DOI: 10.5935/0946-5448.20130002 SUMMARY OF MEETINGS International Tinnitus Journal. 2013;18(1):6-15.

AAO-HNS - Martha Entenmann Tinnitus Research Center Tinnitus Miniseminar 2013

New Concepts in Electrophysiology and Tinnitus

Location-Vancouver, CA.

INTRODUCTION effects of Implants on Brain function, with a focus on the indication for tinnitus of the cochlear implant for attempting The theme of the AAO-HNS Martha Entenmann, tinnitus relief/suppression; and in 2012 brain imaging and Abraham Shulman, M.D., Barbara Goldstein, PhD Inter- tinnitus with the take home message that clinical applica- national Tinnitus Miniseminar, 2013, was “New Concepts tion of the brain imaging technologies of a) Nuclear medi- Electrophysiology and Tinnitus”. cine single photon emission tomography, brain SPECT, The goal was to provide to the otolaryngologist b) Photon emission tomography, brain PET; c) Functional and all tinnitus professionals information of clinically magnetic resolution imaging, fMRI; d) Magnetic emission applicable new and established methods of objective tomography (MEG), and e) Low frequency resolution recording of electrical activity in both ear and brain electromagnetic tomographic analysis (LORETA), provide which can serve as a basis for identification of electro an objectivity for the diagnosis and monitor function for physiologic correlate(s), for all clinical types of tinnitus, subjective aberrant sensory complaint, tinnitus. individual for each tinnitus patient. The take home message and goal for the attendee The focus was on the clinical translation for tinnitus of each miniseminar since 2010 has been the clinical diagnosis and treatment based on: 1) State of the art translation of advances in , sensory physi- clinical translation of electrophysiology of brain activity ology, and auditory science for increasing both an accu- reflective of multiple brain functions in the presence of racy of the tinnitus diagnosis and efficacy for treatment, the tinnitus signal; and 2) Electrophysiology of cochleo- for the ultimate benefit of the tinnitus patient. Diagnostic vestibular function reflective of endolymphatic hydrops, accuracy is reflected in the efