, VU University Medical Center, Amsterdam, The Netherlands. ABSTRACT: Performance on the Sternberg working [email protected] memory task, and MEG cortical response on a variation of the Sternberg task were examined in middle-aged ABSTRACT: Altered oscillatory brain activity in Al- carriers and non-carriers of the APOE epsilon4 allele. zheimer disease (AD) may reflect underlying neuro- Physical activity was also assessed to examine whether pathological changes, and its characterization might exercise level modifies the relationship between APOE lead to new diagnostic possibilities. The present study genotype and neurocognitive function. Regression using quantitative magnetoencephalography was set revealed that high physical activity was associated up to examine power spectrum changes in AD patients, with faster RT in the six- and eight-letter conditions of and their diagnostic strength. Whole-head 151-chan- the Sternberg in epsilon4 carriers, but not in the non-

18 carriers after controlling for age, gender, and educa- provided the largest differences between demented tion (N=54). Furthermore, the MEG analysis revealed patients and control subjects were ordered together. that sedentary epsilon4 carriers exhibited lower right Considering this analysis, we defined two subsets, de- temporal lobe activation on matching probe trials noted by BSS-{15,35} and BSS-{20,30}, which included relative to high-active epsilon4 carriers, while physical 21 components (15-35) and 11 components (20-30), activity did not distinguish non-carriers (N=23). The respectively. We partially reconstructed the MEGs with M170 peak was identified as a potential marker for these subsets. Then, the classification performance was pre-clinical decline as epsilon4 carriers exhibited longer computed with a leave-one-out cross-validation pro- M170 latency, and highly physically active participants cedure for the case where no BSS was applied and for exhibited greater M170 amplitude to matching probe the partial reconstructions BSS-{15,35} and BSS-{20,30}. trials. (18395955) The BSS and component selection procedure improved the classification accuracy from 69.05% to 83.33% using Biol Psychol (2008), Vol. 78, No. 2, pp. 179-87 f(median) with BSS-{15,35} and from 61.91% to 73.81% using SpecEn with BSS-{20,30}. CONCLUSION: These preliminary results lead us to think that the proposed Assessment of classification improvement in procedure based on BSS and selection of significant patients with Alzheimer's disease based on components may improve the classification of AD pa- magnetoencephalogram blind source separation tients using straightforward features from MEG recordings. (18329868) Escudero, J; Hornero, R; Poza, J; Abásolo, D; Fernández, A Artif Intell Med (2008), Vol. 43, No. 1, pp. 75-85 Grupo de Ingeniería Biomédica, E.T.S. Ingenieros de Teleco- municación, University of Valladolid, 47011 Valladolid, Spain. [email protected] Evaluation of spectral ratio measures from spontaneous MEG recordings in patients with OBJECTIVES: In this pilot study, we intended to assess Alzheimer's disease whether a procedure based on blind source separation (BSS) and subsequent partial reconstruction of magne- Poza, J; Hornero, R; Abásolo, D; Fernández, A; Mayo, A toencephalogram (MEG) recordings might enhance the differences between MEGs from Alzheimer's disease Biomedical Engineering Group, E.T.S. Ingenieros de Telecomu- (AD) patients and elderly control subjects. MATERIALS nicación, University of Valladolid, Campus Miguel Delibes, AND METHODS: We analysed MEG background activ- Camino del Cementerio s/n, 47011 Valladolid, Spain. jespoz@ ity recordings acquired with a 148-channel whole-head tel.uva.es magnetometer from 21 AD patients and 21 control subjects. Artefact-free epochs of 20 s were blindly decom- ABSTRACT: Alzheimer's disease (AD) is the most posed using the algorithm for multiple unknown sig- frequent form of dementia in western countries. The nals extraction (AMUSE), which arranges the extracted rise in life expectancy will likely increase its prevalence, components by decreasing linear predictability. Thus, since ageing is the greatest known risk factor. Although the components of diverse epochs and subjects could an early and accurate identification is critical, low be easily compared. Every component was character- diagnostic accuracy is currently reached. Hence, the ised with its median frequency and spectral entropy aim of the present study was to analyse the spontane- (denoted by fmedian and SpecEn, respectively). The ous magnetoencephalographic (MEG) activity from 148 differences between subject groups in these variables channels in 20 AD patients and 21 healthy controls to were statistically evaluated to find out which compo- extract discriminating spectral features. Relative power nents could improve the subject classification. Then, (RP) was calculated in conventional frequency bands these significant components were used to partially and several ratios were defined to emphasise the dif- reconstruct the MEG recordings. RESULTS: The statisti- ferences in its distribution. Both RP values and spectral cal analysis showed that the AMUSE components which ratios were transformed with a principal component

19 analysis to summarise information with minimal loss tral entropies were calculated from the time-frequency of variability. AD patients showed a significant increase distribution of the power spectral density (PSD). The of RP(delta) and RP(theta), along with a decrease of entropies provided statistically significant lower values RP(beta) and RP(gamma). The most significant dif- for AD patients than for controls in all brain regions ferences were reached by spectral ratios using the (p < 0.0005). This fact suggests a significant loss of beta band. Specifically, we obtained 75.0% sensitivity, irregularity in AD patients' MEG activity. Maximal ac- 90.5% specificity and 82.9% accuracy (linear discrimi- curacy of 87.8% was achieved by both the TSE and RSE nant analysis with a leave-one-out cross-validation (90.0%, sensitivity; 85.7%, specificity). The statistically procedure), together with a p-value lower than 0.001 significant results obtained by both the extensive (SSE (one-way analysis of variance with age as a covariate) and RSE) and non-extensive (TSE) spectral entropies using the [RP(alpha)+RP(beta(1))+RP(beta(2))+RP(ga suggest that AD could disturb long and short-range mma)]/[RP(delta)+RP(theta)] ratio. The spectral ratios interactions causing an abnormal brain function. also showed a higher correlation with the severity of (17994279) dementia than individual relative power measures. Our results suggest that the spectral ratios could be useful Ann Biomed Eng (2008), Vol. 36, No. 1, pp. 141-52 descriptors to help in the AD diagnosis, since they effectively summarise the slowing of the AD patients' MEG rhythms in individual indexes and correlate signifi- Analysis of the magnetoencephalogram cantly with the severity of dementia. (18249462) background activity in Alzheimer's disease patients with auto-mutual information Comput Methods Programs Biomed (2008), Vol. 90, No. 2, pp. 137-47 Gómez, C; Hornero, R; Abásolo, D; Fernández, A; Escudero, J

Regional analysis of spontaneous MEG rhythms in Biomedical Engineering Group, E. T. S. Ingenieros de Teleco- patients with Alzheimer's disease using spectral municación, University of Valladolid, Camino del Cementerio entropies s/n, 47011-Valladolid, Spain. [email protected]

Poza, J; Hornero, R; Escudero, J; Fernández, A; Sánchez, CI ABSTRACT: The aim of the present study was to analyse the magnetoencephalogram (MEG) background Biomedical Engineering Group, Department T.S.C.I.T., E.T.S. activity in patients with Alzheimer's disease (AD), one Ingenieros de Telecomunicación, University of Valladolid, of the most frequent disorders among elderly popula- Camino del Cementerio s/n, 47011, Valladolid, Spain. jespoz@ tion. For this pilot study, we recorded the MEGs with a tel.uva.es 148-channel whole-head magnetometer in 20 patients with probable AD and 21 age-matched control sub- ABSTRACT: Alzheimer's disease (AD) is the most com- jects. Artefact-free epochs of 3392 samples were anal- mon form of dementia. Ageing is the greatest known ysed with auto-mutual information (AMI). Average AMI risk factor for this disorder. Therefore, the prevalence of decline rates were lower for the AD patients' recordings AD is expected to increase in western countries due to than for control subjects' ones. Statistically significant the rise in life expectancy. Nowadays, a low diagnosis differences were found using a Student's t-test (p<0.01) accuracy is reached, but an early and accurate identi- in 144 channels. Mean AMI values were analysed with fication of AD should be attempted. In this sense, only a receiver operating characteristic curve. Sensitiv- a few studies have focused on the magnetoencepha- ity, specificity and accuracy values of 75%, 90.5% lographic (MEG) AD patterns. This work represents a and 82.9% were obtained. Our results show that AMI new effort to explore the ability of three entropies from estimations of the magnetic brain activity are different information theory to discriminate between spontane- in both groups, hence indicating an abnormal type of ous MEG rhythms from 20 AD patients and 21 controls. dynamics associated with AD. This study suggests that The Shannon (SSE), Tsallis (TSE), and Rényi (RSE) spec-

20 AMI might help medical doctors in the diagnosis of the Hum Brain Mapp (2008), Vol. 28, No. 11, pp. 1178-93 disease. (17686545)

Comput Methods Programs Biomed (2007), Vol. 87, No. 3, Extraction of spectral based measures from MEG pp. 239-47 background oscillations in Alzheimer's disease

Poza, J; Hornero, R; Abásolo, D; Fernández, A; García, M Phase lag index: assessment of functional connectivity from multi channel EEG and MEG with Grupo de Ingeniería Biomédica, E.T.S. Ingenieros de Telecomu- diminished bias from common sources nicación, University of Valladolid, Camino del Cementerio s/n, 47011 Valladolid, Spain. [email protected] Stam, CJ; Nolte, G; Daffertshofer, A ABSTRACT: In this study, we explored the ability of Department of Clinical Neurophysiology, VU University Medi- several spectral based measures to summarize the in- cal Center, Amsterdam, The Netherlands. [email protected] formation of the power spectral density (PSD) function from spontaneous magnetoencephalographic (MEG) OBJECTIVE: To address the problem of volume con- activity in Alzheimer's disease (AD). The MEGs of 20 AD duction and active reference electrodes in the assess- patients and 21 elderly controls were recorded with ment of functional connectivity, we propose a novel eyes closed at rest during 5 min from 148 channels. measure to quantify phase synchronization, the phase Five spectral parameters were estimated from PSD: lag index (PLI), and compare its performance to the mean frequency (MF), individual alpha frequency (IAF), well-known phase coherence (PC), and to the imagi- transition frequency (TF), 95% spectral edge frequency nary component of coherency (IC). METHODS: The (SEF95) and spectral entropy (SE). To reduce the dimen- PLI is a measure of the asymmetry of the distribution sionality of the problem, we applied a principal compo- of phase differences between two signals. The perfor- nent analysis. According to our results, MF was the best mance of PLI, PC, and IC was examined in (i) a model discriminating index between both groups (85.00% of 64 globally coupled oscillators, (ii) an EEG with an sensitivity, 85.71% specificity) indicating a shift to the absence seizure, (iii) an EEG data set of 15 Alzheimer left of the power spectrum in AD. A significant MEG patients and 13 control subjects, and (iv) two MEG data slowing was also observed using both IAF (p < 0.001) sets. RESULTS: PLI and PC were more sensitive than and TF (p < 0.01). The lowest classification statistics IC to increasing levels of true synchronization in the (65% sensitivity, 66.67% specificity) were obtained with model. PC and IC were influenced stronger than PLI by SEF95. However, these results were also significant (p < spurious correlations because of common sources. All 0.05). This fact points out that there is a variation in the measures detected changes in synchronization during spectral content at high frequencies of AD patients and the absence seizure. In contrast to PC, PLI and IC were controls. Finally, a significant decrease of irregularity in barely changed by the choice of different montages. the AD group was observed with SE, with results close PLI and IC were superior to PC in detecting changes to those obtained with MF (90.00% sensitivity, 76.19% in beta band connectivity in AD patients. Finally, PLI specificity). In conclusion, a complete description of and IC revealed a different spatial pattern of functional PSD can help to increase our insight into brain dysfunc- connectivity in MEG data than PC. CONCLUSION: The tion in AD and to extract spectral patterns specific to PLI performed at least as well as the PC in detecting the disease. (17204443) true changes in synchronization in model and real data but, at the same token and like-wise the IC, it was much Med Eng Phys (2008), Vol. 29, No. 10, pp. 1073-83 less affected by the influence of common sources and active reference electrodes. (17266107)

21 22 Attention Deficit and Hyperactivity Disorder

MEG Analysis of Neural Interactions in Attention- Comput Intell Neurosci (2016), Vol. 2016, pp. 8450241 Deficit/Hyperactivity Disorder

Khadmaoui, A; Gómez, C; Poza, J; Bachil- Pharmaco-MEG evidence for attention related ler, A; Fernández, A; Quintero, J; Hornero, R hyper-connectivity between auditory and prefrontal cortices in ADHD Biomedical Engineering Group, E.T.S. Ingenieros de Telecomu- nicación, Universidad de Valladolid, Campus Miguel Delibes, Heinrichs-Graham, E; Franzen, JD; Knott, NL; Paseo Belén 15, 47011 Valladolid, Spain. White, ML; Wetzel, MW; Wilson, TW

ABSTRACT: The aim of the present study was to Department of Psychology, University of Nebraska, Omaha, explore the interchannel relationships of resting-state NE, USA; Center for Magnetoencephalography (MEG), Univer- brain activity in patients with attention-deficit/hyper- sity of Nebraska Medical Center, Omaha, NE, USA. activity disorder (ADHD), one of the most common mental disorders that develop in children. Magnetoen- ABSTRACT: The ability to attend to particular stimuli cephalographic (MEG) signals were recorded using a while ignoring others is crucial in goal-directed ac- 148-channel whole-head magnetometer in 13 patients tivities and has been linked with prefrontal cortical with ADHD (range: 8-12 years) and 14 control subjects regions, including the dorsolateral prefrontal cortex (range: 8-13 years). Three complementary measures (DLPFC). Both hyper- and hypo-activation in the DLPFC (coherence, phase-locking value, and Euclidean has been reported in patients with attention-deficit/ distance) were calculated in the conventional MEG hyperactivity disorder (ADHD) during many different frequency bands: delta, theta, alpha, beta, and gamma. cognitive tasks, but the network-level effects of such Our results showed that the interactions among MEG aberrant activity remain largely unknown. Using mag- channels are higher for ADHD patients than for control netoencephalography (MEG), we examined functional subjects in all frequency bands. Statistically significant connectivity between regions of the DLPFC and the differences were observed for short-distance values modality-specific auditory cortices during an auditory within right-anterior and central regions, especially at attention task in medicated and un-medicated adults delta, beta, and gamma-frequency bands (p < 0.05; with ADHD, and those without ADHD. Participants Mann-Whitney U test with false discovery rate correc- completed an attention task in two separate sessions tion). These frequency bands also showed statistically (medicated/un-medicated), and each session consisted significant differences in long-distance interactions, of two blocks (attend and no-attend). All MEG data mainly among anterior and central regions, as well as were coregistered to structural MRI, corrected for head among anterior, central, and other areas. These differ- motion, and projected into source space. Subsequently, ences might reflect alterations during brain develop- we computed the phase coherence (i.e., functional ment in children with ADHD. Our results support the connectivity) between DLPFC regions and the audi- role of frontal abnormalities in ADHD pathophysiology, tory cortices. We found that un-medicated adults with which may reflect a delay in cortical maturation in the ADHD exhibited greater phase coherence in the beta frontal cortex. (27118965) (14-30Hz) and gamma frequency (30-56Hz) range in attend and no-attend conditions compared to controls. Stimulant medication attenuated these differences, but did not fully eliminate them. These results suggest that aberrant bottom-up processing may engulf executive resources in ADHD. (24495532)

23 Keywords: Beta; Cortex; DLPFC; Gamma; Magnetoenceph- the MPFC-PCC and LIPL-RIPL pathways in patients with alography; Stimulants ADHD. LIMITATIONS: Modest sample size and lack of duration of patient treatment history may limit the gen- Psychiatry Res (2014), Vol. 221, No. 3, pp. 240-5 eralizability of our findings. CONCLUSION: Adults with ADHD exhibit hyper- and hypoconnectivity between regions of the DMN during rest, which were suppressed Atypical coupling between posterior regions after stimulant medication administration. (23611175) of the default mode network in attention- deficit/hyperactivity disorder: a pharmaco- J Psychiatry Neurosci (2014), Vol. 38, No. 5, pp. 333-40 magnetoencephalography study

Franzen, JD; Heinrichs-Graham, E; White, ML; Behavioral consequences of aberrant alpha Wetzel, MW; Knott, NL; Wilson, TW lateralization in attention-deficit/hyperactivity disorder Department of Psychiatry, University of Nebraska Medical Center, Omaha, NE, USA. ter Huurne, N; Onnink, M; Kan, C; Fran- ke, B; Buitelaar, J; Jensen, O BACKGROUND: Dysfunction in the default mode network (DMN), a group of cortical areas more active Centre for Cognitive Neuroimaging, Radboud Univer- during the resting state, has been linked to attentional sity Medical Centre, Nijmegen NL-6500, The Netherlands. deficits and symptoms associated with attention- [email protected] deficit/hyperactivity disorder (ADHD). Prior imaging studies have shown decreased functional connectivity BACKGROUND: Attention-deficit/hyperactivity disor- between DMN nodes in patients with ADHD, primar- der (ADHD) is characterized by problems in directing ily between anterior and posterior regions. Using and sustaining attention. Recent findings suggest that magnetoencephalography (MEG), we evaluated phase alpha oscillations (8-12 Hz) are crucially involved in gat- coherence (i.e., functional connectivity) among re- ing information between brain regions when allocat- gions of the DMN in healthy controls and adults with ing attention. The current study investigates whether ADHD before and after stimulant therapy. METHODS: aberrant modulation of alpha oscillations contributes We obtained a resting-state MEG recording for all to attention problems in ADHD patients. METHODS: participants. Magnetoencephalography data were Magnetoencephalographic signals were recorded in transformed into a ~30 node regional source model adults with ADHD (n = 17) and healthy control subjects using inverse spatial filtering, including regions cor- (n = 18) while they performed a visuospatial attention responding to the DMN. We computed the zero-lag task. Cues directed attention to the left or right visual phase coherence between these regions pairwise for 5 hemifield with an 80% validity with respect to the distinct frequency bands, and we assessed group and upcoming target. RESULTS: Unlike the control group, medication effects. RESULTS: Twelve adults with and subjects with ADHD showed a higher accuracy for in- 13 without ADHD participated in our study. Functional validly cued right targets compared with invalidly cued connectivity was stronger between particular node left targets (p = .04). This coincided with an inability of pairs and showed frequency-specific effects. Unmedi- the ADHD subjects to sustain the posterior hemispheric cated patients showed reduced phase locking between alpha lateralization in the period before the target posterior cingulate/precuneus regions (PCC) and right for the left cue condition (p = .011). Furthermore, the inferior parietal cortices (RIPL), and between medial control group showed a strong correlation between prefrontal regions (MPFC) and the left inferior parietal the degree of alpha lateralization and the magnitude region (LIPL) and the PCC. Unmedicated patients had of the cueing effect assessed in terms of accuracy (rs increased phase locking between the RIPL and LIPL = .71, p = .001) and reaction times (rs =-.81, p<.001). regions compared with controls. Administration of These correlations were absent in the ADHD group. stimulants improved phase locking abnormalities along CONCLUSIONS: Our results demonstrate that subjects

24 with ADHD have a failure in sustaining hemispheric left inferior parietal, and the left inferior frontal gyrus. alpha lateralization when cued to the left, resulting in These results suggest that psychostimulants strongly an attentional bias to the right visual hemifield. These modulate γ activity in frontal and parietal cortical areas, findings suggest that aberrant modulations of alpha which are known to be central to the brain's core at- oscillations reflect attention problems in ADHD and tentional networks. (22776904) might be related to the neurophysiological substrate of the disorder. (23507001) Neuroreport (2012), Vol. 23, No. 12, pp. 731-5

Keywords: ADHD; attention; bias; electroencephalography; magnetoencephalography (MEG); oscillations Regularity analysis of spontaneous MEG activity in Attention-Deficit/Hyperactivity Disorder Biol Psychiatry (2013), Vol. 74, No. 3, pp. 227-33 Gómez, C; Poza, J; García, M; Fernández, A; Hornero, R

Amphetamines modulate prefrontal γ oscillations Biomedical Engineering Group, Department of Signal Theory during attention processing and Communications, E.T.S. Ingenieros de Telecomunicación, University of Valladolid, Campus Miguel Delibes, 47011 Val- Franzen, JD; Wilson, TW ladolid, Spain. [email protected]

Department of Psychiatry, University of Nebraska Medical ABSTRACT: The aim of this study was to analyze the Center, Omaha, Nebraska, USA. magnetoencephalography (MEG) background activity in Attention-Deficit/Hyperactivity Disorder (ADHD) ABSTRACT: Amphetamine-based medications robustly using a regularity measure: sample entropy (Sam- suppress symptoms of attention-deficit/hyperactivity pEn). Five minutes of recording were acquired with a disorder (ADHD), but their exact mechanisms remain 148-channel whole-head magnetometer in 14 ADHD poorly understood. Recent hemodynamic imaging patients and 14 control subjects. Our results showed studies have suggested that amphetamines may that ADHD patients' MEGs were more regular than con- modulate the prefrontal and anterior cingulate brain trols' recordings. Additionally, there were statistically regions, although few studies have been published significant differences (p < 0.01, Student's t-test with and the results have not been entirely consistent. Bonferroni's correction) at the five analyzed brain areas: Meanwhile, several electrophysiological studies have anterior, central, posterior, left lateral and right lateral. shown that abnormal fast oscillations (in the γ range) Using receiver operating characteristic (ROC) curves, may be closely linked to inattention and other cardinal the highest accuracy (82.14%) was achieved at poste- symptoms of ADHD. In this study, we utilized magne- rior region, whereas the highest area under the ROC toencephalography to examine how amphetamines curves (0.8827) were reached at anterior and central modulate high-frequency brain activity in adults with brain regions. These results suggest the usefulness of ADHD. Participants performed an auditory attention SampEn to reveal an abnormal type of dynamics associ- task, which required sustained attention in one block ated with ADHD. (22254669) and passive listening in a separate block. Participants completed the task twice in the on-medication and Conf Proc IEEE Eng Med Biol Soc (2012), Vol. 2011, pp. off-medication states. All data were analyzed using 1765-8 beamforming techniques to resolve cortical regions showing event-related synchronizations and desyn- chronizations. Our primary findings indicated that oral Gamma-frequency neuronal activity is diminished administration of amphetamine decreased γ-band in adults with attention-deficit/hyperactivity event-related desynchronization activity significantly in disorder: a pharmaco-MEG study the medial prefrontal area and decreased event-related synchronization in bilateral superior parietal areas, Wilson, TW; Wetzel, MW; White, ML; Knott, NL

25 Department of Pharmacology and Experimental Neurosci- ABSTRACT: Previous investigations of the default- ence, University of Nebraska Medical Center-UNMC, Omaha, mode network (DMN) in persons with attention-deficit/ NE, USA. [email protected] hyperactivity disorder (ADHD) have shown reduced functional connectivity between the anterior and ABSTRACT: Attention-deficit/hyperactivity disorder posterior aspects. This finding was originally demon- (ADHD) is a neurobehavioral disorder affecting ap- strated in adults with ADHD, then in youth with ADHD, proximately 4-7% of children and persisting in 2-5% and has been tentatively linked to ultra low frequency of adults. The core symptoms include pervasive oscillations within the DMN. The current study evalu- inattention and inappropriate levels of hyperactivity- ates the specificity of DMN abnormalities to neuronal impulsivity. High-frequency gamma activity has been oscillations in the ultra low frequency range, and implicated in the temporal binding of stimulus proper- examines the regional specificity of these DMN aberra- ties across cortical areas, and is known to be crucial tions in medicated and unmedicated adults with, and for complex information processing and attentional those without ADHD. An individually matched sample processes in particular. Thus, we evaluated the ampli- of adults with and without ADHD completed 6-minute tude of gamma-frequency neural responses in adults sessions of resting-state magnetoencephalography with and those without ADHD, and tested whether (MEG). Participants with ADHD were known responders stimulant medications, the most common treatment to stimulant medications and completed two sessions for ADHD, modulate gamma activity in affected adults. (predrug/postdrug). MEG data were coregistered to the Participants underwent two sessions (~75 min apart) of participant's MRI, corrected for head motion, fitted to a auditory stimulation using stimuli known to elicit 40 Hz regional-level source model, and subjected to spec- gamma-band responses as magnetoencephalography tral analyses to extract neuronal population activity data were acquired. Between sessions, the ADHD group in regions of the DMN. The unmedicated adults with (who were in maintenance therapy) were administered ADHD exhibited broadband deficits in medial prefron- their daily stimulant medication and both groups were tal cortices (MPFC), but not other DMN regions com- told to relax. The primary results indicated that gamma pared to adults without ADHD. Unmedicated patients activity was weaker in the ADHD group during session also showed abnormal cross-frequency coupling in one (pre-drug), but not session two (post-drug), and the gamma range between the MPFC and posterior that gamma activity significantly increased following cingulate areas, and disturbed balance within the DMN stimulant administration in adults with ADHD. These as activity in posterior regions was stronger than frontal results suggest that ADHD is associated with reduced regions at beta and lower frequencies, which dissipated cortical gamma activity and that stimulants may ame- at higher γ-frequencies. Administration of pharmaco- liorate this abnormality. (22219219) therapy significantly increased prefrontal alpha activity (8-14 Hz) in adults with ADHD, and decreased the cross- J Psychopharmacol (2013), Vol. 26, No. 6, pp. 771-7 frequency gamma coupling. These results indicate that neurophysiological aberrations in the DMN of patients with ADHD are not limited to ultra slow oscillations, Broadband neurophysiological abnormalities in and that they may be primarily attributable to abnor- the medial prefrontal region of the default-mode mal broadband activity in the MPFC. (22102400) network in adults with ADHD Hum Brain Mapp (2013), Vol. 34, No. 3, pp. 566-74 Wilson, TW; Franzen, JD; Heinrichs-Graham, E; White, ML; Knott, NL; Wetzel, MW Abnormal neural reactivity to unpredictable Department of Pharmacology and Experimental Neurosci- sensory events in attention-deficit/hyperactivity ence, University of Nebraska Medical Center, Omaha, NE, disorder USA. [email protected] Dockstader, C; Gaetz, W; Cheyne, D; Tannock, R

26 Neurosciences and Mental Health Program, the Hospital for Sick Children, Toronto, Ontario, Canada. BACKGROUND: Cortical oscillations in the sensorimo- Biol Psychiatry (2009), Vol. 66, No. 4, pp. 376-83 tor region in the 8-12-Hz range ("mu rhythms") are associated with basic somatosensory and motor processes as well as top-down processes such as learning, Community participatory research: student nurses attention, expectancy, and inhibition. Recent studies collaborate to reduce lead exposure by educating suggest that reactivity of these rhythms to sensory paint retailers input reflects a link between perception and action and that abnormalities in this reactivity might reflect Gordon, BA; Datema, MR; Slager, D; Mar- impairment in perception-to-action mechanisms. tin, JT; Vander Werf, MC Individuals with attention-deficit/hyperactivity disorder (ADHD) are impaired in tasks requiring sensorimotor Department of Nursing, Calvin College, 1734 Knollcrest Circle, function, attention, expectancy, and inhibition, yet Grand Rapids, MI 49546, USA. [email protected] their sensorimotor mu responses are unknown. Thus, we investigated mu reactivity in a group of adults with ABSTRACT: Collaboration is a hallmark of the nurs- ADHD. METHODS: Sixteen adults with ADHD and 16 ing profession as advocated in practice standards and matched control subjects received median nerve stim- nursing experience. The authors describe a unique ulation in predictable patterns (trains of four stimuli experience in which senior students participated in followed by 4-sec gap) or unpredictable patterns (ran- community-based participatory research, working col- domly presented trains of two, four, or six stimuli fol- laboratively with another school, a community organi- lowed by 4-sec gap). With magnetoencephalography, zation. (19104348) we examined the effects of stimulus patterning (predictable, unpredictable) on mu reactivity to somatosen- Nurse Educ (2009), Vol. 34, No. 1, pp. 43-6 sory stimuli. RESULTS: Compared with control subjects, the ADHD group showed lower mu reactivity overall and no modulation by unpredictable somatosensory input. By contrast, the control group showed robust mu reactivity to stimuli presented in unpredictable but not predictable patterns. These changes were stronger in the contralateral hemisphere compared with the ADHD group. CONCLUSIONS: Cortical mu rhythms are modulated by stimulus predictability and might be involved in attentional alerting (awareness of when an unexpected stimulus occurs). Diminished mu modulation in adult ADHD suggests a possible underlying deficit in the perception-to-action system. (19482264)

27 28 Autism Spectrum Disorders Keywords: Adults; Auditory language discrimination process and laterality; Autism spectrum disorder; Magne- toencephalography; Vowel mismatch fields Abnormal auditory mismatch fields in adults with autism spectrum disorder Neurosci Lett (2019), Vol. 698, pp. 140-145

Matsuzaki, J; Ku, M; Berman, JI; Blaskey, L; Bloy, L; Chen, YH; Dell, J; Edgar, JC; Kuschner, ES; Abnormal cortical activation during silent reading Liu, S; Saby, J; Brodkin, ES; Roberts, TPL in adolescents with autism spectrum disorder

Lurie Family Foundations MEG Imaging Center, Department Ogawa, R; Kagitani-Shimono, K; Matsuzaki, J; of Radiology, Children's Hospital of Philadelphia, 3401 Civic Tanigawa, J; Hanaie, R; Yamamoto, T; Tomi- Center Blvd, Philadelphia, PA, 19104, USA. naga, K; Hirata, M; Mohri, I; Taniike, M

ABSTRACT: The auditory mismatch field (MMF) is a United Graduate School of Child Development, Osaka Uni- pre-attentive processing component, reflecting neural versity, Osaka, Japan. discrimination and inhibitory processing. Abnormal MMFs have been reported in children with autism OBJECTIVE: Autism spectrum disorder (ASD) is a spectrum disorder (ASD) along with an association developmental disorder characterized by communi- with abnormal language comprehension; however, cation deficits and social difficulties, and individuals relatively little is known about MMF abnormalities to with ASD frequently exhibit varied levels of language contrasting vowel stimuli in adults with ASD. To better abilities. However, the neurophysiological mechanisms understand the neurophysiological mechanisms under- underlying their language deficits remain unclear. To lying auditory language discrimination of vowel stimuli gain insight into the neurophysiological mechanisms in individuals with ASD, magnetoencephalography of receptive language deficits, we assessed cortical was used to measure MMFs during an auditory oddball activation patterns in adolescents with ASD during paradigm with vowel stimuli (/a/ and /u/) in adults with silent word-reading. METHODS: We used magnetoen- ASD. MMFs arising from left and right superior tem- cephalography to measure cortical activation during poral gyrus are reported from nine high-functioning a silent word-reading task in 14 adolescent boys with right handed males with ASD (22.22 ± 5.74yrs) and high-functioning ASD and 17 adolescent boys with sixteen typically developing (TD) right handed males typical development (TD). RESULTS: Compared with (27.25 ± 6.63yrs). The MMF was delayed in adults with participants with TD, those with ASD exhibited signifi- ASD (188.90 ± 5.8 ms) as compared to the TD partici- cantly decreased cortical activation in the left middle pants (173.08 ± 4.31 ms, p < 0.05). Replicating previ- temporal gyrus, left temporoparietal junction, bilateral ous findings in children, the earlier M100 component superior temporal gyrus, left posterior insula, and right to single stimulus tokens was also delayed in adults occipitotemporal gyrus, and increased activation in the with ASD (108.59 ± 4.1 ms) compared to the TD partici- right anterior insula. Participants with ASD also exhib- pants (94.60 ± 3.0 ms, p < 0.05). However, there was no ited a lack of left-lateralization in the central sulcus correlation between delayed M100 latency and MMF and abnormal right-lateralization in the anterior insula latency. Furthermore, whereas TD participants showed area. Furthermore, in participants with ASD, we found a leftward lateralization of MMF amplitude, participants that abnormal activation of the right central sulcus with ASD showed an opposite (rightward) lateraliza- correlated significantly with lower visual word compre- tion. Findings suggest that adults with ASD have hension scores, and that decreased activation of the hemispherically- and temporally- abnormal auditory right anterior insula correlated significantly with the discrimination processing in addition to and distinct severity of social interaction difficulties. CONCLUSION: from abnormal neurophysiological mechanisms in Our findings suggest that atypical cortical activation earlier cortical responses. (30599264) and lateralization in the temporal-frontal area, which is associated with higher-order language processing

29 functions, such as semantic analysis, may play a crucial the right inferior frontal gyrus is involved in inhibitory role in visual word comprehension and social interac- control, this finding suggests that children with autism tion difficulties in adolescents with ASD. (30448302) rely on executive functions to bolster their false-belief understanding. (30415185) Keywords: Autism spectrum disorder; Developmental disorders; Language; Lateralization; Magnetoencephalog- Keywords: Autism; Children; False belief; Magnetoenceph- raphy; Temporal-frontal area; Visual word comprehension alography; Theory of mind

Brain Dev (2019), Vol. 41, No. 3, pp. 234-244 Dev Cogn Neurosci (2019), Vol. 34, pp. 139-147

Do you know what I'm thinking? Temporal and Enhanced Early Visual Responses During Implicit spatial brain activity during a theory-of-mind task Emotional Faces Processing in Autism Spectrum in children with autism Disorder

Yuk, V; Urbain, C; Pang, EW; Anagnos- Kovarski, K; Mennella, R; Wong, SM; Dunk- tou, E; Buchsbaum, D; Taylor, MJ ley, BT; Taylor, MJ; Batty, M

Department of Diagnostic Imaging, The Hospital for Sick UMR 1253, iBrain, Université de Tours, Inserm, Centre Universi- Children, Toronto, ON, Canada; Neurosciences and Mental taire de PédoPsychiatrie, Tours, France. klara.kovarski@gmail. Health Program, SickKids Research Institute, The Hospital for com. Sick Children, Toronto, ON, Canada; Department of Psychol- ogy, University of Toronto, Toronto, ON, Canada. Electronic ABSTRACT: Research on Autism Spectrum Disorder address: [email protected]. (ASD) has focused on processing of socially-relevant stimuli, such as faces. Nonetheless, before being 'social', ABSTRACT: The social impairments observed in faces are visual stimuli. The present magnetoencepha- children with autism spectrum disorder are thought to lography study investigated the time course of brain arise in part from deficits in theory of mind, the ability activity during an implicit emotional task in visual to understand other people's thoughts and feelings. emotion-related regions in 19 adults with ASD (mean To determine the temporal-spatial dynamics of brain age 26.3 ± 4.4) and 19 typically developed controls activity underlying these atypical theory-of-mind (26.4 ± 4). The results confirmed previously-reported processes, we used magnetoencephalography to char- differences between groups in brain responses to acterize the sequence of functional brain patterns (i.e. emotion and a hypo-activation in the ASD group in the when and where) related to theory-of-mind reasoning right fusiform gyrus around 150 ms. However, the ASD in 19 high-functioning children with autism compared group also presented early enhanced activity in the to 22 age- and sex-matched typically-developing chil- occipital region. These results support that impaired dren aged 8-12 during a false-belief (theory-of-mind) face processing in ASD might be sustained by atypical task. While task performance did not differ between responses in primary visual areas. (30374763) the two groups, children with autism showed reduced activation in the left temporoparietal junction between 300-375 and 425-500 ms, as well as increased activation in the right inferior frontal gyrus from 325 to 375 ms compared to controls. The overlap in decreased temporoparietal junction activity and increased right inferior frontal gyrus activation from 325 to 375 ms suggests that in children with autism, the right inferior frontal gyrus may compensate for deficits in the temporoparietal junction, a neural theory-of-mind network hub. As

30 Keywords: Autism; Emotion; Face processing; MEG; Visual processing J Autism Dev Disord (2019), Vol. 49, No. 3, pp. 871-886 Keywords: E/I balance; autism; gamma; magnetoencephalography; movement; young children

Altered Gamma Oscillations during Motor Control in J Neurosci (2019), Vol. 38, No. 36, pp. 7878-7886 Children with Autism Spectrum Disorder

An, KM; Ikeda, T; Yoshimura, Y; Hasegawa, C; Saito, Maturational trajectories of local and long-range DN; Kumazaki, H; Hirosawa, T; Minabe, Y; Kikuchi, M functional connectivity in autism during face processing Research Center for Child Mental Development, Kanazawa University, Kanazawa 920-8640, Japan. Mamashli, F; Khan, S; Bharadwaj, H; Losh, A; Pawlyszyn, SM; Hämäläinen, MS; Kenet, T ABSTRACT: Autism is hypothesized to result in a cortical excitatory and inhibitory imbalance driven by Department of Neurology, MGH, Harvard Medical School, inhibitory interneuron dysfunction, which is associ- Boston, Massachusetts. ated with the generation of gamma oscillations. On the other hand, impaired motor control has been widely ABSTRACT: Autism spectrum disorder (ASD) is charac- reported in autism. However, no study has focused on terized neurophysiologically by, among other things, the gamma oscillations during motor control in autism. functional connectivity abnormalities in the brain. In the present study, we investigated the motor-related Recent evidence suggests that the nature of these gamma oscillations in autism using magnetoen- functional connectivity abnormalities might not be cephalography. Magnetoencephalographic signals uniform throughout maturation. Comparing between were recorded from 14 right-handed human children adolescents and young adults (ages 14-21) with ASD with autism (5 female), aged 5-7 years, and age- and and age- and IQ-matched typically developing (TD) IQ-matched 15 typically developing children during individuals, we previously documented, using magne- a motor task using their right index finger. Consistent toencephalography (MEG) data, that local functional with previous studies, the autism group showed a connectivity in the fusiform face areas (FFA) and long- significantly longer button response time and re- range functional connectivity between FFA and three duced amplitude of motor-evoked magnetic fields. We higher order cortical areas were all reduced in ASD. observed that the autism group exhibited a low peak Given the findings on abnormal maturation trajecto- frequency of motor-related gamma oscillations from ries in ASD, we tested whether these results extend to the contralateral primary motor cortex, and these were preadolescent children (ages 7-13). We found that both associated with the severity of autism symptoms. The local and long-range functional connectivity were in autism group showed a reduced power of motor-relat- fact normal in this younger age group in ASD. Combin- ed gamma oscillations in the bilateral primary motor ing the two age groups, we found that local and long- cortex. A linear discriminant analysis using the button range functional connectivity measures were positively response time and gamma oscillations showed a high correlated with age in TD, but negatively correlated classification performance (86.2% accuracy). The altera- with age in ASD. Last, we showed that local functional tions of the gamma oscillations in autism might reflect connectivity was the primary feature in predicting age the cortical excitatory and inhibitory imbalance. Our in ASD group, but not in the TD group. Furthermore, findings provide an important clue into the behavioral local functional connectivity was only correlated with and neurophysiological alterations in autism and a ASD severity in the older group. These results suggest potential biomarker for autism. (30104338) that the direction of maturation of functional connec-

31 tivity for processing of faces from childhood to young predictable information was positively correlated with adulthood is itself abnormal in ASD, and that during source power in the alpha and beta frequency range as the processing of faces, these trajectory abnormalities well as autocorrelation decay time. Predictable infor- are more pronounced for local functional connectivity mation in precuneus and cerebellum was negatively measures than they are for long-range functional con- associated with nonsocial symptom severity, indicating nectivity measures. (29947148) a relevance of the analysis of predictable information for clinical research in ASD. Our findings are compat- Keywords: ASD; MEG; adolescence; coherence; develop- ible with the assumption that use or precision of prior ment; face processing; phase amplitude coupling knowledge is reduced in ASD patients. (29617056)

Hum Brain Mapp (2019), Vol. 39, No. 10, pp. 4094-4104 Keywords: active information storage; autism spectrum disorder; default mode network; information theory; magnetoencephalography; predictive coding theory; Predictable information in neural signals during prior knowledge resting state is reduced in autism spectrum disorder Hum Brain Mapp (2019), Vol. 39, No. 8, pp. 3227-3240 Brodski-Guerniero, A; Naumer, MJ; Moliadze, V; Chan, J; Althen, H; Ferreira-Santos, F; Lizier, JT; Schlitt, S; Kitzerow, J; Schütz, M; Langer, A; Kaiser, J; Freitag, CM; Wibral, M Patterns of altered neural synchrony in the default mode network in autism spectrum disorder MEG Unit, Brain Imaging Center, Goethe University, Frankfurt revealed with magnetoencephalography (MEG): am Main, Germany. Relationship to clinical symptomatology

ABSTRACT: The neurophysiological underpinnings of Lajiness-O'Neill, R; Brennan, JR; Moran, JE; Rich- the nonsocial symptoms of autism spectrum disorder ard, AE; Flores, AM; Swick, C; Goodcase, R; An- (ASD) which include sensory and perceptual atypicali- dersen, T; McFarlane, K; Rusiniak, K; Kovelman, I; ties remain poorly understood. Well-known accounts of Wagley, N; Ugolini, M; Albright, J; Bowyer, SM less dominant top-down influences and more dominant bottom-up processes compete to explain these Eastern Michigan University, Ypsilanti, Michigan. characteristics. These accounts have been recently embedded in the popular framework of predictive {{}, {Label -> LAY SUMMARY}}[[All,1]]<>: Disrupted coding theory. To differentiate between competing neural synchrony may be a primary electrophysi- accounts, we studied altered information dynamics in ological abnormality in autism spectrum disorders ASD by quantifying predictable information in neural (ASD), altering communication between discrete brain signals. Predictable information in neural signals mea- regions and contributing to abnormalities in patterns sures the amount of stored information that is used for of connectivity within identified neural networks. the next time step of a neural process. Thus, predictable Studies exploring brain dynamics to comprehensively information limits the (prior) information which might characterize and link connectivity to large-scale cortical be available for other brain areas, for example, to build networks and clinical symptoms are lagging consider- predictions for upcoming sensory information. We ably. Patterns of neural coherence within the Default studied predictable information in neural signals based Mode Network (DMN) and Salience Network (SN) dur- on resting-state magnetoencephalography (MEG) ing resting state were investigated in 12 children with recordings of 19 ASD patients and 19 neurotypical con- ASD (M (29251830) trols aged between 14 and 27 years. Using whole-brain beamformer source analysis, we found reduced predictable information in ASD patients across the whole brain, but in particular in posterior regions of the default mode network. In these regions, epoch-by-epoch

32 Keywords: autism spectrum disorder; coherence; default Keywords: Autism spectrum disorder; Evoked phase- mode network; gamma; magnetoencephalography; locked γ-oscillations; Magnetoencephalography; Percep- salience network; synchrony tual simultaneity

Autism Res (2019), Vol. 11, No. 3, pp. 434-449 Neurosci Lett (2018), Vol. 665, pp. 86-91

Frontal evoked γ activity modulates behavioural Magnetoencephalography reveals an increased performance in Autism Spectrum Disorders in a non-target P3a, but not target P3b, that is perceptual simultaneity task associated with high non-clinical psychosocial deficits Menassa, DA; Braeutigam, S; Bailey, A; Falter-Wagner, CM Ford, TC; Woods, W; Crewther, DP Oxford Human Brain Activity Centre, Department of Psychia- try, OX3 7JX & Wellcome Centre for Integrative Neuroimaging Centre for Human Psychopharmacology, Faculty of Heath, (WIN), Nuffield Department of Clinical Neurosciences, OX3 Arts and Design, Swinburne University of Technology, Mel- 9DU, University of Oxford, United Kingdom. Electronic ad- bourne, Victoria, Australia. Electronic address: tcford@swin. dress: [email protected]. edu.au.

ABSTRACT: Autism spectrum disorders (ASDs) are ABSTRACT: Auditory processing deficits are frequently associated with anomalies in time perception. In a identified in autism and schizophrenia, and the two perceptual simultaneity task, individuals with ASD disorders have been shown to share psychosocial demonstrate superior performance compared to difficulties. This study used magnetoencephalogra- typically developing (TD) controls. γ-activity, a robust phy to investigate auditory processing differences for marker of visual processing, is reportedly altered in those with a high degree of a non-clinical autistic and ASD in response to a wide variety of tasks and these schizotypal trait phenotype, Social Disorganisation differences may be related to superior performance in (SD). Participants were 18 low (9 female) and 19 high perceptual simultaneity. Using time-frequency analysis, (9 female) SD scorers (18-40 years) who completed a we assessed evoked γ-band phase-locking in magne- three-stimulus auditory oddball paradigm of speech toencephalographic recordings of 16 ASD individuals sounds (standard: 100ms 'o', deviant: 150ms 'o', novel: and 17 age-matched TD controls. Individuals judged 150ms 'e'). Spatio-temporal cluster analysis revealed whether presented visual stimuli were simultaneous increased amplitude for the high SD group in a left (p or asynchronous. We identified left frontal γ-activity in = 0.006) and a right (p = 0.020) hemisphere cluster in ASD, which was associated with a reduced perception response to the novel non-target. No cluster differences of simultaneity. Where feature binding was observed at were found in response to the target deviant. These a neurophysiological level in parieto-occipital cortices findings suggest that those with a high degree of the in ASD in apparent simultaneity (asynchronous stimuli SD phenotype recruit more cortical resources when with short delay between them), this did not predict processing unattended, novel speech stimuli, which the correct behavioural outcome. These findings may lead to psychosocial deficits. (29182941) suggest distinct γ profiles in ASD associated with the perception of simultaneity. (29191694)

33 Keywords: Auditory oddball; Autism; P300; Schizotypy; neuronal strategy reflects a bias in the readiness to Social Disorganisation perform different types of tasks, and in particular a diminished allocation of resources to duration process- Psychiatry Res Neuroimaging (2019), Vol. 271, pp. 1-7 ing which could have cascading effect on learning and development of other cognitive functions. (29085774)

Diminished neural resources allocation to time Keywords: ASD, Autism Spectrum Disorder; Autism processing in Autism Spectrum Disorders Spectrum Disorders; Duration perception; EEG, electroencephalography; Interval timing; MEG, magnetoencepha- Lambrechts, A; Falter-Wagner, CM; van Wassenhove, V lography; Magnetoencephalography; Pitch perception; TDC, typically developing controls Autism Research Group, Department of Psychology, City University London, United Kingdom. Neuroimage Clin (2018), Vol. 17, pp. 124-136

BACKGROUND: Interval timing, the ability to judge the duration of short events, has been shown to be Disconnection from others in autism is more than compromised in Autism Spectrum Disorders (ASD). just a feeling: whole-brain neural synchrony in Timing abilities are ubiquitous and underlie behaviours adults during implicit processing of emotional faces as varied as sensory integration, motor coordination or communication. It has been suggested that atypical Mennella, R; Leung, RC; Taylor, MJ; Dunkley, BT temporal processing in ASD could contribute to some of the disorder's symptoms, in particular motor clum- Department of Diagnostic Imaging, Hospital for Sick siness and difficulties in social interaction and com- Children, 555 University Avenue, Toronto, Ontario M5G 1X8 munication. Recent behavioural investigations have Canada. suggested that interval timing in ASD is characterised by intact sensitivity but reduced precision in duration BACKGROUND: Socio-emotional difficulties in autism judgements. METHODS: In this study we investigated spectrum disorder (ASD) are thought to reflect im- the processing of duration as compared to pitch in a paired functional connectivity within the "social brain". group of high-functioning individuals with ASD using Nonetheless, a whole-brain characterization of the fast magnetoencephalography (MEG). 18 adolescents and responses in functional connectivity during implicit adults with ASD and 18 age- and IQ-matched typically- processing of emotional faces in adults with ASD is developing control (TDC) individuals compared two lacking. METHODS: The present study used magne- consecutive tones according to their duration or pitch toencephalography to investigate early responses in in separate experimental blocks. The analysis was functional connectivity, as measured by interregional carried out exclusively on physically identical stimuli phase synchronization, during implicit processing of (500 Hz tones lasting 600 ms), which served, according angry, neutral and happy faces. The sample ( RESULTS: to instruction, as standard or probe in a Duration or Reduced phase-synchrony in the beta band around Pitch task respectively. RESULTS: Our results suggest 300 ms emerged during processing of angry faces in that compared to TDC individuals, individuals with ASD the ASD compared to TD group, involving key areas of are less able to predict the duration of the standard the social brain. In the same time window, de-synchro- tone accurately, affecting the sensitivity of the compari- nization in the beta band in the amygdala was reduced son process. In addition, contrary to TDC individuals in the ASD group across conditions. CONCLUSIONS: who allocate resources at different times depending on This is the first demonstration of atypical global and the nature of the task (pitch or duration discrimination), local synchrony patterns in the social brain in adults individuals with ASD seem to engage less resources with ASD during implicit processing of emotional faces. for the Duration task than for the Pitch task regardless The present results replicate and substantially extend of the context. Although individuals with ASD showed top-down adaptation to the context of the task, this

34 previous findings on adolescents, highlighting that atypical brain synchrony during processing of socio-emotional stimuli is a hallmark of clinical sequelae in autism. marks a convergence of the autism and schizophrenia (28316771) spectra at a subclinical. These findings have significant implications for future research methodology, as well Keywords: Autism; Emotional faces; Functional connectiv- as clinical practice. (28235554) ity; Magnetoencephalography; Social brain; Young adults Keywords: Autism; Magnetoencephalography; Mismatch Mol Autism (2017), Vol. 8, pp. 7 field; Mismatch negativity; Schizophrenia; Social Disor- ganisation

Mismatch field latency, but not power, may mark a Int J Psychophysiol (2018), Vol. 116, pp. 60-67 shared autistic and schizotypal trait phenotype

Ford, TC; Woods, W; Crewther, DP Developmental changes in neuromagnetic rhythms and network synchrony in autism Centre for Human Psychopharmacology, Faculty of Health, Arts and Design, Swinburne University of Technology, Mel- Vakorin, VA; Doesburg, SM; Leung, RC; Vo- bourne, Victoria, Australia. Electronic address: tcford@swin. gan, VM; Anagnostou, E; Taylor, MJ edu.au. Department of Biomedical Physiology and Kinesiology, ABSTRACT: The auditory mismatch negativity (MMN), Simon Fraser University, Burnaby, British Columbia. a preattentive processing potential, and its magnetic counterpart (MMF) are consistently reported OBJECTIVE: There is gathering consensus that altered as reduced in schizophrenia and autism spectrum connectivity is a hallmark of the autistic brain. This disorders. This study investigates whether MMF includes atypical neural oscillations and their coordi- characteristics differ between subclinically high and nation across brain regions, which are understood to low scorers on the recently discovered shared autism mediate information processing and integration. It re- and schizophrenia phenotype, Social Disorganisation. mains unclear whether and how connectivity in various A total of 18 low (10 females) and 19 high (9 females) neurophysiological frequency ranges develops atypi- Social Disorganisation scorers underwent magnetoen- cally in autism spectrum disorder (ASD). METHODS: To cephalography (MEG) during a MMF paradigm of 50ms address this in a cross-sectional sample, we recorded standard (1000Hz, 85%) and 100ms duration deviant resting-state magnetoencephalography from 134 chil- tones. MMF was measured from the strongest active dren and adolescents with and without ASD, and calcu- magnetometer over the right and left hemispheres lated resting spectral power and inter-regional syn- (consistent across groups) after 100ms. No differ- chrony (functional connectivity). RESULTS: Although ences in MMF power were found, however there was a no overall group differences were observed, significant significant delay in the MMF peak (p=0.007). The P3am alterations in linear and nonlinear age-related changes (following the MMF) was significantly reduced across in resting oscillatory power and network synchrony both hemispheres for the high Social Disorganisation were found. These differences were frequency- and group (p=0.025), there were no specific hemispheric region-specific and implicated brain systems thought differences in P3am power or latency. Right MMF peak to play a prominent role in ASD, such as the frontal latency increased with higher scores on the schizotypal cortex and cerebellum. We also found correlations be- subscales Odd Speech, Odd Behaviour and Constricted tween Autism Diagnostic Observation Schedule scores Affect. Findings suggest that MMF peak latency delay and the degree to which connectivity in cerebellar

35 networks is "idiosyncratic" in an individual with autism. compared to those in the normal control (P < 0.05). INTERPRETATION: We provide the first evidence that Therefore, hypoxia promoted rectal cancer cell progress it is the curvatures of maturational changes in neuro- by increasing HIF-1α to induce EMT. (27966740) physiological oscillations and synchrony, rather than disturbances in a particular direction, that characterize Genet Mol Res (2017), Vol. 15, No. 4 the brain function in individuals with ASD. Moreover, the patterns of idiosyncratic distortions of network synchrony relative to the group curve are associated with A combined study of MEG and pico-Tesla TMS on behavioral symptoms of ASD. Ann Neurol 2017;81:199- children with autism disorder 211. (27977875) Anninos, P; Chatzimichael, A; Adamo- Ann Neurol (2017), Vol. 81, No. 2, pp. 199-211 poulos, A; Kotini, A; Tsagas, N

Laboratory of Medical Physics, School of Medicine, Democri- Hypoxia facilitates epithelial-mesenchymal tus University of Thrace, Alexandroupoli, Greece. transition-mediated rectal cancer progress ABSTRACT: Magnetoencephalographic (MEG) re- Sun, LL; Song, Z; Li, WZ; Tang, SY cordings from the brain of 10 children with autism (6 boys and 4 girls, with ages range from 5-12 years, School of Nursing, The Third Xiangya Hospital of Central mean[Formula: see text][Formula: see text][Formula: South University, China. see text]SD: 8.3[Formula: see text][Formula: see text] [Formula: see text]2.1) were obtained using a whole- ABSTRACT: Rectal cancer is a commonly observed head 122-channel MEG system in a magnetically tumor in clinics, and epithelial-mesenchymal transi- shielded room of low magnetic noise. A double-blind tion (EMT) is very important for tumor invasion and experimental design was used in order to look for pos- metastasis. We established a rectal cancer HCT-116 cell sible effect of external pico-Tesla Transcranial Magnetic hypoxia model and detected cell proliferation, inva- Stimulation (pT-TMS). The pT-TMS was applied on the sion, and EMT-related protein expression in this model, brain of the autistic children with proper field charac- aiming to analyze the effect of hypoxia on rectal cancer teristics (magnetic field amplitude: 1-7.5[Formula: see cell EMT. Rectal cancer cell line HCT-116 was cultured text]pT, frequency: the alpha - rhythm of the patient in normoxic, hypoxic, or anaerobic environment, and 8-13[Formula: see text]Hz). After unblinding it was hypoxia-inducible factor-1α (HIF-1α) mRNA expres- found a significant effect of an increase of frequen- sion was detected in the cells by real-time PCR. Cell cies in the range of 2-7[Formula: see text]Hz across the proliferation was tested by MTT assay; cell invasion was subjects followed by an improvement and normaliza- determined by transwell assay, and HIF-1α, epithelial- tion of their MEG recordings. The statistical analysis of cadherin, and Snail protein levels were evaluated by our results showed a statistical significance at 6 out western blot analysis. HIF-1α mRNA level significantly of 10 patients (60%). It is also observed an increase increased in the anaerobic group compared to that in of alpha activity in autistic children at the end of one the normoxic and hypoxic groups (P < 0.05). HCT-116 month after pT-TMS treatment at home. In conclusion, cell proliferation in the anaerobic group was obviously the application of pT-TMS has the prospective to be a higher than that in the other two groups, with the noninvasive, safe and important modality in the man- hypoxic group showing stronger proliferative abil- agement of autism children. (27875942) ity than the normoxic group (P < 0.05). Compared to the normoxic group, the HCT-116 cells demonstrated enhanced cell invasion and migration in hypoxic and anaerobic groups. HIF-1α and Snail expressions were upregulated, whereas epithelial-cadherin expression had declined in the hypoxic and anaerobic groups,

36 Keywords: MEG; autism children; double blind; pT-TMS Keywords: ADHD, attention deficit hyperactivity disorder; AEF, auditory-evoked field; ASD, autism spectrum disor- J Integr Neurosci (2017), Vol. 15, No. 4, pp. 497-513 der; Autism spectrum disorder (ASD); ECD, equivalent current dipole; Hyperactivity; ISI, inter-stimulus interval; MEG, magnetoencephalography; Magnetoencephalography Synchrony of auditory brain responses predicts (MEG); P1m; TD, typically developing; Young children behavioral ability to keep still in children with autism spectrum disorder: Auditory-evoked Neuroimage Clin (2017), Vol. 12, pp. 300-5 response in children with autism spectrum disorder

Yoshimura, Y; Kikuchi, M; Hiraishi, H; Hasega- Maturation of auditory neural processes in autism wa, C; Takahashi, T; Remijn, GB; Oi, M; Mune- spectrum disorder - A longitudinal MEG study sue, T; Higashida, H; Minabe, Y Port, RG; Edgar, JC; Ku, M; Bloy, L; Mur- Research Center for Child Mental Development, Kanazawa ray, R; Blaskey, L; Levy, SE; Roberts, TPL University, Kanazawa 920-8640, Japan. Lurie Family Foundations MEG Imaging Center, Department ABSTRACT: The auditory-evoked P1m, recorded by of Radiology, Children's Hospital of Philadelphia, Philadel- magnetoencephalography, reflects a central audi- phia, PA, USA. tory processing ability in human children. One recent study revealed that asynchrony of P1m between the BACKGROUND: Individuals with autism spectrum right and left hemispheres reflected a central auditory disorder (ASD) show atypical brain activity, perhaps processing disorder (i.e., attention deficit hyperactivity due to delayed maturation. Previous studies examin- disorder, ADHD) in children. However, to date, the rela- ing the maturation of auditory electrophysiological tionship between auditory P1m right-left hemispheric activity have been limited due to their use of cross- synchronization and the comorbidity of hyperactiv- sectional designs. The present study took a first step in ity in children with autism spectrum disorder (ASD) is examining magnetoencephalography (MEG) evidence unknown. In this study, based on a previous report of of abnormal auditory response maturation in ASD via an asynchrony of P1m in children with ADHD, to clarify the use of a longitudinal design. METHODS: Initially whether the P1m right-left hemispheric synchroni- recruited for a previous study, 27 children with ASD zation is related to the symptom of hyperactivity in and nine typically developing (TD) children, aged 6- to children with ASD, we investigated the relationship 11-years-old, were re-recruited two to five years later. between voice-evoked P1m right-left hemispheric At both timepoints, MEG data were obtained while synchronization and hyperactivity in children with ASD. participants passively listened to sinusoidal pure- In addition to synchronization, we investigated the tones. Bilateral primary/secondary auditory cortex time right-left hemispheric lateralization. Our findings failed domain (100 ms evoked response latency (M100)) and to demonstrate significant differences in these values spectrotemporal measures (gamma-band power and between ASD children with and without the symptom inter-trial coherence (ITC)) were examined. MEG mea- of hyperactivity, which was evaluated using the Autism sures were also qualitatively examined for five children Diagnostic Observational Schedule, Generic (ADOS-G) who exhibited "optimal outcome", participants who subscale. However, there was a significant correlation were initially on spectrum, but no longer met diagnos- between the degrees of hemispheric synchronization tic criteria at follow-up. RESULTS: M100 latencies were and the ability to keep still during 12-minute MEG delayed in ASD versus TD at the initial exam (~ 19 ms) recording periods. Our results also suggested that asyn- and at follow-up (~ 18 ms). At both exams, M100 laten- chrony in the bilateral brain auditory processing system cies were associated with clinical ASD severity. In addi- is associated with ADHD-like symptoms in children tion, gamma-band evoked power and ITC were reduced with ASD. (27551667) in ASD versus TD. M100 latency and gamma-band maturation rates did not differ between ASD and TD.

37 Of note, the cohort of five children that demonstrated these changes appear to represent pathophysiological "optimal outcome" additionally exhibited M100 latency processes; therefore, many prior studies have focused and gamma-band activity mean values in-between TD on atypical auditory responses in ASD. The auditory and ASD at both timepoints. Though justifying only evoked field (AEF), recorded by magnetoencepha- qualitative interpretation, these "optimal outcome" lography, and the synchronization of these processes related data are presented here to motivate future between right and left hemispheres was recently sug- studies. CONCLUSIONS: Children with ASD showed gested to reflect various cognitive abilities in children. perturbed auditory cortex neural activity, as evidenced However, to date, no previous study has focused on by M100 latency delays as well as reduced transient AEF synchronization in ASD subjects. To assess global gamma-band activity. Despite evidence for maturation coordination across spatially distributed brain regions, of these responses in ASD, the neural abnormalities in the analysis of Omega complexity from multichannel ASD persisted across time. Of note, data from the five neurophysiological data was proposed. Using Omega children whom demonstrated "optimal outcome" quali- complexity analysis, we investigated the global coor- tatively suggest that such clinical improvements may dination of AEFs in 3-8-year-old typically developing be associated with auditory brain responses interme- (TD) children (n = 50) and children with ASD (n = 50) diate between TD and ASD. These "optimal outcome" in 50-ms time-windows. Children with ASD displayed related results are not statistically significant though, significantly higher Omega complexities compared likely due to the low sample size of this cohort, and to with TD children in the time-window of 0-50 ms, sug- be expected as a result of the relatively low propor- gesting lower whole brain synchronization in the early tion of "optimal outcome" in the ASD population. Thus, stage of the P1m component. When we analyzed the further investigations with larger cohorts are needed to left and right hemispheres separately, no significant determine if the above auditory response phenotypes differences in any time-windows were observed. These have prognostic utility, predictive of clinical outcome. results suggest lower right-left hemispheric synchroni- (27158589) zation in children with ASD compared with TD children. Our study provides new evidence of aberrant neural Keywords: ASD; Gamma; M100; MEG; Maturation synchronization in young children with ASD by investigating auditory evoked neural responses to the human Neuroimage Clin (2017), Vol. 11, pp. 566-577 voice. (27074011)

PLoS One (2016), Vol. 11, No. 4, pp. e0153077 Atypical Bilateral Brain Synchronization in the Early Stage of Human Voice Auditory Processing in Young Children with Autism Multimodal Diffusion-MRI and MEG Assessment of Auditory and Language System Development in Kurita, T; Kikuchi, M; Yoshimura, Y; Hiraishi, H; Hasega- Autism Spectrum Disorder wa, C; Takahashi, T; Hirosawa, T; Furutani, N; Hi- gashida, H; Ikeda, T; Mutou, K; Asada, M; Minabe, Y Berman, JI; Edgar, JC; Blaskey, L; Kuschner, ES; Levy, SE; Ku, M; Dell, J; Roberts, TP Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Department of Radiology, Children's Hospital of Philadelphi- 920-8640, Japan. aPhiladelphia, PA, USA; Department of Radiology, Perelman School of Medicine, University of PennsylvaniaPhiladelphia, ABSTRACT: Autism spectrum disorder (ASD) has been PA, USA. postulated to involve impaired neuronal cooperation in large-scale neural networks, including cortico-cortical BACKGROUND: Auditory processing and language interhemispheric circuitry. In the context of ASD, altera- impairments are prominent in children with autism tions in both peripheral and central auditory processes spectrum disorder (ASD). The present study integrated have also attracted a great deal of interest because diffusion MR measures of white-matter microstructure

38 and magnetoencephalography (MEG) measures of Keywords: auditory pathways; autism spectrum disorders cortical dynamics to investigate associations between (ASD); diffusion MRI; language; magnetoencephalography brain structure and function within auditory and (MEG); multimodal imaging language systems in ASD. Based on previous findings, abnormal structure-function relationships in audi- Front Neuroanat (2016), Vol. 10, pp. 30 tory and language systems in ASD were hypothesized. METHODS: Evaluable neuroimaging data was obtained from 44 typically developing (TD) children (mean age Enhanced brain signal variability in children with 10.4 ± 2.4 years) and 95 children with ASD (mean age autism spectrum disorder during early childhood 10.2 ± 2.6 years). Diffusion MR tractography was used to delineate and quantitatively assess the auditory ra- Takahashi, T; Yoshimura, Y; Hiraishi, H; Hasegawa, C; diation and arcuate fasciculus segments of the auditory Munesue, T; Higashida, H; Minabe, Y; Kikuchi, M and language systems. MEG was used to measure (1) superior temporal gyrus auditory evoked M100 latency Research Center for Child Mental Development, Kanazawa in response to pure-tone stimuli as an indicator of University, Japan. auditory system conduction velocity, and (2) auditory vowel-contrast mismatch field (MMF) latency as a pas- ABSTRACT: Extensive evidence shows that a core neu- sive probe of early linguistic processes. RESULTS: Atypi- robiological mechanism of autism spectrum disorder cal development of white matter and cortical function, (ASD) involves aberrant neural connectivity. Recent along with atypical lateralization, were present in ASD. advances in the investigation of brain signal variability In both auditory and language systems, white matter have yielded important information about neural net- integrity and cortical electrophysiology were found work mechanisms. That information has been applied to be coupled in typically developing children, with fruitfully to the assessment of aging and mental disor- white matter microstructural features contributing ders. Multiscale entropy (MSE) analysis can characterize significantly to electrophysiological response latencies. the complexity inherent in brain signal dynamics over However, in ASD, we observed uncoupled structure- multiple temporal scales in the dynamics of neural net- function relationships in both auditory and language works. For this investigation, we sought to characterize systems. Regression analyses in ASD indicated that fac- the magnetoencephalography (MEG) signal variability tors other than white-matter microstructure additional- during free watching of videos without sound using ly contribute to the latency of neural evoked responses MSE in 43 children with ASD and 72 typically develop- and ultimately behavior. RESULTS also indicated that ing controls (TD), emphasizing early childhood to older whereas delayed M100 is a marker for ASD severity, childhood: a critical period of neural network matura- MMF delay is more associated with language impair- tion. Results revealed an age-related increase of brain ment. CONCLUSION: Present findings suggest atypical signal variability in a specific timescale in TD children, development of primary auditory as well as auditory whereas atypical age-related alteration was observed language systems in ASD. Findings demonstrate the in the ASD group. Additionally, enhanced brain signal need for additional multimodal studies to better char- variability was observed in children with ASD, and was acterize the different structural features (white matter, confirmed particularly for younger children. In the ASD gray matter, neurochemical concentration) that con- group, symptom severity was associated region-specif- tribute to brain activity, both in typical development ically and timescale-specifically with reduced brain sig- and in ASD. Finally, the neural latency measures were nal variability. These results agree well with a recently found to be of clinical significance, with M100 associ- reported theory of increased brain signal variability ated with overall ASD severity, and with MMF latency during development and aberrant neural connectivity associated with language performance. (27047349) in ASD, especially during early childhood. Results of this study suggest that MSE analytic method might serve as a useful approach for characterizing neurophysiological mechanisms of typical-developing and its alterations in

39 ASD through the detection of MEG signal variability at our results suggest that perceptual integration deficits multiple timescales. (26859309) co-occur with specific patterns of abnormal global and local synchronization in ASD. SIGNIFICANCE STATE- Keywords: autism spectrum disorder; early childhood; MENT: The weak central coherence account proposes a magnetoencephalography; multiscale entropy; signal tendency of individuals with autism spectrum disorders variability; typical-development (ASDs) to focus on details at the cost of an integrated coherent whole. Here, we provide evidence, at the Hum Brain Mapp (2016), Vol. 37, No. 3, pp. 1038-50 behavioral and the neural level, that visual integration in object recognition is impaired in ASD, when details had to be integrated across both visual hemifields. We Perceptual Integration Deficits in Autism found enhanced interhemispheric gamma-band coher- Spectrum Disorders Are Associated with Reduced ence in typically developed participants when commu- Interhemispheric Gamma-Band Coherence nication between cortical hemispheres was required by the task. Importantly, participants with ASD failed to Peiker, I; David, N; Schneider, TR; Nolte, show this enhanced coherence between bilateral pos- G; Schöttle, D; Engel, AK terior superior temporal sulci. The findings suggest that visual integration is disturbed at the local and global Departments of Neurophysiology and Pathophysiology and. synchronization scale, which might bear implications for object recognition in ASD. (26674862) UNLABELLED: The integration of visual details into a holistic percept is essential for object recognition. This Keywords: autism spectrum disorder; coherence; inter- integration has been reported as a key deficit in pa- hemispheric; magnetoencephalography (MEG); oscilla- tients with autism spectrum disorders (ASDs). The weak tion; perceptual integration central coherence account posits an altered disposi- tion to integrate features into a coherent whole in ASD. J Neurosci (2016), Vol. 35, No. 50, pp. 16352-61 Here, we test the hypothesis that such weak perceptual coherence may be reflected in weak neural coherence across different cortical sites. We recorded magneto- Desynchronization of fronto-temporal networks encephalography from 20 adult human participants during working memory processing in autism with ASD and 20 matched controls, who performed a slit-viewing paradigm, in which objects gradually Urbain, C; Vogan, VM; Ye, AX; Pang, passed behind a vertical or horizontal slit so that only EW; Doesburg, SM; Taylor, MJ fragments of the object were visible at any given moment. Object recognition thus required perceptual Department of Diagnostic Imaging, The Hospital for Sick integration over time and, in case of the horizontal slit, Children, Toronto, Canada. also across visual hemifields. ASD participants were selectively impaired in the horizontal slit condition, BACKGROUND: Mounting evidence suggests that indicating specific difficulties in long-range synchroni- autism is a network disorder, characterized by atypical zation between the hemispheres. Specifically, the ASD brain connectivity, especially in the context of high lev- group failed to show condition-related enhancement el cognitive processes such as working memory (WM). of imaginary coherence between the posterior superior Accordingly, atypical WM processes have been related temporal sulci in both hemispheres during horizontal to the social and cognitive deficits observed in children slit-viewing in contrast to controls. Moreover, local syn- with autism spectrum disorder (ASD). METHODS: We chronization reflected in occipitocerebellar beta-band used magnetoencephalography (MEG) to investigate power was selectively reduced for horizontal compared connectivity differences during a high memory load with vertical slit-viewing in ASD. Furthermore, we (2-back) WM task between 17 children with ASD and found disturbed connectivity between right posterior 20 age-, sex-, and IQ-matched controls. RESULTS: We superior temporal sulcus and left cerebellum. Together, identified reduced inter-regional alpha-band (9-15 Hz)

40 phase synchronization in children with ASD during the linearly with the strength of visual motion. Using mag- WM task. Reduced WM-related brain synchronization netoencephalography (MEG), we investigated whether encompassed fronto-temporal networks (ps < 0.04 in individuals with ASD neural activity reflect the coher- corrected) previously associated with challenging high- ence, and thus intensity, of visual motion in a similar level conditions (i.e. the left insula and the anterior fashion. Thirteen adult participants with ASD and 14 cingulate cortex (ACC)) and memory encoding and/or control participants performed a motion direction recognition (i.e. the right middle temporal gyrus and discrimination task with increasing levels of motion co- the right fusiform gyrus). Additionally, we found that herence. A polynomial regression analysis revealed that reduced connectivity processes related to the right gamma-band power increased significantly stronger fusiform were correlated with the severity of symptoms with motion coherence in ASD compared to controls, in children with ASD, suggesting that such atypicali- suggesting excessive visual activation with increasing ties could be directly related to the behavioural deficits stimulus intensity originating from motion-responsive observed. DISCUSSION: This study provides new visual areas V3, V6 and hMT/V5. Enhanced neural evidence of atypical long-range synchronization in chil- responses with increasing stimulus intensity suggest an dren with ASD in fronto-temporal areas that crucially enhanced response gain in ASD. Response gain is con- contribute to challenging WM tasks, but also emotion trolled by excitatory-inhibitory interactions, which also regulation and social cognition processes. Thus, these drive high-frequency oscillations in the gamma-band. results support the network disorder hypothesis of ASD Thus, our data suggest that a disturbed excitatory-in- and argue for a specific pathophysiological contribu- hibitory balance underlies enhanced neural responses tion of brain processes related to working memory and to coherent motion in ASD. (26147342) executive functions on the symptomatology of autism. (26485059) PLoS One (2016), Vol. 10, No. 7, pp. e0132531

Keywords: MEG; alpha oscillations; children; executive functions; phase-locking values Deficits in auditory processing contribute to impairments in vocal affect recognition in autism Hum Brain Mapp (2016), Vol. 37, No. 1, pp. 153-64 spectrum disorders: A MEG study

Demopoulos, C; Hopkins, J; Kopald, BE; Paul- Stronger Neural Modulation by Visual Motion son, K; Doyle, L; Andrews, WE; Lewine, JD Intensity in Autism Spectrum Disorders Department of Radiology & Biomedical Imaging, University Peiker, I; Schneider, TR; Milne, E; Schöttle, D; Vogeley, K; of California-San Francisco. Münchau, A; Schunke, O; Siegel, M; Engel, AK; David, N OBJECTIVE: The primary aim of this study was to Department of Neurophysiology and Pathophysiology, examine whether there is an association between University Medical Center Hamburg-Eppendorf, Hamburg, magnetoencephalography-based (MEG) indices of Germany. basic cortical auditory processing and vocal affect recognition (VAR) ability in individuals with autism ABSTRACT: Theories of autism spectrum disorders spectrum disorder (ASD). METHOD: MEG data were (ASD) have focused on altered perceptual integration collected from 25 children/adolescents with ASD and of sensory features as a possible core deficit. Yet, there 12 control participants using a paired-tone paradigm is little understanding of the neuronal processing of to measure quality of auditory physiology, sensory elementary sensory features in ASD. For typically de- gating, and rapid auditory processing. Group differ- veloped individuals, we previously established a direct ences were examined in auditory processing and vocal link between frequency-specific neural activity and the affect recognition ability. The relationship between intensity of a specific sensory feature: Gamma-band differences in auditory processing and vocal affect activity in the visual cortex increased approximately recognition deficits was examined in the ASD group.

41 RESULTS: Replicating prior studies, participants with the mu-rhythm during resting state in a subset of these ASD showed longer M1n latencies and impaired rapid participants (12 per group, same age range). Two major processing compared with control participants. These significant group differences emerged in the response variables were significantly related to VAR, with the to the vibrotactile stimulus. First, the 50-Hz phase linear combination of auditory processing variables ac- locking component of the cortical response, generated counting for approximately 30% of the variability after locally in the primary (S1) and secondary (S2) somato- controlling for age and language skills in participants sensory cortex, was reduced in the autism group (P < with ASD. CONCLUSIONS: VAR deficits in ASD are typi- 0.003, corrected). Second, feedforward functional con- cally interpreted as part of a core, higher order dysfunc- nectivity between S1 and S2 was increased in the au- tion of the "social brain"; however, these results suggest tism group (P < 0.004, corrected). During resting state, they also may reflect basic deficits in auditory process- there was no group difference in the mu-α rhythm. In ing that compromise the extraction of socially relevant contrast, the mu-β rhythm, which has been associated cues from the auditory environment. As such, they also with feedback connectivity, was significantly reduced suggest that therapeutic targeting of sensory dysfunc- in the autism group (P < 0.04, corrected). Furthermore, tion in ASD may have additional positive implications the strength of the mu-β was correlated to the relative for other functional deficits. (26011112) strength of 50 Hz component of the response to the vibrotactile stimulus (r = 0.78, P < 0.00005), indicat- Neuropsychology (2016), Vol. 29, No. 6, pp. 895-908 ing a shared aetiology for these seemingly unrelated abnormalities. These magnetoencephalography- derived measures were correlated with two different Somatosensory cortex functional connectivity behavioural sensory processing scores (P < 0.01 and P abnormalities in autism show opposite trends, < 0.02 for the autism group, P < 0.01 and P < 0.0001 for depending on direction and spatial scale the typical group), with autism severity (P < 0.03), and with diagnosis (89% accuracy). A biophysically realistic Khan, S; Michmizos, K; Tommerdahl, M; Ga- computational model using data driven feedforward nesan, S; Kitzbichler, MG; Zetino, M; Garel, KL; and feedback parameters replicated the magnetoen- Herbert, MR; Hämäläinen, MS; Kenet, T cephalography data faithfully. The direct observation of both abnormally increased and abnormally decreased 1 Department of Neurology, MGH, Harvard Medical School, functional connectivity in autism occurring simultane- Boston, MA, USA 2 A.A. Martinos Centre for Biomedical Imag- ously in different functional connectivity streams, offers ing, MGH/MIT/Harvard, Boston, MA, USA. a potential unifying framework for the unexplained discrepancies in current findings. Given that cortical ABSTRACT: Functional connectivity is abnormal in feedback, whether local or long-range, is intrinsically autism, but the nature of these abnormalities remains non-linear, while cortical feedforward is generally elusive. Different studies, mostly using functional mag- linear relative to the stimulus, the present results sug- netic resonance imaging, have found increased, de- gest decreased non-linearity alongside an increased creased, or even mixed pattern functional connectivity veridical component of the cortical response in autism. abnormalities in autism, but no unifying framework has (25765326) emerged to date. We measured functional connectivity in individuals with autism and in controls using magnetoencephalography, which allowed us to resolve both the directionality (feedforward versus feedback) and spatial scale (local or long-range) of functional connectivity. Specifically, we measured the cortical response and functional connectivity during a passive 25-Hz vibrotactile stimulation in the somatosensory cortex of 20 typically developing individuals and 15 individuals with autism, all males and right-handed, aged 8-18, and

42 Keywords: autism spectrum disorder; biomarker; coher- regional phase-locking in adolescents with ASD was ence; magnetoencephalography; mu-rhythm; steady- reduced, relative to controls, during the perception of state; vibrotactile angry faces in a distributed network involving the right fusiform gyrus and insula. No significant group differ- Brain (2015), Vol. 138, No. Pt 5, pp. 1394-409 ences were found for happy or neutral faces, or other analyzed frequency ranges. Significant reductions in task-dependent beta connectivity strength, clustering Reduced beta connectivity during emotional face and eigenvector centrality (all P <0.001) in the right processing in adolescents with autism insula were found in adolescents with ASD, relative to controls. CONCLUSIONS: Reduced beta synchro- Leung, RC; Ye, AX; Wong, SM; Taylor, MJ; Doesburg, SM nization may reflect inadequate recruitment of task- relevant networks during emotional face processing in Department of Diagnostic Imaging, Hospital for Sick ASD. The right insula, specifically, was a hub of reduced Children, 555 University Avenue, Toronto, Ontario M5G 1X8 functional connectivity and may play a prominent role Canada ; Department of Psychology, University of Toronto, in the inability to effectively extract emotional informa- 100 St. George Street, 4th Floor, Sidney Smith Hall, Toronto, tion from faces. These findings suggest that functional Ontario M5S 3G3 Canada ; Neuroscience & Mental Health, disconnection in brain networks mediating emotional Hospital for Sick Children Research Institute, 555 University processes may contribute to deficits in social cognition Avenue, Toronto, Ontario M5G 1X8 Canada. in this population. (25371811)

BACKGROUND: Autism spectrum disorder (ASD) Keywords: Affect processing; Autism spectrum disorders; is a neurodevelopmental disorder characterized by Beta-band; Cognitive development; Face processing; impairments in social cognition. The biological basis of Functional connectivity; Graph theory; Magnetoencepha- deficits in social cognition in ASD, and their difficulty lography; Neural oscillation; Neural synchrony; Social in processing emotional face information in particu- cognition lar, remains unclear. Atypical communication within and between brain regions has been reported in ASD. Mol Autism (2014), Vol. 5, No. 1, pp. 51 Interregional phase-locking is a neurophysiological mechanism mediating communication among brain areas and is understood to support cognitive functions. Progressively increased M50 responses to repeated In the present study we investigated interregional mag- sounds in autism spectrum disorder with auditory netoencephalographic phase synchronization during hypersensitivity: a magnetoencephalographic the perception of emotional faces in adolescents with study ASD. METHODS: A total of 22 adolescents with ASD (18 males, mean age =14.2 ± 1.15 years, 22 right-handed) Matsuzaki, J; Kagitani-Shimono, K; Sugata, with mild to no cognitive delay and 17 healthy controls H; Hirata, M; Hanaie, R; Nagatani, F; Tachiba- (14 males, mean age =14.4 ± 0.33 years, 16 right- na, M; Tominaga, K; Mohri, I; Taniike, M handed) performed an implicit emotional processing task requiring perception of happy, angry and neutral Molecular Research Center for Children's Mental Develop- faces while we recorded neuromagnetic signals. The ment, United Graduate School of Child Development, Osaka faces were presented rapidly (80 ms duration) to the University Graduate School of Medicine, Osaka, Japan. left or right of a central fixation cross and participants responded to a scrambled pattern that was presented ABSTRACT: The aim of this study was to investigate the concurrently on the opposite side of the fixation differential time-course responses of the auditory cor- point. Task-dependent interregional phase-locking tex to repeated auditory stimuli in children with autism was calculated among source-resolved brain regions. spectrum disorder (ASD) showing auditory hypersen- RESULTS: Task-dependent increases in interregional sitivity. Auditory-evoked field values were obtained beta synchronization were observed. Beta-band inter- from 21 boys with ASD (12 with and 9 without auditory

43 hypersensitivity) and 15 age-matched typically devel- tones were presented. The presence or absence of a oping controls. M50 dipole moments were significantly STG M50 and M100 was scored. Subjects were grouped increased during the time-course study only in the ASD into younger (6-10 years old) and older groups (11- with auditory hypersensitivity compared with those 15 years old). RESULTS: Although M50 responses were for the other two groups. The boys having ASD with observed equally often in older and younger subjects auditory hypersensitivity also showed more prolonged and equally often in TD and ASD, left and right M50 response duration than those in the other two groups. responses were delayed in ASD - LI and ASD + LI. Group The response duration was significantly related to the comparisons showed that in younger subjects M100 re- severity of auditory hypersensitivity. We propose that sponses were observed more often in TD than ASD + LI auditory hypersensitivity is associated with decreased (90 versus 66%, p = 0.04), with no differences between inhibitory processing, possibly resulting from an abnor- TD and ASD - LI (90 versus 76%, p = 0.14) or between mal sensory gating system or dysfunction of inhibitory ASD - LI and ASD + LI (76 versus 66%, p = 0.53). In older interneurons. (25054201) subjects, whereas no differences were observed between TD and ASD + LI, responses were observed more PLoS One (2015), Vol. 9, No. 7, pp. e102599 often in ASD - LI than ASD + LI. Findings were similar when splitting the ASD group into lower- and higher- cognitive functioning groups. CONCLUSION: Although Missing and delayed auditory responses in young present in all groups, M50 responses were delayed in and older children with autism spectrum disorders ASD. Examining the TD data, findings indicated that by 11 years, a right M100 should be observed in 100% Edgar, JC; Lanza, MR; Daina, AB; Monroe, of subjects and a left M100 in 80% of subjects. Thus, JF; Khan, SY; Blaskey, L; Cannon, KM; Jen- by 11 years, lack of a left and especially right M100 kins, J; Qasmieh, S; Levy, SE; Roberts, TP offers neurobiological insight into sensory processing that may underlie language or cognitive impairment. Department of Radiology, Lurie Family Foundation MEG (24936181) Imaging Center, The Children's Hospital of Philadelphia , Philadelphia, PA , USA. Keywords: M100; M50; autism spectrum disorders; magnetoencephalography; superior temporal gyrus BACKGROUND: The development of left and right superior temporal gyrus (STG) 50 ms (M50) and 100 ms Front Hum Neurosci (2014), Vol. 8, pp. 417 (M100) auditory responses in typically developing (TD) children and in children with autism spectrum disorder (ASD) was examined. Reflecting differential Reduced long-range functional connectivity in development of primary/secondary auditory areas and young children with autism spectrum disorder supporting previous studies, it was hypothesized that whereas left and right M50 STG responses would be Kikuchi, M; Yoshimura, Y; Hiraishi, H; Mune- observed equally often in younger and older children, sue, T; Hashimoto, T; Tsubokawa, T; Takahashi, left and right M100 STG responses would more often T; Suzuki, M; Higashida, H; Minabe, Y be absent in younger than older children. In ASD, delayed neurodevelopment would be indicated via the Research Center for Child Mental Development, Kanazawa observation of a greater proportion of ASD than TD University, Kanazawa 920-8641, Japan, Department of subjects showing missing M100 but not M50 responses Psychiatry and Neurobiology, Graduate School of Medical in both age groups. Missing M100 responses would be Science, Kanazawa University, Kanazawa 920-8641, Japan, observed primarily in children with ASD with language Department of Anesthesiology, Graduate School of Medical impairment (ASD + LI) (and perhaps concomitantly Science, Kanazawa University, Kanazawa 920-8641, Japan, lower general cognitive abilities). METHODS: Thirty- and Department of Neuropsychiatry, University of Toyama, five TD controls, 63 ASD without language impairment Toyama 930-0152, Japan Research Center for Child Mental (ASD - LI), and 38 ASD + LI were recruited. Binaural Development, Kanazawa University, Kanazawa 920-8641,

44 Japan, Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa University, Kanazawa 920-8641, Japan, Department of Anesthesiology, Graduate Keywords: autism spectrum disorder (ASD); coherence; School of Medical Science, Kanazawa University, Kanazawa long-range connectivity; magnetoencephalography 920-8641, Japan, and Department of Neuropsychiatry, (MEG); theta oscillation; young children University of Toyama, Toyama 930-0152, Japan mitsuru@zc4. so-net.ne.jp. Soc Cogn Affect Neurosci (2016), Vol. 10, No. 2, pp. 248-54

ABSTRACT: Autism spectrum disorder (ASD) is often described as a disorder of aberrant neural connectivity. Reduced predictable information in brain signals in Although it is important to study the pathophysiol- autism spectrum disorder ogy of ASD in the developing cortex, the functional connectivity in the brains of young children with ASD Gómez, C; Lizier, JT; Schaum, M; Woll- has not been well studied. In this study, brain activity stadt, P; Grützner, C; Uhlhaas, P; Freitag, CM; was measured non-invasively during consciousness in Schlitt, S; Bölte, S; Hornero, R; Wibral, M 50 young human children with ASD and 50 age- and gender-matched typically developing human (TD) Biomedical Engineering Group, E. T. S. Ingenieros de Teleco- children. We employed a custom child-sized magneto- municación, University of Valladolid Valladolid, Spain. encephalography (MEG) system in which sensors were located as close to the brain as possible for optimal ABSTRACT: Autism spectrum disorder (ASD) is a com- recording in young children. We focused on theta band mon developmental disorder characterized by com- oscillations because they are thought to be involved in munication difficulties and impaired social interaction. long-range networks associated with higher cognitive Recent results suggest altered brain dynamics as a processes. The ASD group showed significantly reduced potential cause of symptoms in ASD. Here, we aim to connectivity between the left-anterior and the right- describe potential information-processing consequenc- posterior areas, exhibiting a decrease in the coherence es of these alterations by measuring active information of theta band (6 Hz) oscillations compared with the TD storage (AIS)-a key quantity in the theory of distributed group. This reduction in coherence was significantly computation in biological networks. AIS is defined as correlated with clinical severity in right-handed chil- the mutual information between the past state of a dren with ASD. This is the first study to demonstrate re- process and its next measurement. It measures the duced long-range functional connectivity in conscious amount of stored information that is used for computa- young children with ASD using a novel MEG approach. tion of the next time step of a process. AIS is high for (24652855) rich but predictable dynamics. We recorded magnetoencephalography (MEG) signals in 10 ASD patients and 14 matched control subjects in a visual task. After a beamformer source analysis, 12 task-relevant sources were obtained. For these sources, stationary baseline activity was analyzed using AIS. Our results showed a decrease of AIS values in the hippocampus of ASD patients in comparison with controls, meaning that brain signals in ASD were either less predictable, reduced in their dynamic richness or both. Our study suggests the usefulness of AIS to detect an abnormal type of dynamics in ASD. The observed changes in AIS are compatible

45 with Bayesian theories of reduced use or precision of superior and precentral gyri and right inferior lobule priors in ASD. (24592235) (300 to 400 ms). CONCLUSIONS: Adolescents with ASD showed recruitment limited largely to the frontal cortex Keywords: active information storage; autism spectrum unlike typically developing adolescents who recruited disorder; complex systems; hippocampus; information parietal and temporal regions as well. These findings theory; magnetoencephalography; predictive coding support the presence of an atypical, restricted inhibitory network in adolescents with ASD compared to Front Neuroinform (2014), Vol. 8, pp. 9 controls. (24485230)

Mol Autism (2014), Vol. 5, No. 1, pp. 6 Is inhibitory control a 'no-go' in adolescents with autism spectrum disorder? Reduced Theta Connectivity during Set-Shifting in Vara, AS; Pang, EW; Doyle-Thomas, KA; Vi- Children with Autism dal, J; Taylor, MJ; Anagnostou, E Doesburg, SM; Vidal, J; Taylor, MJ Neurology, The Hospital for Sick Children, University of Toronto, 555 University Avenue, M5G 1X8 Toronto, Ontario, Department of Diagnostic Imaging, The Hospital for Sick Canada. [email protected]. Children , Toronto, ON , Canada ; Neurosciences & Mental Health Program, The Hospital for Sick Children Research BACKGROUND: Autism spectrum disorder (ASD) Institute , Toronto, ON , Canada ; Department of Medical refers to a range of neurodevelopmental conditions Imaging, University of Toronto , Toronto, ON , Canada ; characterized by social communication deficits, repeti- Department of Psychology, University of Toronto , Toronto, tive behaviours, and restrictive interests. Impaired ON , Canada. inhibition has been suggested to exacerbate the core symptoms of ASD. This is particularly critical during ABSTRACT: Autism spectrum disorder (ASD) is a char- adolescence when social skills are maturing to adult acterized by deficits in social cognition and executive levels. Using magnetoencephalography (MEG), we function. An area of particular difficulty for children identified the location and timing pattern of neural with ASD is cognitive flexibility, such as the ability to activity associated with inhibition in adolescents with shift between attentional or response sets. The biologi- autism, compared to typically developing adolescents. cal basis of such deficits remains poorly understood, METHODS: The MEG data from 15 adolescents with although atypical development of structural and ASD and 15 age-matched controls (13 to 17 years) were functional brain connectivity have been reported in collected during a go/no-go task with inverse ratios of ASD, suggesting that disruptions of normal patterns of go/no-go trials in two conditions: an inhibition condi- inter-regional communication may contribute to cognition (1:2) and a baseline condition (2:1). No-go trials tive problems in this group. The present magnetoen- from the two conditions were analyzed using beam- cephalography study measured inter-regional phase former source localizations from 200 ms to 400 ms post- synchronization while children with ASD and typically stimulus onset. Significant activations were determined developing matched controls (6-14 years of age) per- using permutation testing. RESULTS: Adolescents with formed a set-shifting task. Reduced theta-band phase ASD recruited first the right middle frontal gyrus (200 synchronization was observed in children with ASD to 250 ms) followed by the left postcentral gyrus (250 during extradimensional set-shifting. This reduction to 300 ms) and finally the left middle frontal and right in task-dependent inter-regional connectivity encom- medial frontal gyri (300 to 400 ms). Typically develop- passed numerous areas including multiple frontal lobe ing adolescents recruited first the left middle frontal regions, and indicates that problems with communica- gyrus (200 to 250 ms), followed by the left superior tion among brain areas may contribute to difficulties and inferior frontal gyri (250 to 300 ms), then the right with executive function in ASD. (24294201) middle temporal gyrus (300 to 350 ms), and finally the

46 Keywords: ASD; autism; executive function; functional scales of observation in autism. The lack of behavioral connectivity; magnetoencephalography; neural oscilla- correlation for the findings warrants some caution in in- tion; neural synchrony; set-shifting terpreting the relevance of such changes for language function in ASD. Our findings in parents implicates the Front Hum Neurosci (2013), Vol. 7, pp. 785 gamma- and beta-band ranges as potential compensatory phenomena in autism relatives. (24265611)

Altered oscillation patterns and connectivity during Keywords: Granger causality; beta-band; endophenotype; picture naming in autism functional connectivity; fusiform gyrus; gamma-band; magnetoencephalography; oscillations Buard, I; Rogers, SJ; Hepburn, S; Kronberg, E; Rojas, DC Front Hum Neurosci (2013), Vol. 7, pp. 742 UCD Magnetoencephalography Lab, Department of Psy- chiatry, University of Colorado at Denver - Anschutz Medical Campus Aurora, CO, USA. Maturational differences in thalamocortical white matter microstructure and auditory evoked ABSTRACT: Similar behavioral deficits are shared response latencies in autism spectrum disorders between individuals with autism spectrum disorders (ASD) and their first-degree relatives, such as impaired Roberts, TP; Lanza, MR; Dell, J; Qasmieh, S; Hines, K; face memory, object recognition, and some language Blaskey, L; Zarnow, DM; Levy, SE; Edgar, JC; Berman, JI aspects. Functional neuroimaging studies have reported abnormalities in ASD in at least one brain area Lurie Family Foundation's MEG Imaging Center, Department implicated in those functions, the fusiform gyrus (FG). of Radiology, The Children's Hospital of Philadelphia, Wood High frequency oscillations have also been described Building, Suite 2115, 34th Street and Civic Center Boulevard, as abnormal in ASD in a separate line of research. Philadelphia, PA, USA. Electronic address: robertstim@email. The present study examined whether low- and high- chop.edu. frequency oscillatory power, localized in part to FG and other language-related regions, differs in ASD ABSTRACT: White matter diffusion anisotropy in the subjects and first-degree relatives. Twelve individu- acoustic radiations was characterized as a function of als with ASD, 16 parents of children with ASD, and development in autistic and typically developing chil- 35 healthy controls participated in a picture-naming dren. Auditory-evoked neuromagnetic fields were also task using magnetoencephalography (MEG) to assess recorded from the same individuals and the latency of oscillatory power and connectivity. Relative to controls, the left and right middle latency superior temporal gy- we observed reduced evoked high-gamma activity in rus auditory ~50ms response (M50)(1) was measured. the right superior temporal gyrus (STG) and reduced Group differences in structural and functional auditory high-beta/low-gamma evoked power in the left inferior measures were examined, as were group differences frontal gyrus (IFG) in the ASD group. Finally, reductions in associations between white matter pathways, M50 in phase-locked beta-band were also seen in the ASD latency, and age. Acoustic radiation white matter group relative to controls, especially in the occipital fractional anisotropy did not differ between groups. lobes (OCC). First degree relatives, in contrast, exhibited Individuals with autism displayed a significant M50 higher high-gamma band power in the left STG com- latency delay. Only in typically developing controls, pared with controls, as well as increased high-beta/low- white matter fractional anisotropy increased with age gamma evoked power in the left FG. In the left hemi- and increased white matter anisotropy was associated sphere, beta- and gamma-band functional connectivity with earlier M50 responses. M50 latency, however, de- between the IFG and FG and between STG and OCC creased with age in both groups. Present findings thus were higher in the autism group than in controls. This indicate that although there is loss of a relationship suggests that, contrary to what has been previously de- between white matter structure and auditory cortex scribed, reduced connectivity is not observed across all function in autism spectrum disorders, and although

47 there are delayed auditory responses in individuals pre-stimulus activity was a 'core' abnormality, with with autism than compared with age-matched con- pre-stimulus activity predicting post-stimulus neural trols, M50 latency nevertheless decreases as a function abnormalities, group membership, and clinical symp- of age in autism, parallel to the observation in typically toms (CELF-4 Core Language Index). Deficits in synaptic developing controls (although with an overall latency integration in the auditory cortex are associated with delay). To understand auditory latency delays in autism oscillatory abnormalities in ASD as well as patient and changes in auditory responses as a function of symptoms. Increased pre-stimulus activity in ASD likely age in controls and autism, studies examining white demonstrates a fundamental signal-to-noise deficit matter as well as other factors that influence auditory in individuals with ASD, with elevations in oscillatory latency, such as synaptic transmission, are of interest. activity suggesting an inability to maintain an appropri- (24055954) ate 'neural tone' and an inability to rapidly return to a resting state prior to the next stimulus. (23963591) Keywords: Auditory evoked response; Autism spectrum disorder; Fractional anisotropy; M50; Magnetoencepha- J Autism Dev Disord (2015), Vol. 45, No. 2, pp. 395-405 lography; White matter

Brain Res (2014), Vol. 1537, pp. 79-85 Brain routes for reading in adults with and without autism: EMEG evidence

Neuromagnetic oscillations predict evoked- Moseley, RL; Pulvermüller, F; Mohr, B; Lom- response latency delays and core language deficits bardo, MV; Baron-Cohen, S; Shtyrov, Y in autism spectrum disorders MRC Cognition and Brain Sciences Unit, 15 Chaucer Road, Edgar, JC; Khan, SY; Blaskey, L; Chow, VY; Rey, M; Cambridge, CB2 7EF, UK, [email protected]. Gaetz, W; Cannon, KM; Monroe, JF; Cornew, L; Qa- smieh, S; Liu, S; Welsh, JP; Levy, SE; Roberts, TP ABSTRACT: Reading utilises at least two neural pathways. The temporal lexical route visually maps Department of Radiology, Lurie Family Foundations MEG Im- whole words to their lexical entries, whilst the nonlexi- aging Center, The Children's Hospital of Philadelphia, Wood cal route decodes words phonologically via parietal Bldg, Suite 2115, 34th St. and Civic Center Blvd, Philadelphia, cortex. Readers typically employ the lexical route for PA, 19104, USA, [email protected]. familiar words, but poor comprehension plus precoc- ity at mechanically 'sounding out' words suggests that ABSTRACT: Previous studies have observed evoked differences might exist in autism. Combined MEG/EEG response latency as well as gamma band superior tem- recordings of adults with autistic spectrum conditions poral gyrus (STG) auditory abnormalities in individuals (ASC) and controls while reading revealed preferential with autism spectrum disorders (ASD). A limitation of recruitment of temporal areas in controls and addi- these studies is that associations between these two tional parietal recruitment in ASC. Furthermore, a lack abnormalities, as well as the full extent of oscillatory of differences between semantic word categories was phenomena in ASD in terms of frequency and time, consistent with previous suggestion that people with have not been examined. Subjects were presented pure ASC may lack a 'default' lexical-semantic processing tones at 200, 300, 500, and 1,000 Hz while magnetoen- mode. These results are discussed with reference to cephalography assessed activity in STG auditory areas dual-route models of reading. (23748435) in a sample of 105 children with ASD and 36 typically developing controls (TD). Findings revealed a profile such that auditory STG processes in ASD were characterized by pre-stimulus abnormalities across multiple frequencies, then early high-frequency abnormalities followed by low-frequency abnormalities. Increased

48 J Autism Dev Disord (2014), Vol. 44, No. 1, pp. 137-53 Chest wall reconstruction with methacrylate Research Centre for Child Mental Development, Kanazawa prosthesis in Poland syndrome University, Kanazawa 920-8640, Japan. [email protected]. ne.jp Arango Tomás, E; Baamonde Laborda, C; Al- gar Algar, J; Salvatierra Velázquez, A ABSTRACT: A subset of individuals with autism spectrum disorder (ASD) performs more proficiently on cer- Unidad de Gestión Clínica de Cirugía Torácica y Trasplante tain visual tasks than may be predicted by their general Pulmonar, Hospital Universitario Reina Sofía, Córdoba, cognitive performances. However, in younger children España. Electronic address: [email protected]. with ASD (aged 5 to 7), preserved ability in these tasks and the neurophysiological correlates of their ability ABSTRACT: Poland syndrome is a rare congenital are not well documented. In the present study, we used malformation. This syndrome was described in 1841 a custom child-sized magnetoencephalography system by Alfred Poland at Guy's Hospital in London. It is and demonstrated that preserved ability in the visual characterized by hypoplasia of the breast and nipple, reasoning task was associated with rightward lateralisa- subcutaneous tissue shortages, lack of the costosternal tion of the neurophysiological connectivity between portion of the pectoralis major muscle and associated the parietal and temporal regions in children with ASD. alterations of the fingers on the same side. Corrective In addition, we demonstrated that higher reading/ treatment of the chest and soft tissue abnormalities in decoding ability was also associated with the same lat- Poland syndrome varies according to different authors. eralisation in children with ASD. These neurophysiologi- We report the case of a 17-year-old adolescent who cal correlates of visual tasks are considerably different underwent chest wall reconstruction with a methyl from those that are observed in typically developing methacrylate prosthesis. This surgical procedure is rec- children. These findings indicate that children with ASD ommended for large anterior chest wall defects, and it have inherently different neural pathways that contrib- prevents paradoxical movement. Moreover it provides ute to their relatively preserved ability in visual tasks. for individual remodeling of the defect depending on (23355952) the shape of the patient's chest. (23453291) Sci Rep (2013), Vol. 3, pp. 1139 Keywords: Chest wall reconstruction; Poland syndrome; Reconstrucción con prótesis de metilmetacrilato; Re- construcción de la pared torácica; Reconstruction with Using multiparametric data with missing features methyl methacrylate prosthesis; Síndrome de Poland for learning patterns of pathology

Arch Bronconeumol (2014), Vol. 49, No. 10, pp. 450-2 Ingalhalikar, M; Parker, WA; Bloy, L; Roberts, TP; Verma, R

Section of Biomedical Image Analysis, University of Pennsyl- A custom magnetoencephalography device reveals vania, Philadelphia, PA, USA. Madhura.Ingalhalikar@uphs. brain connectivity and high reading/decoding upenn.edu ability in children with autism ABSTRACT: The paper presents a method for learning Kikuchi, M; Yoshimura, Y; Shitamichi, K; Ueno, multimodal classifiers from datasets in which not all S; Hirosawa, T; Munesue, T; Ono, Y; Tsubokawa, subjects have data from all modalities. Usually, subjects T; Haruta, Y; Oi, M; Niida, Y; Remijn, GB; Taka- with a severe form of pathology are the ones failing hashi, T; Suzuki, M; Higashida, H; Minabe, Y to satisfactorily complete the study, especially when

49 it consists of multiple imaging modalities. A classifier association. We screened a large AgCC cohort (n = 106) capable of handling subjects with unequal numbers with the Autism Spectrum Quotient (AQ) and found of modalities prevents discarding any subjects, as is that 45 % of children, 35 % of adolescents, and 18 % of traditionally done, thereby broadening the scope of adults exceeded the predetermined autism-screening the classifier to more severe pathology. It also allows cut-off. Interestingly, performance on the AQ's imagina- design of the classifier to include as much of the avail- tion domain was inversely correlated with magneto- able information as possible and facilitates testing of encephalography measures of resting-state functional subjects with missing modalities over the constructed connectivity in the right superior temporal gyrus. classifier. The presented method employs an ensemble Individuals with AgCC should be screened for ASD and based approach where several subsets of complete disorders of the corpus callosum should be considered data are formed and trained using individual classi- in autism diagnostic evaluations as well. (23054201) fiers., The output from these classifiers is fused using a weighted aggregation step giving an optimal probabi- J Autism Dev Disord (2013), Vol. 43, No. 5, pp. 1106-18 listic score for each subject. The method is applied to a spatio-temporal dataset for autism spectrum disorders (ASD) (96 patients with ASD and 42 typically develop- Resting-state oscillatory activity in autism spectrum ing controls) that consists of functional features from disorders magnetoencephalography (MEG) and structural connectivity features from diffusion tensor imaging (DTI). A Cornew, L; Roberts, TP; Blaskey, L; Edgar, JC clear distinction between ASD and controls is obtained with an average 5-fold accuracy of 83.3% and testing Lurie Family Foundations MEG Imaging Center, Department accuracy of 88.4%. The fusion classifier performance of Radiology, Children's Hospital of Philadelphia, 2nd Floor is superior to the classification achieved using single Wood Bldg., Room 2115, Mail Stop W02-1010, Philadelphia, modalities as well as multimodal classifier using only PA 19104-4399, USA. complete data (78.3%). The presented multimodal classifier framework is applicable to all modality combina- ABSTRACT: Neural oscillatory anomalies in autism tions. (23286164) spectrum disorders (ASD) suggest an excitatory/inhibitory imbalance; however, the nature and clinical Med Image Comput Comput Assist Interv (2013), Vol. 15, relevance of these anomalies are unclear. Whole-cortex No. Pt 3, pp. 468-75 magnetoencephalography data were collected while 50 children (27 with ASD, 23 controls) underwent an eyes-closed resting-state exam. A Fast Fourier Trans- Autism traits in individuals with agenesis of the form was applied and oscillatory activity examined corpus callosum from 1 to 120 Hz at 15 regional sources. Associations between oscillatory anomalies and symptom severity Lau, YC; Hinkley, LB; Bukshpun, P; Strominger, ZA; were probed. Children with ASD exhibited regionally Wakahiro, ML; Baron-Cohen, S; Allison, C; Auyeung, specific elevations in delta (1-4 Hz), theta (4-8 Hz), alpha B; Jeremy, RJ; Nagarajan, SS; Sherr, EH; Marco, EJ (8-12 Hz), and high frequency (20-120 Hz) power, supporting an imbalance of neural excitation/inhibition as School of Medicine, University of California, San Francisco, a neurobiological feature of ASD. Increased temporal 513 Parnassus Avenue, San Francisco, CA 94143, USA. and parietal alpha power was associated with greater symptom severity and thus is of particular interest. ABSTRACT: Autism spectrum disorders (ASD) have (22207057) numerous etiologies, including structural brain malformations such as agenesis of the corpus callosum (AgCC). We sought to directly measure the occurrence of autism traits in a cohort of individuals with AgCC and to investigate the neural underpinnings of this

50 J Autism Dev Disord (2013), Vol. 42, No. 9, pp. 1884-94 Mol Autism (2011), Vol. 2, pp. 11

Transient and steady-state auditory gamma-band Auditory magnetic mismatch field latency: a responses in first-degree relatives of people with biomarker for language impairment in autism autism spectrum disorder Roberts, TP; Cannon, KM; Tavabi, K; Blaskey, L; Khan, Rojas, DC; Teale, PD; Maharajh, K; Kronberg, E; Young- SY; Monroe, JF; Qasmieh, S; Levy, SE; Edgar, JC peter, K; Wilson, LB; Wallace, A; Hepburn, S Lurie Family Foundations' MEG Imaging Center, Department Department of Psychiatry, University of Colorado Denver, of Radiology, 34th Street and Civic Center Boulevard, Philadel- Aurora, CO, 80241, USA. [email protected]. phia, PA 19104, USA. [email protected]

BACKGROUND: Stimulus-related γ-band oscilla- BACKGROUND: Auditory processing abnormalities tions, which may be related to perceptual binding, are frequently observed in autism spectrum disorders are reduced in people with autism spectrum disor- (ASD), and these abnormalities may have sequelae in ders (ASD). The purpose of this study was to examine terms of clinical language impairment (LI). The present auditory transient and steady-state γ-band findings in study assessed associations between language impair- first-degree relatives of people with ASD to assess the ment and the amplitude and latency of the superior potential familiality of these findings in ASD. METH- temporal gyrus magnetic mismatch field (MMF) in ODS: Magnetoencephalography (MEG) recordings in response to changes in an auditory stream of tones or 21 parents who had a child with an autism spectrum vowels. METHODS: Fifty-one children with ASD, and disorder (pASD) and 20 healthy adult control subjects 27 neurotypical control subjects, all aged 6 to 15 years, (HC) were obtained. Gamma-band phase locking factor underwent neuropsychological evaluation, including (PLF), and evoked and induced power to 32, 40 and 48 tests of language function, as well as magnetoen- Hz amplitude-modulated sounds were measured for cephalographic recording during presentation of tones transient and steady-state responses. Participants were and vowels. The MMF was identified in the difference also tested on a number of behavioral and cognitive waveform obtained from subtraction of responses to assessments related to the broad autism phenotype standard from deviant stimuli. RESULTS: Magnetic (BAP). RESULTS: Reliable group differences were seen mismatch field latency was significantly prolonged (p < primarily for steady-state responses. In the left hemi- .001) in children with ASD, compared with neurotypical sphere, pASD subjects exhibited lower phase-locked control subjects. Furthermore, this delay was most pro- steady-state power in all three conditions. Total γ-band nounced (∼50 msec) in children with concomitant LI, power, including the non-phase-locked component, with significant differences in latency between children was also reduced in the pASD group. In addition, with ASD with LI and those without (p < .01). Receiver pASD subjects had significantly lower PLF than the HC operator characteristic analysis indicated a sensitivity of group. Correlations were seen between MEG measures 82.4% and specificity of 71.2% for diagnosing LI based and BAP measures. CONCLUSIONS: The reduction in on MMF latency. CONCLUSIONS: Neural correlates of steady-state γ-band responses in the pASD group is auditory change detection (the MMF) are significantly consistent with previous results for children with ASD. delayed in children with ASD, and especially those with Steady-state responses may be more sensitive than concomitant LI, suggesting a neurobiological basis as transient responses to phase-locking errors in ASD. well as a clinical biomarker for LI in ASD. (21392733) Together with the lower PLF and phase-locked power in first-degree relatives, correlations between γ-band measures and behavioral measures relevant to the BAP highlight the potential of γ-band deficits as a potential new autism endophenotype. (21729257)

51 Biol Psychiatry (2011), Vol. 70, No. 3, pp. 263-9 Biol Psychiatry (2011), Vol. 68, No. 12, pp. 1100-6

Validating γ oscillations and delayed auditory Decreased brain coordinated activity in autism responses as translational biomarkers of autism spectrum disorders during executive tasks: reduced long-range synchronization in the fronto-parietal Gandal, MJ; Edgar, JC; Ehrlichman, RS; networks Mehta, M; Roberts, TP; Siegel, SJ Perez Velazquez, JL; Barcelo, F; Hung, Y; Lesh- Department of Psychiatry, University of Pennsylvania, Phila- chenko, Y; Nenadovic, V; Belkas, J; Ragha- delphia, 19104, USA. van, V; Brian, J; Garcia Dominguez, L

BACKGROUND: Difficulty modeling complex behav- Brain and Behaviour Centre, Neurosciences & Mental Health ioral phenotypes in rodents (e.g., language) has hin- Programme, Division of Neurology, Hospital for Sick Children, dered pathophysiological investigation and treatment 555 University Avenue, Toronto, Ontario M5G1X8, Canada. development for autism spectrum disorders. Recent human neuroimaging studies, however, have identified ABSTRACT: Current theories of brain function propose functional biomarkers that can be more directly related that the coordinated integration of transient activity to the abnormal neural dynamics of autism spectrum patterns in distinct brain regions is the essence of brain disorders. This study assessed the translational poten- information processing. The behavioural manifesta- tial of auditory evoked-response endophenotypes of tions of individuals with autism spectrum disorders autism in parallel mouse and human studies of autism. (ASD) suggest that their brains have a different style METHODS: Whole-cortex magnetoencephalography of information processing. Specifically, a current trend was recorded in 17 typically developing and 25 autistic is to invoke functional disconnection in the brains of children during auditory pure-tone presentation. individuals with ASD as a possible explanation for some Superior temporal gyrus activity was analyzed in time atypicalities in the behaviour of these individuals. Our and frequency domains. Auditory evoked potentials observations indicate that the coordinated activity in were recorded in mice prenatally exposed to valproic brains of children with autism is lower than that found acid (VPA) and analyzed with analogous methods. in control participants. Disruption of long-range phase RESULTS: The VPA-exposed mice demonstrated selec- synchronization among frontal, parietal and occipital tive behavioral alterations related to autism, including areas was found, derived from magnetoencephalo- reduced social interactions and ultrasonic vocaliza- graphic (MEG) recordings, in high-functioning children tions, increased repetitive self-grooming, and prepulse with ASD during the performance of executive func- inhibition deficits. Autistic subjects and VPA-exposed tion tasks and was associated with impaired execution, mice showed a similar 10% latency delay in the N1/ while enhanced long-range brain synchronization was M100 evoked response and a reduction in γ frequency observed in control children. Specifically, a more signifi- (30-50 Hz) phase-locking factor. Electrophysiological cant prefrontal synchronization was found in control measures were associated with mouse behavioral defi- participants during task performance. In addition, a cits. In mice, γ phase-locking factor was correlated with robust enhancement in synchrony was observed in the expression of the autism risk gene neuroligin-3 and parietal cortex of children with ASD relative to controls, neural deficits were modulated by the mGluR5-recep- which may be related to parietal lobe abnormalities tor antagonist MPEP. CONCLUSIONS: Results demon- detected in these individuals. These results, using syn- strate a novel preclinical approach toward mechanistic chronization analysis of brain electrical signals, provide understanding and treatment development for autism. support for the contention that brains of individuals (21130222) with autism may not be as functionally connected as

52 that of the controls, and may suggest some therapeutic interventions to improve information processing in specific brain areas, particularly prefrontal cortices. (19465065) Unit of Neuropediatrics, Hospital Universitari del Mar, Universitat Autònoma de Barcelona, Passeig Marítim 25-29, Int J Psychophysiol (2009), Vol. 73, No. 3, pp. 341-9 E-08003 Barcelona, Spain. Electronic address: 10030amy@ comb.es.

How somatic cortical maps differ in autistic and OBJECTIVE: To provide further data around magne- typical brains toencephalographic (MEG) findings in early-onset autism spectrum disorders (ASD). METHODS: Thirty-six Coskun, MA; Varghese, L; Reddoch, S; Castillo, EM; Pear- children (mean age 7 years) diagnosed of PDD (DSM-IV, son, DA; Loveland, KA; Papanicolaou, AC; Sheth, BR ICD-10) were studied. There were 22 children with autistic disorder, 9 with Asperger's syndrome, and 5 with Department of Electrical and Computer Engineering, Univer- pervasive developmental disorder not otherwise speci- sity of Houston, Houston, Texas 77204-4005, USA. fied (PDD-NOS). According to the Childhood Autism Rating Scale (CARS), the autistic disorder was mild to ABSTRACT: The comorbidity of 'core characteristics' moderate in 11, and severe in 11. Neuroimaging studies and sensorimotor abnormalities in autism implies using three-dimensional MRI as well as simultaneous abnormalities in brain development of a general and MEG-EEG and fusion techniques through magnetic pervasive nature and atypical organization of sensory source imaging (MSI) were performed, with the aid of cortex. By using magnetoencephalography, we exam- anesthesia in non-cooperative patients. RESULTS: Most ined the cortical response to passive tactile stimula- patients had no EEG abnormalities. All ASD children tion of the thumb and index finger of the dominant showed common specific abnormalities in the shape hand and lip of the individuals with autism spectrum of low amplitude monophasic and biphasic spikes (iso- disorder and typically developing persons. The distance lated or short bursts) as well as acute waves, predomi- between the cortical representations of thumb and the nantly distributed in the perisylvian areas. In Asperger's lip was significantly larger in the autism group than syndrome, epileptiform spikes were mostly found in in typicals. Moreover, in cortex, the thumb is typically the right hemisphere. No lateralized epileptiform activ- closer to the lip than the index finger. This was not ity was observed in non-Asperger's autistic patients. observed in persons with autism. Our findings are argu- CONCLUSIONS: MEG epileptiform activity is frequently ably the first demonstration of abnormality in sensory documented in children with early-onset ASD. SIG- organization in the brains of persons with autism. NIFICANCE: Subclinical epileptiform activity is present (19057419) especially in the perisylvian regions for many patients with ASD. (18164240) Neuroreport (2009), Vol. 20, No. 2, pp. 175-9 Clin Neurophysiol (2008), Vol. 119, No. 3, pp. 626-634

Magnetoencephalographic pattern of epileptiform activity in children with early-onset autism spectrum disorders

Muñoz-Yunta, JA; Ortiz, T; Palau-Baduell, M; Martín-Muñoz, L; Salvadó-Salvadó, B; Valls-Santasusana, A; Perich-Alsina, J; Cristóbal, I; Fernández, A; Maestú, F; Dürsteler, C

53 54 Depression an abnormal network-based mechanism in depression. (30572002)

Dynamic community structure in major depressive Keywords: Community structure; Default Mode Network disorder: A resting-state MEG study (DMN);Central Executive Network (CEN); Major Depressive Disorder (MDD); Salience Network (SN) Tian, S; Chattun, MR; Zhang, S; Bi, K; Tang, H; Yan, R; Wang, Q; Yao, Z; Lu, Q Prog Neuropsychopharmacol Biol Psychiatry (2019), Vol. 92, pp. 39-47 School of Biological Sciences & Medical Engineering, South- east University, Nanjing 210096, China; Child Development and Learning Science, Key Laboratory of Ministry of Educa- Complexity analysis of spontaneous brain activity tion, China. in mood disorders: A magnetoencephalography study of bipolar disorder and major depression BACKGROUND: Major Depressive Disorder (MDD), characterized by depressed mood or anhedonia, is Fernández, A; Al-Timemy, AH; Ferre, F; Rubio, G; Escudero, J associated with altered functional connectivity (FC) within and between large scale networks such as the Department of Psychiatry, Faculty of Medicine, Complutense Default Mode Network (DMN), the Central Executive University, Madrid, Spain; Laboratory of Cognitive and Network (CEN) and the Salience Network (SN). Since Computational Neuroscience, Centre for Biomedical Technol- aberrant FC exhibits temporal variability and could ogy (CTB), Technical University and Complutense University, give rise to distorted reconfiguration of functional Madrid, Spain. Electronic address: [email protected]. brain networks, an in-depth analysis of the community structure could provide further insight into the syn- BACKGROUND AND PURPOSE: The lack of a bio- chrony of networks. We hypothesized that alterations in marker for Bipolar Disorder (BD) causes problems in the dynamic network community structure in MDD could differential diagnosis with other mood disorders such be temporally accompanied by disrupted conscious as major depression (MD), and misdiagnosis frequently states of these three networks. METHODS: 26 MDD occurs. Bearing this in mind, we investigated non- patients and 25 healthy controls were scanned using linear magnetoencephalography (MEG) patterns in a whole-head resting-state Magnetoencephalography BD and MD. METHODS: Lempel-Ziv Complexity (LZC) (MEG) machine. A novel multilayer modularity frame- was used to evaluate the resting-state MEG activity in work explored the functional modulation of these a cross-sectional sample of 60 subjects, including 20 networks. Recruitment (R) and integration (I) provided patients with MD, 16 patients with BD type-I, and 24 the strength of interaction within networks or across control (CON) subjects. Particular attention was paid networks, respectively. RESULTS: The brain regions in to the role of age. The results were aggregated by the DMN, CEN and SN were transiently integrated and scalp region. RESULTS: Overall, MD patients showed segmented in both patients and controls. R of CEN and significantly higher LZC scores than BD patients and I of SN were significantly greater in MDD compared to CONs. Linear regression analyses demonstrated distinct controls. CONCLUSION: Intrinsic resting-state networks tendencies of complexity progression as a function of dynamically interact and reorganize into distinct func- age, with BD patients showing a divergent tendency as tional modules in both patients and controls. However, compared with MD and CON groups. Logistic regres- the CEN "hyper-intertwines" with itself and SN "hyper- sions confirmed such distinct relationship with age, integrates" among the network of interest in depressed which allowed the classification of diagnostic groups. patients compared to controls. Network-level altera- CONCLUSIONS: The patterns of neural complexity in tions in R and I revealed a more generalized system- BD and MD showed not only quantitative differences level effect rather than a focal-wise effect from a neural in their non-linear MEG characteristics but also diver- dynamic perspective. This could potentially highlight gent trajectories of progression as a function of age. Moreover, neural complexity patterns in BD patients

55 resembled those previously observed in schizophrenia, depressed patients stayed longer in the supplementary thus supporting preceding evidence of common neu- microstate compared to healthy controls. During the ropathological processes. (29734005) time spent in the supplementary microstate, an at- tempt to compensate for the aberrant effect of vmPFC Keywords: Bipolar disorder; Lempel-Ziv Complexity; on PCC across DMN subnetworks was possibly made Magnetoencephalography; Mood disorders; Psychosis to balance the self-related processes disturbed by the Continuum dominant pattern. The functional compensation mechanism of the supplementary microstate attached to the Compr Psychiatry (2019), Vol. 84, pp. 112-117 dominant disrupted one provided a possible explanation to the existing inconsistent findings between the anterior and posterior DMN in depression. (29330134) A supplementary functional connectivity microstate attached to the default mode network in depression Keywords: Default mode network; Depression; Dynamic; revealed by resting-state magnetoencephalography Magnetoencephalography; Microstates; Resting-state functional connectivity Zhang, S; Tian, S; Chattun, MR; Tang, H; Yan, R; Bi, K; Yao, Z; Lu, Q Prog Neuropsychopharmacol Biol Psychiatry (2019), Vol. 83, pp. 76-85 School of Biological Sciences & Medical Engineering, South- east University, Nanjing 210096, China; Key Laboratory of Child Development and Learning Science, Southeast Univer- Predictability of depression severity based on sity, Nanjing 210096, China. posterior alpha oscillations

ABSTRACT: Default mode network (DMN) has discern- Jiang, H; Popov, T; Jylänki, P; Bi, K; Yao, Z; able involvement in the representation of negative, Lu, Q; Jensen, O; van Gerven, MA self-referential information in depression. Both increased and decreased resting-state functional con- Academic Department of Psychiatry, Nanjing Brain Hospital, nectivity between the anterior and posterior DMN have Nanjing Medical University, Nanjing 210029, China; Radboud been observed in depression. These conflicting connec- University, Donders Institute for Brain, Cognition and Behav- tivity differences necessitated further exploration of the iour, 6500 HE Nijmegen, The Netherlands. resting-state DMN dysfunction in depression. Hence, we investigated the time-varying dynamic interactions OBJECTIVE: We aimed to integrate neural data and within the DMN via functional connectivity microstates an advanced machine learning technique to predict in a sub-second level. 25 patients with depression and individual major depressive disorder (MDD) patient 25 matched healthy controls were enrolled in the MEG severity. METHODS: MEG data was acquired from 22 analysis. Spherical K-means algorithms embedded MDD patients and 22 healthy controls (HC) resting within an iterative optimization frame were applied awake with eyes closed. Individual power spectra were to sliding windowed correlation matrices, resulting in calculated by a Fourier transform. Sources were recon- sub-second alternations of two functional connectivity structed via beamforming technique. Bayesian linear microstates for groups and highlighting the presence regression was applied to predict depression severity of functional variability. In the power dominant state, based on the spatial distribution of oscillatory power. depressed patients showed a transient decreased pat- RESULTS: In MDD patients, decreased theta (4-8 Hz) tern that reflected inter/intra-subnetwork deregulation. and alpha (8-14 Hz) power was observed in fronto-cen- A supplementary negatively correlated state simultane- tral and posterior areas respectively, whereas increased ously presented with increased connectivity between beta (14-30 Hz) power was observed in fronto-central the ventromedial prefrontal cortex (vmPFC) and the regions. In particular, posterior alpha power was posterior cingulate cortex (PCC), two core nodes for the negatively related to depression severity. The Bayesian anterior and posterior DMN respectively. Additionally, linear regression model showed significant depression

56 severity prediction performance based on the spatial distribution of both alpha (r=0.68, p=0.0005) and beta power (r=0.56, p=0.007) respectively. CONCLUSIONS: Our trols underwent a baseline MEG session with passive findings point to a specific alteration of oscillatory brain viewing of pleasant, unpleasant, and neutral pictures. activity in MDD patients during rest as characterized Fifteen patients were followed-up with a second MEG from MEG data in terms of spectral and spatial distribu- session after 4 weeks of antidepressant monophar- tion. SIGNIFICANCE: The proposed model yielded a macotherapy with mirtazapine. The corresponding quantitative and objective estimation for the depres- controls received no intervention between the mea- sion severity, which in turn has a potential for diagnosis surements. The clinical course of depression was as- and monitoring of the recovery process. (26821982) sessed using the Hamilton Depression scale. RESULTS: Prior to treatment, an overall neocortical hypoactiva- Keywords: Bayesian linear regression; MEG; Major depres- tion during emotional processing, particularly at the sive disorder; Resting state parietal regions and areas at the right temporoparietal junction, as well as abnormal valence-specific reactions Clin Neurophysiol (2016), Vol. 127, No. 4, pp. 2108-14 at the right parietal and bilateral dorsolateral prefrontal cortex (dlPFC) regions were observed in patients compared to controls. These effects occurred <150 ms, Magnetoencephalographic Correlates of Emotional suggesting dysfunctional processing of emotional stim- Processing in Major Depression Before and After uli at a preconscious level. Successful antidepressant Pharmacological Treatment treatment resulted in a normalization of the hypoactivation at the right parietal and right temporoparietal Domschke, K; Zwanzger, P; Rehbein, MA; Stein- regions. Accordingly, both dlPFC regions revealed an berg, C; Knoke, K; Dobel, C; Klinkenberg, I; Kugel, increase of activity after therapy. CONCLUSIONS: The H; Kersting, A; Arolt, V; Pantev, C; Junghofer, M present study provides neurophysiological evidence for dysfunctional emotional processing in a fronto- Department of Psychiatry, University of Muenster, Germany parieto-temporal network, possibly contributing to the (Drs Domschke, Zwanzger, Knoke, and Arolt); Department of pathogenesis of MDD. These activation patterns might Psychiatry, University of Wuerzburg, Germany (Dr Domschke); have the potential to serve as biomarkers of treatment Institute of Biomagnetism and Biosignal Analysis, Univer- success. (26259960) sity of Muenster, Germany (Ms Rehbein and Klinkenberg, Drs Steinberg, Dobel, Pantev, and Junghofer); Department Keywords: Dorsolateral prefrontal cortex; EEG; IAPS; MDD; of Radiology, University of Muenster, Germany (Dr Kugel); MEG; parietal hypoactivation; temporoparietal junction Department of Psychosomatic Medicine, University of Leipzig, Germany (Dr Kersting). Int J Neuropsychopharmacol (2016), Vol. 19, No. 2

BACKGROUND: In major depressive disorder (MDD), electrophysiological and imaging studies suggest Group differences in MEG-ICA derived resting state reduced neural activity in the parietal and dorsolateral networks: Application to major depressive disorder prefrontal cortex regions. In the present study, neural correlates of emotional processing in MDD were Nugent, AC; Robinson, SE; Cop- analyzed for the first time in a pre-/post-treatment pola, R; Furey, ML; Zarate, CA design by means of magnetoencephalography (MEG), allowing for detecting temporal dynamics of brain Experimental Therapeutics and Pathophysiology Branch, activation. METHODS: Twenty-five medication-free National Institute of Mental Health, National Institutes of Caucasian in-patients with MDD and 25 matched con-

57 Health, Bethesda, MD, USA. Electronic address: nugenta@ MDD. Findings of increased connectivity between the mail.nih.gov. amygdala and cortical nodes further support the role of amygdalar networks in mediated depressive symptom- UNLABELLED: Functional magnetic resonance imag- atology. CLINICAL TRIALS IDENTIFIER: NCT00024635 ing (fMRI) studies have revealed the existence of robust, (ZIA-MH002927-04). (26032890) interconnected brain networks exhibiting correlated low frequency fluctuations during rest, which can be Keywords: Depression; Magnetoencephalography (MEG); derived by examining inherent spatio-temporal pat- Network terns in functional scans independent of any a priori model. In order to explore the electrophysiological Neuroimage (2016), Vol. 118, pp. 1-12 underpinnings of these networks, analogous techniques have recently been applied to magnetoencephalography (MEG) data, revealing similar networks Baseline working memory activation deficits in that exhibit correlated low frequency fluctuations in dimensional anxious depression as detected by the power envelope of beta band (14-30Hz) power. magnetoencephalography However, studies to date using this technique have concentrated on healthy subjects, and no method Ionescu, DF; Nugent, AC; Luckenbaugh, DA; has yet been presented for group comparisons. We Niciu, MJ; Richards, EM; Zarate, CA; Furey, ML extended the ICA resting state MEG method to enable group comparisons, and demonstrate the technique 1Department of Psychiatry,Massachusetts General in a sample of subjects with major depressive disor- Hospital,Boston,MA,USA. der (MDD). We found that the intrinsic resting state networks evident in fMRI appeared to be disrupted OBJECTIVE: Anxiety often co-occurs with major de- in individuals with MDD compared to healthy partici- pressive disorder (MDD). This preliminary study sought pants, particularly in the subgenual cingulate, although to ascertain the extent to which anxious depression the electrophysiological correlates of this are unknown. drives group neurobiological differences between pa- Networks extracted from a combined group of healthy tients with MDD and healthy volunteers (HVs). METH- and MDD participants were examined for differ- ODS: Magnetoencephalography beta-band frequency ences between groups. Individuals with MDD showed was used to compare differences in brain response reduced correlations between the subgenual anterior during the N-back working memory task between 30 cingulate (sgACC) and hippocampus in a network with medication-free patients with treatment-resistant MDD primary nodes in the precentral and middle frontal gyri. (anxious depression=18; nonanxious depression=12) Individuals with MDD also showed increased correla- and 28 HVs. RESULTS: Compared to HVs, patients with tions between insulo-temporal nodes and amygdala anxious depression had significantly reduced desyn- compared to healthy controls. To further support our chronisation (less activation) in the left precuneus, methods and findings, we present test/re-test reliability right cuneus, and left insula extending into the inferior on independent recordings acquired within the same and middle frontal cortex during the 2-back condition session. Our results demonstrate that group analyses compared with the 1-back condition of the N-back are possible with the resting state MEG-independent working memory task--indicating less activation of component analysis (ICA) technique, highlighting a these neural networks in patients with anxious depres- new pathway for analysis and discovery. This study sion during the condition with the highest level of task also provides the first evidence of altered sgACC con- demands. No other significant group differences were nectivity with a motor network. This finding, reliable found during the working memory conditions. CON- across multiple sessions, suggests that the sgACC may CLUSION: This preliminary study suggests that a subset partially mediate the psychomotor symptoms of MDD of patients--those with anxious depression--may be via synchronized changes in beta-band power, and driving observed group differences between patients expands the idea of the sgACC as a hub region mediat- with MDD and HVs. Further neurobiological studies and ing cognitive and emotional symptomatic domains in replication experiments are necessary to determine the

58 extent to which this subgroup has preferentially influ- dysfunction in MDD when dealing with emotional enced our understanding of the underlying neurobiol- stimuli. (22750155) ogy of depression. (25600154) Neurosci Lett (2012), Vol. 523, No. 2, pp. 125-30 Keywords: N-back task; anxious depression; magnetoencephalography (MEG); major depressive disorder; neurobiology Synaptic potentiation is critical for rapid antidepressant response to ketamine in treatment- Acta Neuropsychiatr (2016), Vol. 27, No. 3, pp. 143-52 resistant major depression

Cornwell, BR; Salvadore, G; Furey, M; Marquardt, Impaired prefrontal-amygdala effective CA; Brutsche, NE; Grillon, C; Zarate, CA connectivity is responsible for the dysfunction of emotion process in major depressive disorder: a Section on Neurobiology of Fear and Anxiety, National Insti- dynamic causal modeling study on MEG tute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA. [email protected] Lu, Q; Li, H; Luo, G; Wang, Y; Tang, H; Han, L; Yao, Z BACKGROUND: Clinical evidence that ketamine, a non- Research Centre for Learning Science, Southeast University, selective N-methyl-D-aspartate receptor (NMDAR) an- Nanjing 210096, China. [email protected] tagonist, has therapeutic effects within hours in people suffering from depression suggests that modulating ABSTRACT: Depression is proved to be associated with glutamatergic neurotransmission is a fundamental the dysfunction of prefrontal-limbic neural circuit, es- step in alleviating the debilitating symptoms of mood pecially during emotion processing procedure. Related disorders. Acutely, ketamine increases extracellular explorations have been undertaken from the aspects glutamate levels, neuronal excitability, and spontane- of abnormal activation and functional connectivity. ous γ oscillations, but it is unknown whether these However, the mechanism of the dysfunction of coordi- effects are key to the mechanism of antidepressant nated interactions remains unknown and is still a mat- action of ketamine. METHODS: Twenty drug-free major ter of debate. The present study gave direct evidence of depressive disorder patients received a single, open- this issue from the aspect of effective connectivity via label intravenous infusion of ketamine hydrochloride dynamic causal modeling (DCM). 20 major depressive (.5 mg/kg). Magnetoencephalographic recordings were disorder (MDD) patients and 20 healthy controls were made approximately 3 days before and approximately recruited to attend facial emotional stimulus during 6.5 hours after the infusion, whereas patients passively MEG recording. Bayesian model selection (BMS) was received tactile stimulation to the right and left index applied to choose the best model. Results under the fingers and also while they rested (eyes-closed). Antide- optimal model showed that top-down endogenous pressant response was assessed by percentage change effective connectivity from the dorsolateral prefrontal in Montgomery-Åsberg Depression Rating Scale cortex (DLPFC) to the amygdala was greatly impaired scores. RESULTS: Patients with robust improvements in in patients relative to health controls; while bottom-up depressive symptoms 230 min after infusion (respond- endogenous effective connectivity from the amyg- ers) exhibited increased cortical excitability within dala to the anterior cingulate cortex (ACC) as well as this antidepressant response window. Specifically, we modulatory effective connectivity from ACC to DLPFC found that stimulus-evoked somatosensory cortical re- was significantly increased. We inferred the incapable sponses increase after infusion, relative to pretreatment DLPFC failed to exert influence on amygdala, and responses in responders but not in treatment nonre- finally lead to enhanced amygdala-ACC and ACC-DLPFC sponders. Spontaneous somatosensory cortical γ-band bottom-up effects. Such impaired prefrontal-amygdala activity during rest did not change within the same connectivity was supposed to be responsible for the timeframe after ketamine in either responders or non- responders. CONCLUSIONS: These findings suggest

59 NMDAR antagonism does not lead directly to increased objective marker of depression and its remission after cortical excitability hours later and thus might not be treatment. (21708836) sufficient for therapeutic effects of ketamine to take hold. Rather, increased cortical excitability as depres- J Psychopharmacol (2013), Vol. 26, No. 5, pp. 636-43 sive symptoms improve is consistent with the hypothesis that enhanced non-NMDAR-mediated glutamatergic neurotransmission via synaptic potentiation is central Anterior cingulate desynchronization and to the antidepressant effect of ketamine. (22521148) functional connectivity with the amygdala during a working memory task predict rapid antidepressant Biol Psychiatry (2013), Vol. 72, No. 7, pp. 555-61 response to ketamine

Salvadore, G; Cornwell, BR; Sambataro, F; Latov, D; Complexity analysis of spontaneous brain activity: Colon-Rosario, V; Carver, F; Holroyd, T; DiazGranados, N; effects of depression and antidepressant treatment Machado-Vieira, R; Grillon, C; Drevets, WC; Zarate, CA

Méndez, MA; Zuluaga, P; Hornero, R; Gómez, C; Escu- Experimental Therapeutics, Mood and Anxiety Disorders Pro- dero, J; Rodríguez-Palancas, A; Ortiz, T; Fernández, A gram, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA. [email protected]. Departamento de Psiquiatría y Psicología Médica, Universi- gov dad Complutense de Madrid, Madrid, Spain. maria.mendez@ kcl.ac.uk ABSTRACT: Pregenual anterior cingulate cortex (pgACC) hyperactivity differentiates treatment re- ABSTRACT: Magnetoencephalography (MEG) allows sponders from non-responders to various pharmaco- the real-time recording of neural activity and oscillatory logical antidepressant interventions, including ket- activity in distributed neural networks. We applied a amine, an N-methyl-D-aspartate receptor antagonist. non-linear complexity analysis to resting-state neural Evidence of pgACC hyperactivition during non-emo- activity as measured using whole-head MEG. Record- tional working memory tasks in patients with major ings were obtained from 20 unmedicated patients with depressive disorder (MDD) highlights the importance major depressive disorder and 19 matched healthy con- of this region for processing both emotionally salient trols. Subsequently, after 6 months of pharmacological and cognitive stimuli. However, it is unclear whether treatment with the antidepressant mirtazapine 30 mg/ pgACC activity might serve as a potential biomarker of day, patients received a second MEG scan. A measure of antidepressant response during working memory tasks the complexity of neural signals, the Lempel-Ziv Com- as well, in line with previous research with emotionally plexity (LZC), was derived from the MEG time series. We arousing tasks. This study tested the hypothesis that found that depressed patients showed higher pre- during the N-back task, a widely used working memory treatment complexity values compared with controls, paradigm, low pretreatment pgACC activity, as well and that complexity values decreased after 6 months as coherence between the pgACC and the amygdala, of effective pharmacological treatment, although would be correlated with the clinical improvement this effect was statistically significant only in younger after ketamine. Magnetoencephalography (MEG) re- patients. The main treatment effect was to recover the cordings were obtained from 15 drug-free patients with tendency observed in controls of a positive correlation MDD during working memory performance 1 to 3 days between age and complexity values. Importantly, the before receiving a single ketamine infusion. Functional reduction of complexity with treatment correlated with activation patterns were analyzed using advanced MEG the degree of clinical symptom remission. We suggest source analysis. Source coherence analyses were con- that LZC, a formal measure of neural activity complex- ducted to quantify the degree of long-range functional ity, is sensitive to the dynamic physiological changes connectivity between the pgACC and the amygdala. observed in depression and may potentially offer an Patients who showed the least engagement of the pgACC in response to increased working memory load

60 showed the greatest symptomatic improvement within 4 h of ketamine administration (r=0.82, p=0.0002, false discovery rate (FDR) <0.05). Pretreatment functional Psychophysiology (2009), Vol. 46, No. 1, pp. 52-61 connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change (r=-0.73, p=0.0021, FDR <0.05).These Increased anterior cingulate cortical activity in data implicate the pgACC and its putative interaction response to fearful faces: a neurophysiological with the amygdala in predicting antidepressant re- biomarker that predicts rapid antidepressant sponse to ketamine in a working memory task context. response to ketamine (20393460) Salvadore, G; Cornwell, BR; Colon-Rosario, V; Cop- Neuropsychopharmacology (2010), Vol. 35, No. 7, pp. pola, R; Grillon, C; Zarate, CA; Manji, HK 1415-22 Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Department of Preattentive dysfunction in major depression: a Health and Human Services, Bethesda, Maryland, USA. magnetoencephalography study using auditory mismatch negativity BACKGROUND: Most patients with major depressive disorder (MDD) experience a period of lengthy trial Takei, Y; Kumano, S; Hattori, S; Uehara, T; Kawaku- and error when trying to find optimal antidepressant bo, Y; Kasai, K; Fukuda, M; Mikuni, M treatment; identifying biomarkers that could predict response to antidepressant treatment would be of Department of Psychiatry and Human Behavior, Gunma enormous benefit. We tested the hypothesis that University Graduate School of Medicine, Gunma, Japan. pretreatment anterior cingulate cortex (ACC) activity could be a putative biomarker of rapid antidepressant ABSTRACT: Information processing deficits in major response to ketamine, in line with previous findings depressive disorder have been infrequently examined that investigated the effects of conventional antide- electrophysiologically. Its preattentive and sensory pressants. We also investigated patterns of ACC activity information processing was examined using mismatch to rapid presentation of fearful faces compared with field (MMNm) and P1m components, respectively, by the normal habituation observed in healthy sub- magnetoencephalography. Fourteen major depressive jects. METHODS: We elicited ACC activity in drug- disorder patients and 19 healthy volunteers partici- free patients with MDD (n = 11) and healthy control pated in the study. MMNm was elicited in response to subjects (n = 11) by rapidly presenting fearful faces, a duration and frequency changes of pure-tone stimuli paradigm known to activate rostral regions of the ACC. and in response to a vowel across-category change. Spatial-filtering analyses were performed on magne- The magnetic global field power (mGFP) of MMNm was toencephalographic (MEG) recordings, which offer the significantly smaller in the major depressive disorder temporal precision necessary to estimate ACC activity patients than in the healthy volunteers, although that elicited by the rapid presentation of stimuli. Magneto- of P1m did not differ between the two groups. Informa- encephalographic recordings were obtained only once tion processing at the preattentive level is impaired for both patients and control subjects. Patients were functionally in major depressive disorder, and this subsequently administered a single ketamine infusion dysfunction is not due to the dysfunction at the lower followed by assessment of depressive symptoms 4 level of information processing. (19055502) hours later. RESULTS: Although healthy subjects had decreased neuromagnetic activity in the rostral ACC across repeated exposures, patients with MDD showed

61 robust increases in pretreatment ACC activity. Notably, this increase was positively correlated with subsequent rapid antidepressant response to ketamine. Exploratory analyses showed that pretreatment amygdala activity was negatively correlated with change in depressive symptoms. CONCLUSIONS: Pretreatment rostral ACC activation may be a useful biomarker that identifies a subgroup of patients who will respond favorably to ketamine's antidepressant effects. (18822408)

Biol Psychiatry (2009), Vol. 65, No. 4, pp. 289-95

62 Dyslexia Keywords: KIAA0319; gene; mechanisms; neural variability; reading; subgroups

Increased variability of stimulus-driven cortical Dev Cogn Neurosci (2019), Vol. 34, pp. 7-17 responses is associated with genetic variability in children with and without dyslexia Aberrant resting-state functional brain networks in Centanni, TM; Pantazis, D; Truong, DT; Gru- dyslexia: Symbolic mutual information analysis of en, JR; Gabrieli, JDE; Hogan, TP neuromagnetic signals

McGovern Institute for Brain Research and Department of Dimitriadis, SI; Simos, PG; Fletcher, JΜ; Papanicolaou, AC Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Psychol- Artificial Intelligence and Information Analysis Laboratory, ogy, Texas Christian University, Fort Worth, TX, USA. Electronic Department of Informatics, Aristotle University, Thessaloniki, address: [email protected]. Greece; 3rd Department of Neurology, Medical School, Aristo- tle University of Thessaloniki, Thessaloniki, Greece. Electronic ABSTRACT: Individuals with dyslexia exhibit increased address: [email protected]. brainstem variability in response to sound. It is unknown as to whether increased variability extends to ABSTRACT: Neuroimaging studies have identified a neocortical regions associated with audition and read- variety of structural and functional connectivity abnor- ing, extends to visual stimuli, and whether increased malities in students experiencing reading difficulties. variability characterizes all children with dyslexia or, The present study adopted a novel approach to assess instead, a specific subset of children. We evaluated the dynamics of resting-state neuromagnetic record- the consistency of stimulus-evoked neural responses ings in the form of symbolic sequences (i.e., repeated in children with (N = 20) or without dyslexia (N = 12) patterns of neuromagnetic fluctuations within and/or as measured by magnetoencephalography (MEG). between sensors). Participants were 25 students expe- Approximately half of the children with dyslexia had riencing severe reading difficulties (RD) and 27 age- significantly higher levels of variability in cortical re- matched non-impaired readers (NI) aged 7-14 years. sponses to both auditory and visual stimuli in multiple Sensor-level data were first represented as symbolic nodes of the reading network. There was a significant sequences in eight conventional frequency bands. and positive relationship between the number of risk Next, dominant types of sensor-to-sensor interactions alleles at rs6935076 in the dyslexia-susceptibility gene in the form of intra and cross-frequency coupling were KIAA0319 and the degree of neural variability in pri- computed and subjected to graph modeling to assess mary auditory cortex across all participants. This gene group differences in global network characteristics. As has been linked with neural variability in rodents and a group RD students displayed predominantly within- in typical readers. These findings indicate that unstable frequency interactions between neighboring sensors representations of auditory and visual stimuli in audi- which may reflect reduced overall global network tory and other reading-related neocortical regions are efficiency and cost-efficiency of information transfer. In present in a subset of children with dyslexia and sup- contrast, sensor networks among NI students featured port the link between the gene KIAA0319 and the audi- a higher proportion of cross-frequency interactions. tory neural variability across children with or without Brain-reading achievement associations highlighted dyslexia. (29894888) the role of left hemisphere temporo-parietal functional networks, at rest, for reading acquisition and ability. (29476872)

63 Keywords: Connectomics; Dyslexia; Functional connectiv- Keywords: Compensation; Dyslexics; MEG; Morphological; ity; Graph theory; Intrinsic coupling modes; Magnetoen- Semantic cephalography (MEG); Symbolic dynamics Cortex (2018), Vol. 92, pp. 204-221 Int J Psychophysiol (2019), Vol. 126, pp. 20-29

Greater Repertoire and Temporal Variability of Spatiotemporal reorganization of the reading Cross-Frequency Coupling (CFC) Modes in Resting- network in adult dyslexia State Neuromagnetic Recordings among Children with Reading Difficulties Cavalli, E; Colé, P; Pattamadilok, C; Badier, JM; Zielinski, C; Chanoine, V; Ziegler, JC Dimitriadis, SI; Laskaris, NA; Simos, PG; Fletcher, JM; Papanicolaou, AC Aix-Marseille Université and CNRS, Laboratoire de Psy- chologie Cognitive (UMR 7290), Fédération de recherche 3C, Artificial Intelligence and Information Analysis Laboratory, Marseille, France; Aix-Marseille Université, Brain and Lan- Department of Informatics, Aristotle UniversityThessaloniki, guage Research Institute, Aix-en-Provence, France. Electronic Greece; Neuroinformatics Group, Department of Informatics, address: [email protected]. Aristotle UniversityThessaloniki, Greece.

ABSTRACT: Developmental dyslexia is characterized ABSTRACT: Cross-frequency, phase-to-amplitude by impairments in reading fluency and spelling that coupling (PAC) between neuronal oscillations at rest persist into adulthood. Here, we hypothesized that may serve as the substrate that supports information high-achieving adult dyslexics (i.e., university students exchange between functionally specialized neuronal with a history of dyslexia) manage to cope with these populations both within and between cortical regions. deficits by relying to a greater extent on morphological The study utilizes novel algorithms to identify promi- information than do non-impaired adult readers. We nent instantaneous modes of cross-frequency coupling used magnetoencephalography (MEG) in a primed lexi- and their temporal stability in resting state magnetoen- cal decision task, in which we contrasted orthographic, cephalography (MEG) data from 25 students experienc- morphological and semantic processing. Behavioral ing severe reading difficulties (RD) and 27 age-matched results confirmed that adult dyslexics did indeed rely to non-impaired readers (NI). Phase coherence estimates a greater extent on the semantic properties of mor- were computed in order to identify the prominent phemes than controls. In line with this, MEG results mode of PAC interaction for each sensor, sensor pair, showed early morphological effects (100-200 msec) and pair of frequency bands (from δ to γ) at succes- in a frontal network, which reflected the contribution sive time windows of the continuous MEG record. The of semantic processing. The same effects occurred degree of variability in the characteristic frequency-pair much later in controls (∼400 msec). In contrast, con- PAC(f1-f2) modes over time was also estimated. Results trols showed early orthographic priming effects in revealed a wider repertoire of prominent PAC interac- posterior left inferior temporal gyrus (LITG) at around tions in RD as compared to NI students, suggesting an 130 msec, which were not seen in dyslexics. In the LITG, altered functional substrate for information exchange dyslexics showed only late activation of semantic and between neuronal assemblies in the former group. orthographic information. The present results suggest a Moreover, RD students showed significant variability in spatiotemporal reorganization of the reading network, PAC modes over time. This temporal instability of PAC in which morphological information located in frontal values was particularly prominent: (a) within and be- regions is activated earlier in high-achieving adults tween right hemisphere temporo-parietal and occipito- dyslexics than controls. (28505581) temporal sensors and, (b) between left hemisphere frontal, temporal, and occipito-temporal sensors and corresponding right hemisphere sites. Altered modes of neuronal population coupling may help account

64 for extant data revealing reduced, task-related neu- processing steps. The present findings, thus, strengthen rophysiological and hemodynamic activation in left proposals assuming that improper low-frequency hemisphere regions involved in the reading network in acoustic entrainment affects speech sampling. This low RD. Moreover, the spatial distribution of pronounced speech-brain synchronization has the strong potential instability of cross-frequency coupling modes in this to cause severe consequences for both phonological group may provide an explanation for previous reports and reading skills. Interestingly, the reduced speech- suggesting the presence of inefficient compensatory brain synchronization in dyslexic readers compared mechanisms to support reading. (27199698) to normal readers (and its higher-order consequences across the speech processing network) appears pre- Keywords: chronnectome analysis; cross-frequency served through the development from childhood to coupling; dyslexia; functional connectivity; magnetoen- adulthood. Thus, the evaluation of speech-brain syn- cephalography; oscillopathies; phase-amplitude coupling; chronization could possibly serve as a diagnostic tool resting state for early detection of children at risk of dyslexia. Hum Brain Mapp 37:2767-2783, 2016. © 2016 Wiley Periodi- Front Hum Neurosci (2016), Vol. 10, pp. 163 cals, Inc. (27061643)

Keywords: auditory entrainment; developmental dislexia; Out-of-synchrony speech entrainment in effective connectivity; magnetoencephalography; speech developmental dyslexia perception

Molinaro, N; Lizarazu, M; Lallier, M; Bour- Hum Brain Mapp (2018), Vol. 37, No. 8, pp. 2767-83 guignon, M; Carreiras, M

BCBL, Basque Center on Cognition, Brain and Language, San Low frequency overactivation in dyslexia: Evidence Sebastian, Spain. from resting state Magnetoencephalography

ABSTRACT: Developmental dyslexia is a reading Pagnotta, MF; Zouridakis, G; Lianyang Li, ; Lizara- disorder often characterized by reduced awareness of zu, M; Lallier, M; Molinaro, N; Carreiras, M speech units. Whether the neural source of this phonological disorder in dyslexic readers results from the ABSTRACT: In this study, we compared the brain acti- malfunctioning of the primary auditory system or dam- vation profiles obtained from resting state Magnetoen- aged feedback communication between higher-order cephalographic (MEG) activity in 15 dyslexic patients phonological regions (i.e., left inferior frontal regions) with the profiles of 15 normal controls, using power and the auditory cortex is still under dispute. Here we spectral density (PSD) analysis. We first estimated recorded magnetoencephalographic (MEG) signals intracranial dipolar MEG sources on a dense grid on the from 20 dyslexic readers and 20 age-matched controls cortical surface and then projected these sources on a while they were listening to ∼10-s-long spoken sen- standardized atlas with 68 regions of interest (ROIs). Av- tences. Compared to controls, dyslexic readers had (1) eraging the PSD values of all sources in each ROI across an impaired neural entrainment to speech in the delta all control subjects resulted in a normative database band (0.5-1 Hz); (2) a reduced delta synchronization that was used to convert the PSD values of dyslexic in both the right auditory cortex and the left inferior patients into z-scores in eight distinct frequency bands. frontal gyrus; and (3) an impaired feedforward func- We found that dyslexic patients exhibited statistically tional coupling between neural oscillations in the right significant overactivation in the delta band (0.1-4 Hz) in auditory cortex and the left inferior frontal regions. This the right temporal (entorhinal and insula), left inferior shows that during speech listening, individuals with frontal (Broca's area), and right inferior frontal regions. developmental dyslexia present reduced neural syn- Overactivation may be interpreted as a compensatory chrony to low-frequency speech oscillations in primary mechanism for reading characterizing dyslexic patients. auditory regions that hinders higher-order speech These findings suggest that resting-state MEG activa-

65 tion maps may be used as specific biomarkers that can showed significant increase in cerebellar oscillatory help with the diagnosis of and assess the efficacy of alpha power following training. In addition, across both intervention in dyslexia. (26737893) time points, inter-hemispheric alpha coherence was higher in the dyslexic group compared to the control Conf Proc IEEE Eng Med Biol Soc (2016), Vol. 2015, pp. group. In conclusion, the current findings suggest 6959-62 that the combination of motor and language training embedded in QMT increases cerebellar oscillatory activity in dyslexics and improves reading performance. Changes in cerebellar activity and inter- These results support the hypothesis that the cerebel- hemispheric coherence accompany improved lum plays a role in skilled reading, and begin to unravel reading performance following Quadrato Motor the underlying mechanisms that mediate cerebellar Training contribution in cognitive and neuronal augmentation. (24847224) Ben-Soussan, TD; Avirame, K; Glicksohn, J; Gold- stein, A; Harpaz, Y; Ben-Shachar, M Keywords: MEG; alpha power; cerebellum; coherence; dyslexia; motor training; reading The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan University Ramat-Gan, Israel Front Syst Neurosci (2014), Vol. 8, pp. 81 ; Research Institute for Neuroscience, Education and Didac- tics, Cognitive Neurophysiology Laboratory, Patrizio Paoletti Foundation Assisi, Italy. Lateralized auditory brain function in children with normal reading ability and in children with dyslexia ABSTRACT: Dyslexia is a multifactorial reading deficit that involves multiple brain systems. Among other Johnson, BW; McArthur, G; Hautus, M; theories, it has been suggested that cerebellar dysfunc- Reid, M; Brock, J; Castles, A; Crain, S tion may be involved in dyslexia. This theory has been supported by findings from anatomical and functional ARC Centre of Excellence in Cognition and its Disorders, imaging. A possible rationale for cerebellar involve- Macquarie University, NSW 2109, Australia. blake.johnson@ ment in dyslexia could lie in the cerebellum's role as mq.edu.au an oscillator, producing synchronized activity within neuronal networks including sensorimotor networks ABSTRACT: We examined central auditory processing critical for reading. If these findings are causally in typically- and atypically-developing readers. Concur- related to dyslexia, a training regimen that enhances rent EEG and MEG brain measurements were obtained cerebellar oscillatory activity should improve reading from a group of 16 children with dyslexia aged 8-12 performance. We examined the cognitive and neural years, and a group of 16 age-matched children with effects of Quadrato Motor Training (QMT), a structured normal reading ability. Auditory responses were sensorimotor training program that involves sequenc- elicited using 500ms duration broadband noise. These ing of motor responses based on verbal commands. responses were strongly lateralized in control children. Twenty-two adult Hebrew readers (12 dyslexics and 10 Children with dyslexia showed significantly less laterali- controls) were recruited for the study. Using Magne- sation of auditory cortical functioning, and a different toencephalography (MEG), we measured changes in pattern of development of auditory lateralization with alpha power and coherence following QMT in a within- age. These results provide further evidence that the subject design. Reading performance was assessed core neurophysiological deficit of dyslexia is a problem pre- and post-training using a comprehensive battery in the balance of auditory function between the two of behavioral tests. Our results demonstrate improved hemispheres. (23333528) performance on a speeded reading task following one month of intensive QMT in both the dyslexic and control groups. Dyslexic participants, but not controls,

66 Neuropsychologia (2013), Vol. 51, No. 4, pp. 633-41 Gamma phase locking modulated by phonological Neuroreport (2013), Vol. 23, No. 14, pp. 851-6 contrast during auditory comprehension in reading disability Altered low-γ sampling in auditory cortex accounts Han, J; Mody, M; Ahlfors, SP for the three main facets of dyslexia

Athinoula A. Martinos Center for Biomedical Imaging, Massa- Lehongre, K; Ramus, F; Villiermet, chusetts General Hospital/Harvard Medical School, Charles- N; Schwartz, D; Giraud, AL town, MA 02129, USA. [email protected] Inserm U960-Ecole Normale Supérieure, 75005 Paris, France. ABSTRACT: Children with specific reading impairment may have subtle deficits in speech perception related ABSTRACT: It has recently been conjectured that to difficulties in phonological processing. The aim of dyslexia arises from abnormal auditory sampling. What this study was to examine brain oscillatory activity re- sampling rate is altered and how it affects reading lated to phonological processing in the context of audi- remains unclear. We hypothesized that by impairing tory sentence comprehension using magnetoencepha- phonemic parsing abnormal low-gamma sampling lography to better understand these deficits. Good and could yield phonemic representations of unusual poor readers, 16-18 years of age, were tested on speech format and disrupt phonological processing and verbal perception of sentence-terminal incongruent words memory. Using magnetoencephalography and behav- that were phonologically manipulated to be similar or ioral tests, we show in dyslexic subjects a reduced left- dissimilar to corresponding congruent target words. hemisphere bias for phonemic processing, reflected in Functional coupling between regions was measured less entrainment to ≈30 Hz acoustic modulations in left using phase-locking values (PLVs). Gamma-band (30-45 auditory cortex. This deficit correlates with measures of Hz) PLV between auditory cortex and superior temporal phonological processing and rapid naming. We further sulcus in the right hemisphere was differentially modu- observed enhanced cortical entrainment at rates be- lated in the two groups by the degree of phonological yond 40 Hz in dyslexics and show that this particularity contrast between the congruent and the incongru- is associated with a verbal memory deficit. These data ent target words in the latency range associated with suggest that a single auditory anomaly, i.e., phone- semantic processing. Specifically, the PLV was larger in mic oversampling in left auditory cortex, accounts for the phonologically similar than in the phonologically three main facets of the linguistic deficit in dyslexia. dissimilar condition in the good readers. This pattern (22196341) was reversed in the poor readers, whose lower PLV in the phonologically similar condition may be indicative Neuron (2012), Vol. 72, No. 6, pp. 1080-90 of the impaired phonological coding abilities of the group, and consequent vulnerability under perceptu- ally demanding conditions. Overall, the results support Engagement of temporal lobe regions predicts the role of gamma oscillations in spoken language response to educational interventions in adolescent processing. (22889887) struggling readers

Rezaie, R; Simos, PG; Fletcher, JM; Cirino, PT; Vaughn, S; Papanicolaou, AC

67 Department of Pediatrics, Children's Learning Institute, Uni- lography (MEG). Based on their scores on standardized versity of Texas Health Science Center, Houston, Texas 77030, reading fluency tests 1 year later, students with RD who USA. [email protected] showed significant improvement were classified as Adequate Responders (AR) whereas those not dem- ABSTRACT: Brain activation profiles obtained using onstrating such gains were classified as Inadequate magnetoencephalography were compared between Responders (IR). At baseline, activation profiles of the middle-school students experiencing reading difficul- AR group featured increased activity in the left supra- ties and non-reading-impaired students during perfor- marginal and angular gyri, as well as in the superior mance of a continuous printed word recognition task. and middle temporal gyri, bilaterally compared to IR. Struggling readers underwent small-group remedial in- The degree of activity in these regions was a significant struction, and students who showed significant gains in predictor of the amount of subsequent gains in reading word reading efficiency at a one-year follow-up assess- fluency. These results extend previous functional brain ment were classified as Adequate Responders whereas imaging findings of beginning readers, suggesting that those not demonstrating such gains as Inadequate recruitment of brain areas that typically serve as key Responders. At baseline, compared to Inadequate Re- components of the brain circuit for reading is an impor- sponders, the activation profiles of Adequate Respond- tant factor in determining response to intervention in ers featured increased activity in the left middle, supe- older struggling readers. (21740612) rior temporal, and ventral occipitotemporal regions, as well as in the right mesial temporal cortex. The degree J Int Neuropsychol Soc (2012), Vol. 17, No. 5, pp. 875-85 of activity in these regions was a significant predictor of improvement in word reading efficiency beyond the prediction afforded by baseline reading accuracy or The timing and strength of regional brain activation fluency measures. The engagement of brain areas that associated with word recognition in children with typically serve as key components of the brain circuit reading difficulties for reading may be an important factor in predicting response to intervention in older students who experi- Rezaie, R; Simos, PG; Fletcher, JM; Juranek, J; Ciri- ence reading difficulties. (21978010) no, PT; Li, Z; Passaro, AD; Papanicolaou, AC

Dev Neuropsychol (2012), Vol. 36, No. 7, pp. 869-88 Department of Pediatrics, Children's Learning Institute, Uni- versity of Texas Health Science Center at Houston Houston, TX, USA. Temporo-parietal brain activity as a longitudinal predictor of response to educational interventions ABSTRACT: The study investigates the relative de- among middle school struggling readers gree and timing of cortical activation across parietal, temporal, and frontal regions during performance of Rezaie, R; Simos, PG; Fletcher, JM; Cirino, a continuous visual-word recognition task in children PT; Vaughn, S; Papanicolaou, AC who experience reading difficulties (N = 44, RD) and typical readers (N = 40, NI). Minimum norm estimates Department of Pediatrics, Children's Learning Institute, Uni- of regional neurophysiological activity were obtained versity of Texas Health Science Center at Houston, Houston, from magnetoencephalographic recordings. Children Texas 77030 USA. [email protected] with RD showed bilaterally reduced neurophysiological activity in the superior and middle temporal gyri, and ABSTRACT: Spatiotemporal brain activation profiles increased activity in rostral middle frontal and ventral were obtained from 27 middle school students experi- occipitotemporal cortices, bilaterally. The temporal encing difficulties in reading comprehension as well as profile of activity in the RD group, featured near-simul- word-level skills (RD) and 23 age- and IQ-matched non- taneous activity peaks in temporal, inferior parietal, and reading impaired students during performance of an prefrontal regions, in contrast to a clear temporal pro- oral pseudoword reading task using Magnetoencepha- gression of activity among these areas in the NI group.

68 These results replicate and extend previous MEG and Neurosci Lett (2011), Vol. 488, No. 2, pp. 123-8 fMRI results demonstrating atypical, latency-dependent attributes of the brain circuit involved in word reading in children with reading difficulties. (21647211) Auditory word perception in sentence context in reading-disabled children Keywords: dyslexia; functional brain imaging; magnetoencephalography; middle temporal gyrus; reading Mody, M; Wehner, DT; Ahlfors, SP

Front Hum Neurosci (2011), Vol. 5, pp. 45 Athinoula A.Martinos Center for Biomedical Imaging, Massa- chusetts General Hospital, 14913th Street, Rm 2301, Charles- town, MA 02129, USA. [email protected] Dynamic task-specific brain network connectivity in children with severe reading difficulties ABSTRACT: Reading difficulties seem to be related to a phonological deficit that has its origin in poor speech Vourkas, M; Micheloyannis, S; Simos, PG; Rezaie, perception. As such, disabled readers may use contex- R; Fletcher, JM; Cirino, PT; Papanicolaou, AC tual cues to compensate for their weak speech perception abilities. We compared good and poor readers, Technological Education Institute of Crete, Estavromenos, 7-13 years old, on auditory perception of words varying Heraklion 71004, Crete, Greece. [email protected] in phonological contrast, in congruent versus incongruent sentence contexts. Both groups did worse in the ABSTRACT: We investigated patterns of sensor- phonologically similar than in the phonologically dis- level functional connectivity derived from single-trial similar incongruent condition. Magnetoencephalogra- whole-head magnetoencephalography data during a phy revealed differential activation between the groups pseudoword reading and a letter-sound naming task as a function of phonological contrast in left superior in children with reading difficulties (RD) and children temporal gyrus between 200 and 300 ms, suggesting with no reading impairments (NI). The Phase Lag Index that poor readers may have processed phonologically (PLI), a linear and nonlinear estimator, computed for similar incongruent stimuli as congruent. The results each pair of sensors, was used to construct graphs and are consistent with a phonological account of reading obtain estimates of local and global network efficiency disability. (18815588) according to graph theory. In the 8-13 Hz (alpha band) and 20-30 Hz (gamma band) range, RD students Neuroreport (2008), Vol. 19, No. 16, pp. 1567-71 showed significantly lower global efficiency than NI children, for the entire MEG recording epoch. RD students also displayed reduced local network efficiency in the alpha band. Correlations between phonological decoding ability and graph metrics were particularly evident during the task that posed significant demands for phonological decoding, and followed distinct time courses depending on signal frequency. Results are consistent with the notion of task-dependent, aberrant long- and short-range functional connectivity in RD children. (21073917)

69 70 Epilepsy

Magnetoencephalography for epileptic focus more focal involvement in an additional 32%. Patients localization in a series of 1000 cases who proceeded to surgery showed a significantly higher percentage of monofocal magnetoencephalography Rampp, S; Stefan, H; Wu, X; Kaltenhäuser, M; Maess, B; results. Complete magnetoencephalography resection Schmitt, FC; Wolters, CH; Hamer, H; Kasper, BS; Schwab, was associated with significantly higher chances to S; Doerfler, A; Blümcke, I; Rössler, K; Buchfelder, M achieve seizure freedom in the short and long-term. Diagnostic accuracy was significant in temporal and Department of Neurosurgery, University Hospital Erlangen, extra-temporal lobe cases, but was significantly higher Germany. in extra-temporal lobe epilepsy (diagnostic odds ratios of 4.4 and 41.6). Odds ratios were also higher in non-le- ABSTRACT: The aim of epilepsy surgery in patients sional versus lesional cases (42.0 versus 6.2). The results with focal, pharmacoresistant epilepsies is to remove show that magnetoencephalography provides non- the complete epileptogenic zone to achieve long- redundant information, which significantly contributes term seizure freedom. In addition to a spectrum of to patient selection, focus localization and ultimately diagnostic methods, magnetoencephalography focus long-term seizure freedom after epilepsy surgery. Spe- localization is used for planning of epilepsy surgery. cifically in extra-temporal lobe epilepsy and non-lesion- We present results from a retrospective observational al cases, magnetoencephalography provides excellent cohort study of 1000 patients, evaluated using magne- accuracy. (31373622) toencephalography at the University Hospital Erlangen over the time span of 28 years. One thousand consecu- Keywords: epilepsy; epilepsy surgery; long-term outcome; tive cases were included in the study, evaluated at the magnetic source imaging; magnetoencephalography University Hospital Erlangen between 1990 and 2018. All patients underwent magnetoencephalography as Brain (2019), Vol. 142, No. 10, pp. 3059-3071 part of clinical workup for epilepsy surgery. Of these, 405 underwent epilepsy surgery after magnetoencephalography, with postsurgical follow-ups of up to Magnetoencephalography and ictal SPECT in 20 years. Sensitivity for interictal epileptic activity was patients with failed epilepsy surgery evaluated, in addition to concordance of localization with the consensus of presurgical workup on a lobar El Tahry, R; Wang, ZI; Thandar, A; Podkorytova, I; Krishnan, level. We evaluate magnetoencephalography charac- B; Tousseyn, S; Guiyun, W; Burgess, RC; Alexopoulos, AV teristics of patients who underwent epilepsy surgery versus patients who did not proceed to surgery. In Cliniques Universitaires Saint Luc, Av Hippocrate 10, 1200 operated patients, resection of magnetoencephalog- Brussels, Belgium; Institute of Neuroscience, Université raphy localizations were related to postsurgical seizure Catholique de Louvain, Av Mounier 53 & 73, 1200 Brussels, outcomes, including long-term results after several Belgium. years. In comparison, association of lesionectomy with seizure outcomes was analysed. Measures of diagnostic OBJECTIVE: Selected patients with intractable focal accuracy were calculated for magnetoencephalography epilepsy who have failed a previous epilepsy surgery resection and lesionectomy. Sensitivity for interictal can become seizure-free with reoperation. Preoperative epileptic activity was 72% with significant differences evaluation is exceedingly challenging in this cohort. We between temporal and extra-temporal lobe epilepsy. aim to investigate the diagnostic value of two noninva- Magnetoencephalography was concordant with the sive approaches, magnetoencephalography (MEG) and presurgical consensus in 51% and showed additional or ictal single-photon emission computed tomography

71 (SPECT), in patients with failed epilepsy surgery. METH- Importance: Literature on ictal magnetoencephalog- ODS: We retrospectively included a consecutive cohort raphy (MEG) in clinical practice and the relationship of patients who failed prior resective epilepsy surgery, to other modalities is limited because of the brevity of underwent re-evaluation including MEG and ictal routine studies. Objective: To investigate the utility SPECT, and had another surgery after the re-evaluation. and reliability of ictal MEG in the localization of the epi- The relationship between resection and localization leptogenic zone. Design, Setting, and Participants: from each test was determined, and their association A retrospective medical record review and prospective with seizure outcomes was analyzed. RESULTS: A total analysis of a novel ictal rhythm analysis method was of 46 patients were included; 21 (46%) were seizure- conducted at a tertiary epilepsy center with a wide free at 1-year followup after reoperation. Twenty-seven base of referrals for epilepsy surgery evaluation and (58%) had a positive MEG and 31 (67%) had a positive included consecutive cases of patients who experi- ictal SPECT. The resection of MEG foci was significantly enced epileptic seizures during routine MEG studies associated with seizure-free outcome (p = 0.002). Over- from March 2008 to February 2012. A total of 377 lap of ictal SPECT hyperperfusion zones with resection studies screened. Data were analyzed from November was significantly associated with seizure-free out- 2011 to October 2015. Main Outcomes and Measures: come in the subgroup of patients with injection time Presurgical workup and interictal and ictal MEG data ≤20 seconds(p = 0.03), but did not show significant were reviewed. The localizing value of using extended- association in the overall cohort (p = 0.46) although source localization of a narrow band identified visually all injections were ictal. Patients whose MEG and ictal at onset was analyzed. Results: Of the 44 included pa- SPECT were concordant on a sublobar level had a sig- tients, the mean (SD) age at the time of recording was nificantly higher chance of seizure freedom (p = 0.05). 19.3 (14.9) years, and 25 (57%) were male. The mean CONCLUSIONS: MEG alone achieved successful duration of recording was 51.2 minutes. Seizures were localization in patients with failed epilepsy surgery with provoked by known triggers in 3 patients and were a statistical significance. Only ictal SPECT with early spontaneous otherwise. Twenty-five patients (57%) had injection (≤20 seconds) had good localization value. 1 seizure, 6 (14%) had 2, and 13 (30%) had 3 or more. Sublobar concordance between both tests was sig- Magnetoencephalography single equivalent current nificantly associated with seizure freedom. SPECT can dipole analysis was possible in 29 patients (66%), of provide essential information in MEG-negative cases whom 8 (28%) had no clear interictal discharges. Sub- and vice versa. SIGNIFICANCE: Our results emphasize lobar concordance between ictal and interictal dipoles the importance of considering a multimodal presurgi- was seen in 18 of 21 patients (86%). Three patients cal evaluation including MEG and SPECT in all patients (7%) showed clear ictal MEG patterns without electro- with a previous failed epilepsy surgery. (29920428) encephalography changes. Ictal MEG dipoles correlated with the lobe of onset in 7 of 8 patients (88%) Keywords: Epilepsy; Failed surgery; MEG; SPECT who underwent intracranial electroencephalography evaluations. Reasons for failure to identify ictal dipoles Clin Neurophysiol (2019), Vol. 129, No. 8, pp. 1651-1657 included diffuse or poor dipolar ictal patterns, no MEG changes, and movement artifact. Resection of areas containing a minimum-norm estimate of a narrow Assessment of the Utility of Ictal band at onset, not single equivalent current dipole, was Magnetoencephalography in the Localization of the associated with sustained seizure freedom. Conclu- Epileptic Seizure Onset Zone sions and Significance: Ictal MEG data can provide reliable localization, including in cases that are difficult Alkawadri, R; Burgess, RC; Kakisaka, Y; to localize by other modalities. These findings support Mosher, JC; Alexopoulos, AV the use of extended-source localization for seizures recorded during MEG. (29889930) The Epilepsy Center at Cleveland Clinic Foundation, Cleve- land, Ohio.

72 JAMA Neurol (2019), Vol. 75, No. 10, pp. 1264-1272 teristics in epilepsy. This approach may allow for the definition of more specific markers of different epilepsy syndromes, and increased MEG-based resting-state Increased Functional MEG Connectivity as a functional connectivity seems to be a common feature Hallmark of MRI-Negative Focal and Generalized in MRI-negative epilepsy syndromes. (29766384) Epilepsy Keywords: Graph theory; Imaginary part of coherency; Li Hegner, Y; Marquetand, J; Elshahabi, A; Interictal; Resting state; Whole brain Klamer, S; Lerche, H; Braun, C; Focke, NK Brain Topogr (2019), Vol. 31, No. 5, pp. 863-874 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Hope- Seyler-Straße 3, 72076, Tübingen, Germany. yiwen.li@med. Magnetoencephalographic Spike Analysis in uni-tuebingen.de. Patients With Focal Cortical Dysplasia: What Defines a "Dipole Cluster"? ABSTRACT: Epilepsy is one of the most prevalent neurological diseases with a high morbidity. Accumu- Tanaka, N; Papadelis, C; Tamilia, E; AlHilani, M; lating evidence has shown that epilepsy is an arche- Madsen, JR; Pearl, PL; Stufflebeam, SM typical neural network disorder. Here we developed a non-invasive cortical functional connectivity analysis Athinoula A. Martinos Center for Biomedical Imaging, Mas- based on magnetoencephalography (MEG) to assess sachusetts General Hospital, Charlestown, Massachusetts. commonalities and differences in the network phe- Electronic address: [email protected]. notype in different epilepsy syndromes (non-lesional/ cryptogenic focal and idiopathic/genetic generalized BACKGROUND: The purpose of this study is to clarify epilepsy). Thirty-seven epilepsy patients with normal the source distribution patterns of magnetoencepha- structural brain anatomy underwent a 30-min resting lographic spikes correlated with postsurgical seizure- state MEG measurement with eyes closed. We only ana- free outcome in pediatric patients with focal cortical lyzed interictal epochs without epileptiform discharges. dysplasia. PATIENTS AND METHODS: Thirty-two The imaginary part of coherency was calculated as an patients with pathologically confirmed focal cortical indicator of cortical functional connectivity in five clas- dysplasia were divided into seizure-free and seizure- sical frequency bands. This connectivity measure was persistent groups according to their surgical outcomes computed between all sources on individually recon- based on Engel classification. In each patient, presurgi- structed cortical surfaces that were surface-aligned cal magnetoencephalography was reviewed. Dipole to a common template. In comparison to healthy sources of magnetoencephalographic spikes were controls, both focal and generalized epilepsy patients calculated according to a single dipole model. We ob- showed widespread increased functional connectivity tained the following quantitative indices for evaluating in several frequency bands, demonstrating the poten- dipole distribution: maximum distance over all pairs of tial of elevated functional connectivity as a common dipoles, standard deviation of the distances between pathophysiological hallmark in different epilepsy each dipole and the mean coordinate of all dipoles, types. Furthermore, the comparison between focal and average nearest neighbor distance, the rate of dipoles generalized epilepsies revealed increased network con- located within 10, 20, and 30 mm from the mean coor- nectivity in bilateral mesio-frontal and motor regions dinate, and the rate of dipoles included in the resec- specifically for the generalized epilepsy patients. Our tion. These indices were compared between the two study indicated that the surface-based normalization of patient groups. RESULTS: Average nearest neighbor MEG sources of individual brains enables the compari- distance was significantly smaller in the seizure-free son of imaging findings across subjects and groups on group than in the seizure-persistent group (P = 0.008). a united platform, which leads to a straightforward and The rates of dipoles located within 10, 20, and 30 mm effective disclosure of pathological network charac- from the mean coordinate were significantly higher in

73 the seizure-free group (P = 0.001, 0.001, 0.005, respec- one. Good surgical outcome was achieved in 11 out of tively). The maximum distance, standard deviation, 17 patients who proceeded to epilepsy surgery. Nine and resection rate of dipoles did not show a significant out of eleven had MEG clusters corresponding to the difference between the two groups. CONCLUSIONS: A resection area, and MEG findings would have allowed spatially restricted dipole distribution of magnetoen- for direct surgery (avoiding icEEG) in 2/11. Six patients cephalographic spikes is correlated with postsurgical had poor outcome including three patients where seizure-free outcomes in patients with focal cortical MEG would have significantly changed the outcome dysplasia. The distribution can be assessed by quantita- by modifying the resection margin. Magnetoencepha- tive indices that are clinically useful in the presurgical lography provided superior information in 3 patients evaluation of these patients. (29685607) where inadequate coverage precluded accurate mapping of the epileptogenic zone. CONCLUSION: In this Keywords: Epilepsy surgery; Equivalent current dipole; Fo- single center retrospective study, MEG would have cal cortical dysplasia; Magnetoencephalography; Source changed patient management, icEEG planning, and localization surgical outcome in a significant percentage of patients with NLRFE and should be considered in the presurgi- Pediatr Neurol (2019), Vol. 83, pp. 25-31 cal workup in those patients. (29253675)

Keywords: Epilepsy; Magnetoencephalograpy; Nonle- The clinical impact of integration of sional; Refractory magnetoencephalography in the presurgical workup for refractory nonlesional epilepsy Epilepsy Behav (2018), Vol. 79, pp. 34-41

Mohamed, IS; Bouthillier, A; Bérubé, A; Cossette, P; Finet, P; Saint-Hilaire, JM; Robert, M; Nguyen, DK Magnetoencephalographic imaging of ictal high-frequency oscillations (80-200 Hz) in IWK Health Center, Department of Pediatrics, Division of Neu- pharmacologically resistant focal epilepsy rology, Halifax, Canada; University of Alabama, Department of Pediatrics, Division of Neurology, Birmingham, AL, USA. Velmurugan, J; Nagarajan, SS; Mariyappa, N; Ravi, SG; Thennarasu, K; Mundlamuri, RC; Raghavendra, OBJECTIVE: For patients with nonlesional refractory K; Bharath, RD; Saini, J; Arivazhagan, A; Rajan, J; Ma- focal epilepsy (NLRFE), localization of the epileptogenic hadevan, A; Rao, MB; Satishchandra, P; Sinha, S zone is more arduous, and intracranial electroencephalography (EEG) (icEEG) is frequently required. Planning Department of Clinical Neurosciences, National Institute of for icEEG is dependent on combined data from multiple Mental Health and Neurosciences, Bangalore, India. noninvasive modalities. We report the negative impact of lack of integration of magnetoencephalography OBJECTIVE: Specificity of ictal high-frequency oscilla- (MEG) in the presurgical workup in NLRFE. METHODS: tions (HFOs) in identifying epileptogenic abnormality is Observational MEG case series involving 31 consecutive significant, compared to the spikes and interictal HFOs. patients with NLRFE in an academic epilepsy center. The objectives of the study were to detect and to local- For various reasons, MEG data were not analyzed in a ize ictal HFOs by magnetoencephalography (MEG) for timely manner to be included in the decision-making identifying the seizure onset zone (SOZ), evaluate the process. The presumed impact of MEG was assessed cortical excitability from preictal to ictal transition, and retrospectively. RESULTS: Magnetoencephalography establish HFO concordance rates with other modali- would have changed the initial management in 21/31 ties and postsurgical resection. METHODS: Sixty-seven (68%) had MEG results been available by reducing the patients with drug-resistant epilepsy had at least 1 number of intracranial electrodes, modifying their posi- spontaneous seizure each during MEG acquisition, and tion, allowing for direct surgery, canceling the intra- analysis was carried out on 20 seizures from 20 patients. cranial study, or providing enough evidence to justify Ictal MEG data were bandpass filtered (80-200 Hz) to

74 visualize, review, and analyze the HFOs co-occurring Keywords: MEG; MRI-negative epilepsy; MSI; SEEG; presur- with ictal spikes. Source montages were generated on gical evaluation both hemispheres, mean fast Fourier transform was computed on virtual time series for determining the Brain (2018), Vol. 139, No. 11, pp. 2935-2947 preictal to ictal spectral power transition, and source reconstruction was performed with sLORETA and beamformers. The concordance rates of ictal MEG HFOs (SOZ) Resective surgery for medically refractory was estimated with 4 reference epileptogenic regions. epilepsy using intraoperative MRI and functional RESULTS: In each subject, transient bursts of high-fre- neuronavigation: the Erlangen experience of 415 quency oscillatory cycles, distinct from the background patients activity, were observed in the periictal continuum. Time-frequency analysis showed significant spectral Roessler, K; Hofmann, A; Sommer, B; Grum- power surge (85-160 Hz) during ictal state (P < .05) mich, P; Coras, R; Kasper, BS; Hamer, HM; Blumcke, compared to preictal state, but there was no variation I; Stefan, H; Nimsky, C; Buchfelder, M in the peak HFO frequencies (P > .05) for each subgroup and at each source montage. HFO source localization Departments of 1 Neurosurgery. was consistent between algorithms (k = 0.857 ± 0.138), with presumed epileptogenic zone (EZ) comparable to OBJECTIVE: Intraoperative overestimation of resection other modalities. In patients who underwent surgery volume in epilepsy surgery is a well-known problem (n = 6), MEG HFO SOZ was concordant with the pre- that can lead to an unfavorable seizure outcome. sumed EZ and the surgical resection site (100%), and Intraoperative MRI (iMRI) combined with neuronaviga- all were seizure-free during follow-up. SIGNIFICANCE: tion may help surgeons avoid this pitfall and facilitate HFOs could be detected in the MEG periictal state, and visualization and targeting of sometimes ill-defined its sources were accurately localized. During preictal to heterogeneous lesions or epileptogenic zones and ictal transition, HFOs exhibited dynamic augmentation may increase the number of complete resections and in intrinsic epileptogenicity. Spatial overlap of ictal HFO improve seizure outcome. METHODS: To investigate sources was consistent with EZ determinants and the this hypothesis, the authors conducted a retrospec- surgical resection area. (29111591) tive clinical study of consecutive surgical procedures performed during a 10-year period for epilepsy in Keywords: ictal HFO; ictal MEG; seizure onset zone; source which they used neuronavigation combined with iMRI localization; surgical outcome and functional imaging (functional MRI for speech and motor areas; diffusion tensor imaging for pyramidal, Epilepsia (2018), Vol. 59, No. 1, pp. 190-202 speech, and visual tracts; and magnetoencephalography and electrocorticography for spike detection). Altogether, there were 415 patients (192 female and Correlating magnetoencephalography to stereo- 223 male, mean age 37.2 years; 41% left-sided lesions electroencephalography in patients undergoing and 84.9% temporal epileptogenic zones). The mean epilepsy surgery preoperative duration of epilepsy was 17.5 years. The most common epilepsy-associated pathologies Murakami, H; Wang, ZI; Marashly, A; Krishnan, B; Prayson, included hippocampal sclerosis (n = 146 [35.2%]), long- RA; Kakisaka, Y; Mosher, JC; Bulacio, J; Gonzalez-Martinez, term epilepsy-associated tumor (LEAT) (n = 67 [16.1%]), JA; Bingaman, WE; Najm, IM; Burgess, RC; Alexopoulos, AV cavernoma (n = 45 [10.8%]), focal cortical dysplasia (n = 31 [7.5%]), and epilepsy caused by scar tissue (n = 23 Department of Neurosurgery, Brain Research Institute, Ni- [5.5%]). RESULTS: In 11.8% (n = 49) of the surgeries, an igata University, Niigata, Japan. intraoperative second-look surgery (SLS) after incomplete resection verified by iMRI had to be performed. ABSTRACT: {}[[1]]<> (27567464) Of those incomplete resections, LEATs were involved most often (40.8% of intraoperative SLSs, 29.9% of

75 patients with LEAT). In addition, 37.5% (6 of 16) of Department of Pediatrics, Hokkaido University Graduate patients in the diffuse glioma group and 12.9% of the School of Medicine, North 15 West 7, Kita-ku, Sapporo, Japan. patients with focal cortical dysplasia underwent an SLS. Electronic address: [email protected]. Moreover, iMRI provided additional advantages during implantation of grid, strip, and depth electrodes and PURPOSE: This study focused on the characteristic enabled intraoperative correction of electrode position needle-like epileptic spikes of short duration and steep in 13.0% (3 of 23) of the cases. Altogether, an excellent shape seen on magnetoencephalography (MEG) in seizure outcome (Engel Class I) was found in 72.7% of patients diagnosed with focal cortical dysplasia (FCD) the patients during a mean follow-up of 36 months morphologically. We aimed to validate the analysis of (range 3 months to 10.8 years). The greatest likelihood MEG spike morphology as a noninvasive method of of an Engel Class I outcome was found in patients with identifying the presence and location of FCD. METH- cavernoma (83.7%), hippocampal sclerosis (78.8%), ODS: MEG was collected by 204-channel helmet- and LEAT (75.8%). Operative revisions that resulted shaped gradiometers. We analyzed MEG spike sources from infection occurred in 0.3% of the patients, from for 282 patients with symptomatic localization-related hematomas in 1.6%, and from hydrocephalus in 0.8%. epilepsy. MEG showed clustered equivalent current Severe visual field defects were found in 5.2% of the dipoles when superimposed on their three-dimension- patients, aphasia in 5.7%, and hemiparesis in 2.7%, and al-magnetic resonance images (MRI) in 85 patients. the total mortality rate was 0%. CONCLUSIONS: Neu- Fifty-seven patients were excluded from our study, ronavigation combined with iMRI was beneficial during because they had destructive brain lesions or an insuf- surgical procedures for epilepsy and led to favorable ficient number of spikes for statistical analysis. Twenty- seizure outcome with few specific complications. A eight patients (18 males, 10 females; aged 1-34 years) significantly higher resection volume associated with a were finally matched to our inclusion criteria, and higher chance of favorable seizure outcome was found, were categorized into three groups: FCD (7 patients), especially in lesional epilepsy involving LEAT or diffuse non-FCD (10 patients), and non-lesion (11 patients), glioma. (26926055) based on the MRI findings. We measured the duration, amplitude, and tilt manually for at least 15 spikes per Keywords: CM = cavernous malformation; DTI = diffu- patient, and compared the three groups using a one- sion tensor imaging; ECoG = electrocorticography; EZ = way analysis of variance, followed by the Tukey test epileptogenic zone; FCD = focal cortical dysplasia; FOV = when statistically significant (p < 0.05). In 17 patients field of view; HS = hippocampal sclerosis; LEAT = long- with visible MRI lesions, we investigated the correlation term epilepsy-associated tumor; MEG = magnetoenceph- between the depth of the lesion and the tilt using the alography; MPRAGE = magnetization-prepared rapid- Pearson product moment correlation. RESULTS: The acquisition gradient echo; drug-resistant epilepsy; fMRI = average spike duration was significantly shorter in the functional MRI; functional MRI; iMRI = intraoperative MRI; FCD and non-lesion groups than in the non-FCD group intraoperative MRI; neuronavigation; resective epilepsy (p < 0.05). The average amplitude was not significantly surgery; seizure outcome; surgical complications different between the three groups. The average spike tilt was significantly steeper in the FCD group than in Neurosurg Focus (2016), Vol. 40, No. 3, pp. E15 the non-FCD group (p = 0.0058). There was no significant difference between FCD and non-lesion patients in both duration and tilt. Our additional study revealed The presence of short and sharp MEG spikes implies a significant negative correlation between the depth focal cortical dysplasia of the lesion and the average tilt (p = 0.0009). SIGNIFI- CANCE: MEG epileptiform discharges of short duration Ueda, Y; Egawa, K; Ito, T; Takeuchi, F; Na- and steep tilt characterize FCD, especially when located kajima, M; Otsuka, K; Asahina, N; Takahashi, at the superficial neocortical gyrus. We speculate that K; Nakane, S; Kohsaka, S; Shiraishi, H this particular spike morphology results from the intrinsic epileptogenicity of FCD. Morphological analysis of MEG spikes can evaluate the etiology of epileptogenic

76 lesions and detect a strong, localized epileptogenic fo- individuals with MEG findings that were nonspecific to cus such as that typically observed in FCD. (26088897) or discordant with the region of resection (χ(2) = 26.4, p < 0.001). MEG reliability was comparable in patients Keywords: Epilepsy; Focal cortical dysplasia; Magnetoen- with or without localized scalp electroencephalography cephalography; Spike morphology; Waveform analysis (EEG), and overall, localizing MEG findings predicted seizure freedom with an odds ratio of 5.11 (95% confi- Epilepsy Res (2016), Vol. 114, pp. 141-6 dence interval [CI] 2.23-11.8). SIGNIFICANCE: MEG is a valuable tool for noninvasive interictal spike mapping in epilepsy surgery, including patients with nonlocal- Epileptogenic zone localization using ized findings receiving long-term EEG monitoring, and magnetoencephalography predicts seizure freedom localization of the epileptogenic zone using MEG is as- in epilepsy surgery sociated with improved seizure outcomes. (25921215)

Englot, DJ; Nagarajan, SS; Imber, BS; Ray- Keywords: Epilepsy surgery; Epileptogenic zone; Interictal gor, KP; Honma, SM; Mizuiri, D; Mantle, M; spike; Magnetic source imaging; Magnetoencephalogra- Knowlton, RC; Kirsch, HE; Chang, EF phy

UCSF Comprehensive Epilepsy Center, University of California, Epilepsia (2015), Vol. 56, No. 6, pp. 949-58 San Francisco, San Francisco, California, U.S.A.

OBJECTIVE: The efficacy of epilepsy surgery depends Magnetic source imaging in posterior cortex critically upon successful localization of the epilepto- epilepsies genic zone. Magnetoencephalography (MEG) enables noninvasive detection of interictal spike activity in Badier, JM; Bartolomei, F; Chauvel, P; Bénar, CG; Gavaret, M epilepsy, which can then be localized in three dimensions using magnetic source imaging (MSI) techniques. INSERM UMR 1106, Institut de Neurosciences des Systèmes, However, the clinical value of MEG in the presurgical 13005, Marseille, France. epilepsy evaluation is not fully understood, as studies to date are limited by either a lack of long-term seizure ABSTRACT: Posterior cortex epilepsies (PCE) are outcomes or small sample size. METHODS: We per- characterized by less satisfying postoperative results formed a retrospective cohort study of patients with than temporal lobe epilepsies and are thus challenging focal epilepsy who received MEG for interictal spike for non-invasive presurgical investigations. The objec- mapping followed by surgical resection at our institu- tive of this study was to evaluate the performance of tion. RESULTS: We studied 132 surgical patients, with magnetic source imaging (MSI) in PCE, validating the mean postoperative follow-up of 3.6 years (minimum results by the SEEG (stereoelectroencephalography) 1 year). Dipole source modeling was successful in 103 definition of irritative and epileptogenic zones (IZ and patients (78%), whereas no interictal spikes were seen EZ). Fourteen PCE surgery candidates were investi- in others. Among patients with successful dipole mod- gated using MSI and SEEG. LCMV (Linearly Constrained eling, MEG findings were concordant with and specific Minimum Variance) and MUSIC algorithms were used. to the following: (1) the region of resection in 66% IZ was quantified using a semi-automatic detection of of patients, (2) invasive electrocorticography (ECoG) interictal spikes. EZ was quantified using the epilepto- findings in 67% of individuals, and (3) the magnetic genicity index (EI) method that accounts for both the resonance imaging (MRI) abnormality in 74% of cases. propensity of a brain area to generate rapid discharges MEG showed discordant lateralization in ~5% of cases. and the time for this area to get involved in the sei- After surgery, 70% of all patients achieved seizure free- zure. EI values range from 0 (no epileptogenicity) to dom (Engel class I outcome). Whereas 85% of patients 1 (maximal epileptogenicity). Levels of concordance with concordant and specific MEG findings became between MSI and IZ, MSI and EZ were determined as seizure-free, this outcome was achieved by only 37% of follows: A = localized on MSI and SEEG for the site of

77 value 1 (IZ and EZ quantification), B = localized on MSI relationship between the MEG focus and the surgically and SEEG for a part of the IZ or a structure involved resected regions were correlated with the epilepsy in the EZ (without the maximal value 1), C = localized surgery outcome. RESULTS: Thirty-six of the 50 pa- on MSI and not SEEG, D = localized on SEEG and not tients with positive MEG and ICEEG findings underwent MSI, E = localized on MSI and SEEG, discordant for site. epilepsy surgery, and 27 (75%) of the patients had an Five PCE cases were characterized by focal IZ, nine by anatomical concordance of MEG/ICEEG. Among the distributed IZ between several distant brain areas. MSI patients with concordant MEG/ICEEG, the seizure free allowed to determinate IZ in 4/5 focal IZ cases. In case outcome rate was significantly higher compared to the of distributed IZ, levels of concordance were A (2 cases), discordant group [18/27 (66.7%) patients concordant B (4 cases) and D (3 cases). In most distributed cases, vs. 1/9 (11.1%) patients discordant (p<0.006)]. Nineteen MSI allowed to localize only a part of the IZ. Medial (53%) of the 36 patients had complete resection when temporal involvement in the IZ was frequent (9/12 the MEG focus overlapped with the resection area, and cases) and not evidenced by MSI. The brain area that 15 (79%) of these 19 patients became seizure-free fol- demonstrated the maximal value of EI was shown by lowing surgery (p<0.001); 17 (47%) of the 36 patients MSI in four out of five (80 %) focal IZ cases, in two out of had an MEG focus that was not completely resected nine (22 %) distributed cases. MSI results depend on IZ (the MEG foci of 7 patients partially overlapped the characteristics. A distributed IZ organization presents resection areas, and 10 patients had MEG foci that were difficulties for MSI and highlights the need for further in a different area from the resection area), and 13/17 methodological approaches. (25352165) (76.5%) patients had seizure recurrences (p<0.001). CONCLUSIONS: Both the anatomical concordance of Brain Topogr (2015), Vol. 28, No. 1, pp. 162-71 MEG/ICEEG and the complete resection of the MEG foci significantly increased the chance of seizure-free outcomes following epilepsy surgery. (25241140) The correlation of magnetoencephalography to intracranial EEG in localizing the epileptogenic Keywords: Cluster dipoles, Intractable epilepsy; Epilepsy zone: a study of the surgical resection outcome surgery outcome; Intracranial EEG; Magnetoencephalog- raphy Almubarak, S; Alexopoulos, A; Von-Podewils, F; Wang, ZI; Kakisaka, Y; Mosher, JC; Bulacio, J; Epilepsy Res (2015), Vol. 108, No. 9, pp. 1581-90 González-Martínez, J; Bingaman, W; Burgess, RC

Cleveland Clinic Epilepsy Center, Neurological Institute, Cleve- Clinical relevance of source location in frontal lobe land, OH, USA; MEG Lab, National Neurosciences Institute, epilepsy and prediction of postoperative long-term King Fahad Medical City, Riyadh, Saudi Arabia; Pediatric outcome Neurology Division, Pediatrics Department, University of Saskatchewan, Saskatoon, Canada. Electronic address: Mu, J; Rampp, S; Carrette, E; Roessler, K; Sommer, B; [email protected]. Schmitt, FC; De Tiège, X; Hamer, H; Boon, P; Pauli, E; Bluemcke, I; Zhou, D; Buchfelder, M; Stefan, H OBJECTIVES: To evaluate the agreement between magnetoencephalography (MEG) and intracranial Department of Neurology, University Hospital Erlangen, electroencephalography (ICEEG) results, to determine Erlangen, Germany; Department of Neurology, West China the characteristics that lead to concordance, and to Hospital, Sichuan University, Chengdu, Sichuan, PR China. assess how these factors relate to favorable epilepsy Electronic address: [email protected]. surgery outcome. MATERIALS: This retrospective study reviewed 50 patients who had positive MEG findings PURPOSE: To evaluate the value of magnetoencepha- and ICEEG recordings between 2008 and 2010. The lography (MEG) source localization in localization of anatomical concordance between MEG and ICEEG epileptic activities and predicting surgical outcome in recordings, the features of the MEG focus, and the frontal lobe epilepsies (FLE). METHODS: Forty-six pa-

78 tients with presurgical MEG evaluation and intractable FLE surgery (28 male patients) were analyzed retrospectively with a mean follow-up of 5 years. Dipole analysis was PURPOSE: To investigate the utility of magnetic performed for MEG source imaging (MSI). The local- source imaging (MSI) and ictal single photon emission ization of dipole clusters in relation to the dominant computed tomography (SPECT), each compared with hemisphere, lesions, resection cavity and functional intracranial electroencephalography (EEG) (ICEEG), cortex were analyzed. The predictive value of MSI in to localize the epileptogenic zone (EZ) and predict respect to clinical outcome with long-term postopera- epilepsy surgery outcome in patients with nonlesional tive follow up was evaluated. RESULTS: Interictal focal neocortical focal epilepsy. METHODS: Studied were epileptic activities were found in 82.6% (38/46) patients 14 consecutive patients with nonlesional neocortical with monofocal activity 81.6% (31/38) and multifocal epilepsy who underwent presurgical evaluation includ- activities 18.4% (7/38). Seizure free rate was 47.9% at ing ICEEG, positive MSI, and localizing subtraction Ictal the mean follow-up of 5.0 ± 4.0 years (median 11.5, SPECT coregistered to MRI (SISCOM) analysis. Follow-up range 2-57). Seizure recurrence mainly occurred in after epilepsy surgery was ≥ 24 months. ICEEG, MSI, and the first 1 year after surgery. In the monofocal epilep- SPECT results were classified using a sublobar classifica- tic activity group, 58.1% (18/31) of the patients were tion. KEY FINDINGS: Of 14 patients, 6 (42.9%) became seizure free, predicitng postoperative seizure freedom seizure-free after surgery. Sublobar ICEEG focus was better than multifocal localization 0% (0/7) (p=0.028). completely resected in 11 patients; 5 (45.5%) of them Dipole clusters were completely resected in 70.9% of became seizure- free. Concordance of ICEEG and MSI monofocal activity patients, which had higher seizure and complete focus resection was found in 5 (35.7%) free rates compared to partial resection (p=0.002). In patients; 80% of them became seizure-free. Sublobar patients with surgery in the dominant hemisphere, ICEEG-MSI concordance and complete focus resection seizure control was less likely (p=0.006). CONCLUSION: significantly increased the chance of seizure freedom MSI contributes to the clinical prediction of postopera- after epilepsy surgery (p = 0.038). In contrast, of the 6 tive outcome in FLE patients. MSI may non-invasively patients (42.9%) with concordant ICEEG and SISCOM disclose early epileptogenic lesions, pointing to a and complete focus resection, only 66.7% became resectable lesion, and it then facilitates shortcut route seizure-free (p = 0.138). Assuming concordant results, of presurgical evaluation. (24854960) the additive value to ICEEG alone for localizing the EZ is higher with ICEEG-MSI (odds ratio 14) compared Keywords: Focal cortical dysplasia; Frontal lobe epilepsy; to ICEEG-SISCOM (odds ratio 6). SIGNIFICANCE: This Magnetoencephalography; Postoperative outcome; study shows that combination of MSI and/or SISCOM Seizure freedom with ICEEG is useful in the presurgical evaluation of patients with nonlesional neocortical epilepsy. Con- Seizure (2015), Vol. 23, No. 7, pp. 553-9 cordant test results of either MSI or SISCOM with ICEEG provide useful additive information for that provided by ICEEG alone to localize the EZ in this most challeng- Magnetic source imaging and ictal SPECT in MRI- ing group of patients. When sublobar concordance negative neocortical epilepsies: additional value with ICEEG is observed, MSI is more advantageous and comparison with intracranial EEG compared to SISCOM in predicting seizure-free epilepsy surgery outcome. (23106128) Schneider, F; Irene Wang, Z; Alexopoulos, AV; Almubarak, S; Kakisaka, Y; Jin, K; Nair, D; Mosher, JC; Najm, IM; Burgess, RC

Cleveland Clinic Epilepsy Center, Neurological Institute, Cleve- land, Ohio, USA. [email protected]

79 Epilepsia (2013), Vol. 54, No. 2, pp. 359-69 Department of Neurology and Clinical Neurophysiology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands. Magnetic source imaging in non-lesional neocortical epilepsy: additional value and ABSTRACT: Magnetoencephalography (MEG) is used in comparison with ICEEG the presurgical work-up of patients with focal epilepsy. In particular, localization of MEG interictal spikes may Schneider, F; Alexopoulos, AV; Wang, Z; Almubarak, S; guide or replace invasive electroencephalography Kakisaka, Y; Jin, K; Nair, D; Mosher, JC; Najm, IM; Burgess, RC monitoring that is required in difficult cases. From literature, it is not clear which MEG source localization Cleveland Clinic Epilepsy Center, Neurological Institute, 9500 method performs best in this clinical setting. Therefore, Euclid Avenue, Desk S-51, Cleveland, OH 44195, USA. felix. we applied three source localization methods to the [email protected] same data from a large patient group for which a gold standard, interictal spikes as identified in electrocor- OBJECTIVE: To investigate the utility of magnetic ticography (ECoG), was available. The methods used source imaging (MSI) for localizing the epileptogenic were multiple signal classification (MUSIC), Synthetic zone (EZ) and predicting epilepsy surgery outcome in Aperture Magnetometry kurtosis [SAM(g2)], and stan- non-lesional neocortical focal epilepsy (NLNE) patients. dardized low-resolution electromagnetic tomography. METHODS: Data from 18 consecutive patients with MEG and ECoG data from 38 patients with refractory NLNE who underwent presurgical evaluation includ- focal epilepsy were obtained. Results of the three ing intracranial electroencephalography (ICEEG) and source localization methods applied to the interictal MSI were studied. Follow-up after epilepsy surgery was MEG data were assigned to predefined anatomical ≥24 months. Intracranial electroencephalography and regions. Interictal spikes as identified in ECoG were also MSI results were classified using a sublobar classifica- assigned to these regions. Identified regions by each tion. RESULTS: Sublobar ICEEG focus was completely MEG method were compared to ECoG. Sensitivity and resected in 15 patients; seizure-free rate was 60%. positive predictive value (PPV) of each MEG method Eight patients showed sublobar-concordant ICEEG/ were calculated. All three MEG methods showed a MSI results and complete resection of both regions; similar overall correlate with ECoG spikes, but the seizure-free rate was 87.5%. Seizure-free rate in cases methods differ in which regions they detect. The choice not matching these criteria was only 30% (p=0.013). of the inverse model thus has an unexpected influence CONCLUSIONS: Magnetoencephalography is a useful on the results of magnetic source imaging. Combining tool to localize the EZ and determine the site of surgical inverse methods and seeking consensus can be used resection in NLNE patients. When sublobar concor- to improve specificity at the cost of some sensitivity. dance with ICEEG is observed, MSI increases the predic- Combining MUSIC with SAM(g2) gives the best results tive value for a seizure-free epilepsy surgery outcome (sensitivity = 38% and PPV = 82%). (22431346) in these patients. (22542998)

Epilepsy Behav (2012), Vol. 24, No. 2, pp. 234-40

Inverse modeling in magnetic source imaging: Comparison of MUSIC, SAM(g2), and sLORETA to interictal intracranial EEG de Gooijer-van de Groep, KL; Lei- jten, FS; Ferrier, CH; Huiskamp, GJ

80 Keywords: interictal; intracranial EEG monitoring; inverse lepsy (p≤0.001). These changes had a clear impact on modeling; irritative zone; magnetoencephalography; clinical management in 13% of all patients. CONCLU- source localization SION: MSI is a clinically relevant, non-invasive neuroimaging technique for the presurgical evaluation of Hum Brain Mapp (2014), Vol. 34, No. 9, pp. 2032-44 patients with refractory focal epilepsy and, particularly, in patients with presumed extratemporal and undetermined localisation epilepsy. (22262910) Clinical added value of magnetic source imaging in the presurgical evaluation of refractory focal J Neurol Neurosurg Psychiatry (2012), Vol. 83, No. 4, pp. epilepsy 417-23

De Tiège, X; Carrette, E; Legros, B; Vonck, K; Op de Beeck, M; Bourguignon, M; Massager, N; Da- Evaluation of postoperative sharp waveforms vid, P; Van Roost, D; Meurs, A; Lapere, S; Deb- through EEG and magnetoencephalography laere, K; Goldman, S; Boon, P; Van Bogaert, P Lee, JW; Tanaka, N; Shiraishi, H; Milligan, TA; Dworetzky, Magnetoencephalography Unit, Laboratoire de Car- BA; Khoshbin, S; Stufflebeam, SM; Bromfield, EB tographiefonctionnelle du Cerveau, Université Libre de Bruxelles(ULB), Brussels, Belgium. [email protected] Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. [email protected] OBJECTIVE: This prospective, bicentre, blinded, inten- tion to treat study assessed the clinical added value of ABSTRACT: EEGs obtained after craniotomy are dif- magnetic source imaging (MSI) in the presurgical evalu- ficult to read because of a breach rhythm consisting of ation of patients with refractory focal epilepsy (RFE). unfiltered sharply contoured physiologic waveforms METHODS: 70 consecutive patients with RFE (42 men; that can mimic interictal epileptiform discharges. Mag- mean age 31.5 years, range 3-63) from two Belgian netoencephalography (MEG) is less affected by the skull centres were prospectively included. All patients under- breach. The postcraniotomy EEG and MEG scans of 20 went conventional non-invasive presurgical evaluation patients were reviewed by two experienced electroen- (CNIPE) and a whole head magnetoencephalography cephalographers. Larger interrater variability was found recording (Elekta Neuromag). Equivalent current for EEG as compared with MEG. Review of patients who dipoles corresponding to interictal epileptiform dis- had postoperative seizures suggested that EEG was charges (IED) were fitted in the patients' spherical head more sensitive but less specific than MEG in detecting model and coregistered on their MRI to produce MSI interictal epileptiform discharges. Furthermore, several results. Results of CNIPE were first discussed blinded to instances of sharp waveforms that were difficult to the MSI results in respective multidisciplinary epilepsy evaluate on EEG were found to be more easily interpre- surgery meetings to determine the presumed locali- table on MEG. MEG may also help determine whether sation of the epileptogenic zone and to set surgical asymmetries in physiologic rhythms on EEG result or additional presurgical plans. MSI results were then from the skull defect or are pathologic. MEG should be discussed multidisciplinarily. MSI influence on the initial considered as an adjunctive study in patients with a management plan was assessed. RESULTS: Based on breach rhythm for evaluation of interictal epileptiform CNIPE, 21 patients had presumed extratemporal epi- discharges and cerebral dysfunction. (20087209) lepsy, 38 had presumed temporal epilepsy and 11 had undetermined localisation epilepsy. MSI showed IED in 52 patients (74.5%) and changed the initial management in 15 patients (21%). MSI related changes were significantly more frequent in patients with presumed extratemporal or undetermined localisation epilepsy compared with patients with presumed temporal epi-

81 J Clin Neurophysiol (2010), Vol. 27, No. 1, pp. 7-11 Epilepsia (2009), Vol. 50, No. 10, pp. 2242-8

Lateralizing language with magnetic source Magnetic source imaging for the surgical evaluation imaging: validation based on the Wada test of electroencephalography-confirmed secondary bilateral synchrony in intractable epilepsy Doss, RC; Zhang, W; Risse, GL; Dickens, DL Chang, EF; Nagarajan, SS; Mantle, Minnesota Epilepsy Group, P.A., St Paul, Minnesota 55102, M; Barbaro, NM; Kirsch, HE USA. [email protected] Department of Neurological Surgery, University of California, PURPOSE: Magnetoencephalography (MEG)/mag- San Francisco, 505 Parnassus Avenue, Room M779, San Fran- netic source imaging (MSI) is a noninvasive functional cisco, California 94143, USA. [email protected] neuroimaging procedure used to localize language- specific regions in the brain. The Wada test, or in- OBJECT: Routine scalp electroencephalography (EEG) tracarotid amobarbital procedure (IAP), is the gold cannot always distinguish whether generalized epi- standard in determining speech/language lateraliza- leptiform discharges are the result of primary bilateral tion for presurgical planning, although it is invasive synchrony or secondary bilateral synchrony (SBS) from and associated with morbidity. The purpose of this a focal origin; this is an important distinction because study is to provide further validation on the use of MSI the latter may be amenable to resection. Whole-head for presurgical language lateralization by comparing magnetoencephalography (MEG) has superior spatial results against the IAP. METHODS: The sample con- resolution compared with traditional EEG, and can po- sisted of 35 patients with epilepsy and/or brain tumor tentially elucidate seizure foci in challenging epilepsy undergoing presurgical evaluation at the Minnesota cases in which patients are undergoing evaluation for Epilepsy Group. All patients received both an IAP and surgery. METHODS: Sixteen patients with medically MSI to determine hemispheric language dominance. intractable epilepsy in whom SBS was suspected were For MSI, a 148-channel MEG system was used to record referred for magnetic source (MS) imaging. All patients activation of language-specific cortex by an auditory had bilateral, synchronous, widespread, and most often word-recognition task. RESULTS: The MSI and IAP were generalized spike-wave discharges on scalp EEG stud- concordant in determining language in the hemi- ies, plus some other clinical (for example, seizure semi- sphere to be treated in 86% of the cases with sensitivity ology) or MR imaging feature (for example, focal lesion) and specificity values of 80% and 100%, respectively. suggesting focal onset and hence possible surgical CONCLUSIONS: The results from this study are consis- candidacy. The MS imaging modality is the combina- tent with prior research findings comparing functional tion of whole-head MEG and parametric reconstruc- neuroimaging procedures to the IAP in determining tion of corresponding electrical brain sources. An MEG language lateralization in presurgical patients. The and simultaneous EEG studies were recorded with a current study provides an important replication and 275-channel whole-head system. Single-equivalent support for Papanicolaou et al.'s findings in 2004 using current dipoles were estimated from the MEG data, and a consecutive clinical sample from a different institu- dipole locations and orientations were superimposed tion. An unusually high rate of atypical IAP language on patients' MR images. RESULTS: The MS imaging cases in this sample and differences between the two studies revealed focal dipole clusters in 12 (75%) of the procedures are believed to explain the noted discrep- 16 patients, of which a single dipole cluster was identi- ancies. MSI is a viable noninvasive alternative to the IAP fied in 7 patients (44%). Patient age, seizure type, dura- in the presurgical determination of language lateralization of disease, video-EEG telemetry, and MR imaging tion. (19674060) results were analyzed to determine factors predictive of having clusters revealed on MS imaging. Of these factors, only focal MR imaging anatomical abnormalities were associated with dipole clusters (chi-square test, p

82 = 0.03). Selective resections (including the dipole clus- tion, including 17 where MSI changed the decision. ter) in 7 (87%) of 8 patients resulted in seizure-free or Additional electrodes in 4 patients covered the correct: rare seizure outcomes (Engel Classes I and II). CONCLU- hemisphere in 3, lobe in 3, and sublobar ictal onset SIONS: Magnetic source imaging may provide noninva- zone in 1. MSI avoided contralateral electrodes in 2, sive anatomical and neurophysiological confirmation of who both localized on ICEEG. MSI added information localization in patients in whom there is a suspicion of to ICEEG in 1. CONCLUSION: Magnetic source imaging SBS (based on clinical or MR imaging data), especially (MSI) provided nonredundant information in 33% of in those with an anatomical lesion. Identification of a patients. In those who have undergone surgery to date, focal seizure origin has significant implications for both MSI added useful information that changed treatment resective and nonresective treatment of intractable in 6 (9%), without increasing complications. MSI has epilepsy. (19575574) benefited 21% who have gone to surgery. (18809834)

J Neurosurg (2010), Vol. 111, No. 6, pp. 1248-56 Neurology (2008), Vol. 71, No. 13, pp. 990-6

Influence of magnetic source imaging for planning Magnetoencephalography is more successful for intracranial EEG in epilepsy screening and localizing frontal lobe epilepsy than electroencephalography Sutherling, WW; Mamelak, AN; Thyerlei, D; Male- eva, T; Minazad, Y; Philpott, L; Lopez, N Ossenblok, P; de Munck, JC; Co- lon, A; Drolsbach, W; Boon, P Huntington Medical Research Institutes, 10 Pico, Pasadena, CA 91105, USA. [email protected] Epilepsy Centre Kempenhaeghe, Heeze, The Netherlands. os- [email protected] BACKGROUND: Magnetic source imaging (MSI) is used routinely in epilepsy presurgical evaluation and in PURPOSE: The diagnosis of frontal lobe epilepsy may mapping eloquent cortex for surgery. Despite increas- be compounded by poor electroclinical localization, ing use, the diagnostic yield of MSI is uncertain, with due to distributed or rapidly propagating epilepti- reports varying from 5% to 35%. To add benefit, a form activity. This study aimed at developing opti- diagnostic technique should influence decisions made mal procedures for localizing interictal epileptiform from other tests, and that influence should yield better discharges (IEDs) of patients with localization related outcomes. We report preliminary results of an ongoing, epilepsy in the frontal lobe. To this end the localization long-term clinical study in epilepsy, where MSI changed results obtained for magnetoencephalography (MEG) surgical decisions. METHODS: We determined whether and electroencephalography (EEG) were compared MSI changed the surgical decision in a prospective, systematically using automated analysis procedures. blinded, crossover-controlled, single-treatment, ob- METHODS: Simultaneous recording of interictal EEG servational case series. Sixty-nine sequential patients and MEG was successful for 18 out of the 24 patients diagnosed with partial epilepsy of suspected neocorti- studied. Visual inspection of these recordings revealed cal origin had video-EEG and imaging. All met criteria IEDs with varying morphology and topography. Cluster for intracranial EEG (ICEEG). At a surgical conference, analysis was used to classify these discharges on the a decision was made before and after presentation of basis of their spatial distribution followed by equivalent MSI. Cases where MSI altered the decision were noted. dipole analysis of the cluster averages. The locations RESULTS: MSI gave nonredundant information in 23 of the equivalent dipoles were compared with the patients (33%). MSI added ICEEG electrodes in 9 (13%) location of the epileptogenic lesions of the patient or, and changed the surgical decision in another 14 (20%). if these were not visible at MRI with the location of the Based on MSI, 16 patients (23%) were scheduled for interictal onset zones identified by subdural electro- different ICEEG coverage. Twenty-eight have gone to encephalography. RESULTS: Generally IEDs were more ICEEG, 29 to resection, and 14 to vagal nerve stimula- abundantly in MEG than in the EEG recordings. Fur-

83 thermore, the duration of the MEG spikes, measured from the onset till the spike maximum, was in most patients shorter than the EEG spikes. In most patients, distinct spike subpopulations were found with clearly different topographical field maps. Cluster analysis of MEG spikes followed by dipole localization was successful (n = 14) for twice as many patients as for EEG source analysis (n = 7), indicating that the localizability of interictal MEG is much better than of interictal EEG. CONCLUSIONS: The automated procedures developed in this study provide a fast screening method for identifying the distinct categories of spikes and the brain areas responsible for these spikes. The results show that MEG spike yield and localization is superior compared with EEG. This finding is of importance for the diagnosis and preoperative evaluation of patients with frontal lobe epilepsy. (17662061)

Epilepsia (2008), Vol. 48, No. 11, pp. 2139-49

84 Migraine be relative to the pain-module mechanism in migraine brains. Thus, our data improved the apprehension of the cortical disorder of migraine in the high-frequency Abnormality of visual neuromagnetic activation in domain. (30651072) female migraineurs without aura between attacks Keywords: Magnetoencephalography; Migraine; Visual Zhou, ZY; Yu, YW; Wu, D; Liu, HX; Xiang, evoked magnetic fields J; Wu, T; Chen, QQ; Wang, XS J Headache Pain (2019), Vol. 20, No. 1, pp. 7 The Department of Neurology, Nanjing Brain Hospital, Nanjing Medical University, Guang Zhou Road 264, Nanjing, Jiangsu, 210029, People's Republic of China. Abnormal functional connectivity under somatosensory stimulation in migraine: a multi- OBJECTIVE: The present study aimed to preliminary frequency magnetoencephalography study explore the abnormal neuromagnetic activation in female migraine patients between attacks using magne- Ren, J; Xiang, J; Chen, Y; Li, F; Wu, T; Shi, J toencephalography (MEG) and pattern reversed visual evoked magnetic fields (PR-VEFs). METHODS: A total of Department of Neurology, The Affiliated Brain Hospital of 17 female migraine subjects during the headache-free Nanjing Medical University, Nanjing, 210029, Jiangsu, China. phase and 17 healthy controls (HC) were studied using a 275-channel magnetoencephalography (MEG) sys- BACKGROUND: Although altered neural networks tem. In this study, visual evoked magnetic fields (VEFs) have been demonstrated in recent MEG (magnetoen- were generated by a pattern-reversal check as the cephalography) research in migraine patients during visual stimulus. The average of 100 VEFs was evolved by resting state, it is unknown whether this alteration different half patterns were averaged and used to ana- can be detected in task-related networks. The present lyze waveform, spectrum, and source location within study aimed to investigate the abnormalities of the two frequency ranges (5-100 and 100-1000 Hz), respec- frequency-specific somatosensory-related network in tively. RESULTS: In migraine subjects, the latency of migraine patients by using MEG. METHODS: Twenty- second peak of VEFs (VIIs) showed significant prolonga- two migraineurs in the interictal phase and twenty-two tions when compared with HC. On the sensor level, the sex- and age-matched healthy volunteers were studied cortical spectral power in migraine subjects was similar using a whole-head magnetoencephalography (MEG) to that of HC in the 5-100 Hz range and was lower in the system. Electrical stimuli were delivered alternately to 1000-1000 Hz range. There was a decrement of source the median nerve on the right wrists of all subjects. strength in the visual cortex in migraine patients when MEG data were analyzed in a frequency range of compared to HC in both the 5-100 and 100-1000 Hz fre- 1-1000 Hz in multiple bands. RESULTS: The brain net- quency range. Moreover, there was a similar odds of ac- work patterns revealed that the patients with migraine tivation in 5-100 and 100-1000 Hz frequency ranges in exhibited remarkably increased functional connectiv- the area beyond the primary visual cortex between the ity in the high-frequency (250-1000 Hz) band between two groups. In addition, no correlation was observed the sensory cortex and the frontal lobe. The results of between clinical data (intensity of headache, head- quantitative analysis of graph theory showed that the ache-history duration, the frequency of headaches) and patients had (1) an increased degree of connectivity MEG results. CONCLUSIONS: The findings presented in the theta (4-8 Hz), beta (13-30 Hz) and gamma (30- in the current study, suggested that interictal cortical 80 Hz) bands; (2) an increased connectivity strength in activation following a visual stimulus was low in female the beta (13-30 Hz) and gamma (30-80 Hz) bands; (3) an migraine patients. The low pre-activation was detected increased path length in the beta (13-30 Hz), gamma in the visual cortex using VEF and MEG in both low and (30-80 Hz) and ripple (80-250 Hz) bands; and (4) an high-frequency band. Our results add to the existing increased clustering coefficient in the theta (4-8 Hz), evidence that cortical interictal excitability change may beta (13-30 Hz) and gamma (30-80 Hz) bands. CONCLU-

85 SIONS: The results indicate that migraine is associated responses and gating ratios of cSII and iSII did not differ with aberrant connections from the somatosensory among the groups. Conclusions Somatosensory gating cortex to the frontal lobe. The frequency-specific is altered in migraine and associated with headache increases in connectivity in terms of strength, path chronification. Further studies must clarify if this abnor- length and clustering coefficients support the notion mal sensory modulation is a true gating deficit inde- that migraineurs have elevated cortical networks. This pendent of low preexcitation level. (28540738) alteration in functional connectivity may be involved in somatosensory processing in migraine patients and Keywords: Sensory gating; chronic migraine; magnetoen- may contribute to understanding migraine patho- cephalography (MEG); migraine; primary somatosensory physiology and to providing convincing evidence for a cortex spatially targeted migraine therapy. (30626318) Cephalalgia (2019), Vol. 38, No. 4, pp. 744-753 Keywords: Functional connectivity; Magnetoencephalog- raphy; Migraine; Multi-frequency; Somatosensory Quantitative neuromagnetic signatures of aberrant J Headache Pain (2019), Vol. 20, No. 1, pp. 3 cortical excitability in pediatric chronic migraine

Leiken, KA; Xiang, J; Curry, E; Fujiwara, H; Rose, Somatosensory gating is altered and DF; Allen, JR; Kacperski, JE; O'Brien, HL; Kab- associated with migraine chronification: A bouche, MA; Powers, SW; Hershey, AD magnetoencephalographic study Division of Neurology, Cincinnati Children's Hospital Medical Hsiao, FJ; Wang, SJ; Lin, YY; Fuh, JL; Ko, Center, 3333 Burnet Avenue, MLC 2015, Cincinnati, OH, 45220, YC; Wang, PN; Chen, WT USA. [email protected].

1 Brain Research Center, National Yang-Ming University, BACKGROUND: Reports have suggested that abnor- Taipei, Taiwan. mal cortical excitability may be associated with acute migraines. The present study quantitatively assesses ABSTRACT: Background Brain excitability is changed the degree of cortical excitability in chronic migraine in migraine but not fully characterized yet. This study as compared to acute migraine and healthy controls explored if somatosensory gating is altered in migraine within the pediatric population. METHODS: We inves- and linked to migraine chronification. Methods Paired tigated 27 children suffering from chronic migraine, 27 electrical stimuli were delivered to the left index fingers children suffering from acute migraine, and 27 healthy of 21 patients with migraine without aura (MO), 22 pa- controls using a magnetoencephalography (MEG) sys- tients with chronic migraine (CM), and 36 controls. The tem, recording at a sampling rate of 6000 Hz. All groups first and second responses to the paired stimuli were were age-matched and gender-matched. Neuromag- obtained from the contralateral primary (cSI), contra- netic brain activation was elicited by a finger-tapping lateral secondary (cSII) and ipsilateral secondary (iSII) motor task. The spatiotemporal and spectral signatures somatosensory cortices to compute the gating ratios of MEG data within a 5-2884 Hz range were analyzed (second vs. first response strengths). Results The first using Morlet wavelet transform and beamformer analy- and second cSI responses and gating ratios differed ses. RESULTS: Compared with controls, the chronic in all groups ( p < 0.05); the responses were typically migraine group showed (1) significantly prolonged smaller in the MO and CM groups. The cSI gating ratio latencies of movement-elicited magnetic fields (MEFs) increased as a continuum across controls (0.73 ± 0.04, between 5 and 100 Hz; (2) increased spectral power be- p < 0.001), MO (0.83 ± 0.04) to CM (0.97 ± 0.06) and was tween 100 and 200 Hz, and between 2200 and 2800 Hz; higher in CM vs. controls ( p < 0.001). When MO and and (3) a higher likelihood of neuromagnetic activation CM were combined, cSI gating ratio was associated in the ipsilateral sensorimotor cortices, supplementary with headache frequency (r = 0.418, p = 0.005). Paired motor area, and occipital regions. Compared with acute

86 migraine group, chronic migraine patients showed (1) significantly higher odds of having strong MEFs after 150 ms; and (2) significantly higher odds of having neuromag- two frequency ranges (55-90 Hz, p < 0.001) and (90-200 netic activation from the deep brain areas. CONCLU- Hz, p < 0.004). But the power value showed no signifi- SIONS: Results demonstrated that chronic migraine cantly differences between control and migraines in all subjects were not only different from the healthy con- frequency ranges (p > 0.05). All the clinical characteris- trols, but also different from acute migraine subjects. tics had no significant correlation with aberrant brain The chronification of migraines may be associated with activity. CONCLUSIONS: The results demonstrated elevated cortical excitability, delayed and spread neural that migraine subjects in resting state had significantly response, as well as aberrant activation from deep brain aberrant ictal brain activity that can be measured with areas. (27113076) neuromagnetic imaging techniques. The findings may facilitate the development of new therapeutic strate- Keywords: Deep brain sources; High frequency oscilla- gies in migraine treatment via alterations in cortical tions; Magnetoencephalography (MEG); Migraine; Pediat- excitability with TMS and other medications in the ric; Wavelet transform future. (25968099)

J Headache Pain (2016), Vol. 17, pp. 46 J Headache Pain (2015), Vol. 16, pp. 525

Resting state brain activity in patients with Abnormal cortical activation in females with acute migraine: a magnetoencephalography study migraine: a magnetoencephalography study

Liu, H; Ge, H; Xiang, J; Miao, A; Tang, L; Ge, HT; Liu, HX; Xiang, J; Miao, AL; Tang, L; Guan, Wu, T; Chen, Q; Yang, L; Wang, X QS; Wu, T; Chen, QQ; Yang, L; Wang, XS

The Department of Neurology, Nanjing Brain Hospital, The Department of Neurology, Nanjing Brain Hospital, Nan- Nanjing Medical University, Guang Zhou Road 264, Nanjing, jing Medical University, Nanjing, Jiangsu, PR China. Jiangsu, 210029, China, [email protected]. OBJECTIVE: The objective of this study was to inves- BACKGROUND: Recent advances in migraine research tigate functional abnormalities of the brain in females have shown that the cerebral cortex serves a primary with migraine using magnetoencephalography (MEG) role in the pathogenesis of migraine. Since aberrant and a finger-tapping task. METHODS: Twenty-nine brain activity in migraine can be noninvasively de- female patients with migraine (aged 16-40years) and tected with magnetoencephalography (MEG), The age- and gender-matched healthy controls were stud- object of this study was to investigate the resting state ied with an MEG system at a sampling rate of 6000Hz. cortical activity differences between migraineurs and MEG recordings were performed during an attack in controls and its related clinical characteristics. METH- migraineurs with and without aura. Neuromagnetic ODS: Twenty-two subjects with an acute migraine and brain activation was elicited by a finger-tapping task. twenty-two age- and gender-matched controls were The latency and amplitude of neuromagnetic re- studied using MEG. MEG recordings were recorded sponses were analyzed with averaged waveforms in 120 seconds during the headache attack. Analyze the frequency range of 5-100Hz. The Morlet wavelet MEG signals from low (1-4 Hz) to high (200-1000 and beamformers were used to analyze the spectral Hz)-frequency ranges. RESULTS: In comparison with and spatial signatures of MEG data from subjects in two the controls, brain activity in migraine subjects was frequency ranges of 5-100 and 100-1000Hz. RESULTS: significantly different from that of the controls both in The latency of motor-evoked magnetic fields evoked

87 by finger movement was significantly prolonged in mi- was elicited by a standardized, validated finger-tapping graineurs as compared with controls. Neuromagnetic task. Low-frequency brain activation (1~50 Hz) was spectral power in the motor cortex in migraineurs was analyzed with waveform measurements and high- significantly elevated. There were significantly higher frequency oscillations (65-150 Hz) were analyzed with odds of activation in 5-30, 100-300 and 500-700Hz wavelet-based beamforming. MEG waveforms showed frequency ranges in the ipsilateral primary motor corti- that the ictal latency of low-frequency brain activation ces and the supplementary motor area in migraineurs was significantly delayed as compared with controls, as compared with controls. CONCLUSIONS: Neuro- while the interictal latency of brain activation was magnetic signal abnormalities in this study suggest similar to that of controls. The ictal amplitude of low- cortical hyperexcitability in females with migraine frequency brain activation was significantly increased during migraine attack, which could be measured as compared with controls, while the interictal ampli- and analyzed with MEG signal in a frequency range of tude of brain activation was similar to that of controls. 5-1000Hz. SIGNIFICANCE: These findings may help to The ictal source power of high-frequency oscillations identify neurophysiological biomarkers for studying was significantly stronger than that of the controls, mechanisms of migraine, and may facilitate to develop while the interictal source power of high-frequency new therapeutic strategies for migraine by alterations oscillations was significantly weaker than that of con- in cortical excitability. (24854723) trols. The results suggest that aberrant low-frequency brain activation in migraine during a headache attack Keywords: Magnetic source imaging (MSI); Magnetoen- returned to normal interictally. However, high-frequen- cephalography (MEG); Migraine cy oscillations changed from ictal hyper-activation to interictal hypo-activation. Noninvasive assessment of Clin Neurophysiol (2015), Vol. 126, No. 1, pp. 170-9 cortical abnormality in migraine with MEG opens a new window for developing novel therapeutic strategies for childhood migraine by maintaining a balanced cortical Neuromagnetic abnormality of motor cortical excitability. (24386250) activation and phases of headache attacks in childhood migraine PLoS One (2014), Vol. 8, No. 12, pp. e83669

Xiang, J; Degrauw, X; Korman, AM; Allen, JR; O'Brien, HL; Kabbouche, MA; Powers, SW; Hershey, AD Aberrant neuromagnetic activation in the motor cortex in children with acute migraine: a Division of Neurology, Cincinnati Children's Hospital Medical magnetoencephalography study Center, Cincinnati, Ohio, United States of America ; Depart- ment of Pediatrics, University of Cincinnati, College of Medi- Guo, X; Xiang, J; Wang, Y; O'Brien, H; Kab- cine, Cincinnati, Ohio, United States of America. bouche, M; Horn, P; Powers, SW; Hershey, AD

ABSTRACT: The cerebral cortex serves a primary role Department of Human Anatomy and Histology-Embryology, in the pathogenesis of migraine. This aberrant brain Xi'an Jiaotong University, School of Medicine, Xi'an, Shaanxi, activation in migraine can be noninvasively detected People's Republic of China. with magnetoencephalography (MEG). The objective of this study was to investigate the differences in mo- ABSTRACT: Migraine attacks have been shown to in- tor cortical activation between attacks (ictal) and pain terfere with normal function in the brain such as motor free intervals (interictal) in children and adolescents or sensory function. However, to date, there has been with migraine using both low- and high-frequency no clinical neurophysiology study focusing on the mo- neuromagnetic signals. Thirty subjects with an acute tor function in children with migraine during headache migraine and 30 subjects with a history of migraine, attacks. To investigate the motor function in children while pain free, were compared to age- and gender- with migraine, twenty-six children with acute migraine, matched controls using MEG. Motor cortical activation meeting International Classification of Headache Dis-

88 orders criteria and age- and gender-matched healthy remitted from CM to EM after topiramate treatment. children were studied using a 275-channel magnetoen- RESULTS: In total, 10 CM patients remitted to EM after cephalography system. A finger-tapping paradigm was treatment. In the follow-up study of these patients dur- designed to elicit neuromagnetic activation in the mo- ing the interictal stage, the P100m at block 1 decreased tor cortex. Children with migraine showed significantly in amplitude from 53.6 ± 6.6 nAm before remission prolonged latency of movement-evoked magnetic to 43.0 ± 5.1 nAm (p = 0.028), and the responses at fields (MEF) during finger movement compared with subsequent blocks switched from habituation (ampli- the controls. The correlation coefficient of MEF latency tude block 30 < block 1 before remission, p = 0.011) to and age in children with migraine was significantly dif- potentiation (block 2 > block 1, p = 0.028). CONCLU- ferent from that in healthy controls. The spectral power SION: The pattern of P100m responses to consecutive of high gamma (65-150 Hz) oscillations during finger stimulation changes with the transition from CM to EM. movement in the primary motor cortex is also signifi- Visual cortex plasticity might be a potential biomarker cantly higher in children with migraine than in controls. reflecting clinical remission of CM. (22529191) The alteration of responding latency and aberrant high gamma oscillations suggest that the developmental Cephalalgia (2012), Vol. 32, No. 7, pp. 537-43 trajectory of motor function in children with migraine is impaired during migraine attacks and/or developmentally delayed. This finding indicates that childhood Identification of abnormal neuromagnetic migraine may affect the development of brain function signatures in the motor cortex of adolescent and result in long-term problems. (23185541) migraine

PLoS One (2013), Vol. 7, No. 11, pp. e50095 Wang, X; Xiang, J; Wang, Y; Pardos, M; Meng, L; Huo, X; Korostenskaja, M; Pow- ers, SW; Kabbouche, MA; Hershey, AD Visual cortex excitability and plasticity associated with remission from chronic to episodic migraine MEG Center, Department of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA. Chen, WT; Wang, SJ; Fuh, JL; Ko, YC; Lee, YC; Hämäläinen, MS; Lin, YY OBJECTIVE: To investigate the functional abnormalities of the motor cortices in children with migraine Neurological Institute, Taipei Veterans General Hospital, using magnetoencephalography (MEG) and a finger- Taipei, Taiwan, Republic of China. tapping task. BACKGROUND: Cortical hyperexcitability has been reported in adults with migraine using OBJECTIVE: Previous magnetoencephalographic MEG. Many children with migraine report difficulty (MEG) studies showed different P100m (where 'm' with motor functioning. There is no report on motor- denotes the magnetic counterpart of P100 in conven- evoked magnetic activation in children with migraine tional visual evoked potentials) responses between using MEG and the latest signal processing methods. episodic migraine (EM) and chronic migraine (CM) METHODS: Ten children with migraine (all female, 9 interictally. This study investigated the changes of right-handed and 1 left-handed, aged 13-17 years) visual P100m in CM patients who remitted to EM from and 10 age- and gender-matched healthy children CM after treatment. METHODS: At baseline, 25 patients were studied with a 275-channel MEG system. After with CM were studied interictally. For each patient, 30 hearing a unilateral, randomly presented sound cue sequential blocks of 50 P100m responses were ob- (500 Hz, 30 milliseconds square tone), each subject tained by MEG. Sub-averaged amplitudes at blocks 2, 9, immediately performed a brisk index finger tapping 16, 23 and 30 were further compared with that at block with either the right or the left index finger. The audi- 1 to assess response habituation or potentiation (i.e. tory stimuli consisted of 200 trials of square tone, 100 significant decrease or increase at either block vs block trials per ear, randomly distributed. The latency and 1). The same study was repeated in those patients who amplitude of neuromagnetic responses were analyzed

89 90 with averaged waveforms. Neuromagnetic sources were estimated using synthetic aperture magnetometry (SAM). SAM images were normalized for each participant ment than peri-ictal patients in the second (28.1 +/- for group comparison. RESULTS: In comparison with 38.3% vs. -3.2 +/- 19.2%), fourth (22.7 +/- 31.2% vs. -5.7 healthy children, children with migraine had prolonged +/- 22.3%) and fifth (20.5 +/- 30.4% vs. -10.8 +/- 30.1%) latency of motor-evoked magnetic response in the blocks (P < 0.05). There was no significant difference right hemispheres during left finger movement (62.33 at other check sizes or between peri-ictal patients and +/- 34.55 milliseconds vs 34.9 +/- 17.29 milliseconds, P controls. In conclusion, there may be peri-ictal normal- < .05). In addition, children with migraine had stron- ization of visual cortical excitability changes in migraine ger activation in the motor cortex during right finger that is dependent on the spatial frequency of the movement (8097.46 +/- 5168.99 vs 4697.54 +/- 3194.74, stimuli and reflects a dynamic modulation of cortical P < .05). CONCLUSIONS: The results suggest that there activities. (19558536) are neurophysiological changes in the motor cortices of children with migraine that can be measured with neu- Cephalalgia (2009), Vol. 29, No. 11, pp. 1202-11 romagnetic imaging techniques. The findings expand the ability to study the cerebral mechanisms of migraine using MEG and may facilitate the development of new therapeutic strategies in migraine treatment via alterations in cortical excitability. (20487034)

Headache (2010), Vol. 50, No. 6, pp. 1005-16

Peri-ictal normalization of visual cortex excitability in migraine: an MEG study

Chen, WT; Wang, SJ; Fuh, JL; Lin, CP; Ko, YC; Lin, YY

Institute of Neuroscience, National Yang-Ming University, Taipei, 112 Taiwan.

ABSTRACT: To delineate if the change in cortical excitability persists across migraine attacks, visual evoked magnetic fields (VEF) were measured in patients with migraine without aura during the interictal (n = 26) or peri-ictal (n = 21) periods, and were compared with 30 healthy controls. The visual stimuli were checkerboard reversals with four different check sizes (15', 30', 60' and 120'). For each check size, five sequential blocks of 50 VEF responses were recorded to calculate the percentage change of the P100m amplitude in the second to the fifth blocks in comparison with the first block. At check size 120', interictal patients showed a larger amplitude increment than controls [28.1 +/- 38.3% (s.d.) vs. 8.7 +/- 21.3%] in the second block and a larger incre-

91 92 Multiple Sclerosis Keywords: Multiple Sclerosis; cerebral blood flow; functional MRI; magnetoencephalography; neurovascular coupling; visual function Neurovascular Coupling During Visual Stimulation in Multiple Sclerosis: A MEG-fMRI Study Neuroscience (2019), Vol. 403, pp. 54-69

Stickland, R; Allen, M; Magazzini, L; Singh, KD; Wise, RG; Tomassini, V A reduced somatosensory gating response in individuals with multiple sclerosis is related to Cardiff University Brain Research Imaging Centre (CUBRIC), walking impairment Cardiff University School of Psychology, Maindy Road, Cardiff CF24 4HQ, UK. Arpin, DJ; Gehringer, JE; Wilson, TW; Kurz, MJ

ABSTRACT: The process of neurovascular coupling Department of Physical Therapy, Munroe-Meyer Institute, ensures that increases in neuronal activity are fed University of Nebraska Medical Center, Omaha, Nebraska. by increases in cerebral blood flow. Evidence suggests that neurovascular coupling may be impaired in ABSTRACT: When identical stimuli are presented in Multiple Sclerosis (MS) due to a combination of brain rapid temporal succession, neural responses to the sec- hypoperfusion, altered cerebrovascular reactivity and ond stimulation are often weaker than those observed oxygen metabolism, and altered levels of vasoac- for the first. This phenomenon is termed sensory gating tive compounds. Here, we tested the hypothesis that and is believed to be an adaptive feature that helps neurovascular coupling is impaired in MS. We char- prevent higher-order cortical centers from being flood- acterized neurovascular coupling as the relationship ed with unnecessary information. Recently, sensory between changes in neuronal oscillatory power within gating in the somatosensory system has been linked to the gamma frequency band (30-80 Hz), as measured by deficits in tactile discrimination. Additionally, studies magnetoencephalography (MEG), and associated he- have linked poor tactile discrimination with impaired modynamic changes (blood oxygenation level depen- walking and balance in individuals with multiple scle- dent, BOLD, and cerebral blood flow, CBF) as measured rosis (MS). In this study, we examine the neural basis of by functional MRI. We characterized these responses in somatosensory gating in patients with MS and healthy the visual cortex in 13 MS patients and in 10 matched controls and assess the relationship between somato- healthy controls using a reversing checkerboard sensory gating and walking performance. We used stimulus at five visual contrasts. There were no signifi- magnetoencephalography to record neural responses cant group differences in visual acuity, P100 latencies, to paired-pulse electrical stimulation applied to the occipital gray matter (GM) volumes and baseline CBF. right posterior tibial nerve. All participants also walked However, in the MS patients we found a significant re- across a digital mat, which recorded their spatiotempo- duction in peak gamma power, BOLD and CBF respons- ral gait kinematics. Our results showed the amplitude es. There were no significant differences in neurovascu- of the response to the second stimulation was sharply lar coupling between groups, in the visual cortex. Our reduced only in controls, resulting in a significantly results suggest that neuronal and vascular responses reduced somatosensory gating in the patients with MS. are altered in MS. Gamma power reduction could be No group differences were observed in the amplitude an indicator of GM dysfunction, possibly mediated by of the response to the first stimulation nor the latency GABAergic changes. Altered hemodynamic responses of the neural response to either the first or second stim- confirm previous reports of a vascular dysfunction in ulation. Interestingly, the altered somatosensory gating MS. Despite altered neuronal and vascular responses, responses were correlated with aberrant spatiotempo- neurovascular coupling appears to be preserved in ral gait kinematics in the patients with MS. These results MS, at least within the range of damage and disability suggest that inhibitory GABA circuits may be altered in studied here. (29580963) patients with MS, which impacts somatosensory gating

93 and contributes to the motor performance deficits seen gest that a disruption of gray matter network topology in these patients. (28724780) is important to understand alterations in functional connectivity in MS as regional gray matter fails to take Keywords: cortical inhibition; magnetoencephalography; into account the inherent connectivity structure of the paired-pulse; sensory gating brain. (25053254)

J Neurophysiol (2018), Vol. 118, No. 4, pp. 2052-2058 Keywords: functional connectivity; functional networks; magnetic resonance imaging; magnetoencephalography; multiple sclerosis; structural covariance networks Disruption of structural and functional networks in long-standing multiple sclerosis Hum Brain Mapp (2015), Vol. 35, No. 12, pp. 5946-61

Tewarie, P; Steenwijk, MD; Tijms, BM; Daams, M; Balk, LJ; Stam, CJ; Uitdehaag, BM; Polman, CH; Geurts, JJ; Cognitive and clinical dysfunction, altered MEG Barkhof, F; Pouwels, PJ; Vrenken, H; Hillebrand, A resting-state networks and thalamic atrophy in multiple sclerosis Department of Neurology, Neuroscience Campus Am- sterdam, VU University Medical Center, Amsterdam, The Tewarie, P; Schoonheim, MM; Stam, CJ; van der Meer, Netherlands. ML; van Dijk, BW; Barkhof, F; Polman, CH; Hillebrand, A

ABSTRACT: Both gray matter atrophy and disrup- Department of Neurology, VU University Medical Center, tion of functional networks are important predictors Amsterdam, The Netherlands. [email protected] for physical disability and cognitive impairment in multiple sclerosis (MS), yet their relationship is poorly ABSTRACT: The relation between pathological findings understood. Graph theory provides a modality invari- and clinical and cognitive decline in Multiple Sclerosis ant framework to analyze patterns of gray matter remains unclear. Here, we tested the hypothesis that morphology and functional coactivation. We investi- altered functional connectivity could provide a miss- gated, how gray matter and functional networks were ing link between structural findings, such as thalamic affected within the same MS sample and examined atrophy and white matter lesion load, and clinical their interrelationship. Magnetic resonance imaging and cognitive dysfunction. Resting-state magnetoen- and magnetoencephalography (MEG) were performed cephalography recordings from 21 MS patients and in 102 MS patients and 42 healthy controls. Gray matter 17 gender- and age matched controls were projected networks were computed at the group-level based onto atlas-based regions-of-interest using beamform- on cortical thickness correlations between 78 regions ing. Average functional connectivity was computed for across subjects. MEG functional networks were com- each ROI and literature-based resting-state networks puted at the subject level based on the phase-lag index using the phase-lag index. Structural measures of between time-series of regions in source-space. In MS whole brain and thalamic atrophy and lesion load were patients, we found a more regular network organiza- estimated from MRI scans. Global analyses showed tion for structural covariance networks and for func- lower functional connectivity in the alpha2 band and tional networks in the theta band, whereas we found higher functional connectivity in the beta band in a more random network organization for functional patients with Multiple Sclerosis. Additionally, alpha2 networks in the alpha2 band. Correlation analysis band functional connectivity was lower for the patients revealed a positive association between covariation in in two resting-state networks, namely the default thickness and functional connectivity in especially the mode network and the visual network. Higher beta theta band in MS patients, and these results could not band functional connectivity was found in the default be explained by simple regional gray matter thickness mode network and in the temporo-parietal network. measurements. This study is a first multimodal graph Lower alpha2 band functional connectivity in the visual analysis in a sample of MS patients, and our results sug- network was related to lower thalamic volumes. Beta

94 band functional connectivity correlated positively with higher bi-parietally (theta-band) but markedly lower disability scores, most prominently in the default mode left temporally (upper alpha- and beta-band). Lower network, and correlated negatively with cognitive per- cognitive performance correlated to decreased nodal formance in this network. These findings illustrate the centrality over left temporal (lower alpha-band) and relationship between thalamic atrophy, altered func- right temporal (beta-band) sensors, and to increased tional connectivity and clinical and cognitive dysfunc- nodal centrality over right parieto-temporal sensors tion in MS, which could serve as a bridge to understand (beta-band). Network changes were most pronounced how neurodegeneration is associated with altered in male patients. CONCLUSIONS: Partial functional functional connectivity and subsequently clinical and disconnection of the temporal regions was associated cognitive decline. (23935983) with cognitive dysfunction in MS; increased centrality in parietal hubs may reflect a shift from temporal PLoS One (2014), Vol. 8, No. 7, pp. e69318 to possibly less efficient parietal processing. To better understand patterns and dynamics of these network changes, longitudinal studies are warranted, also ad- Cognitive dysfunction in early multiple sclerosis: dressing the influence of gender. (22848712) altered centrality derived from resting-state functional connectivity using magneto- PLoS One (2013), Vol. 7, No. 7, pp. e42087 encephalography

Hardmeier, M; Schoonheim, MM; Geurts, JJ; Hil- Thalamocortical sensorimotor circuit in lebrand, A; Polman, CH; Barkhof, F; Stam, CJ multiple sclerosis: an integrated structural and electrophysiological assessment Department of Clinical Neurophysiology, VU University Medi- cal Center, Amsterdam, The Netherlands. mhardmeier@uhbs. Dell'Acqua, ML; Landi, D; Zito, G; Zappasodi, F; Lu- ch poi, D; Rossini, PM; Filippi, MM; Tecchio, F

BACKGROUND: Cognitive dysfunction in multiple scle- Neurologia Clinica, Universitá Campus Bio-Medico, Roma, rosis (MS) is frequent. Insight into underlying mecha- Italy. nisms would help to develop therapeutic strategies. OBJECTIVE: To explore the relationship of cognitive ABSTRACT: Demyelination and axonal damage are performance to patterns of nodal centrality derived pathologic hallmarks of multiple sclerosis (MS), leading from magneto-encephalography (MEG). METHODS: to loss of neuronal synchronization, functional discon- 34 early relapsing-remitting MS patients (median EDSS nection amongst brain relays, and clinical sequelae. To 2.0) and 28 age- and gender-matched healthy controls investigate these properties, the primary component (HC) had a MEG, a neuropsychological assessment and of the sensorimotor network was analyzed in mildly structural MRI. Resting-state functional connectivity disabled Relapsing-Remitting MS patients without was determined by the synchronization likelihood. sensory symptoms at the time of the investigation. Eigenvector Centrality (EC) was used to quantify for By magnetoencephalography (MEG), the recruitment each sensor its connectivity and importance within the pattern within the primary sensory (S1) and motor (M1) network. A cognition-score was calculated, and normal- areas was estimated through the morphology of the ized grey and white matter volumes were determined. early components of somatosensory evoked magnetic EC was compared per sensor and frequency band be- fields (SEFs), after evaluating the S1 responsiveness tween groups using permutation testing, and related to to sensory inputs from the contralateral arm. In each cognition. RESULTS: Patients had lower grey and white hemisphere, network recruitment properties were matter volumes than HC, male patients lower cognitive correlated with ispilateral thalamus volume, estimated performance than female patients. In HC, EC distribu- by morphometric techniques upon high-resolution 3D tion showed highest nodal centrality over bi-parietal structural magnetic resonance images (MRI). S1 activa- sensors ("hubs"). In patients, nodal centrality was even tion was preserved, whereas SEF morphology was strik-

95 ingly distorted in MS patients, marking a disruption of lesion load. A local index of ICC in a circumscribed brain primary somatosensory network patterning. An unbal- primary area was altered in mildly disabled RR-multiple ance of S1-M1 dynamic recruitment was documented sclerosis patients, also in absence of any impairment of and correlated with the thalamic volume reduction in central sensory conduction. In conclusion, the diffuse the left hemisphere. These findings support the model damage influencing the multi-nodal network subtend- of MS as a disconnection syndrome, with major sus- ing complex cerebral functions also affects intrinsic ceptibility to damage experienced by nodes belonging cortical connectivity. The S1 ICC index is proposed as a to more frequently recruited and highly specialized highly sensitive and simple-to-test functional measure networks. (20162580) for the evaluation of intra-cortical synchronization mechanisms in RR-multiple sclerosis. (18502782) Hum Brain Mapp (2011), Vol. 31, No. 10, pp. 1588-600 Brain (2008), Vol. 131, No. Pt 7, pp. 1783-92

Intra-cortical connectivity in multiple sclerosis: a neurophysiological approach

Tecchio, F; Zito, G; Zappasodi, F; Dell' Acqua, ML; Landi, D; Nardo, D; Lupoi, D; Rossini, PM; Filippi, MM

1Istituto Scienze Unità MEG, Dipartimento di Neuroscienze, Ospedale Fatebenefratelli, Isola Tiberina, 00186 Rome, Italy. [email protected]

ABSTRACT: Multiple sclerosis is an autoimmune disease predominantly affecting the white matter of the CNS, causing--among functional sequelae-cortico- -cortical partial or total disconnection. Since functional connectivity linking cerebral regions is reliably reflected by synchronization of their neuronal firing, in this study an electrophysiological parameter measured by magnetoencephalography was used to quantify an intracortical connectivity (ICC) index focused on the primary somatosensory cortical areas (S1). Twenty-one patients affected by mild (Extended Disability Scale Score, median 1,5) relapsing-remitting (RR) multiple sclerosis in the remitting phase without clinically evident sensory impairment were evaluated. Three dimensional MRI was used to quantify the lesion load, discriminating black hole and non-black hole portions, normalized by individual brain volumes. When matched with a control population, multiple sclerosis patients showed a reduced ICC combined with the complete loss of the finger-dependent functional specialization in S1 cortex of the dominant hemisphere. No association was found between ICC impairment and disease duration, or pro- longation of the central sensory conduction time, presence of spinal cord lesions and ongoing disease modifying therapy. The ICC index slightly correlated with the

96 Neoplasms

Histopathologic and Clinical Correlation of Aberrant Keywords: Accumulated source imaging; Brain activities; Neuromagnetic Activities with Low to High Glioma; Magnetoencephalography; Multiple frequency Frequency of Gliomas analysis

Yang, K; Chen, J; Xiang, J; Liu, H; Zou, Y; Kan, W; Liu, Y; Li, L World Neurosurg (2019), Vol. 123, pp. e609-e620

Department of Neurosurgery, the Affiliated Brain Hospital of Nanjing Medical University, Nanjing, China. Cognitive functioning and functional brain networks in postoperative WHO grade I OBJECTIVE: To quantify the low- to high-frequency meningioma patients range of abnormal brain activities and assess the histopathologic and clinical correlation in patients with van Nieuwenhuizen, D; Douw, L; Klein, M; Peerdeman, glioma. METHODS: Twenty-five patients with glioma SM; Heimans, JJ; Reijneveld, JC; Stam, CJ; Hillebrand, A and 20 healthy controls were examined with a magnetoencephalography (MEG) system. MEG data collected Department of Neurology, Amsterdam University Medical in 6 frequency bands, including 1-4 Hz, 4-8 Hz, 8-12 Hz, Centers, Location VUmc, Amsterdam, The Netherlands. Dvan- 12-30 Hz, 30-45 Hz, and 55-75 Hz, were analyzed by [email protected]. neuropathology to assess neuromagnetic signatures of glioma grade. RESULTS: Compared with controls, INTRODUCTION: Meningioma patients often have patients with glioma showed greatly altered brain subtle cognitive deficits that might be attributed to the activities in 4-8 Hz, 8-12 Hz, and 55-75 Hz. Magnetic tumor itself, to surgical treatment, or to the occurrence source power of brain activities in 4-8 Hz and 55-75 of seizures and their treatment. Magnetoencepha- Hz in patients with high-grade gliomas significantly lography (MEG) analysis of resting-state functional differed from that in patients with low-grade gliomas. networks (RSNs) could help to understand the neuro- The magnitude of source power of brain activities physiological basis of cognitive impairment in these in 4-8 Hz and 55-75 Hz had marked correlation with patients. We explored the correlation between RSN the grading of gliomas in histopathological analyses. functional connectivity and topology of functional CONCLUSIONS: The degree of neuromagnetic source networks on the one hand, and cognition on the other abnormality is a potential biomarker for noninvasive hand in WHO grade I meningioma patients. METHODS: assessment of glioma grade. Because MEG tests can be Twenty adult WHO grade I meningioma patients who performed noninvasively and preoperatively, MEG may had undergone tumor resection, as well as 20 healthy play an important role in clinical biopsies and surgical matched controls, were included. Neuropsychologi- planning for patients with brain gliomas in the future. cal assessment was done through a standardized test (30529596) battery. MEG data were recorded, and projected to the anatomical space of the Automated Anatomical Labeling atlas. Functional connectivity (PLI), within the default mode network (DMN) and the bilateral frontoparietal networks were correlated to cognitive performance. Minimum spanning tree (MST) characteristics were correlated with cognitive functioning. RESULTS: Compared to healthy controls, meningioma patients had lower working memory capacity (p = 0.037). Within the patient group, lower working memory performance

97 was associated with lower DMN connectivity and a tively assessed by immunohistochemistry. Peritumor lower maximum MST degree in the theta band (resp. and global oscillatory brain activity was then compared p = 0.044 and p = 0.003). CONCLUSIONS: This study between different levels of NLGN3 expression with shows that cognitive functioning is correlated with Kruskal-Wallis tests. Cox proportional hazards analyses functional connectivity in the default mode network were performed to estimate the predictive value of and hub-pathology in WHO grade I meningioma oscillatory brain activity for PFS. RESULTS: Patients with patients. Future longitudinal studies are needed to low expression of NLGN3 had lower levels of global os- corroborate these findings and to further investigate cillatory brain activity than patients with higher NLGN3 the pathophysiology of cognitive deficits and possible expression (P < 0.001). Moreover, lower peritumor (haz- changes in functional brain networks in meningioma ard ratio 2.17, P = 0.008) and global oscillatory brain ac- patients. (30219943) tivity (hazard ratio 2.10, P = 0.008) predicted longer PFS. CONCLUSIONS: Lower levels of peritumor and global Keywords: Cognitive functioning; Functional connectivity; oscillatory brain activity are related to lower NLGN3 Magnetoencephalography; Meningioma; Minimum span- expression and longer PFS, corroborating preclinical ning tree; Resting-state networks research. This study highlights the important interplay between macroscopically measured brain activity and J Neurooncol (2019), Vol. 140, No. 3, pp. 605-613 glioma progression, and may lead to new therapeutic interventions in diffuse glioma patients. (30094719)

Oscillatory brain activity associates with Keywords: Glioma; Magnetoencephalography; NLGN3; neuroligin-3 expression and predicts progression Neurophysiology; Tumor progression free survival in patients with diffuse glioma J Neurooncol (2018), Vol. 140, No. 2, pp. 403-412 Derks, J; Wesseling, P; Carbo, EWS; Hillebrand, A; van Dellen, E; de Witt Hamer, PC; Klein, M; Schenk, GJ; Geurts, JJG; Reijneveld, JC; Douw, L Localized N20 Component of Somatosensory Evoked Magnetic Fields in Frontoparietal Department of Anatomy & Neurosciences, VU University Brain Tumor Patients Using Noise-Normalized Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Approaches Netherlands. Elaina, NS; Malik, AS; Shams, WK; Badrud- INTRODUCTION: Diffuse gliomas have local and global din, N; Abdullah, JM; Reza, MF effects on neurophysiological brain functioning, which are often seen as 'passive' consequences of the tumor. Center for Intelligent Signal & Imaging Research (CISIR), However, seminal preclinical work has shown a promi- Department of Electrical & Electronic Engineering, University nent role for neuronal activity in glioma growth: medi- Technology PETRONAS, Bandar Seri Iskandar, 31750, Tronoh, ated by neuroligin-3 (NLGN3), increased neuronal activ- Perak, Malaysia. ity causes faster glioma growth. It is unclear whether the same holds true in patients. Here, we investigate PURPOSE: To localize sensorimotor cortical activation whether lower levels of oscillatory brain activity relate in 10 patients with frontoparietal tumors using quan- to lower NLGN3 expression and predict longer pro- titative magnetoencephalography (MEG) with noise- gression free survival (PFS) in diffuse glioma patients. normalized approaches. MATERIAL AND METHODS: METHODS: Twenty-four newly diagnosed patients with Somatosensory evoked magnetic fields (SEFs) were diffuse glioma underwent magnetoencephalography elicited in 10 patients with somatosensory tumors and and subsequent tumor resection. Oscillatory brain in 10 control participants using electrical stimulation of activity was approximated by calculating broadband the median nerve via the right and left wrists. We local- power (0.5-48 Hz) of the magnetoencephalography. ized the N20m component of the SEFs using dynamic NLGN3 expression in glioma tissue was semi-quantita- statistical parametric mapping (dSPM) and standard-

98 ized low-resolution brain electromagnetic tomography their role in the maintenance of cognition in individu- (sLORETA) combined with 3D magnetic resonance als with processing deficits is unclear. We examined imaging (MRI). The obtained coordinates were com- gamma oscillations using magnetoencephalography pared between groups. Finally, we statistically evalu- (MEG) in children undergoing CRT to test whether ated the N20m parameters across hemispheres using gamma characteristics can be a signature of cognitive non-parametric statistical tests. RESULTS: The N20m impairment in this population. We collected resting- sources were accurately localized to Brodmann area 3b state data as well as data from baseline and active in all members of the control group and in seven of the periods during two visual-motor reaction time tasks of patients; however, the sources were shifted in three pa- varying cognitive loads from 18 healthy children and 20 tients relative to locations outside the primary somato- patients. We found that only high-gamma oscillations sensory cortex (SI). Compared with the affected (tumor) (60-100 Hz), and not low-gamma oscillations (30-59 hemispheres in the patient group, N20m amplitudes Hz), showed significant group differences in absolute and the strengths of the current sources were signifi- power levels. Overall, compared with healthy children, cantly lower in the unaffected hemispheres and in both patients showed the following: (1) lower total high- hemispheres of the control group. These results were gamma (60-100 Hz) power during the resting state, as consistent for both dSPM and sLORETA approaches. well as during task-related baseline and performance CONCLUSION: Tumors in the sensorimotor cortex lead measures; (2) no change in gamma reactivity to increas- to cortical functional reorganization and an increase in es in cognitive load; and (3) slower processing speeds N20m amplitude and current-source strengths. Noise- both inside and outside MEG. Our findings show that normalized approaches for MEG analysis that are inte- high-gamma oscillations are disrupted in children after grated with MRI show accurate and reliable localization treatment for a brain tumor. The temporal dynamic of of sensorimotor function. (28116447) the high-gamma response during information processing may index cognitive impairment in humans with Keywords: Brodmann area 3b; Frontoparietal tumor; neurological injury. (24966381) Magnetoencephalography; Noise-normalized approach; Somatosensory evoked magnetic fields Keywords: brain tumor; children; cranial radiation therapy; gamma oscillations; magnetoencephalography; visual- Clin Neuroradiol (2018), Vol. 28, No. 2, pp. 267-281 motor

J Neurosci (2014), Vol. 34, No. 26, pp. 8813-24 Gamma deficits as a neural signature of cognitive impairment in children treated for brain tumors Local MEG networks: the missing link between Dockstader, C; Wang, F; Bouffet, E; Mabbott, DJ protein expression and epilepsy in glioma patients?

The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Douw, L; de Groot, M; van Dellen, E; Aronica, E; Heimans, Canada [email protected]. JJ; Klein, M; Stam, CJ; Reijneveld, JC; Hillebrand, A

ABSTRACT: Cognitive impairment is consistently re- Department of Neurology, VU University Medical Center, ported in children treated for brain tumors, particularly Neuroscience Campus Amsterdam, De Boelelaan 1117, 1081 in the categories of processing speed, memory, and HV, Amsterdam, The Netherlands; Department of Radiology, attention. Although tumor site, hydrocephalus, chemo- Athinoula A. Martinos Center for Biomedical Imaging, Mas- therapy, and cranial radiation therapy (CRT) are all asso- sachusetts General Hospital, 149 13th Street, Charlestown, ciated with poorer function, CRT predicts the greatest MA 02134, USA; Department of Radiology, Harvard Medical deficits. There is a particularly high correlation between School, Boston, MA, USA. Electronic address: douw@nmr. CRT and slowed information-processing speed. Cortical mgh.harvard.edu. gamma-band oscillations have been associated with processing behaviorally relevant information; however,

99 ABSTRACT: Connectivity and network analysis in neu- controls. Finally, we related network characteristics to roscience has been applied to multiple spatial scales, seizure frequency and cognitive performance within but the links between these different scales have rarely patient groups. METHODS: We constructed functional been investigated. In tumor-related epilepsy, altered networks from pre-surgical resting-state magnetoen- network topology is related to behavior, but the mo- cephalography (MEG) recordings of 13 LGG patients, 12 lecular basis of these observations is unknown. We elu- HGG patients, 10 NGL patients, and 36 healthy controls. cidate the associations between microscopic features Normalized clustering coefficient and average shortest of brain tumors, local network topology, and functional path length as well as modular structure and network patient status. We hypothesize that expression of synchronizability were computed for each group. Cog- proteins related to tumor-related epilepsy is directly nitive performance was assessed in a subset of 11 LGG correlated with network characteristics of the tumor and 10 HGG patients. RESULTS: LGG patients showed area. Glioma patients underwent magnetoencephalog- decreased network synchronizability and decreased raphy, and functional network topology of the tumor global integration compared to healthy controls in the area was used to predict tissue protein expression theta frequency range (4-8 Hz), similar to NGL patients. patterns of tumor tissue collected during neurosurgery. HGG patients' networks did not significantly differ from Protein expression and network topology were inter- those in controls. Network characteristics correlated dependent; in particular between-module connectivity with clinical presentation regarding seizure frequency was selectively associated with two epilepsy-related in LGG patients, and with poorer cognitive perfor- proteins. Total number of seizures was related to both mance in both LGG and HGG glioma patients. CONCLU- the role of the tumor area in the functional network SION: Lesion histology partly determines differences in and to protein expression. Importantly, classification of functional networks in glioma patients suffering from protein expression was predicted by between-module epilepsy. We suggest that differences between LGG and connectivity with up to 100% accuracy. Thus, network HGG patients' networks are explained by differences topology may serve as an intermediate level between in plasticity, guided by the particular lesional growth molecular features of tumor tissue and symptomatol- pattern. Interestingly, decreased synchronizability and ogy in brain tumor patients, and can potentially be decreased global integration in the theta band seem to used as a non-invasive marker for microscopic tissue make LGG and NGL patients more prone to the occur- characteristics. (23507380) rence of seizures and cognitive decline. (23166829)

Neuroimage (2013), Vol. 75, pp. 195-203 PLoS One (2013), Vol. 7, No. 11, pp. e50122

MEG network differences between low- and high- Neural correlates of delayed visual-motor grade glioma related to epilepsy and cognition performance in children treated for brain tumours van Dellen, E; Douw, L; Hillebrand, A; Ris-Hilgersom, IH; Dockstader, C; Gaetz, W; Bouffet, E; Tabori, U; Schoonheim, MM; Baayen, JC; De Witt Hamer, PC; Ve- Wang, F; Bostan, SR; Laughlin, S; Mabbott, DJ lis, DN; Klein, M; Heimans, JJ; Stam, CJ; Reijneveld, JC The Hospital for Sick Children, Department of Psychology, Department of Neurology, VU University Medical Center, Toronto, ON, Canada. Amsterdam, The Netherlands. ABSTRACT: Both structural and functional neural OBJECTIVE: To reveal possible differences in whole integrity is critical for healthy cognitive function and brain topology of epileptic glioma patients, being performance. Across studies, it is evident that children low-grade glioma (LGG) and high-grade glioma (HGG) who are affected by neurological insult commonly patients. We studied functional networks in these demonstrate impaired cognitive abilities. Children patients and compared them to those in epilepsy treated with cranial radiation for brain tumours suffer patients with non-glial lesions (NGL) and healthy substantial structural damage and exhibit a particularly

100 high correlation between the degree of neural injury Leiden University, Wassenaarseweg 52, P,O, Box 9555, 2300 and cognitive deficits. However the pathophysiology RB, Leiden, The Netherlands. underlying impaired cognitive performance in this population, and many other paediatric populations BACKGROUND: Prophylaxis to prevent relapses in the affected by neurological injury or disease, is unknown. central nervous system after childhood acute lympho- We wished to investigate the characteristics of neuro- blastic leukemia (ALL) used to consist of both intrathe- nal function during visual-motor task performance in a cal chemotherapy (CT) and cranial irradiation (CRT). group of children who were treated with cranial radia- CRT was mostly abolished in the eighties because of tion for brain tumours. We used Magnetoencephalogra- its neurotoxicity, and replaced with more intensive phy to investigate neural function during visual-motor intrathecal CT. In this study, a group of survivors treated reaction time (RT) task performance in 15 children with CRT before 1983 and another group treated treated with cranial radiation for Posterior Fossa malig- without CRT thereafter are investigated 20-25 years nant brain tumours and 17 healthy controls. We found later, giving a much stronger perspective on long-term that, relative to controls, the patient group showed: 1) quality of life than previous studies. The outcomes will delayed latencies for neural activation in both visual help to better understand these groups' current needs and motor cortices; 2) muted motor responses in the and will aid in anticipating late effects of prophylactic alpha (8-12Hz) and beta (13-29Hz) bandwidths, and 3) CRT that is currently applied for other diseases. This potentiated visual and motor responses in the gamma study evaluates oscillatory neuronal activity in these (30-100Hz) bandwidth. Collectively these observations long-term survivors. Power spectrum deviations are indicate impaired neural processing during visual-mo- hypothesized to correlate with cognitive dysfunction. tor RT performance in this population and that delays METHODS: Resting state eyes-closed magnetoenceph- in the speed of visual and motor neuronal process- alography (MEG) recordings were obtained from 14 ing both contribute to the delays in the behavioural ALL survivors treated with CT + CRT, 18 treated with CT response. As increases in gamma activity are often ob- alone and 35 controls. Relative spectral power was cal- served with increases in attention and effort, increased culated in the δ, θ, α1, α2, β and γ frequency bands. The gamma activities in the patient group may reflect Amsterdam Neuropsychological Tasks (ANT) program compensatory neural activity during task performance. was used to assess cognition in the executive functions This is the first study to investigate neural function in domain. MEG data and ANT scores were correlated. real-time during cognitive performance in paediatric RESULTS: In the CT + CRT group, relative θ power was brain tumour patients. (23102743) slightly increased (p = 0.069) and α2 power was significantly decreased (p = 0.006). The CT + CRT group per- Keywords: Brain tumours; Cognition; Magnetoencepha- formed worse on various cognitive tests. A deficiency lography; Neurological insult; Visual–motor processing in visuomotor accuracy, especially of the right hand, could be clearly associated with the deviating regional Cortex (2014), Vol. 49, No. 8, pp. 2140-50 θ and α2 powers (0.471 < r < 0.697). A significant association between decreased regional α2 power and less attentional fluctuations was found for CT + CRT patients Long-term effects of cranial irradiation and as well as controls (0.078 < r < 0.666). Patients treated intrathecal chemotherapy in treatment of childhood with CT alone displayed a power spectrum similar to leukemia: a MEG study of power spectrum and controls, except for a significantly increased level of correlated cognitive dysfunction left frontal α2 power (p = 0.030). CONCLUSIONS: The tendency towards global slowing of brain oscillatory Daams, M; Schuitema, I; van Dijk, BW; van Dulmen-den activity, together with the fact that dementia has been Broeder, E; Veerman, AJ; van den Bos, C; de Sonneville, LM reported as a late effect of CRT and the neuropsychological deficiencies currently present, suggest that the Department of Clinical Child and Adolescent Studies, Faculty irradiated brain might be aging faster and could be at of Social Sciences & Leiden Institute for Brain and Cognition, risk for early-onset dementia. The CT group showed no signs of early aging. (22928913)

101 BMC Neurol (2013), Vol. 12, pp. 84 brain network topology is related to greater vulnerability to seizures. Thus, functional connectivity and brain network architecture may prove to be important Epilepsy is related to theta band brain connectivity parameters of tumor-related epilepsy. (20731854) and network topology in brain tumor patients BMC Neurosci (2010), Vol. 11, pp. 103 Douw, L; van Dellen, E; de Groot, M; Hei- mans, JJ; Klein, M; Stam, CJ; Reijneveld, JC Disturbed functional brain networks and Department of Neurology, VU University Medical Center, neurocognitive function in low-grade glioma Amsterdam, The Netherlands. [email protected] patients: a graph theoretical analysis of resting- state MEG BACKGROUND: Both epilepsy patients and brain tumor patients show altered functional connectivity and Bosma, I; Reijneveld, JC; Klein, M; Douw, L; less optimal brain network topology when compared van Dijk, BW; Heimans, JJ; Stam, CJ to healthy controls, particularly in the theta band. Fur- thermore, the duration and characteristics of epilepsy Department of Neurology, VU University Medical Center, may also influence functional interactions in brain Amsterdam, the Netherlands. [email protected]. networks. However, the specific features of connectivity and networks in tumor-related epilepsy have not BACKGROUND: To understand neurophysiological been investigated yet. We hypothesize that epilepsy mechanisms underlying cognitive dysfunction in low- characteristics are related to (theta band) connectivity grade glioma (LGG) patients by evaluating the spatial and network architecture in operated glioma patients structure of 'resting-state' brain networks with graph suffering from epileptic seizures. Included patients theory. METHODS: Standardized tests measuring 6 participated in a clinical study investigating the effect neurocognitive domains were administered in 17 LGG of levetiracetam monotherapy on seizure frequency in patients and 17 healthy controls. Magnetoencepha- glioma patients, and were assessed at two time points: lography (MEG) recordings were conducted during directly after neurosurgery (t1), and six months later eyes-closed 'resting state'. The phase lag index (PLI) was (t2). At these time points, magnetoencephalography computed in seven frequency bands to assess function- (MEG) was recorded and information regarding clinical al connectivity between brain areas. Spatial patterns status and epilepsy history was collected. Functional were characterized with graph theoretical measures connectivity was calculated in six frequency bands, as such as clustering coefficient (local connectivity), path were a number of network measures such as normal- length (global integration), network small world-ness ized clustering coefficient and path length. RESULTS: (ratio of clustering coefficient/path length) and degree At the two time points, MEG registrations were per- correlation (the extent to which connected nodes formed in respectively 17 and 12 patients. No changes have similar degrees). RESULTS: Compared to healthy in connectivity or network topology occurred over controls, patients performed poorer on psychomotor time. Increased theta band connectivity at t1 and functioning, attention, information processing, and t2 was related to a higher total number of seizures. working memory. Patients displayed higher short- and Furthermore, higher number of seizures was related to long-distance synchronization and clustering coef- a less optimal, more random brain network topology. ficient in the theta band, whereas a lower clustering Other factors were not significantly related to function- coefficient and small world-ness were observed in al connectivity or network topology. CONCLUSIONS: the beta band. A lower degree correlation was found These results indicate that (pathologically) increased in the upper gamma band. LGG patients with higher theta band connectivity is related to a higher number clustering coefficient, longer path length, and lower of epileptic seizures in brain tumor patients, suggesting degree correlations in delta and lower alpha band were that theta band connectivity changes are a hallmark of characterized by poorer neurocognitive performance. tumor-related epilepsy. Furthermore, a more random CONCLUSION: LGG patients display higher short- and

102 long-distance synchronization within the theta band. neurocognitive functioning. In summary, LGG patients Network analysis revealed changes (in particularly showed a complex overall pattern of differences in the theta, beta, and upper gamma band) suggesting functional resting-state connectivity compared with disturbed network architecture. Moreover, correlations healthy controls. The significant correlations between between network characteristics and neurocognitive neurocognitive performance and functional connec- performance were found, Widespread changes in the tivity in various frequencies and across multiple brain strength and spatial organization of brain networks areas suggest that the observed neurocognitive deficits may be responsible for cognitive dysfunction in glioma in these patients can possibly be attributed to differ- patients. (19698149) ences in functional connectivity due to tumor and/or treatment. (18650489) Nonlinear Biomed Phys (2011), Vol. 3, No. 1, pp. 9 Neuro Oncol (2008), Vol. 10, No. 5, pp. 734-44

Synchronized brain activity and neurocognitive function in patients with low-grade glioma: a magnetoencephalography study

Bosma, I; Douw, L; Bartolomei, F; Heimans, JJ; van Dijk, BW; Postma, TJ; Stam, CJ; Reijneveld, JC; Klein, M

Department of Neurology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. [email protected]

ABSTRACT: We investigated the mechanisms underlying neurocognitive dysfunction in patients with low- grade glioma (LGG) by relating functional connectivity revealed by magnetoencephalography to neurocognitive function. We administered a battery of standardized neurocognitive tests measuring six neurocognitive domains to a group of 17 LGG patients and 17 healthy controls, matched for age, sex, and educational level. Magnetoencephalography recordings were conducted during an eyes-closed "resting state," and synchronization likelihood (a measure of statistical correlation between signals) was computed from the delta to gamma frequency bands to assess functional connectivity between different brain areas. We found that, compared with healthy controls, LGG patients performed more poorly in psychomotor function, attention, information processing, and working memory. LGG patients also had significantly higher long-distance synchronization scores in the delta, theta, and lower gamma frequency bands than did controls. In contrast, patients displayed a decline in synchronization likelihood in the lower alpha frequency band. Within the delta, theta, and lower and upper gamma bands, increasing short- and long-distance connectivity was associated with poorer

103 104 Pain Clin Exp Rheumatol (2019), Vol. 37 Suppl 116, No. 1, pp. 70-74

Brain responses to other people's pain in fibromyalgia: a magnetoencephalography study Expectation violation and attention to pain jointly modulate neural gain in somatosensory cortex Goldstein, A; Zeev-Wolf, M; Herz, N; Ablin, JN Fardo, F; Auksztulewicz, R; Allen, M; Di- Department of Psychology & Gonda Brain Research Centre, etz, MJ; Roepstorff, A; Friston, KJ Bar Ilan University, Israel. Danish Pain Centre, Department of Clinical Medicine, Aarhus OBJECTIVES: We investigated whether the central pain University, 8000 Aarhus, Denmark; Interacting Minds Centre, symptoms in fibromyalgia syndrome (FM) are related Aarhus University, 8000 Aarhus, Denmark; Institute of Cogni- to defective top-down sensorimotor regulation. The tive Neuroscience, University College London, London WC1N pain matrix was activated in a top-down manner by 3AR, United Kingdom. Electronic address: francesca@clin. presenting pictures of painful situations while record- au.dk. ing brain activity using magnetoencephalography (MEG). We investigated alpha desynchronisation in FM ABSTRACT: The neural processing and experience of patients and healthy controls in response to pictures pain are influenced by both expectations and atten- depicting pain. METHODS: 19 FM patients and 14 age- tion. For example, the amplitude of event-related pain matched healthy controls (age 20-60) were recruited. responses is enhanced by both novel and unexpected Participants were shown photographs of right hands pain, and by moving the focus of attention towards a and feet in situations depicting pain or of control situa- painful stimulus. Under predictive coding, this con- tions with no depiction of pain. MEG was recorded in a gruence can be explained by appeal to a precision- whole-head 248-sensor system as subjects laid supine. weighting mechanism, which mediates bottom-up and RESULTS: In healthy controls exposure to pictures top-down attentional processes by modulating the depicting painful situations elicited a decrease in alpha influence of feedforward and feedback signals through- activity (10Hz) at 100-500ms post-stimulus, which was out the cortical hierarchy. The influence of expectation significantly more pronounced than the one elicited by and attention on pain processing can be mapped onto non-painful content mostly on sensors above the right changes in effective connectivity between or within sensorimotor cortex. However, FM patients did not specific neuronal populations, using a canonical micro- show significant differences in alpha activity between circuit (CMC) model of hierarchical processing. We thus responses to pain and no-pain pictures. CONCLU- implemented a CMC within dynamic causal modelling SIONS: Consistent with previous findings, healthy for magnetoencephalography in human subjects, to participants displayed stronger alpha desynchronisa- investigate how expectation violation and attention to tion for pain pictures, indicating automatic disinhibi- pain modulate intrinsic (within-source) and extrinsic tion of the sensorimotor cortices in response to the (between-source) connectivity in the somatosensory observation of pain in others. We found evidence for hierarchy. This enabled us to establish whether both a deficient modulation of sensorimotor cortex in FM expectancy and attentional processes are mediated patients. The lack of differential response suggests that by a similar precision-encoding mechanism within a they perceived relatively neutral pictures as potentially network of somatosensory, frontal and parietal sources. painful, at least in this setting. Our findings suggest We found that both unexpected and attended pain that defective top-down regulation may play a role in modulated the gain of superficial pyramidal cells in pri- the pathogenesis of FM. (30652680) mary and secondary somatosensory cortex. This modulation occurred in the context of increased lateralized recurrent connectivity between somatosensory and fronto-parietal sources, driven by unexpected painful occurrences. Finally, the strength of effective connectiv-

105 ity parameters in S1, S2 and IFG predicted individual predictors of children's neural empathic response, pin- differences in subjective pain modulation ratings. Our point a decrease in top-down socio-cognitive mecha- findings suggest that neuromodulatory gain control in nisms as potential pathways for the cross-generational the somatosensory hierarchy underlies the influence transfer of vulnerability from mothers with depression of both expectation violation and attention on cortical to their offspring and highlight the need for early inter- processing and pain perception. (28341164) ventions focused on enhancing maternal attunement. (27993224) Neuroimage (2018), Vol. 153, pp. 109-121 Keywords: alpha oscillations; empathy; magnetoencephalography; maternal depression; mother–child interaction Maternal Depression Across the First Years of Life Impacts the Neural Basis of Empathy J Am Acad Child Adolesc Psychiatry (2017), Vol. 56, No. 1, in Preadolescence pp. 20-29.e3

Pratt, M; Goldstein, A; Levy, J; Feldman, R Adolescents growing up amidst intractable conflict Bar-Ilan University, Ramat-Gan, Israel. attenuate brain response to pain of outgroup

OBJECTIVE: Exposure to maternal depression across Levy, J; Goldstein, A; Influs, M; Masalha, the first years of life markedly increases children's S; Zagoory-Sharon, O; Feldman, R susceptibility to psychopathology, yet no study has tested its effects on the maturation of children's social Gonda Multidisciplinary Brain Research Center, Bar-Ilan brain. METHOD: Using a birth cohort of mothers with University, Ramat Gan 5290002, Israel. no contextual risk (N = 1,983), families were followed at 7 time points from birth to 11 years and repeatedly ABSTRACT: Adolescents' participation in intergroup assessed for maternal depression across the first 6 years conflicts comprises an imminent global risk, and to form 2 cohorts: mothers continuously depressed understanding its neural underpinnings may open from birth to 6 years and controls without depression. new perspectives. We assessed Jewish-Israeli and At 11 years of age, children's (n = 72; depressed, n = 27; Arab-Palestinian adolescents for brain response to the nondepressed, n = 45) brain response to others' pain pain of ingroup/outgroup protagonists using magne- was measured by magnetoencephalography. RESULTS: toencephalography (MEG), one-on-one positive and Preadolescents displayed a unique oscillatory pat- conflictual interactions with an outgroup member, atti- tern with higher alpha power to pain versus no pain tudes toward the regional conflict, and oxytocin levels. expressing as alpha rebound, not alpha suppression, A neural marker of ingroup bias emerged, expressed at a late time window (1,100-1,300 ms post-stimulus) via alpha modulations in the somatosensory cortex (S1) in the supplementary motor area. This suggests that that characterized an automatic response to the pain of top-down processing in areas of the pain matrix can all protagonists followed by rebound/enhancement to underpin the maturation of vicarious empathy. Chil- ingroup pain only. Adolescents' hostile social interac- dren of mothers with depression showed enhanced tions with outgroup members and uncompromising alpha rebound to pain in the right posterior superior attitudes toward the conflict influenced this neural temporal gyrus, which was unrelated to emotion detec- marker. Furthermore, higher oxytocin levels in the tion abilities, pointing to decreased late processing of Jewish-Israeli majority and tighter brain-to-brain syn- others' overwhelming experiences in socio-cognitive chrony among group members in the Arab-Palestinian areas. Alpha power in the posterior superior temporal minority enhanced the neural ingroup bias. Findings gyrus was predicted by higher maternal intrusiveness suggest that in cases of intractable intergroup conflict, and lower synchrony across early childhood. CONCLU- top-down control mechanisms may block the brain's SION: These findings, from the first study to examine evolutionary-ancient resonance to outgroup pain, maternal depression and early caregiving as long-term pinpointing adolescents' interpersonal and sociocog-

106 nitive processes as potential targets for intervention. effects, (b) NCM>Fatigue>Pain for non-HLA-related (27849588) effects, and (c) HLA-related>non-HLA-related effects for all symptoms. These effects had widespread but Keywords: alpha oscillations; brain-to-brain synchrony; distinct distributions in sensor space that allowed the empathy; intergroup conflict; oxytocin orderly separation of the 6 terms (3 symptom domains×2 HLA factors) in a multidimensional plot, where Proc Natl Acad Sci U S A (2018), Vol. 113, No. 48, pp. one dimension separated the symptoms and the other 13696-13701 the HLA relation. INTERPRETATION: These findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural Brain Correlates of Human Leukocyte Antigen (HLA) influences on NCM, Pain and Fatigue symptom severity Protection in Gulf War Illness (GWI) in GWI. FUNDING: U.S. Department of Veterans Affairs and University of Minnesota. (27765642) James, LM; Engdahl, BE; Leuthold, AC; Georgopoulos, AP Keywords: Gulf War Illness (GWI); Human Leukocyte Anti- Brain Sciences Center, Department of Veterans Affairs Health gen; Magnetoencephalography; Veterans Care System, Minneapolis, MN 55417, USA; Center for Cogni- tive Sciences, University of Minnesota, Minneapolis, MN EBioMedicine (2017), Vol. 13, pp. 72-79 55455, USA; Department of Psychiatry, University of Minne- sota Medical School, Minneapolis, MN 55455, USA. Decoding the perception of endogenous pain from BACKGROUND: We recently reported that six alleles resting-state MEG from class II genes of the Human Leukocyte Antigen (HLA) confer protection from Gulf War Illness (GWI) Kuo, PC; Chen, YT; Chen, YS; Chen, LF (Georgopoulos et al., 2015). The most significant effect is exerted on Neurological-Cognitive-Mood (NCM), Department of Computer Science, National Chiao Tung Pain, and Fatigue symptoms, such that higher number University, Hsinchu, Taiwan. of copies of the protective alleles are associated with lower symptom severity. Here we tested the hypothesis ABSTRACT: Decoding the neural representations of that this effect is exerted by modulating the strength of pain is essential to obtaining an objective assessment neural synchronicity. METHODS: Eighty-one Gulf War as well as an understanding of its underlying mecha- veterans (65 with GWI and 16 healthy controls) under- nisms. The complexities involved in the subjective went a magnetoencephalography (MEG) scan to assess experience of pain make it difficult to obtain a quan- the strength of brain synchronicity by computing zero- titative assessment from the induced spatiotemporal lag crosscorrelations (and their Fisher z transforms) be- patterns of brain activity of high dimensionality. Most tween prewhitened MEG time series. A high-resolution previous studies have investigated the perception of HLA genotyping determined the number of copies, k, pain by analyzing the amplitude or spatial patterns in of the 6 protective alleles above in each participant. We the response of the brain to external stimulation. This tested the hypothesis above by regressing NCM, Pain study investigated the decoding of endogenous pain and Fatigue symptom severity against the interaction perceptions according to resting-state magnetoen- term, k×z (HLA-related effect), while including z (non- cephalographic (MEG) recordings. In our experiments, HLA-related effect), gender and age as covariates. The we applied a beamforming method to calculate the k×z and z terms assessed HLA- and non-HLA-related brain activity for every brain region and examined effects, respectively, of neural synchronicity on symp- temporal and spectral features of brain activity for pre- tom severity. The distributions of these effects in sensor dicting the intensity of perceived pain in patients with space were visualized using statistical heatmaps. FIND- primary dysmenorrhea undergoing menstrual pain. INGS: We found significant, graded HLA- and non-HLA- Our results show that the asymmetric index of sample related effects: (a) NCM>Pain>Fatigue for HLA-related entropy in the precuneus and the sample entropy in

107 the left posterior cingulate gyrus were the most infor- This may suggest that individuals exposed to extreme mative characteristics associated with the perception pain may perceive neutral stimuli as potentially threat- of menstrual pain. The correlation coefficient (ρ=0.64, ening. Our findings demonstrate alterations in pain p<0.001) between the predicted and self-reported pain perception following extreme pain exposure, chart the scores demonstrated the high prediction accuracy. In sequence from automatic to evaluative pain process- addition to the estimated brain activity, we were able ing, and emphasize the importance of considering past to predict accurate pain scores directly from MEG chan- experiences in studying the neural response to others' nel signals (ρ=0.65, p<0.001). These findings suggest states. (27032959) the possibility of using the proposed model based on resting-state MEG to predict the perceived intensity of Keywords: Alpha suppression; MEG; Pain perception; endogenous pain. (27746387) Posterior cingulate cortex

Keywords: Decoding; Endogenous pain; Pain perception; Cogn Affect Behav Neurosci (2017), Vol. 16, No. 4, pp. Resting-state MEG 662-71

Neuroimage (2018), Vol. 144, No. Pt A, pp. 1-11 Cortical reorganization after macroreplantation at the upper extremity: a magnetoencephalographic Prior exposure to extreme pain alters neural study response to pain in others Blume, KR; Dietrich, C; Huonker, R; Götz, T; Sens, E; Eidelman-Rothman, M; Goldstein, A; Weisman, O; Schnei- Friedel, R; Hofmann, GO; Miltner, WH; Weiss, T derman, I; Zagoory-Sharon, O; Decety, J; Feldman, R 1 Department of Biological and Clinical Psychology, Friedrich Gonda Multidisciplinary Brain Research Center, Bar-Ilan Schiller University, 07743 Jena, Germany. University, Ramat-Gan, Israel, 52900. ABSTRACT: With the development of microsurgical ABSTRACT: In the extant literature examining the brain techniques, replantation has become a feasible alterna- mechanisms implicated in pain perception, research- tive to stump treatment after the amputation of an ers have theorized that the overlapping responses to extremity. It is known that amputation often induces pain in the self and in others mark the human capacity phantom limb pain and cortical reorganization within for empathy. Here we investigated how prior exposure the corresponding somatosensory areas. However, to extreme pain affects pain perception, by assess- whether replantation reduces the risk of comparable ing the dynamics of pain processing in veterans who persisting pain phenomena as well as reorganization were previously exposed to severe injury. Forty-three of the primary somatosensory cortex is still widely participants (28 pain-exposed and 15 controls) under- unknown. Therefore, the present study aimed to went whole-head magnetoencephalography (MEG) investigate the potential development of persistent while viewing photographs of limbs in painful and pain and cortical reorganization of the hand and lip nonpainful (neutral) conditions. Among controls, an areas within the sensory cortex by means of magneto- early (0-220 ms) "pain effect" in the posterior cingulate encephalographic dipole analyses after replantation and sensorimotor cortices, and a later (760-900 ms) of a traumatically amputated upper limb proximal "pain effect" in the posterior cingulate cortex, superior to the radiocarpal joint. Cortical reorganization was temporal gyrus/insula, and fusiform gyrus were found, investigated in 13 patients with limb replantation using indicated by enhanced alpha suppression to the pain air puff stimulation of the phalanges of both thumbs versus nonpain conditions. Importantly, pain-exposed and both corners of the lower lip. Displacement of participants exhibited an atypical pain response in the the centre of gravity of lip and thumb representations posterior cingulate cortex, indicated by a normative re- and increased cortical activity were found in the limb sponse to pain, but no pain-to-no-pain differentiation. and face areas of the primary somatosensory cortex

108 contralateral to the replanted arm when compared to latory gamma in SI during stimulation, the strength the ipsilateral hemisphere. Thus, cortical reorganization of the gamma power was found to increase with in the primary somatosensory cortex also occurs after increasing stimulus intensity at both pain and sub-pain replantation of the upper extremity. Patients' reports thresholds. These results suggest that evoked gamma of pain in the replanted body part were negatively cor- oscillations in SI are not specific to pain but may have related with the amount of cortical reorganization, i.e. a role in encoding somatosensory stimulus intensity. the more pain the patients reported, the less reorgani- (23874282) zation of the subjects' hand representation within the primary somatosensory cortex was observed. Longi- Keywords: electrical; gamma; pain; primary somatosen- tudinal studies in patients after macroreplantation are sory cortex; stimulus intensity necessary to assess whether the observed reorganization in the primary somatosensory cortex is a result of Front Hum Neurosci (2013), Vol. 7, pp. 362 changes within the representation of the replanted arm and/or neighbouring representations and to assess the relationship between the development of persistent Neonatal pain-related stress, functional cortical pain and reorganization. (24480484) activity and visual-perceptual abilities in school-age children born at extremely low gestational age Keywords: cortical reorganization; macroreplantation; magnetoencephalography; primary somatosensory cor- Doesburg, SM; Chau, CM; Cheung, TP; Moi- tex; somatosensation; somatosensory-evoked magnetic seev, A; Ribary, U; Herdman, AT; Miller, SP; fields Cepeda, IL; Synnes, A; Grunau, RE

Brain (2014), Vol. 137, No. Pt 3, pp. 757-69 Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada; Program in Neurosciences and Mental Health, The Hospital for Sick Children Research Gamma oscillatory amplitude encodes stimulus Institute, Toronto, ON, Canada; Department of Medical Imag- intensity in primary somatosensory cortex ing, University of Toronto, Toronto, ON, Canada. Electronic address: [email protected]. Rossiter, HE; Worthen, SF; Witton, C; Hall, SD; Furlong, PL ABSTRACT: Children born very prematurely (< or =32 Aston Brain Centre, School of Life and Health Sciences, Aston weeks) often exhibit visual-perceptual difficulties at University Birmingham, UK ; Sobell Department of Motor school-age, even in the absence of major neurological Neuroscience and Movement Disorders, UCL Institute of impairment. The alterations in functional brain activity Neurology London, UK. that give rise to such problems, as well as the relationship between adverse neonatal experience and neu- ABSTRACT: Gamma oscillations have previously been rodevelopment, remain poorly understood. Repeated linked to pain perception and it has been hypothesized procedural pain-related stress during neonatal inten- that they may have a potential role in encoding pain in- sive care has been proposed to contribute to altered tensity. Stimulus response experiments have reported neurocognitive development in these children. Due to an increase in activity in the primary somatosensory critical periods in the development of thalamocortical cortex (SI) with increasing stimulus intensity, but the systems, the immature brain of infants born at extreme- specific role of oscillatory dynamics in this change in ly low gestational age (ELGA; < or =28 weeks) may have activation remains unclear. In this study, Magneto- heightened vulnerability to neonatal pain. In a cohort encephalography (MEG) was used to investigate the of school-age children followed since birth we assessed changes in cortical oscillations during four different relations between functional brain activity measured intensities of a train of electrical stimuli to the right using magnetoencephalogragy (MEG), visual-percep- index finger, ranging from low sensation to strong pain. tual abilities and cumulative neonatal pain. We demon- In those participants showing changes in evoked oscil- strated alterations in the spectral structure of sponta-

109 neous cortical oscillatory activity in ELGA children at music" within the entrainment method exerted major school-age. Cumulative neonatal pain-related stress effects on gamma-band activity in primary and second- was associated with changes in background cortical ary somatosensory cortices. Pain music, in contrast to rhythmicity in these children, and these alterations in healing music, increased pain ratings in parallel with spontaneous brain oscillations were negatively corre- an increase in gamma-band activity in somatosensory lated with visual-perceptual abilities at school-age, and brain structures. In conclusion, our data suggest that were not driven by potentially confounding neonatal the 2 music therapy approaches operationalized in this variables. These findings provide the first evidence study seem to modulate pain perception through at linking neonatal pain-related stress, the development least 2 different mechanisms, involving changes of ac- of functional brain activity, and school-age cognitive tivity in the delta and gamma bands at different stages outcome in these vulnerable children. (23711638) of the pain processing system. (23414577)

Keywords: Child development; Cognition; Cognitive out- Pain (2013), Vol. 154, No. 4, pp. 539-47 come; Development; Magnetoencephalography; Neona- tal pain; Neural oscillation; Pain; Perception; Prematurity; Preterm; Resting-state; Spontaneous brain activity; Visual Acupuncture induces divergent alterations of perception functional connectivity within conventional frequency bands: evidence from MEG recordings Pain (2014), Vol. 154, No. 10, pp. 1946-52 You, Y; Bai, L; Dai, R; Zhong, C; Xue, T; Wang, H; Liu, Z; Wei, W; Tian, J The influence of music and music therapy on pain-induced neuronal oscillations measured by Intelligent Medical Research Center, Institute of Automation, magnetencephalography Chinese Academy of Sciences, Beijing, China.

Hauck, M; Metzner, S; Rohlffs, F; Lorenz, J; Engel, AK ABSTRACT: As an ancient Chinese healing modality which has gained increasing popularity in modern soci- Department of Neurophysiology and Pathophysiology, ety, acupuncture involves stimulation with fine needles University Medical Center Hamburg-Eppendorf, Hamburg, inserted into acupoints. Both traditional literature and Germany. [email protected] clinical data indicated that modulation effects largely depend on specific designated acupoints. However, ABSTRACT: Modern forms of music therapy are clinical- scientific representations of acupoint specificity remain ly established for various therapeutic or rehabilitative controversial. In the present study, considering the new goals, especially in the treatment of chronic pain. How- findings on the sustained effects of acupuncture and ever, little is known about the neuronal mechanisms its time-varied temporal characteristics, we employed that underlie pain modulation by music. Therefore, we an electrophysiological imaging modality namely attempted to characterize the effects of music therapy magnetoencephalography with a temporal resolution on pain perception by comparing the effects of 2 dif- on the order of milliseconds. Taken into account the ferent therapeutic concepts, referred to as receptive differential band-limited signal modulations induced and entrainment methods, on cortical activity recorded by acupuncture, we sought to explore whether or not by magnetencephalography in combination with laser stimulation at Stomach Meridian 36 (ST36) and a near- heat pain. Listening to preferred music within the re- by non-meridian point (NAP) would evoke divergent ceptive method yielded a significant reduction of pain functional connectivity alterations within delta, theta, ratings associated with a significant power reduction of alpha, beta and gamma bands. Whole-head scanning delta-band activity in the cingulate gyrus, which sug- was performed on 28 healthy participants during an gests that participants displaced their focus of atten- eyes-closed no-task condition both preceding and fol- tion away from the pain stimulus. On the other hand, lowing acupuncture. Data analysis involved calculation listening to self-composed "pain music" and "healing of band-limited power (BLP) followed by pair-wise BLP

110 correlations. Further averaging was conducted to ob- were attended or ignored. Spatial attention was associ- tain local and remote connectivity. Statistical analyses ated with a lateralization of anticipatory pre-stimulus revealed the increased connection degree of the left alpha activity. Alpha activity was lower over primary temporal cortex within delta (0.5-4 Hz), beta (13-30 Hz) somatosensory areas when the contralateral hand was and gamma (30-48 Hz) bands following verum acu- attended compared to when the ipsilateral hand was puncture. Moreover, we not only validated the closer attended, in line with the notion that oscillatory alpha linkage of the left temporal cortex with the prefrontal activity regulates the flow of incoming information by and frontal cortices, but further pinpointed that such engaging and/or disengaging early sensory areas. On patterns were more extensively distributed in the ST36 the contrary, post-stimulus alpha activity, for stimuli on group in the delta and beta bands compared to the re- either hand, was consistently decreased with attention striction only to the delta band for NAP. Psychophysical over contralateral areas. Most likely, this finding reflects results for significant pain threshold elevation further an increased cortical activation and enhanced alerting confirmed the analgesic effect of acupuncture at ST36. if a painful stimulus is attended. The present results In conclusion, our findings may provide a new perspec- show that spatial attention results in a modulation of tive to lend support for the specificity of neural expres- both pre- and post-stimulus alpha activity associated sion underlying acupuncture. (23152881) with pain. This flexible regulation of alpha activity matches findings from other modalities. We conclude PLoS One (2013), Vol. 7, No. 11, pp. e49250 that the assumed functional role of alpha activity as a top-down controlled gating mechanism includes pain processing and most likely represents a unified mecha- Pre- and post-stimulus alpha activity shows nism used throughout the brain. (22659486) differential modulation with spatial attention during the processing of pain Neuroimage (2012), Vol. 62, No. 3, pp. 1965-74

May, ES; Butz, M; Kahlbrock, N; Hoogen- boom, N; Brenner, M; Schnitzler, A Sensorimotor Alpha Activity is Modulated in Response to the Observation of Pain in Others Heinrich-Heine-University Düsseldorf, Medical Faculty, Institute of Clinical Neuroscience and Medical Psychology, Whitmarsh, S; Nieuwenhuis, IL; Barendregt, HP; Jensen, O Universitätsstrasse 1, D-40225 Düsseldorf, Germany. Donders Institute for Brain, Cognition and Behaviour, Rad- ABSTRACT: Extensive work using magneto- and boud University Nijmegen Nijmegen, Netherlands. electroencephalography (M/EEG) suggests that cortical alpha activity represents a top-down controlled ABSTRACT: The perception-action account of empa- gating mechanism employed by processes like atten- thy states that observation of another person's state tion across different modalities. However, it is not yet automatically activates a similar state in the observer. clear to what extent this presumed gating function of It is still unclear in what way ongoing sensorimotor alpha activity also applies to the processing of pain. alpha oscillations are involved in this process. Although In the current study, a spatial attention paradigm was they have been repeatedly implicated in (biological) employed requiring subjects to attend to painful laser action observation and understanding communica- stimuli on one hand while ignoring stimuli on the other tive gestures, less is known about their role in vicarious hand. Simultaneously, brain activity was recorded with pain observation. Their role is understood as provid- MEG. In order to disentangle pre- and post-stimulus ing a graded inhibition through functional inhibition, effects of attention, alpha activity was analyzed during thereby streamlining information flow through the time windows in anticipation of and in response to cortex. Although alpha oscillations have been shown to painful laser stimulation. Painful laser stimuli led to a have at least visual and sensorimotor origins, only the suppression of alpha activity over both ipsi- and contra- latter are expected to be involved in the empathetic lateral primary somatosensory areas irrespective if they response. Here, we used magnetoencephalography,

111 allowing us to spatially distinguish and localize oscilla- intracutaneous inputs were higher when pain stimuli tory components using beamformer source reconstruc- were presented together with emotional facial expres- tion. Subjects observed realistic pictures of limbs in sions than when they were presented with a neutral painful and no-pain (control) conditions. As predicted, facial expression. Source reconstruction using linear time-frequency analysis indeed showed increased beamforming revealed pain-induced early (70-270 alpha suppression in the pain condition compared to ms) oscillatory beta-band activity (BBA; 15-25 Hz) and the no-pain condition. Although both pain and no-pain gamma-band activity (GBA; 60-80 Hz) in the sensorimo- conditions suppressed alpha- and beta-band activity at tor cortex. The presentation of faces with emotional both posterior and central sensors, the pain condition expressions compared to faces with neutral expressions suppressed alpha more only at central sensors. Source led to a stronger bilateral suppression of the pain- reconstruction localized these differences along the induced BBA, possibly reflecting enhanced response central sulcus. Our results could not be accounted for readiness of the sensorimotor system. Moreover, pain- by differences in the evoked fields, suggesting a unique induced GBA in the sensorimotor cortex was larger for role of oscillatory activity in empathetic responses. We faces expressing fear than for faces expressing anger, argue that alpha oscillations provide a unique measure which might reflect the facilitation of avoidance-mo- of the underlying functional architecture of the brain, tivated behavior triggered by the concurrent presen- suggesting an automatic disinhibition of the senso- tation of faces with fearful expressions and painful rimotor cortices in response to the observation of pain stimuli. Thus, the presence of emotional cues, like in others. (22007165) facial expressions from people surrounding us, while receiving acute pain may facilitate neuronal processes Keywords: MEG; alpha; beamformer; empathy; mu- involved in the preparation and execution of adequate rhythm; oscillations; pain; sensorimotor protective motor responses. (21994371)

Front Hum Neurosci (2011), Vol. 5, pp. 91 J Neurosci (2011), Vol. 31, No. 41, pp. 14542-50

Emotional facial expressions modulate pain- Anesthetic block of pain-related cortical activity in induced beta and gamma oscillations in patients with peripheral nerve injury measured by sensorimotor cortex magnetoencephalography

Senkowski, D; Kautz, J; Hauck, M; Zim- Theuvenet, PJ; de Munck, JC; Peters, MJ; van mermann, R; Engel, AK Ree, JM; Lopes da Silva, FL; Chen, AC

Department of Neurophysiology and Pathophysiology, Uni- Department of Anesthesiology-Pain Clinic, Medical Centre versity Medical Center Hamburg-Eppendorf, 20246 Hamburg, Alkmaar, Alkmaar, The Netherlands. [email protected] Germany. [email protected] BACKGROUND: This study examined whether chronic ABSTRACT: Painful events in our environment are neuropathic pain, modulated by a local anesthetic often accompanied by stimuli from other sensory block, is associated with cortical magnetic field chang- modalities. These stimuli may influence the percep- es. METHODS: In a group of 20 patients with pain tion and processing of acute pain, in particular when caused by unilateral traumatic peripheral nerve injury, a they comprise emotional cues, like facial expressions of local block with lidocaine 1% was administered and the people surrounding us. In this whole-head magnetoen- cortical effects were measured and compared with a cephalography (MEG) study, we examined the neuronal control group. The global field power (GFP), describing mechanisms underlying the influence of emotional distribution of cortical activation after median and ul- (fearful, angry, or happy) compared to neutral facial nar nerve stimulation, was plotted and calculated. The expressions on the processing of pain in humans. In- effects on the affected hemisphere and the unaffected dependent of their valence, subjective pain ratings for hemisphere (UH) before and after a block of the injured

112 nerve were statistically evaluated. RESULTS: Major of the intensity of heat and burning pain during differences based on the GFP curves, at a component repeated laser stimulation in spite of only mild (4.8°C) between 50 ms - 90 ms (M70), were found in patients: increase of skin temperature from the first stimulus to in the affected hemisphere the M70 GFP peak values the tenth stimulus. The mean reaction time, evaluated were statistically significantly larger in comparison with in six subjects, was 1.33 s, confirming involvement of the UH, and the GFP curves differed morphologically. C fibres. The neuromagnetic fields were modelled by Interestingly, the mean UH responses were reduced in five equivalent source dipoles located in the occipital comparison with the control group, a finding suggest- cortex, cerebellum, posterior cingulate cortex, and left ing that the UH is also part of the cortical changes. At and right operculo-insular cortex. The only component M70, the GFP curves and values in the affected hemi- showing statistically significant changes during repeti- sphere were modulated by a local block of the median tive laser stimulation was the late component of the or the ulnar nerve. The most likely location of cortical contralateral operculo-insular source peaking at 1.05 s adaptation is in the primary somatosensory cortex. after stimulus onset. The amplitude increases of the late CONCLUSIONS: Cortical activation is enhanced in the component of the contralateral operculo-insular source affected hemisphere compared with the UH and is dipole correlated with the subjects' numerical ratings modulated by a local block. The UH in neuropathic pain of warmth and pain. Results point to a pivotal role of changes as well. Evoked fields may offer an opportunity the contralateral operculo-insular region in processing to monitor the effectiveness of treatments of neuro- of C-fibre mediated pain during repeated subnoxious pathic pain in humans. (21685789) laser stimulation. (21572954)

Anesthesiology (2011), Vol. 115, No. 2, pp. 375-86 PLoS One (2011), Vol. 6, No. 5, pp. e19744

Cortical activation changes during repeated laser World Health Day 2011--antimicrobial resistance: stimulation: a magnetoencephalographic study no action today, no cure tomorrow

Stancak, A; Alghamdi, J; Nurmikko, TJ Hsueh, PR

Department of Experimental Psychology, Institute of Psychol- Department of Laboratory Medicine, National Taiwan ogy, Health, and Society, University of Liverpool, Liverpool, University Hospital, National Taiwan University College of United Kingdom. [email protected] Medicine, Taipei, Taiwan.

ABSTRACT: Repeated warm laser stimuli produce a ABSTRACT: {}[[1]]<> (21540002) progressive increase of the sensation of warmth and heat and eventually that of a burning pain. The pain J Formos Med Assoc (2011), Vol. 110, No. 4, pp. 213-4 resulting from repetitive warm stimuli is mediated by summated C fibre responses. To shed more light on the cortical changes associated with pain during fMRI and MEG analysis of visceral pain in healthy repeated subnoxious warm stimulation, we analysed volunteers magnetoencephalographic (MEG) evoked fields in eleven subjects during application of repetitive warm Smith, JK; Humes, DJ; Head, KE; Bush, D; laser stimuli to the dorsum of the right hand. One set of White, TP; Stevenson, CM; Brookes, MJ; Mar- stimuli encompassed 10 laser pulses occurring at 2.5 s ciani, L; Spiller, RC; Gowland, PA; Francis, ST intervals. Parameters of laser stimulation were opti- mised to elicit a pleasant warm sensation upon a single School of Physics and Astronomy, Sir Peter Mansfield Mag- stimulus with a rise of skin temperature after repeated netic Resonance Centre, University of Nottingham, Notting- stimulation not exceeding the threshold of C mechano- ham, UK. heat fibres. Subjects reported a progressive increase

113 BACKGROUND: Although many studies of pain- ABSTRACT: Complex Regional Pain Syndrome (CRPS) ful rectal stimulation have found activation in the is a neuropathic disease that presents a continuing insula, cingulate, somatosensory, prefrontal cortices challenge in terms of pathophysiology, diagnosis, and and thalamus, there is considerable variability when treatment. Recent studies of neuropathic pain, in both comparing functional magnetic resonance imaging animals and patients, have established a direct relation- (fMRI) results. Multiple factors may be responsible, ship between abnormal thalamic rhythmicity related to including the model used in fMRI data analysis. Here, Thalamo-cortical Dysrhythmia (TCD) and the occur- we assess the temporal response of activity to rectal rence of central pain. Here, this relationship has been barostat distension using novel fMRI and magnetoen- examined using magneto-encephalographic (MEG) cephalography (MEG) analysis. METHODS: Liminal and imaging in CRPS Type I, characterized by the absence painful rectal barostat balloon inflation thresholds were of nerve lesions. The study addresses spontaneous assessed in 14 female healthy volunteers. Subliminal, MEG activity from 13 awake, adult patients (2 men, 11 liminal and painful 40s periods of distension were ap- women; age 15-62), with CRPS Type I of one extrem- plied in a pseudo-randomized paradigm during fMRI ity (duration range: 3months to 10years) and from and MEG neuroimaging. Functional MRI data analysis 13 control subjects. All CRPS I patients demonstrated was performed comparing standard box-car models peaks in power spectrum in the delta (<4Hz) and/or of the full 40s of stimulus (Block) with models of the theta (4-9Hz) frequency ranges resulting in a charac- inflation (Ramp-On) and deflation (Ramp-Off) of the teristically increased spectral power in those ranges barostat. Similar models were used in MEG analysis of when compared to control subjects. The localization oscillatory activity. KEY RESULTS: Modeling the data of such abnormal activity, implemented using inde- using a standard Block analysis failed to detect areas of pendent component analysis (ICA) of the sensor data, interest found to be active using Ramp-On and Ramp- showed delta and/or theta range activity localized to Off models. Ramp-On generated activity in anterior the somatosensory cortex corresponding to the pain insula and cingulate regions and other pain-matrix localization, and to orbitofrontal-temporal cortices associated areas. Ramp-Off demonstrated activity of a related to the affective pain perception. Indeed, CRPS network of posterior insula, SII and posterior cingulate. Type I patients presented abnormal brain activity typi- Active areas were consistent with those identified from cal of TCD, which has both diagnostic value indicating MEG data. CONCLUSIONS & INFERENCES: In studies a central origin for this ailment and a potential treat- of visceral pain, fMRI model design strongly influences ment interest involving pharmacological and electrical the detected activity and must be accounted for to ef- stimulation therapies. (20338687) fectively explore the fMRI data in healthy subjects and within patient groups. In particular a strong cortical Pain (2010), Vol. 150, No. 1, pp. 41-51 response is detected to inflation and deflation of the barostat, rather than to its absolute volume. (21507149) Functional integration within the human pain Neurogastroenterol Motil (2011), Vol. 23, No. 7, pp. 648- system as revealed by Granger causality e260 Ploner, M; Schoffelen, JM; Schnitzler, A; Gross, J

Abnormal thalamocortical activity in patients with Department of Neurology, Technische Universität München, Complex Regional Pain Syndrome (CRPS) type I Germany. [email protected]

Walton, KD; Dubois, M; Llinás, RR ABSTRACT: Pain is a complex experience subserved by an extended network of brain areas. However, the func- Dept. of Physiology & Neuroscience, New York University tional integration among these brain areas, i.e., how School of Medicine, 550 First Ave., New York, NY 10016, USA. they interact and communicate to generate a coherent pain percept and an adequate behavioral response is largely unknown. Here, we used magnetoencephalog-

114 raphy to investigate functional integration among pain- scores for the affective-motivational pain dimension related cortical activations in terms of Granger causality did not differ between both conditions. Therefore, and compared it with tactile-related activations. The concerning the sensory dimension of the human pain results show causal influences of primary somatosen- experience we conclude that the S2 cortex is involved sory cortex on secondary somatosensory cortex for in the encoding of quality discrimination. (19231261) tactile-related but not for pain-related activations, which supports the proposition of a partially parallel Eur J Pain (2010), Vol. 13, No. 10, pp. 1048.e1-7 organization of pain processing in the human brain. Furthermore, during a simple reaction time task, the strength of causal influences between somatosensory Gender differences in the mu rhythm during areas but not the latencies between activations cor- empathy for pain: an electroencephalographic related significantly with the speed of reaction times. study These findings show how the analysis of functional integration complements traditional analyses of elec- Yang, CY; Decety, J; Lee, S; Chen, C; Cheng, Y trophysiological data and provides novel and behaviorally relevant information about the organization of the Institute of Computer, Communication and System Engineer- human pain system. (19479728) ing, Ching-Yun University, Chungli, Taiwan.

Hum Brain Mapp (2010), Vol. 30, No. 12, pp. 4025-32 ABSTRACT: Our recent magnetoencephalography study demonstrated that the mu rhythm can reliably indicate sensorimotor resonance during the perception Quality discrimination for noxious stimuli in of pain in others (Cheng, Y., Yang, C.Y., Lin, C.P., Lee, P.L., secondary somatosensory cortex: a MEG-study Decety, J., 2008b. The perception of pain in others suppresses somatosensory oscillations: a magnetoenceph- Maihöfner, C; Kaltenhäuser, M alography study. NeuroImage 40, 1833-1840). The current study further investigated the neurophysiological Department of Neurology, University of Erlangen-Nuremberg, mechanism underpinning empathy for pain in relation Schwabachanlage 6, D-91054 Erlangen, Germany. christian. with gender through the measurements of the electro- maihoefner@uk-erlangen encephalographic mu suppression in healthy female (N=16) and male (N=16) adults during the observation ABSTRACT: A complex cortical network is believed to of body parts in painful or no-painful situations. The encode the multi-dimensionality of the human pain results demonstrate that both genders exhibited senso- experience. In the present study, we used magnetoen- rimotor activation related to pain empathy. However, cephalography (MEG) to examine whether the cortical females showed stronger mu suppressions than males processing of noxious stimuli with different psycho- when watching the painful as well as the non-painful physical properties differs in primary (S1) and second- situations. Further, the mu suppression for pain empa- ary (S2) somatosensory cortices. Noxious low (condition thy was positively correlated with the scoring on the 1) and high (condition 2) current density stimulations personal distress subscale of the interpersonal reactiv- of equal stimulus intensities were applied at the left ity index only in the female participants. The present forearm in 12 subjects in a randomised order. Con- findings suggest the existence of a gender difference in comitantly, subjects had to evaluate the corresponding pain empathy in relation with the sensorimotor cortex sensory-discriminative and affective-motivational pain resonance. The mu rhythm can be a potential biomark- dimensions. MEG revealed an increased activation of er of empathic mimicry. (19083993) bilateral secondary somatosensory cortices (S2) during condition 2 compared to condition 1. Higher activations of bilateral S2 were significantly correlated with higher scores for the sensory-discriminative component during condition 2. In contrast, corresponding

115 Brain Res (2009), Vol. 1251, pp. 176-84 ABSTRACT: Accumulating evidence demonstrates that similar neural circuits are activated during the first- hand experience of pain and the observation of pain in Evoked magnetic fields following noxious laser others. However, most functional MRI studies did not stimulation of the thigh in humans detect signal change in the primary somatosensory cortex during pain empathy. To test if the perception Nakata, H; Tamura, Y; Sakamoto, K; Akat- of pain in others involves the primary somatosensory suka, K; Hirai, M; Inui, K; Hoshiyama, M; Saitoh, cortex, neuromagnetic oscillatory activity was recorded Y; Yamamoto, T; Katayama, Y; Kakigi, R from the primary somatosensory cortex in 16 participants while they observed static pictures depicting Department of Integrative Physiology, National Institute for body parts in painful and non-painful situations. The Physiological Sciences, Myodaiji, Okazaki, 444-8585, Japan. left median nerve was stimulated at the wrist, and the [email protected] poststimulus rebounds of the approximately 10-Hz somatosensory cortical oscillations were quantified. ABSTRACT: Primary somatosensory cortex (SI) and Compared to the baseline condition, the level of the posterior parietal cortex (PPC) are activated by nox- approximately 10-Hz oscillations was suppressed dur- ious stimulation. In neurophysiological studies using ing both of the observational situations, indicating magnetoencephalography (MEG), however, it has been the activation of the primary somatosensory cortex. difficult to separate the activity in SI from that in PPC Importantly, watching painful compared to non-painful following stimulation of the upper limb, since the hand situations suppressed somatosensory oscillations to a area of SI is very close to PPC. Therefore, we investi- significant stronger degree. In addition, the suppres- gated human pain processing using MEG following sion caused by perceiving others in the painful relative the application of a thulium-YAG laser to the left thigh to the non-painful situations correlated with the per- to separate the activation of SI and PPC, and to clarify spective taking subscale of the interpersonal reaction the time course of the activities involved. The results index. These results, consistent with the mirror-neuron indicated that cortical activities were recorded around system, demonstrate that the perception of pain in SI, contralateral secondary somatosensory cortex (cSII), others modulates neural activity in primary somatosen- ipsilateral secondary somatosensory cortex (iSII), and sory cortex and supports the idea that the perception PPC between 150-185 ms. The precise location of PPC of pain in others elicits subtle somatosensory activity was indicated to be the inferior parietal lobule (IPL), that may be difficult to detect by fMRI techniques. corresponding to Brodmann's area 40. The mean peak (18353686) latencies of SI, cSII, iSII and IPL were 152, 170, 181, and 183 ms, respectively. This is the first study to clarify the Neuroimage (2008), Vol. 40, No. 4, pp. 1833-40 time course of the activities of SI, SII, and PPC in human pain processing using MEG. (18585060) Noxious counterirritation in patients with advanced Neuroimage (2008), Vol. 42, No. 2, pp. 858-68 osteoarthritis of the knee reduces MCC but not SII pain generators: A combined use of MEG and EEG

The perception of pain in others Quante, M; Hille, S; Schofer, MD; Lorenz, J; Hauck, M suppresses somatosensory oscillations: a magnetoencephalography study Specialist Centre for Spinal Surgery, Hospital Neustadt, Neus- tadt in Holstein, Germany. Cheng, Y; Yang, CY; Lin, CP; Lee, PL; Decety, J ABSTRACT: CHRONIC PAIN IS MAINLY A RESULT OF Institute of Neuroscience, School of Life Science, National TWO PROCESSES: peripheral and central sensitization, Yang-Ming University, Taipei, Taiwan. which can result in neuroplastic changes. Previous psychophysical studies suggested a decrease of the

116 so-called pain-inhibiting-pain effect (DNIC) in chronic healthy subjects. The subject's task was to count rare pain patients. We aimed to study the DNIC effect on the painful electrical stimuli applied to one finger, while ig- neuronal level using magnetoencephalography and noring frequent stimuli at a different finger. A high de- electroencephalography in 12 patients suffering from tection ratio was observed for all blocks and subjects. advanced unilateral knee osteoarthritis (OA). DNIC was Early evoked oscillations in the delta-band increased induced in patients by provoking the typical OA pain with higher stimulus intensity and directed attention, by a slightly hyperextended joint position, while they most prominently at contralateral sensorimotor sites. received short electrical pain stimuli. Although the Furthermore, suppression and rebound of beta activ- patients did not report a reduction of electrical pain ity were observed after painful stimulation. Moreover, perception, the cingulate gyrus showed a decrease of induced oscillatory activity in the high gamma-band activation during provoked OA pain, while activity in increased with directed attention, an effect being the secondary somatosensory cortex did not change. significantly stronger for high compared with low Based on much stronger DNIC induction at comparable stimulus intensity. Coupling analysis performed for this intensities of an acute counterirritant pain in healthy high gamma response revealed stronger functional subjects this result suggests a deficit of DNIC in OA pa- interactions between ipsilateral and contralateral sites tients. We suggest that the strength of DNIC is subject during attention. We conclude that pain-induced high- to neuronal plasticity of descending inhibitory pain frequency activity in sensorimotor areas may reflect systems and diminishes during the development of a an attentional augmentation of processing, leading to chronic pain condition. (21197282) enhanced saliency of pain-related signals and thus to more efficient processing of this information by down- Keywords: DNIC; EEG; MEG; chronic pain; counterirritation; stream cortical centers. (17728441) osteoarthritis J Neurosci (2007), Vol. 27, No. 35, pp. 9270-7 J Pain Res (2011), Vol. 1, pp. 1-8

Attention to painful stimulation enhances gamma- band activity and synchronization in human sensorimotor cortex

Hauck, M; Lorenz, J; Engel, AK

Department of Neurophysiology and Pathophysiology, Uni- versity Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. [email protected]

ABSTRACT: A number of cortical regions are involved in processing pain-related information. The SI and SII somatosensory cortices process mainly sensory discriminative attributes but also play an important role in recognition and memory of painful events. Regions such as SII and the posterior insula appear to be the first stations that house processes by which attention profoundly shapes both behavioral responses and subjective pain experience. We investigated the influence of directed attention on pain-induced oscillations and synchronization processes using magnetoencephalogram in combination with an oddball paradigm in 20

117 118 Parkinson's Disease Keywords: Cortical responses; Deep brain stimulation; Magnetoencephalography

Distinct cortical responses evoked by electrical Neuroimage Clin (2019), Vol. 20, pp. 1246-1254 stimulation of the thalamic ventral intermediate nucleus and of the subthalamic nucleus The significance of brain oscillations in motor Hartmann, CJ; Hirschmann, J; Vesper, J; sequence learning: Insights from Parkinson's Wojtecki, L; Butz, M; Schnitzler, A disease

Department of Neurology, Medical Faculty, Heinrich-Heine Meissner, SN; Krause, V; Südmey- University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, er, M; Hartmann, CJ; Pollok, B Germany; Institute of Clinical Neuroscience and Medical Psy- chology, Medical Faculty, Heinrich-Heine University Düssel- Institute of Clinical Neuroscience and Medical Psychology, dorf, Moorenstrasse 5, 40225 Düsseldorf, Germany. Electronic Medical Faculty, Heinrich-Heine-University, Duesseldorf, Ger- address: [email protected]. many. Electronic address: sarah.meissner@uni-duesseldorf. de. OBJECTIVE: To investigate the spatial and temporal pattern of cortical responses evoked by deep brain ABSTRACT: Motor sequence learning plays a pivotal stimulation (DBS) of the subthalamic nucleus (STN) role in various everyday activities. Motor-cortical beta and ventral intermediate nucleus of the thalamus oscillations have been suggested to be involved in this (VIM). METHODS: We investigated 7 patients suffering type of learning. In Parkinson's disease (PD), oscillatory from Essential tremor (ET) and 7 patients with Parkin- activity within cortico-basal-ganglia circuits is altered. son's Disease (PD) following the implantation of DBS Pathologically increased beta oscillations have received electrodes (VIM for ET patients, STN for PD patients). particular attention as they may be associated with Magnetoencephalography (MEG) was used to record motor symptoms such as akinesia. In the present mag- cortical responses evoked by electric stimuli that were netoencephalography (MEG) study, we investigated applied via the DBS electrode in trains of 5 Hz. Dipole PD patients and healthy controls (HC) during implicit fitting was applied to reconstruct the origin of evoked motor sequence learning with the aim to shed light on responses. RESULTS: Both VIM and STN DBS led to the relation between changes of cortical brain oscilla- short latency cortical responses at about 1 ms. The tions and motor learning in PD with a particular focus pattern of medium and long latency cortical responses on beta power. To this end, 20 PD patients (ON medica- following VIM DBS consisted of peaks at 13, 40, 77, tion) and 20 age- and sex-matched HC were trained on and 116 ms. The associated equivalent dipoles were a serial reaction time task while neuromagnetic activity localized within the central sulcus, 3 patients showed was recorded using a 306-channel whole-head MEG an additional response in the cerebellum at 56 ms. STN system. PD patients showed reduced motor sequence DBS evoked cortical responses peaking at 4 ms, 11 ms, acquisition and were more susceptible to interference and 27 ms, respectively. While most dipoles were local- by random trials after training on the task as com- ized in the pre- or postcentral gyrus, the distribution pared to HC. Behavioral differences were paralleled by was less homogenous compared to VIM stimulation changes at the neurophysiological level. Diminished and partially included prefrontal brain areas. CONCLU- sequence acquisition was paralleled by less training- SION: MEG enables localization of cortical responses related beta power suppression in motor-cortical evoked by DBS of the VIM and the STN, especially in the areas in PD patients as compared to HC. In addition, sensorimotor cortex. Short latency responses of 1 ms PD patients exhibited reduced training-related theta suggest cortical modulation which bypasses synaptic activity in motor-cortical areas paralleling susceptibil- transmission, i.e. antidromic activation of corticofugal ity to interference. The results support the hypothesis fiber pathways. (30420259) that the acquisition of a new motor sequence relies on suppression of motor-cortical beta oscillations, while

119 motor-cortical theta activity might be related to stabili- Keywords: Advanced Parkinson’s disease; Beta band sup- zation of the learned sequence as indicated by reduced pression; Deep brain stimulation; Magnetoencephalogra- susceptibility to interference. Both processes appear to phy; Subthalamic nucleus be impaired in PD. (30128283) Neurosci Lett (2019), Vol. 683, pp. 48-53 Keywords: Implicit motor learning; Interference; Magne- toencephalography (MEG); Motor control; Oscillatory beta activity; SRTT Changes in resting-state directed connectivity in cortico-subcortical networks correlate with Neuroimage Clin (2019), Vol. 20, pp. 448-457 cognitive function in Parkinson's disease

Boon, LI; Hillebrand, A; Olde Dub- Spontaneous sensorimotor cortical activity is belink, KTE; Stam, CJ; Berendse, HW suppressed by deep brain stimulation in patients with advanced Parkinson's disease Department of Neurology, Amsterdam Neuroscience, VU Uni- versity Medical Center, De Boelelaan 1117, 1081 HV Amster- Luoma, J; Pekkonen, E; Airaksinen, K; Helle, dam, The Netherlands. Electronic address: [email protected]. L; Nurminen, J; Taulu, S; Mäkelä, JP OBJECTIVE: The pathophysiological mechanisms BioMag Laboratory, HUS Medical Imaging Center, University underlying Parkinson's disease (PD)-related cognitive of Helsinki and Helsinki University Hospital, Finland. decline and conversion to PD dementia are poorly understood. In the healthy human brain, stable patterns ABSTRACT: Advanced Parkinson's disease (PD) is of posterior-to-anterior cortical information flow have characterized by an excessive oscillatory beta band recently been demonstrated in the higher frequency activity in the subthalamic nucleus (STN). Deep brain bands using magnetoencephalography (MEG). In this stimulation (DBS) of STN alleviates motor symptoms study we estimated PD-related changes in information in PD and suppresses the STN beta band activity. The flow patterns, as well as the contribution of subcorti- effect of DBS on cortical sensorimotor activity is more cal regions. METHODS: Resting-state MEG recordings ambiguous; both increases and decreases of beta band were acquired in moderately advanced PD patients activity have been reported. Non-invasive studies with (n=34; mean Hoehn and Yahr-stage 2.5) and healthy simultaneous DBS are problematic due to DBS-induced controls (n=12). MEG signals were projected to both artifacts. We recorded magnetoencephalography cortical and subcortical brain regions, following which (MEG) from 16 advanced PD patients with and without we estimated the balance between incoming and STN DBS during rest and wrist extension. The strong outgoing information flow per region. RESULTS: In PD magnetic artifacts related to stimulation were removed patients, compared to controls, preferential beta band by temporal signal space separation. MEG oscilla- information outflow was significantly higher for the tory activity at 5-25 Hz was suppressed during DBS basal ganglia and frontotemporal cortical regions, and in a widespread frontoparietal region, including the significantly lower for parieto-occipital regions. In ad- sensorimotor cortex identified by the cortico-muscular dition, in patients, low preferential information outflow coherence. The strength of suppression did not corre- from occipital regions correlated with poor global late with clinical improvement. Our results indicate that cognitive performance. CONCLUSION: In the PD brain, alpha and beta band oscillations are suppressed at the a shift in balance towards more anterior-to-posterior frontoparietal cortex by STN DBS in PD. (29940326) beta band information flow takes place and is associated with poorer cognitive performance. SIGNIFICANCE: Our results indicate that a reversal of the physiological posterior-to-anterior information flow may be an important mechanism in PD-related cognitive decline. (28558317)

120 Keywords: Atlas-based beamforming; Cognition; Direc- activity within cortico-basal-ganglia circuits. Deep brain tional connectivity; Magnetoencephalography (MEG); stimulation of the subthalamic nucleus is an effective Parkinson’s disease; Subcortical regions treatment for Parkinson's disease, but its influence on synchronous activity in cortico-basal-ganglia loops Clin Neurophysiol (2017), Vol. 128, No. 7, pp. 1319-1326 remains to be fully characterized. Here, we demonstrate that deep brain stimulation selectively suppresses certain spatially and spectrally segregated resting state Combined MEG and pT-TMS study in Parkinson's subthalamic nucleus-cortical networks. To this end we disease used a validated and novel approach for performing simultaneous recordings of the subthalamic nucleus Anninos, P; Adamopoulos, A; Kotini, A; Tsagas, N and cortex using magnetoencephalography (during concurrent subthalamic nucleus deep brain stimula- Laboratory of Medical Physics, School of Medicine, Democri- tion). Our results highlight that clinically effective tus University of Thrace, Alexandroupoli, 68100, Greece. subthalamic nucleus deep brain stimulation suppresses synchrony locally within the subthalamic nucleus in ABSTRACT: Magnetoencephalographic (MEG) record- the low beta oscillatory range and furthermore that ings of the brain in Parkinson's disease were obtained the degree of this suppression correlates with clinical in order to look for possible effect of pico-Tesla tran- motor improvement. Moreover, deep brain stimulation scranial magnetic stimulation (pT-TMS). We found a sig- relatively selectively suppressed synchronization of nificant effect of an increase of frequencies in the range activity between the subthalamic nucleus and mesial of 2-7 Hz across subjects. In addition, we observed the premotor regions, including the supplementary motor mean peak frequency difference within the 2-7 Hz band areas. These mesial premotor regions were predomi- towards frequencies of less or equal to those frequen- nantly coupled to the subthalamic nucleus in the high cies of the alpha frequency range (8-13 Hz). (27198581) beta frequency range, but the degree of deep brain stimulation-associated suppression in their coupling Keywords: MEG; Parkinson disease; double-blind design; to the subthalamic nucleus was not found to correlate pT-TMS with motor improvement. Beta band coupling between the subthalamic nucleus and lateral motor areas was J Integr Neurosci (2017), Vol. 15, No. 2, pp. 145-62 not influenced by deep brain stimulation. Motor cortical coupling with subthalamic nucleus predominantly involved driving of the subthalamic nucleus, with those Deep brain stimulation modulates synchrony drives in the higher beta frequency band having much within spatially and spectrally distinct resting state shorter net delays to subthalamic nucleus than those in networks in Parkinson's disease the lower beta band. These observations raise the possibility that cortical connectivity with the subthalamic Oswal, A; Beudel, M; Zrinzo, L; Limousin, P; nucleus in the high and low beta bands may reflect Hariz, M; Foltynie, T; Litvak, V; Brown, P coupling mediated predominantly by the hyperdirect and indirect pathways to subthalamic nucleus, respec- Nuffield Department of Clinical Neurosciences, John Radcliffe tively, and that subthalamic nucleus deep brain stimu- Hospital, Oxford, UK Medical Research Council Brain Network lation predominantly suppresses the former. Yet only Dynamics Unit, University of Oxford, UK Wellcome Trust Cen- the change in strength of local subthalamic nucleus tre for Neuroimaging, UCL Institute of Neurology, 12 Queen oscillations correlates with the degree of improvement Square, London, UK. during deep brain stimulation, compatible with the current view that a strengthened hyperdirect pathway ABSTRACT: Chronic dopamine depletion in Parkin- is a prerequisite for locally generated beta activity but son's disease leads to progressive motor and cognitive that it is the severity of the latter that may determine or impairment, which is associated with the emergence index motor impairment. (27017189) of characteristic patterns of synchronous oscillatory

121 Keywords: Parkinson’s disease; deep brain stimulation; to the interpretation of oscillatory activity within the local field potential; magnetoencephalography; resting cortico-basal ganglia circuit. (26971483) state networks Keywords: Beta oscillations; Cross-frequency coupling; Brain (2017), Vol. 139, No. Pt 5, pp. 1482-96 Local field potentials; Motor system; Parkinson’s disease; Subthalamic nucleus

Subthalamic nucleus phase-amplitude coupling Clin Neurophysiol (2016), Vol. 127, No. 4, pp. 2010-9 correlates with motor impairment in Parkinson's disease Effects of rhythmic stimulus presentation on van Wijk, BC; Beudel, M; Jha, A; Oswal, A; oscillatory brain activity: the physiology of cueing Foltynie, T; Hariz, MI; Limousin, P; Zrinzo, L; in Parkinson's disease Aziz, TZ; Green, AL; Brown, P; Litvak, V te Woerd, ES; Oostenveld, R; Bloem, Wellcome Trust Centre for Neuroimaging, UCL Institute of BR; de Lange, FP; Praamstra, P Neurology, 12 Queen Square, WC1N 3BG London, United Kingdom. Electronic address: vanwijk.bernadette@gmail. Dept. of Neurology, Radboud University Medical Centre, com. Radboud University, Nijmegen, The Netherlands ; Donders Institute for Brain, Cognition and Behaviour, Radboud Univer- OBJECTIVE: High-amplitude beta band oscillations sity, Nijmegen, The Netherlands. within the subthalamic nucleus are frequently associated with Parkinson's disease but it is unclear how they ABSTRACT: The basal ganglia play an important might lead to motor impairments. Here we investigate role in beat perception and patients with Parkinson's a likely pathological coupling between the phase of disease (PD) are impaired in perception of beat-based beta band oscillations and the amplitude of high- rhythms. Rhythmic cues are nonetheless beneficial in frequency oscillations around 300 Hz. METHODS: We gait rehabilitation, raising the question how rhythm analysed an extensive data set comprising resting- improves movement in PD. We addressed this question state recordings obtained from deep brain stimulation with magnetoencephalography recordings during a electrodes in 33 patients before and/or after taking choice response task with rhythmic and non-rhythmic dopaminergic medication. We correlated mean values modes of stimulus presentation. Analyses focused on (i) of spectral power and phase-amplitude coupling with entrainment of slow oscillations, (ii) the depth of beta severity of hemibody bradykinesia/rigidity. In addition, power modulation, and (iii) whether a gain in modu- we used simultaneously recorded magnetoencepha- lation depth of beta power, due to rhythmicity, is of lography to look at functional interactions between predictive or reactive nature. The results show weaker the subthalamic nucleus and ipsilateral motor cortex. phase synchronisation of slow oscillations and a rela- RESULTS: Beta band power and phase-amplitude tive shift from predictive to reactive movement-related coupling within the subthalamic nucleus correlated beta suppression in PD. Nonetheless, rhythmic stimulus positively with severity of motor impairment. This ef- presentation increased beta modulation depth to the fect was more pronounced within the low-beta range, same extent in patients and controls. Critically, this gain whilst coherence between subthalamic nucleus and selectively increased the predictive and not reactive motor cortex was dominant in the high-beta range. movement-related beta power suppression. Operation CONCLUSIONS: We speculate that the beta band of a predictive mechanism, induced by rhythmic stimu- might impede pro-kinetic high-frequency activity pat- lation, was corroborated by a sensory gating effect in terns when phase-amplitude coupling is prominent. the sensorimotor cortex. The predictive mode of cue Furthermore, results provide evidence for a functional utilisation points to facilitation of basal ganglia-pre- subdivision of the beta band into low and high fre- motor interactions, contrasting with the popular view quencies. SIGNIFICANCE: Our findings contribute that rhythmic stimulation confers a special advantage

122 in PD, based on recruitment of alternative pathways. frequency increased significantly when stimulation was (26509117) on compared with off state. In addition, the relative power dropped in delta, whereas it rose in beta over Keywords: Basal ganglia; Beta oscillations; Magnetoen- the whole cortex. Through the course of stimulation, cephalography; Parkinson’s disease; Rhythmic cueing the Unified Parkinson Disease Rating Scale III rigidity and tremor scores correlated with the relative power of Neuroimage Clin (2016), Vol. 9, pp. 300-9 alpha over left parietal. CONCLUSIONS: Subthalamic nucleus deep brain stimulation improves the symptoms of PD by suppressing the synchronization of alpha Resting state cortical oscillations of patients rhythm in somatomotor region. (25233246) with Parkinson disease and with and without subthalamic deep brain stimulation: a J Clin Neurophysiol (2016), Vol. 32, No. 2, pp. 109-18 magnetoencephalography study

Cao, C; Li, D; Jiang, T; Ince, NF; Zhan, Cortico-muscular coherence in advanced S; Zhang, J; Sha, Z; Sun, B Parkinson's disease with deep brain stimulation

Department of Functional Neurosurgery, Affiliated Ruijin Airaksinen, K; Mäkelä, JP; Nurminen, J; Luoma, Hospital, Shanghai JiaoTong University School of Medicine, J; Taulu, S; Ahonen, A; Pekkonen, E Shanghai, China; †Department of Biomedical Engineering, University of Houston, Houston, Texas, U.S.A.; and ‡Depart- BioMag Laboratory, HUS Medical Imaging Center, Helsinki ment of Neurology, University of Minnesota, Minneapolis, University Central Hospital, Finland; Department of Neurol- Minnesota, U.S.A. ogy, Helsinki University Central Hospital, Finland. Electronic address: [email protected]. PURPOSE: In this study, we investigate the modification to cortical oscillations of patients with Parkinson OBJECTIVE: Cortico-muscular coherence (CMC) is disease (PD) by subthalamic deep brain stimulation thought to reflect the interplay between cortex and (STN-DBS). METHODS: Spontaneous cortical oscilla- muscle in motor coordination. In Parkinson's disease tions of patients with PD were recorded with magne- (PD) patients, levodopa has been shown to enhance toencephalography during on and off subthalamic CMC. This study examined whether subthalamic nucleus deep brain stimulation states. Several features nucleus (STN) deep brain stimulation (DBS) affects the such as average frequency, average power, and relative CMC in advanced PD. METHODS: Magnetoencepha- subband power in regions of interest were extracted lography (MEG) and electromyography (EMG) measure- in the frequency domain, and these features were cor- ments were done simultaneously both with DBS on and related with Unified Parkinson Disease Rating Scale III off to determine the CMC during wrist extension. The evaluation. The same features were also investigated in spatiotemporal signal space separation (tSSS) was used patients with PD without surgery and healthy controls. for artifact suppression. RESULTS: CMC peaks between RESULTS: Patients with Parkinson disease without 13 and 25 Hz were found in 15 out of 19 patients. The surgery compared with healthy controls had a signifi- effect of DBS on CMC was variable. Moreover, the cor- cantly lower average frequency and an increased aver- relation between CMC and motor performance was age power in 1 to 48 Hz range in whole cortex. Higher inconsistent; stronger CMC did not necessarily indicate relative power in theta and simultaneous decrease in better function albeit tremor and rigidity may diminish beta and gamma over temporal and occipital were also the CMC. Patients having CMC between 13 and 25 Hz observed in patients with PD. The Unified Parkinson had the best motor scores at the group level. CONCLU- Disease Rating Scale III rigidity score correlated with SIONS: DBS modifies the CMC in advanced PD with the average frequency and with the relative power large interindividual variability. SIGNIFICANCE: DBS of beta and gamma in frontal areas. During subtha- does not systematically modify CMC amplitude in ad- lamic nucleus deep brain stimulation, the average vanced PD. The results suggest that some components

123 of the CMC may be related to the therapeutic effects of power > median (HR 2.82; p = 0.037). In combination, DBS. (25218364) baseline cognitive performance and neurophysiologic measures had even stronger predictive value, with Keywords: Cortico-muscular coherence; Deep brain stim- the combination of impaired fronto-executive task ulation; Magnetoencephalography; Parkinson disease; performance and low beta power being associated Rigidity; Subthalamic nucleus with the highest dementia risk (both risk factors vs none: HR 27.3; p < 0.001). CONCLUSIONS: Combining Clin Neurophysiol (2015), Vol. 126, No. 4, pp. 748-55 neurophysiologic markers with cognitive assessment can substantially improve dementia risk profiling in PD, providing potential benefits for clinical care as well as Predicting dementia in Parkinson disease by for the future development of therapeutic strategies. combining neurophysiologic and cognitive markers (24353335)

Olde Dubbelink, KT; Hillebrand, A; Twisk, JW; Deijen, Neurology (2014), Vol. 82, No. 3, pp. 263-70 JB; Stoffers, D; Schmand, BA; Stam, CJ; Berendse, HW

From the Department of Neurology, Neuroscience Campus Neuromagnetic evidence of abnormal movement- Amsterdam (K.T.E.O.D., D.S., H.W.B.), Department of Clinical related beta desynchronization in Parkinson's Neurophysiology and Magnetoencephalography Center disease (A.H., C.J.S.), and Department of Clinical Epidemiology and Biostatistics (J.W.R.T.). VU University Medical Center, Am- Heinrichs-Graham, E; Wilson, TW; Santamaria, PM; sterdam; Department of Clinical Neuropsychology (J.B.D.), Heithoff, SK; Torres-Russotto, D; Hutter-Saunders, JA; VU University, Amsterdam; and Department of Psychology Estes, KA; Meza, JL; Mosley, RL; Gendelman, HE (B.A.S.), University of Amsterdam, the Netherlands. Department of Psychology, University of Nebraska, Omaha, OBJECTIVE: To assess the ability of neurophysiologic NE, USA, Center for Magnetoencephalography. markers in conjunction with cognitive assessment to improve prediction of progression to dementia in ABSTRACT: Parkinson's disease (PD) is a neurodegen- Parkinson disease (PD). METHODS: Baseline cognitive erative disorder associated with debilitating mo- assessments and magnetoencephalographic record- tor, posture, and gait abnormalities. Human studies ings from 63 prospectively included PD patients with- recording local field potentials within the subthalamic out dementia were analyzed in relation to PD-related nucleus and scalp-based electroencephalography have dementia (PDD) conversion over a 7-year period. We shown pathological beta synchronization throughout computed Cox proportional hazard models to assess the cortical-basal ganglia motor network in PD. Sup- the risk of converting to dementia conveyed by cogni- pression of such pathological beta synchronization tive and neurophysiologic markers in individual as well has been associated with improved motor function, as combined risk factor analyses. RESULTS: Nineteen which may explain the effectiveness of deep-brain patients (30.2%) developed dementia. Baseline cogni- stimulation. We used magnetoencephalography (MEG) tive performance and neurophysiologic markers each to investigate neural population-level beta responses, individually predicted conversion to PDD. Of the cogni- and other oscillatory activity, during a motor task in tive test battery, performance on a posterior (pattern unmedicated patients with PD and a matched group of recognition memory score < median; hazard ratio (HR) healthy adults. MEG is a noninvasive neurophysiologi- 6.80; p = 0.001) and a fronto-executive (spatial span cal technique that permits the recording of oscillatory score < median; HR 4.41; p = 0.006) task most strongly activity during movement planning, execution, and predicted dementia conversion. Of the neurophysi- termination phases. Each of these phases was indepen- ologic markers, beta power < median was the strongest dently examined using beamforming to distinguish the PDD predictor (HR 5.21; p = 0.004), followed by peak brain areas and movement phases, where pathological frequency < median (HR 3.97; p = 0.016) and theta oscillations exist during motor control. Patients with PD

124 exhibited significantly diminished beta desynchroniza- is more marked in the on than in the off dopaminergic tion compared with controls prior to and during move- medication state. The difference in alpha band coher- ment, which paralleled reduced alpha desynchroniza- ence on and off medication was found to correlate with tion. This study is the first to systematically investigate the drug related improvement in clinical parameters. neural oscillatory responses in PD during distinct stages Overall, the movement-related behaviour of activities of motor control (e.g. planning, execution, and termina- in the alpha band in patients with PD serves to high- tion) and indicates that these patients have significant light the role of dopamine in modulating large-scale, difficulty suppressing cortical beta synchronization interregional synchronisation. (23277109) during movement planning, which may contribute to their diminished movement capacities. (23645717) Neuroimage (2013), Vol. 70, pp. 132-42

Keywords: MEG; cortex; magnetoencephalography; motor control; oscillations Differential modulation of STN-cortical and cortico- muscular coherence by movement and levodopa in Cereb Cortex (2015), Vol. 24, No. 10, pp. 2669-78 Parkinson's disease

Hirschmann, J; Özkurt, TE; Butz, M; Homburger, M; Elben, Movement related dynamics of subthalmo-cortical S; Hartmann, CJ; Vesper, J; Wojtecki, L; Schnitzler, A alpha connectivity in Parkinson's disease Institute of Clinical Neuroscience and Medical Psychology, Oswal, A; Brown, P; Litvak, V Medical Faculty, Heinrich-Heine-University Düsseldorf, Düs- seldorf, Germany. Wellcome Trust Centre for Neuroimaging, UCL Institute of Neurology, 12 Queen Square, London WC1N 3BG, UK. ABSTRACT: Previous research suggests that oscillatory coupling between cortex, basal ganglia and muscles ABSTRACT: Functional neurosurgical techniques plays an important role in motor behavior. Further- provide a unique opportunity to explore patterns of more, there is evidence that oscillatory coupling is interaction between the cerebral cortex and basal altered in patients with movement disorders such as ganglia in patients with Parkinson's disease (PD). Parkinson's disease (PD). In this study, we performed Previous work using simultaneous magnetoencephalo- simultaneous magnetoencephalography (MEG), local graphic (MEG) and local field potential (LFP) recordings field potential (LFP) and electromyogram (EMG) record- from the region of the subthalamic nucleus (STNr) has ings in PD patients selected for therapeutic subtha- characterised resting patterns of connectivity in the lamic nucleus (STN) stimulation. Patients were recorded alpha and beta frequency bands and their modula- (i) after withdrawal of anti-parkinsonian medication tion by dopaminergic medication. Recently we have (OFF) and (ii) after levodopa administration (ON). We also characterised the effect of movement on patterns analyzed STN-cortical and cortico-muscular coherence of gamma band coherence between the STNr and during static forearm contraction and repetitive hand cortical sites. Here we specifically investigate how the movement in order to evaluate modulations of coher- prominent coherence between the STNr and temporal ence by movement and medication. Based on previous cortex in the alpha band is modulated by movement results from studies investigating resting state coher- both on and off dopaminergic medication in patients ence in PD patients, we selected primary motor cortex following the insertion of Deep Brain Stimulation (DBS) (M1) and superior temporal gyrus (STG) as regions of electrodes. We show that movement is associated with interest. We found beta coherence between M1 and a suppression of local alpha power in the temporal STN to be suppressed by administration of levodopa. cortex and STNr that begins about 2s prior to a self- M1-muscular coherence was strongly reduced in the paced movement and is independent of dopaminergic alpha and beta band during repetitive movement status. In contrast, the peak reduction in coherence compared to static contraction, but was unaffected by between these sites occurs after movement onset and administration of levodopa. Strong STG-STN but not

125 STG-muscular coherence could be observed in the al- the two structures. We observed discrete peaks in M1 pha band. Coherence with STG was modulated neither and STN power at 60-90 Hz and at 300-400 Hz. All these by movement nor by medication. Finally, we found power peaks increased with movement and levodopa both M1-STN and M1-muscular beta coherence to be treatment. Only STN activity at 60-90 Hz was coher- negatively correlated with UPDRS akinesia and rigidity ent with activity in M1. Directionality analysis showed sub-scores in the OFF state. The present study provides that STN gamma activity at 60-90 Hz tended to drive new insights into the functional roles of STN-cortical gamma activity in M1. The effects of levodopa on both and cortico-muscular coherence and their relationship local and distant synchronization at 60-90 Hz correlated to PD symptoms. The results indicate that STN-cortical with the degree of improvement in bradykinesia-rigid- and cortico-muscular coupling are correlated, but can ity as did local STN activity at 300-400 Hz. Despite this, be modulated independently. Moreover, they show there were no effects of movement type, nor interac- differences in their frequency-specific topography. We tions between movement type and levodopa in the conclude that they represent partly independent sub- STN, nor in the coherence between STN and M1. We loops within the motor system. Given their negative conclude that synchronization at 60-90 Hz in the basal correlation with akinesia, neither can be considered ganglia cortical network is prokinetic but likely through "antikinetic". (23247184) a modulatory effect rather than any involvement in explicit motor processing. (22855804) Neuroimage (2013), Vol. 68, pp. 203-13 J Neurosci (2012), Vol. 32, No. 31, pp. 10541-53

Movement-related changes in local and long-range synchronization in Parkinson's disease revealed Motor-cortical oscillations in early stages of by simultaneous magnetoencephalography and Parkinson's disease intracranial recordings Pollok, B; Krause, V; Martsch, W; Wach, Litvak, V; Eusebio, A; Jha, A; Oostenveld, R; C; Schnitzler, A; Südmeyer, M Barnes, G; Foltynie, T; Limousin, P; Zrinzo, L; Hariz, MI; Friston, K; Brown, P University of Düsseldorf, Medical Faculty, Institute of Clinical Neuroscience and Medical Psychology, Department of Neu- Sobell Department of Motor Neuroscience, UCL Institute of rology, Düsseldorf, Germany. bettina.pollok@uni-duesseldorf. Neurology, London, WC1N 3BG, United Kingdom, Depart- de ment of Clinical Neurology, University of Oxford, Oxford, OX3 9DU, United Kingdom. [email protected] ABSTRACT: Pathophysiological changes in basal ganglia-thalamo-cortical circuits are well established in ABSTRACT: Functional neurosurgery has afforded the idiopathic Parkinson's disease (PD). However, it remains opportunity to assess interactions between popula- open whether such alterations already occur at early tions of neurons in the human cerebral cortex and stages representing a characteristic neurophysiologi- basal ganglia in patients with Parkinson's disease cal marker of PD. Therefore, the present study aims (PD). Interactions occur over a wide range of frequen- at elucidating changes of synchronised oscillatory cies, and the functional significance of those >30 Hz activity in early PD patients. In this study, we performed is particularly unclear. Do they improve movement, whole-head magnetoencephalography (MEG) in a and, if so, in what way? We acquired simultaneously resting condition and during steady state contraction magnetoencephalography and direct recordings from of the more severely affected forearm in 10 drug–na- the subthalamic nucleus (STN) in 17 PD patients. We ex- ive, de novo patients, in 10 early-stage patients with amined the effect of synchronous and sequential finger chronic medication and in 10 age-matched control movements and of the dopamine prodrug levodopa subjects. While cortico-muscular coherence (CMC) did on induced power in the contralateral primary motor not differ between groups, patients showed increased cortex (M1) and STN and on the coherence between sensori-motor cortical power at beta frequency (13–30

126 Hz) during rest as well as during isometric contraction In PD patients, decreasing cognitive performance was compared to controls. In healthy control subjects the associated with increases in delta and theta power, as power of the contralateral hemisphere was significantly well as decreases in alpha1, alpha2, and gamma power, suppressed during isometric contraction. By contrast, whereas increasing motor impairment was associated both hemispheres were activated equally strongly in with a theta power increase only. The present longitu- de novo patients. In medicated patients, the pattern dinal study revealed widespread progressive slowing was found to be reversed. Contralateral beta power was of oscillatory brain activity in initially nondemented significantly correlated with motor impairment during PD patients, independent of aging effects. The slow- isometric contraction but not during rest. The present ing of oscillatory brain activity strongly correlated with results suggest that the reduced ability of the primary cognitive decline and therefore holds promise as an motor cortex to disengage from increased beta band early marker for the development of dementia in PD. oscillations during the execution of movements is an (22495052) early marker of PD. (22547636) Neurobiol Aging (2013), Vol. 34, No. 2, pp. 408-18 J Physiol (2013), Vol. 590, No. 13, pp. 3203-12

Complexity analysis of resting-state MEG activity in Cognitive decline in Parkinson's disease is early-stage Parkinson's disease patients associated with slowing of resting-state brain activity: a longitudinal study Gómez, C; Olde Dubbelink, KT; Stam, CJ; Abá- solo, D; Berendse, HW; Hornero, R Olde Dubbelink, KT; Stoffers, D; Deijen, JB; Twisk, JW; Stam, CJ; Berendse, HW E T S Ingenieros de Telecomunicación, University of Vallado- lid, Valladolid, Spain. [email protected] Department of Neurology, Neuroscience Campus Amster- dam, VU University Medical Center, Amsterdam, The Nether- ABSTRACT: The aim of the present study was to lands. [email protected] analyze resting-state brain activity in patients with Parkinson's disease (PD), a degenerative disorder of ABSTRACT: The pathophysiological mechanisms of the nervous system. Magnetoencephalography (MEG) Parkinson's disease (PD)-related dementia (PDD) are signals were recorded with a 151-channel whole-head still poorly understood. Previous studies using electro- radial gradiometer MEG system in 18 early-stage un- encephalography (EEG) and magnetoencephalography treated PD patients and 20 age-matched control sub- (MEG) have demonstrated widespread slowing of oscil- jects. Artifact-free epochs of 4 s (1250 samples) were latory brain activity as a neurophysiological charac- analyzed with Lempel-Ziv complexity (LZC), applying teristic of PD-related dementia. Here, we use MEG to two- and three-symbol sequence conversion methods. longitudinally study early changes in oscillatory brain The results showed that MEG signals from PD patients activity in initially nondemented PD patients that may are less complex than control subjects' recordings. We be associated with cognitive decline. Using a longitudi- found significant group differences (p-values <0.01) for nal design, resting-state MEG recordings were per- the 10 major cortical areas analyzed (e.g., bilateral fron- formed twice at an approximate 4-year interval in 14 tal, central, temporal, parietal, and occipital regions). In healthy controls and 49 PD patients. Changes in peak addition, using receiver-operating characteristic curves frequency and in relative spectral power for 10 brain with a leave-one-out cross-validation procedure, a clas- regions were analyzed in relation to clinical measures sification accuracy of 81.58% was obtained. In order to of cognitive and motor function. In contrast to healthy investigate the best combination of LZC results for clas- controls, PD patients showed a slowing of the domi- sification purposes, a forward stepwise linear discriminant peak frequency. Furthermore, analysis per fre- nant analysis with leave-one out cross-validation was quency band revealed an increase in theta power over employed. LZC results (three-symbol sequence conver- time, along with decreases in alpha1 and alpha2 power. sion) from right parietal and temporal brain regions

127 were automatically selected by the model. With this Neuroimage (2011), Vol. 55, No. 3, pp. 1159-68 procedure, an accuracy of 84.21% (77.78% sensitivity, 90.0% specificity) was achieved. Our findings demonstrate the usefulness of LZC to detect an abnormal type Slowing of M1 activity in Parkinson's disease during of dynamics associated with PD. (21969108) rest and movement--an MEG study

Ann Biomed Eng (2012), Vol. 39, No. 12, pp. 2935-44 Vardy, AN; van Wegen, EE; Kwakkel, G; Berendse, HW; Beek, PJ; Daffertshofer, A

Distinct oscillatory STN-cortical loops revealed Faculty of Human Movement Sciences, Research Institute by simultaneous MEG and local field potential MOVE, VU University Amsterdam, Amsterdam, The Nether- recordings in patients with Parkinson's disease lands. [email protected]

Hirschmann, J; Özkurt, TE; Butz, M; Homburger, M; Elben, OBJECTIVE: Parkinson's disease is characterized by S; Hartmann, CJ; Vesper, J; Wojtecki, L; Schnitzler, A motor and cognitive problems that are accompanied by slowing of neural activity. This study examined Institute of Clinical Neuroscience and Medical Psychology, the relationship between neural slowing and disease Medical Faculty, Heinrich-Heine-University Düsseldorf, Düs- severity during rest and motor performance. METH- seldorf, Germany. ODS: Primary motor activity was assessed by means of magnetoencephalography during rest and rhythmic ABSTRACT: Neuronal oscillations are assumed to play movements. Motor output and event-related cortical a pivotal role in the pathophysiology of Parkinson's power in the alpha and beta frequency bands were disease (PD). Neurons in the subthalamic nucleus (STN) determined. UPDRS total and subscores were used to generate oscillations which are coupled to rhythmic pinpoint correlates of neural slowing (change of power population activity both in other basal ganglia nuclei towards lower frequencies) during both resting state and cortical areas. In order to localize these cortical and the production of rhythmic movements. RESULTS: areas, we recorded local field potentials (LFPs) and By design, motor performance was similar for both the magnetoencephalography (MEG) simultaneously in PD patients and the controls. PD patients showed slowing patients undergoing surgery for deep brain stimulation of neural activity which increased with disease sever- (DBS). Patients were withdrawn from antiparkinsonian ity. Slowing during rest showed the clearest correlation medication and recorded at rest. We scanned the entire with cognitive UPDRS subscores, whereas slowing dur- brain for oscillations coherent with LFPs recorded from ing movement correlated best with the motor UPDRS the STN with a frequency domain beamformer. Coher- subscore. CONCLUSIONS: These results suggest that ent activity in the low (12-20 Hz) and high (20-35 Hz) slowing is functionally modulated and that different beta range was found in the ipsilateral sensorimotor mechanisms are responsible for neural slowing during and the premotor cortex. Coherence in the alpha range rest versus movement. SIGNIFICANCE: Neural slowing (7-12 Hz) was observed at various locations in the must be viewed in a broader context than previously ipsilateral temporal lobe. In a subset of subjects, the thought because it is not solely related to impaired superior temporal gyrus consistently showed coherent motor performance but also to impaired cognition. alpha oscillations. Our findings provide new insights (21109487) into patterns of frequency-specific functional connectivity between basal ganglia and cortex and suggest that simultaneous inter-regional interactions may be segregated in the frequency domain. Furthermore, they demonstrate that simultaneous MEG-LFP recordings are a powerful tool to study interactions between brain areas in PD patients undergoing surgery for DBS. (21122819)

128 Clin Neurophysiol (2011), Vol. 122, No. 4, pp. 789-95 Hum Brain Mapp (2011), Vol. 32, No. 7, pp. 1091-9

Effects of DBS on auditory and somatosensory Dopaminergic modulation of cortico-cortical processing in Parkinson's disease functional connectivity in Parkinson's disease: an MEG study Airaksinen, K; Mäkelä, JP; Taulu, S; Ahonen, A; Nurminen, J; Schnitzler, A; Pekkonen, E Stoffers, D; Bosboom, JL; Wolt- ers, ECh; Stam, CJ; Berendse, HW BioMag Laboratory, HUSLAB, Helsinki University Central Hos- pital (HUCH), Finland. [email protected] Institute for Clinical and Experimental Neurosciences, Depart- ment of Neurology, VU University Medical Center, Amster- ABSTRACT: Motor symptoms of Parkinson's disease dam, The Netherlands. [email protected] (PD) can be relieved by deep brain stimulation (DBS). The mechanism of action of DBS is largely unclear. ABSTRACT: Recent studies have demonstrated Magnetoencephalography (MEG) studies on DBS pa- increased resting-state cortico-cortical functional tients have been unfeasible because of strong mag- connectivity in untreated Parkinson's disease (PD). netic artifacts. An artifact suppression method known We set out to determine whether this connectivity as spatiotemporal signal space separation (tSSS) has can be modulated by dopamine replacement therapy mainly overcome these difficulties. We wanted to clarify (DRT) and explore the relationship of therapy-induced whether tSSS enables noninvasive measurement of the changes in connectivity with motor improvement in modulation of cortical activity caused by DBS. We have the relatively early stages of DRT in PD. Whole-head studied auditory and somatosensory-evoked fields magnetoencephalography was performed in an (AEFs and SEFs) of advanced PD patients with bilateral eyes-closed resting-state condition in 37 patients with subthalamic nucleus (STN) DBS using MEG. AEFs were levodopa-treated PD (Hoehn and Yahr stages 1-3) both elicited by 1-kHz tones and SEFs by electrical pulses in a practically defined "OFF" and in the "ON" medica- to the median nerve with DBS on and off. Data could tion state. Data analysis involved calculation of three be successfully acquired and analyzed from 12 out synchronisation likelihood (SL; a general measure of of 16 measured patients. The motor symptoms were linear and non-linear temporal correlations between significantly relieved by DBS, which clearly enhanced time series) measures which reflect functional coupling the ipsilateral auditory N100m responses in the right within and between ten major cortical areas in five hemisphere. Contralateral N100m responses and frequency bands. The transition from the "OFF" to the somatosensory P60m responses also had a tendency "ON" state led to increases of SL in the 4-30 Hz range, to increase when bilateral DBS was on. MEG with tSSS most conspicuously with regard to local SL, in tandem offers a novel and powerful tool to investigate DBS with motor improvement. We found a negative correla- modulation of the evoked cortical activity in PD with tion between the change in local beta SL and the re- high temporal and spatial resolution. The results sug- duction of parkinsonism after DRT. Patients presenting gest that STN-DBS modulates auditory processing in with relatively large motor responses (41% or better) advanced PD. Hum Brain Mapp, 2011. © 2010 Wiley- actually showed decreases in local beta SL. The present Liss, Inc. (20645306) study shows that the already elevated levels of resting- state cortico-cortical functional connectivity in the 4-30 Hz range in mild to moderate PD are on average increased even further by DRT. However, a strong motor response appears to be associated with decreases in local beta-band coupling, which may constitute a risk factor for the development of motor response fluctuations or dyskinesias. (18590728)

129 Exp Neurol (2008), Vol. 213, No. 1, pp. 191-5 Neuroimage (2008), Vol. 41, No. 2, pp. 212-22

Increased cortico-cortical functional connectivity in early-stage Parkinson's disease: an MEG study

Stoffers, D; Bosboom, JL; Deijen, JB; Wolt- ers, ECh; Stam, CJ; Berendse, HW

Institute for Clinical and Experimental Neurosciences, Depart- ment of Neurology, VU University Medical Center, Amster- dam, The Netherlands. [email protected]

ABSTRACT: We set out to determine whether changes in resting-state cortico-cortical functional connectivity are a feature of early-stage Parkinson's disease (PD), explore how functional coupling might evolve over the course of the disease and establish its relationship with clinical deficits. Whole-head magnetoencephalography was performed in an eyes-closed resting-state condition in 70 PD patients with varying disease duration (including 18 recently diagnosed, drug-naive patients) in an "OFF" medication state and 21 controls. Neuro- psychological testing was performed in all subjects. Data analysis involved calculation of three synchronization likelihood (SL, a general measure of linear and non-linear temporal correlations between time series) measures which reflect functional connectivity within (local) and between (intrahemispheric and interhemispheric) ten major cortical regions in five frequency bands. Recently diagnosed, drug-naive patients showed an overall increase in alpha1 SL relative to controls. Cross-sectional analysis in all patients revealed that disease duration was positively associated with alpha2 and beta SL measures, while severity of parkinsonism was positively associated with theta and beta SL measures. Moderately advanced patients had increases in theta, alpha1, alpha2 and beta SL, particularly with regard to local SL. In recently diagnosed patients, cognitive perseveration was associated with increased interhemispheric alpha1 SL. Increased resting-state cortico-cortical functional connectivity in the 8-10 Hz alpha range is a feature of PD from the earliest clinical stages onward. With disease progression, neighboring frequency bands become increasingly involved. These findings suggest that changes in functional coupling over the course of PD may be linked to the topographical progression of pathology over the brain. (18395468)

130 Post-traumatic Stress Keywords: Amygdala; Functional connectivity; Implicit emotional face processing; Magnetoencephalography Disorder (MEG); Military combat soldiers; Post-traumatic stress disorder; Prefrontal cortex Post-traumatic stress disorder and chronic hyperconnectivity in emotional processing Neuroimage Clin (2019), Vol. 20, pp. 197-204

Dunkley, BT; Wong, SM; Jetly, R; Wong, JK; Taylor, MJ Increased Small-World Network Topology Following Department of Diagnostic Imaging, The Hospital for Sick Deployment-Acquired Traumatic Brain Injury Children, Toronto, Canada; Neurosciences & Mental Health Associated with the Development of Post-Traumatic Program, The Hospital for Sick Children Research Institute, To- Stress Disorder ronto, Canada; Department of Medical Imaging, University of Toronto, Toronto, Canada. Electronic address: ben.dunkley@ Rowland, JA; Stapleton-Kotloski, JR; Dob- sickkids.ca. bins, DL; Rogers, E; Godwin, DW; Taber, KH

ABSTRACT: Post-traumatic stress disorder (PTSD) is 1 Research and Academic Affairs Service Line, W.G. "Bill" Hef- associated with heightened responses to threaten- ner VA Medical Center , Salisbury, North Carolina. ing stimuli, particularly aggression-related emotional facial expressions. The stability over time of this ABSTRACT: Cross-sectional and longitudinal studies in neurophysiological 'hyperactive' threat response has active duty and veteran cohorts have both demonstrat- not been determined. We studied implicit emotional ed that deployment-acquired traumatic brain injury face processing in soldiers with and without PTSD at (TBI) is an independent risk factor for developing post- two time-points (roughly 2 years apart) using mag- traumatic stress disorder (PTSD), beyond confounds netoencephalography to determine the response of such as combat exposure, physical injury, predeploy- oscillations and synchrony to happy and angry faces, ment TBI, and pre-deployment psychiatric symptoms. and the reliability of this marker for PTSD over time. This study investigated how resting-state brain net- At the initial time-point we had 20 soldiers with and works differ between individuals who developed PTSD 25 without PTSD; 35 returned for follow-up testing and those who did not following deployment-acquired 2 years later, and included 13 with and 22 without TBI. Participants included postdeployment veterans PTSD. A mixed-effects analysis was used. There were no with deployment-acquired TBI history both with and significant differences (albeit a slight reduction) in the without current PTSD diagnosis. Graph metrics, includ- severity of PTSD between the two time-points. MEG ing small-worldness, clustering coefficient, and modu- contrasts of the neurophysiological networks involved larity, were calculated from individually constructed in the processing of angry vs. happy faces showed that whole-brain networks based on 5-min eyes-open the PTSD group had elevated oscillatory connectivity resting-state magnetoencephalography (MEG) record- for angry faces. Maladaptive hypersynchrony in PTSD ings. Analyses were adjusted for age and premorbid for threatening faces was seen in subcortical regions, IQ. Results demonstrated that participants with cur- including the thalamus, as well as the ventromedial rent PTSD displayed higher levels of small-worldness, prefrontal cortex, cingulum gyri, inferior temporal and F(1,12) = 5.364, p < 0.039, partial eta squared = 0.309, parietal regions. These results are generally consistent and Cohen's d = 0.972, and clustering coefficient, F(1, with prior studies and our own, and we demonstrate 12) = 12.204, p < 0.004, partial eta squared = 0.504, and that this hyperconnectivity was stable over a two year Cohen's d = 0.905, than participants without current period, in line with essentially stable symptomatology. PTSD. There were no between-group differences in Together, these results are consistent with the theory modularity or the number of modules present. These that hypervigilance in PTSD is driven by bottom-up, findings are consistent with a hyperconnectivity rapid processing of threat-related stimuli that engage a hypothesis of the effect of TBI history on functional widespread network working in synchrony. (30094169) networks rather than a disconnection hypothesis,

131 demonstrating increased levels of clustering coefficient Keywords: Bottom-up; Fear; Magnetoencephalography; rather than a decrease as might be expected; however, Military; Oscillatory activity; Posttraumatic stress these results do not account for potential changes in brain structure. These results demonstrate the potential Biol Psychol (2019), Vol. 132, pp. 228-232 pathological sequelae of changes in functional brain networks following deployment-acquired TBI and represent potential neurobiological changes associated Attention training modulates resting-state with deployment-acquired TBI that may increase the neurophysiological abnormalities in posttraumatic risk of subsequently developing PTSD. (29634322) stress disorder

Keywords: graph theory; magnetoencephalography; post- Badura-Brack, A; McDermott, TJ; Becker, KM; traumatic stress disorder; risk factor; traumatic brain injury Ryan, TJ; Khanna, MM; Pine, DS; Bar-Haim, Y; Heinrichs-Graham, E; Wilson, TW Brain Connect (2019), Vol. 8, No. 4, pp. 205-211 Department of Psychology, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA. Electronic address: Veterans with PTSD demonstrate amygdala [email protected]. hyperactivity while viewing threatening faces: A MEG study ABSTRACT: Recent research indicates the relative benefits of computerized attention control treatment (ACT) Badura-Brack, A; McDermott, TJ; Heinrichs-Graham, E; and attention bias modification treatment (ABMT) for Ryan, TJ; Khanna, MM; Pine, DS; Bar-Haim, Y; Wilson, TW posttraumatic stress disorder (PTSD); however, neural changes underlying these therapeutic effects remain Department of Psychology, Creighton University, Omaha, NE, unknown. This study examines how these two types of USA. Electronic address: [email protected]. attention training modulate neurological dysfunction in veterans with PTSD. A community sample of 46 com- ABSTRACT: Posttraumatic stress disorder (PTSD) is a bat veterans with PTSD participated in a randomized major psychiatric disorder that is prevalent in combat double-blinded clinical trial of ACT versus ABMT and veterans. Previous neuroimaging studies have found 32 of those veterans also agreed to undergo resting- elevated amygdala activity in PTSD in response to state magnetoencephalography (MEG) recordings. threatening stimuli, but previous work has lacked Twenty-four veterans completed psychological and the temporal specificity to study fast bottom-up fear MEG assessments at pre- and post-training to evaluate responses involving the amygdala. Forty-four combat treatment effects. MEG data were imaged using an ad- veterans, 28 with PTSD and 16 without, completed vanced Bayesian reconstruction method and examined psychological testing and then a face-processing task using statistical parametric mapping. In this report, we during magnetoencephalography (MEG). The result- focus on the neural correlates and the differential treating MEG data were pre-processed, transformed into ment effects observed using MEG; the results of the full the time-frequency domain, and then imaged using a clinical trial have been described elsewhere. Our results beamforming approach. We found that veterans with indicated that ACT modulated occipital and ABMT PTSD exhibited significantly stronger oscillatory activ- modulated medial temporal activity more strongly ity from 50 to 450 ms in the left amygdala compared than the comparative treatment. PTSD symptoms to veterans without PTSD while processing threaten- decreased significantly from pre- to post-test. These ing faces. This group difference was not present while initial neurophysiological outcome data suggest that viewing neutral faces. The current study shows that ACT modulates visual pathways, while ABMT modulates amygdala hyperactivity in response to threatening cues threat-processing regions, but that both are associated begins quickly in PTSD, which makes theoretical sense with normalizing aberrant neural activity in veterans as an adaptive bottom-up fear response. (29309826) with PTSD. (29174765)

132 Keywords: Attention training; Cortical; MEG; Magnetoen- Keywords: Childhood adversities; Dissociation; MEG spon- cephalography; PTSD; Treatment taneous activity; PTSD; Trauma

Psychiatry Res Neuroimaging (2019), Vol. 271, pp. 135-141 J Affect Disord (2018), Vol. 218, pp. 428-436

Oscillatory magnetic brain activity is related to Resilience and cross-network connectivity: A neural dissociative symptoms and childhood adversities - model for post-trauma survival A study in women with multiple trauma Brunetti, M; Marzetti, L; Sepede, G; Zappasodi, F; Pizzella, V; Schalinski, I; Moran, JK; Elbert, T; Reindl, V; Wienbruch, C Sarchione, F; Vellante, F; Martinotti, G; Di Giannantonio, M

Department of Psychology, University of Konstanz, Germany. Institute for Advanced Biomedical Technologies, University of Electronic address: [email protected]. Chieti, Italy; Department of Neuroscience, Imaging & Clinical Science, University of Chieti, Italy. Electronic address: mbru- BACKGROUND: Individuals with trauma-related [email protected]. disorders are complex and heterogeneous; part of this complexity derives from additional psychopathology ABSTRACT: Literature on the neurobiological bases like dissociation as well as environmental adversi- of Post-Traumatic Stress Disorder (PTSD) considers ties such as traumatic stress, experienced throughout medial Prefrontal cortex (mPFC), a core region of the the lifespan. Understanding the neurophysiological Default Mode Network (DMN), as a region involved in abnormalities in Post-traumatic stress disorder (PTSD) response regulation to stressors. Disrupted function- requires a simultaneous consideration of these factors. ing of the DMN has been recognized at the basis of METHODS: Resting state magnetoencephalography the pathophysiology of a number of mental disorders. (MEG) recordings were obtained from 41 women with Furthermore, in the evaluation of the protective factors PTSD and comorbid depressive symptoms, and 16 to trauma consequence, an important role has been as- healthy women. Oscillatory brain activity was extracted signed to resilience. Our aim was to investigate the spe- for five frequency bands and 11 source locations, and cific relation of resilience and PTSD symptoms severity analyzed in relation to shutdown dissociation and with resting state brain connectivity in a traumatized adversity-related measures. RESULTS: Dissociative population using magnetoencephalography (MEG), a symptoms were related to increased delta and lowered non-invasive imaging technique with high temporal beta power. Adversity-related measures modulated resolution and documented advantages in clinical ap- theta and alpha oscillatory power (in particular child- plications. Nineteen Trauma Exposed non-PTSD (TENP) hood sexual abuse) and differed between patients and and 19 PTSD patients participated to a resting state controls. LIMITATIONS: Findings are based on women MEG session. MEG functional connectivity of mPFC with comorbid depressive symptoms and therefore seed to the whole brain was calculated. Correlation may not be applicable for men or groups with other between mPFC functional connectivity and Clinician clinical profiles. In respect to childhood adversities, we Administered PTSD Scale (CAPS) or Connor-Davidson had no reliable source for the early infancy. CONCLU- Resilience Scale (CD-RISC) total score was also assessed. SION: Trauma-related abnormalities in neural organiza- In the whole group, it has been evidenced that the tion vary with both exposure to adversities as well as higher was the resilience, the lower was the cross-net- their potential to evoke ongoing shutdown responses. work connectivity between DMN and Salience Network (28505586) (SN) nodes. Contrarily, in the TENP group, the negative correlation between resilience and DMN-SN cross- interaction disappeared, suggesting a protective role of resilience for brain functioning. Regarding our findings as a continuum between healthy and pathological after trauma outcomes, we could suggest a link between re-

133 silience and the good dialogue between the networks ing rare stimuli and for emotion regulation. This may needed to face a traumatic event and its long-term explain the hypervigilance and attention problems consequence on individuals' lives. (28408294) commonly reported by patients. SIGNIFICANCE: The current findings contribute to a better understanding Keywords: Default Mode Network (DMN); Magnetoen- of the mechanisms underlying the attention deficiency cephalography (MEG); PTSD; Resilience; Resting state in PTSD, and highlight altered activity in specific frontal functional connectivity (RSFC); Salience Network (SN) regions as potential biomarkers. (27565249)

Prog Neuropsychopharmacol Biol Psychiatry (2018), Vol. Keywords: Attention; MEG; Novelty P3; Oddball; P300; 77, pp. 110-119 PTSD

Clin Neurophysiol (2017), Vol. 127, No. 10, pp. 3268-76 Neural correlates of attention bias in posttraumatic stress disorder Post-Traumatic Stress Constrains the Dynamic Herz, N; Reuveni, I; Goldstein, A; Peri, T; Sch- Repertoire of Neural Activity reiber, S; Harpaz, Y; Bonne, O Mišić, B; Dunkley, BT; Sedge, PA; Da Costa, L; Fati- Department of Psychology, Bar-Ilan University, Israel. ma, Z; Berman, MG; Doesburg, SM; McIntosh, AR; Grodecki, R; Jetly, R; Pang, EW; Taylor, MJ OBJECTIVE: Patients suffering from posttraumatic stress disorder (PTSD) exhibit hyper arousal symptoms Department of Psychological and Brain Sciences, Indiana and attention problems which were frequently inves- University, Bloomington, Indiana 47405, [email protected]. tigated using the P3 event-related potentials (ERPs). Our study aimed at providing more precise knowledge UNLABELLED: Post-traumatic stress disorder (PTSD) is of the functional significance of the P3 alteration seen an anxiety disorder arising from exposure to a traumat- in PTSD by revealing its spatio-temporal dynamics. ic event. Although primarily defined in terms of behav- METHODS: Fifteen PTSD patients and fifteen healthy ioral symptoms, the global neurophysiological effects trauma-exposed controls participated in a three-tone of traumatic stress are increasingly recognized as a criti- "oddball" task while their brain activity was recorded cal facet of the human PTSD phenotype. Here we use by magnetoencephalography (MEG). They were asked magnetoencephalographic recordings to investigate to detect rare target tones and ignore standard tones two aspects of information processing: inter-regional and infrequent threatening distractors. An adaptive communication (measured by functional connectivity) spatial-filter method (SAM beamformer) was applied and the dynamic range of neural activity (measured for source estimation. RESULTS: Compared with in terms of local signal variability). We find that both controls, PTSD patients had more incorrect responses measures differentiate soldiers diagnosed with PTSD to standard stimuli. On the brain level, PTSD patients from soldiers without PTSD, from healthy civilians, and showed hyperactivity in the dorsolateral prefrontal from civilians with mild traumatic brain injury, which is cortex and anterior cingulate cortex in response to commonly comorbid with PTSD. Specifically, soldiers standard sounds, decreased activity in those regions with PTSD display inter-regional hypersynchrony at in response to threatening distractors, and decreased high frequencies (80-150 Hz), as well as a concomi- orbitofrontal activity in response to target stimuli. CON- tant decrease in signal variability. The two patterns CLUSIONS: Increased frontal activation in response to are spatially correlated and most pronounced in a left standard, neutral, stimuli may reflect greater resource temporal subnetwork, including the hippocampus and allocation dedicated to cognitive control mechanisms amygdala. We hypothesize that the observed hyper- during routine functioning in PTSD. Decreased fron- synchrony may effectively constrain the expression of tal activation in response to rare stimuli may reflect local dynamics, resulting in less variable activity and a subsequently reduced residual resources for detect- reduced dynamic repertoire. Thus, the re-experiencing

134 phenomena and affective sequelae in combat-related depression. We found that veterans with PTSD exhib- PTSD may result from functional networks becoming ited significantly reduced activity during early (0-125 "stuck" in configurations reflecting memories, emo- ms) tactile processing compared with combat controls. tions, and thoughts originating from the traumatizing Specifically, veterans with PTSD had weaker activity in experience. SIGNIFICANCE STATEMENT: The present the left postcentral gyrus, left superior parietal area, study investigates the effects of post-traumatic stress and right prefrontal cortex in response to nonthreat- disorder (PTSD) in combat-exposed soldiers. We find ening tactile stimulation relative to veterans without that soldiers with PTSD exhibit hypersynchrony in a PTSD. The magnitude of activity in these brain regions circuit of temporal lobe areas associated with learning was inversely correlated with symptom severity, and memory function. This rigid functional architecture indicating that those with the most severe PTSD had is associated with a decrease in signal variability in the the most abnormal neural responses. Our findings are same areas, suggesting that the observed hypersyn- consistent with a resource allocation view of perceptual chrony may constrain the expression of local dynamics, processing in PTSD, which directs attention away from resulting in a reduced dynamic range. Our findings nonthreatening sensory information. (26184460) suggest that the re-experiencing of traumatic events in PTSD may result from functional networks becom- Keywords: MEG; Magnetoencephalography; Military; ing locked in configurations that reflect memories, Oscillation; PTSD; Somatosensory; Tactile emotions, and thoughts associated with the traumatic experience. (26758834) Psychiatry Res (2016), Vol. 233, No. 2, pp. 194-200

Keywords: MEG; PTSD; TBI; connectivity; dynamics; network Soldiers With Posttraumatic Stress Disorder See a World Full of Threat: Magnetoencephalography J Neurosci (2016), Vol. 36, No. 2, pp. 419-31 Reveals Enhanced Tuning to Combat-Related Cues

Todd, RM; MacDonald, MJ; Sedge, P; Rob- Decreased somatosensory activity to non- ertson, A; Jetly, R; Taylor, MJ; Pang, EW threatening touch in combat veterans with posttraumatic stress disorder Department of Psychology, University of British Columbia, Vancouver, British Columbia. Electronic address: becket. Badura-Brack, AS; Becker, KM; McDermott, TJ; Ryan, TJ; [email protected]. Becker, MM; Hearley, AR; Heinrichs-Graham, E; Wilson, TW BACKGROUND: Posttraumatic stress disorder (PTSD) Department of Psychology, Creighton University, Omaha, NE, is linked to elevated arousal and alterations in cogni- USA. Electronic address: [email protected]. tive processes. Yet, whether a traumatic experience is linked to neural and behavioral differences in selective ABSTRACT: Posttraumatic stress disorder (PTSD) is a attentional tuning to traumatic stimuli is not known. severe psychiatric disorder prevalent in combat veter- The present study examined selective awareness of ans. Previous neuroimaging studies have demonstrated threat stimuli and underlying temporal-spatial patterns that patients with PTSD exhibit abnormal responses to of brain activation associated with PTSD. METHODS: non-threatening visual and auditory stimuli, but have Participants were 44 soldiers from the Canadian Armed not examined somatosensory processing. Thirty male Forces, 22 with PTSD and 22 without. All completed combat veterans, 16 with PTSD and 14 without, com- neuropsychological tests and clinical assessments. pleted a tactile stimulation task during a 306-sensor Magnetoencephalography data were collected while magnetoencephalography (MEG) recording. Signifi- participants identified two targets in a rapidly pre- cant oscillatory neural responses were imaged using a sented stream of words. The first target was a number beamforming approach. Participants also completed and the second target was either a combat-related or clinical assessments of PTSD, combat exposure, and neutral word. The difference in accuracy for combat-

135 related versus neutral words was used as a measure of yielded chance-level classifications. We conclude that, attentional bias. RESULTS: All soldiers showed a bias if properly processed, fMRI has the prospect of aiding for combat-related words. This bias was enhanced in significantly in PTSD diagnosis. Twenty-five brain areas the PTSD group, and behavioral differences were as- were most prominently involved in correct subject clas- sociated with distinct patterns of brain activity. At early sification, including areas from all cortical lobes and the latencies, non-PTSD soldiers showed activation of mid- left pallidum. (26070898) line frontal regions associated with fear regulation (90- 340 ms after the second target presentation), whereas Exp Brain Res (2016), Vol. 233, No. 9, pp. 2695-705 those with PTSD showed greater visual cortex activation linked to enhanced visual processing of trauma stimuli (200-300 ms). CONCLUSIONS: These findings Neural communication in posttraumatic growth suggest that attentional biases in PTSD are linked to deficits in very rapid regulatory activation observed in Anders, SL; Peterson, CK; James, LM; Eng- healthy control subjects. Thus, sufferers with PTSD may dahl, B; Leuthold, AC; Georgopoulos, AP literally see a world more populated by traumatic cues, contributing to a positive feedback loop that perpetu- Brain Sciences Center (11B), Minneapolis Veterans Affairs ates the effects of trauma. (26094019) Health Care System, One Veterans Drive, Minneapolis, MN, 55417, USA. Keywords: Affect-biased attention; Attentional bias; At- tentional blink; Beamforming; Magnetoencephalography ABSTRACT: Posttraumatic growth (PTG), or positive (MEG); Posttraumatic stress disorder (PTSD); Soldiers psychological changes following exposure to traumatic events, is commonly reported among trauma survivors. Biol Psychiatry (2016), Vol. 78, No. 12, pp. 821-9 In the present study, we examined neural correlates of PTG in 106 veterans with PTSD and 193 veteran controls using task-free magnetoencephalography Diagnosis of posttraumatic stress disorder (PTSD) (MEG), diagnostic interviews and measures of PTG, and based on correlations of prewhitened fMRI data: traumatic event exposure. Global synchronous neural outcomes and areas involved interactions (SNIs) were significantly modulated downward with increasing PTG scores in controls (p = .005), Christova, P; James, LM; Engdahl, BE; but not in veterans with PTSD (p = .601). This effect Lewis, SM; Georgopoulos, AP was primarily characterized by negative slopes in local neural networks, was strongest in the medial prefrontal Brain Sciences Center, Minneapolis Veterans Affairs Health cortex, and was much stronger and more extensive in Care System, Minneapolis, MN, 55417, USA. the control than the PTSD group. The present study complements previous research highlighting the role ABSTRACT: Successful diagnosis of PTSD has been of neural adaptation in healthy functioning. (25893907) achieved using neural correlations from prewhitened magnetoencephalographic (MEG) time series Exp Brain Res (2016), Vol. 233, No. 7, pp. 2013-20 (Georgopoulos et al. in J Neural Eng 7:16011, 2010. doi:10.1088/1741-2560/7/1/016011; James et al. 2015). Here, we show that highly successful classification Development and application of a diagnostic of PTSD and control subjects can be obtained using algorithm for posttraumatic stress disorder neural correlations from prewhitened resting-state fMRI data. All but one PTSD (14/15; sensitivity = 93.3 %) and James, LM; Belitskaya-Lévy, I; Lu, Y; Wang, H; Eng- all but one control (20/21; specificity = 95.2 %) subjects dahl, BE; Leuthold, AC; Georgopoulos, AP were correctly classified using 15 out of 2701 possible correlations between 74 brain areas. In contrast, Brain Sciences Center, Minneapolis Veterans Affairs Health correlations of the same but non-prewhitened data Care System, Minneapolis, MN, USA; Department of Psychia-

136 try, University of Minnesota Medical School, Minneapolis, MN, Keywords: Biomarker; Magnetoencephalography; Post- USA; Center for Cognitive Sciences, University of Minnesota, traumatic stress disorder; ROC curve; Regression analysis; Minneapolis, MN, USA. Electronic address: lisa.james2@ Veterans va.gov. Psychiatry Res (2015), Vol. 231, No. 1, pp. 1-7 ABSTRACT: Intact cognitive functions rely on synchronous neural activity; conversely, alterations in synchrony are thought to underlie psychopathol- Voxel-wise resting-state MEG source magnitude ogy. We recently demonstrated that anomalies in imaging study reveals neurocircuitry abnormality synchronous neural interactions (SNI) determined by in active-duty service members and veterans with magnetoencephalography represent a putative PTSD PTSD biomarker. Here we develop and apply a regression- based diagnostic algorithm to further validate SNI as a Huang, MX; Yurgil, KA; Robb, A; Angeles, A; Diwa- PTSD biomarker in 432 veterans (235 controls; 138 pure kar, M; Risbrough, VB; Nichols, SL; McLay, R; Theil- PTSD; 59 PTSD plus comorbid disorders). Correlation mann, RJ; Song, T; Huang, CW; Lee, RR; Baker, DG coefficients served as proximities in multidimensional scaling (MDS) to obtain a two-dimensional representa- Radiology, Research, and Psychiatry Services, VA San Diego tion of the data. In addition, least absolute shrinkage Healthcare System, San Diego, CA, USA ; Department of Radi- and selection operator (LASSO) regression was used to ology, University of California San Diego, San Diego, CA, USA. derive a diagnostic algorithm for PTSD. Performance of this algorithm was assessed by the area under the re- ABSTRACT: Post-traumatic stress disorder (PTSD) is a ceiver operating characteristic (ROC) curves, sensitivity, leading cause of sustained impairment, distress, and and specificity in 1000 randomly divided testing and poor quality of life in military personnel, veterans, and validation datasets and in independent samples. MDS civilians. Indirect functional neuroimaging studies revealed that individuals with PTSD, regardless of co- using PET or fMRI with fear-related stimuli support a morbid psychiatric conditions, are highly distinct from PTSD neurocircuitry model that includes amygdala, controls. Similarly, application of the LASSO regression- hippocampus, and ventromedial prefrontal cortex derived prediction model demonstrated remarkable (vmPFC). However, it is not clear if this model can fully classification accuracy (AUCs≥0.93 for men, AUC=0.82 account for PTSD abnormalities detected directly by for women). Neural functioning in individuals with electromagnetic-based source imaging techniques PTSD, regardless of comorbid psychiatric diagnoses, in resting-state. The present study examined resting- can be used as a diagnostic test to determine patient state magnetoencephalography (MEG) signals in 25 disease status, further validating SNI as a PTSD bio- active-duty service members and veterans with PTSD marker. (25433425) and 30 healthy volunteers. In contrast to the healthy volunteers, individuals with PTSD showed: (1) hyperactivity from amygdala, hippocampus, posterolateral orbitofrontal cortex (OFC), dorsomedial prefrontal cortex (dmPFC), and insular cortex in high-frequency (i.e., beta, gamma, and high-gamma) bands; (2) hypoactivity from vmPFC, Frontal Pole (FP), and dorsolateral prefrontal cortex (dlPFC) in high-frequency bands; (3) extensive hypoactivity from dlPFC, FP, anterior temporal lobes, precuneous cortex, and sensorimotor cortex in alpha and low-frequency bands; and (4) in individuals with PTSD, MEG activity in the left amygdala and posterolateral OFC correlated positively with PTSD symptom scores, whereas MEG activity in vmPFC and precuneous correlated negatively with symptom score.

137 The present study showed that MEG source imaging with scores on the well-established PTSD Checklist technique revealed new abnormalities in the resting- (PCL). These findings indicate that atypical synchronous state electromagnetic signals from the PTSD neurocir- neural interactions may underlie the psychological cuitry. Particularly, posterolateral OFC and precuneous symptoms of PTSD, whilst also having utility as a poten- may play important roles in the PTSD neurocircuitry tial biomarker to aid in the diagnosis and monitoring of model. (25180160) the disorder. (25180157)

Keywords: Amygdala; MEG; Orbitofrontal cortex; Post- Keywords: Functional connectivity; Magnetoencepha- traumatic stress disorder; Precuneous; Ventromedial lography (MEG); Neural network; Post-traumatic stress prefrontal cortex disorder; Resting-state

Neuroimage Clin (2015), Vol. 5, pp. 408-19 Neuroimage Clin (2015), Vol. 5, pp. 377-84

Resting-state hippocampal connectivity correlates Colour or shape: examination of neural processes with symptom severity in post-traumatic stress underlying mental flexibility in posttraumatic stress disorder disorder

Dunkley, BT; Doesburg, SM; Sedge, PA; Gro- Pang, EW; Sedge, P; Grodecki, R; Robertson, A; decki, RJ; Shek, PN; Pang, EW; Taylor, MJ MacDonald, MJ; Jetly, R; Shek, PN; Taylor, MJ

Department of Diagnostic Imaging, The Hospital for Sick 1] Division of Neurology, Hospital for Sick Children, Toronto, Children, Toronto, Canada ; Neuroscience & Mental Health ON, Canada [2] Neurosciences and Mental Health, SickKids Program, The Hospital for Sick Children Research Institute, Research Institute, Toronto, ON, Canada [3] Department of Toronto, Canada. Paediatrics, University of Toronto, Toronto, ON, Canada.

ABSTRACT: Post-traumatic stress disorder (PTSD) is a ABSTRACT: Posttraumatic stress disorder (PTSD) is a serious mental health injury which can manifest after mental disorder that stems from exposure to one or experiencing a traumatic life event. The disorder is more traumatic events. While PTSD is thought to result characterized by symptoms of re-experiencing, avoid- from a dysregulation of emotional neurocircuitry, neu- ance, emotional numbing and hyper-arousal. Whilst rocognitive difficulties are frequently reported. Mental its aetiology and resultant symptomology are better flexibility is a core executive function that involves understood, relatively little is known about the underly- the ability to shift and adapt to new information. It is ing cortical pathophysiology, and in particular whether essential for appropriate social-cognitive behaviours. changes in functional connectivity may be linked to Magnetoencephalography (MEG), a neuroimaging the disorder. Here, we used non-invasive neuroimaging modality with high spatial and temporal resolution, has with magnetoencephalography to examine functional been used to track the progression of brain activation connectivity in a resting-state protocol in the combat- during tasks of mental flexibility called set-shifting. We related PTSD group (n = 23), and a military control hypothesized that the sensitivity of MEG would be able group (n = 21). We identify atypical long-range hyper- to capture the abnormal neurocircuitry implicated in connectivity in the high-gamma-band resting-state PTSD and this would negatively impact brain regions networks in a combat-related PTSD population com- involved in set-shifting. Twenty-two soldiers with PTSD pared to soldiers who underwent comparable envi- and 24 matched control soldiers completed a colour- ronmental exposure but did not develop PTSD. Using shape set-shifting task. MEG data were recorded and graph analysis, we demonstrate that apparent network source localized to identify significant brain regions connectivity of relevant brain regions is associated with involved in the task. Activation latencies were ob- cognitive-behavioural outcomes. We also show that left tained by analysing the time course of activation in hippocampal connectivity in the PTSD group correlates each region. The control group showed a sequence of

138 activity that involved dorsolateral frontal cortex, insula or slope, is the primary outcome measure for these and posterior parietal cortices. The soldiers with PTSD analyses. RESULTS: Global synchronous neural inter- showed these activations but they were interrupted by actions were significantly modulated downward with activations in paralimbic regions. This is consistent with increasing lifetime trauma scores in resilient control models of PTSD that suggest dysfunctional neurocir- veterans (P = .003) but not in veterans with PTSD (P = cuitry is driven by hyper-reactive limbic areas that are .91). This effect, which was primarily characterized by not appropriately modulated by prefrontal cortical con- negative slopes (i.e., decorrelations) in small neural trol regions. This is the first study identifying the timing networks, was strongest in the right superior temporal and location of atypical neural responses in PTSD with gyrus. Significant negative slopes were more common, set-shifting and supports the model that hyperactive stronger, and observed between sensors at shorter limbic structures negatively impact cognitive function. distances than positive slopes in both hemispheres (P < (25093599) .001 for all) for controls but not for veterans with PTSD. CONCLUSIONS. Neural modulation involving decorrela- Transl Psychiatry (2015), Vol. 4, pp. e421 tion of neural networks in the right superior temporal gyrus and, to a lesser extent, other areas distinguishes resilient veterans from those with PTSD and is postu- Neural network modulation by trauma as a marker lated to have an important role in healthy response to of resilience: differences between veterans with trauma. (23426853) posttraumatic stress disorder and resilient controls JAMA Psychiatry (2013), Vol. 70, No. 4, pp. 410-8 James, LM; Engdahl, BE; Leuthold, AC; Lewis, SM; Van Kampen, E; Georgopoulos, AP Early processing of threat cues in posttraumatic Brain Sciences Center, Minneapolis Veterans Affairs Health stress disorder-evidence for a cortical vigilance- Care System, MN 55417, USA avoidance reaction

IMPORTANCE: Posttraumatic stress disorder (PTSD) Adenauer, H; Pinösch, S; Catani, C; Gola, and resilience reflect 2 distinct outcomes after ex- H; Keil, J; Kissler, J; Neuner, F posure to potentially traumatic events. The neural mechanisms underlying these different outcomes are Department of Psychology, University of Konstanz, Konstanz, not well understood. OBJECTIVE: To examine the ef- Germany. [email protected] fect of trauma on synchronous neural interactions for veterans with PTSD and resilient controls using magne- BACKGROUND: The present study investigated the toencephalography. DESIGN: Participants underwent influence of posttraumatic stress disorder (PTSD) on diagnostic interviews, a measure of exposure to poten- early visual processing of affective stimuli in survivors tially traumatic events, and magnetoencephalography. of war and torture. METHODS: Trauma-exposed refu- SETTING: U.S. Department of Veterans Affairs medical gees with (n = 36) and without (n = 21) PTSD as well as center. PARTICIPANTS: Eighty-six veterans with PTSD unexposed control subjects (n = 16) participated in a and 113 resilient control veterans recruited from a large magnetoencephalography study with pictures that var- Midwestern Medical Center. MAIN OUTCOME MEA- ied in emotional content. RESULTS: We found evidence SURES: Multiple regression analyses were performed for a biphasic cortical response in patients with PTSD in to examine the effect of lifetime trauma on global and comparison with the two control groups. In response to local synchronous neural interactions. In analyses ex- aversive (relative to neutral or positive) pictures, PTSD amining the local synchronous neural interactions, the patients showed elevated cortical activity over right partial regression coefficient indicates the strength and prefrontal areas as early as 130-160 msec after stimulus direction of the effect of trauma on the synchronous onset followed by a decrease of the affect-related re- interactions between the 2 neural signals recorded sponse in the parieto-occipital cortex at 206-256 msec. by a pair of sensors. The partial regression coefficient, CONCLUSIONS: The increased early activity in the right

139 prefrontal cortex most likely represents an enhanced sive stimuli, which was related to dissociative symp- alarm response or the fear network toward aversive toms as well as to torture severity. The results indicate stimuli in PTSD, whereas the subsequent decreased a different pattern of cortical activation driven by aver- activation in right parieto-occipital areas in response sive stimuli depending on the experience of multiple to aversive pictures seems to reflect the tendency to traumatic events and PTSD. Whereas, a decreased visual disengage from emotional content. This finding is processing of aversive stimuli seems to be associated consistent with the hypothesis of a vigilance-avoidance with trauma exposure in general, the superior parietal reaction pattern to threat in anxiety disorders and activity might represent a specific process linked to the helps to reconcile contradicting results of over- and diagnosis of PTSD. (19360450) under-responsiveness in the sensory processing of threatening stimuli in PTSD. (20619396) Eur Arch Psychiatry Clin Neurosci (2009), Vol. 259, No. 6, pp. 340-51 Biol Psychiatry (2010), Vol. 68, No. 5, pp. 451-8

Altered oscillatory brain dynamics after repeated Pattern of cortical activation during processing of traumatic stress aversive stimuli in traumatized survivors of war and torture Kolassa, IT; Wienbruch, C; Neuner, F; Schau- er, M; Ruf, M; Odenwald, M; Elbert, T Catani, C; Adenauer, H; Keil, J; Aichinger, H; Neuner, F Department of Psychology, Clinical & Neuropsychology, Uni- Clinical Psychology and Psychotherapy Unit, Department of versity of Konstanz, 78457 Konstanz, Germany. Iris.Kolassa@ Psychology, University of Bielefeld, 33501 Bielefeld, Germany. uni-konstanz.de [email protected] BACKGROUND: Repeated traumatic experiences, ABSTRACT: Posttraumatic stress disorder (PTSD) has e.g. torture and war, lead to functional and structural been associated with an altered processing of threat- cerebral changes, which should be detectable in corti- related stimuli. In particular, an attentional bias towards cal dynamics. Abnormal slow waves produced within threat cues has been consistently found in behavioral circumscribed brain regions during a resting state studies. However, it is unclear whether increased at- have been associated with lesioned neural circuitry in tention towards threat cues translates into preferential neurological disorders and more recently also in mental processing as neurophysiological studies have yielded illness. METHODS: Using magnetoencephalographic inconsistent findings. The aim of the present study was (MEG-based) source imaging, we mapped abnormal to investigate the neocortical activity related to the distributions of generators of slow waves in 97 sur- processing of aversive stimuli in patients with PTSD. vivors of torture and war with posttraumatic stress 36 survivors of war and torture with PTSD, 21 Trauma disorder (PTSD) in comparison to 97 controls. RESULTS: Controls and 20 Unexposed Subjects participated in a PTSD patients showed elevated production of focally visual evoked magnetic field study using flickering pic- generated slow waves (1-4 Hz), particularly in left tem- tures of varying affective valence as stimulus material. poral brain regions, with peak activities in the region of Minimum norm source localization was carried out to the insula. Furthermore, differential slow wave activ- estimate the distribution of sources of the evoked neu- ity in right frontal areas was found in PTSD patients romagnetic activity in the brain. Statistical permutation compared to controls. CONCLUSION: The insula, as a analyses revealed reduced steady-state visual evoked site of multimodal convergence, could play a key role in field amplitudes over occipital areas in response to understanding the pathophysiology of PTSD, possibly aversive pictures for PTSD patients and for Trauma accounting for what has been called posttraumatic Controls in comparison to unexposed subjects. Further- alexithymia, i.e., reduced ability to identify, express and more, PTSD patients showed a hyperactivation of the regulate emotional responses to reminders of traumat- superior parietal cortex selectively in response to aver- ic events. Differences in activity in right frontal areas

140 may indicate a dysfunctional PFC, which may lead to diminished extinction of conditioned fear and reduced inhibition of the amygdala. (17941996)

BMC Psychiatry (2008), Vol. 7, pp. 56

141 142 Presurgical Functional Keywords: Functional outcome; Hemispherectomy; Rasmussen’s encephalitis (or Rasmussen encephalitis, RE); Mapping Seizure outcome

Timing and type of hemispherectomy for Epilepsy Res (2018), Vol. 132, pp. 109-115 Rasmussen's encephalitis: Analysis of 45 patients

Guan, Y; Chen, S; Liu, C; Du, X; Zhang, Change in presurgical diagnostic imaging Y; Chen, S; Wang, J; Li, T; Luan, G evaluation affects subsequent pediatric epilepsy surgery outcome Department of Neurosurgery, Sanbo Brain Hospital Capital Medical University, 100093 Beijng, China. Rubinger, L; Chan, C; D'Arco, F; Moineddin, R; Muthaf- far, O; Rutka, JT; Snead, OC; Smith, ML; Widjaja, E OBJECTIVE: To describe the surgery outcomes of RE patients in one centerto identify the indication for Neuroscience and Mental Health, Hospital for Sick Children, surgical treatment that results in the most favorable Toronto, Ontario, Canada. outcome. METHOD: Forty-five RE patients from a single center were retrospectively reviewed. Preoperative OBJECTIVE: Since 2008, we have changed our pre- evaluations included assessments of clinical manifes- surgical diagnostic imaging evaluation for medically tations, cognitive status, a physical examination, MRI, refractory focal epilepsy to include high-resolution positron emission tomography (PET), electroencepha- epilepsy protocol on 3 T magnetic resonance imaging lography (EEG), and magnetoencephalography (MEG). (MRI), and combined magnetoencephalography and The surgical outcomes included seizure outcome, 18-fluorodeoxyglucose-positron emission tomography neurological function, EEG, a cognitive evaluation, and (FDG-PET) in selected patients with normal or subtle antiepileptic drug withdrawal. RESULTS: A total of 45 changes on MRI or discordant diagnostic tests. The children (29 male) with RE were included in this study. aim of this study was to evaluate the effectiveness of The mean follow-up period from the first operation was the change in imaging practice on epilepsy surgery 31.7months (range 6-96). The patients who under- outcome in a tertiary pediatric epilepsy surgery center. went anatomical hemispherectomy or hemisphere METHODS: The change in practice occurred in early disconnection had better seizure outcomes without 2008, and patients were classified based on old or new greater perioperative complications compared with the practice. The patient characteristics, surgical variables, patients who underwent functional hemispherectomy. and seizure-free surgical outcome were compared, Reoperative hemispherectomy was a safe and effec- and the trend in seizure-free outcome over time was tive treatment for patients with postoperative epilepsy assessed. RESULTS: There was a trend for increased ab- recurrence. After the last surgery, 34 patients (74.4%) normal MRI (92% vs. 86%, respectively, p = 0.062), and were evaluated as Engel class I. Most of the patients increased utilization of FDG-PET (34% vs. 3% respec- had favorable neurological outcomes. Analysis revealed tively, p < 0.001) with new relative to old practice. There that the patientswith IQs greater 70 who underwent were no statistically significant differences in invasive operations were more likely to suffer from IQ declines monitoring, location, and type of surgery and histology but were also more likely to have higher IQs in the between the two periods (all p > 0.05). During the old future. SIGNIFICANCE: Compared with functional practice, there was no statistically significant change hemispherectomy and hemisphere disconnection, in yearly trend of seizure-free outcome (odds ratio anatomical hemispherectomy elicited better seizure [OR] 0.960, 95% confidence interval [CI] 0.875-1.053, outcomes with an acceptable level of complications. p = 0.386). The change in practice in 2008 was associ- Early stage operations might lead to better cognitive ated with a significant improvement in seizure-free status, but they are associated with a high risk of IQ outcome (OR 1.535, 95% CI 1.100-2.142, p = 0.012). decline. (28399506) During the new practice, there was a significant positive trend in yearly seizure-free outcome (OR 1.219,

143 95% CI 1.053-1.411, p = 0.008), after adjusting for age at PTN stimulation activated 86.6% in the contralateral S1, seizure onset, invasive monitoring, location and type of with ipsilateral activation < 0.5%. Motor cortex activa- surgery, histology, MRI, magnetoencephalography, and tion localized contralaterally in 76.1% (5.2% ipsilateral, FDG-PET. SIGNIFICANCE: We have found an improve- 7.6% bilateral and 11.1% failures) of all motor MEG ment in seizure-free surgical outcome following the recordings. The ipsilateral motor responses were found change in imaging practice. This study highlights the in 43 (14%) out of 308 patients with motor recordings importance of optimizing and improving presurgical (range: 8.3-50%, depending on the underlying pathol- diagnostic imaging evaluation to improve surgical ogy), and had a higher occurrence in the foot than outcome. (26715387) in the hand (motor_foot 44.8% versus motor_hand 29.6%, p = 0.031). Ipsilateral motor responses tended Keywords: 18-Fluorodeoxyglucose-positron emission to be more frequent in patients with a history of stroke, tomography; Magnetic resonance imaging; Magnetoen- traumatic brain injury (TBI) or developmental brain cephalography; Seizure-free outcome lesions (p = 0.063). CONCLUSIONS: MEG localization of sensorimotor cortex activation was more success- Epilepsia (2016), Vol. 57, No. 1, pp. 32-40 ful for the hand compared to the foot. In patients with neural lesions, there were signs of brain reorganization as measured by more frequent ipsilateral motor cortical Magnetoencephalographic study of hand and foot activation of the foot in addition to the traditional sen- sensorimotor organization in 325 consecutive sory and motor activation patterns in the contralateral patients evaluated for tumor or epilepsy surgery hemisphere. The presence of ipsilateral neural reorganization, especially around the foot motor area, suggests Willemse, RB; Hillebrand, A; Ron- that careful mapping of the hand and foot in both con- ner, HE; Vandertop, WP; Stam, CJ tralateral and ipsilateral hemispheres prior to surgery might minimize postoperative deficits. (26693401) Neurosurgical Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands. Keywords: Brain mapping; Brain neoplasms; Cortical reorganization; Epilepsy; Magnetoencephalography OBJECTIVES: The presence of intracranial lesions or epilepsy may lead to functional reorganization and Neuroimage Clin (2016), Vol. 10, pp. 46-53 hemispheric lateralization. We applied a clinical magnetoencephalography (MEG) protocol for the localization of the contralateral and ipsilateral S1 and M1 of the foot Reliability for non-invasive somatosensory cortex and hand in patients with non-lesional epilepsy, stroke, localization: Implications for pre-surgical mapping developmental brain injury, traumatic brain injury and brain tumors. We investigated whether differences Solomon, J; Boe, S; Bardouille, T in activation patterns could be related to underlying pathology. METHODS: Using dipole fitting, we local- Laboratory for Brain Recovery and Function, Dalhousie Uni- ized the sources underlying sensory and motor evoked versity, 5869 University Avenue, Halifax, Nova Scotia, Canada magnetic fields (SEFs and MEFs) of both hands and feet B3H 1X7; Department of Psychology and Neuroscience, Dal- following unilateral stimulation of the median nerve housie University, 1355 Oxford Street, Halifax, Nova Scotia, (MN) and posterior tibial nerve (PTN) in 325 consecutive Canada B3H 4R2. Electronic address: [email protected]. patients. The primary motor cortex was localized using beamforming following a self-paced repetitive motor OBJECTIVES: In patients with epilepsy or space oc- task for each hand and foot. RESULTS: The success rate cupying tumors in cortical regions, surgical resection for motor and sensory localization for the feet was sig- is often considered as the primary treatment. Pre- nificantly lower than for the hands (motor_hand 94.6% surgical neuroimaging can provide a detailed map of versus motor_feet 81.8%, p < 0.001; sensory_hand pathological and functional cortex, leading to safer 95.3% versus sensory_feet 76.0%, p < 0.001). MN and surgery. Mapping can be achieved non-invasively using

144 magnetoencephalography (MEG), and is concordant sive monitoring with subdural electrodes is required with invasive findings. However, the reliability of MEG to adequately map the epileptogenic focus. The risks mapping between sessions is not well established. The of invasive monitoring include the need for 2 opera- inter-session reliability is an important property in pre- tions, infection, and CSF leak. The aim of this study was surgical mapping to establish resection margins, but to evaluate the feasibility and outcomes of resective repeated scans are impracticable. The present study epilepsy surgery guided by magnetoencephalography sought to quantify the intersession reliability of MEG (MEG) in children who would have otherwise been localization of somatosensory cortex (S1). PATIENTS candidates for electrode implantation. METHODS: AND METHODS: Eighteen healthy individuals under- The authors reviewed the records of patients undergo- went MEG sessions on 3 consecutive days. Five partici- ing resective epilepsy surgery at the Hospital for Sick pants were excluded due to technical issues during one Children between 2001 and 2010. They identified cases of the three days. Each session included clinical-style in which resections were based on MEG data and no S1 localization using electrical stimuli to each median intracranial recordings were performed. Each patient's nerve at sub-motor thresholds. The 35 ms peak of the chart was reviewed for presentation, MRI findings, MEG somatosensory evoked field was used for localizing findings, surgical procedure, pathology, and surgical S1 in each session using a single equivalent current outcome. RESULTS: Sixteen patients qualified for the dipole model. Intersession reliability was quantified study. All patients had localized spike clusters on MEG using two methods. Average Euclidean Distance (AED) and most had abnormal findings on MRI. Resection was quantified the difference in localization between each carried out in each case based on the MEG data linked session and the inter-session mean localization. Session to neuronavigation and supplemented with intraopera- Euclidean Distance (SED) quantified the difference in tive neuromonitoring. Overall, 62.5% of patients were localization between each pair of sessions. RESULTS seizure free following surgery, and 20% of patients ex- AND DISCUSSION: Results showed the AED was 4.8 ± perienced an improvement in seizures without attain- 1.9 mm, whereas the SED was 8.3 ± 3.4mm. While the ing seizure freedom. In 2 cases, additional surgery was AED values obtained parallel those reported previously performed subsequently with intracranial monitoring in smaller samples, the SED values were substantially in attempts to obtain seizure control. CONCLUSIONS: larger. CONCLUSION: Clinicians should consider up MEG is a viable alternative to invasive monitoring with to an 8mm confidence interval around the estimated intracranial electrodes for planning of resective surgery location of S1 based on MEG pre-surgical mapping. in carefully selected pediatric patients with localization- (26519893) related epilepsy. Good candidates for this approach include patients who have a well-delineated, localized Keywords: Intersession reliability; Magnetoencephalogra- spike cluster on MEG that is concordant with findings phy; Median nerve stimulation; Neurosurgery; Pre-surgical of other preoperative evaluations and patients with mapping; Somatosensory cortex; Source localization prior brain pathologies that make the implantation of subdural and depth electrodes somewhat problematic. Clin Neurol Neurosurg (2016), Vol. 139, pp. 224-9 (25238627)

Keywords: EEG = electroencephalography; MEG; MEG Magnetoencephalography-guided resection of = magnetoencephalography; PET = positron emission epileptogenic foci in children tomography; SPECT = single-photon emission CT; VEEG

Albert, GW; Ibrahim, GM; Otsubo, H; Ochi, A; Go, CY; Snead, OC; Drake, JM; Rutka, JT

Division of Neurosurgery, Arkansas Children's Hospital;

OBJECT: Resective surgery is increasingly used in the management of pediatric epilepsy. Frequently, inva-

145 = video EEG; fMRI = functional MRI; intractable epilepsy; tion of the MEGSS cluster along with PC/E can provide magnetoencephalography; surgery favorable seizure outcomes. (25014323)

J Neurosurg Pediatr (2015), Vol. 14, No. 5, pp. 532-7 Keywords: ECoG = electrocorticography; EEG = electroencephalography; MEG = magnetoencephalography; MEGSS = MEG spike sources; PC/E = porencephalic cyst/ Magnetoencephalography helps delineate the encephalomalacia; encephalomalacia; epilepsy; epilep- extent of the epileptogenic zone for surgical togenic zone; magnetoencephalography; porencephalic planning in children with intractable epilepsy due cyst; surgical planning to porencephalic cyst/encephalomalacia J Neurosurg Pediatr (2014), Vol. 14, No. 3, pp. 271-8 Bennett-Back, O; Ochi, A; Widjaja, E; Nambu, S; Kamiya, A; Go, C; Chuang, S; Rutka, JT; Drake, J; Snead, OC; Otsubo, H Clinical relevance of source location in frontal lobe Division of Neurology and. epilepsy and prediction of postoperative long-term outcome OBJECT: Porencephalic cyst/encephalomalacia (PC/E) is a brain lesion caused by ischemic insult or hemorrhage. Mu, J; Rampp, S; Carrette, E; Roessler, K; Sommer, B; The authors evaluated magnetoencephalography Schmitt, FC; De Tiège, X; Hamer, H; Boon, P; Pauli, (MEG) spike sources (MEGSS) to localize the epilepto- E; Bluemcke, I; Zhou, D; Buchfelder, M; Stefan, H genic zone in children with intractable epilepsy secondary to PC/E. METHODS: The authors retrospectively Department of Neurology, University Hospital Erlangen, studied 13 children with intractable epilepsy secondary Erlangen, Germany; Department of Neurology, West China to PC/E (5 girls and 8 boys, age range 1.8-15 years), Hospital, Sichuan University, Chengdu, Sichuan, PR China. who underwent prolonged scalp video-electroen- Electronic address: [email protected]. cephalography (EEG), MRI, and MEG. Interictal MEGSS locations were compared with the ictal and interictal PURPOSE: To evaluate the value of magnetoencepha- zones as determined from scalp video-EEG. RESULTS: lography (MEG) source localization in localization of Magnetic resonance imaging showed PC/E in extratem- epileptic activities and predicting surgical outcome poral lobes in 3 patients, within the temporal lobe in 2 in frontal lobe epilepsies (FLE). METHODS: Forty-six patients, and in both temporal and extratemporal lobes patients with presurgical MEG evaluation and intrac- in 8 patients. Magnetoencephalographic spike sources table FLE surgery (28 male patients) were analyzed were asymmetrically clustered at the margin of PC/E retrospectively with a mean follow-up of 5 years. Dipole in all 13 patients. One cluster of MEGSS was observed analysis was performed for MEG source imaging (MSI). in 11 patients, 2 clusters in 1 patient, and 3 clusters The localization of dipole clusters in relation to the in 1 patient. Ictal EEG discharges were lateralized and dominant hemisphere, lesions, resection cavity and concordant with MEGSS in 8 patients (62%). Interictal functional cortex were analyzed. The predictive value of EEG discharges were lateralized and concordant with MSI in respect to clinical outcome with long-term post- MEGSS hemisphere in 9 patients (69%). Seven patients operative follow up was evaluated. RESULTS: Interictal underwent lesionectomy in addition to MEGSS cluster- focal epileptic activities were found in 82.6% (38/46) ectomy with (2 patients) and without (5 patients) intra- patients with monofocal activity 81.6% (31/38) and cranial video-EEG. Temporal lobectomy was performed multifocal activities 18.4% (7/38). Seizure free rate was in 1 patient and hemispherectomy in another. Eight of 47.9% at the mean follow-up of 5.0 ± 4.0 years (median 9 patients achieved seizure freedom following surgery. 11.5, range 2-57). Seizure recurrence mainly occurred in CONCLUSIONS: Magnetoencephalography delineated the first 1 year after surgery. In the monofocal epilep- the extent of the epileptogenic zone adjacent to PC/E tic activity group, 58.1% (18/31) of the patients were in patients with intractable epilepsy. Complete resec- seizure free, predicitng postoperative seizure freedom better than multifocal localization 0% (0/7) (p=0.028).

146 Dipole clusters were completely resected in 70.9% of accomplished. Eight of 14 (57%) complete resections monofocal activity patients, which had higher seizure were achieved only by performing an intraoperative free rates compared to partial resection (p=0.002). In image update. Neurological deterioration was found patients with surgery in the dominant hemisphere, permanently in 2 patients. After a mean follow-up of seizure control was less likely (p=0.006). CONCLUSION: 43.8 ± 23.8 months, 15 patients (79%) became seizure MSI contributes to the clinical prediction of postopera- free (Engel class Ia). CONCLUSIONS: Despite the highly tive outcome in FLE patients. MSI may non-invasively eloquent location of tumors causing intractable epilep- disclose early epileptogenic lesions, pointing to a sy, our multimodal approach led to complete resection resectable lesion, and it then facilitates shortcut route in more than two-thirds of patients with an acceptable of presurgical evaluation. (24854960) neurological morbidity and excellent long-term seizure control. (24356382) Keywords: Focal cortical dysplasia; Frontal lobe epilepsy; Magnetoencephalography; Postoperative outcome; Stereotact Funct Neurosurg (2014), Vol. 92, No. 1, pp. 59- Seizure freedom 67

Seizure (2015), Vol. 23, No. 7, pp. 553-9 The utility of magnetoencephalography in the presurgical evaluation of refractory insular epilepsy Frameless stereotactic functional neuronavigation combined with intraoperative magnetic resonance Mohamed, IS; Gibbs, SA; Robert, M; Bouthilli- imaging as a strategy in highly eloquent located er, A; Leroux, JM; Khoa Nguyen, D tumors causing epilepsy Division of Neurology, Department of Pediatrics, IIWK Health Sommer, B; Grummich, P; Hamer, H; Bluemcke, Center, Halifax, NS, Canada. I; Coras, R; Buchfelder, M; Roessler, K PURPOSE: To study the utility of magnetoencephalog- Department of Neurosurgery, University Hospital Erlangen, raphy (MEG) in patients with refractory insular epilepsy. Erlangen, Germany. Covered by highly functional temporal, frontal, and parietal opercula, insular-onset seizures can manifest a BACKGROUND: Intractable epilepsy due to tumors variety of ictal symptoms falsely leading to a diagnosis located in highly eloquent brain regions is often con- of temporal, frontal, or parietal lobe seizures. Lack of sidered surgically inaccessible because of a high risk recognition of insular seizures may be responsible for of postoperative neurological deterioration. Intraop- some epilepsy surgery failures. METHODS: We retro- erative MRI and functional navigation contribute to spectively reviewed and analyzed MEG data in 14 pa- overcome this problem. OBJECTIVES: To retrospec- tients with refractory insular seizures defined through tively investigate the long-term results and impact of intracranial electroencephalography (EEG) or by the functional neuronavigation and 1.5-tesla intraoperative presence of an epileptogenic lesion in the insula with MRI on patients who underwent surgery of tumors compatible seizure semiology. MEG was performed as associated with epilepsy located close to or within part of the noninvasive presurgical evaluation, using a eloquent brain areas. METHODS: Nineteen patients (9 275-channel whole head MEG system. MEG data were female, 10 male, mean age 41.4 ± 13.4 years, 11 low- analyzed using a single equivalent current dipole mod- grade and 8 high-grade glial tumors) were evaluated el. MEG localization was compared to interictal positron preoperatively using BOLD imaging, diffusion-tensor emission tomography (PET) and ictal single photon imaging tractography and magnetoencephalography. emission computed tomography (SPECT) results and to Functional data were implemented into neuronaviga- the resection margin. KEY FINDINGS: Three patterns tion in this multimodal approach. RESULTS: In 14 of 19 of MEG spike sources were observed. Seven patients patients (74%), complete resection was achieved, and showed an anterior operculoinsular clusters and two in 5 patients significant tumor volume reduction was patients had a posterior operculoinsular cluster. No

147 spikes were detected in one patient, and the remaining the recognition of the somatosensory cortex. Patients four patients showed a diffuse perisylvian distribution. who underwent surgery after presurgical planning Spike sources showed uniform orientation perpendicu- using MEG suffered no new somatosensory deficits, lar to the sylvian fissure. Nine patients proceeded to in- indicating the valuable role of pre-surgical mapping sular epilepsy surgery with favorable surgical outcome. using MEG in the surgical planning. (23797479) Among patients with anterior operculoinsular cluster who proceeded to have surgery, MEG provided superi- Stereotact Funct Neurosurg (2014), Vol. 91, No. 5, pp. 314- or information to ictal SPECT in four of six patients and 22 to interictal PET in five of six patients. SIGNIFICANCE: MEG is useful in identifying patients who are likely to benefit from epilepsy surgery targeting the insula, Correlation between magnetoencephalography- particularly if a tight dipole cluster is identified even if based "clusterectomy" and postoperative seizure other noninvasive modalities fail to produce localizing freedom results. (24117237) Vadera, S; Jehi, L; Burgess, RC; Shea, K; Alexopoulos, Keywords: Epilepsy surgery; Insula; Magnetoencephalog- AV; Mosher, J; Gonzalez-Martinez, J; Bingaman, W raphy; Refractory epilepsy Department of Neurosurgery, Cleveland Clinic Foundation, Epilepsia (2013), Vol. 54, No. 11, pp. 1950-9 9500 Euclid Ave, Cleveland, OH 44195, USA. [email protected]

OBJECT: During the presurgical evaluation of patients Preoperative magnetoencephalographic sensory with medically intractable focal epilepsy, a variety cortex mapping of noninvasive studies are performed to localize the hypothetical epileptogenic zone and guide the resec- Niranjan, A; Laing, EJ; Laghari, FJ; Rich- tion. Magnetoencephalography (MEG) is becoming ardson, RM; Lunsford, LD increasingly used in the clinical realm for this purpose. No investigators have previously reported on coregis- Department of Neurological Surgery, University of Pittsburgh teration of MEG clusters with postoperative resection and UPMC Brain Mapping Center, Pittsburgh, Pa., USA. cavities to evaluate whether complete "clusterectomy" (resection of the area associated with MEG clusters) ABSTRACT: The use of functional neuroimaging holds was performed or to compare these findings with the promise of improving neurosurgical outcomes by postoperative seizure-free outcomes. METHODS: providing preoperative localization of critical brain The authors retrospectively reviewed the charts and functions. The brain representation of somatosensory imaging studies of 65 patients undergoing MEG fol- function can be effectively localized using magneto- lowed by resective epilepsy surgery from 2009 until encephalography (MEG) in both normal subjects and 2012 at the Cleveland Clinic. Preoperative MEG studies in patients with tumors, vascular malformation, and were fused with postoperative MRI studies to evaluate epilepsy. This study investigates the pattern of somato- whether clusters were within the resected area. These sensory localization in 45 patients. Thirty-two of these data were then correlated with postoperative seizure patients underwent subsequent resective surgery for freedom. RESULTS: Sixty-five patients were included in brain pathologies. Electrical stimulation of the me- this study. The average duration of follow-up was 13.9 dian nerve was conducted, and the most prominent months, the mean age at surgery was 23.1 years, and somatosensory peak in the resultant averaged data the mean duration of epilepsy was 13.7 years. In 30 pa- was localized using the single equivalent current dipole tients, the main cluster was located completely within technique. Results showed that this peak localized the resection cavity, in 28 it was completely outside either to the central or postcentral sulcus of the so- the resection cavity, and in 7 it was partially within the matosensory cortex. We found that neither age nor the resection cavity. Seventy-four percent of patients were presence of brain pathologies had significant effect on seizure free at 12 months after surgery, and this rate

148 decreased to 60% at 24 months. Improved likelihood of both the proportion <70% and multiple dipoles clus- seizure freedom was seen with complete clusterectomy ters were post-operatively seizure free. CONCLUSION: in patients with localization outside the temporal lobe Number and density of clustered spike dipole sources (extra-temporal lobe epilepsy) (p = 0.04). CONCLU- within the surgical resection volume is not associated SIONS: In patients with preoperative MEG studies that with postoperative seizure-free outcome. MSI success- show clusters in surgically accessible areas outside fully localized the perilesional epileptogenic zone in the temporal lobe, we suggest aggressive resection to cases with localized MRI lesions, but not in cases with improve the chances for seizure freedom. When the normal MRI in this study. Even if MEG localizes spikes to cluster is found within the temporal lobe, further di- a single focal region, confirmation of epilepsy localiza- agnostic testing may be required to better localize the tion with intracranial EEG is still recommended in cases epileptogenic zone. (23724843) with non-lesional MRI. (23689013)

Neurosurg Focus (2014), Vol. 34, No. 6, pp. E9 Keywords: 3D post-resection analysis; Magnetic source imaging (MSI); Pediatric neocortical epilepsy; Surgical outcome Magnetic source imaging (MSI) in children with neocortical epilepsy: surgical outcome association Epilepsy Res (2014), Vol. 106, No. 1-2, pp. 164-72 with 3D post-resection analysis

Kim, H; Kankirawatana, P; Killen, J; Harrison, A; Interictal MEG reveals focal cortical dysplasias: Oh, A; Rozzelle, C; Blount, J; Knowlton, R special focus on patients with no visible MRI lesions

Pediatric Neurology, Emory University School of Medicine, Wilenius, J; Medvedovsky, M; Gaily, E; Metsähonkala, Atlanta, GA 30322, USA. [email protected] L; Mäkelä, JP; Paetau, A; Valanne, L; Paetau, R

OBJECTIVE: To investigate the validity of magnetic BioMag Laboratory, HUS Medical Imaging Center, Hospital source imaging (MSI) to localize seizure-onset zone District of Helsinki and Uusimaa, Finland. using 3D analysis of pre-operative MSI source imaging coregistered to post-resection MRI following neocorti- PURPOSE: To investigate the value of interictal magne- cal epilepsy surgery. METHODS: Twenty-two children toencephalography (MEG) in localizing epileptogenic who had MSI and epilepsy surgery were studied cortex in epilepsy surgery patients with focal cortical (median age=11 years, 1 year 2 months-22 years). Only dysplasias (FCD), particularly in patients having no seven (31.8%) had localized lesions on pre-operative visible MRI lesions. METHODS: Thirty-four patients conventional brain MRIs. Sixteen (72.7%) underwent with FCD and preoperative MEG were retrospectively intracranial EEG monitoring. Mean post-operative evaluated. Interictal MEG spike source localizations in follow-up was 4.7 years (1 year 3 months-8 years 2 respect to the resected area were studied using post- months). Fifteen patients (68%) were seizure-free. MEG operative MR imaging. The possible predictive value spike dipole sources were superimposed onto post- of MEG-findings in respect to the clinical outcome was operative MRIs. The number and proportion of spike evaluated. Results from intracranial recordings were dipoles within resection volume were calculated and also compared with the MEG localizations. RESULTS: compared between seizure free and non-free groups. Interictal MEG spikes were observed in all but one RESULTS: Both number of dipole clusters and propor- patient. 17 of the 34 (50%) patients became seizure tion of dipoles in resection volume were not associated free (Engel class I). In patients with MEG dipole clusters with seizure-free outcome (p>0.05). In seven cases with (n=20) and Engel class I or II (n=15) 49% of the source MRI lesions, six of these with a ≥70% dipoles within the clusters were removed on the average; the correspond- resection margin were seizure-free, while one with the ing value in patients with Engel class III or IV (n=5) was proportion <70% was not seizure-free. Further, among 5.5% (p=0.02). Seven (54%) of the 13 patients with an the 15 cases with non-localized or normal MRI, five with MRI-negative lesion achieved Engel class I; the out-

149 comes did not differ from patients having a visible MRI izing or nonconcordant in four patients; two patients lesion (n=21; p=0.82). The concordance between MEG had Engel I and two had Engel II-IV outcomes. FDG-PET localizations and the invasive studies was good in nine was concordant with surgical resection in 14 patients; of the 13 patients with no visible MRI lesions CONCLU- 9 had Engel I outcome, and 5 had Engel II-IV outcome. SION: MEG is particularly useful in finding small FCDs FDG-PET was nonlocalizing or nonconcordant in seven not visible on MRI. A more complete removal of MEG patients with Engel I, and one with Engel III outcome. source cluster area is associated with better clinical The sensitivity, specificity, PPV, and NPV of MEG outcome These features make it a valuable tool in pre- were 85.0%, 99.1%, 94.4%, and 97.3%, respectively. surgical evaluation of patients with intractable focal- The sensitivity, specificity, PPV, and NPV of FDG-PET type epilepsy and normal MRI. (23587673) were 65.0%, 94.4%, 68.4%, and 93.6%, respectively. There was no significant difference between MEG Keywords: Epilepsy; Epilepsy surgery; Focal cortical dys- and FDG-PET for concordance with surgical resection plasia; Magnetoencephalography (χ(2) = 2.794, p = 0.095). FDG-PET + MEG, defined as two tests concordant with surgical resection, had Epilepsy Res (2014), Vol. 105, No. 3, pp. 337-48 reduced sensitivity and NPV, but increased specificity and PPV (55.0%, 92.3%, 100%, and 100%, respectively) relative to individual tests. FDG-PET/MEG, defined as FDG-PET and magnetoencephalography in one or both test(s) concordant with surgical resection, presurgical workup of children with localization- had increased sensitivity and NPV but reduced specific- related nonlesional epilepsy ity (95.0%, 99.0%, and 93.5%, respectively) relative to individual tests. SIGNIFICANCE: The two tests FDG-PET Widjaja, E; Shammas, A; Vali, R; Otsubo, H; and MEG were complementary in the assessment of Ochi, A; Snead, OC; Go, C; Charron, M children with localization-related epilepsy, particularly when one test was nonlocalizing or nonconcordant. Diagnostic Imaging, Hospital for Sick Children, Toronto, (23398491) Ontario, Canada. [email protected] Epilepsia (2013), Vol. 54, No. 4, pp. 691-9 PURPOSE: 2-[18F]Fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) and magnetoencephalography (MEG) may assist in identifying the epilep- Localization value of magnetoencephalography togenic zone in children with nonlesional localization- interictal spikes in adult nonlesional neocortical related epilepsy. The aim of this study was to evaluate epilepsy sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of FDG-PET, MEG, Jeong, W; Chung, CK; Kim, JS FDG-PET + MEG, and FDG-PET/MEG in children with nonlesional localization-related epilepsy. METHODS: MEG Center, Department of Neurosurgery, Seoul National Twenty-six children with localization-related epilepsy University Hospital, Seoul, Korea. and who had normal or subtle changes on magnetic resonance imaging (MRI) underwent FDG-PET and ABSTRACT: Few studies have included magnetoen- MEG. Twenty-two patients had surgical resection, and cephalography (MEG) when assessing the diagnostic surgical outcome was assessed using Engel classifi- value of presurgical modalities in a nonlesional epilep- cation. In patients with Engel I seizure outcome, we sy population. Here, we compare single photon emis- assessed the sensitivity, specificity, PPV, and NPV of sion computed tomography (SPECT), positron emission lobar localization of MEG, FDG-PET, FDG-PET + MEG, tomography (PET), video-EEG (VEEG), and MEG, with and FDG-PET/MEG. KEY FINDINGS: Sixteen (72.7%) of intracranial EEG (iEEG) to determine the value of indi- 22 had Engel I seizure outcome. MEG was concordant vidual modalities to surgical decisions. We analyzed 23 with surgical resection in 18 patients, 14 had Engel I, adult epilepsy patients with no abnormal MRI findings and four had Engel II-IV outcomes. MEG was nonlocal- who had undergone surgical resection. Localization of

150 individual presurgical tests was determined for hemi- tion. KEY FINDINGS: Of 14 patients, 6 (42.9%) became spheric and lobar locations based on visual analysis. seizure-free after surgery. Sublobar ICEEG focus was Each localization result was compared with the ictal completely resected in 11 patients; 5 (45.5%) of them onset zone (IOZ) defined by using iEEG. The highest to became seizure- free. Concordance of ICEEG and MSI the lowest hemispheric concordance rates were MEG and complete focus resection was found in 5 (35.7%) (83%) > ictal VEEG (78%) > PET (70%) > ictal SPECT patients; 80% of them became seizure-free. Sublobar (57%). The highest to lowest lobar concordance rates ICEEG-MSI concordance and complete focus resection were ictal VEEG = MEG (65%) > PET (57%) > ictal SPECT significantly increased the chance of seizure freedom (52%). Statistical analysis showed MEG to have a higher after epilepsy surgery (p = 0.038). In contrast, of the 6 hemispheric concordance than that of ictal SPECT (P = patients (42.9%) with concordant ICEEG and SISCOM 0.031). We analyzed the effects of MEG clustered-area and complete focus resection, only 66.7% became resection on surgical outcome. Patients who had resec- seizure-free (p = 0.138). Assuming concordant results, tion of MEG clusters showed a better surgical outcome the additive value to ICEEG alone for localizing the than those without such resection (P = 0.038). It is EZ is higher with ICEEG-MSI (odds ratio 14) compared suggested that MEG-based localization had the highest to ICEEG-SISCOM (odds ratio 6). SIGNIFICANCE: This concordance with the iEEG-defined IOZ. Furthermore, study shows that combination of MSI and/or SISCOM MEG cluster resection has prognostic significance in with ICEEG is useful in the presurgical evaluation of predicting surgical outcome. (23166423) patients with nonlesional neocortical epilepsy. Con- cordant test results of either MSI or SISCOM with ICEEG Keywords: Magnetoencephalography; Nonlesional Epi- provide useful additive information for that provided lepsy; Presurgical Evaluation; Surgical Outcome by ICEEG alone to localize the EZ in this most challenging group of patients. When sublobar concordance J Korean Med Sci (2013), Vol. 27, No. 11, pp. 1391-7 with ICEEG is observed, MSI is more advantageous compared to SISCOM in predicting seizure-free epilepsy surgery outcome. (23106128) Magnetic source imaging and ictal SPECT in MRI- negative neocortical epilepsies: additional value Epilepsia (2013), Vol. 54, No. 2, pp. 359-69 and comparison with intracranial EEG

Schneider, F; Irene Wang, Z; Alexopoulos, AV; Almubarak, S; Magnetoencephalographic imaging of resting- Kakisaka, Y; Jin, K; Nair, D; Mosher, JC; Najm, IM; Burgess, RC state functional connectivity predicts postsurgical neurological outcome in brain gliomas Cleveland Clinic Epilepsy Center, Neurological Institute, Cleve- land, Ohio, USA. [email protected] Tarapore, PE; Martino, J; Guggisberg, AG; Owen, J; Honma, SM; Findlay, A; Berger, MS; Kirsch, HE; Nagarajan, SS PURPOSE: To investigate the utility of magnetic source imaging (MSI) and ictal single photon emission Department of Neurological Surgery, University of California- computed tomography (SPECT), each compared with San Francisco, San Francisco, California 94143-0628, USA. intracranial electroencephalography (EEG) (ICEEG), to localize the epileptogenic zone (EZ) and predict BACKGROUND: The removal of brain tumors in epilepsy surgery outcome in patients with nonlesional perieloquent or eloquent cortex risks causing new neocortical focal epilepsy. METHODS: Studied were neurological deficits in patients. The assessment of the 14 consecutive patients with nonlesional neocortical functionality of perilesional tissue is essential to avoid epilepsy who underwent presurgical evaluation includ- postoperative neurological morbidity. OBJECTIVE: ing ICEEG, positive MSI, and localizing subtraction Ictal To evaluate preoperative magnetoencephalography- SPECT coregistered to MRI (SISCOM) analysis. Follow-up based functional connectivity as a predictor of short- after epilepsy surgery was ≥ 24 months. ICEEG, MSI, and and medium-term neurological outcome after removal SPECT results were classified using a sublobar classifica- of gliomas in perieloquent and eloquent areas. METH-

151 ODS: Resting-state whole-brain magnetoencephalog- this study, the authors compared the accuracy of TMS raphy recordings were obtained from 79 consecutive to both DCS and MEG imaging. METHODS: Patients subjects with focal brain gliomas near or within motor, with tumors in proximity to primary motor cortex un- sensory, or language areas. Neural activity was estimat- derwent preoperative TMS and MEG imaging for motor ed using adaptive spatial filtering. The mean imaginary mapping. The patients subsequently underwent motor coherence between voxels in and around brain tumors mapping via intraoperative DCS. The loci of maximal was compared with contralesional voxels and used response were recorded from each modality and com- as an index of their functional connectivity with the pared. Motor strength was assessed at 3 months post- rest of the brain. The connectivity values of the tissue operatively. RESULTS: Transcranial magnetic stimula- resected during surgery were correlated with the early tion and MEG imaging were performed on 24 patients. (1 week postoperatively) and medium-term (6 months Intraoperative DCS yielded 8 positive motor sites in 5 postoperatively) neurological morbidity. RESULTS: Pa- patients. The median distance ± SEM between TMS and tients undergoing resection of tumors with decreased DCS motor sites was 2.13 ± 0.29 mm, and between TMS functional connectivity had a 29% rate of a new and MEG imaging motor sites was 4.71 ± 1.08 mm. In neurological deficit 1 week after surgery and a 0% rate no patients did DCS motor mapping reveal a motor site at 6-month follow-up. Patients undergoing resection that was unrecognized by TMS. Three of 24 patients of tumors with increased functional connectivity had developed new, early neurological deficit in the form a 60% rate of a new deficit at 1 week and a 25% rate at of upper-extremity paresis. At the 3-month follow- 6 months. CONCLUSION: Magnetoencephalography up evaluation, 2 of these patients were significantly connectivity analysis gives a valuable preoperative improved, experiencing difficulty only with fine motor evaluation of the functionality of the tissue surround- tasks; the remaining patient had improvement to 4/5 ing tumors in perieloquent and eloquent areas. These strength. There were no deaths over the course of the data may be used to optimize preoperative patient study. CONCLUSIONS: Maps of the motor system gen- counseling and surgical strategy. (22895403) erated with TMS correlate well with those generated by both MEG imaging and DCS. Negative TMS mapping Neurosurgery (2013), Vol. 71, No. 5, pp. 1012-22 also correlates with negative DCS mapping. Navigated TMS is an accurate modality for noninvasively generat- ing preoperative motor maps. (22702484) Preoperative multimodal motor mapping: a comparison of magnetoencephalography imaging, J Neurosurg (2012), Vol. 117, No. 2, pp. 354-62 navigated transcranial magnetic stimulation, and direct cortical stimulation Magnetoencephalography in pediatric lesional Tarapore, PE; Tate, MC; Findlay, AM; Honma, epilepsy surgery SM; Mizuiri, D; Berger, MS; Nagarajan, SS Kim, H; Lim, BC; Jeong, W; Kim, JS; Chae, JH; Department of Neurological Surgery, University of California, Kim, KJ; Chung, CK; Hwang, YS; Hwang, H San Francisco, California 94143, USA. Department of Pediatrics, Seoul National University Bundang OBJECT: Direct cortical stimulation (DCS) is the gold- Hospital, Seongnam, Korea. standard technique for motor mapping during craniotomy. However, preoperative noninvasive motor ABSTRACT: This study was performed to assess the mapping is becoming increasingly accurate. Two such usefulness of magnetoencephalography (MEG) as a noninvasive modalities are navigated transcranial presurgical evaluation modality in Korean pediatric magnetic stimulation (TMS) and magnetoencephalog- patients with lesional localization-related epilepsy. raphy (MEG) imaging. While MEG imaging has already The medical records and MEG findings of 13 pediatric been extensively validated as an accurate modality of patients (6 boys and 7 girls) with localization-related noninvasive motor mapping, TMS is less well studied. In epilepsy, who underwent epilepsy surgery at Seoul

152 National University Children's Hospital, were retrospec- Eight patients showed sublobar-concordant ICEEG/ tively reviewed. The hemispheric concordance rate was MSI results and complete resection of both regions; 100% (13/13 patients). The lobar or regional concor- seizure-free rate was 87.5%. Seizure-free rate in cases dance rate was 77% (10/13 patients). In most cases, not matching these criteria was only 30% (p=0.013). the MEG spike sources were clustered in the proximity CONCLUSIONS: Magnetoencephalography is a useful of the lesion, either at one side of the margin (nine tool to localize the EZ and determine the site of surgical patients) or around the lesion (one patient); clustered resection in NLNE patients. When sublobar concor- spike sources were distant from the lesion in one pa- dance with ICEEG is observed, MSI increases the predic- tient. Among the patients with clustered spike sources tive value for a seizure-free epilepsy surgery outcome near the lesion, further extensions (three patients) and in these patients. (22542998) distal scatters (three patients) were also observed. MEG spike sources were well lateralized and localized even Epilepsy Behav (2012), Vol. 24, No. 2, pp. 234-40 in two patients without focal epileptiform discharges in the interictal scalp electroencephalography. Ten patients (77%) achieved Engel class I postsurgical seizure Dynamics of hemispheric dominance for language outcome. It is suggested that MEG is a safe and useful assessed by magnetoencephalographic imaging presurgical evaluation modality in pediatric patients with lesion localization-related epilepsy. (22690099) Findlay, AM; Ambrose, JB; Cahn-Weiner, DA; Houde, JF; Honma, S; Hinkley, LB; Berger, MS; Nagarajan, SS; Kirsch, HE Keywords: Epilepsy Surgery; Localization; Magnetic Source Imaging; Magnetoencephalography; Spike Source Department of Radiology and Biomedical Imaging, Univer- sity of California at San Francisco, USA. J Korean Med Sci (2012), Vol. 27, No. 6, pp. 668-73 OBJECTIVE: The goal of the current study was to examine the dynamics of language lateralization using Magnetic source imaging in non-lesional magnetoencephalographic (MEG) imaging, to deter- neocortical epilepsy: additional value and mine the sensitivity and specificity of MEG imaging, comparison with ICEEG and to determine whether MEG imaging can become a viable alternative to the intracarotid amobarbital proce- Schneider, F; Alexopoulos, AV; Wang, Z; Almubarak, S; dure (IAP), the current gold standard for preoperative Kakisaka, Y; Jin, K; Nair, D; Mosher, JC; Najm, IM; Burgess, RC language lateralization in neurosurgical candidates. METHODS: MEG was recorded during an auditory Cleveland Clinic Epilepsy Center, Neurological Institute, 9500 verb generation task and imaging analysis of oscilla- Euclid Avenue, Desk S-51, Cleveland, OH 44195, USA. felix. tory activity was initially performed in 21 subjects with [email protected] epilepsy, brain tumor, or arteriovenous malformation who had undergone IAP and MEG. Time windows OBJECTIVE: To investigate the utility of magnetic and brain regions of interest that best discriminated source imaging (MSI) for localizing the epileptogenic between IAP-determined left or right dominance for zone (EZ) and predicting epilepsy surgery outcome in language were identified. Parameters derived in the non-lesional neocortical focal epilepsy (NLNE) patients. retrospective analysis were applied to a prospective METHODS: Data from 18 consecutive patients with cohort of 14 patients and healthy controls. RESULTS: NLNE who underwent presurgical evaluation includ- Power decreases in the beta frequency band were ing intracranial electroencephalography (ICEEG) and consistently observed following auditory stimulation in MSI were studied. Follow-up after epilepsy surgery was inferior frontal, superior temporal, and parietal corti- ≥24 months. Intracranial electroencephalography and ces; similar power decreases were also seen in inferior MSI results were classified using a sublobar classifica- frontal cortex prior to and during overt verb generation. RESULTS: Sublobar ICEEG focus was completely tion. Language lateralization was clearly observed to be resected in 15 patients; seizure-free rate was 60%. a dynamic process that is bilateral for several hundred

153 milliseconds during periods of auditory perception and nonaffected homologue area in the same frequency overt speech production. Correlation with the IAP was bands. These results indicate that pathological levels seen in 13 of 14 (93%) prospective patients, with the of synchronization exist within the tumor space and test demonstrating a sensitivity of 100% and specificity that MEG may be a viable tool for noninvasively dif- of 92%. INTERPRETATION: Our results demonstrate ex- ferentiating gliomas by their grade. Although these cellent correlation between MEG imaging findings and results should be considered preliminary and are only the IAP for language lateralization, and provide new correlative in nature, these data suggest that MEG can insights into the spatiotemporal dynamics of cortical potentially detect neurophysiological signatures or speech processing. (22522481) markers that predict the inherent grade of a glial tumor. (22447561) Ann Neurol (2012), Vol. 71, No. 5, pp. 668-86 Neuro Oncol (2012), Vol. 14, No. 5, pp. 624-30

Potential role for magnetoencephalography in distinguishing low- and high-grade gliomas: Clinical added value of magnetic source imaging a preliminary study with histopathological in the presurgical evaluation of refractory focal confirmation epilepsy

Wilson, TW; Heinrichs-Graham, E; Aizenberg, MR De Tiège, X; Carrette, E; Legros, B; Vonck, K; Op de Beeck, M; Bourguignon, M; Massager, N; Da- Department of Pharmacology and Experimental Neu- vid, P; Van Roost, D; Meurs, A; Lapere, S; Deb- roscience, Center for Magnetoencephalography, Univer- laere, K; Goldman, S; Boon, P; Van Bogaert, P sity of Nebraska Medical Center, Omaha, NE 68198, USA. [email protected] Magnetoencephalography Unit, Laboratoire de Car- tographiefonctionnelle du Cerveau, Université Libre de ABSTRACT: Gliomas are the most common form of Bruxelles(ULB), Brussels, Belgium. [email protected] tumor in the CNS and are exceptionally heterogeneous. Accurately characterizing gliomas, in terms of grade OBJECTIVE: This prospective, bicentre, blinded, inten- and type, is essential for predicting the rate of tumor tion to treat study assessed the clinical added value of progression. Histopathological grading and analysis magnetic source imaging (MSI) in the presurgical evalu- based on biopsied tissue remains the gold standard, ation of patients with refractory focal epilepsy (RFE). but non- and semi-invasive neuroimaging also plays a METHODS: 70 consecutive patients with RFE (42 men; key role. Neuroimaging has been used to guide and op- mean age 31.5 years, range 3-63) from two Belgian timize biopsies for several decades, but more recently centres were prospectively included. All patients under- molecular imaging and variants of MRI have shown went conventional non-invasive presurgical evaluation promise in independently predicting glioma grade. (CNIPE) and a whole head magnetoencephalography Here we evaluated whether magnetoencephalographic recording (Elekta Neuromag). Equivalent current (MEG) measurements of population-level physiology dipoles corresponding to interictal epileptiform dis- within the glioma space were predictive of the inherent charges (IED) were fitted in the patients' spherical head grade of the tissue, based on definitive histopathologi- model and coregistered on their MRI to produce MSI cal analyses. High-density MEG data were recorded results. Results of CNIPE were first discussed blinded to from 11 patients who were undergoing functional the MSI results in respective multidisciplinary epilepsy mapping in preparation for resective surgery. The pri- surgery meetings to determine the presumed locali- mary results indicated that glioma grade was positively sation of the epileptogenic zone and to set surgical correlated with the local amplitude of activity within or additional presurgical plans. MSI results were then the glioma space in the theta (4-7 Hz), alpha (8-14 Hz), discussed multidisciplinarily. MSI influence on the initial and beta bands (14-30 Hz). Additionally, activity within management plan was assessed. RESULTS: Based on the glioma was significantly elevated relative to the CNIPE, 21 patients had presumed extratemporal epi-

154 lepsy, 38 had presumed temporal epilepsy and 11 had Alterations in functional connectivity, as characterized undetermined localisation epilepsy. MSI showed IED in by the phase lag index (PLI), within the default mode 52 patients (74.5%) and changed the initial manage- network (DMN), executive control network (ECN), and ment in 15 patients (21%). MSI related changes were left- and right-sided frontoparietal networks (FPN) were significantly more frequent in patients with presumed compared to cognitive changes. RESULTS: Lower alpha extratemporal or undetermined localisation epilepsy band DMN connectivity was increased after surgery, compared with patients with presumed temporal epi- and this increase was related to improved verbal lepsy (p≤0.001). These changes had a clear impact on memory functioning. Similarly, right FPN connectivity clinical management in 13% of all patients. CONCLU- was increased after resection in the upper alpha band, SION: MSI is a clinically relevant, non-invasive neuro- which correlated with improved attention, working imaging technique for the presurgical evaluation of memory and executive functioning. DISCUSSION: In- patients with refractory focal epilepsy and, particularly, creased alpha band RSN functional connectivity in MEG in patients with presumed extratemporal and undeter- recordings correlates with improved cognitive outcome mined localisation epilepsy. (22262910) after resective surgery. The mechanisms resulting in functional connectivity alterations after resection J Neurol Neurosurg Psychiatry (2012), Vol. 83, No. 4, pp. remain to be elucidated. Importantly, our findings 417-23 indicate that connectivity of MEG RSNs may be used for presurgical prediction of cognitive outcome in future studies. (24179752) Connectivity in MEG resting-state networks increases after resective surgery for low-grade Keywords: Cognition; Functional connectivity; Glioma; glioma and correlates with improved cognitive Magnetoencephalography; Resective surgery; Resting- performance state networks van Dellen, E; de Witt Hamer, PC; Douw, L; Klein, M; Neuroimage Clin (2013), Vol. 2, pp. 1-7 Heimans, JJ; Stam, CJ; Reijneveld, JC; Hillebrand, A

Department of Neurology, VU University Medical Center, MEG in frontal lobe epilepsies: localization and Amsterdam, The Netherlands. postoperative outcome

PURPOSE: Low-grade glioma (LGG) patients often Stefan, H; Wu, X; Buchfelder, M; Rampp, S; have cognitive deficits. Several disease- and treatment Kasper, B; Hopfengärtner, R; Schmitt, F; Dör- related factors affect cognitive processing. Cogni- fler, A; Blümcke, I; Zhou, D; Weigel, D tive outcome of resective surgery is unpredictable, both for improvement and deterioration, especially Neurological Clinic, University Hospital Erlangen, Erlangen, for complex domains such as attention and executive Germany. [email protected] functioning. MEG analysis of resting-state networks (RSNs) is a good candidate for presurgical prediction of PURPOSE: This study aimed to analyze magneto- cognitive outcome. In this study, we explore the rela- encephalography (MEG) localizations of epileptic tion between alterations in connectivity of RSNs and clusters in different cortical regions of the frontal lobe changes in cognitive processing after resective surgery, and relate these findings to postoperative outcomes as a stepping stone to ultimately predict postsurgical associated with frontal lobe epilepsy (FLE). METH- cognitive outcome. METHODS: Ten patients with LGG ODS: Thirty-nine patients from the Epilepsy Center of were included, who had no adjuvant therapy. MEG Erlangen-Nuremberg University with or without lesions recording and neuropsychological assessment were on their magnetic resonance imaging (MRI) scans un- obtained before and after resective surgery. MEG data derwent MEG measurements and operation and were were recorded during a no-task eyes-closed condition, then analyzed retrospectively. MEG data were obtained and projected to the anatomical space of the AAL atlas. using systems with either 74 or 248 channels. Single

155 dipole analysis assuming a spherical head model was monitoring. Surgical outcomes were assessed based performed for localization. KEY FINDINGS: Epileptic on more than 1-year of post-surgical follow-up using clusters were detected by MEG in 30 patients, corre- Engel classification system. RESULTS: As we expected, sponding to a sensitivity of 76.9%; there was a sensi- both favorable outcomes (Engel class I or II) and seizure tivity of 66.7% (20 of 30) in patients with monofocal freedom outcomes (Engel class IA) were higher for the activity (70% had an Engel class 1 outcome) and 33.3% concordance condition (MEG findings are concordant (10 of 30) in patients with multifocal activity (20% had with MRI or iVEEG findings) versus the discordance con- an Engel class 1 outcome). Of the patients who had iso- dition. Also the seizure free rate was significantly higher lated clusters, the distance between the MEG localiza- (χ2=5.24, P<0.05) for the patients with lesional NE than tions and the respective lesions was equal to or <3 cm for the patients with nonlesional NE. In 30% of the in 90% (18 of 20) of patients (13 of them had an Engel patients with nonlesional NE, the MEG findings proved class 1 outcome) and >3 cm in 10% (2 of 20) of patients to be valuable for intracranial electrode implantation. (one of them had an Engel class 1 outcome). A statisti- CONCLUSIONS: This study demonstrates that a favor- cal difference was found between the outcomes of able post-surgical outcome can be obtained in most patients with a single focus and with multiple foci (p < patients with concordant MEG and MRI results even 0.05). SIGNIFICANCE: Patients with a single focus had without extraoperative iVEEG monitoring, which indi- better postoperative outcomes compared with patients cates that the concordance among different modalities with multiple foci. MEG localizations close to the lesion could indicate a likelihood of better postsurgical out- marked the lesion or its surrounding network as epi- comes. However, extraoperative iVEEG monitoring re- leptogenic. Therefore, source localization can provide mains prerequisite to the patients with discordant MEG important information for the presurgical evaluation of and MRI findings. For nonlesional cases, our results patients with FLE. (21933178) showed that MEG could provide critical information in the placement of intracranial electrodes. (21782477) Epilepsia (2012), Vol. 52, No. 12, pp. 2233-8 Seizure (2012), Vol. 20, No. 9, pp. 692-700

Interictal magnetoencephalographic findings related with surgical outcomes in lesional and Resting functional connectivity in patients with nonlesional neocortical epilepsy brain tumors in eloquent areas

Zhang, R; Wu, T; Wang, Y; Liu, H; Zou, Y; Liu, Martino, J; Honma, SM; Findlay, AM; Guggisberg, AG; W; Xiang, J; Xiao, C; Yang, L; Fu, Z Owen, JP; Kirsch, HE; Berger, MS; Nagarajan, SS

Department of Neurosurgery, Brain Hospital Affiliated of Department of Neurological Surgery, Hospital Universitario Nanjing Medical University, Nanjing, China. Marqués de Valdecilla, Instituto de Formación e Investigación Marqués de Valdecilla, Santander, Cantabria, Spain. PURPOSE: To investigate whether interictal magnetoencephalography (MEG) concordant with other OBJECTIVE: Resection of brain tumors adjacent to techniques can predict surgical outcome in patients eloquent areas represents a challenge in neurosurgery. with lesional and nonlesional refractory neocortical If maximal resection is desired without inducing post- epilepsy (NE). METHODS: 23 Patients with lesional NE operative neurological deficits, a detailed knowledge and 20 patients with nonlesional NE were studied. MEG of the functional topography in and around the tumor was recorded for all patients with a 275 channel whole- is crucial. The aim of the present work is to evaluate head system. Synthetic aperture magnetometry (SAM) the value of preoperative magnetoencephalography with excess kurtosis (g2) and conventional Equivalent (MEG) imaging of functional connectivity to predict Current Dipole (ECD) were used for MEG data analy- the results of intraoperative electrical stimulation (IES) sis. 27 Patients underwent long-term extraoperative mapping, the clinical gold standard for neurosurgical intracranial video electroencephalography (iVEEG) localization of functional areas. METHODS: Resting-

156 state whole-cortex MEG recordings were obtained from erated from 10 min of spontaneous brain activity and 57 consecutive subjects with focal brain tumors near compared to surgically resected brain areas outlined on or within motor, sensory, or language areas. Neural each subject's magnetic resonance image (MRI). Coher- activity was estimated using adaptive spatial filter- ence values were averaged independently for each ing algorithms, and the mean imaginary coherence hemisphere to ascertain the laterality of the epileptic between the rest of the brain and voxels in and around network. Reliability between runs was established by brain tumors were compared to the mean imaginary calculating the correlation between epochs. Match coherence between the rest of the brain and contral- rates compared the results of each of the two MEG esional voxels as an index of functional connectivity. analyses with optimal postoperative outcome. KEY IES mapping was performed in all subjects. The cortical FINDINGS: The ECD method provided an overall match connectivity pattern near the tumor was compared to rate of 50% (13/16 cases) for Engel class I outcomes, the IES results. RESULTS: Maps with decreased resting- with 37% (11/30 cases) found to be indeterminate state functional connectivity in the entire tumor area (i.e., no spikes identified on MEG). Coherence analysis had a negative predictive value of 100% for absence of provided an overall match rate of 77% (20/26 cases). Of eloquent cortex during IES. Maps showing increased 19 cases without evidence of mesial temporal sclero- resting-state functional connectivity within the tumor sis, coherence analysis correctly lateralized the side of area had a positive predictive value of 64% for finding TLE in 11 cases (58%). Sensitivity of the ECD method language, motor, or sensory cortical sites during IES was 41% (indeterminate cases included) and that of mapping. INTERPRETATION: Preoperative resting state the coherence method 73%, with a positive predictive MEG connectivity analysis is a useful noninvasive tool value of 70% for an Engel class Ia outcome. Intrasubject to evaluate the functionality of the tissue surrounding coherence imaging reliability was consistent from run- tumors within eloquent areas, and could potentially to-run (correlation > 0.90) using three 10-min epochs. contribute to surgical planning and patient counseling. SIGNIFICANCE: MEG coherence analysis has greater (21400562) sensitivity than the ECD method for lateralizing TLE and demonstrates reliable stability from run-to-run. Ann Neurol (2011), Vol. 69, No. 3, pp. 521-32 It, therefore, improves upon the capability of MEG in providing further information of use in clinical decision-making where the laterality of TLE is questioned. An assessment of MEG coherence imaging in the (21366556) study of temporal lobe epilepsy Epilepsia (2011), Vol. 52, No. 6, pp. 1110-9 Elisevich, K; Shukla, N; Moran, JE; Smith, B; Schultz, L; Mason, K; Barkley, GL; Tepley, N; Gumenyuk, V; Bowyer, SM Refined analysis of complex language Department of Neurosurgery, Henry Ford Health System, representations by non-invasive neuroimaging Detroit, Michigan, USA. techniques

PURPOSE: This study examines whether magneto- Ota, T; Kamada, K; Kawai, K; Yumoto, M; Aoki, S; Saito, N encephalographic (MEG) coherence imaging is more sensitive than the standard single equivalent dipole Department of Neurosurgery, The University of Tokyo, Tokyo, (ECD) model in lateralizing the site of epileptogenicity Japan. in patients with drug-resistant temporal lobe epilepsy (TLE). METHODS: An archival review of ECD MEG analy- OBJECTIVE: The determination of language lateralisa- ses of 30 presurgical patients with TLE was undertaken tion is important for patients with medically intractable with data extracted subsequently for coherence analy- epilepsy or a brain tumour near the language areas to sis by a blinded reviewer for comparison of accuracy of avoid the risk of post-surgical language deficits. The lateralization. Postoperative outcome was assessed by aim of this study was to evaluate the clinical useful- Engel classification. MEG coherence images were gen- ness of near-infrared spectroscopy (NIRS) to identify

157 language lateralisation compared with functional MRI with a 275 channel whole-head system with simulta- (fMRI) and magnetoencephalography (MEG) in mul- neous 21-channel scalp EEG during inpatient admis- tiple language tasks. METHODS: We investigated 28 sion one day prior to surgical resection. The patients' patients whose language dominance was evaluated by surgical outcomes were classified based on one-year the Wada test. fMRI, MEG and NIRS were performed to follow-up after surgery. RESULTS: Nineteen of the 22 investigate language representation. All patients were patients (86.4%) had interictal spikes during the EEG asked to read three-letter words silently for fMRI and and MEG recordings. Thirteen of 19 patients (68.4%) MEG (Kana reading) and to write words beginning with demonstrated unilateral temporal dipoles ipsilateral to a visually presented letter (word generation) for NIRS. the site of surgery. Among these patients, five (38.5%) The laterality index was calculated to assess language patients had horizontal dipoles, one (7.7%) patient had lateralisation in each investigation. RESULTS: In 24 vertical dipoles, and seven (53.8%) patients had both cases (85.7%), of which two investigations showed the horizontal and vertical dipoles. Sixty percent of patients same laterality, the results had perfect concordance with non-localizing ictal scalp EEG had well-localized with the Wada test. In patients with left dominance, the spikes on MSI ipsilateral to the side of surgery and sensitivity and specificity of fMRI, MEG and NIRS was 66.7% of patients with non-localizing MRI had well- 95.0% and 62.5%, 100% and 87.5%, 75.0% and 87.5%, localized spikes on MSI ipsilateral to the side of surgery. respectively. In three patients with right lateralization, Concordance between MSI localization and the side only NIRS showed a significant increase of oxygenat- of lobectomy was not associated with a likelihood of ed-haemoglobin in the right inferior frontal region, an excellent postsurgical outcome. CONCLUSIONS: indicating right dominance. CONCLUSION: We estab- MSI can detect medial temporal spikes. It may provide lished a method to determine language lateralisation important localizing information in patients with MTLE, by co-utilising fMRI, MEG and NIRS with high reliability. especially when MRI and/or ictal scalp EEG are not lo- NIRS recognised atypical language representation, in calizing. SIGNIFICANCE: This study demonstrates that addition to fMRI and MEG. While fMRI, MEG and NIRS MSI has a good ability to detect interictal spikes from are not currently as accurate as the Wada test in deter- mesial temporal structures. (20064741) mining language lateralisation, this non-invasive and repeatable method has great potential as an alternative Clin Neurophysiol (2010), Vol. 121, No. 3, pp. 325-31 to the Wada test in time following further research and refinement of these techniques. (20825290) Neurosurgical management of intractable rolandic Br J Neurosurg (2011), Vol. 25, No. 2, pp. 197-202 epilepsy in children: role of resection in eloquent cortex. Clinical article

Interictal MEG/MSI in intractable mesial temporal Benifla, M; Sala, F; Jane, J; Otsubo, H; Ochi, A; Drake, J; lobe epilepsy: spike yield and characterization Weiss, S; Donner, E; Fujimoto, A; Holowka, S; Widjaja, E; Snead, OC; Smith, ML; Tamber, MS; Rutka, JT Kaiboriboon, K; Nagarajan, S; Mantle, M; Kirsch, HE Divisions of Neurosurgery, The Hospital for Sick Children, The UCSF Epilepsy Center, Department of Neurology, USA. University of Toronto, Ontario, Canada.

OBJECTIVE: To evaluate the ability of MEG to detect OBJECT: The authors undertook this study to review medial temporal spikes in patients with known medial their experience with cortical resections in the rolandic temporal lobe epilepsy (MTLE) and to use magnetic region in children with intractable epilepsy. METH- source imaging (MSI) with equivalent current dipoles to ODS: The authors retrospectively reviewed the medi- examine localization and orientation of spikes and their cal records obtained in 22 children with intractable relation to surgical outcome. METHODS: We prospec- epilepsy arising from the rolandic region. All patients tively obtained MSI on a total of 25 patients previously underwent preoperative electroencephalography diagnosed with intractable MTLE. MEG was recorded (EEG), MR imaging, prolonged video-EEG recordings,

158 functional MR imaging, magnetoencephalography, and J Neurosurg Pediatr (2009), Vol. 4, No. 3, pp. 199-216 in some instances PET/SPECT studies. In 21 patients invasive subdural grid and depth electrode monitoring was performed. Resection of the epileptogenic zones in Lateralizing language with magnetic source the rolandic region was undertaken in all cases. Seizure imaging: validation based on the Wada test outcome was graded according to the Engel classification. Functional outcome was determined using vali- Doss, RC; Zhang, W; Risse, GL; Dickens, DL dated outcome scores. RESULTS: There were 10 girls and 12 boys, whose mean age at seizure onset was 3.2 Minnesota Epilepsy Group, P.A., St Paul, Minnesota 55102, years. The mean age at surgery was 10 years. Seizure USA. [email protected] duration prior to surgery was a mean of 7.4 years. Nine patients had preoperative hemiparesis. Neuropsycho- PURPOSE: Magnetoencephalography (MEG)/mag- logical testing revealed impairment in some domains in netic source imaging (MSI) is a noninvasive functional 19 patients in whom evaluation was possible. Magnetic neuroimaging procedure used to localize language- resonance imaging abnormalities were identified in 19 specific regions in the brain. The Wada test, or inpatients. Magnetoencephalography was performed in tracarotid amobarbital procedure (IAP), is the gold all patients and showed perirolandic spike clusters on standard in determining speech/language lateraliza- the affected side in 20 patients. The mean duration of tion for presurgical planning, although it is invasive invasive monitoring was 4.2 days. The mean number of and associated with morbidity. The purpose of this seizures during the period of invasive monitoring was study is to provide further validation on the use of MSI 17. All patients underwent resection that involved pri- for presurgical language lateralization by comparing mary motor and/or sensory cortex. The most common results against the IAP. METHODS: The sample con- pathological entity encountered was cortical dysplasia, sisted of 35 patients with epilepsy and/or brain tumor in 13 children. Immediately postoperatively, 20 patients undergoing presurgical evaluation at the Minnesota had differing degrees of hemiparesis, from mild to se- Epilepsy Group. All patients received both an IAP and vere. The hemiparesis improved in all affected patients MSI to determine hemispheric language dominance. by 3-6 months postoperatively. With a mean follow-up For MSI, a 148-channel MEG system was used to record of 4.1 years (minimum 2 years), seizure outcome in 14 activation of language-specific cortex by an auditory children (64%) was Engel Class I and seizure outcome in word-recognition task. RESULTS: The MSI and IAP were 4 (18%) was Engel Class II. In this series, seizure out- concordant in determining language in the hemi- come following perirolandic resection was intimately sphere to be treated in 86% of the cases with sensitivity related to the child's age at the time of surgery. By uni- and specificity values of 80% and 100%, respectively. variate logistic regression analysis, age at surgery was a CONCLUSIONS: The results from this study are consis- statistically significant factor predicting seizure out- tent with prior research findings comparing functional come (p < 0.024). CONCLUSIONS: Resection of rolandic neuroimaging procedures to the IAP in determining cortex for intractable epilepsy is possible with expected language lateralization in presurgical patients. The morbidity. Accurate mapping of regions of functional current study provides an important replication and cortex and epileptogenic zones may lead to improved support for Papanicolaou et al.'s findings in 2004 using seizure outcome in children with intractable rolandic a consecutive clinical sample from a different institu- epilepsy. It is important to counsel patients and families tion. An unusually high rate of atypical IAP language preoperatively to prepare them for possible worsened cases in this sample and differences between the two functional outcome involving motor, sensory and/or procedures are believed to explain the noted discrep- language pathways. (19772403) ancies. MSI is a viable noninvasive alternative to the IAP in the presurgical determination of language lateralization. (19674060)

159 Epilepsia (2009), Vol. 50, No. 10, pp. 2242-8 localization from seizure semiology, electroencephalo- gram, and magnetic resonance imaging. (19557860)

Effect of epilepsy magnetic source imaging on Ann Neurol (2009), Vol. 65, No. 6, pp. 716-23 intracranial electrode placement

Knowlton, RC; Razdan, SN; Limdi, N; Elgavish, RA; Killen, Temporo-parietal theta activity correlates with J; Blount, J; Burneo, JG; Ver Hoef, L; Paige, L; Faught, E; misery perfusion in arterial occlusive disease Kankirawatana, P; Bartolucci, A; Riley, K; Kuzniecky, R Ohtomo, S; Nakasato, N; Shimizu, H; Seki, Epilepsy Center, Department of Neurology, University of S; Kanno, A; Kumabe, T; Tominaga, T Alabama at Birmingham, School of Medicine, Birmingham, AL 35294-0001, USA. [email protected] Department of Neurosurgery, Kohnan Hospital, Sendai, Japan. OBJECTIVE: Intracranial electroencephalography (ICEEG) with chronically implanted electrodes is a costly OBJECTIVE: Temporo-parietal theta activity (TPTA), of- invasive diagnostic procedure that remains necessary ten detected in hemispheres with internal carotid (ICA) for a large proportion of patients who undergo evalu- or middle cerebral artery (MCA) occlusive lesions, is ation for epilepsy surgery. This study was designed to more clearly separated from occipital alpha activity by evaluate whether magnetic source imaging (MSI), a magnetoencephalography (MEG) than electroencepha- noninvasive test based on magnetoencephalography lography. The present study investigated whether TPTA source localization, can supplement ICEEG by affect- is correlated with misery perfusion, a surgically correct- ing electrode placement to improve sampling of the able type of hemodynamic impairment. METHODS: seizure onset zone(s). METHODS: Of 298 consecutive Awake MEG was measured in 56 patients with ICA or epilepsy surgery candidates (between 2001 and 2006), MCA occlusive lesions. Regional cerebral blood flow 160 patients were prospectively enrolled by insufficient (rCBF) and regional cerebrovascular reactivity (rCVR) localization from seizure monitoring and magnetic res- to acetazolamide were measured in the MCA terri- onance imaging results. Before presenting MSI results, tory by xenon-133 single-photon emission computed decisions were made whether to proceed with ICEEG, tomography. MEG was repeated in 10 patients after and if so, where to place electrodes such that the hy- vascular reconstruction surgery. RESULTS: Fourteen pa- pothetical seizure-onset zone would be sampled. MSI tients showed TPTA in the lesion hemisphere (n=13) or results were then provided with allowance of changes bilaterally (n=1). The presence of TPTA was significantly to the original plan. RESULTS: MSI indicated additional correlated with both reduced rCBF and reduced rCVR electrode coverage in 18 of 77 (23%) ICEEG cases. In (P=0.0009). After surgery, TPTA disappeared in 7 of the 39% (95% confidence interval, 16.4-61.4), seizure-onset 10 studied patients. CONCLUSIONS: The presence of ICEEG patterns involved the additional electrodes in- TPTA suggests misery perfusion, which is characterized dicated by MSI. Sixty-two patients underwent surgical by reduced rCBF and reduced rCVR. SIGNIFICANCE: resection based on ICEEG recording of seizures. Highly MEG can detect the presence of reversible and surgi- localized MSI was significantly associated with seizure- cally remediable cerebral ischemia before the develop- free outcome (mean, 3.4 years; minimum, >1 year) for ment of complete infarction. (19539523) the entire surgical population (n = 62). INTERPRETA- TION: MSI spike localization increases the chance that the seizure-onset zone is sampled when patients undergo ICEEG for presurgical epilepsy evaluations. The clinical impact of this effect, improving diagnostic yield of ICEEG, should be considered in surgery candidates who do not have satisfactory indication of epilepsy

160 Clin Neurophysiol (2009), Vol. 120, No. 7, pp. 1227-34 Neurosurgery (2009), Vol. 64, No. 3 Suppl, pp. ons177-85; discussion ons186

Presurgical localization of primary motor cortex in pediatric patients with brain lesions by the use of Changing ictal-onset EEG patterns in children with spatially filtered magnetoencephalography cortical dysplasia

Gaetz, W; Cheyne, D; Rutka, JT; Drake, J; Beni- Galicia, E; Imai, K; Mohamed, IS; Go, C; Fuji- fla, M; Strantzas, S; Widjaja, E; Holowka, S; moto, A; Ochi, A; Sakuta, R; Halliday, W; Rutka, Tovar-Spinoza, Z; Otsubo, H; Pang, EW JT; Chuang, SH; Snead, OC; Otsubo, H

Department of Diagnostic Imaging, Hospital for Sick Chil- Division of Neurology, The Hospital for Sick Children, Toronto, dren, Toronto, Canada. [email protected] Ontario, Canada.

OBJECTIVE: The objective of this study was to confirm PURPOSE: Cortical dysplasia (CD) is intrinsically epi- the efficacy of spatially filtered magnetoencephalogra- leptogenic. We hypothesize that CDs clinically emerg- phy for the preoperative localization of primary motor ing in the early developing brain tend to extend into cortex in pediatric patients with focal lesions in the multifocal or larger epileptic networks to pronounce region of the sensorimotor cortex. METHODS: We re- intractability in contrast to CDs which clinically emerge corded movement-related magnetoencephalographic at a later age. METHODS: We evaluated the spatial and activity in 10 pediatric patients (age range, 7-18 years; temporal profiles of ictal-onset EEG patterns in children mean age, 12.5 years) undergoing presurgical evalua- with histopathologically confirmed CD. We designated tion for focal brain lesion resection. Participants made Group A as children with changing ictal-onset EEG transient movements of the right and left index finger patterns over time, and Group B without change. We in response to a visual cue. The premovement motor compared seizure profiles, consecutive scalp video- field component in the averaged brain response was EEGs (VEEGs), MRI, MEG, and surgical outcomes. localized with a newly developed beamformer spatial RESULTS: We found 14 children consisting of 10 Group filter algorithm. Cortical mapping of motor cortex A patients (7 girls) and 4 Group B patients (all boys). intraoperatively was conducted in 5 of the 10 patients. Eight (80%) Group A patients had their seizure onset RESULTS: The motor field time-locked to electromy- <5 years while all Group B patients had seizure onset ography onset was successfully localized to cortical >or=5 years (p<.05). Changes of ictal onset EEG pattern areas corresponding to the hand region primary motor in Group A consisted of bilateral (4 patients), extend- cortex in 95% of cases (9 of 10 from nonlesional hemi- ing (2); extending and bilateral (2); and generalized (2). sphere; 10 of 10 from lesional hemisphere). Intraopera- We saw MRI lesions (6) and single clustered MEG spike tive electrocortical stimulation activated the expected sources (MEGSSs) in (5). Six patients underwent surgery muscles at motor field coregistered cortical source loca- before 15 years of age, and 4 of them attained seizure tions in all cases tested (n = 5). Using these methods, freedom. All 4 Group B patients had MRI lesions and we also found that displacement of the sensorimotor single clustered MEGSSs. Three patients underwent cortex by space-occupying tumors did not interfere surgery after 15 years of age. All 4 patients attained sei- with the localization of motor cortex. CONCLUSION: zure freedom. CONCLUSION: Ictal-onset EEG patterns We conclude that noninvasive localization of the pri- change over time in children with early seizure onset mary motor cortex can be reliably performed by using and intractable epilepsy caused by CD. Younger epilep- spatially filtered magnetoencephalography techniques, tic children with CD more frequently have multifocal which provide a robust and accurate measurement epileptogenic foci or larger epileptogenic foci. Early of motor cortical function for the purpose of surgical resection of CD, guided by MRI, MEG, and intracranial guidance. (19240567) video EEG, resulted in seizure freedom despite changes in ictal-onset EEG patterns. (18834684)

161 Brain Dev (2009), Vol. 31, No. 8, pp. 569-76 Epilepsy Res (2009), Vol. 82, No. 2-3, pp. 147-55

Characteristics of MEG and MRI between Taylor's Preoperative localization of hand motor focal cortical dysplasia (type II) and other cortical cortex by adaptive spatial filtering of dysplasia: surgical outcome after complete magnetoencephalography data resection of MEG spike source and MR lesion in pediatric cortical dysplasia Nagarajan, S; Kirsch, H; Lin, P; Find- lay, A; Honma, S; Berger, MS Widjaja, E; Otsubo, H; Raybaud, C; Ochi, A; Chan, D; Rutka, JT; Snead, OC; Halliday, W; Sa- Biomagnetic Imaging Laboratory, Department of Radiology, kuta, R; Galicia, E; Shelef, I; Chuang, SH University of California, San Francisco, California 94143-0628, USA. [email protected] Diagnostic Imaging, The Hospital for Sick Children, Ontario, Canada. [email protected] OBJECT: The goal of this study was to examine the sensitivity and specificity in preoperative localization PURPOSE: Cortical dysplasia (CD) has been classified as of hand motor cortex by imaging regional event- Taylor's focal cortical dysplasia (FCD type II) or other CD related desynchronization (ERD) of brainwaves in the (FCD type I and mild malformation of cortical develop- beta frequency band (15-25 Hz) involved in self-paced ment) based on histological findings. The aims of this movement. METHODS: Using magnetoencephalog- study were to determine whether MRI and magnetoen- raphy (MEG), the authors measured ERD that occurred cephalography (MEG) could distinguish between these before self-paced unilateral index finger flexion in 66 two groups and to evaluate surgical outcomes. METH- patients with brain tumors, epilepsy, and arteriovenous ODS: We evaluated the MRI features, MEG spike source malformations. RESULTS: The authors applied an adap- (MEGSS) patterns (clusters or scatters) and postsurgical tive spatial filtering algorithm to MEG data and found seizure outcomes of 27 children with CD. RESULTS: that peaks of the tomographic distribution of beta- Thirteen patients had Taylor's FCD and 14 had other CD. band ERD sources reliably localized hand motor cortex MRI showed visible lesion in 22 (81%) patients. Tapering compared with electrical cortical stimulation. They also of abnormal white matter signals to the ventricles and observed high specificity in estimating contralateral cortical thickening were more prevalent in Taylor's FCD; hand motor cortical representations relative to somato- focal hypoplasia and white matter atrophy were more sensory cortex. Neither presence nor location of tumor prevalent in other CD. MEG showed spike sources in 26 changed the qualitative or quantitative location of (96%) patients. Taylor's FCD showed clustered MEGSSs motor cortex relative to somatosensory cortex. CON- in 6, both clustered and scattered MEGSSs in 5 and scat- CLUSIONS: An imaging protocol using ERD obtained tered MEGSSs in 2; other CD demonstrated clusters in 2, by adaptive spatial filtering of MEG data can be used cluster and scatter in 10 and scatter in 1. Eleven (85%) for extremely reliable preoperative localization of hand of 13 patients who had complete resection of clustered motor cortex. (18671634) MEGSSs achieved Engel class I outcome, but 4 (44%) of 9 patients with incomplete resections achieved J Neurosurg (2008), Vol. 109, No. 2, pp. 228-37 class I. Fifteen (88%) of 17 patients who had complete resection of MRI lesions achieved class I, but 1 (33%) of 3 patients with incomplete lesionectomy was class I. Treatment-related changes in functional There was no difference in surgical outcomes between connectivity in brain tumor patients: a Taylor's FCD and other CD. CONCLUSIONS: Surgical magnetoencephalography study outcome was the same in both groups following complete removal of areas containing clustered MEGSSs Douw, L; Baayen, H; Bosma, I; Klein, M; Vandertop, and MR lesions. (18774695) P; Heimans, J; Stam, K; de Munck, J; Reijneveld, J

162 Department of Neurology, VU University Medical Center, tion of spike-related high-frequency power changes Amsterdam, The Netherlands. [email protected] is unknown. In this study, we localized the sources of spike-locked power increases in the beta and gamma ABSTRACT: Widespread disturbances in resting state band with magnetoencephalography and an adaptive functional connectivity between remote brain areas spatial filtering technique and tested the usefulness of have been demonstrated in patients with brain tumors. these reconstructions for determining the epileptogen- Functional connectivity has been associated with ic zone in a population of 27 consecutive presurgical neurocognitive deficits in these patients. Thus far, it is patients with medication refractory partial epilepsies. unknown how (surgical) treatment affects functional The reliability of this approach was compared to the connectivity. Functional connectivity before and after performance of conventional MEG techniques such tumor resection was compared in primary brain tumor as equivalent current dipole (ECD) models. In patients patients. Data from 15 newly diagnosed brain tumor with good surgical outcome after a mean follow-up patients were analyzed. Patients underwent tumor time of 16 months (Engel class I or II), the surgically resection, and both preoperative (up to five months resected area was identified with an accuracy of 85% prior to surgery) and postoperative (up to ten months by sources of spike-locked beta/gamma activity, which following surgery) resting state magnetoencephalog- compared favorably with the accuracy of 69% found raphy (MEG) recordings. Seven of the patients (47%) for ECD models of single spikes. In patients with a total underwent radiotherapy after neurosurgery. Functional of more than 50 spikes in their recordings, the accura- connectivity was assessed by the phase lag index (PLI), cies increased to 100% vs. 88%, respectively. Imaging a measure of the correlation between MEG sensors that of spike-locked beta/gamma power changes therefore is not sensitive to volume conduction. PLIs were aver- seems to be a reliable and fast alternative to conven- aged to one short-distance and two long-distance (in- tional MEG techniques for localizing epileptogenic terhemispheric and intrahemispheric) scores in seven tissue, in particular, if more than 50 interictal spikes can frequency bands. We found that functional connectiv- be recorded. (17977022) ity changed in a complex manner after tumor resection, depending on frequency band and functional con- Neuroimage (2008), Vol. 39, No. 2, pp. 661-8 nectivity type. Post-hoc analyses yielded a significant decrease of interhemispheric PLI in the theta band after tumor resection. This result proved to be robust Mapping functional connectivity in patients with and was not influenced by radiotherapy or a variety of brain lesions tumor- and patient-related factors. (18534578) Guggisberg, AG; Honma, SM; Findlay, AM; Da- Exp Neurol (2008), Vol. 212, No. 2, pp. 285-90 lal, SS; Kirsch, HE; Berger, MS; Nagarajan, SS

Biomagnetic Imaging Lab, Department of Radiology, Univer- Fast oscillations associated with interictal spikes sity of California San Francisco, San Francisco, CA 94143- localize the epileptogenic zone in patients with 0628, USA. [email protected] partial epilepsy OBJECTIVE: The spatial distribution of functional con- Guggisberg, AG; Kirsch, HE; Mantle, nectivity between brain areas and the disturbance in- MM; Barbaro, NM; Nagarajan, SS troduced by focal brain lesions are poorly understood. Based on the rationale that damaged brain tissue is dis- Biomagnetic Imaging Laboratory, Department of Radiol- connected from the physiological interactions among ogy, University of California San Francisco, San Francisco, CA healthy areas, this study aimed to map the functional- 94143-0628, USA. [email protected] ity of brain areas according to their connectivity with other areas. METHODS: Magnetoencephalography ABSTRACT: Although interictal epileptic spikes are recordings of spontaneous cortical activity during rest- defined as fast transient activity, the spatial distribu- ing state were obtained from 15 consecutive patients

163 with focal brain lesions and from 14 healthy control location of face somatosensory cortex obtained with subjects. Neural activity in the brain was estimated somatosensory evoked fields during preoperative MEG using an adaptive spatial filtering technique. The mean with the mouth motor areas identified during intraop- imaginary coherence between brain voxels was then erative electrocortical stimulation (ECS) mapping in 13 calculated as an index of functional connectivity. RE- patients undergoing resection of brain tumor. RE- SULTS: Imaginary coherence was greatest in the alpha SULTS: In this group of patients, ECS mouth motor sites frequency range corresponding to the human cortical were usually anterior and lateral to MEG localizations idling rhythm. In healthy subjects, functionally critical of lip somatosensory cortex. The consistent quantita- brain areas such as the somatosensory and language tive relationship between results of these two mapping cortices had the highest alpha coherence. When com- procedures allows the practitioner to predict the loca- pared with healthy control subjects, all lesion patients tion of mouth motor cortex based on noninvasive pre- had diffuse or scattered brain areas with decreased operative MEG measurements. CONCLUSIONS: Based alpha coherence. Patients with lesion-induced neuro- on this result, the authors suggest that somatosensory logical deficits displayed decreased connectivity esti- mapping using MEG can be used to guide intraopera- mates in the corresponding brain area compared with tive mapping and neurosurgical planning. (17886544) intact contralateral regions. In tumor patients without preoperative neurological deficits, brain areas show- J Neurosurg (2007), Vol. 107, No. 3, pp. 481-7 ing decreased coherence could be surgically resected without the occurrence of postoperative deficits. INTERPRETATION: Resting state coherence measured Neuromagnetic localization of spike sources in with magnetoencephalography is capable of map- perilesional, contralateral mirror, and ipsilateral ping the functional connectivity of the brain, and can remote areas in patients with cavernoma therefore offer valuable information for use in planning resective surgeries in patients with brain lesions, as well Jin, K; Nakasato, N; Shamoto, H; Kan- as investigations into structural-functional relationships no, A; Itoyama, Y; Tominaga, T in healthy subjects. (17894381) Department of Neurology, Tohoku University Graduate Ann Neurol (2008), Vol. 63, No. 2, pp. 193-203 School of Medicine, Sendai, Japan.

PURPOSE: To assess neuromagnetic spike localization Predicting the location of mouth motor cortex in as an indication for extended lesionectomy of caver- patients with brain tumors by using somatosensory noma. METHODS: Electroencephalography (EEG) and evoked field measurements magnetoencephalography (MEG) was simultaneously recorded in 17 patients (8 men, mean age 29.7 years) Kirsch, HE; Zhu, Z; Honma, S; Find- with single cavernoma. The location of the equivalent lay, A; Berger, MS; Nagarajan, SS current dipole (ECD) of the interictal spikes was correlated with the lesion shown by magnetic resonance University of California San Francisco Epilepsy Center, Depart- imaging. RESULTS: Preoperative ECD localization ment of Neurology, USA. was classified into four types: perilesional, adjacent to the cavernoma only (n = 6); mirror, adjacent to the OBJECT: Before resective brain surgery, localization of lesion and at the contralateral homologous site (n = the functional regions is necessary to minimize post- 5); remote, mainly at a remote site in the ipsilateral operative deficits. The face area has been relatively diffi- hemisphere (n = 3); and no spikes (n = 3). The spikes cult to map noninvasively by using functional imaging were detected by only MEG in two of five "mirror" and techniques. Preoperative localization of face somato- all three "remote" patients. In the mirror group, con- sensory cortex with magnetoencephalography (MEG) tralateral spikes were synchronized with the ipsilateral may allow the surgeon to predict the location of mouth spikes, or also occurred independently. Two "perile- motor areas. METHODS: The authors compared the sional" and two "mirror" patients became seizure-free

164 and spike-free after extended lesionectomy. In contrast, the other two "mirror" patients had residual seizures and spikes after pure lesionectomy. CONCLUSION: The detectability of mirror and remote spikes was higher by MEG than by EEG, whereas the detectability of perilesional spikes was similar by MEG and EEG. Therefore, the use of both EEG and MEG will provide the maximum information about spike distribution and propagation. Residual seizures and spikes after pure lesionectomy, but not after extended lesionectomy, in the "mirror" patients suggest the importance of resection of the perilesional irritable zone. Extended resection of the irritable cortex surrounding cavernoma is recommended for better seizure control, particularly in "mirror" patients. (17666072)

Epilepsia (2008), Vol. 48, No. 11, pp. 2160-6

165 166 Schizophrenia Keywords: Alpha band; Beta band; MEG; Negative symptoms; Neural oscillations; Positive symptoms; Resting- state; Schizophrenia MEG resting-state oscillations and their relationship to clinical symptoms in schizophrenia Neuroimage Clin (2019), Vol. 20, pp. 753-761

Zeev-Wolf, M; Levy, J; Jahshan, C; Peled, A; Levkovitz, Y; Grinshpoon, A; Goldstein, A Changes in electrophysiological markers of cognitive control after administration of Gonda Brain Research Center, Bar Ilan University, Ramat-Gan, galantamine Israel; Department of Education, Ben Gurion University, Beer Sheva, Israel. Electronic address: [email protected]. Gascoyne, LE; Mullinger, KJ; Robson, SE; Ku- mar, J; O'Neill, GC; Palaniyappan, L; Mor- ABSTRACT: Neuroimaging studies suggest that schizo- ris, PG; Liddle, EB; Brookes, MJ; Liddle, PF phrenia is characterized by disturbances in oscillatory activity, although at present it remains unclear whether Sir Peter Mansfield Imaging Centre, School of Physics and these neural abnormalities are driven by dimensions Astronomy, University of Nottingham, University Park, Not- of symptomatology. Examining different subgroups tingham, UK. Electronic address: lauren.gascoyne@notting- of patients based on their symptomatology is thus ham.ac.uk. very informative in understanding the role of neural oscillation patterns in schizophrenia. In the present ABSTRACT: The healthy brain is able to maintain a study we examined whether neural oscillations in the stable balance between bottom-up sensory processing delta, theta, alpha, beta and gamma bands correlate and top-down cognitive control. The neurotransmitter with positive and negative symptoms in individuals acetylcholine plays a substantial role in this. Disrup- with schizophrenia (SZ) during rest. Resting-state brain tion of this balance could contribute to symptoms activity of 39 SZ and 25 neurotypical controls was re- occurring in psychosis, including subtle disruption of corded using magnetoencephalography. Patients were motor control and aberrant appropriation of salience categorized based on the severity of their positive and to external stimuli; however the pathological mecha- negative symptoms. Spectral analyses of beamformer nisms are poorly understood. On account of the role data revealed that patients high in positive symptoms beta oscillations play in mediating cognitive control, showed widespread low alpha power, and alpha power investigation of beta oscillations is potentially infor- was negatively correlated with positive symptoms. In mative about such mechanisms. Here, we used mag- contrast, patients high in negative symptoms showed netoencephalography to investigate the effect of the greater beta power in left hemisphere regions than acetylcholinesterase-inhibitor, galantamine, on beta those low in negative symptoms, and beta power was oscillations within the sensorimotor region during both positively correlated with negative symptoms. We fur- a sensorimotor task and a relevance-modulation task in ther discuss these findings and suggest that different healthy participants, employing a double blind ran- neural mechanisms may underlie positive and negative domized placebo controlled cross-over design. In the symptoms in schizophrenia. (30238919) galantamine condition, we found a significant reduction in the post-movement beta rebound in the case of executed movements and also in a planned but not executed movement. In the latter case, the effect was significantly greater following task-relevant compared with irrelevant stimuli. The results suggest that the action of galantamine reduces the influence of top-down cognitive processing relative to bottom-up perceptual processing in a manner resembling changes previously reported in schizophrenia. (30090697)

167 Keywords: Acetylcholine; Beta oscillations; Magnetoen- Keywords: Dorsal visual stream; Magnetoencephalogra- cephalography; PMBR; Schizophrenia phy; Multisensory integration; Parietal lobe; Schizophre- nia; Visual field Neuroimage Clin (2019), Vol. 20, pp. 228-235 Psychiatry Res Neuroimaging (2019), Vol. 278, pp. 56-64

Neuroimaging investigations of dorsal stream processing and effects of stimulus synchrony in Identifying auditory cortex encoding abnormalities schizophrenia in schizophrenia: The utility of low-frequency versus 40 Hz steady-state measures Sanfratello, L; Aine, C; Stephen, J Edgar, JC; Fisk, CL; Chen, YH; Stone-Howell, B; Liu, S; The Mind Research Network, 1101 Yale Blvd NE, Albuquerque, Hunter, MA; Huang, M; Bustillo, J; Cañive, JM; Miller, GA NM 87106 USA. Electronic address: [email protected]. The Children's Hospital of Philadelphia and University of ABSTRACT: Impairments in auditory and visual pro- Pennsylvania, Philadelphia, Pennsylvania, USA. cessing are common in schizophrenia (SP). In the unisensory realm visual deficits are primarily noted for the ABSTRACT: Magnetoencephalography (MEG) and EEG dorsal visual stream. In addition, insensitivity to timing have identified poststimulus low frequency and 40 Hz offsets between stimuli are widely reported for SP. The steady-state auditory encoding abnormalities in schizo- aim of the present study was to test at the physiological phrenia (SZ). Negative findings have also appeared. To level differences in dorsal/ventral stream visual pro- identify factors contributing to these inconsistencies, cessing and timing sensitivity between SP and healthy healthy control (HC) and SZ group differences were controls (HC) using MEG and a simple auditory/visual examined in MEG and EEG source space and EEG sensor task utilizing a variety of multisensory conditions. The space, with better group differentiation hypothesized paradigm included all combinations of synchronous/ for source than sensor measures given greater predic- asynchronous and central/peripheral stimuli, yield- tive utility for source measures. Fifty-five HC and 41 ing 4 task conditions. Both HC and SP groups showed chronic SZ were presented 500 Hz sinusoidal stimuli activation in parietal areas (dorsal visual stream) during modulated at 40 Hz during simultaneous whole-head all multisensory conditions, with parietal areas showing MEG and EEG. MEG and EEG source models using left decreased activation for SP relative to HC, and a signifi- and right superior temporal gyrus (STG) dipoles esti- cantly delayed peak of activation for SP in intraparietal mated trial-to-trial phase similarity and percent change sulcus (IPS). We also observed a differential effect of from prestimulus baseline. Group differences in post- stimulus synchrony on HC and SP parietal response. stimulus low-frequency activity and 40 Hz steady-state Furthermore, a (negative) correlation was found be- response were evaluated. Several EEG sensor analysis tween SP positive symptoms and activity in IPS. Taken strategies were also examined. Poststimulus low- together, our results provide evidence of impairment frequency group differences were observed across all of the dorsal visual stream in SP during a multisensory methods. Given an age-related decrease in left STG 40 task, along with an altered response to timing offsets Hz steady-state activity in HC (HC > SZ), 40 Hz steady- between presented multisensory stimuli. (29884441) state group differences were evident only in younger participants' source measures. Findings thus indicated that optimal data collection and analysis methods depend on the auditory encoding measure of interest. In addition, whereas results indicated that HC and SZ auditory encoding low-frequency group differences are generally comparable across modality and analysis strategy (and thus not dependent on obtaining construct-valid measures of left and right auditory cortex

168 activity), 40 Hz steady-state group-difference findings tal theta-frequency ERS for encoding is most predictive are much more dependent on analysis strategy, with of poor WM in schizophrenia. SIGNIFICANCE: Time-fre- 40 Hz steady-state source-space findings providing the quency-spatial analysis identified process- and frequen- best group differentiation. (29570815) cy-specific neural synchrony abnormalities underlying WM deficits in schizophrenia. (29197736) Keywords: auditory encoding; electroencephalography; magnetoencephalography; schizophrenia; superior tem- Keywords: Cortical source analysis; Magnetoencephalog- poral gyrus raphy (MEG); Neural oscillation; Schizophrenia; Working memory Psychophysiology (2019), Vol. 55, No. 8, pp. e13074 Clin Neurophysiol (2018), Vol. 129, No. 1, pp. 210-221

Abnormal cortical neural synchrony during working memory in schizophrenia Magnetoencephalography reveals an increased non-target P3a, but not target P3b, that is Kang, SS; MacDonald, AW; Chafee, MV; Im, CH; associated with high non-clinical psychosocial Bernat, EM; Davenport, ND; Sponheim, SR deficits

Department of Psychiatry, University of Missouri-Kansas City, Ford, TC; Woods, W; Crewther, DP Kansas City, MO 64108, USA. Electronic address: kangseung@ umkc.edu. Centre for Human Psychopharmacology, Faculty of Heath, Arts and Design, Swinburne University of Technology, Mel- OBJECTIVE: To better understand the origins of bourne, Victoria, Australia. Electronic address: tcford@swin. working memory (WM) impairment in schizophrenia edu.au. we investigated cortical oscillatory activity in people with schizophrenia (PSZ) while they performed a WM ABSTRACT: Auditory processing deficits are frequently task requiring encoding, maintenance, and retrieval/ identified in autism and schizophrenia, and the two manipulation processes of spatial information. METH- disorders have been shown to share psychosocial ODS: We examined time-frequency synchronous difficulties. This study used magnetoencephalogra- energy of cortical source signals that were derived from phy to investigate auditory processing differences for magnetoencephalography (MEG) localized to cortical those with a high degree of a non-clinical autistic and regions using WM-related hemodynamic responses schizotypal trait phenotype, Social Disorganisation and individualized structural head-models. RESULTS: (SD). Participants were 18 low (9 female) and 19 high Compared to thirteen healthy controls (HC), twelve PSZ (9 female) SD scorers (18-40 years) who completed a showed performance deficits regardless of WM-load three-stimulus auditory oddball paradigm of speech or duration. During encoding, PSZ had early theta and sounds (standard: 100ms 'o', deviant: 150ms 'o', novel: delta event-related synchrony (ERS) deficits in prefron- 150ms 'e'). Spatio-temporal cluster analysis revealed tal and visual cortices which worsened with greater increased amplitude for the high SD group in a left (p memory load and predicted WM performance. During = 0.006) and a right (p = 0.020) hemisphere cluster in prolonged maintenance of material, PSZ showed defi- response to the novel non-target. No cluster differences cient beta event-related desynchrony (ERD) in dorso- were found in response to the target deviant. These lateral prefrontal, posterior parietal, and visual cortices. findings suggest that those with a high degree of the In retrieval, PSZ showed reduced delta/theta ERS in SD phenotype recruit more cortical resources when the anterior prefrontal and ventral visual cortices and processing unattended, novel speech stimuli, which diminished gamma ERS in the premotor and posterior may lead to psychosocial deficits. (29182941) parietal cortices. CONCLUSIONS: Although beta/gamma cortical neural oscillatory deficits for maintenance/ retrieval are evident during WM, the abnormal prefron-

169 Keywords: Auditory oddball; Autism; P300; Schizotypy; Keywords: Biomarker; Bipolar disorder; Connectivity; First Social Disorganisation episode; Mismatch negativity; Schizophrenia

Psychiatry Res Neuroimaging (2019), Vol. 271, pp. 1-7 Schizophr Res (2018), Vol. 193, pp. 313-318

Dissociable auditory mismatch response The 40-Hz Auditory Steady-State Response in and connectivity patterns in adolescents Patients With Schizophrenia: A Meta-analysis with schizophrenia and adolescents with bipolar disorder with psychosis: A Thuné, H; Recasens, M; Uhlhaas, PJ magnetoencephalography study Institute of Neuroscience and Psychology, University of Braeutigam, S; Dima, D; Frangou, S; James, A Glasgow, Glasgow, Scotland.

Oxford Human Brain Activity Center, Department of Psychia- Importance: The neurobiological mechanisms un- try, University of Oxford, OX3 7JX, UK. Electronic address: sven. derlying circuit dysfunctions in schizophrenia remain [email protected]. poorly understood. The 40-Hz auditory steady-state response (ASSR) has been suggested as a potential BACKGROUND: There is overlap between schizophre- biomarker for schizophrenia. Objectives: To provide a nia and bipolar disorder regarding genetic risk as well meta-analytical insight into the presence of 40-Hz ASSR as neuropsychological and structural brain deficits. impairments in patients with schizophrenia and to Finding common and distinct event-response potential examine the effects of the participant group, stimulus (ERP) responses and connectivity patterns may offer parameters, and analysis and recording techniques. potential biomarkers to distinguish the disorders. OB- Data Sources: Searches were conducted in PubMed JECTIVE: To examine the neuronal auditory response and reference lists of appropriate publications to iden- elicited by a roving mismatch negativity (MMN) para- tify relevant studies published from November 1999 to digm using magnetoencephalography (MEG). PARTICI- March 2016. Initial literature searches were performed PANTS: 15 Adolescents with schizophrenia (ASZ), 16 with combinations of the following search terms: (1) adolescents with bipolar disorder with psychosis (ABP), auditory steady state response, (2) schizophrenia, (3) and 14 typically developing individuals (TD) METHODS: 40 Hz, (4) EEG, (5) MEG, and (6) steady state response. The data were analysed using time-series techniques Study Selection: Original articles reporting 40-Hz and dynamic causal modelling (DCM). OUTCOME MEA- ASSR data on patients with schizophrenia (chronic or SURES: MEG difference wave (deviant - standard) at first episode) compared with healthy controls using primary auditory (~90ms), MMN (~180ms) and long la- electroencephalographic (EEG) and magnetoencepha- tency (~300ms). RESULTS: The amplitude of difference lographic (MEG) recordings. Data Extraction and wave showed specific patterns at all latencies. Most Synthesis: Hedges g effect sizes were calculated using notably, it was significantly reduced ABP compared sample sizes, P values, and/or Cohen d effect sizes from to both controls and ASZ at early latencies. In con- 20 studies. Effect size data were pooled using random- trast, the amplitude was significantly reduced in ASZ effects models. Publication bias was corrected for using compared to both controls and ABP. The DCM analysis funnel plots, the Egger regression test, and a trim and showed differential connectivity patterns in all three fill test. The contributions of study design parameters groups. Most notably, inter-hemispheric connections and participant characteristics were assessed using a were strongly dominated by the right side in ASZ only. mixed linear model approach and subsequent post hoc CONCLUSIONS: Dissociable patterns of the primary t tests. The present analysis was performed during the auditory response and MMN response indicate possible period from November 2015 to March 2016. Main Out- developmentally sensitive, but separate biomarkers for comes and Measures: Random model Hedges g effect schizophrenia and bipolar disorder. (28760539) sizes for auditory steady-state amplitude and phase- locking measures from sensor/electrode and sources-

170 space responses in EEG and MEG studies. Results: Of tions between independent component timecourses, the 20 studies analyzed (representing a total of 590 to estimate intra- and intern-network connectivity. healthy controls and 606 patients with schizophrenia), This analysis enables group-level inference and testing 17 reported significant reductions in 40-Hz ASSR spec- of between-group differences. Resting state MEG and tral power and/or phase locking in patients with schizo- fMRI data were acquired from a large sample of healthy phrenia compared with healthy controls (Hedges g controls (n=45) and schizophrenia patients (n=46). effect: -0.58 [power] and -0.46 [phase]). Effect sizes from Group spatial ICA was performed on fMRI and MEG spectral power and phase-locking measures did not dif- data to extract intrinsic fMRI and MEG networks and to fer significantly (95% CI, -0.49 to 0.22; t = -0.80; P = .43). compensate for signal leakage in MEG. Similar, but not Stimulus characteristics and analysis methods were not identical spatial independent components were de- associated with the findings of 40-Hz ASSR impairment tected for MEG and fMRI. Analysis of functional network in schizophrenia. Conclusions and Relevance: The connectivity (FNC; i.e., pairwise correlations in network 40-Hz ASSR spectral power and phase-locking deficits (ICA component) timecourses) revealed a differential are robust in schizophrenia, which suggests that these between-modalities pattern, with greater connectivity measures could be useful probes for assessing circuit among occipital networks in fMRI and among frontal dysfunctions in the disorder. Moreover, these findings networks in MEG. Most importantly, significant differ- should motivate large-scale studies of the longitudinal ences between controls and patients were observed in expression in patients with schizophrenia and at-risk both modalities. MEG FNC results in particular indicat- populations, to further validate the 40-Hz ASSR as a ed dysfunctional hyperconnectivity within frontal and potential biomarker. (27732692) temporal networks in patients, while in fMRI FNC was always greater for controls than for patients. This is the JAMA Psychiatry (2017), Vol. 73, No. 11, pp. 1145-1153 first study to apply group spatial ICA as an approach to leakage correction, and as such our results may be biased by spatial leakage effects. Results suggest that Magnetoencephalographic and functional MRI combining these two neuroimaging modalities reveals connectomics in schizophrenia via intra- and inter- additional disease-relevant patterns of connectiv- network connectivity ity that were not detectable with fMRI or MEG alone. (27725313) Houck, JM; Çetin, MS; Mayer, AR; Bustillo, JR; Ste- phen, J; Aine, C; Cañive, J; Perrone-Bizzozero, Keywords: Functional connectivity; Imaging; MEG; Resting N; Thoma, RJ; Brookes, MJ; Calhoun, VD state connectivity; Schizophrenia

Center on Alcoholism, Substance Abuse, and Addictions, Neuroimage (2018), Vol. 145, No. Pt A, pp. 96-106 University of New Mexico, Albuquerque, New Mexico, United States; Mind Research Network, Albuquerque, New Mexi- co, United States. Electronic address: [email protected]. Magnetoencephalographic recording of auditory mismatch negativity in response to duration and ABSTRACT: Examination of intrinsic functional connec- frequency deviants in a single session in patients tivity using functional MRI (fMRI) has provided impor- with schizophrenia tant findings regarding dysconnectivity in schizophrenia. Extending these results using a complementary Suga, M; Nishimura, Y; Kawakubo, Y; Yumoto, M; Kasai, K neuroimaging modality, magnetoencephalography (MEG), we present the first direct comparison of func- Department of Rehabilitation, The University of Tokyo, Tokyo, tional connectivity between schizophrenia patients Japan. and controls, using these two modalities combined. We developed a novel MEG approach for estimation of AIM: Auditory mismatch negativity (MMN) and its mag- networks using MEG that incorporates spatial indepen- netoencephalographic (MEG) counterpart (MMNm) dent component analysis (ICA) and pairwise correla- are an established biological index in schizophrenia

171 research. MMN in response to duration and frequency power ratio (BPR) and the window power ratio (WPR) deviants may have differential relevance to the patho- were extracted from MEG data in five frequency bands, physiology and clinical stages of schizophrenia. MEG four time windows of word processing, and at locations has advantage in that it almost purely detects MMNm covering whole head. Cluster-based nonparametric arising from the auditory cortex. However, few previ- permutation tests were employed to identify SPRs that ous MEG studies on schizophrenia have simultaneously show significant between-group difference. Machine assessed MMNm in response to duration and frequency learning based feature selection and classification tech- deviants or examined the effect of chronicity on the niques were then employed to select optimal combina- group difference. METHODS: Forty-two patients with tions of the significant SPR features, and distinguish chronic schizophrenia and 74 matched control subjects schizophrenia patients from healthy controls. We iden- participated in the study. Using a whole-head MEG, tified three BPR clusters and three WPR clusters that MMNm in response to duration and frequency deviants show significant oscillation power difference between of tones was recorded while participants passively lis- groups. These include the theta/delta, alpha/delta and tened to an auditory sequence. RESULTS: Compared to beta/delta BPRs during base-to-encode and encode healthy subjects, patients with schizophrenia exhibited time windows, and the beta band WPR from base to en- significantly reduced powers of MMNm in response to code and from encode to post-encode windows. Based duration deviant in both hemispheres, whereas MMNm on two WPR and one BPR features combined, over 95% in response to frequency deviant did not differ be- cross-validation classification accuracy was achieved tween the two groups. These results did not change ac- using three different linear classifiers separately. These cording to the chronicity of the illness. CONCLUSION: features may have potential as quantitative markers These results, obtained by using a sequence-enabling that discriminate schizophrenia patients and healthy simultaneous assessment of both types of MMNm, sug- controls; however, this needs further validation on gest that MEG recording of MMN in response to dura- larger samples. (27071182) tion deviant may be a more sensitive biological marker of schizophrenia than MMN in response to frequency IEEE Trans Neural Syst Rehabil Eng (2017), Vol. 24, No. 11, deviant. Our findings represent an important first step pp. 1148-1158 towards establishment of MMN as a biomarker for schizophrenia in real-world clinical psychiatry settings. (27162140) Frequency-specific disruptions of neuronal oscillations reveal aberrant auditory processing in Keywords: duration; frequency; magnetoencephalogra- schizophrenia phy; mismatch negativity; schizophrenia Hayrynen, LK; Hamm, JP; Sponheim, SR; Clementz, BA Psychiatry Clin Neurosci (2017), Vol. 70, No. 7, pp. 295-302 Departments of Psychology and Neuroscience, University of Georgia, Athens, Georgia, USA. Abnormal Neural Oscillations in Schizophrenia Assessed by Spectral Power Ratio of MEG During ABSTRACT: Individuals with schizophrenia exhibit Word Processing abnormalities in evoked brain responses in oddball paradigms. These could result from (a) insufficient Xu, T; Stephane, M; Parhi, KK salience-related cortical signaling (P300), (b) insufficient suppression of irrelevant aspects of the auditory ABSTRACT: This study investigated spectral power of environment, or (c) excessive neural noise. We tested neural oscillations associated with word processing in whether disruption of ongoing auditory steady-state schizophrenia. Magnetoencephalography (MEG) data responses at predetermined frequencies informed were acquired from 12 schizophrenia patients and 10 which of these issues contribute to auditory stimulus healthy controls during a visual word processing task. relevance processing abnormalities in schizophrenia. Two spectral power ratio (SPR) feature sets: the band Magnetoencephalography data were collected for

172 15 schizophrenia and 15 healthy subjects during an connectivity can be computed between frequency auditory oddball paradigm (25% targets; 1-s inter- bands. This pan-spectral network hierarchy likely stimulus interval). Auditory stimuli (pure tones: 1 kHz helps to mediate simultaneous formation of multiple standards, 2 kHz targets) were administered during brain networks, which support ongoing task demand. four continuous background (auditory steady-state) However, to date it has been largely overlooked, with stimulation conditions: (1) no stimulation, (2) 24 Hz, (3) many electrophysiological functional connectivity 40 Hz, and (4) 88 Hz. The modulation of the auditory studies treating individual frequency bands in isolation. steady-state response (aSSR) and the evoked responses Here, we combine oscillatory envelope based func- to the transient stimuli were quantified and compared tional connectivity metrics with a multi-layer network across groups. In comparison to healthy participants, framework in order to derive a more complete picture the schizophrenia group showed greater disruption of of connectivity within and between frequencies. We the ongoing aSSR by targets regardless of steady-state test this methodology using MEG data recorded dur- frequency, and reduced amplitude of both M100 and ing a visuomotor task, highlighting simultaneous and M300 event-related field components. During the no- transient formation of motor networks in the beta stimulation condition, schizophrenia patients showed band, visual networks in the gamma band and a beta to accentuation of left hemisphere 40 Hz response to gamma interaction. Having tested our method, we use both standard and target stimuli, indicating an effort it to demonstrate differences in occipital alpha band to enhance local stimulus processing. Together, these connectivity in patients with schizophrenia compared findings suggest abnormalities in auditory stimulus rel- to healthy controls. We further show that these con- evance processing in schizophrenia patients stem from nectivity differences are predictive of the severity of insufficient amplification of salient stimuli. (26933842) persistent symptoms of the disease, highlighting their clinical relevance. Our findings demonstrate the unique Keywords: Auditory; ERP; MEG; Oddball; Schizophrenia; potential of MEG to characterise neural network forma- Steady-state tion and dissolution. Further, we add weight to the argument that dysconnectivity is a core feature of the Psychophysiology (2017), Vol. 53, No. 6, pp. 786-95 neuropathology underlying schizophrenia. (26908313)

Keywords: Functional connectivity; MEG; Magnetoen- A multi-layer network approach to MEG cephalography; Motor cortex; Multi-layer networks; connectivity analysis Neural oscillations; Schizophrenia; Visual cortex

Brookes, MJ; Tewarie, PK; Hunt, BAE; Robson, SE; Neuroimage (2018), Vol. 132, pp. 425-438 Gascoyne, LE; Liddle, EB; Liddle, PF; Morris, PG

Sir Peter Mansfield Imaging Centre, School of Physics and Deficient attention modulation of lateralized alpha Astronomy, University of Nottingham, University Park, Not- power in schizophrenia tingham NG7 2RD, United Kingdom. Electronic address: [email protected]. Kustermann, T; Rockstroh, B; Kienle, J; Miller, GA; Popov, T

ABSTRACT: Recent years have shown the critical im- Department of Psychology, University of Konstanz, Konstanz, portance of inter-regional neural network connectivity Germany. in supporting healthy brain function. Such connectivity is measurable using neuroimaging techniques such as ABSTRACT: Modulation of 8-14 Hz (alpha) activity in MEG, however the richness of the electrophysiological posterior brain regions is associated with covert atten- signal makes gaining a complete picture challenging. tion deployment in visuospatial tasks. Alpha power Specifically, connectivity can be calculated as statistical decrease contralateral to to-be-attended stimuli is be- interdependencies between neural oscillations within lieved to foster subsequent processing, such as reten- a large range of different frequency bands. Further, tion of task-relevant input. Degradation of this alpha-

173 regulation mechanism may reflect an early stage of and healthy control subjects based on using both fMRI disturbed attention regulation contributing to impaired and band limited envelope correlation metrics in MEG attention and working memory commonly found in to interrogate functional network components in the schizophrenia. The present study tested this hypothesis resting state. Our results show that the combination of of early disturbed attention regulation by examining these two methods provide valuable information that alpha power modulation in a lateralized cued delayed captures fundamental characteristics of brain network response task in 14 schizophrenia patients (SZ) and 25 connectivity in schizophrenia. Such information is use- healthy controls (HC). Participants were instructed to ful for prediction of schizophrenia patients. Classifica- remember the location of a 100-ms saccade-target cue tion accuracy performance was improved significantly in the left or right visual hemifield in order to perform (up to ≈ 7%) relative to only the fMRI method and (up a delayed saccade to that location after a retention to ≈ 21%) relative to only the MEG method. (26736831) interval. As expected, alpha power decrease during the retention interval was larger in contralateral than Conf Proc IEEE Eng Med Biol Soc (2016), Vol. 2015, pp. ipsilateral posterior regions, and SZ showed less of this 2629-32 lateralization than did HC. In particular, SZ failed to show hemifield-specific alpha modulation in posterior right hemisphere. Results suggest less efficient modula- Abnormal visuomotor processing in schizophrenia tion of alpha oscillations that are considered critical for attention deployment and item encoding and, hence, Robson, SE; Brookes, MJ; Hall, EL; Palaniyappan, L; may affect subsequent spatial working memory perfor- Kumar, J; Skelton, M; Christodoulou, NG; Qureshi, A; mance. (26854181) Jan, F; Katshu, MZ; Liddle, EB; Liddle, PF; Morris, PG

Keywords: Alpha oscillations; Cued delayed response; Sir Peter Mansfield Imaging Centre, School of Physics and Magnetoencephalography; Schizophrenia Astronomy, University of Nottingham, University Park, Not- tingham NG7 2RD, UK. Psychophysiology (2017), Vol. 53, No. 6, pp. 776-85 ABSTRACT: Subtle disturbances of visual and motor function are known features of schizophrenia and can Multimodal based classification of schizophrenia greatly impact quality of life; however, few studies patients investigate these abnormalities using simple visuomotor stimuli. In healthy people, electrophysiological Cetin, MS; Houck, JM; Vergara, VM; Miller, RL; Calhoun, V data show that beta band oscillations in sensorimotor cortex decrease during movement execution (event- ABSTRACT: Schizophrenia is currently diagnosed by related beta desynchronisation (ERBD)), then increase physicians through clinical assessment and their evalu- above baseline for a short time after the movement ation of patient's self-reported experiences over the (post-movement beta rebound (PMBR)); whilst in visual longitudinal course of the illness. There is great interest cortex, gamma oscillations are increased throughout in identifying biologically based markers at the onset of stimulus presentation. In this study, we used a self- illness, rather than relying on the evolution of symp- paced visuomotor paradigm and magnetoencepha- toms across time. Functional network connectivity lography (MEG) to contrast these responses in patients shows promise in providing individual subject predic- with schizophrenia and control volunteers. We found tive power. The majority of previous studies considered significant reductions in the peak-to-peak change the analysis of functional connectivity during resting- in amplitude from ERBD to PMBR in schizophrenia state using only fMRI. However, exclusive reliance on compared with controls. This effect was strongest in pa- fMRI to generate such networks, may limit inference on tients who made fewer movements, whereas beta was dysfunctional connectivity, which is hypothesized to not modulated by movement in controls. There was no underlie patient symptoms. In this work, we propose a significant difference in the amplitude of visual gamma framework for classification of schizophrenia patients between patients and controls. These data demon-

174 strate that clear abnormalities in basic sensorimotor BACKGROUND: Increased temporal and frontal slow- processing in schizophrenia can be observed using a wave delta (1-4 Hz) and theta (4-7 Hz) activities are very simple MEG paradigm. (27872809) the most consistent resting-state neural abnormalities reported in schizophrenia. The frontal lobe is associated Keywords: Electrophysiological processes; Magnetoen- with negative symptoms and cognitive abilities such cephalography; Motor cortex; Schizophrenia; Visual cortex as attention, with negative symptoms and impaired attention associated with poor functional capacity. Neuroimage Clin (2018), Vol. 12, pp. 869-878 AIMS: To establish whether frontal dysfunction, as indexed by slowing, would be associated with functional impairments. METHOD: Eyes-closed magnetoencepha- Frontal slow-wave activity as a predictor of negative lography data were collected in 41 participants with symptoms, cognition and functional capacity in schizophrenia and 37 healthy controls, and frequency- schizophrenia domain source imaging localised delta and theta activity. RESULTS: Elevated delta and theta activity in Chen, YH; Stone-Howell, B; Edgar, JC; Huang, M; Wootton, right frontal and right temporoparietal regions was C; Hunter, MA; Lu, BY; Sadek, JR; Miller, GA; Cañive, JM observed in the schizophrenia v. CONTROL GROUP: In schizophrenia, right-frontal delta activity was uniquely Yu-Han Chen, PhD, The Children's Hospital of Philadelphia associated with negative but not positive symptoms. and University of Pennsylvania, Department of Radiology, In the full sample, increased right-frontal delta activ- Philadelphia; Breannan Stone-Howell, MS, New Mexico Ray- ity predicted poorer attention and functional capacity. mond G. Murphy VA Healthcare System, Psychiatry Research, CONCLUSIONS: Our findings suggest that treatment- Albuquerque, and The University of New Mexico School of associated decreases in slow-wave activity could be ac- Medicine, Department of Psychiatry, Albuquerque, New companied by improved functional outcome and thus Mexico; J. Christopher Edgar, PhD, The Children's Hospital of better prognosis. (26206861) Philadelphia and University of Pennsylvania, Department of Radiology, Philadelphia; Mingxiong Huang, PhD, University Br J Psychiatry (2016), Vol. 208, No. 2, pp. 160-7 of California, San Diego, Department of Radiology, and San Diego VA Healthcare System, Department of Radiology, San Diego, California; Cassandra Wootton, BS, New Mexico Ray- Auditory Cortical Plasticity Drives Training-Induced mond G. Murphy VA Healthcare System, Psychiatry Research, Cognitive Changes in Schizophrenia Albuquerque, and The University of New Mexico School of Medicine, Department of Psychiatry, Albuquerque, New Mex- Dale, CL; Brown, EG; Fisher, M; Herman, AB; Dowling, AF; ico; Michael A. Hunter, BS, New Mexico Raymond G. Murphy Hinkley, LB; Subramaniam, K; Nagarajan, SS; Vinogradov, S VA Healthcare System, Psychiatry Research, Albuquerque, The University of New Mexico School of Medicine, Department Department of Radiology and Biomedical Imaging, Univer- of Psychiatry and Department of Psychology, Albuquerque, sity of California, San Francisco, San Francisco, CA; Northern New Mexico; Brett Y. Lu, MD, PhD, The University of Hawaii at California Institute for Research and Education (NCIRE), San Manoa, Department of Psychiatry, Honolulu, Hawaii; Joseph Francisco Veterans' Affairs Medical Center, San Francisco, CA; R. Sadek, PhD, New Mexico Raymond G. Murphy VA Health- [email protected]. care System, Psychiatry Research, Albuquerque, New Mexico; Gregory A. Miller, PhD, University of California, Los Angeles, ABSTRACT: Schizophrenia is characterized by dysfunc- Department of Psychology, Los Angeles, California; José M. tion in basic auditory processing, as well as higher- Canĩve, MD, New Mexico Raymond G. Murphy VA Healthcare order operations of verbal learning and executive System, Psychiatry Research, Albuquerque, and The University functions. We investigated whether targeted cogni- of New Mexico School of Medicine, Department of Psychiatry, tive training of auditory processing improves neural Albuquerque, New Mexico, USA [email protected]. responses to speech stimuli, and how these changes relate to higher-order cognitive functions. Patients with schizophrenia performed an auditory syllable identi-

175 fication task during magnetoencephalography before and how a dysregulated clocking mechanism accounts and after 50 hours of either targeted cognitive train- for diminished cognitive performance. Neuromagnetic ing or a computer games control. Healthy comparison oscillatory activity was related to cognitive perfor- subjects were assessed at baseline and after a 10 week mance assessed by the MATRICS Consensus Cognitive no-contact interval. Prior to training, patients (N = 34) Battery in 58 healthy individuals (HC) and 46 schizo- showed reduced M100 response in primary auditory phrenia patients (SZ). HC showed a correlation be- cortex relative to healthy participants (N = 13). At reas- tween gamma-band oscillations (>40 Hz) and working sessment, only the targeted cognitive training patient memory performance. This relationship was disrupted group (N = 18) exhibited increased M100 responses. in several ways in SZ. First, patients evidenced lower Additionally, this group showed increased induced gamma power, poorer working memory performance, high gamma band activity within left dorsolateral pre- and no relationship between these measures. Second, frontal cortex immediately after stimulus presentation, the power spectra were dominated by ~10 Hz alpha and later in bilateral temporal cortices. Training-related oscillations with no group differences in amplitude. changes in neural activity correlated with changes However, analysis of phase-to-amplitude coupling in executive function scores but not verbal learning (PAC) revealed exaggerated clocking of gamma activity and memory. These data suggest that computerized by alpha phase in SZ, associated with poor working cognitive training that targets auditory and verbal memory performance. Third, despite entrainment by learning operations enhances both sensory responses the same 10 Hz clock, gamma amplitude was abnor- in auditory cortex as well as engagement of prefrontal mally distributed across the duty cycle in SZ, a potential regions, as indexed during an auditory processing task consequence of compromised interneuron inhibition. with low demands on working memory. This neural Fourth, SZ showed over-engagement of a fronto-pari- circuit enhancement is in turn associated with better etal network measured by gamma phase coherence, executive function but not verbal memory. (26152668) suggesting a brain state hindering cognitive output. Such an endogenous temporal organization may be a Schizophr Bull (2016), Vol. 42, No. 1, pp. 220-8 core dysfunction in SZ: a segregation/integration input imbalance fostering reduced cognitive performance and compromised behavioral output. (26143206) Same clock, different time read-out: Spontaneous brain oscillations and their relationship to deficient Neuroimage (2016), Vol. 119, pp. 316-24 coding of cognitive content

Popov, T; Popova, P Targeted training modifies oscillatory brain activity in schizophrenia patients Radboud University, Donders Institute for Brain, Cogni- tion and Behaviour, 6500 HE, Nijmegen, The Netherlands; Popov, TG; Carolus, A; Schubring, D; Pop- Department of Psychology, PO Box 904, University Konstanz, ova, P; Miller, GA; Rockstroh, BS D-78457 Konstanz, Germany. Electronic address: t.popov@ donders.ru.nl. Department of Psychology, University Konstanz, PO Box 905, Konstanz D-78457, Germany. ABSTRACT: Neuronal oscillations provide an efficient means of communication, fostering functional neural ABSTRACT: Effects of both domain-specific and states supporting action and reaction. High in the ac- broader cognitive remediation protocols have been tion hierarchy, cognitive abilities are severely compro- reported for neural activity and overt performance in mised in neuropsychiatric disease such as schizophre- schizophrenia (SZ). Progress is limited by insufficient nia. Current thinking highlights a clocking mechanism knowledge of relevant neural mechanisms. Addressing provided by the phase of an ongoing slow oscillation neuronal signal resolution in the auditory system as a that offers a temporal frame for coding of perceptual mechanism contributing to cognitive function and dys- and computational elements. Yet unclear is whether function in schizophrenia, the present study compared

176 effects of two neuroplasticity-based training protocols ABSTRACT: Hypofunctioning of the N-methyl-D- targeting auditory-verbal or facial affect discrimina- aspartate receptor (NMDA-R) has been prominently tion accuracy and a standard rehabilitation protocol on implicated in the pathophysiology of schizophrenia magnetoencephalographic (MEG) oscillatory brain ac- (ScZ). The current study tested the effects of ketamine, tivity in an auditory paired-click task. SZ were randomly a dissociative anesthetic and NMDA-R antagonist, on assigned to either 20 daily 1-hour sessions over 4 weeks resting-state activity recorded with magnetoencepha- of auditory-verbal training (N = 19), similarly intense lography (MEG) in healthy volunteers. In a single-blind facial affect discrimination training (N = 19), or 4 weeks cross-over design, each participant (n = 12) received, of treatment as usual (TAU, N = 19). Pre-training, the on 2 different sessions, a subanesthetic dose of S- 57 SZ showed smaller click-induced posterior alpha ketamine (0.006 mg/Kg) and saline injection. MEG-data power modulation than did 28 healthy comparison par- were analyzed at sensor- and source-level in the beta ticipants, replicating Popov et al. (2011b). Abnormally (13-30 Hz) and gamma (30-90 Hz) frequency ranges. In small alpha decrease 300-800 ms around S2 improved addition, connectivity analysis at source-level was per- more after targeted auditory-verbal training than after formed using transfer entropy (TE). Ketamine increased facial affect training or TAU. The improvement in oscil- gamma-power while beta-band activity was decreased. latory brain dynamics with training correlated with Specifically, elevated 30-90 Hz activity was pronounced improvement on a measure of verbal learning. Results in subcortical (thalamus and hippocampus) and cortical replicate previously reported effects of neuroplasticity- (frontal and temporal cortex) regions, whilst reductions based psychological training on oscillatory correlates of in beta-band power were localized to the precuneus, auditory stimulus differentiation, encoding, and updat- cerebellum, anterior cingulate, temporal and visual ing and indicate specificity of cortical training effects. cortex. TE analysis demonstrated increased information (26082889) transfer in a thalamo-cortical network after ketamine administration. The findings are consistent with the Keywords: Alpha oscillations; BFP, Brain Fitness Program; pronounced dysregulation of high-frequency oscil- Brain dynamics; CRT, cognitive remediation treatment; lations following the inhibition of NMDA-R in animal Cognitive training; FAT, facial affect training; HC, healthy models of ScZ as well as with evidence from electro- comparison participants; MEG, magnetoencephalog- encephalogram-data in ScZ-patients and increased raphy; Neuroplasticity; Paired-click; SZ, schizophrenia functional connectivity during early illness stages. patients; Schizophrenia Moreover, our data highlight the potential contribution of thalamo-cortical connectivity patterns towards Neuroimage Clin (2016), Vol. 7, pp. 807-14 ketamine-induced neuronal dysregulation, which may be relevant for the understanding of ScZ as a disorder of disinhibition of neural circuits. (25987642) Ketamine Dysregulates the Amplitude and Connectivity of High-Frequency Oscillations in Keywords: GABA; MEG; NMDA-receptor; gamma-band Cortical-Subcortical Networks in Humans: Evidence oscillations; ketamine; schizophrenia From Resting-State Magnetoencephalography- Recordings Schizophr Bull (2016), Vol. 41, No. 5, pp. 1105-14

Rivolta, D; Heidegger, T; Scheller, B; Sauer, A; Schaum, M; Birkner, K; Singer, W; Wibral, M; Uhlhaas, PJ Complexity measures in magnetoencephalography: measuring "disorder" in schizophrenia Department of Neurophysiology, Max Planck Institute for Brain Research, Frankfurt am Main, Germany; Ernst Strüng- Brookes, MJ; Hall, EL; Robson, SE; Price, D; Palaniyap- mann Institute for Neuroscience (ESI) in cooperation with pan, L; Liddle, EB; Liddle, PF; Robinson, SE; Morris, PG Max Planck Society (ESI), Frankfurt am Main, Germany; School of Psychology, University of East London (UEL), Lon- don, UK;

177 Sir Peter Mansfield Magnetic Resonance Centre, School of ABSTRACT: Hippocampal theta-band oscillations are Physics and Astronomy, University of Nottingham, University thought to facilitate the co-ordination of brain activ- Park, Nottingham, United Kingdom. ity across distributed networks, including between the hippocampus and prefrontal cortex (PFC). Impair- ABSTRACT: This paper details a methodology which, ments in hippocampus-PFC functional connectivity are when applied to magnetoencephalography (MEG) data, implicated in schizophrenia and are associated with a is capable of measuring the spatio-temporal dynamics polymorphism within the ZNF804A gene that shows of 'disorder' in the human brain. Our method, which is a genome-wide significant association with schizo- based upon signal entropy, shows that spatially sepa- phrenia. However, the mechanisms by which ZNF804A rate brain regions (or networks) generate temporally affects hippocampus-PFC connectivity are unknown. independent entropy time-courses. These time-courses We used a multimodal imaging approach to investi- are modulated by cognitive tasks, with an increase in gate the impact of the ZNF804A polymorphism on local neural processing characterised by localised and hippocampal theta and hippocampal network coactiv- transient increases in entropy in the neural signal. We ity. Healthy volunteers homozygous for the ZNF804A explore the relationship between entropy and the more rs1344706 (A[risk]/C[nonrisk]) polymorphism were established time-frequency decomposition methods, imaged at rest using both magnetoencephalography which elucidate the temporal evolution of neural oscil- (MEG) and functional magnetic resonance imaging lations. We observe a direct but complex relationship (fMRI). A dual-regression approach was used to investi- between entropy and oscillatory amplitude, which gate coactivations between the hippocampal network suggests that these metrics are complementary. Finally, and other brain regions for both modalities, focus- we provide a demonstration of the clinical utility of our ing on the theta band in the case of MEG. We found a method, using it to shed light on aberrant neurophysi- significant decrease in intrahippocampal theta (using ological processing in schizophrenia. We demonstrate MEG) and greater coactivation of the superior frontal significantly increased task induced entropy change gyrus with the hippocampal network (using fMRI) in in patients (compared to controls) in multiple brain risk versus nonrisk homozygotes. Furthermore, these regions, including a cingulo-insula network, bilateral measures showed a significant negative correlation. insula cortices and a right fronto-parietal network. Our demonstration of an inverse relationship between These findings demonstrate potential clinical utility hippocampal theta and hippocampus-PFC coactivation for our method and support a recent hypothesis that supports a role for hippocampal theta in coordinating schizophrenia can be characterised by abnormalities in hippocampal-prefrontal activity. The ZNF804A-related the salience network (a well characterised distributed differences that we find in hippocampus-PFC coacti- network comprising bilateral insula and cingulate corti- vation are consistent with previously reported asso- ces). (25886553) ciations with functional connectivity and with these changes lying downstream of altered hippocampal PLoS One (2016), Vol. 10, No. 4, pp. e0120991 theta. Changes in hippocampal-PFC co-ordination, driven by differences in oscillatory activity, may be one mechanism by which ZNF804A impacts on brain func- Modulation of hippocampal theta and tion and risk for psychosis. (25757652) hippocampal-prefrontal cortex function by a schizophrenia risk gene

Cousijn, H; Tunbridge, EM; Rolinski, M; Wallis, G; Col- clough, GL; Woolrich, MW; Nobre, AC; Harrison, PJ

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford,, United Kingdom; Oxford Centre for Human Brain Activity, University of Oxford, Warneford Hospital, Oxford, United Kingdom.

178 Keywords: ZNF804A; functional magnetic resonance conclude that PLV analysis of the oscillatory patterns of imaging; hippocampus; magnetoencephalography; oscil- MEG recordings in the ultraslow frequency bands sug- lation; psychosis gest their functional significance in intra-regional signal coherence and provide a higher rate of classification of Hum Brain Mapp (2016), Vol. 36, No. 6, pp. 2387-95 patients and normal subjects than the other spectral domains examined. (25592429)

Ultra-slow frequency bands reflecting potential Keywords: MEG; PLV; SVM; Ultra Low Frequency; classifica- coherence between neocortical brain regions tion; schizophrenia

Zhang, X; Wang, YT; Wang, Y; Jung, TP; Neuroscience (2015), Vol. 289, pp. 71-84 Huang, M; Cheng, CK; Mandell, AJ

Institute of Electronic Science and Engineering, Nanjing Uni- Intraindividual neurophysiological variability in versity of Posts and Telecommunications, Nanjing, Jiangsu ultra-high-risk for psychosis and schizophrenia 210003, PR China; Department of Computer Science and patients: single-trial analysis Engineering, University of California at San Diego, La Jolla, CA 92093, USA. Shin, KS; Kim, JS; Kim, SN; Hong, KS; O'Donnell, BF; Chung, CK; Kwon, JS ABSTRACT: Recent studies of electromagnetic ultraslow waves (∼0.1Hz) have suggested that they play a Clinical Cognitive Neuroscience Center, Neuroscience Insti- role in the integration of otherwise disassociated brain tute, SNU-MRC , Seoul, Korea. regions supporting vital functions (Ackermann and Borbely, 1997; Picchioni et al., 2010; Knyazev, 2012; Le BACKGROUND: Intraindividual variability in neuro- Bon et al., 2012). We emphasize this spectral domain physiological responses is an important factor in the in probing sensor coherence issues raised by these study of schizophrenia. Interestingly, this variability studies using Hilbert phase coherences in the human strongly predicts individual differences in cognitive MEG. In addition, we ask: will temporal-spatial phase processing. Neurobiological abnormalities that pres- coherence in regional brain oscillations obtained from ent during the prodromal phase of schizophrenia are the ultraslow spectral bands of multi-channel magne- not well characterized. However, these symptoms may toencephalograms (MEG) differentiate resting, "task- provide insight into the key circuits involved in the free" MEG records of normal control and schizophrenic disorder. AIMS: To investigate the variability in mag- subjects? The goal of the study is a comparison of the netoencephalographic responses at ultrahigh risk and relative persistence of intra-regional phase locking schizophrenia patients. METHODS: Twenty-four ultra- values (PLVs), among 10, region-defined, sensors in high risk, 21 patients with schizophrenia and 28 healthy examined in the resting multichannel, MEG records as controls were evaluated. The intraindividual variability a function of spectral frequency bands and diagnostic was estimated by calculating the s.d. of the across-trial category. The following comparison of Hilbert-trans- amplitude in responses to deviant and standard stimuli. form-engendered relative phases of each designated The degree of phase locking across trials was calculated spectral band was made using their pair-wise PLVs. by intertrial coherence. RESULTS: Greater variability in This indicated the proportion of shared cycle time in the responses to deviant and standard tones was noted which the phase relations between the index location in the schizophrenia and ultrahigh risk groups com- and reference leads were maintained. Leave one out, pared with controls. Variability in response to standard bootstrapping of the PLVs via a support vector machine stimuli was positively correlated with the amplitude (SVM), classified clinical status with 97.3% accuracy. It for the standard stimuli in all of the groups. Moreover, was generally the case that spectral bands ∼1.0Hz gen- schizophrenia patients displayed lower alpha and theta erated the highest values of the PLVs and discriminated intertrial coherence compared with ultrahigh risk and best between control and patient populations. We controls. Mismatch negativity amplitude was corre-

179 lated with the alpha intertrial coherence in all groups. multisensory gamma-band power differently by group. Taken together, the augmented variability and reduced Furthermore, gamma-band power in these regions pre- inter-trial coherence provide empirical evidence for dicted performance in select measures of the Measure- increased amplitude and phase inconsistencies in ment and Treatment Research to Improve Cognition schizophrenia and ultrahigh risk. CONCLUSIONS: The in Schizophrenia (MATRICS) test battery differently by results implicate widespread dysfunction in amplitude group. These results reveal a unique pattern of task- modulation and phase concentration in schizophrenia related gamma-band power in schizophrenia patients and ultrahigh risk, as well as evidence for early am- relative to controls that may indicate reduced inhibition plitude and phase disruption. These finding suggest in combination with impaired oscillatory mechanisms intraindividual variability and intertrial coherence ap- in patients with schizophrenia. (25414652) pear to be important indicators of pathophysiological processing. (27336039) Keywords: MEG; audio-visual; event-related oscillations; gamma; magnetoencephalography; multisensory; schizo- NPJ Schizophr (2016), Vol. 1, pp. 15031 phrenia; time-frequency

Front Hum Neurosci (2014), Vol. 8, pp. 788 Multisensory stimuli elicit altered oscillatory brain responses at gamma frequencies in patients with schizophrenia Power spectral aspects of the default mode network in schizophrenia: an MEG study Stone, DB; Coffman, BA; Bustillo, JR; Aine, CJ; Stephen, JM Kim, JS; Shin, KS; Jung, WH; Kim, SN; Kwon, JS; Chung, CK The Mind Research Network and Lovelace Biomedical and Environmental Research Institute Albuquerque, NM, USA. MEG Center, Department of Neurosurgery, Seoul National University Hospital, Seoul, South Korea. [email protected]. ABSTRACT: Deficits in auditory and visual unisensory responses are well documented in patients with schizo- BACKGROUND: Symptoms of schizophrenia are related phrenia; however, potential abnormalities elicited from to deficits in self-monitoring function, which may be multisensory audio-visual stimuli are less understood. a consequence of irregularity in aspects of the default Further, schizophrenia patients have shown abnormal mode network (DMN). Schizophrenia can also be patterns in task-related and task-independent oscilla- characterized by a functional abnormality of the brain tory brain activity, particularly in the gamma frequency activity that is reflected in the resting state. Oscilla- band. We examined oscillatory responses to basic tory analysis provides an important understanding of unisensory and multisensory stimuli in schizophrenia resting brain activity. However, conventional methods patients (N = 46) and healthy controls (N = 57) using using electroencephalography are restricted because magnetoencephalography (MEG). Time-frequency of low spatial resolution, despite their excellent tempo- decomposition was performed to determine regions ral resolution.The aim of this study was to investigate of significant changes in gamma band power by group resting brain oscillation and the default mode network in response to unisensory and multisensory stimuli based on a source space in various frequency bands relative to baseline levels. Results showed significant such as theta, alpha, beta, and gamma using magneto- behavioral differences between groups in response encephalography. In addition, we investigated whether to unisensory and multisensory stimuli. In addition, these resting and DMN activities could distinguish time-frequency analysis revealed significant decreases schizophrenia patients from normal controls. To do this, and increases in gamma-band power in schizophrenia the power spectral density of each frequency band at patients relative to healthy controls, which emerged rest was imaged and compared on a spatially normal- both early and late over both sensory and frontal ized brain template in 20 patients and 20 controls. regions in response to unisensory and multisensory RESULTS: The spatial distribution of DMN activity in stimuli. Unisensory gamma-band power predicted the alpha band was similar to that found in previous

180 fMRI studies. The posterior cingulate cortex (PCC) and power in the gamma band (t 35 = -2.56, p = 0.015) com- lateral inferior parietal cortex were activated at rest, pared to controls. There were no group differences in while the medial prefrontal cortex (MPFC) was deacti- baseline gamma power, transient or sustained gamma vated at rest rather than during the task. Although the frequency, alpha band responses or pattern onset visu- MPFC and PCC regions exhibited contrasting activation al-evoked responses. CONCLUSIONS: Gamma power patterns, these two regions were significantly coherent is increased in remitted SABP, which reflects an ab- at rest. The DMN and resting activities of the PCC were normality in the cortical inhibitory-excitatory balance. increased in schizophrenia patients, predominantly in Although an interaction between gamma power and the theta and alpha bands. CONCLUSIONS: By using medication can not be ruled out, there were no group MEG to identify the DMN regions, predominantly in differences in evoked responses or baseline measures. the alpha band, we found that both resting and DMN Further work is needed in other clinical populations activities were augmented in the posterior cingulate and at-risk relatives. Pharmaco-magnetoencephalogra- in schizophrenia patients. Furthermore, schizophrenia phy studies will help to elucidate the specific GABA and patients exhibited decreased coherence between the glutamate pathways affected. (25115407) PCC and MPFC in the gamma band at rest. (25189680) Keyword: visual BMC Neurosci (2015), Vol. 15, pp. 104 Psychol Med (2015), Vol. 45, No. 4, pp. 783-94

Increased visual gamma power in schizoaffective bipolar disorder Functional cognitive and cortical abnormalities in chronic and first-admission schizophrenia Brealy, JA; Shaw, A; Richardson, H; Singh, KD; Muthukumaraswamy, SD; Keedwell, PA Carolus, AM; Schubring, D; Popov, TG; Pop- ova, P; Miller, GA; Rockstroh, BS Institute of Psychological Medicine and Clinical Neuro- sciences, MRC Centre for Neuropsychiatric Genetics and Department of Psychology, University of Konstanz, Germany. Genomics,Cardiff University School of Medicine,Hadyn Ellis Electronic address: [email protected]. Building, Cardiff,UK. ABSTRACT: Evoked and induced event-related neu- BACKGROUND: Electroencephalography and mag- ral oscillations have recently been proposed as a key netoencephalography (MEG) studies have identified mechanism supporting higher-order cognition. Cogni- alterations in gamma-band (30-80 Hz) cortical activity tive decay and abnormal electromagnetic sensory in schizophrenia and mood disorders, consistent with gating reliably distinguish schizophrenia (SZ) patients neural models of disturbed glutamate (and GABA) and healthy individuals, demonstrated in chronic (CHR) neuron influence over cortical pyramidal cells. Genetic and first-admission (FA) patients. Not yet determined evidence suggests specific deficits in GABA-A receptor is whether altered event-related modulation of oscil- function in schizoaffective bipolar disorder (SABP), a latory activity is manifested at early stages of SZ, thus clinical syndrome with features of both bipolar disorder reflects and perhaps embodies the development of and schizophrenia. This study investigated gamma os- psychopathology, and provides a mechanism for the cillations in this under-researched disorder. METHOD: gating deficit. The present study compared behavioral MEG was used to measure induced gamma and evoked and functional brain measures in CHR and FA samples. responses to a visual grating stimulus, known to be a Cognitive test performance (MATRICS Consortium potent inducer of primary visual gamma oscillations, Cognitive Battery, MCCB), neuromagnetic event-related in 15 individuals with remitted SABP, defined using fields (M50 gating ratio), and oscillatory dynamics Research Diagnostic Criteria, and 22 age- and sex- (evoked and induced modulation of 8-12Hz alpha) dur- matched healthy controls. RESULTS: Individuals with ing a paired-click task were assessed in 35 CHR and 31 SABP demonstrated increased sustained visual cortical FA patients meeting the criteria for ICD-10 diagnoses

181 of schizophrenia as well as 28 healthy comparison sub- Germany, and Institute of Neuroscience and Psychology, jects (HC). Both patient groups displayed poorer cogni- University of Glasgow, Glasgow G12 8QB, United Kingdom. tive performance, higher M50 ratio (poorer sensory gating), and less induced modulation of alpha activity ABSTRACT: Schizophrenia is characterized by dysfunc- than did HC. Induced alpha power decrease in bilateral tions in neural circuits that can be investigated with posterior regions varied with M50 ratio in HC but not electrophysiological methods, such as EEG and MEG. In SZ, whereas orbitofrontal alpha power decrease was the present human study, we examined event-related related to M50 ratio in SZ but not HC. Results suggest fields (ERFs), in a sample of medication-naive, first- disruption of oscillatory dynamics at early stages of episode schizophrenia (FE-ScZ) patients (n = 14) and illness, which may contribute to deficient information healthy control participants (n = 17) during perception sampling, memory updating, and higher cognitive of Mooney faces to investigate the integrity of neuro- functioning. (24933246) magnetic responses and their experience-dependent modification. ERF responses were analyzed for M100, Keywords: Alpha oscillations; Cognitive deficit; First admis- M170, and M250 components at the sensor and source sion; MEG; Schizophrenia; Sensory gating levels. In addition, we analyzed peak latency and adaptation effects due to stimulus repetition. FE-ScZ Schizophr Res (2015), Vol. 157, No. 1-3, pp. 40-7 patients were characterized by significantly impaired sensory processing, as indicated by a reduced discrimination index (A'). At the sensor level, M100 and M170 Source-reconstruction of event-related fields responses in FE-ScZ were within the normal range, reveals hyperfunction and hypofunction of cortical whereas the M250 response was impaired. However, circuits in antipsychotic-naive, first-episode source localization revealed widespread elevated schizophrenia patients during Mooney face activity for M100 and M170 in FE-ScZ and delayed peak processing latencies for the M100 and M250 responses. In addition, M170 source activity in FE-ScZ was not modulated Rivolta, D; Castellanos, NP; Stawowsky, C; Helbling, S; by stimulus repetitions. The present findings suggest Wibral, M; Grützner, C; Koethe, D; Birkner, K; Kranas- that neural circuits in FE-ScZ may be characterized by ter, L; Enning, F; Singer, W; Leweke, FM; Uhlhaas, PJ a disturbed balance between excitation and inhibition that could lead to a failure to gate information flow and Department of Neurophysiology, Max Planck Institute for abnormal spreading of activity, which is compatible Brain Research and Ernst Strüngmann Institute (ESI) for Neu- with dysfunctional glutamatergic neurotransmission. roscience in Cooperation with Max Planck Society, Frankfurt (24760850) am Main 60528, Germany, School of Psychology, University of East London, London E15 4LZ, United Kingdom, Laboratory Keywords: ERFs; M170; MEG; Mooney faces; face process- of Cognitive and Computational Neuroscience, Center for ing; first-episode psychosis Biomedical Technology, Universidad Politécnica de Madrid, Madrid 28223, Spain, MEG Unit, Brain Imaging Centre, Jo- J Neurosci (2014), Vol. 34, No. 17, pp. 5909-17 hann Wolfgang Goethe University, Frankfurt am Main 60529, Germany, Institute for Medical Psychology, Johann Wolfgang Goethe University, Frankfurt am Main 60054, Germany, Cortical thickness as a contributor to abnormal Department of Psychiatry and Psychotherapy, University of oscillations in schizophrenia? Cologne, Cologne 50924, Germany, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medi- Edgar, JC; Chen, YH; Lanza, M; Howell, B; cal Faculty Mannheim, Heidelberg University, Mannheim Chow, VY; Heiken, K; Liu, S; Wootton, C; Hunt- 68159, Germany, Department of General Psychiatry, Medical er, MA; Huang, M; Miller, GA; Cañive, JM Faculty Heidelberg, Heidelberg University, Heidelberg 69115, Germany, Frankfurt Institute for Advanced Studies, Johann The Children's Hospital of Philadelphia and University of Wolfgang Goethe University, Frankfurt am Main 60438, Pennsylvania, Philadelphia, PA, USA.

182 INTRODUCTION: Although brain rhythms depend Keywords: Alpha; Auditory; Gamma; Magnetoencepha- on brain structure (e.g., gray and white matter), to our lography; Schizophrenia; Superior temporal gyrus; Theta knowledge associations between brain oscillations and structure have not been investigated in healthy Neuroimage Clin (2015), Vol. 4, pp. 122-9 controls (HC) or in individuals with schizophrenia (SZ). Observing function-structure relationships, for example establishing an association between brain Evidence for dysregulated high-frequency oscillations (defined in terms of amplitude or phase) oscillations during sensory processing in and cortical gray matter, might inform models on the medication-naïve, first episode schizophrenia origins of psychosis. Given evidence of functional and structural abnormalities in primary/secondary audi- Sun, L; Castellanos, N; Grützner, C; Koethe, D; Rivolta, D; tory regions in SZ, the present study examined how Wibral, M; Kranaster, L; Singer, W; Leweke, MF; Uhlhaas, PJ superior temporal gyrus (STG) structure relates to auditory STG low-frequency and 40 Hz steady-state Department of Neurophysiology, Max-Planck Institute for activity. Given changes in brain activity as a function of Brain Research, Deutschordenstr, 46, Frankfurt am Main, age, age-related associations in STG oscillatory activity 60528, Germany; Department of Radiology, Massachusetts were also examined. METHODS: Thirty-nine individuals General Hospital, Harvard University, Cambridge, MA 02129, with SZ and 29 HC were recruited. 40 Hz amplitude- USA. modulated tones of 1 s duration were presented. MEG and T1-weighted sMRI data were obtained. Using the INTRODUCTION: High-frequency oscillations are sources localizing 40 Hz evoked steady-state activity important for sensory processing and dysfunc- (300 to 950 ms), left and right STG total power and tions in the amplitude and synchrony of beta- and inter-trial coherence were computed. Time-frequency gamma-band oscillations have been demonstrated in group differences and associations with STG structure schizophrenia (ScZ). However, the presence of aber- and age were also examined. RESULTS: Decreased total rant high-frequency oscillations in first-episode (FE), power and inter-trial coherence in SZ were observed medication-naive patients during sensory processing is in the left STG for initial post-stimulus low-frequency unclear. METHODS: Magnetoencephalographic (MEG) activity (~ 50 to 200 ms, ~ 4 to 16 Hz) as well as 40 Hz data were recorded from 15 never-medicated, FE-ScZ steady-state activity (~ 400 to 1000 ms). Left STG 40 Hz patients and 20 matched healthy controls during the total power and inter-trial coherence were positively perception of Mooney faces. MEG data were analysed associated with left STG cortical thickness in HC, not for spectral power and single-sensor phase-locking in in SZ. Left STG post-stimulus low-frequency and 40 Hz the beta (13-25Hz) and gamma- (25-140Hz) frequency total power were positively associated with age, again range. RESULTS: FE-ScZ patients were characterized only in controls. DISCUSSION: Left STG low-frequency by significantly impaired sensory processing as indi- and steady-state gamma abnormalities distinguish SZ cated by a reduced discrimination index (A'). Impaired and HC. Disease-associated damage to STG gray matter behavioural performance in ScZ-patients was accom- in schizophrenia may disrupt the age-related left STG panied by decreased spectral power in the high- (60- gamma-band function-structure relationships ob- 120Hz) gamma-band range. In contrast, oscillations in served in controls. (24371794) the lower (25-60Hz) gamma-band were largely intact and beta-band oscillations were increased. Analysis of cross-frequency coupling showed a reduced correlation between 60 and 120Hz amplitude values and beta-band power in FE-ScZ-patients relative to controls. DISCUSSION: Our findings show that impaired sensory processing in medication-naive, FE-schizophrenia is related to a dysregulation of neural oscillations which involves both an impairment in the generation of high gamma-band activity as well as a failure to downregu-

183 late task-irrelevant beta-band activity. Because of the tionship between these measures across both subjects interrelationship of these dysfunctions and the role of and sensors that varied over frequency bands and was inhibitory networks in the shaping of high-frequency more pronounced in controls than in patients. The activity, aberrant neural oscillations in FE-schizophrenia topological organization of connectivity was altered in may be linked to dysfunctions in the excitation-inhibi- schizophrenia specifically in high frequency [Formula: tion (E/I)-balance. (24016727) see text] and [Formula: see text] band networks as well as in the [Formula: see text]-[Formula: see text] cross- Keywords: First-episode; High-frequency oscillations; MEG; frequency networks. Network topology varied over Neural synchrony; Perceptual organization; Schizophrenia trials to a greater extent in patients than in controls, suggesting disease-associated alterations in dynamic Schizophr Res (2014), Vol. 150, No. 2-3, pp. 519-25 network properties of brain function. Our results identify signatures of aberrant neurophysiological behavior in schizophrenia across uni-, bi- and multivariate scales Intra- and inter-frequency brain network structure and lay the groundwork for further clinical studies that in health and schizophrenia might lead to the discovery of new intermediate phenotypes. (23991097) Siebenhühner, F; Weiss, SA; Coppo- la, R; Weinberger, DR; Bassett, DS PLoS One (2014), Vol. 8, No. 8, pp. e72351

Department of Physics, University of California Santa Bar- bara, Santa Barbara, California, USA. Dynamics of alpha oscillations elucidate facial affect recognition in schizophrenia ABSTRACT: Empirical studies over the past two decades have provided support for the hypothesis that Popov, TG; Rockstroh, BS; Popova, P; Carolus, AM; Miller, GA schizophrenia is characterized by altered connectivity patterns in functional brain networks. These alterations Department of Psychology, University of Konstanz, Konstanz, have been proposed as genetically mediated diag- Germany. nostic biomarkers and are thought to underlie altered cognitive functions such as working memory. However, ABSTRACT: Impaired facial affect recognition is the nature of this dysconnectivity remains far from characteristic of schizophrenia and has been related understood. In this study, we perform an extensive to impaired social function, but the relevant neural analysis of functional connectivity patterns extracted mechanisms have not been fully identified. The present from MEG data in 14 subjects with schizophrenia and study sought to identify the role of oscillatory alpha ac- 14 healthy controls during a 2-back working memory tivity in that deficit during the process of facial emotion task. We investigate uni-, bi- and multivariate properties recognition. Neuromagnetic brain activity was moni- of sensor time series by computing wavelet entropy of tored while 44 schizophrenia patients and 44 healthy and correlation between time series, and by construct- controls viewed 5-s videos showing human faces ing binary networks of functional connectivity both gradually changing from neutral to fearful or happy within and between classical frequency bands ([For- expressions or from the neutral face of one poser to mula: see text], [Formula: see text], [Formula: see text], the neutral face of another. Recognition performance and [Formula: see text]). Networks are based on the was determined separately by self-report. Relative to mutual information between wavelet time series, and prestimulus baseline, controls exhibited a 10- to 15-Hz estimated for each trial window separately, enabling power increase prior to full recognition and a 10- to 15- us to consider both network topology and network Hz power decrease during the postrecognition phase. dynamics. We observed significant decreases in time These results support recent proposals about the series entropy and significant increases in functional function of alpha-band oscillations in normal stimulus connectivity in the schizophrenia group in comparison evaluation. The patients failed to show this sequence to the healthy controls and identified an inverse rela- of alpha power increase and decrease and also showed

184 low 10- to 15-Hz power and high 10- to 15-Hz connec- (SP vs. HC) and three components that captured the tivity during the prestimulus baseline. In light of the predominant sensory responses in the MEG data. Lower proposal that a combination of alpha power increase FA values in bilateral posterior parietal regions, which and functional disconnection facilitates information include anterior/posterior association tracts, were as- intake and processing, the finding of an abnormal sociated with reduced MEG amplitude (120-170 ms) of association of low baseline alpha power and high con- the visual response in occipital sensors in SP relative to nectivity in schizophrenia suggests a state of impaired HC. Additionally, increased FA in a right medial fron- readiness that fosters abnormal dynamics during facial tal region was linked with larger amplitude late MEG affect recognition. (23943514) activity (300-400 ms) in bilateral central channels for SP relative to HC. Step-wise linear regression provided Cogn Affect Behav Neurosci (2014), Vol. 14, No. 1, pp. evidence that right temporal, occipital and late central 364-77 components were significant predictors of reaction time and cognitive performance based on the Measure- ment and Treatment Research to Improve Cognition in Using joint ICA to link function and structure using Schizophrenia (MATRICS) cognitive assessment battery. MEG and DTI in schizophrenia These results point to dysfunction in a posterior visual processing network in schizophrenia, with reduced Stephen, JM; Coffman, BA; Jung, RE; MEG amplitude, reduced FA and poorer overall perfor- Bustillo, JR; Aine, CJ; Calhoun, VD mance on the MATRICS. Interestingly, the spatial location of the MEG activity and the associated FA regions The Mind Research Network and Lovelace Biomedical and are spatially consistent with white matter regions that Environmental Research Institute, 1101 Yale Blvd NE, Albu- subserve these brain areas. This novel approach pro- querque, NM 87106, USA. Electronic address: jstephen@mrn. vides evidence for significant pairing between function org. (neurophysiology) and structure (white matter integrity) and demonstrates that this multivariate, multimodal ABSTRACT: In this study we employed joint indepen- integration technique is sensitive to group differences dent component analysis (jICA) to perform a novel in function and structure. (23777757) multivariate integration of magnetoencephalography (MEG) and diffusion tensor imaging (DTI) data to in- Keywords: A; AV; DTI; Diffusion tensor imaging (DTI); ECG; vestigate the link between function and structure. This EEG; EOG; FA; HC; HPI; IC; ISI; Joint independent compo- model-free approach allows one to identify covariation nent analysis (jICA); L; LFP; MEG; Magnetoencephalogra- across modalities with different temporal and spatial phy (MEG); Multimodal integration; Multisensory integra- scales [temporal variation in MEG and spatial variation tion; R; RT; SP; Schizophrenia; V; auditory; auditory/visual; in fractional anisotropy (FA) maps]. Healthy controls diffusion tensor imaging; electrocardiogram; electroen- (HC) and patients with schizophrenia (SP) participated cephalography; electrooculogram; fractional anisotropy; in an auditory/visual multisensory integration para- head position indicator; healthy control; independent digm to probe cortical connectivity in schizophrenia. component; interstimulus interval; jICA; joint indepen- To allow direct comparisons across participants and dent component analysis; left; local field power; magne- groups, the MEG data were registered to an average head position and regional waveforms were obtained by calculating the local field power of the planar gradiometers. Diffusion tensor images obtained in the same individuals were preprocessed to provide FA maps for each participant. The MEG/FA data were then integrated using the jICA software (http://mialab.mrn. org/software/fit). We identified MEG/FA components that demonstrated significantly different (p<0.05) covariation in MEG/FA data between diagnostic groups

185 toencephalography; reaction time; right; schizophrenia Keywords: MEG; gamma; perceptual organization; schizo- patient; visual phrenia; synchrony

Neuroimage (2014), Vol. 83, pp. 418-30 Front Hum Neurosci (2013), Vol. 7, pp. 88

Deficits in high- (>60 Hz) gamma-band oscillations Multidimensional analysis of the abnormal neural during visual processing in schizophrenia oscillations associated with lexical processing in schizophrenia Grützner, C; Wibral, M; Sun, L; Rivolta, D; Singer, W; Maurer, K; Uhlhaas, PJ Xu, T; Stephane, M; Parhi, KK

Department of Neurophysiology, Max-Planck Institute for Department of Electrical & Computer Engineering, University Brain Research Frankfurt am Main, Germany. of Minnesota, Minneapolis, MN, USA.

ABSTRACT: Current theories of the pathophysiology ABSTRACT: The neural mechanisms of language of schizophrenia have focused on abnormal tempo- abnormalities, the core symptoms in schizophrenia, ral coordination of neural activity. Oscillations in the remain unclear. In this study, a new experimental gamma-band range (>25 Hz) are of particular interest paradigm, combining magnetoencephalography (MEG) as they establish synchronization with great precision techniques and machine intelligence methodologies, in local cortical networks. However, the contribution of was designed to gain knowledge about the frequency, high gamma (>60 Hz) oscillations toward the patho- brain location, and time of occurrence of the neural os- physiology is less established. To address this issue, we cillations that are associated with lexical processing in recorded magnetoencephalographic (MEG) data from schizophrenia. The 248-channel MEG recordings were 16 medicated patients with chronic schizophrenia and obtained from 12 patients with schizophrenia and 10 16 controls during the perception of Mooney faces. healthy controls, during a lexical processing task, where MEG data were analysed in the 25-150 Hz frequency the patients discriminated correct from incorrect lexi- range. Patients showed elevated reaction times and re- cal stimuli that were visually presented. Event-related duced detection rates during the perception of upright desynchronization/synchronization (ERD/ERS) was Mooney faces while responses to inverted stimuli were computed along the frequency, time, and space dimen- intact. Impaired processing of Mooney faces in schizo- sions combined, that resulted in a large spectral-spa- phrenia patients was accompanied by a pronounced tial-temporal ERD/ERS feature set. Machine intelligence reduction in spectral power between 60-120 Hz (effect techniques were then applied to select a small subset size: d = 1.26) which was correlated with disorganized of oscillation patterns that are abnormal in patients symptoms (r = -0.72). Our findings demonstrate that with schizophrenia, according to their discriminating deficits in high gamma-band oscillations as measured power in patient and control classification. Patients by MEG are a sensitive marker for aberrant cortical with schizophrenia showed abnormal ERD/ERS pat- functioning in schizophrenia, suggesting an impor- terns during both lexical encoding and post-encoding tant aspect of the pathophysiology of the disorder. periods. The top-ranked features were located at the (23532620) occipital and left frontal-temporal areas, and covered a wide frequency range, including δ (1-4 Hz), α (8-12 Hz), β (12-32 Hz), and γ (32-48 Hz) bands. These top features could discriminate the patient group from the control group with 90.91% high accuracy, which demonstrates significant brain oscillation abnormalities in patients with schizophrenia at the specific frequency, time, and brain location indicated by these top features. As neural oscillation abnormality may be due to the mechanisms

186 of the disease, the spectral, spatial, and temporal tory-verbal discrimination and memory additionally content of the discriminating features can offer useful normalized alpha desynchronization, associated with information for helping understand the physiological improved elaborative processing. The latter presumably basis of the language disorder in schizophrenia, as well contributes to improved auditory gating and cognitive as the pathology of the disease itself. (23513013) function. CONCLUSIONS/SIGNIFICANCE: Results suggest that dysfunctional interplay of ocillatory activity Keywords: lexical processing; machine intelligence; mag- that may contribute to auditory processing disruption netoencephalograhy; neural oscillation; schizophrenia in schizophrenia can be modified by targeted training. (22815697) Clin EEG Neurosci (2013), Vol. 44, No. 2, pp. 135-43 PLoS One (2013), Vol. 7, No. 7, pp. e39051

Adjusting brain dynamics in schizophrenia by means of perceptual and cognitive training Temporal and frontal cortical thickness associations with M100 auditory activity and attention in Popov, T; Rockstroh, B; Weisz, N; Elbert, T; Miller, GA healthy controls and individuals with schizophrenia

Department of Psychology, University of Konstanz, Konstanz, Edgar, JC; Hunter, MA; Huang, M; Smith, AK; Chen, Germany. [email protected] Y; Sadek, J; Lu, BY; Miller, GA; Cañive, JM

BACKGROUND: In a previous report we showed that Department of Neuroradiology, The Children's Hospital of cognitive training fostering auditory-verbal discrimina- Philadelphia, Philadelphia, PA 19104, USA. edgarj@email. tion and working memory normalized magnetoen- chop.edu cephalographic (MEG) M50 gating ratio in schizophrenia patients. The present analysis addressed whether BACKGROUND: Although gray matter (GM) abnormali- training effects on M50 ratio and task performance are ties are frequently observed in individuals with schizo- mediated by changes in brain oscillatory activity. Such phrenia (SCZ), the functional consequences of these evidence should improve understanding of the role of structural abnormalities are not yet understood. The oscillatory activity in phenomena such as M50 ratio, the present study sought to better understand GM abnor- role of dysfunctional oscillatory activity in processing malities in SCZ by examining associations between abnormalities in schizophrenia, and mechanisms of ac- GM and two putative functional SCZ biomarkers: weak tion of cognitive training. METHODOLOGY/PRINCIPAL 100 ms (M100) auditory responses and impairment FINDINGS: Time-locked and non-time-locked oscilla- on tests of attention. METHODS: Data were available tory activity was measured together with M50 ratio in from 103 subjects (healthy controls=52, SCZ=51). GM a paired-click design before and after a 4-week training cortical thickness measures were obtained for supe- of 36 patients randomly assigned to specific cogni- rior temporal gyrus (STG) and prefrontal cortex (PFC). tive exercises (CE) or standard (comparison) cognitive Magnetoencephalography (MEG) provided measures of training (CP). Patient data were compared to those left and right STG M100 source strength. Subjects were of 15 healthy controls who participated in two MEG administered the Trail Making Test A and the Connors' measurements 4 weeks apart without training. Training Continuous Performance Test to assess attention. RE- led to more time-locked gamma-band response and SULTS: A strong trend indicated less GM cortical thick- more non-time-locked alpha-band desynchronization, ness in SCZ than controls in both regions and in both moreso after CE than after CP. Only after CE, increased hemispheres (p=0.06). Individuals with SCZ had weaker alpha desynchronization was associated with normal- M100 responses than controls bilaterally, and individu- ized M50 ratio and with improved verbal memory als with SCZ performed more poorly than controls performance. Thus, both types of cognitive training on tests of attention. Across groups, left STG GM was normalized gamma activity, associated with improved positively associated with left M00 source strength. In stimulus encoding. More targeted training of audi- SCZ only, less left and right STG and PFC GM predicted

187 poorer performance on tests of attention. After remov- manifests as a reduced M100 dipole moment. The ing variance in attention associated with age, associa- relationship between abnormal M100, thinning of tions between GM and attention remained significant cortical generators and their symptomatology were only in left and right STG. CONCLUSIONS: Reduced GM shown to exist prior to the onset of overt psychosis and cortical thickness may serve as a common substrate for progressively worsen over time. Therefore, they may be multiple functional abnormalities in SCZ, with struc- a potential indicator of the development of schizophre- tural-functional abnormalities in STG GM especially nia. (22759440) prominent. As suggested by others, functional abnormalities in SCZ may be a consequence of elimination of Schizophr Res (2013), Vol. 140, No. 1-3, pp. 93-8 the neuropil (dendritic arbors and associated synaptic infrastructure) between neuron bodies. (22766129) Magnetoencephalography study of right parietal Schizophr Res (2013), Vol. 140, No. 1-3, pp. 250-7 lobe dysfunction of the evoked mirror neuron system in antipsychotic-free schizophrenia

Neuromagnetic auditory response and its relation Kato, Y; Muramatsu, T; Kato, M; Shibu- to cortical thickness in ultra-high-risk for psychosis kawa, Y; Shintani, M; Mimura, M

Shin, KS; Jung, WH; Kim, JS; Jang, JH; Department of Neuropsychiatry, Keio University School of Hwang, JY; Chung, CK; Kwon, JS Medicine, Tokyo, Japan. [email protected]

Clinical Cognitive Neuroscience Center, Neuroscience Insti- INTRODUCTION: Patients with schizophrenia com- tute, SNU-MRC, Seoul, Republic of Korea. monly exhibit deficits of non-verbal communication in social contexts, which may be related to cognitive dys- BACKGROUND: Higher cognitive dysfunction, lower function that impairs recognition of biological motion. perceptual disturbance and its relation to the structures Although perception of biological motion is known to that implicate such processes have been considered as be mediated by the mirror neuron system, there have key features in patients with schizophrenia. However, been few empirical studies of this system in patients little is known about the relationship between percep- with schizophrenia. METHODS: Using magnetoen- tual processing and structural deficits in ultra-high-risk cephalography, we examined whether antipsychotic- for psychosis. METHODS: We investigated the dipole free schizophrenia patients displayed mirror neuron moment of M100 auditory evoked response using a system dysfunction during observation of biological magnetoencephalography in 18 patients with schizo- motion (jaw movement of another individual). RE- phrenia, 16 ultra-high-risk for psychosis and 16 healthy SULTS: Compared with normal controls, the patients controls, and their relation to cortical thinning on Hes- with schizophrenia had fewer components of both the chl's gyrus and planum temporale. RESULTS: The audi- waveform and equivalent current dipole, suggesting tory evoked M100 dipole moment was decreased in the aberrant brain activity resulting from dysfunction of ultra-high-risk subjects and in the patients with schizo- the right inferior parietal cortex. They also lacked the phrenia. Ultra-high-risk subjects showed impaired changes of alpha band and gamma band oscillation right M100 dipole magnitude, similar to patients with seen in normal controls, and had weaker phase-locking schizophrenia. Robust correlations between the cortical factors and gamma-synchronization predominantly thickness of left Heschl's gyrus and the left M100 dipole in right parietal cortex. CONCLUSIONS: Our findings moment were found in patients with schizophrenia. demonstrate that untreated patients with schizophre- Moreover, correlations were also evident between right nia exhibit aberrant mirror neuron system function Heschl's gyrus and right M100 in subjects at ultra-high- based on the right inferior parietal cortex, which is risk for psychosis. CONCLUSIONS: The primary feature characterized by dysfunction of gamma-synchroniza- of auditory perception in ultra-high-risk subjects and tion in the right parietal lobe during observation of schizophrenia patients is an encoding deficit that biological motion. (22132217)

188 PLoS One (2012), Vol. 6, No. 11, pp. e28087 PLoS One (2012), Vol. 6, No. 10, pp. e24929

Effects of metabotropic glutamate receptor 3 Aberrant auditory processing in schizophrenia and genotype on phonetic mismatch negativity in subjects at ultra-high-risk for psychosis

Kawakubo, Y; Suga, M; Tochigi, M; Yumoto, Shin, KS; Kim, JS; Kim, SN; Koh, Y; Jang, JH; An, M; Itoh, K; Sasaki, T; Kano, Y; Kasai, K SK; O'Donnell, BF; Chung, CK; Kwon, JS

Department of Child Neuropsychiatry, University of Tokyo, Neuroscience Institute, Seoul National University-Medical Tokyo, Japan. [email protected] Research Center, Seoul, Korea.

BACKGROUND: The genetic and molecular basis of ABSTRACT: The N1 and the mismatch negativity glutamatergic dysfunction is one key to understand (MMN) responses observed in electroencephalographic schizophrenia, with the identification of an interme- and magnetoencephalographic (MEG) recordings diate phenotype being an essential step. Mismatch reflect sensory processing, sensory memory, and negativity (MMN) or its magnetic counterpart, mag- adaptation and are usually abnormal in patients with netic mismatch field (MMF) is an index of preattentive schizophrenia. However, their differential sensitivity to change detection processes in the auditory cortex and ultra-high-risk (UHR) status is controversial. The current is generated through glutamatergic neurotransmis- study evaluated the sensitivity of MEG N1m, N1m ad- sion. We have previously shown that MMN/MMF in aptation, and magnetic counterpart of MMN (MMNm) response to phoneme change is markedly reduced in in 16 UHR subjects, 15 schizophrenia patients, and 18 schizophrenia. Variations in metabotropic glutamate healthy controls (HCs) during a passive auditory odd- receptor (GRM3) may be associated with schizophrenia, ball task. N1m adaptation was assessed using the differ- and has been shown to affect cortical function. Here we ence in N1m dipole moment between the first and last investigated the effect of GRM3 genotypes on phonetic standard tones in a standard stimulus sequence. N1m MMF in healthy men. METHODS: MMF in response adaptation occurred in HCs, whereas neither the UHR to phoneme change was recorded using magnetoen- nor the schizophrenia groups showed adaptation to cephalography in 41 right-handed healthy Japanese the standard tone on repeated presentations. The UHR men. Based on previous genetic association studies in group had values between those for HCs and schizo- schizophrenia, 4 candidate SNPs (rs6465084, rs2299225, phrenia patients. Additionally, MMNm dipole moment rs1468412, rs274622) were genotyped. RESULTS: GRM3 was reduced in both the UHR and patient groups com- rs274622 genotype variations significantly predicted pared with HCs, whereas the UHR and schizophrenia MMF strengths (p = 0.009), with C carriers exhibiting groups did not differ from each other. These findings significantly larger MMF strengths in both hemispheres indicated that both N1m adaptation and MMNm were compared to the TT subjects. CONCLUSIONS: These re- altered in UHR subjects and in schizophrenia patients, sults suggest that variations in GRM3 genotype modu- despite unaffected N1m dipole moment to the first late the auditory cortical response to phoneme change standard tones. Moreover, both UHR and schizophre- in humans. MMN/MMF, particularly those in response nia groups failed to show adaptation of the N1m to to speech sounds, may be a promising and sensitive repeated standard tones. This failure in adaptation was intermediate phenotype for clarifying glutamatergic more severe in patients than UHR subjects, suggest- dysfunction in schizophrenia. (22022368) ing that auditory adaptation may be sensitive to the progression of the illness and be an early biomarker of UHR for psychosis. Deficits in auditory sensory memory, on the other hand, may be similarly impaired in both groups. (22021663)

189 Schizophr Bull (2013), Vol. 38, No. 6, pp. 1258-67 Schizophr Bull (2013), Vol. 38, No. 6, pp. 1216-24

Auditory cortex responsiveness during talking and Imaging of thalamocortical dysrhythmia in listening: early illness schizophrenia and patients at neuropsychiatry clinical high-risk for psychosis Schulman, JJ; Cancro, R; Lowe, S; Lu, Perez, VB; Ford, JM; Roach, BJ; Loewy, RL; Stu- F; Walton, KD; Llinás, RR art, BK; Vinogradov, S; Mathalon, DH Department of Physiology and Neuroscience, New York Uni- Department of Psychiatry, University of California, San Fran- versity School of Medicine New York, NY, USA. cisco (UCSF), San Francisco, CA 94121, USA. ABSTRACT: Abnormal brain activity dynamics, in the OBJECTIVE: The corollary discharge mechanism is sense of a thalamocortical dysrhythmia (TCD), has been theorized to dampen sensations resulting from our proposed as the underlying mechanism for a subset own actions and distinguish them from environmental of disorders that bridge the traditional delineations of events. Deficits in this mechanism in schizophrenia may neurology and neuropsychiatry. In order to test this contribute to misperceptions of self-generated sensa- proposal from a psychiatric perspective, a study using tions as originating from external stimuli. We previously magnetoencephalography (MEG) was implemented in found attenuated speech-related suppression of audi- subjects with schizophrenic spectrum disorder (n = 14), tory cortex in chronic patients, consistent with such obsessive-compulsive disorder (n = 10), or depres- deficits. Whether this abnormality precedes psychosis sive disorder (n = 5) and in control individuals (n = 18). onset, emerges early in the illness, and/or progressively Detailed CNS electrophysiological analysis of these pa- worsens with illness chronicity, is unknown. METHODS: tients, using MEG, revealed the presence of abnormal Event-related potentials (ERPs) were recorded from theta range spectral power with typical TCD character- schizophrenia patients (SZ; n = 75) and age-matched istics, in all cases. The use of independent component healthy controls (HC; n = 77). A subsample of early ill- analysis and minimum-norm-based methods localized ness schizophrenia patients (ESZ; n = 39) was compared such TCD to ventromedial prefrontal and temporal with patients at clinical high-risk for psychosis (CHR; n = cortices. The observed mode of oscillation was spec- 35) and to a subgroup of age-matched HC (n = 36) dur- trally equivalent but spatially distinct from that of TCD ing a Talk-Listen paradigm. The N1 ERP component was observed in other related disorders, including Parkin- elicited by vocalizations as subjects talked (Talk) and son's disease, central tinnitus, neuropathic pain, and heard them played back (Listen). RESULTS: As shown autism. The present results indicate that the functional previously, SZ showed attenuated speech-related N1 basis for much of these pathologies may relate most suppression relative to HC. This was also observed in fundamentally to the category of calcium channelopa- ESZ. N1 suppression values in CHR were intermediate thies and serve as a model for the cellular substrate for to HC and ESZ and not statistically distinguishable from low-frequency oscillations present in these psychiatric either comparison group. Age-corrected N1 Talk-Listen disorders, providing a basis for therapeutic strategies. difference z scores were not correlated with illness (21863138) duration in the full SZ sample. CONCLUSIONS: Putative dysfunction of the corollary discharge mechanism during speech is evident early in the illness and is stable over its course. The intermediate effects in CHR patients may reflect the heterogeneity of this group, requiring longitudinal follow-up data to address if speech-related N1 suppression abnormalities are a risk marker for conversion to psychosis. (21993915)

190 Keywords: depression; gamma; magnetoencephalogra- stable outpatients. Our findings indicate that this level phy; obsessive–compulsive disorder; schizophrenia; theta of functional disconnection between cortical regions is an important treatment target in SZ. (21861988) Front Hum Neurosci (2011), Vol. 5, pp. 69 Biol Psychiatry (2012), Vol. 70, No. 12, pp. 1134-42

Clinical symptoms and alpha band resting-state functional connectivity imaging in patients with Reduced high and low frequency gamma schizophrenia: implications for novel approaches to synchronization in patients with chronic treatment schizophrenia

Hinkley, LB; Vinogradov, S; Guggisberg, AG; Tsuchimoto, R; Kanba, S; Hirano, S; Oribe, N; Ueno, T; Fisher, M; Findlay, AM; Nagarajan, SS Hirano, Y; Nakamura, I; Oda, Y; Miura, T; Onitsuka, T

Department of Radiology and Biomedical Imaging, Univer- Department of Neuropsychiatry, Graduate School of Medical sity of California, San Francisco, California 94143, USA. Sciences, Kyushu University, Fukuoka, Japan.

BACKGROUND: Schizophrenia (SZ) is associated with ABSTRACT: Schizophrenia has been conceptualized functional decoupling between cortical regions, but we by dysfunctional cognition and behavior related to do not know whether and where this occurs in low- abnormalities in neural circuitry. The functioning of frequency electromagnetic oscillations. The goal of this the neural circuitry can be assessed using the auditory study was to use magnetoencephalography (MEG) to steady state response (ASSR). Moreover, in recent years, identify brain regions that exhibit abnormal resting- research on high (>60 Hz) gamma band oscillations has state connectivity in the alpha frequency range in pa- become of increasing interest. The current study used tients with schizophrenia and investigate associations whole-head, 306-channel magnetoencephalography between functional connectivity and clinical symptoms (MEG) and investigated low and high gamma band os- in stable outpatient participants. METHODS: Thirty cillations with the ASSR. The subjects comprised 17 pa- patients with SZ and 15 healthy comparison partici- tients with schizophrenia and 22 controls. The current pants were scanned in resting-state MEG (eyes closed). study investigated the MEG-ASSR elicited by click trains Functional connectivity MEG source data were recon- of 20-, 30-, 40- and 80-Hz frequencies, and symptom- structed globally in the alpha range, quantified by the ASSR associations in patients with schizophrenia. The mean imaginary coherence between a voxel and the mean power, phase-locking factor, dipole moments rest of the brain. RESULTS: In patients, decreased con- and source locations of the ASSR were estimated. The nectivity was observed in left prefrontal cortex (PFC) main findings were: (1) patients with schizophrenia and right superior temporal cortex, whereas increased showed bilaterally reduced ASSR power and dipole connectivity was observed in left extrastriate cortex moments specific to the 40-Hz and 80-Hz frequencies; and the right inferior PFC. Functional connectivity (2) patients with schizophrenia showed less right- of left inferior parietal cortex was negatively related greater-than-left 40-Hz ASSR power and phase-locking to positive symptoms. Low left PFC connectivity was factor compared with healthy subjects, indicating that associated with negative symptoms. Functional con- schizophrenics may be characterized by an abnormal nectivity of midline PFC was negatively correlated with asymmetry of the 40-Hz ASSR; (3) increased severity depressed symptoms. Functional connectivity of right of global hallucinatory experiences was significantly PFC was associated with other (cognitive) symptoms. associated with smaller left 80-Hz MEG-ASSR in patients CONCLUSIONS: This study demonstrates direct func- with schizophrenia. The current study highlights the tional disconnection in SZ between specific cortical high and low frequency gamma abnormalities and pro- fields within low-frequency resting-state oscillations. vides clear evidence that schizophrenia is characterized Impaired alpha coupling in frontal, parietal, and tempo- by abnormalities in neural circuitry. (21849245) ral regions is associated with clinical symptoms in these

191 Schizophr Res (2012), Vol. 133, No. 1-3, pp. 99-105 Neurosci Res (2012), Vol. 71, No. 3, pp. 235-43

Decreased α event-related synchronization in the Neural basis of semantic priming in schizophrenia left posterior temporal cortex in schizophrenia: a during a lexical decision task: a magneto- magnetoencephalography-beamformer study encephalography study

Ikezawa, K; Ishii, R; Iwase, M; Kurimoto, R; Canuet, L; Vistoli, D; Passerieux, C; Houze, B; Har- Takahashi, H; Nakahachi, T; Azechi, M; Ohi, K; Fuku- dy-Baylé, MC; Brunet-Gouet, E moto, M; Yasuda, Y; Iike, N; Takaya, M; Yamamori, H; Kazui, H; Hashimoto, R; Yoshimine, T; Takeda, M EA 4047, Université de Versailles Saint-Quentin, Service de Psychiatrie Adulte, Centre Hospitalier de Versailles, Fonda- Department of Psychiatry, Osaka University Graduate School tion FondaMental, 177 route de Versailles, 78150 Le Chesnay, of Medicine, D3, 2-2 Yamadaoka, Suita, Osaka, 565-0871, France. [email protected] Japan. ABSTRACT: Numerous behavioral and electrophysi- ABSTRACT: Alpha rhythm is one of the most promi- ological studies have provided evidence of abnormal nent electromagnetic changes in the brain, and elec- semantic processing in schizophrenia. However, the troencephalography (EEG) alpha reactivity disturbance neural basis of these deficits is poorly understood. We may sometimes represent an early sign of cerebral investigated magnetic cortical responses elicited by dysfunction. Although magnetoencephalography a word-pair lexical decision task in 20 patients with (MEG) has a better spatial resolution than EEG, it has schizophrenia and 12 healthy control subjects. The task not extensively been used to explore alpha-power involved presentation of a prime word (200 ms), fol- change deficits in schizophrenia as a possible neuro- lowed by a blank (250 ms), and then a target stimulus physiological marker of the disease. The purpose of this (1200 ms); the subject had to decide whether the target study was to use MEG to identify abnormalities in alpha was a real word or not. During this task, bilateral tem- synchronization induced by eye-closing in schizo- poral and left prefrontal activations were observed in phrenia patients compared to healthy controls, and to both groups. However, in contrast to controls, patients investigate whether alpha reactivity deficits correlate with schizophrenia did not show increased activation with clinical features of the disorder. MEG data were in the left temporal and anterior cingulate cortices recorded in 22 schizophrenia patients and 20 age- and between 200 and 450 ms in response to semantic gender-matched controls during eyes-open/eyes- incongruity. These results suggested that schizophrenia closed resting states. Cortical sources of event-related was associated with a functional disturbance in some synchronization (ERS) were estimated using multiple semantic regions that gave rise to the N400 compo- source beamformer, and BrainVoyager was used for nent. Moreover, a significant modulation in the right statistic group analysis. A significant decrease in ERS in temporal cortex was observed in patients, but not in the upper alpha band (10-13 Hz) was found in the left controls. This suggested the existence of alternative posterior temporal region in schizophrenia patients processes in patients because both groups showed relative to controls, and this activity showed correlation similar behavioral priming. Finally, we elucidated some with visual memory scores. This upper alpha ERS deficit functional abnormalities in the semantic network dur- may indicate left temporal dysfunction and visual-in- ing prime word processing in patients, indicated by formation processing impairment in schizophrenia, and prolonged activation compared to healthy controls. upon further confirmation it might represent a neuro- Thus, in addition to context integration impairment, physiological state marker of the disorder. (21801762) abnormal activations during the prime word provided new evidence of context processing deficits in schizophrenia. (21684123)

192 Schizophr Res (2011), Vol. 130, No. 1-3, pp. 114-22 Clin Neurophysiol (2012), Vol. 122, No. 12, pp. 2365-74

Reduced mismatch negativity and increased Evoked and induced oscillatory activity variability of brain activity in schizophrenia contributes to abnormal auditory sensory gating in schizophrenia Jordanov, T; Popov, T; Weisz, N; Elbert, T; Paul-Jordanov, I; Rockstroh, B Popov, T; Jordanov, T; Weisz, N; El- bert, T; Rockstroh, B; Miller, GA Department of Psychology, University of Konstanz, Konstanz, Germany. todor.iordanov@uni-konstanz Department of Psychology, University of Konstanz, Germany. [email protected] OBJECTIVES: Schizophrenia patients commonly exhibit smaller amplitudes of mismatch negativity (MMN) ABSTRACT: The ratio of magnetoencephalogram- than in controls. It remains unclear whether this results recorded brain responses occurring 50ms after paired from deficient processes indexed by MMN or 'normally' clicks (S2-evoked M50/S1-evoked M50) serves as a though more variable processing. The present mag- measure of sensory gating. An abnormally large ratio netoencephalographic study addressed this question is commonly found in schizophrenia. Whether this ab- by analyzing intra-individual trial-by-trial variability normality indicates impaired gating is debated. Using and MMN amplitude. METHODS: Twenty inpatients event-related oscillations the present study sought to meeting ICD criteria for schizophrenia and 18 healthy elucidate processes contributing to the phenomenon controls participated in an auditory oddball experi- of altered M50 gating ratio. Schizophrenia inpatients ment. The neuromagnetic mismatch field (MMNm) (n=50) showed the expected large M50 gating ratio was defined as the difference waveform deviant minus relative to 48 healthy controls, which correlated with standard tone response. Variability index (VI) in differ- less induced frontally generated activity in the 10- ent frequency bands was quantified as trial-by-trial 15Hz frequency band starting 200ms before the onset variation of stimulus-evoked responses and epoch-by- of S2. Patients also produced smaller alpha (8-12Hz) epoch variation of signal amplitude during a resting and gamma (60-80Hz) responses to S1. Results sug- condition. RESULTS: Patients displayed a smaller gest that the deviant gating ratio in schizophrenia is a MMNm amplitude and higher VI during the oddball consequence of a complex alteration in the processing experiment and during the resting condition than in of incoming information that cannot be attributed to controls. VI and MMNm amplitude were correlated in impaired gating alone. (21316464) controls, but not in patients. CONCLUSION: Reduced MMN in schizophrenia cannot be explained by aug- Neuroimage (2011), Vol. 56, No. 1, pp. 307-14 mented variability of brain activity; deficient auditory sensory memory and stimulus related phase-locking may characterize the disorder. SIGNIFICANCE: Un- Specific cognitive training normalizes auditory derstanding the contribution of diminished temporal sensory gating in schizophrenia: a randomized trial stability of neuronal network dynamics to schizophrenia is crucial in modeling the impact of such instability Popov, T; Jordanov, T; Rockstroh, B; El- on performance and thus for understanding deviant bert, T; Merzenich, MM; Miller, GA attention and memory functions. (21620765) Department of Psychology, University of Konstanz, Konstanz, Germany.

BACKGROUND: The ratio of scalp-recorded brain responses occurring 50 msec after paired clicks (S2- evoked P50/S1-evoked P50) serves as a measure of

193 sensory gating. An abnormally large ratio is commonly nia, we examined alpha oscillations in schizophrenia found in schizophrenia and is considered as a sign of and in the prodromal phase of psychosis. METHODS: reduced sensory gating or otherwise dysfunctional The present study compared alpha oscillations us- organization of the auditory/verbal system as a fac- ing measures of both spectral power and inter-trial tor contributing to psychopathology and cognitive coherence in 17 subjects at ultra-high-risk, 10 patients dysfunction in schizophrenia. This initial randomized with schizophrenia, and 18 matched normal control clinical trial compared the efficacy of two 4-week, subjects. Whole-head magnetoencephalography computer-based cognitive training methods that (MEG) was conducted during an auditory oddball task emphasize either auditory discrimination and verbal to investigate alpha brain activity related to selective memory or a broader range of cognitive functions in attention to target stimuli and selective inhibition of schizophrenia. METHODS: Thirty-nine schizophrenia irrelevant stimuli. RESULTS: Patients with schizophre- patients (ICD-F20.0 diagnosis) were assigned to Cogni- nia showed diminished alpha event-related desynchro- tive Exercises (CE) or Cognitive Package (Cogpack). nization compared with the control subjects, while The M50, the magnetoencephalographic analogue of the ultra-high-risk subjects had values intermediate electroencephalographic P50, and performance on between the control subjects and schizophrenia verbal learning and memory tests were used to evalu- patients. Similarly, alpha inter-trial phase coherence ate training effects. RESULTS: As expected, patients was lower in the schizophrenia patients than the exhibited higher pretreatment gating ratios than 28 ultra-high-risk subjects, and lower in the ultra-high-risk age-matched healthy comparison participants. Gating subjects than the normal control subjects. Furthermore, ratios decreased after CE but not after Cogpack. Cogni- alpha band activity in the parieto-occipital region was tive test performance improved more after CE than more severely depressed in the schizophrenia patients after Cogpack. CONCLUSIONS: Appropriately specific than the ultra-high-risk subjects. CONCLUSIONS: The psychological training changes the neural performance altered alpha band activity in the ultra-high-risk group in schizophrenia, normalizing sensory and cognitive indicates that a deficit in top-down attentional control function. (21092939) exists before the onset of psychosis. The alpha event- related desynchronization and inter-trial coherence Biol Psychiatry (2011), Vol. 69, No. 5, pp. 465-71 may reflect a functional decline in the prodromal phase of schizophrenia. (21036541)

An MEG study of alpha modulation in patients Schizophr Res (2011), Vol. 126, No. 1-3, pp. 36-42 with schizophrenia and in subjects at high risk of developing psychosis MEG does not reveal impaired sensory gating in Koh, Y; Shin, KS; Kim, JS; Choi, JS; Kang, DH; Jang, first-episode schizophrenia JH; Cho, KH; O'Donnell, BF; Chung, CK; Kwon, JS Bachmann, S; Weisbrod, M; Röhrig, M; Schröder, Clinical Cognitive Neuroscience Center, Neuroscience Insti- J; Thomas, C; Scherg, M; Rupp, A tute, SNU-MRC, Seoul, Republic of Korea. Department of Psychiatry, Psychotherapy and Psychosomat- BACKGROUND: Selective attention involves a dynamic ics, University Hospitals Halle/Saale, Julius-Kühn-Str. 7, 06112 interaction between attentional control systems and Halle (Saale), Germany. [email protected]. brain oscillations. In auditory processing, selective at- de tention toward task-relevant stimuli and the inhibition of irrelevant information can be considered as aspects OBJECTIVE: The inability to adequately suppress the of top-down attentional control. Oscillatory rhythms in second of two identical stimuli is called sensory gating the alpha band have been found to play an important deficit and can be studied by recording evoked po- role during top-down processing. Because attention tentials to auditory stimuli, e.g. the P50 and the N100. deficits have been noted in patients with schizophre- It has been considered the physiological correlate of

194 schizophrenia patients' perception of being flooded by an advanced, high-resolution MEG source-imaging sensory impressions. According to the notion that the method was applied to assess activity throughout the gating deficit constitutes a genetic trait, we expected brain. In nineteen healthy subjects, attention-related to demonstrate the phenomenon in first-episode activation was seen in a sensorimotor network involv- schizophrenia patients by using Magnetencephalogra- ing primary somatosensory (S1), secondary somato- phy (MEG). METHODS: Eighteen inpatients in remission sensory (S2), primary motor (M1), pre-motor (PMA), of their first psychotic episode and 24 healthy, age- and and paracentral lobule (PCL) areas. A frontal-parietal- sex-matched control subjects participated in the study. temporal "attention network", containing dorsal- and Diagnoses, psychopathology, and handedness were ventral-lateral prefrontal cortex (DLPFC and VLPFC), assessed with established instruments. Stimulation orbitofrontal cortex (OFC), anterior cingulate cortex was performed with the double click paradigm (ISI (ACC), superior parietal lobule (SPL), inferior parietal 500 ms, ITI 9-10 s). MEG recordings of 15 patients and lobule (IPL)/supramarginal gyrus (SMG), and temporal 18 controls entered further analyses with the software lobe areas, was also activated. Seventeen individuals BESA for spatio-temporal source analyses and statisti- with schizophrenia showed early attention-related cal analyses with MATLAB. RESULTS: Neither P50 nor hyperactivations in S1 and M1 but hypo-activation in N100 responses differed statistically between the S1, S2, M1, and PMA at later latency in the sensorimotor groups, which means that gating was not impaired network. Within this attention network, hypoactiva- in this sample of first-episode schizophrenia patients. tion was found in SPL, DLPFC, orbitofrontal cortex, and CONCLUSIONS: These results are not in line with the the dorsal aspect of ACC. Hyperactivation was seen in majority of studies on sensory gating in schizophrenia, SMG/IPL, frontal pole, and the ventral aspect of ACC in however, studies on first-episode patients are scarce. patients. These findings link attention-related somato- The most likely reasons for not observing a gating sensory deficits to dysfunction in both sensorimotor deficit in our study are patients' first-episode status and and frontal-parietal-temporal networks in schizophre- atypical antipsychotic medication. (20447805) nia. (19943100)

Schizophr Res (2010), Vol. 121, No. 1-3, pp. 131-8 Brain Topogr (2010), Vol. 23, No. 1, pp. 82-104

Somatosensory system deficits in schizophrenia Timing is everything: neural response dynamics revealed by MEG during a median-nerve oddball during syllable processing and its relation to task higher-order cognition in schizophrenia and healthy comparison subjects Huang, MX; Lee, RR; Gaa, KM; Song, T; Har- rington, DL; Loh, C; Theilmann, RJ; Edgar, JC; Dale, CL; Findlay, AM; Adcock, RA; Vertinski, M; Fisher, Miller, GA; Canive, JM; Granholm, E M; Genevsky, A; Aldebot, S; Subramaniam, K; Luks, TL; Simpson, GV; Nagarajan, SS; Vinogradov, S Research, Radiology, and Psychiatry Services, VA San Diego Healthcare System, CA, USA. [email protected] Department of Radiology and Biomedical Imaging, Univer- sity of California, San Francisco, CA, USA. ABSTRACT: Although impairments related to somatosensory perception are common in schizophrenia, ABSTRACT: Successful linguistic processing requires they have rarely been examined in functional imaging efficient encoding of successively-occurring auditory studies. In the present study, magnetoencephalogra- input in a time-constrained manner, especially under phy (MEG) was used to identify neural networks that noisy conditions. In this study we examined the early support attention to somatosensory stimuli in healthy neural response dynamics to rapidly-presented succes- adults and abnormalities in these networks in patient sive syllables in schizophrenia participants and healthy with schizophrenia. A median-nerve oddball task was comparison subjects, and investigated the effects of used to probe attention to somatosensory stimuli, and noise on these responses. We used magnetoencepha-

195 lography (MEG) to reveal the time-course of stimulus- OBJECTIVE: To investigate whether temporo-spatial locked activity over bilateral auditory cortices during patterns of brain oscillations extracted from multi- discrimination of syllable pairs that differed either in channel magnetoencephalogram (MEG) recordings voice onset time (VOT) or place of articulation (POA), in in a working memory task can be used successfully as the presence or absence of noise. We also examined the a biometric marker to discriminate between healthy association of these early neural response patterns to control subjects and patients with schizophrenia. higher-order cognitive functions. The M100 response, METHODS: Five letters appearing sequentially on a arising from auditory cortex and its immediate envi- screen had to be memorized. The letters constituted a rons, showed less attenuation to the second syllable in word in one condition and a pronounceable non-word patients with schizophrenia than healthy comparison in the other. Power changes of 248 channel MEG data subjects during VOT-based discrimination in noise. were extracted in frequency sub-bands and a two-step M100 response amplitudes were similar between filter and search algorithm was used to select informa- groups for the first syllable during all three discriminative features that discriminated patients and controls. tion conditions, and for the second syllable during RESULTS: The discrimination between patients and VOT-based discrimination in quiet and POA-based dis- controls was greater in the word condition than in the crimination in noise. Across subjects, the lack of M100 non-word condition. Furthermore, in the word condi- attenuation to the second syllable during VOT-based tion, the most discriminant patterns were extracted discrimination in noise was associated with poorer task in delta (1-4 Hz), alpha (12-16 Hz) and beta (16-24 Hz) accuracy, lower education and IQ, and lower scores on frequency bands. These features were located in the measures of Verbal Learning and Memory and Global left dorso-frontal, occipital and left fronto-temporal, Cognition. Because the neural response to the first respectively. CONCLUSION: The analysis of the oscilla- syllable was not significantly different between groups, tory patterns of MEG recordings in the working memo- nor was a schizophrenia-related difference obtained in ry task provided a high level of correct classification of all discrimination tasks, early linguistic processing dys- patients and controls. SIGNIFICANCE: We show, using function in schizophrenia does not appear to be due to a newly developed algorithm, that the temporo-spatial general sensory input problems. Rather, data suggest patterns of brain oscillations can be used as biometric that faulty temporal integration occurs during succes- marker that discriminate schizophrenia patients and sive syllable processing when the signal-to-noise ratio healthy controls. (19467924) is low. Further, the neural mechanism by which the second syllable is suppressed during noise-challenged Clin Neurophysiol (2009), Vol. 120, No. 6, pp. 1123-34 VOT discrimination appears to be important for higher- order cognition and provides a promising target for neuroscience-guided cognitive training approaches to Pre-attentive auditory processing in ultra-high-risk schizophrenia. (19879305) for schizophrenia with magnetoencephalography

Int J Psychophysiol (2010), Vol. 75, No. 2, pp. 183-93 Shin, KS; Kim, JS; Kang, DH; Koh, Y; Choi, JS; O'Donnell, BF; Chung, CK; Kwon, JS

Classification of schizophrenia with spectro- Interdisciplinary Program in Cognitive Science, Seoul Na- temporo-spatial MEG patterns in working memory tional University, Seoul, Korea.

Ince, NF; Pellizzer, G; Tewfik, AH; Nelson, K; Leu- BACKGROUND: It is uncertain whether the neuro- thold, A; McClannahan, K; Stephane, M biological abnormalities in schizophrenia emerge at the first episode of the disorder or are present during Brain Sciences Center, VA Medical Center, Minneapolis, MN, the prodromal phase. Recent neuroimaging studies USA. [email protected] indicate that some brain abnormalities are present in subjects at ultra-high-risk (UHR) for schizophrenia. Pre- attentive auditory deficits, which represent a core fea-

196 ture of schizophrenia, were investigated in individuals tor machine has been used to select a small subset of at UHR for schizophrenia. METHODS: We assessed early features with recursive feature elimination technique auditory processing indexed by the magnetoencepha- (SVM-RFE) and the reduced subset was used for clas- lographic mismatch negativity magnetic counterpart sification. We note that the discrimination between (MMNm) component elicited during a passive oddball patients and controls in the word condition was higher paradigm in UHR individuals. Sixteen individuals at than in the non-word condition (91.8% vs 83.8%). Fur- UHR for schizophrenia on the basis of clinical crite- thermore, in the word condition, the most discriminant ria and 18 healthy control subjects matched for age, patterns were extracted in delta (1-4 Hz), theta (4-8Hz) gender, and education participated. A duration-deviant and alpha (12-16 Hz) frequency bands. We note that oddball paradigm was used to obtain MMNm dipole these features were located around the left frontal, left moment, which was measured with cortical source temporal and occipital areas, respectively. Our results modeling. RESULTS: The UHR group showed a smaller indicate that the proposed approach can quantify dis- right MMNm dipole moment than those of the con- criminative neural patterns associated to a functional trol group. Group difference was observed in MMNm task in spatial, spectral and temporal domain. Moreover dipole latency, suggestive of slowed processing. The these features provide interpretable information to the left MMNm dipole moment was negatively correlated medical expert about physiological basis of the illness with clinical symptoms measured by the Compre- and can be effectively used as a biometric marker to hensive Assessment of At-Risk Mental States positive recognize schizophrenia in clinical practice. (19163476) symptom score. CONCLUSIONS: Our findings suggest that deficits in the early stage of auditory processing Conf Proc IEEE Eng Med Biol Soc (2009), Vol. 2008, pp. in individuals at UHR for schizophrenia exist before the 3554-7 onset of psychosis. The MMNm dipole moment might reflect the functional decline at the prodromal stage of schizophrenia. (19200950) Schizophrenia diagnosis and anterior hippocampal volume make separate contributions to sensory Biol Psychiatry (2009), Vol. 65, No. 12, pp. 1071-8 gating

Thoma, RJ; Hanlon, FM; Petropoulos, H; Miller, GA; Selection of spectro-temporal patterns in Moses, SN; Smith, A; Parks, L; Lundy, SL; Sanchez, multichannel MEG with support vector machines for NM; Jones, A; Huang, M; Weisend, MP; Cañive, JM schizophrenia classification Department of Psychiatry, University of New Mexico, Albu- Ince, NF; Goksu, F; Pellizzer, G; Tewfik, A; Stephane, M querque, New Mexico 87131-0001, USA. [email protected]. edu Departments of Electrical and Computer Engineering and Neuroscience, University of Minnesota, USA. [email protected] ABSTRACT: Impaired P50 gating is thought to reflect a core deficit in schizophrenia, but the relevant neural ABSTRACT: We present a new framework for the diag- network is not well understood. The present study used nosis of schizophrenia based on the spectro-temporal EEG and MEG to assess sensory gating and volumetric patterns selected by a support vector machine from MRI to measure hippocampal volume to investigate multichannel magnetoencephalogram (MEG) record- relationships between them in 22 normal controls and ings in a verbal working memory task. In the experi- 22 patients with schizophrenia. In the schizophrenia mental paradigm, five letters appearing sequentially on group, anterior but not posterior hippocampal volume a screen were memorized by subjects. The letters con- was smaller, and both the P50 and M50 gating ratios stituted a word in one condition and a pronounceable were larger (worse) than in controls. Independent of nonword in the other. Power changes were extracted group, left-hemisphere M50 gating ratio correlated as features in frequency subbands of 248 channel MEG negatively with left anterior hippocampal volume, and data to form a rich feature dictionary. A support vec- right-hemisphere M50 gating ratio correlated nega-

197 tively with right anterior hippocampal volume. Schizo- identifying speech sounds. Moreover, the present study phrenia diagnosis predicted M50 gating independent suggests that schizophrenia might be characterized of hippocampal volume. These results are consistent by an opposite pattern of hemispheric lateralization in with the finding that hippocampus is a critical part of auditory evoked oscillations. (18463243) a fronto-temporal circuit involved in auditory gating. (18823427) J Neurosci (2008), Vol. 28, No. 19, pp. 4897-903

Psychophysiology (2009), Vol. 45, No. 6, pp. 926-35 Optimized mismatch negativity paradigm reflects deficits in schizophrenia patients. A combined EEG Abnormal neural oscillatory activity and MEG study to speech sounds in schizophrenia: a magnetoencephalography study Thönnessen, H; Zvyagintsev, M; Harke, KC; Boers, F; Dammers, J; Norra, Ch; Mathiak, K Hirano, S; Hirano, Y; Maekawa, T; Obayashi, C; Oribe, N; Kuroki, T; Kanba, S; Onitsuka, T Department of Psychiatry and Psychotherapy, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany. Department of Neuropsychiatry, Graduate School of Medical [email protected] Sciences, Kyushu University, Fukuoka 812-8582, Japan. ABSTRACT: Mismatch negativity (MMN) and its neu- ABSTRACT: Schizophrenia impairs many cognitive romagnetic analog (MMNm) are event-related brain functions, and abnormalities in language processing responses elicited by changes in a sequence of audi- have been proposed as one of the bases for this dis- tory events and indexes early cognitive processing. order. Previously, it was reported that different mag- It consistently detects neural processing deficits in netoencephalography (MEG) patterns of the evoked schizophrenia. So far MMN is assessed with different oscillatory activity (eOA) of 20-45 Hz to speech and methods (electroencephalography, EEG; magnetoen- nonspeech sounds were evidence of a fast mechanism cephalography, MEG) and with different paradigms: the for the representation and identification of speech "traditional" oddball design with rare deviants (20%) sounds in humans. The current study tested the hy- or the "optimum" design with 50% deviants varying in pothesis that the schizophrenics would show abnor- one of five parameters each. These MMN measures may mal neural oscillatory activity, as measured by eOA, to not reflect one unitary mechanism which is equally speech and nonspeech sounds. Twenty patients and affected in schizophrenia. We compared both designs 23 control subjects participated in this study. MEG in 12 patients with schizophrenia and controls using responses to speech and nonspeech sounds were re- MEG and EEG. Automated, observer-independent data corded and eOA power and phase locking at 20-45 Hz analysis rendered the procedures suitable for clinical were analyzed. Patients showed significantly delayed applications. The optimum design was fastest to detect peak latencies of the eOA power and phase locking to MMN and MEG had the best signal-to-noise ratio. In speech sounds in the left hemisphere and to non- addition MMN was mostly reduced in schizophrenia if speech sounds in the right hemisphere. Patients also measured with MEG in the optimum paradigm. Opti- showed a significantly reduced eOA power to speech mized paradigms improve sensitivity and speed for the sounds in the left hemisphere in 0-50 ms and a signifi- detection of schizophrenia endophenotypes. Dysfunc- cantly larger eOA power to speech sounds in the left tions in this disorder may lie primarily in the fast and hemisphere in 100-150 ms. In addition, the analyses of automatic encoding of stimulus features at the auditory the lateralization index revealed the pattern of hemi- cortex. (18060677) spheric lateralization to be the opposite in patients. These results indicated that patients showed different characteristics of eOA compared with normal controls, probably related to deficits in a fast mechanism for

198 Biol Psychol (2008), Vol. 77, No. 2, pp. 205-16 Schizophr Res (2008), Vol. 98, No. 1-3, pp. 278-86

The perception of emotion-free faces in Abnormal oscillatory brain dynamics in schizophrenia: a magneto-encephalography study schizophrenia: a sign of deviant communication in neural network? López-Ibor, JJ; López-Ibor, MI; Méndez, MA; Morón, MD; Ortiz-Terán, L; Fernandez, A; Diaz-Marsá, M; Ortiz, T Rockstroh, BS; Wienbruch, C; Ray, WJ; Elbert, T

The Institute of Psychiatry and Mental Health, San Carlos Department of Psychology, University of Konstanz, PO Box University Hospital, Department of Psychiatry and Medical D23 D-78457, Konstanz, Germany. brigitte.rockstroh@uni- Psychology, Complutense University, Madrid, Spain. jli@lopez- konstanz.de ibor.com BACKGROUND: Slow waves in the delta (0.5-4 Hz) OBJECTIVE: To analyze how patients suffering from frequency range are indications of normal activity schizophrenia perceive faces of unknown individuals in sleep. In neurological disorders, focal electric and that show no actual emotions in order to investigate magnetic slow wave activity is generated in the vicinity the attribution of meanings to a relatively non-sig- of structural brain lesions. Initial studies, including our nificant but complex sensory experience. DESIGN: own, suggest that the distribution of the focal concen- Analysis of baseline and poststimulation magneto- tration of generators of slow waves (dipole density in encephalographic recordings. The stimuli consisted the delta frequency band) also distinguishes patients of four pictures with neutral emotional expression of with psychiatric disorders such as schizophrenia, af- male and female faces of Spanish individuals unknown fective disorders, and posttraumatic stress disorder. to research subjects. PARTICIPANTS: Twelve right- METHODS: The present study examined the distribu- handed patients suffering from schizophrenia (DSM tion of focal slow wave activity (ASWA: abnormal slow IV-TR criteria), age 18-65, with active delusional activity wave activity) in 116 healthy subjects, 76 inpatients (SAPS score in delusions above 39) and 15 right-hand- with schizophrenic or schizoaffective diagnoses and ed sex- and age-matched control subjects. RESULTS: 42 inpatients with affective (ICD-10: F3) or neurotic/ Compared to controls patients have a significant higher reactive (F4) diagnoses using a newly refined measure activity of both hemispheres (0-700 ms) being the of dipole density. Based on 5-min resting magneto- activity in the right hemisphere (RH) higher than in encephalogram (MEG), sources of activity in the 1-4 the left hemisphere (LH). Patients also have a higher Hz frequency band were determined by equivalent activity on the middle fusiform gyrus (BA 37) in the LH dipole fitting in anatomically defined cortical regions. (200-300 ms), on the superior temporal areas (BA 22, RESULTS: Compared to healthy subjects the schizo- 41 and 42) in both hemispheres (100-700 ms) and on phrenia sample was characterized by significantly more the temporal pole (BA 38) in the RH (300-400 ms) and intense slow wave activity, with maxima in frontal and a lower activity in the LH of the latter. CONCLUSIONS: central areas. In contrast, affective disorder patients The areas that are more activated in our study are those exhibited less slow wave generators mainly in frontal involved in the process of thinking, in attributing mean- and central regions when compared to healthy subjects ings to perceptions and in activities such as theory of and schizophrenia patients. In both samples, frontal mind, which are essential for social interaction. The an- ASWA were related to affective symptoms. CONCLU- terior temporal areas less activated indicate a reduced SION: In schizophrenic patients, the regions of ASWA semantic memory for faces that could explain the social correspond to those identified for gray matter loss. This withdrawal of schizophrenia. These alterations are sug- suggests that ASWA might be evaluated as a measure gestive of a dysfunction of left hemisphere neuronal of altered neuronal network architecture and commu- networks. (17964761) nication, which may mediate psychopathological signs. (17760978)

199 BMC Psychiatry (2007), Vol. 7, pp. 44

Manifest disease and motor cortex reactivity in twins discordant for schizophrenia

Schürmann, M; Järveläinen, J; Avikainen, S; Can- non, TD; Lönnqvist, J; Huttunen, M; Hari, R

Brain Research Unit, Helsinki University of Technology, Fin- land. [email protected]

ABSTRACT: Schizophrenia is often associated with difficulties in distinguishing between actions of self and of others. This could reflect dysfunction of the mirror neuron system which directly matches observed and executed actions. We studied 11 people with schizophrenia and their co-twins without manifest disease, using stimulus-induced changes in the magnetoencephalographic approximately 20 Hz rhythm as an index of activation in the motor cortex part of the mirror neuron system. During action observation and execution, motor cortex reaction was weaker in those with schizophrenia than in their co-twins, suggesting a disease-related dysfunction of motor cognition. (17666504)

Br J Psychiatry (2008), Vol. 191, pp. 178-9

200 Sclerosis with TSC. The seizure outcome was not related to the clustered MEGSS within RA, since the grids were essentially planned to cover and resect the clustered MEGSS Magnetoencephalography spike sources interrelate surrounding tubers. The maximal possible resection the extensive epileptogenic zone of tuberous of scattered MEGSS correlated with improved seizure sclerosis complex outcome in TSC. Some parts of the epileptogenic zone disrupted by multiple tubers did not have a sufficiently Okanishi, T; Akiyama, T; Mayo, E; Honda, Y; Ueda-Kawada, large area to produce clustered MEGSS. Although the C; Nakajima, M; Homma, Y; Ochi, A; Go, C; Widjaja, E; wide distribution of scattered MEGSS is not interpreted Chuang, SH; Rutka, JT; Drake, J; Snead, OC; Otsubo, H as epileptogenic, they might be interrelated with clustered MEGSS to project a complex epilepsy network Division of Neurology, The Hospital for Sick Children, PO Box and be part of the extensive epileptogenic zones found M5G, 1X8, Toronto, Ontario, Canada. Electronic address: in TSC. (27693986) [email protected]. Keywords: Epilepsy surgery; Epileptic network; Intractable OBJECTIVE: We hypothesized that the extensive epilepsy; Magnetoencephalography; Seizure outcome; epileptic network in patients with tuberous sclerosis Tuberous sclerosis complex complex (TSC) manifests as clustered and scattered distributions of magnetoencephalography spike sources Epilepsy Res (2018), Vol. 127, pp. 302-310 (MEGSS). METHODS: We retrospectively analyzed presurgical MEG in 15 patients with TSC. We performed single moving dipole analysis to localize and classify Functional substrate for memory function clustered and scattered MEGSS. We compared the num- differences between patients with left and right ber of electrodes within the resected area (RA) and the mesial temporal lobe epilepsy associated with proportions of clustered and scattered MEGSS within hippocampal sclerosis RA with the seizure outcome. RESULTS: The number of electrodes within RA ranged from 29 to 83 (mean=51). Jin, SH; Chung, CK The MEGSS were distributed over multiple lobes (3-8; mean=5.9) and bilaterally in 14 patients. Clusters of Neuroscience Research Institute, Seoul National University MEGSS ranged from 1 to 4 (mean=1.4). The number College of Medicine, Seoul, Republic of Korea. of MEGSS ranged in total from 28 to 139 (mean=70); in the clusters, 10-128 (mean=49); and in the scatters, OBJECTIVE: Little is known about the functional 0-45 (mean=21). Four patients achieved an Engel class I substrate for memory function differences in patients surgical outcome, four, a class II outcome; five, a class III with left or right mesial temporal lobe epilepsy (mTLE) outcome; and two, a class IV outcome. The proportion associated with hippocampal sclerosis (HS) from an of MEGSS ranged in total from 0 to 92% (mean=57%) electrophysiological perspective. To characterize these within RA; 0-100% (mean=67%) in the resection differences, we hypothesized that hippocampal theta hemisphere; 0-100% (mean=63%) in the clusters; and connectivity in the resting-state might be different 0-81% (mean=28%) in the scatters. Univariate ordinal between patients with left and right mTLE with HS and logistic regression analyses showed that the proportion be correlated with memory performance. METHODS: of scattered MEGSS within RA (p=0.049) significantly Resting-state hippocampal theta connectivity, identi- correlated with seizure outcomes. Multivariate analyses fied via whole-brain magnetoencephalography, was using three covariates (number of electrodes, propor- evaluated. Connectivity and memory function in 41 pa- tions of clustered and scattered MEGSS within RA) tients with mTLE with HS (left mTLE=22; right mTLE=19) showed that only the proportion of scattered MEGSS were compared with those in 46 age-matched healthy within RA significantly correlated with seizure out- controls and 28 patients with focal cortical dysplasia comes (p=0.016). SIGNIFICANCE: MEG data showed (FCD) but without HS. RESULTS: Connectivity between a wide distribution of multilobar MEGSS in patients the right hippocampus and the left middle frontal

201 gyrus was significantly stronger in patients with right epileptic activity. Language acquisition and develop- mTLE than in patients with left mTLE. Moreover, this ment seems to be altered in a significant proportion connectivity was positively correlated with delayed of patients with TSC. In the present study, we used verbal recall and recognition scores in patients with magnetoencephalography (MEG) to investigate spatio- mTLE. Patients with left mTLE had greater delayed recall temporal cerebral language processing in subjects with impairment than patients with right mTLE and FCD. TSC and epilepsy during a reading semantic decision Similarly, delayed recognition performance was worse task, compared to healthy control participants. METH- in patients with left mTLE than in patients with right ODS: Fifteen patients with TSC and 31 healthy subjects mTLE and FCD. No significant differences in memory performed a lexico-semantic decision task during MEG function between patients with right mTLE and FCD recording. Minimum-norm estimates (MNE) were com- were detected. Patients with right mTLE showed puted allowing identification of cerebral generators of significantly stronger hippocampal theta connectivity language evoked fields (EF) in each subject. RESULTS: between the right hippocampus and left middle frontal Source analysis of the language EF demonstrated early gyrus than patients with FCD and left mTLE. CONCLU- bilateral medial occipital activation (125ms) followed SION: Our results suggest that right hippocampal-left by a fusiform gyrus activation around 135ms. At 270ms middle frontal theta connectivity could be a functional post stimuli presentation, a strong cerebral activa- substrate that can account for differences in memory tion was recorded in the left basal temporal language function between patients with left and right mTLE. area. Finally, cerebral activations were measured in This functional substrate might be related to different Wernicke's area followed by Broca's area. The healthy compensatory mechanisms against the structural hip- control group showed larger and earlier language pocampal lesions in left and right mTLE groups. Given activations in Broca and Wernicke's areas compared to the positive correlation between connectivity and TSC patients. Moreover, cerebral activation from Broca's delayed verbal memory function, hemispheric-specific area was greater than activation from Wernicke's area in hippocampal-frontal theta connectivity assessment both groups, but this difference between anterior and could be useful as an electrophysiological indicator of posterior regions was smaller in the TSC group. Finally, delayed verbal memory function in patients with mTLE the activation latency difference between Broca and with HS. (26300534) Wernicke's areas was greater in healthy controls than in TSC patients, which shows that activations in these Keywords: Functional substrate; Hippocampal sclerosis; areas are more serial in control subjects compared to Memory; Mesial temporal lobe epilepsy; Resting-state TSC patients in whom activations occur more simulta- magnetoencephalography neously. CONCLUSIONS: This is the first study to investigate cerebral language pattern in patients with TSC. Epilepsy Behav (2016), Vol. 51, pp. 251-8 Compared to healthy controls, atypical neuromagnetic language responses may reflect cerebral reorganization in these patients in response to early epileptogenic Diffuse cerebral language representation in activity or presence at birth of multiple brain lesions. tuberous sclerosis complex (23092910)

Gallagher, A; Tanaka, N; Suzuki, N; Liu, Epilepsy Res (2013), Vol. 104, No. 1-2, pp. 125-33 H; Thiele, EA; Stufflebeam, SM

Athinoula A. Martinos Center for Biomedical Imaging, 149 Thirteenth Street, Charlestown, MA 02129, USA. anneg@nmr. mgh.harvard.edu

INTRODUCTION: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder affecting multiple organs, including the brain, and very often associated with

202 Stroke magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. Deep brain stimulation of the ventral DBS-induced changes in event-related fields could striatal area for poststroke pain syndrome: a potentially serve as biomarkers for clinical outcomes. magnetoencephalography study (29384450)

Gopalakrishnan, R; Burgess, RC; Malone, DA; Lempka, Keywords: chronic pain; deep brain stimulation; event-re- SF; Gale, JT; Floden, DP; Baker, KB; Machado, AG lated fields; magnetoencephalography; pain anticipation

Center for Neurological Restoration, Neurological Institute, J Neurophysiol (2019), Vol. 119, No. 6, pp. 2118-2128 Cleveland Clinic , Cleveland, Ohio.

ABSTRACT: Poststroke pain syndrome (PSPS) is an Randomized trial of transcranial direct current often intractable disorder characterized by hemiparesis stimulation for poststroke dysphagia associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative Suntrup-Krueger, S; Ringmaier, C; Muhle, P; Woll- approaches targeting affective-cognitive spheres have brink, A; Kemmling, A; Hanning, U; Claus, I; War- started to show promise. Recently, we demonstrated necke, T; Teismann, I; Pantev, C; Dziewas, R that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of Department of Neurology, University Hospital Münster, Albert pain in patients with PSPS. In the present study, we Schweitzer Campus 1 Münster. examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could OBJECTIVE: We evaluated whether transcranial direct serve as signatures of treatment effects. We recorded current stimulation (tDCS) is able to enhance dysphagia event-related fields (ERFs) of pain anticipation using rehabilitation following stroke. Besides relating clinical magnetoencephalography (MEG) in 10 patients with effects with neuroplastic changes in cortical swallow- PSPS preoperatively and postoperatively in DBS OFF ing processing, we aimed to identify factors influencing and ON states. Simple visual cues evoked anticipa- treatment success. METHODS: In this double-blind, tion as patients awaited a painful (PS) or nonpainful randomized study, 60 acute dysphagic stroke patients stimulus (NPS) to the nonaffected or affected extremity. received contralesional anodal (1mA, 20 minutes) or Preoperatively, ERFs showed no difference between PS sham tDCS on 4 consecutive days. Swallowing function and NPS anticipation to the affected extremity, possibly was thoroughly assessed before and after the interven- due to loss of salience in a network saturated by pain tion using the validated Fiberoptic Endoscopic Dys- experience. DBS significantly modulated the early N1, phagia Severity Scale (FEDSS) and clinical assessment. consistent with improvements in affective networks In 10 patients, swallowing-related brain activation was involving restoration of salience and discrimination recorded applying magnetoencephalography before capacity. Additionally, DBS suppressed the posterior and after the intervention. Voxel-based statistical le- P2 (aberrant anticipatory anxiety) while enhancing the sion pattern analysis was also performed. RESULTS: anterior N1 (cognitive and emotional regulation) in Study groups did not differ according to demographic responders. DBS-induced changes in ERFs could poten- data, stroke characteristics, or baseline dysphagia tially serve as signatures for clinical outcomes. NEW & severity. Patients treated with tDCS showed greater NOTEWORTHY We examined the electrophysiological improvement in FEDSS than the sham group (1.3 vs 0.4 correlates of pain affect in poststroke pain patients who points, mean difference = 0.9, 95% confidence inter- underwent deep brain stimulation (DBS) targeting the val [CI] = 0.4-1.4, p < 0.0005). Functional recovery was ventral striatal area under a randomized, controlled accompanied by a significant increase of activation trial. DBS significantly modulated early event-related (p < 0.05) in the contralesional swallowing network components, particularly N1 and P2, measured with after real but not sham tDCS. Regarding predictors of

203 treatment success, for every hour earlier that treatment ery. Importantly, the rebound strength was lower than was initiated, there was greater improvement on the that of the controls in the AH and UH also to healthy- FEDSS (adjusted odds ratio = 0.99, 95% CI = 0.98-1.00, hand stimulation despite of intact afferent input. In the p < 0.05) in multivariate analysis. Stroke location in the AH, the rebound strength to impaired-hand stimulation right insula and operculum was indicative of worse correlated with hand motor recovery. CONCLUSIONS: response to tDCS (p < 0.05). INTERPRETATION: Applica- Motor cortex excitability is increased bilaterally after tion of tDCS over the contralesional swallowing motor stroke and decreases concomitantly with recovery. cortex supports swallowing network reorganization, Motor cortex excitability changes are related to both thereby leading to faster rehabilitation of acute post- alterations in local excitatory-inhibitory circuits and stroke dysphagia. Early treatment initiation seems ben- changes in afferent input. Fluent sensorimotor integra- eficial. tDCS may be less effective in right-hemispheric tion, which is closely coupled with excitability changes, insulo-opercular stroke. Ann Neurol 2018;83:328-340. seems to be a key factor for motor recovery. (28164736) (29350775) Keywords: beta rhythm; motor cortex excitability; passive Ann Neurol (2019), Vol. 83, No. 2, pp. 328-340 movement; proprioception; stroke recovery

Neurorehabil Neural Repair (2017), Vol. 31, No. 5, pp. 475- Strength of ~20-Hz Rebound and Motor Recovery 486 After Stroke

Parkkonen, E; Laaksonen, K; Piitulainen, H; Pe- Cortical Excitability Measured with nTMS and MEG kkola, J; Parkkonen, L; Tatlisumak, T; Forss, N during Stroke Recovery

1 Department of Neuroscience and Biomedical Engineering, Mäkelä, JP; Lioumis, P; Laaksonen, K; Forss, N; Aalto University School of Science, Espoo, Finland. Tatlisumak, T; Kaste, M; Mustanoja, S

BACKGROUND: Stroke is a major cause of disability BioMag Laboratory, HUS Medical Imaging Center, Helsinki worldwide, and effective rehabilitation is crucial to University Hospital and University of Helsinki, 00029 Helsinki, regain skills for independent living. Recently, novel Finland. therapeutic approaches manipulating the excitatory- inhibitory balance of the motor cortex have been intro- OBJECTIVE: Stroke alters cortical excitability both duced to boost recovery after stroke. However, stroke- in the lesioned and in the nonlesioned hemisphere. induced neurophysiological changes of the motor Stroke recovery has been studied using transcranial cortex may vary despite of similar clinical symptoms. magnetic stimulation (TMS). Spontaneous brain oscil- Therefore, better understanding of excitability changes lations and somatosensory evoked fields (SEFs) mea- after stroke is essential when developing and targeting sured by magnetoencephalography (MEG) are modi- novel therapeutic approaches. OBJECTIVE AND METH- fied in stroke patients during recovery. METHODS: ODS: We identified recovery-related alterations in We recorded SEFs and spontaneous MEG activity and motor cortex excitability after stroke using magnetoen- motor threshold (MT) short intracortical inhibition (SICI) cephalography. Dynamics (suppression and rebound) and intracortical facilitation (ICF) with navigated TMS of the ~20-Hz motor cortex rhythm were monitored (nTMS) at one and three months after first-ever hemi- during passive movement of the index finger in 23 spheric ischemic strokes. Changes of MEG and nTMS stroke patients with upper limb paresis at acute phase, parameters attributed to gamma-aminobutyrate and 1 month, and 1 year after stroke. RESULTS: After stroke, glutamate transmission were compared. RESULTS: ICF the strength of the ~20-Hz rebound to stimulation of correlated with the strength and extent of SEF source both impaired and healthy hand was decreased with areas depicted by MEG at three months. The nTMS MT respect to the controls in the affected (AH) and unaf- and event-related desynchronization (ERD) of beta- fected (UH) hemispheres, and increased during recov- band MEG activity and SICI and the beta-band MEG

204 event-related synchronization (ERS) were correlated, tion was detected better by MSE and beta power. The but less strongly. CONCLUSIONS: This first report using findings also suggest that MSE is specifically sensitive sequential nTMS and MEG in stroke recovery found to electrophysiological dysfunction in perilesional tis- intra- and interhemispheric correlations of nTMS and sue, while spectral measures were additionally affected MEG estimates of cortical excitability. ICF and SEF pa- by an increase in rolandic beta power with advanced rameters, MT and the ERD of the lesioned hemisphere, age. Furthermore, perilesional electrophysiological ab- and SICI and ERS of the nonlesioned hemisphere were normalities in the left hemisphere were correlated with correlated. Covarying excitability in the lesioned and the degree of language task-induced activation in the nonlesioned hemispheres emphasizes the importance right hemisphere. Finally, we demonstrate that single of the hemispheric balance of the excitability of the subject spectral and nonlinear analyses can identify sensorimotor system. (26491569) dysfunctional perilesional regions within individual patients that may be ideal targets for interventions with Neural Plast (2016), Vol. 2015, pp. 309546 noninvasive brain stimulation. (26106540)

Keywords: Beamformer source reconstruction; Chronic MEG-based detection and localization of stroke; Magnetoencephalography; Time–frequency perilesional dysfunction in chronic stroke analysis

Chu, RK; Braun, AR; Meltzer, JA Neuroimage Clin (2016), Vol. 8, pp. 157-69

University of Toronto, Department of Psychology, 100 St. George Street, 4th Floor, Sidney Smith Hall, Toronto, ON M5S Cortical mechanisms of mirror therapy after stroke 3G3, Canada ; Rotman Research Institute, Baycrest Centre, 3560 Bathurst St., Toronto, ON M6A 2E1, Canada. Rossiter, HE; Borrelli, MR; Borchert, RJ; Bradbury, D; Ward, NS ABSTRACT: Post-stroke impairment is associated not only with structural lesions, but also with dysfunction UCL Institute of Neurology, London, UK [email protected]. in surviving perilesional tissue. Previous studies using equivalent current dipole source localization of MEG/ BACKGROUND AND OBJECTIVE: Mirror therapy is a EEG signals have demonstrated a preponderance new form of stroke rehabilitation that uses the mirror of slow-wave activity localized to perilesional areas. reflection of the unaffected hand in place of the affect- Recent studies have also demonstrated the utility of ed hand to augment movement training. The mecha- nonlinear analyses such as multiscale entropy (MSE) for nism of mirror therapy is not known but is thought quantifying neuronal dysfunction in a wide range of pa- to involve changes in cerebral organization. We used thologies. The current study utilized beamformer-based magnetoencephalography (MEG) to measure changes reconstruction of signals in source space to compare in cortical activity during mirror training after stroke. spectral and nonlinear measures of electrical activity in In particular, we examined movement-related changes perilesional and healthy cortices. Data were collected in the power of cortical oscillations in the beta (15-30 from chronic stroke patients and healthy controls, both Hz) frequency range, known to be involved in move- young and elderly. We assessed relative power in the ment. METHODS: Ten stroke patients with upper limb delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz) and beta paresis and 13 healthy controls were recorded using (15-30 Hz) frequency bands, and also measured the MEG while performing bimanual hand movements in nonlinear complexity of electrical activity using MSE. 2 different conditions. In one, subjects looked directly Perilesional tissue exhibited a general slowing of the at their affected hand (or dominant hand in controls), power spectrum (increased delta/theta, decreased and in the other, they looked at a mirror reflection of beta) as well as a reduction in MSE. All measures tested their unaffected hand in place of their affected hand. were similarly sensitive to changes in the posterior The movement-related beta desynchronization was perilesional regions, but anterior perilesional dysfunc- calculated in both primary motor cortices. RESULTS:

205 Movement-related beta desynchronization was sym- MRBD was seen in those with more motor impairment. metrical during bilateral movement and unaltered by We speculate that impaired modulation of beta oscilla- the mirror condition in controls. In the patients, move- tions during affected hand grip is detrimental to motor ment-related beta desynchronization was generally control, highlighting this as a potential therapeutic smaller than in controls, but greater in contralesional target in neurorehabilitation. (25080568) compared to ipsilesional motor cortex. This initial asymmetry in movement-related beta desynchronization Keywords: beta oscillations; magnetoencephalography; between hemispheres was made more symmetrical motor cortex; stroke by the presence of the mirror. CONCLUSIONS: Mirror therapy could potentially aid stroke rehabilitation by J Neurophysiol (2015), Vol. 112, No. 9, pp. 2053-8 normalizing an asymmetrical pattern of movement-related beta desynchronization in primary motor cortices during bilateral movement. (25326511) Laterality of brain activity during motor imagery is modulated by the provision of source level Keywords: MEG; beta oscillations; mirror therapy; motor neurofeedback cortex; stroke Boe, S; Gionfriddo, A; Kraeutner, S; Trem- Neurorehabil Neural Repair (2016), Vol. 29, No. 5, pp. 444- blay, A; Little, G; Bardouille, T 52 Laboratory for Brain Recovery and Function, Dalhousie University, Halifax, Nova Scotia, Canada; School of Physio- Do movement-related beta oscillations change after therapy, Dalhousie University, Halifax, Nova Scotia, Canada; stroke? Department of Psychology and Neuroscience, Dalhousie University, Halifax Nova Scotia, Canada. Electronic address: Rossiter, HE; Boudrias, MH; Ward, NS [email protected].

Sobell Department of Motor Neuroscience and Movement ABSTRACT: Motor imagery (MI) may be effective as an Disorders, UCL Institute of Neurology, London, United King- adjunct to physical practice for motor skill acquisition. dom [email protected]. For example, MI is emerging as an effective treatment in stroke neurorehabilitation. As in physical practice, ABSTRACT: Stroke is the most common cause of physi- the repetitive activation of neural pathways during cal disability in the world today. While the key element MI can drive short- and long-term brain changes that of rehabilitative therapy is training, there is currently underlie functional recovery. However, the lack of much interest in approaches that "prime" the primary feedback about MI performance may be a factor limit- motor cortex to be more excitable, thereby increasing ing its effectiveness. The provision of feedback about the likelihood of experience-dependent plasticity. Cor- MI-related brain activity may overcome this limitation tical oscillations reflect the balance of excitation and by providing the opportunity for individuals to monitor inhibition, itself a key determinant of the potential for their own performance of this endogenous process. We experience-dependent plasticity. In the motor system, completed a controlled study to isolate neurofeedback beta-band oscillations are important and are thought as the factor driving changes in MI-related brain activity to maintain the resting sensorimotor state. Here we across repeated sessions. Eighteen healthy participants examined motor cortex beta oscillations during rest took part in 3 sessions comprised of both actual and and unimanual movement in a group of stroke patients imagined performance of a button press task. During and healthy control subjects, using magnetoencepha- MI, participants in the neurofeedback group received lography. Movement-related beta desynchronization source level feedback based on activity from the left (MRBD) in contralateral primary motor cortex was and right sensorimotor cortex obtained using magne- found to be significantly reduced in patients compared toencephalography. Participants in the control group with control subjects. Within the patient group, smaller received no neurofeedback. MI-related brain activity

206 increased in the sensorimotor cortex contralateral to with a bilateral frontotemporal network, encompassing the imagined movement across sessions in the neuro- feedforward and feedback connections. Comparison of feedback group, but not in controls. Task performance specific network parameters between groups revealed improved across sessions but did not differ between that patients displayed selective network adjustments. groups. Our results indicate that the provision of Specifically, backward connectivity from anterior to neurofeedback during MI allows healthy individuals to posterior temporal lobe was decreased in the ipsile- modulate regional brain activity. This finding has the sional hemisphere, whereas it was enhanced in the potential to improve the effectiveness of MI as a tool in contralesional hemisphere. These results reinforce the neurorehabilitation. (24999037) relevance of ATL in semantic memory, as well as its amodal organization, and highlight the role of feed- Keywords: Cortical oscillations; Functional neuroimaging; back connections in enabling the integration of the Imagery; Magnetoencephalography; Neurofeedback semantic information. (23904604)

Neuroimage (2015), Vol. 101, pp. 159-67 J Neurosci (2013), Vol. 33, No. 31, pp. 12679-88

Anterobasal temporal lobe lesions alter recurrent Alterations in spontaneous brain oscillations during functional connectivity within the ventral pathway stroke recovery during naming Laaksonen, K; Helle, L; Parkkonen, L; Kirveskari, E; Mäkelä, Campo, P; Poch, C; Toledano, R; Igoa, JM; JP; Mustanoja, S; Tatlisumak, T; Kaste, M; Forss, N Belinchón, M; García-Morales, I; Gil-Nagel, A Brain Research Unit, O.V. Lounasmaa Laboratory and MEG Department of Basic Psychology, Autonoma University of Core, Aalto Neuroimaging, Aalto University, Aalto, Espoo, Madrid, 28049 Madrid, Spain. Finland. [email protected]

ABSTRACT: An increasing amount of evidence sup- ABSTRACT: Amplitude or frequency alterations of ports a crucial role for the anterior temporal lobe (ATL) spontaneous brain oscillations may reveal pathologi- in semantic processing. Critically, a selective disruption cal phenomena in the brain or predict recovery from of the functional connectivity between left and right brain lesions, but the temporal evolution and the ATLs in patients with chronic aphasic stroke has been functional significance of these changes is not well illustrated. The aim of the current study was to evalu- known. We performed follow-up recordings of spon- ate the consequences that lesions on the ATL have taneous brain oscillations with whole-head MEG in 16 on the neurocognitive network supporting semantic patients with first-ever stroke in the middle cerebral cognition. Unlike previous work, in this magnetoen- artery territory, affecting upper limb motor function, cephalography study we selected a group of patients 1-7 days (T0), 1 month (T1), and 3 months (T2) after with small lesions centered on the left anteroventral stroke, with concomitant clinical examination. Clini- temporal lobe before surgery. We then used an effec- cal test results improved significantly from T0 to T1 tive connectivity method (i.e., dynamic causal model- or T2. During recovery (at T1 and T2), the strength of ing) to investigate the consequences that these lesions temporo-parietal ≈ 10-Hz oscillations in the affected have on the functional interactions within the network. hemisphere (AH) was increased as compared with the This approach allowed us to evaluate the directional- unaffected hemisphere. Abnormal low-frequency mag- ity of the causal interactions among brain regions and netic activity (ALFMA) at ≈ 1 Hz in the AH was detected their associated connectivity strengths. Behaviorally, in the perilesional cortex in seven patients at T0. In we found that semantic processing was altered when four of these, ALFMA persisted at T2. In patients with patients were compared with a strictly matched group ALFMA, the lesion size was significantly larger than in of controls. Dynamic causal modeling for event related the rest of the patients, and worse clinical outcome was responses revealed that picture naming was associated observed in patients with persisting ALFMA. Our results

207 indicate that temporo-parietal ≈ 10-Hz oscillations toencephalography; nerve injury; neural regeneration; are enhanced in the AH during recovery from stroke. regeneration Moreover, stroke causes ALFMA, which seems to persist in patients with worse clinical outcome. (23593414) Neural Regen Res (2015), Vol. 7, No. 24, pp. 1906-13

PLoS One (2013), Vol. 8, No. 4, pp. e61146 Resting state α-band functional connectivity and recovery after stroke Changes of auditory evoked magnetic fields in patients after acute cerebral infarction using Westlake, KP; Hinkley, LB; Bucci, M; Guggisberg, AG; magnetoencephalography Byl, N; Findlay, AM; Henry, RG; Nagarajan, SS

Sun, Z; Song, C; Sun, J; Li, L; Dong, Y; Department of Radiology and Biomedical Imaging, Universi- Wang, J; Wu, J; Cui, W; Wu, Y; Lv, P ty of California, San Francisco, 513 Parnassus s362, Box 0628, San Francisco, CA 94143, USA. Department of Neurology, Hebei Medical University, Shiji- azhuang 050017, Hebei Province, China. ABSTRACT: After cerebral ischemia, disruption and subsequent reorganization of functional connections ABSTRACT: Auditory evoked magnetic fields were occur both locally and remote to the lesion. However, recorded from 15 patients with acute cerebral infarc- the unpredictable timing and extent of sensorimotor tion and 11 healthy volunteers using magnetoencepha- recovery reflects a gap in understanding of these un- lography. The auditory stimuli of 2 kHz pure tone were derlying neural mechanisms. We aimed to identify the binaurally presented with an interstimulus interval of plasticity of alpha-band functional neural connections 1 second. The intensity of stimuli was 90 dB and the within the perilesional area and the predictive value of stimulus duration was 8 ms. The results showed that functional connectivity with respect to motor recovery the M100 was the prominent response, peaking ap- of the upper extremity after stroke. Our results show proximately 100 ms after stimulus onset in all subjects. improvements in upper extremity motor recovery in re- It originated from the area close to Heschl's gyrus. In lation to distributed changes in MEG-based alpha band the patient group, the peak latency of M100 responses functional connectivity, both in the perilesional area was significantly prolonged, and the mean strength and contralesional cortex. Motor recovery was found of equivalent current dipole was significantly smaller to be predicted by increased connectivity at baseline in the affected hemisphere. The three-dimensional in the ipsilesional somatosensory area, supplementary inter-hemispheric difference of the M100 positions was motor area, and cerebellum, contrasted with reduced increased in the patient group. Our experimental find- connectivity of contralesional motor regions, after con- ings suggested that impairment of cerebral function in trolling for age, stroke onset-time and lesion size. These patients with acute ischemic stroke can be detected us- findings support plasticity within a widely distributed ing magnetoencephalography with the higher spatial neural network and define brain regions in which the resolution and temporal resolution. Magnetoencepha- extent of network participation predicts post-stroke lography could provide objective and sensitive indices recovery potential. (22750324) to estimate auditory cortex function in patients with acute cerebral infarction. (25624818) Exp Neurol (2012), Vol. 237, No. 1, pp. 160-9

Keywords: Heschl's gyrus; acute cerebral infarction; auditory evoked magnetic fields; brain functional impairment; Effect of afferent input on motor cortex excitability cerebral ischemia; equivalent current dipole; magne- during stroke recovery

Laaksonen, K; Kirveskari, E; Mäkelä, JP; Kaste, M; Mus- tanoja, S; Nummenmaa, L; Tatlisumak, T; Forss, N

208 Brain Research Unit, O.V. Lounasmaa Laboratory, School cal signals derived from MEG were observed here at of Science, Aalto University, FI-00076 Aalto, Espoo, Finland. very different frequency scales. Slow signals below 0.1 [email protected] Hz were extracted by independent component analysis and are associated with the sustained activation of OBJECTIVE: Afferent input is proposed to mediate its the motor cortex, the dcMEG motor activation. MEG- effect on motor functions by modulating the excit- EMG coupling phenomena in the 10-30 Hz range were ability of the motor cortex. We aimed to clarify - in a analyzed using the imaginary part of coherency and longitudinal study - how afferent input affects motor are attributed to cortico-muscular coupling driving the cortex excitability after stroke and how it is associated muscles. Additionally a signal from the somatosensory with recovery of hand function. METHODS: The mo- cortex due to an electrical stimulation at the wrist, the tor cortex excitability was studied by measuring the N20m, was recorded as a physiological marker. Field reactivity of the motor cortex beta rhythm to somato- maps and time series associated with the three types of sensory stimulation. We recorded the amplitude of signals are presented for one patient and one control the suppression and subsequent rebound of the beta subject as the signal quality of the patient data was oscillations during tactile finger stimulation with MEG not sufficient to achieve a group result. The feasibility in 23 first-ever stroke patients within one week and at 1 of a comprehensive electrophysiological measuring and 3 months after stroke, with concomitant evaluation and analysis procedure of the motor function for stroke of hand function. RESULTS: The strength of the beta research is demonstrated by the results. (22027256) rhythm rebound, suggested to reflect decreased motor cortex excitability, was weak in the affected hemi- Physiol Meas (2012), Vol. 32, No. 11, pp. 1737-46 sphere after stroke and it was subsequently increased during recovery. The rebound strength correlated with hand function tests in all recordings. CONCLUSION: Activation in parietal operculum parallels motor Motor cortex excitability is modulated by afferent input recovery in stroke after stroke. The motor cortex excitability is increased in the AH acutely after stroke and decreases in parallel Forss, N; Mustanoja, S; Roiha, K; Kirveskari, E; with recovery of hand function. SIGNIFICANCE: The Mäkelä, JP; Salonen, O; Tatlisumak, T; Kaste, M results implicate the importance of parallel recovery of both sensory and motor systems in functional recovery Brain Research Unit, Low Temperature Laboratory, Aalto after stroke. (22721651) University, Espoo, Finland. [email protected]

Clin Neurophysiol (2013), Vol. 123, No. 12, pp. 2429-36 ABSTRACT: Motor recovery after stroke requires continuous interaction of motor and somatosensory systems. Integration of somatosensory feedback with Characterization of motor and somatosensory motor programs is needed for the automatic adjust- function for stroke patients ment of the speed, range, and strength of the movement. We recorded somatosensory evoked fields (SEFs) Sander, TH; Leistner, S; Geisler, F; Mackert, BM; Trahms, L to tactile finger stimulation with whole-scalp magnetoencephalography in 23 acute stroke patients at 1 week, Physikalisch-Technische Bundesanstalt, Abbestrasse 2-12, 1 month, and 3 months after stroke to investigate how Berlin, Germany. [email protected] deficits in the somatosensory cortical network affect motor recovery. SEFs were generated in the contra- ABSTRACT: In a pilot study, stroke patients with a lateral primary somatosensory cortex (SI) and in the lesion related to the motor system were studied using bilateral parietal opercula (PO) in controls and patients. magnetoencephalography (MEG) and electromyog- In the patients, SI amplitude or latency did not correlate raphy (EMG). The patients performed sustained finger with any of the functional outcome measures used. In movements for 30 s followed by 30 s of rest and 20 contrast, the contralateral PO (cPO) amplitude to the repetitions of this sequence in total. Task-related corti- affected hand stimuli correlated significantly with hand

209 function in the acute phase and during recovery; the generators coordinate the pharyngeal swallowing weaker the PO activation, the clumsier the hand was. phase. The observed right hemispheric lateralization in At 1 and 3 months, enhancement of the cPO activa- brainstem stroke can therefore be interpreted as acute tion paralleled the improvement of the hand function. cortical compensation of subcortically caused dyspha- Whole-scalp magnetoencephalography measurements gia. The reduction of activation in brainstem stroke pa- revealed that dysfunction of somatosensory cortical tients and dysphagic patients with cortical stroke could areas distant from the ischemic lesion may affect the be explained in terms of diaschisis. (21392404) motor recovery. Activation strength of the PO paralleled motor recovery after stroke, suggesting that the BMC Neurol (2011), Vol. 11, pp. 34 PO area is an important hub in mediating modulatory afferent input to motor cortex. (21425393) Auditory and cognitive deficits associated Hum Brain Mapp (2012), Vol. 33, No. 3, pp. 534-41 with acquired amusia after stroke: a magnetoencephalography and neuropsychological follow-up study Cortical swallowing processing in early subacute stroke Särkämö, T; Tervaniemi, M; Soinila, S; Autti, T; Silven- noinen, HM; Laine, M; Hietanen, M; Pihko, E Teismann, IK; Suntrup, S; Warnecke, T; Steinsträter, O; Fischer, M; Flöel, A; Ringelstein, EB; Pantev, C; Dziewas, R Cognitive Brain Research Unit, Institute of Behavioural Sci- ences, University of Helsinki, Helsinki, Finland. teppo.sarka- Department of Neurology, University of Muenster, Albert- [email protected] Schweitzer-Str,33, 48149 Muenster, Germany. i.teismann@ uni-muenster.de ABSTRACT: Acquired amusia is a common disorder after damage to the middle cerebral artery (MCA) BACKGROUND: Dysphagia is a major complication territory. However, its neurocognitive mechanisms, in hemispheric as well as brainstem stroke patients especially the relative contribution of perceptual and causing aspiration pneumonia and increased mortality. cognitive factors, are still unclear. We studied cognitive Little is known about the recovery from dysphagia after and auditory processing in the amusic brain by per- stroke. The aim of the present study was to determine forming neuropsychological testing as well as magne- the different patterns of cortical swallowing process- toencephalography (MEG) measurements of frequency ing in patients with hemispheric and brainstem stroke and duration discrimination using magnetic mismatch with and without dysphagia in the early subacute negativity (MMNm) recordings. Fifty-three patients with phase. METHODS: We measured brain activity by a left (n = 24) or right (n = 29) hemisphere MCA stroke mean of whole-head MEG in 37 patients with differ- (MRI verified) were investigated 1 week, 3 months, and ent stroke localisation 8.2+/-4.8 days after stroke to 6 months after the stroke. Amusia was evaluated using study changes in cortical activation during self-paced the Montreal Battery of Evaluation of Amusia (MBEA). swallowing. An age matched group of healthy subjects We found that amusia caused by right hemisphere served as controls. Data were analyzed by means of damage (RHD), especially to temporal and frontal areas, synthetic aperture magnetometry and group analyses was more severe than amusia caused by left hemi- were performed using a permutation test. RESULTS: sphere damage (LHD). Furthermore, the severity of Our results demonstrate strong bilateral reduction of amusia was found to correlate with weaker frequency cortical swallowing activation in dysphagic patients MMNm responses only in amusic RHD patients. Addi- with hemispheric stroke. In hemispheric stroke without tionally, within the RHD subgroup, the amusic patients dysphagia, bilateral activation was found. In the small who had damage to the auditory cortex (AC) showed group of patients with brainstem stroke we observed a worse recovery on the MBEA as well as weaker MMNm reduction of cortical activation and a right hemispheric responses throughout the 6-month follow-up than the lateralization. CONCLUSION: Bulbar central pattern non-amusic patients or the amusic patients without AC

210 damage. Furthermore, the amusic patients both with amplitudes were significantly correlated with improve- and without AC damage performed worse than the ment on several behavioral indices of motor function. non-amusic patients on tests of working memory, at- DISCUSSION: These case-series data indicate that tention, and cognitive flexibility. These findings suggest oscillatory MEG responses may be useful in gauging domain-general cognitive deficits to be the primary plasticity in motor cortices following therapy in stroke mechanism underlying amusia without AC damage patients. (20947491) whereas amusia with AC damage is associated with both auditory and cognitive deficits. (21152040) Neurorehabil Neural Repair (2011), Vol. 25, No. 2, pp. 188- 93 PLoS One (2011), Vol. 5, No. 12, pp. e15157

Reorganization of the primary somatosensory Oscillatory MEG motor activity reflects therapy- cortex during stroke recovery related plasticity in stroke patients Roiha, K; Kirveskari, E; Kaste, M; Mustanoja, S; Wilson, TW; Fleischer, A; Archer, D; Hayasaka, S; Sawaki, L Mäkelä, JP; Salonen, O; Tatlisumak, T; Forss, N

Wake Forest University School of Medicine, Winston-Salem, Brain Research Unit, Low Temperature Laboratory, Aalto Uni- North Carolina, USA. [email protected] versity, FI-02015 Aalto, Espoo, Finland. [email protected]

BACKGROUND: A goal of stroke rehabilitation is to OBJECTIVE: Animal and human studies have indicated harness the capacity of the brain to reorganize follow- that stroke induces reorganization of the motor and so- ing neurological damage and enable restoration of matosensory cortices. We aimed to clarify how changes function. OBJECTIVE: To understand how neural oscil- in the primary somatosensory (SI) cortex correlate with latory motor responses change following a therapeutic stroke recovery. METHODS: We recorded somatosenso- intervention and to illuminate whether these neuro- ry evoked fields (SEFs) with magnetoencephalography physiological alterations correlate with improvements from 15 patients with stroke affecting upper extremity on behavioral measurements. METHODS: Magneto- motor function. The size of the hand representation encephalography (MEG) was used to evaluate plastic- in the SI cortex was calculated from the Euclidean ity in motor networks following 2 weeks of intensive distance between the sources of SEFs to thumb and task-oriented therapy, which was paired with sham or little finger tactile stimulation. The measurements peripheral nerve stimulation (PNS). Patients completed were made at 1-7 days (T₀), at 1 (T₁), and at 3 months unilateral finger tapping before and 3 weeks after (T₂) after stroke, with concomitant evaluation of hand therapy as whole-head MEG data were acquired. MEG function. RESULTS: The affected hand function was data were imaged using beamforming, and the result- improved at T₁ and T₂ compared with T₀ (p<0.01). At T₁, ing event-related synchronizations and desynchroniza- the SI hand representation in the affected hemisphere tions (ERSs/ERDs) were subjected to region-of-interest was enlarged compared with T₀ or T₂ (12.6±0.8 at T₁ vs. (ROI) analyses. For each ROI, the authors compared the 9.6±0.8 mm at T₀ and 10.2±0.8 at T₂, p<0.05). In patients baseline and postintervention MEG response ampli- with subcortical infarction, the increase in cortical tude, volume, and peak location for premovement β representation at T₁ correlated strongly with impair- ERD, movement-onset γ ERS, and postmovement β ment of hand function (r=0.8, p<0.01). CONCLUSION: ERS. RESULTS: Following therapy, all patients showed Reorganization of the SI cortex provokes a transient reduced postmovement β ERS response amplitudes in enlargement of the hand representation that normaliz- bilateral precentral gyri and reduced γ ERS amplitudes es as hand functions are regained. SIGNIFICANCE: The in the precentral gyrus of the affected hemisphere. This temporal evolution of plastic changes during stroke latter response also distinguished treatment groups, recovery might be useful in evaluating motor recovery. as the posttherapy γ reduction was greater in patients (20673646) who received PNS. Finally, both β and γ response

211 Clin Neurophysiol (2011), Vol. 122, No. 2, pp. 339-45 J Cogn Neurosci (2010), Vol. 22, No. 12, pp. 2716-27

Music and speech listening enhance the recovery of Neuronal functionality assessed by early sensory processing after stroke magnetoencephalography is related to oxidative stress system in acute ischemic stroke Särkämö, T; Pihko, E; Laitinen, S; Forsblom, A; Soinila, S; Mikkonen, M; Autti, T; Silvennoinen, HM; Erkkilä, Assenza, G; Zappasodi, F; Squitti, R; Altamura, C; J; Laine, M; Peretz, I; Hietanen, M; Tervaniemi, M Ventriglia, M; Ercolani, M; Quattrocchi, CC; Lupoi, D; Passarelli, F; Vernieri, F; Rossini, PM; Tecchio, F Cognitive Brain Research Unit, Department of Psychology, University of Helsinki, Finland. [email protected] Dipartimento di Neuroscienze, Università Campus Bio-Medi- co, Rome, Italy. [email protected] ABSTRACT: Our surrounding auditory environment has a dramatic influence on the development of basic ABSTRACT: The hypoxic brain damage induced by auditory and cognitive skills, but little is known about stroke is followed by an ischemia-reperfusion injury how it influences the recovery of these skills after modulated by oxidative stress. Magnetoencephalo- neural damage. Here, we studied the long-term effects graphic (MEG) recording of rest and evoked cortical of daily music and speech listening on auditory sensory activities is a sensitive method to analyse functional memory after middle cerebral artery (MCA) stroke. In changes following the acute ischemic damage. We the acute recovery phase, 60 patients who had middle aimed at investigating whether MEG signals are related cerebral artery stroke were randomly assigned to a mu- to oxidative stress compounds in acute stroke. Eigh- sic listening group, an audio book listening group, or teen stroke patients and 20 controls were enrolled. All a control group. Auditory sensory memory, as indexed subjects underwent MEG assessment to record back- by the magnetic MMN (MMNm) response to changes in ground activity and somatosensory evoked responses sound frequency and duration, was measured 1 week (M20 and M30) of rolandic regions, neurological exami- (baseline), 3 months, and 6 months after the stroke nation assessed by National Institute of Health Stroke with whole-head magnetoencephalography record- Scale (NIHSS) and plasmatic measurement of copper, ings. Fifty-four patients completed the study. Results iron, zinc, ceruloplasmin, transferrin, total peroxides showed that the amplitude of the frequency MMNm and Total Anti-Oxidant Status. Magnetic Resonance increased significantly more in both music and audio was performed to estimate the lesion site and volume. book groups than in the control group during the Delta power and M20 equivalent current dipole (ECD) 6-month poststroke period. In contrast, the duration strength in the affected hemisphere (AH) correlated MMNm amplitude increased more in the audio book with NIHSS scores (respectively, rho=.692, p=.006 and group than in the other groups. Moreover, changes in rho=-.627, p=.012) and taken together explained 67% the frequency MMNm amplitude correlated significant- of NIHSS variability (p=.004). Higher transferrin and ly with the behavioral improvement of verbal memory lower peroxides levels correlated with better clinical and focused attention induced by music listening. status (respectively, rho=-.600, p=.014 and rho=.599, These findings demonstrate that merely listening to p=.011). Transferrin also correlated with AH M20 ECD music and speech after neural damage can induce strength (rho=.638 p=.014) and inversely with AH long-term plastic changes in early sensory processing, delta power (rho=-.646 p=.023) and the lesion volume, which, in turn, may facilitate the recovery of higher especially in cortico-subcortical stroke (p=.037). Our cognitive functions. The neural mechanisms potentially findings strengthen MEG reliability in honing the evalu- underlying this effect are discussed. (19925203) ation of neuronal damage in acute ischemic stroke also demonstrating an association between the MEG parameters most representing the clinical status and the oxidative stress compounds. Our results meet at

212 a possible protective role of transferrin in limiting the alterations related to atherosclerotic occlusive vascular oxidative damage in acute stroke. (19010427) disease. (18635836)

Neuroimage (2009), Vol. 44, No. 4, pp. 1267-73 Stroke (2008), Vol. 39, No. 10, pp. 2769-75

Ipsilateral motor-related hyperactivity in patients Aberrant cortical functionality and somatosensory with cerebral occlusive vascular disease deficits after stroke

Oshino, S; Kato, A; Hirata, M; Kishima, H; Castillo, EM; Boake, C; Breier, JI; Men, D; Gar- Saitoh, Y; Fujinaka, T; Yoshimine, T za, HM; Passaro, A; Papanicolaou, AC

Department of Neurosurgery, Osaka University Graduate Center for Clinical Neurosciences, Department of Pediatrics, School of Medicine, Suita, Osaka, Japan. s-oshino@nsurg. The University of Texas Medical School, Houston, Texas 77030, med.osaka-u.ac.jp USA. [email protected]

BACKGROUND AND PURPOSE: Cerebral occlusive ABSTRACT: Damage and/or disconnection of the vascular disease is an established risk factor for isch- primary somatosensory cortex (SI) after stroke leads emic stroke; however, little is known about its effects to deficits in touch perception. We used magnetoen- on brain function in patients without stroke. To detect cephalography to test whether specific patterns of possible functional alterations, we used magnetoen- functionality of the somatosensory cortex are associat- cephalography and evaluated cerebral cortical activity ed with different degrees of postacute somatosensory during hand motor tasks in a group of such patients. deficit. Nineteen postacute unilateral stroke patients Method- Event-related desynchronization (ERD) during suffering different degrees of somatosensory deficit (six hand-grasping and self-paced finger-tapping tasks nonexistent, six moderate, and seven severe) and eight was examined in 38 right-hand-dominant patients aged-matched controls underwent high-resolution MRI with occlusive disease of the internal carotid or middle and whole-head magnetoencephalography recordings cerebral artery caused by diverse pathologies (ath- of somatosensory-evoked fields and of spontaneous erosclerosis, 28; others, 10) and in 8 control subjects. slow oscillatory activity. Amplitude of SI activation after All patients had no apparent motor impairments. The tactile stimulation in the affected and nonaffected spatial distribution and the intensity (t value) of ERD hemispheres and delta dipole density (DDD) in the in the beta band were analyzed with synthetic aper- postcentral areas were estimated and compared across ture magnetometry. According to the laterality index the four groups. Severe postacute somatosensory calculated from the ratios of peak t values on ipsilateral deficit was accompanied, in all cases, with absence of SI vs contralateral (with respect to the hand movement) responses to stimulation in the affected hand and a sig- hemispheres, the distribution of ERD was classified into nificant asymmetry in postcentral DDD toward the af- 3 patterns: contralateral, bilateral, and ipsilateral. RE- fected hemisphere. Patients with moderate sensory loss SULTS: Abnormal ipsilateral dominant distribution of showed asymmetry in their postcentral DDD (four cases beta ERD was observed significantly more often during toward the affected hemisphere and two toward the contralesional hand grasping in patients with athero- unaffected) but no atypical amplitudes in SI activation. sclerotic vascular lesion. It was accompanied by sig- Recordings in stroke patients without somatosensory nificantly higher t values on the ipsilateral hemisphere, deficit did not differ from those obtained in controls without a decrease in those on the contralateral side. for SI amplitude or postcentral DDD. In stroke patients, The age, the rating scores of periventricular hyperinten- amplitude of SI responses and postcentral DDD show sity, and ventricular size were all significantly higher in a negative correlation. Lack of activation of SI cortex patients who showed the ipsilateral-dominant pattern. after stimulation of the affected hand and spontaneous CONCLUSIONS: Abnormal ipsilateral hyperactivity slow oscillatory activity in postcentral areas are neuro- may indicate the presence of subclinical functional

213 physiological correlates of somatosensory deficit in the postacute phase of stroke. (18469729)

J Clin Neurophysiol (2008), Vol. 25, No. 3, pp. 132-8

Interhemispheric asymmetry of primary hand representation and recovery after stroke: a MEG study

Tecchio, F; Zappasodi, F; Tombini, M; Cau- lo, M; Vernieri, F; Rossini, PM

ISTC-CNR, Unità MEG, Dip. Neuroscienze, Fatebenefratelli Hospital, 39, Isola Tiberina, 00186 Rome, Italy. franca.tec- [email protected]

ABSTRACT: In patients affected by monohemispheric stroke in the middle cerebral artery territory, who do not regain a normal neurological function, a positive contribution to the clinical recovery seems to be made by the involvement of primary hand representation areas in the affected hemisphere (AH), excessively asymmetric to its homologous in the unaffected hemisphere (UH). We investigated primary sensory hand areas in 41 chronic patients who had improved their clinical status without reaching complete recovery. The location and strength of the first cerebral sources activated by a contralateral galvanic median nerve stimulation (M20 and M30) were evaluated in both hemispheres, together with their interhemispheric differences. The source displacement in the AH with respect to the UH was positively correlated with clinical recovery (Spearman's rho=0.584, p=0.003). The excessive interhemispheric asymmetry - as defined on the basis of reference ranges in the healthy population - could be interpreted as the involvement of neuronal pools in the AH outside the hand 'omega zone' of the Rolandic sulcus, revealing the presence of plasticity phenomena. The present data provide support to a positive role of cerebral plasticity phenomena, partially contributing to post-stroke recovery in patients unable to achieve normal neurological function. (17543542)

Neuroimage (2007), Vol. 36, No. 4, pp. 1057-64

214 Tinnitus Biomed Res Int (2016), Vol. 2015, pp. 489619

Source-Space Cross-Frequency Amplitude- Impact of Spectral Notch Width on Amplitude Coupling in Tinnitus Neurophysiological Plasticity and Clinical Effectiveness of the Tailor-Made Notched Music Zobay, O; Adjamian, P Training

MRC Institute of Hearing Research, University Park, Notting- Wunderlich, R; Lau, P; Stein, A; Engell, A; ham NG7 2RD, UK. Wollbrink, A; Rudack, C; Pantev, C

ABSTRACT: The thalamocortical dysrhythmia (TCD) Institute for Biomagnetism and Biosignalanalysis, University model has been influential in the development of theo- Hospital of Münster, Münster, Germany; Institute for Physio- retical explanations for the neurological mechanisms logical Psychology, University of Bielefeld, Bielefeld, Germany. of tinnitus. It asserts that thalamocortical oscillations lock a region in the auditory cortex into an ectopic ABSTRACT: Tinnitus, the ringing in the ears that is un- slow-wave theta rhythm (4-8 Hz). The cortical area related to any external source, causes a significant loss surrounding this region is hypothesized to generate in quality of life, involving sleep disturbance and de- abnormal gamma (>30 Hz) oscillations ("edge effect") pression for 1 to 3% of the general population. While in giving rise to the tinnitus percept. Consequently, the the first place tinnitus may be triggered by damage to model predicts enhanced cross-frequency coherence the inner ear cells, the neural generators of subjective in a broad range between theta and gamma. In this tinnitus are located in central regions of the nervous magnetoencephalography study involving tinnitus and system. A loss of lateral inhibition, tonotopical reorga- control cohorts, we investigated this prediction. Using nization and a gain-increase in response to the sensory beamforming, cross-frequency amplitude-amplitude deprivation result in hypersensitivity and hyperactivity coupling (AAC) was computed within the auditory in certain regions of the auditory cortex. In the tailor- cortices for frequencies (f1, f2) between 2 and 80 Hz. made notched music training (TMNMT) patients listen We find the AAC signal to decompose into two distinct to music from which the frequency spectrum of the components at low (f1, f2 < 30 Hz) and high (f1, f2 > tinnitus has been removed. This evokes strong lateral 30 Hz) frequencies, respectively. Studying the correla- inhibition from neurons tuned to adjacent frequen- tion of AAC with several key covariates (age, hearing cies onto the neurons involved in the tinnitus percept. level (HL), tinnitus handicap and duration, and HL at A reduction of tinnitus loudness and tinnitus-related tinnitus frequency), we observe a statistically significant neural activity was achieved with TMNMT in previ- association between age and low-frequency AAC. Con- ous studies. As the effect of lateral inhibition depends trary to the TCD predictions, however, we do not find on the bandwidth of the notch, in the current study any indication of statistical differences in AAC between we altered the notch width to find the most effective tinnitus and controls and thus no evidence for the notch width for TMNMT. We compared 1-octave notch predicted enhancement of cross-frequency coupling in width with ½-octave and ¼-octave. Participants chose tinnitus. (26665004) their favorite music for the training that included three month of two hours daily listening. The outcome was measured by means of standardized questionnaires and magnetoencephalography. We found a general reduction of tinnitus distress in all administered tinnitus questionnaires after the training. Additionally, tinnitus- related neural activity was reduced after the training. Nevertheless, notch width did not have an influence on the behavioral or neural effects of TMNMT. This could

215 be due to a non-linear resolution of lateral inhibition in cortical area. Overall, inhibition of tinnitus related neu- high frequencies. (26406446) ral activity could be strengthened in people affected with tinnitus by increasing spectral energy contrast in PLoS One (2016), Vol. 10, No. 9, pp. e0138595 TMNM, confirming the concepts of inhibition-induced plasticity via TMNM and spectral energy contrasts. (25951605) Enhancing inhibition-induced plasticity in tinnitus- -spectral energy contrasts in tailor-made notched PLoS One (2016), Vol. 10, No. 5, pp. e0126494 music matter

Stein, A; Engell, A; Lau, P; Wunderlich, R; Junghoefer, Source space estimation of oscillatory power and M; Wollbrink, A; Bruchmann, M; Rudack, C; Pantev, C brain connectivity in tinnitus

Institute for Biomagnetism and Biosignalanalysis, University Zobay, O; Palmer, AR; Hall, DA; Sereda, M; Adjamian, P of Muenster, Muenster, Germany. MRC Institute of Hearing Research, University Park, Notting- ABSTRACT: Chronic tinnitus seems to be caused by re- ham, United Kingdom. duced inhibition among frequency selective neurons in the auditory cortex. One possibility to reduce tinnitus ABSTRACT: Tinnitus is the perception of an internally perception is to induce inhibition onto over-activated generated sound that is postulated to emerge as a neurons representing the tinnitus frequency via tailor- result of structural and functional changes in the brain. made notched music (TMNM). Since lateral inhibition However, the precise pathophysiology of tinnitus is modifiable by spectral energy contrasts, the ques- remains unknown. Llinas' thalamocortical dysrhythmia tion arises if the effects of inhibition-induced plasticity model suggests that neural deafferentation due to can be enhanced by introducing increased spectral hearing loss causes a dysregulation of coherent activity energy contrasts (ISEC) in TMNM. Eighteen participants between thalamus and auditory cortex. This leads to a suffering from chronic tonal tinnitus, pseudo randomly pathological coupling of theta and gamma oscillatory assigned to either a classical TMNM or an ISEC-TMNM activity in the resting state, localised to the auditory group, listened to notched music for three hours on cortex where normally alpha oscillations should occur. three consecutive days. The music was filtered for both Numerous studies also suggest that tinnitus percep- groups by introducing a notch filter centered at the tion relies on the interplay between auditory and individual tinnitus frequency. For the ISEC-TMNM group non-auditory brain areas. According to the Global Brain a frequency bandwidth of 3/8 octaves on each side Model, a network of global fronto-parietal-cingulate of the notch was amplified, additionally, by about 20 areas is important in the generation and maintenance dB. Before and after each music exposure, participants of the conscious perception of tinnitus. Thus, the rated their subjectively perceived tinnitus loudness on distress experienced by many individuals with tinni- a visual analog scale. During the magnetoencephalo- tus is related to the top-down influence of this global graphic recordings, participants were stimulated with network on auditory areas. In this magnetoencepha- either a reference tone of 500 Hz or a test tone with a lographic study, we compare resting-state oscillatory carrier frequency representing the individual tinnitus activity of tinnitus participants and normal-hearing pitch. Perceived tinnitus loudness was significantly controls to examine effects on spectral power as well reduced after TMNM exposure, though TMNM type as functional and effective connectivity. The analysis is did not influence the loudness ratings. Tinnitus related based on beamformer source projection and an atlas- neural activity in the N1m time window and in the so based region-of-interest approach. We find increased called tinnitus network comprising temporal, parietal functional connectivity within the auditory cortices in and frontal regions was reduced after TMNM expo- the alpha band. A significant increase is also found for sure. The ISEC-TMNM group revealed even enhanced the effective connectivity from a global brain network inhibition-induced plasticity in a temporal and a frontal to the auditory cortices in the alpha and beta bands.

216 We do not find evidence of effects on spectral power. Neural Plast (2014), Vol. 2014, pp. 516163 Overall, our results provide only limited support for the thalamocortical dysrhythmia and Global Brain models of tinnitus. (25799178) Modulatory effects of spectral energy contrasts on lateral inhibition in the human auditory cortex: an PLoS One (2015), Vol. 10, No. 3, pp. e0120123 MEG study

Stein, A; Engell, A; Okamoto, H; Wollbrink, A; Playing and listening to tailor-made notched Lau, P; Wunderlich, R; Rudack, C; Pantev, C music: cortical plasticity induced by unimodal and multimodal training in tinnitus patients Institute for Biomagnetism and Biosignalanalysis, University Hospital, Münster, Germany. Pape, J; Paraskevopoulos, E; Bruchmann, M; Wollbrink, A; Rudack, C; Pantev, C ABSTRACT: We investigated the modulation of lateral inhibition in the human auditory cortex by means of Institute for Biomagnetism and Biosignalanalysis, University magnetoencephalography (MEG). In the first experi- of Münster, Malmedyweg 15, 48149 Münster, Germany. ment, five acoustic masking stimuli (MS), consisting of noise passing through a digital notch filter which was ABSTRACT: BACKGROUND. The generation and centered at 1 kHz, were presented. The spectral energy maintenance of tinnitus are assumed to be based on contrasts of four MS were modified systematically by maladaptive functional cortical reorganization. Listen- either amplifying or attenuating the edge-frequency ing to modified music, which contains no energy in the bands around the notch (EFB) by 30 dB. Additionally, range of the individual tinnitus frequency, can inhibit the width of EFB amplification/attenuation was varied the corresponding neuronal activity in the auditory (3/8 or 7/8 octave on each side of the notch). N1m and cortex. Music making has been shown to be a power- auditory steady state responses (ASSR), evoked by a ful stimulator for brain plasticity, inducing changes in test stimulus with a carrier frequency of 1 kHz, were multiple sensory systems. Using magnetoencepha- evaluated. A consistent dependence of N1m responses lographic (MEG) and behavioral measurements we upon the preceding MS was observed. The minimal evaluated the cortical plasticity effects of two months N1m source strength was found in the narrowest am- of (a) active listening to (unisensory) versus (b) learn- plified EFB condition, representing pronounced lateral ing to play (multisensory) tailor-made notched music inhibition of neurons with characteristic frequencies in nonmusician tinnitus patients. Taking into account corresponding to the center frequency of the notch the fact that uni- and multisensory trainings induce (NOTCH CF) in secondary auditory cortical areas. We different patterns of cortical plasticity we hypothesized tested in a second experiment whether an even nar- that these two protocols will have different affects. rower bandwidth of EFB amplification would result in RESULTS. Only the active listening (unisensory) group further enhanced lateral inhibition of the NOTCH CF. showed significant reduction of tinnitus related activity Here three MS were presented, two of which were mod- of the middle temporal cortex and an increase in the ified by amplifying 1/8 or 1/24 octave EFB width around activity of a tinnitus-coping related posterior parietal the notch. We found that N1m responses were again area. CONCLUSIONS. These findings indicate that active significantly smaller in both amplified EFB conditions as listening to tailor-made notched music induces greater compared to the NFN condition. To our knowledge, this neuroplastic changes in the maladaptively reorganized is the first study demonstrating that the energy and cortical network of tinnitus patients while additional width of the EFB around the notch modulate lateral integration of other sensory modalities during training inhibition in human secondary auditory cortical areas. reduces these neuroplastic effects. (24895541) Because it is assumed that chronic tinnitus is caused by a lack of lateral inhibition, these new insights could be used as a tool for further improvement of tinnitus treatments focusing on the lateral inhibition of neurons

217 corresponding to the tinnitus frequency, such as the Hear Res (2014), Vol. 302, pp. 50-9 tailor-made notched music training. (24349019)

PLoS One (2014), Vol. 8, No. 12, pp. e80899 rTMS induced tinnitus relief is related to an increase in auditory cortical alpha activity

Auditory evoked magnetic fields in individuals with Müller, N; Lorenz, I; Langguth, B; Weisz, N tinnitus Università degli Studi di Trento, Center for Mind/Brain Sci- Sereda, M; Adjamian, P; Edmondson- ences, Mattarello, Italy. [email protected] Jones, M; Palmer, AR; Hall, DA ABSTRACT: Chronic tinnitus, the continuous per- National Institute for Health Research Nottingham Hearing ception of a phantom sound, is a highly prevalent Biomedical Research Unit, School of Clinical Sciences, Univer- audiological symptom. A promising approach for the sity of Nottingham, Ropewalk House, 113 The Ropewalk, NG1 treatment of tinnitus is repetitive transcranial magnetic 5DU, Nottingham, UK. Magdalena.Sereda@nottingham. stimulation (rTMS) as this directly affects tinnitus-relat- ac.uk ed brain activity. Several studies indeed show tinnitus relief after rTMS, however effects are moderate and ABSTRACT: Some forms of tinnitus are likely to be vary strongly across patients. This may be due to a lack perceptual consequences of altered neural activity in of knowledge regarding how rTMS affects oscillatory the central auditory system triggered by damage to the activity in tinnitus sufferers and which modulations auditory periphery. Animal studies report changes in are associated with tinnitus relief. In the present study the evoked responses after noise exposure or ototoxic we examined the effects of five different stimulation drugs in inferior colliculus and auditory cortex. How- protocols (including sham) by measuring tinnitus loud- ever, human electrophysiological evidence is rather ness and tinnitus-related brain activity with Magneto- equivocal: increased, reduced or no difference in N1/ encephalography before and after rTMS. Changes in N1m evoked amplitudes and latencies in tinnitus par- oscillatory activity were analysed for the stimulated ticipants have been reported. The present study used auditory cortex as well as for the entire brain regarding magnetoencephalography to seek evidence for altered certain frequency bands of interest (delta, theta, alpha, evoked responses in people with tinnitus compared gamma). In line with the literature the effects of rTMS to controls (hearing loss matched and normal hearing) on tinnitus loudness varied strongly across patients. in four different stimulus categories (a control tone, a This variability was also reflected in the rTMS effects tone corresponding to the audiometric edge, to the on oscillatory activity. Importantly, strong reductions dominant tinnitus pitch and a tone within the area of in tinnitus loudness were associated with increases in hearing loss). Results revealed that amplitudes of the alpha power in the stimulated auditory cortex, while evoked responses differed depending on the tone an unspecific decrease in gamma and alpha power, category. N1m amplitude to the dominant tinnitus particularly in left frontal regions, was linked to an pitch and the frequency within the area of hearing loss increase in tinnitus loudness. The identification of alpha were reduced compared to the other two categories. power increase as main correlate for tinnitus reduction Given that tinnitus pitch is typically within the area of sheds further light on the pathophysiology of tinnitus. hearing loss, the differences in the evoked responses This will hopefully stimulate the development of more pattern in tinnitus participants seem to be related more effective therapy approaches. (23390539) to the hearing loss than to the presence of tinnitus. (23639335)

218 PLoS One (2013), Vol. 8, No. 2, pp. e55557 the 'no tinnitus with normal hearing' group. A planned comparison indicated that this effect was unlikely to be driven by the hearing loss alone, but could pos- Female sex workers in Africa: epidemiology sibly be a consequence of tinnitus and hearing loss. overview, data gaps, ways forward A further interpretative linkage to tinnitus was given by the result that the delta activity tended to reduce Ngugi, EN; Roth, E; Mastin, T; Nderitu, MG; Yasmin, S when tinnitus was masked. High-frequency activity in the gamma band (25-80 Hz) was not correlated with [email protected] tinnitus (or hearing loss). The findings partly support the thalamocortical dysrhythmia model and suggest ABSTRACT: {}[[1]]<> (23237069) that slow-wave (delta band) activity may be a more reliable correlate of tinnitus than high-frequency activity. SAHARA J (2013), Vol. 9, No. 3, pp. 148-53 (22791191)

J Assoc Res Otolaryngol (2013), Vol. 13, No. 5, pp. 715-31 Neuromagnetic indicators of tinnitus and tinnitus masking in patients with and without hearing loss Music-induced cortical plasticity and lateral Adjamian, P; Sereda, M; Zobay, O; Hall, DA; Palmer, AR inhibition in the human auditory cortex as foundations for tonal tinnitus treatment MRC Institute of Hearing Research, University Park, Notting- ham, UK NG7 2RD. [email protected] Pantev, C; Okamoto, H; Teismann, H

ABSTRACT: Tinnitus is an auditory phenomenon char- Institute for Biomagnetism and Biosignalanalysis, University acterised by the perception of a sound in the absence of Münster Münster, Germany. of an external auditory stimulus. Chronic subjective tinnitus is almost certainly maintained via central ABSTRACT: Over the past 15 years, we have studied mechanisms, and this is consistent with observed mea- plasticity in the human auditory cortex by means of sures of altered spontaneous brain activity. A number magnetoencephalography (MEG). Two main topics nur- of putative central auditory mechanisms for tinnitus tured our curiosity: the effects of musical training on have been proposed. The influential thalamocortical plasticity in the auditory system, and the effects of lat- dysrhythmia model suggests that tinnitus can be attrib- eral inhibition. One of our plasticity studies found that uted to the disruption of coherent oscillatory activity listening to notched music for 3 h inhibited the neuro- between thalamus and cortex following hearing loss. nal activity in the auditory cortex that corresponded to However, the extent to which this disruption specifi- the center-frequency of the notch, suggesting suppres- cally contributes to tinnitus or is simply a consequence sion of neural activity by lateral inhibition. Subsequent of the hearing loss is unclear because the necessary research on this topic found that suppression was matched controls have not been tested. Here, we rigor- notably dependent upon the notch width employed, ously test several predictions made by this model in that the lower notch-edge induced stronger attenu- four groups of participants (tinnitus with hearing loss, ation of neural activity than the higher notch-edge, tinnitus with clinically normal hearing, no tinnitus with and that auditory focused attention strengthened the hearing loss and no tinnitus with clinically normal hear- inhibitory networks. Crucially, the overall effects of ing). Magnetoencephalography was used to measure lateral inhibition on human auditory cortical activity oscillatory brain activity within different frequency were stronger than the habituation effects. Based on bands in a 'resting' state and during presentation of a these results we developed a novel treatment strategy masking noise. Results revealed that low-frequency ac- for tonal tinnitus-tailor-made notched music training tivity in the delta band (1-4 Hz) was significantly higher (TMNMT). By notching the music energy spectrum in the 'tinnitus with hearing loss' group compared to around the individual tinnitus frequency, we intended

219 to attract lateral inhibition to auditory neurons involved group (n = 10) and a non-tinnitus group (n = 16). The in tinnitus perception. So far, the training strategy has latency and amplitude of the most prominent deflec- been evaluated in two studies. The results of the initial tion, N100m, was compared between the two groups. long-term controlled study (12 months) supported the RESULTS: There was a significant difference in the pure validity of the treatment concept: subjective tinnitus tone audiogram on the spasm side compared with the loudness and annoyance were significantly reduced af- non-spasm side. After stimulation on the spasm side, ter TMNMT but not when notching spared the tinnitus the amplitude of the N100m peak in the contralateral frequencies. Correspondingly, tinnitus-related auditory hemisphere was lower in the subjective tinnitus group evoked fields (AEFs) were significantly reduced after than in the non-tinnitus group. CONCLUSIONS: Our training. The subsequent short-term (5 days) training results indicate that MEG can detect differences in study indicated that training was more effective in cortical activity between hemifacial spasm patients the case of tinnitus frequencies ≤ 8 kHz compared to with and without tinnitus. This suggests that MEG can tinnitus frequencies >8 kHz, and that training should identify changes in cortical activity associated with be employed over a long-term in order to induce more non-motor symptoms. (22116454) persistent effects. Further development and evaluation of TMNMT therapy are planned. A goal is to transfer this Acta Neurochir (Wien) (2012), Vol. 154, No. 3, pp. 509-15 novel, completely non-invasive and low-cost treatment approach for tonal tinnitus into routine clinical practice. (22754508) Short and intense tailor-made notched music training against tinnitus: the tinnitus frequency Keywords: human auditory cortex; lateral inhibition; matters music-induced cortical plasticity; tailor-made notched music training; tonal tinnitus treatment Teismann, H; Okamoto, H; Pantev, C

Front Syst Neurosci (2012), Vol. 6, pp. 50 Institute for Biomagnetism and Biosignalanalysis, University of Muenster, Muenster, Germany. h.teismann@uni-muenster. de Assessment of non-motor hearing symptoms in hemifacial spasm using magnetoencephalography ABSTRACT: Tinnitus is one of the most common diseases in industrialized countries. Here, we developed Park, YS; Kim, BS; Lee, DK; Lee, SK; Kwon, and evaluated a short-term (5 subsequent days) and HC; Kim, K; Lee, YH; Chang, JW intensive (6 hours/day) tailor-made notched music training (TMNMT) for patients suffering from chronic, Department of Neurosurgery, Yonsei University College of tonal tinnitus. We evaluated (i) the TMNMT efficacy in Medicine, 134 Shinchon-Dong, Seodaemoon-Gu, Seoul, terms of behavioral and magnetoencephalographic Korea. outcome measures for two matched patient groups with either low (≤8 kHz, N = 10) or high (>8 kHz, N = 10) BACKGROUND: Hemifacial spasm patients often suf- tinnitus frequencies, and the (ii) persistency of the fer from non-motor symptoms such as tinnitus. These TMNMT effects over the course of a four weeks post- non-motor symptoms are known to be associated with training phase. The results indicated that the short- changes in cortical activity. Magnetoencephalography term intensive TMNMT took effect in patients with tin- (MEG) is a technique that can record brain activity nitus frequencies ≤8 kHz: subjective tinnitus loudness, noninvasively. To determine the usefulness of MEG in tinnitus-related distress, and tinnitus-related auditory assessing changes in cortical activity associated with cortex evoked activity were significantly reduced after non-motor hearing symptoms in hemifacial spasm TMNMT completion. However, in the patients with patients. METHODS: We used MEG to evaluate the tinnitus frequencies >8 kHz, significant changes were reactivity of the auditory cortex in 26 hemifacial spasm not observed. Interpreted in their entirety, the results patients. We divided patients into a subjective tinnitus also indicated that the induced changes in auditory

220 cortex evoked neuronal activity and tinnitus loudness nuities of hearing loss at high frequencies that were were not persistent, encouraging the application of particularly pronounced in the left ear. (21198988) the TMNMT as a longer-term training. The findings are essential in guiding the intended transfer of this neuro- Eur J Neurosci (2011), Vol. 33, No. 3, pp. 568-75 scientific treatment approach into routine clinical practice. (21935438) Mapping cortical hubs in tinnitus PLoS One (2012), Vol. 6, No. 9, pp. e24685 Schlee, W; Mueller, N; Hartmann, T; Keil, J; Lorenz, I; Weisz, N Rapid increases of gamma power in the auditory cortex following noise trauma in humans Department of Psychology, University of Konstanz, Germany. [email protected] Ortmann, M; Müller, N; Schlee, W; Weisz, N BACKGROUND: Subjective tinnitus is the perception Institute for Biomagnetism and Biosignalanalysis, University of a sound in the absence of any physical source. It has of Münster, Münster, Germany. [email protected] been shown that tinnitus is associated with hyperactivity of the auditory cortices. Accompanying this hyper- ABSTRACT: Tinnitus is an auditory perception in the activity, changes in non-auditory brain structures have absence of any external sound source. It has been sug- also been reported. However, there have been no stud- gested that tinnitus is related to enhanced synchroniza- ies on the long-range information flow between these tion of neuronal activity in the auditory cortex. Usually regions. RESULTS: Using Magnetoencephalography, we a hearing damage can be identified suggesting audito- investigated the long-range cortical networks of chron- ry deprivation to central auditory regions to be funda- ic tinnitus sufferers (n = 23) and healthy controls (n = mental for neurophysiological processes related to tin- 24) in the resting state. A beamforming technique was nitus. Until now, human research has been conducted applied to reconstruct the brain activity at source level on patients with chronic tinnitus (>6 months). However, and the directed functional coupling between all voxels neuronal activity accompanying auditory deprivation was analyzed by means of Partial Directed Coherence. and putatively tinnitus may not remain constant over Within a cortical network, hubs are brain structures that time, making it difficult to directly relate outcomes either influence a great number of other brain regions of current animal studies (acute tinnitus) to chronic or that are influenced by a great number of other brain tinnitus in humans, and vice versa. We investigated regions. By mapping the cortical hubs in tinnitus and 14 amateur rock musicians who frequently reported a controls we report fundamental group differences in short-term tinnitus immediately after band practice. the global networks, mainly in the gamma frequency Magnetoencephalographic resting-state recordings, range. The prefrontal cortex, the orbitofrontal cortex audiometry and tinnitus testing were performed at and the parieto-occipital region were core structures two separate occasions: with and without previous in this network. The information flow from the global exposure to loud music. Analyses revealed that tran- network to the temporal cortex correlated positively sient tinnitus was accompanied by temporary hearing with the strength of tinnitus distress. CONCLUSION: loss in both ears and increased gamma activity in the With the present study we suggest that the hyperactiv- right auditory cortex in 13 out of 14 cases. Additionally, ity of the temporal cortices in tinnitus is integrated in tinnitus frequency was strongly correlated to hearing a global network of long-range cortical connectivity. loss. Analogous to animal studies, our results show for Top-down influence from the global network on the the first time in humans that noise trauma leads rapidly temporal areas relates to the subjective strength of the to increased neuronal synchrony in the auditory cortex. tinnitus distress. (19930625) Importantly, the strongly right-lateralized effect implies that it does not reflect tinnitus percept per se. This could rather have been triggered by greater disconti-

221 BMC Biol (2010), Vol. 7, pp. 80 impact of this finding to tinnitus therapies using Tran- scranial Magnetic Stimulation (TMS). (19228390)

Abnormal resting-state cortical coupling in chronic BMC Neurosci (2009), Vol. 10, pp. 11 tinnitus

Schlee, W; Hartmann, T; Langguth, B; Weisz, N Using auditory steady state responses to outline the functional connectivity in the tinnitus brain Department of Psychology, University of Konstanz, Konstanz, Germany. [email protected] Schlee, W; Weisz, N; Bertrand, O; Hartmann, T; Elbert, T

BACKGROUND: Subjective tinnitus is characterized Department of Psychology, University of Konstanz, Konstanz, by an auditory phantom perception in the absence of Germany. [email protected] any physical sound source. Consequently, in a quiet environment, tinnitus patients differ from control BACKGROUND: Tinnitus is an auditory phantom participants because they constantly perceive a sound perception that is most likely generated in the cen- whereas controls do not. We hypothesized that this tral nervous system. Most of the tinnitus research has difference is expressed by differential activation of dis- concentrated on the auditory system. However, it was tributed cortical networks. RESULTS: The analysis was suggested recently that also non-auditory structures based on a sample of 41 participants: 21 patients with are involved in a global network that encodes subjec- chronic tinnitus and 20 healthy control participants. tive tinnitus. We tested this assumption using auditory To investigate the architecture of these networks, we steady state responses to entrain the tinnitus network used phase locking analysis in the 1-90 Hz frequency and investigated long-range functional connectivity range of a minute of resting-state MEG recording. We across various non-auditory brain regions. METHODS found: 1) For tinnitus patients: A significant decrease of AND FINDINGS: Using whole-head magnetoencepha- inter-areal coupling in the alpha (9-12 Hz) band and an lography we investigated cortical connectivity by increase of inter-areal coupling in the 48-54 Hz gamma means of phase synchronization in tinnitus subjects frequency range relative to the control group. 2) For and healthy controls. We found evidence for a deviating both groups: an inverse relationship (r = -.71) of the pattern of long-range functional connectivity in tinni- alpha and gamma network coupling. 3) A discrimina- tus that was strongly correlated with individual ratings tion of 83% between the patient and the control group of the tinnitus percept. Phase couplings between the based on the alpha and gamma networks. 4) An effect anterior cingulum and the right frontal lobe and phase of manifestation on the distribution of the gamma couplings between the anterior cingulum and the right network: In patients with a tinnitus history of less than parietal lobe showed significant condition x group 4 years, the left temporal cortex was predominant in interactions and were correlated with the individual tin- the gamma network whereas in patients with tinnitus nitus distress ratings only in the tinnitus condition and duration of more than 4 years, the gamma network was not in the control conditions. CONCLUSIONS: To the more widely distributed including more frontal and best of our knowledge this is the first study that dem- parietal regions. CONCLUSION: In the here presented onstrates existence of a global tinnitus network of long- data set we found strong support for an alteration of range cortical connections outside the central auditory long-range coupling in tinnitus. Long-range coupling system. This result extends the current knowledge of in the alpha frequency band was decreased for tin- how tinnitus is generated in the brain. We propose that nitus patients while long-range gamma coupling was this global extend of the tinnitus network is crucial for increased. These changes discriminate well between the continuos perception of the tinnitus tone and a tinnitus and control participants. We propose a tin- therapeutical intervention that is able to change this nitus model that integrates this finding in the current network should result in relief of tinnitus. (19005566) knowledge about tinnitus. Furthermore we discuss the

222 PLoS One (2009), Vol. 3, No. 11, pp. e3720 ments have been reported in the delta frequency band for tinnitus at rest, this result conforms to our assumption that a normalization of oscillatory properties of Transient reduction of tinnitus intensity is marked cortical networks is a prerequisite for attenuating the by concomitant reductions of delta band power tinnitus sensation. For RI to have therapeutic significance however, this normalization would have to be Kahlbrock, N; Weisz, N stabilized. (18199318)

Department of Psychology, University of Konstanz, Konstanz, BMC Biol (2008), Vol. 6, pp. 4 Germany. [email protected]

BACKGROUND: Tinnitus is an auditory phantom phenomenon characterized by the sensation of sounds without objectively identifiable sound sources. To date, its causes are not well understood. Previous research found altered patterns of spontaneous brain activity in chronic tinnitus sufferers compared to healthy controls, yet it is unknown whether these abnormal oscillatory patterns are causally related to the tinnitus sensation. Partial support for this notion comes from a neurofeedback approach developed by our group, in which significant reductions in tinnitus loudness could be achieved in patients who successfully normalized their patterns of spontaneous brain activity. The current work attempts to complement these studies by scrutinizing how modulations of tinnitus intensity alter ongoing oscillatory activity. RESULTS: In the present study the relation between tinnitus sensation and spontaneous brain activity was investigated using residual inhibition (RI) to reduce tinnitus intensity and source-space projected magnetencephalographic (MEG) data to index brain activity. RI is the sustained reduction (criteria: 50% for at least 30 s) in tinnitus loudness after cessation of a tonal tinnitus masker. A pilot study (n = 38) identified 10 patients who showed RI. A significant reduction of power in the delta (1.3-4.0 Hz) frequency band was observed in temporal regions during RI (p

223 224 Traumatic Brain Injuries Keywords: Low frequency activity; Magnetoencepha- lography (MEG); Oscillations; Repeated measurements; Resting-state; Traumatic brain injury (TBI) Theta-Band Oscillations as an Indicator of Mild Traumatic Brain Injury Brain Topogr (2019), Vol. 31, No. 6, pp. 1037-1046

Kaltiainen, H; Helle, L; Liljeström, M; Renvall, H; Forss, N Attentional dysfunction and recovery in concussion: Department of Neuroscience and Biomedical Engineering, effects on the P300m and contingent magnetic School of Science, Aalto University, P.O. Box 12200, 00076, variation Aalto, Espoo, Finland. [email protected]. Petley, L; Bardouille, T; Chiasson, D; Froese, P; Pat- ABSTRACT: Mild traumatic brain injury (mTBI) patients terson, S; Newman, A; Omisade, A; Beyea, S continue to pose a diagnostic challenge due to their diverse symptoms without trauma-specific changes a Biomedical Translational Imaging Centre (BIOTIC), IWK in structural imaging. We addressed here the possible Health Centre , Halifax, Nova Scotia , Canada. early changes in spontaneous oscillatory brain activity after mTBI, and their feasibility as an indicator of injury PRIMARY OBJECTIVE: To examine the effect of concus- in clinical evaluation. We recorded resting-state magne- sion on indices of attention using magnetoencepha- toencephalography (MEG) data in both eyes-open and lography. METHODS AND PROCEDURES: Thirteen pa- eyes-closed conditions from 26 patients (11 females tients were recruited from the emergency department and 15 males, aged 20-59) with mTBI 6 days-6 months and scanned within 3-6 days of injury. Five returned for after the injury, and compared their spontaneous follow-up scans one and three months post-injury. Thir- oscillatory activity to corresponding data from 139 teen healthy controls also completed testing. During healthy controls. Twelve of the patients underwent a MEG acquisition, participants performed the Attention follow-up measurement at 6 months. Ten of all patients Network Test (ANT). Cognitive evoked responses to were without structural lesions in MRI. At single-subject this task include a cue-evoked P300m, a contingent level, aberrant 4-7 Hz (theta) band activity exceeding magnetic variation (CMV) and a target-evoked P300m. the + 2 SD limit of the healthy subjects was visible in The Rivermead Postconcussion Symptom Question- 7 out of 26 patients; three out of the seven patients naire and Sport Concussion Assessment Tool (SCAT3) with abnormal theta activity were without any detect- were administered in all sessions. RESULTS: Patients able lesions in MRI. Of the patients that participated in suffering from concussion had slower response times the follow-up measurements, five showed abnormal and benefitted more from spatial cues than did con- theta activity in the first recording, but only two in the trols. Global activation for all three evoked responses second measurement. Our results suggest that aber- was lower for patients than controls. In a small sample rant theta-band oscillatory activity can provide an early of patients who returned for follow-up, the CMV and objective sign of brain dysfunction after mTBI. In 3/7 target P300m improved with recovery. CONCLUSIONS: patients, the slow-wave activity was transient and vis- MEG-evoked responses to the ANT reveal neurophysio- ible only in the first recording, urging prompt timing for logical evidence of attentional dysfunction within days the measurements in clinical settings. (30097835) of injury. A pattern of improvement was also observed over the course of three months for the P300m, while behavioural performance did not change significantly. Further development of this method may yield a useful adjunct to neurological examination for concussion diagnosis and monitoring. (29355389)

225 Keywords: ANT; MEG; Mtbi; attention network test; mag- PLoS Comput Biol (2017), Vol. 12, No. 12, pp. e1004914 netoencephalography; visual attention

Brain Inj (2019), Vol. 32, No. 4, pp. 464-473 Reduced prefrontal MEG alpha-band power in mild traumatic brain injury with associated posttraumatic stress disorder symptoms Detecting Mild Traumatic Brain Injury Using Resting State Magnetoencephalographic Connectivity Popescu, M; Hughes, JD; Popescu, EA; Riedy, G; DeGraba, TJ

Vakorin, VA; Doesburg, SM; da Cos- National Intrepid Center of Excellence, Walter Reed National ta, L; Jetly, R; Pang, EW; Taylor, MJ Military Medical Center, Bethesda, MD, USA.

Department of Biomedical Physiology and Kinesiology, OBJECTIVE: To determine if changes in cortical alpha- Simon Fraser University, Burnaby, British Columbia, Canada. band power in patients with mild traumatic brain injury (mTBI) are associated with the severity of their ABSTRACT: Accurate means to detect mild traumatic post-traumatic stress disorder (PTSD) symptoms, and if brain injury (mTBI) using objective and quantitative injury severity and level of exposure to psychologically measures remain elusive. Conventional imaging typi- traumatic events are predictors of these electrophysi- cally detects no abnormalities despite post-concussive ological changes. METHODS: Resting-state magneto- symptoms. In the present study, we recorded resting encephalographic recordings were analyzed in 32 pa- state magnetoencephalograms (MEG) from adults tients with mTBI. Alpha-band power was estimated for with mTBI and controls. Atlas-guided reconstruction of each patient in 68 cortical regions and was compared resting state activity was performed for 90 cortical and between groups of patients with low versus high PTSD subcortical regions, and calculation of inter-regional symptoms severity. RESULTS: Participants with high oscillatory phase synchrony at various frequencies PTSD symptom severity showed reduced alpha-band was performed. We demonstrate that mTBI is associ- power bilaterally in the superior and middle frontal gyri ated with reduced network connectivity in the delta and frontal poles, and in the left inferior frontal gyrus. and gamma frequency range (>30 Hz), together with Alpha-band power in bilateral middle frontal gyri and increased connectivity in the slower alpha band (8-12 frontal poles was negatively correlated with scores Hz). A similar temporal pattern was associated with cor- reflecting symptoms of emotional numbing. Loss of relations between network connectivity and the length consciousness (LOC) associated with mTBI and level of time between the injury and the MEG scan. Using of exposure to psychologically traumatic events were such resting state MEG network synchrony we were predictors of decreased prefrontal alpha-band power in able to detect mTBI with 88% accuracy. Classification some of these regions. CONCLUSION: Altered prefron- confidence was also correlated with clinical symptom tal alpha-band activity, shown to be partly explained by severity scores. These results provide the first evidence mTBI-related LOC, is associated with PTSD symptoms that imaging of MEG network connectivity, in com- severity. SIGNIFICANCE: Our findings will guide future bination with machine learning, has the potential to studies addressing the electrophysiological mecha- accurately detect and determine the severity of mTBI. nisms underlying a higher incidence of PTSD in patients (27906973) with mTBI. (27472543)

226 Keywords: Alpha-band oscillations; Magnetoencepha- Keywords: Biomarkers; Computational connectomics; lography; Post-traumatic stress disorder; Resting-state; Diagnosis; MEG; Mild traumatic brain injury; Tensors Traumatic brain injury Neuroimage Clin (2016), Vol. 9, pp. 519-31 Clin Neurophysiol (2017), Vol. 127, No. 9, pp. 3075-3085

Low-frequency connectivity is associated with mild Functional connectivity changes detected with traumatic brain injury magnetoencephalography after mild traumatic brain injury Dunkley, BT; Da Costa, L; Bethune, A; Jetly, R; Pang, EW; Taylor, MJ; Doesburg, SM Dimitriadis, SI; Zouridakis, G; Rezaie, R; Ba- bajani-Feremi, A; Papanicolaou, AC Department of Diagnostic Imaging, The Hospital for Sick Children, Toronto, Canada ; Neuroscience & Mental Health Artificial Intelligence and Information Analysis Laboratory, Program, The Hospital for Sick Children Research Institute, Department of Informatics, Aristotle University of Thes- Toronto, Canada. saloniki, 54124, Greece ; NeuroInformatics Group, Aristotle University of Thessaloniki, Greece. ABSTRACT: Mild traumatic brain injury (mTBI) occurs from a closed-head impact. Often referred to as concus- ABSTRACT: Mild traumatic brain injury (mTBI) may sion, about 20% of cases complain of secondary psy- affect normal cognition and behavior by disrupting the chological sequelae, such as disorders of attention and functional connectivity networks that mediate efficient memory. Known as post-concussive symptoms (PCS), communication among brain regions. In this study, we these problems can severely disrupt the patient's qual- analyzed brain connectivity profiles from resting state ity of life. Changes in local spectral power, particularly Magnetoencephalographic (MEG) recordings obtained low-frequency amplitude increases and/or peak alpha from 31 mTBI patients and 55 normal controls. We used slowing have been reported in mTBI, but large-scale phase-locking value estimates to compute functional connectivity metrics based on inter-regional amplitude connectivity graphs to quantify frequency-specific correlations relevant for integration and segregation in couplings between sensors at various frequency bands. functional brain networks, and their association with Overall, normal controls showed a dense network of disorders in cognition and behaviour, remain relatively strong local connections and a limited number of long- unexplored. Here, we used non-invasive neuroimaging range connections that accounted for approximately with magnetoencephalography to examine functional 20% of all connections, whereas mTBI patients showed connectivity in a resting-state protocol in a group with networks characterized by weak local connections mTBI (n = 20), and a control group (n = 21). We ob- and strong long-range connections that accounted served a trend for atypical slow-wave power changes for more than 60% of all connections. Comparison of in subcortical, temporal and parietal regions in mTBI, the two distinct general patterns at different frequen- as well as significant long-range increases in amplitude cies using a tensor representation for the connectivity envelope correlations among deep-source, temporal, graphs and tensor subspace analysis for optimal feature and frontal regions in the delta, theta, and alpha bands. extraction showed that mTBI patients could be sepa- Subsequently, we conducted an exploratory analysis of rated from normal controls with 100% classification patterns of connectivity most associated with variabil- accuracy in the alpha band. These encouraging findings ity in secondary symptoms of mTBI, including inat- support the hypothesis that MEG-based functional tention, anxiety, and depression. Differential patterns connectivity patterns may be used as biomarkers that of altered resting state neurophysiological network can provide more accurate diagnoses, help guide connectivity were found across frequency bands. This treatment, and monitor effectiveness of intervention in indicated that multiple network and frequency specific mTBI. (26640764) alterations in large scale brain connectivity may contribute to overlapping cognitive sequelae in mTBI. In

227 conclusion, we show that local spectral power content were found in cortical areas, consistent with cognitive can be supplemented with measures of correlations in impairments on exams. Results provide more objective amplitude to define general networks that are atypical evidence that there may be subtle changes to the neu- in mTBI, and suggest that certain cognitive difficulties robiological integrity of the brain that can be detected are mediated by disturbances in a variety of alterations by MEG. Further, these findings suggest that these in network interactions which are differentially ex- abnormalities are associated with cognitive outcomes pressed across canonical neurophysiological frequency and may account, at least in part, for long-term PCS in ranges. (25844315) those who have sustained an mTBI. (25808909)

Keywords: Anxiety; Attention; Depression; Functional con- Keywords: executive functioning; magnetoencephalogra- nectivity; Magnetoencephalography (MEG); Mild traumat- phy (MEG); mild traumatic brain injury (mTBI); neuropsy- ic brain injury (mTBI); Neural oscillations; Resting-state chological testing; postconcussive syndrome (PCS)

Neuroimage Clin (2016), Vol. 7, pp. 611-21 J Neurotrauma (2016), Vol. 32, No. 19, pp. 1510-21

Magnetoencephalography Slow-Wave Detection Delayed and disorganised brain activation detected in Patients with Mild Traumatic Brain Injury and with magnetoencephalography after mild traumatic Ongoing Symptoms Correlated with Long-Term brain injury Neuropsychological Outcome da Costa, L; Robertson, A; Bethune, A; Mac- Robb Swan, A; Nichols, S; Drake, A; Angeles, A; Donald, MJ; Shek, PN; Taylor, MJ; Pang, EW Diwakar, M; Song, T; Lee, RR; Huang, MX Division of Neurosurgery, Sunnybrook Hospital, University of 1 Research Services, VA San Diego Healthcare System , San Toronto, Toronto, Ontario, Canada Department of Medical Diego, California. Imaging, Sunnybrook Hospital, University of Toronto, Toronto, Ontario, Canada. ABSTRACT: Mild traumatic brain injury (mTBI) is common in the United States, accounting for as many as BACKGROUND: Awareness to neurocognitive issues af- 75-80% of all TBIs. It is recognized as a significant public ter mild traumatic brain injury (mTBI) is increasing, but health concern, but there are ongoing controversies re- currently no imaging markers are available for mTBI. garding the etiology of persistent symptoms post-mTBI. Advanced structural imaging recently showed micro- This constellation of nonspecific symptoms is referred structural tissue changes and axonal injury, mild but to as postconcussive syndrome (PCS). The present likely sufficient to lead to functional deficits. Magneto- study combined results from magnetoencephalogra- encephalography (MEG) has high temporal and spatial phy (MEG) and cognitive assessment to examine group resolution, combining structural and electrophysi- differences and relationships between brain activity ological information, and can be used to examine brain and cognitive performance in 31 military and civilian activation patterns of regions involved with specific individuals with a history of mTBI+PCS and 33 matched tasks. METHODS: 16 adults with mTBI and 16 matched healthy control subjects. An operator-free analysis was controls were submitted to neuropsychological testing used for MEG data to increase reliability of the tech- (Wechsler Abbreviated Scale of Intelligence (WASI); nique. Subjects completed a comprehensive neuro- Conners; Alcohol Use Disorders Identification Test psychological assessment, and measures of abnormal (AUDIT); Generalised Anxiety Disorder Seven-item Scale slow-wave activity from MEG were collected. Results (GAD-7); Patient Health Questionnaire (PHQ-9); Symp- demonstrated significant group differences on mea- tom Checklist and Symptom Severity Score (SCAT2)) sures of executive functioning and processing speed. and MEG while tested for mental flexibility (Intra-Extra In addition, significant correlations between slow-wave Dimensional set-shifting tasks). Three-dimensional activity on MEG and patterns of cognitive functioning maps were generated using synthetic aperture magne-

228 tometry beamforming analyses to identify differences we develop a voxel-based whole-brain MEG slow- in regional activation and activation times. Reaction wave imaging approach for detecting abnormality in times and accuracy between groups were compared patients with mTBI on a single-subject basis. A norma- using 2×2 mixed analysis of variance. FINDINGS: tive database of resting-state MEG source magnitude While accuracy was similar, patients with mTBI reaction images (1-4 Hz) from 79 healthy control subjects was time was delayed and sequence of activation of brain established for all brain voxels. The high-resolution regions disorganised, with involvement of extra regions MEG source magnitude images were obtained by our such as the occipital lobes, not used by controls. Ex- recent Fast-VESTAL method. In 84 mTBI patients with amination of activation time showed significant delays persistent post-concussive symptoms (36 from blasts, in the right insula and left posterior parietal cortex in and 48 from non-blast causes), our method detected patients with mTBI. CONCLUSIONS: Patients with mTBI abnormalities at the positive detection rates of 84.5%, showed significant delays in the activation of important 86.1%, and 83.3% for the combined (blast-induced areas involved in executive function. Also, more regions plus with non-blast causes), blast, and non-blast mTBI of the brain are involved in an apparent compensatory groups, respectively. We found that prefrontal, pos- effort. Our study suggests that MEG can detect subtle terior parietal, inferior temporal, hippocampus, and neural changes associated with cognitive dysfunction cerebella areas were particularly vulnerable to head and thus, may eventually be useful for capturing and trauma. The result also showed that MEG slow-wave tracking the onset and course of cognitive symptoms generation in prefrontal areas positively correlated with associated with mTBI. (25324505) personality change, trouble concentrating, affective la- bility, and depression symptoms. Discussion is provided Keywords: BRAIN MAPPING; COGNITIVE ELECTROPHYSIOL- regarding the neuronal mechanisms of MEG slow-wave OGY; HEAD INJURY generation due to deafferentation caused by axonal injury and/or blockages/limitations of cholinergic J Neurol Neurosurg Psychiatry (2015), Vol. 86, No. 9, pp. transmission in TBI. This study provides an effective way 1008-15 for using MEG slow-wave source imaging to localize affected areas and supports MEG as a tool for assisting the diagnosis of mTBI. (25009772) Single-subject-based whole-brain MEG slow-wave imaging approach for detecting abnormality in Keywords: Axonal injury; Blast; Magnetoencephalography; patients with mild traumatic brain injury Slow-wave; Traumatic brain injury

Huang, MX; Nichols, S; Baker, DG; Robb, A; Ange- Neuroimage Clin (2015), Vol. 5, pp. 109-19 les, A; Yurgil, KA; Drake, A; Levy, M; Song, T; McLay, R; Theilmann, RJ; Diwakar, M; Risbrough, VB; Ji, Z; Huang, CW; Chang, DG; Harrington, DL; Muzzatti, L; Complexity analysis of resting state Canive, JM; Christopher Edgar, J; Chen, YH; Lee, RR magnetoencephalography activity in traumatic brain injury patients Radiology, Research, and Psychiatry Services, VA San Diego Healthcare System, San Diego, CA, USA ; Department of Radi- Luo, Q; Xu, D; Roskos, T; Stout, J; Kull, L; Cheng, X; ology, University of California, San Diego, CA, USA. Whitson, D; Boomgarden, E; Gfeller, J; Bucholz, RD

ABSTRACT: Traumatic brain injury (TBI) is a leading 1 Department of Neurosurgery, Saint Louis University School cause of sustained impairment in military and civilian of Medicine, Saint Louis University , St. Louis, Missouri. populations. However, mild TBI (mTBI) can be difficult to detect using conventional MRI or CT. Injured brain ABSTRACT: Diagnosis of mild traumatic brain inju- tissues in mTBI patients generate abnormal slow-waves ries (TBIs) has been difficult because of the absence (1-4 Hz) that can be measured and localized by resting- of obvious focal brain lesions, using conventional state magnetoencephalography (MEG). In this study, computed tomography (CT) or magnetic resonance

229 imaging (MRI) scans, in a large percentage of TBIs. One scans during recovery from TBI. METHODS: Magne- useful measure that can characterize potential tissue toencephalography maps of functional connectivity and neural network damage objectively is Lempel-Ziv in the alpha (8- to 12-Hz) band from 21 patients who complexity (LZC) applied to magnetoencephalography sustained a TBI were compared with those from 18 age- (MEG) signals. LZC is a model-independent estimator and sex-matched controls. Regions of altered func- of system complexity that estimates the number of tional connectivity in each patient were detected in different patterns in a sequence. We hypothesized that automated fashion through atlas-based registration to because of the potential network damage, TBIs would the control database. The extent of reduced functional show a reduced level of complexity in regions that are connectivity in the patient group was tested for correla- impaired. We included 18 healthy controls and 18 mili- tions with clinical characteristics of the injury as well as tary veterans with TBI in the study. Resting state MEG with findings on 3-T MRI. Finally, the authors compared data were acquired, and the LZCs were analyzed across initial connectivity maps with 2-year follow-up func- the whole brain. Our results indicated reduced com- tional connectivity in a subgroup of 5 patients with TBI. plexity in multiple brain areas in TBI patients relative to RESULTS: Fourteen male and 7 female patients (17-53 the healthy controls. In addition, we detected several years old, median 29 years) were enrolled. By Glasgow neuropsychological measures associated with motor Coma Scale (GCS) criteria, 11 patients had mild, 1 had responses, visual perception, and memory, correlated moderate, and 3 had severe TBI, and 6 had no GCS with LZC, which likely explains some of the cognitive score recorded. On 3-T MRI, 16 patients had abnormal deficits in TBI patients. (23692211) findings attributable to the trauma and 5 had findings in the normal range. As a group, the patients with TBI J Neurotrauma (2014), Vol. 30, No. 20, pp. 1702-9 had significantly lower functional connectivity than controls (p < 0.01). Three of the 5 patients with normal findings on 3-T MRI showed regions of abnormally Resting state magnetoencephalography functional reduced MEG functional connectivity. No significant connectivity in traumatic brain injury correlations were seen between extent of functional disconnection and injury severity or posttraumatic Tarapore, PE; Findlay, AM; Lahue, SC; Lee, H; Honma, SM; symptoms (p > 0.05). In the subgroup undergoing Mizuiri, D; Luks, TL; Manley, GT; Nagarajan, SS; Mukherjee, P 2-year follow-up, the second MEG scan demonstrated a significantly lower percentage of voxels with decreased Department of Neurological Surgery, University of California, connectivity (p < 0.05) than the initial MEG scan. CON- San Francisco, California 94107-0946, USA. CLUSIONS: A rapid automated resting-state MEG imaging technique demonstrates abnormally decreased OBJECT: Traumatic brain injury (TBI) is one of the lead- functional connectivity that may persist for years after ing causes of morbidity worldwide. One mechanism by TBI, including cases classified as "mild" by GCS criteria. which blunt head trauma may disrupt normal cogni- Disrupted MEG connectivity can be detected even in tion and behavior is through alteration of functional some patients with normal findings on 3-T MRI. Analy- connectivity between brain regions. In this pilot study, sis of follow-up MEG scans in a subgroup of patients the authors applied a rapid automated resting state shows that, over time, the abnormally reduced connec- magnetoencephalography (MEG) imaging technique tivity can improve, suggesting neuroplasticity during suitable for routine clinical use to test the hypothesis the recovery from TBI. Resting state MEG deserves that there is decreased functional connectivity in pa- further investigation as a prognostic and predictive bio- tients with TBI compared with matched controls, even marker for TBI. (23600939) in cases of mild TBI. Furthermore, they posit that these abnormal reductions in MEG functional connectivity can be detected even in TBI patients without specific evidence of traumatic lesions on 3-T MR images. Finally, they hypothesize that the reductions of functional connectivity can improve over time across serial MEG

230 J Neurosurg (2013), Vol. 118, No. 6, pp. 1306-16 correlated significantly with the total post-concussive symptom scores in TBI patients. This study provides a foundation for using MEG low-frequency source imag- An automatic MEG low-frequency source imaging ing to support the clinical diagnosis of TBI. (22542638) approach for detecting injuries in mild and moderate TBI patients with blast and non-blast Neuroimage (2012), Vol. 61, No. 4, pp. 1067-82 causes

Huang, MX; Nichols, S; Robb, A; Angeles, A; Drake, Brain signal variability relates to stability of A; Holland, M; Asmussen, S; D'Andrea, J; Chun, behavior after recovery from diffuse brain injury W; Levy, M; Cui, L; Song, T; Baker, DG; Hammer, P; McLay, R; Theilmann, RJ; Coimbra, R; Diwakar, M; Raja Beharelle, A; Kovačević, N; McIntosh, AR; Levine, B Boyd, C; Neff, J; Liu, TT; Webb-Murphy, J; Farinpour, R; Cheung, C; Harrington, DL; Heister, D; Lee, RR Rotman Research Institute of Baycrest Centre, Toronto, Canada. [email protected] Radiology, Research, Rehab, and Psychiatry Services, VA San Diego Healthcare System, San Diego, CA, USA. mxhuang@ ABSTRACT: Variability or noise is an unmistakable fea- ucsd.edu ture of neural signals; however such fluctuations have been regarded as not carrying meaningful information ABSTRACT: Traumatic brain injury (TBI) is a leading or as detrimental for neural processes. Recent empirical cause of sustained impairment in military and civil- and computational work has shown that neural sys- ian populations. However, mild (and some moderate) tems with a greater capacity for information processing TBI can be difficult to diagnose because the injuries are able to explore a more varied dynamic repertoire, are often not detectable on conventional MRI or CT. and the hallmark of this is increased irregularity or Injured brain tissues in TBI patients generate abnormal variability in the neural signal. How this variability in low-frequency magnetic activity (ALFMA, peaked at 1-4 neural dynamics affects behavior remains unclear. Here, Hz) that can be measured and localized by magnetoen- we investigated the role of variability of magnetoencephalography (MEG). We developed a new automated cephalography signals in supporting healthy cognitive MEG low-frequency source imaging method and ap- functioning, measured by performance on an attention plied this method in 45 mild TBI (23 from combat-relat- task, in healthy adults and in patients with traumatic ed blasts, and 22 from non-blast causes) and 10 moder- brain injury. As an index of variability, we calculated ate TBI patients (non-blast causes). Seventeen of the multiscale entropy, which quantifies the temporal patients with mild TBI from blasts had tertiary injuries predictability of a time series across progressively resulting from the blast. The results show our method more coarse time scales. We found lower variability in detected abnormalities at the rates of 87% for the mild traumatic brain injury patients compared to controls, TBI group (blast-induced plus non-blast causes) and arguing against the idea that greater variability reflects 100% for the moderate group. Among the mild TBI dysfunctional neural processing. Furthermore, higher patients, the rates of abnormalities were 96% and 77% brain signal variability indicated improved behavioral for the blast and non-blast TBI groups, respectively. The performance for all participants. This relationship was spatial characteristics of abnormal slow-wave genera- statistically stronger for people with brain injury, dem- tion measured by Z scores in the mild blast TBI group onstrating that those with higher brain signal variability significantly correlated with those in non-blast mild were also those who had recovered the most cognitive TBI group. Among 96 cortical regions, the likelihood of ability. Rather than impede neural processing, cortical abnormal slow-wave generation was less in the mild signal variability within an optimal range enables the TBI patients with blast than in the mild non-blast TBI exploration of diverse functional configurations, and patients, suggesting possible protective effects due to may therefore play a vital role in healthy brain function. the military helmet and armor. Finally, the number of (22261371) cortical regions that generated abnormal slow-waves

231 Neuroimage (2012), Vol. 60, No. 2, pp. 1528-37 Neuroimage (2011), Vol. 55, No. 3, pp. 1189-99

Principles of recovery from traumatic brain injury: Reorganization of functional connectivity as a reorganization of functional networks correlate of cognitive recovery in acquired brain injury Castellanos, NP; Leyva, I; Buldú, JM; Bajo, R; Paúl, N; Cuesta, P; Ordóñez, VE; Pascua, CL; Castellanos, NP; Paúl, N; Ordóñez, VE; Demuynck, O; Bajo, Boccaletti, S; Maestú, F; del-Pozo, F R; Campo, P; Bilbao, A; Ortiz, T; del-Pozo, F; Maestú, F

Cognitive and Computational Neuroscience Laboratory, Cen- Laboratory of Cognitive and Computational Neuroscience, tre for Biomedical Technology, Technical University of Madrid Centre for Biomedical Technology, Universidad Politécnica de and Complutense University of Madrid, Spain. nazareth@ Madrid, Spain. [email protected] pluri.ucm.es ABSTRACT: Cognitive processes require a functional ABSTRACT: Recovery after brain injury is an excellent interaction between specialized multiple, local and platform to study the mechanism underlying brain remote brain regions. Although these interactions can plasticity, the reorganization of networks. Do com- be strongly altered by an acquired brain injury, brain plex network measures capture the physiological and plasticity allows network reorganization to be principal- cognitive alterations that occurred after a traumatic ly responsible for recovery. The present work evaluates brain injury and its recovery? Patients as well as control the impact of brain injury on functional connectivity subjects underwent resting-state MEG recording patterns. Networks were calculated from resting-state following injury and after neurorehabilitation. Next, magnetoencephalographic recordings from 15 brain network measures such as network strength, path injured patients and 14 healthy controls by means of length, efficiency, clustering and energetic cost were wavelet coherence in standard frequency bands. We calculated. We show that these parameters restore, in compared the parameters defining the network, such many cases, to control ones after recovery, specifically as number and strength of interactions as well as their in delta and alpha bands, and we design a model that topology, in controls and patients for two conditions: gives some hints about how the functional networks following a traumatic brain injury and after a reha- modify their weights in the recovery process. Positive bilitation treatment. A loss of delta- and theta-based correlations between complex network measures and connectivity and conversely an increase in alpha- and some of the general index of the WAIS-III test were beta-band-based connectivity were found. Further- found: changes in delta-based path-length and those more, connectivity parameters approached controls in in Performance IQ score, and alpha-based normalized all frequency bands, especially in slow-wave bands. A global efficiency and Perceptual Organization Index. correlation between network reorganization and cogni- These results indicate that: 1) the principle of recovery tive recovery was found: the reduction of delta-band- depends on the spectral band, 2) the structure of the based connections and the increment of those based functional networks evolves in parallel to brain recov- on alpha band correlated with Verbal Fluency scores, as ery with correlations with neuropsychological scales, well as Perceptual Organization and Working Memory and 3) energetic cost reveals an optimal principle of Indexes, respectively. Additionally, changes in connec- recovery. (21195199) tivity values based on theta and beta bands correlated with the Patient Competency Rating Scale. The current study provides new evidence of the neurophysiological mechanisms underlying neuronal plasticity processes after brain injury, and suggests that these changes are related with observed changes at the behavioural level. (20826433)

232 Brain (2010), Vol. 133, No. Pt 8, pp. 2365-81 J Neurotrauma (2010), Vol. 26, No. 8, pp. 1213-26

Integrated imaging approach with MEG and DTI to Magnetoencephalographic study of posterior tibial detect mild traumatic brain injury in military and nerve stimulation in patients with intracranial civilian patients lesions around the central sulcus

Huang, MX; Theilmann, RJ; Robb, A; Angeles, A; Willemse, RB; de Munck, JC; van't Ent, D; Ris, Nichols, S; Drake, A; D'Andrea, J; Levy, M; Hol- P; Baayen, JC; Stam, CJ; Vandertop, WP land, M; Song, T; Ge, S; Hwang, E; Yoo, K; Cui, L; Baker, DG; Trauner, D; Coimbra, R; Lee, RR Department of Neurosurgery, VU University Medical Center, Amsterdam, The Netherlands. [email protected] Research, Radiology, Rehabilitation, and Psychiatry Services, VA San Diego Healthcare System, San Diego, California, USA. OBJECTIVE: To study interhemispheric differences of [email protected] somatosensory evoked field (SEF) characteristics and the spatial distribution of equivalent current dipole ABSTRACT: Traumatic brain injury (TBI) is a leading sources in patients with unilateral hemispheric lesions cause of sustained impairment in military and civil- around the central sulcus region. METHODS: In 17 ian populations. However, mild (and some moderate) patients with perirolandic lesions, averaged somato- TBI can be difficult to diagnose due to lack of obvious sensory responses after posterior tibial nerve stimu- external injuries and because the injuries are often lation at the ankle were recorded with magnetoen- not visible on conventional acute MRI or CT. Injured cephalography. Dipole source solutions in the affected brain tissues in TBI patients generate pathological low- (AH) and unaffected (UH) hemispheres were analyzed frequency neuronal magnetic signal (delta waves 1-4 and compared for latency, equivalent current dipole Hz) that can be measured and localized by magnetoen- strength, root mean square, and spatial distribution in cephalography (MEG). We hypothesize that abnormal relation to clinical findings. RESULTS: Three main SEF MEG delta waves originate from gray matter neurons components, P45m, N60m, and P75m, were identi- that experience de-afferentation due to axonal injury to fied in the hemisphere contralateral to the stimulated the underlying white matter fiber tracts, which is mani- nerve. Dipole strength for the P45m component was fested on diffusion tensor imaging (DTI) as reduced significantly higher in the AH compared with the UH. fractional anisotropy. The present study used a neuro- SEF characteristics in the AH and UH showed no signifi- imaging approach integrating findings of magneto- cant differences with respect to component latency or encephalography (MEG) and diffusion tensor imaging dipole strength of the N60m and P75m components. (DTI), evaluating their utility in diagnosing mild TBI in Interdipole location asymmetries exceeded 1.0 cm in 10 subjects in whom conventional CT and MRI showed 71% of the patients. Comparison of the posterior tibial no visible lesions in 9. The results show: (1) the integrat- nerve evoked responses (P45m and N60m) in patients ed approach with MEG and DTI is more sensitive than with motor deficits and patients without deficits conventional CT and MRI in detecting subtle neuronal showed that these responses are enlarged in the AH injury in mild TBI; (2) MEG slow waves in mild TBI pa- when perirolandic lesions are present. Patients with tients originate from cortical gray matter areas that ex- motor deficits also showed an increased response for perience de-afferentation due to axonal injuries in the P45m in the UH. CONCLUSION: The results of poste- white matter fibers with reduced fractional anisotropy; rior tibial nerve SEFs suggest spatial and functional (3) findings from the integrated imaging approach are changes in the somatosensory network as a result of consistent with post-concussive symptoms; (4) in some perirolandic lesions with a possible relationship with cases, abnormal MEG delta waves were observed in clinical symptoms. The results can provide further basis subjects without obvious DTI abnormality, indicating for the evaluation of cortical changes in the presence of that MEG may be more sensitive than DTI in diagnosing perirolandic lesions. (18162900) mild TBI. (19385722)

233 Neurosurgery (2008), Vol. 61, No. 6, pp. 1209-17; discussion 1217-8

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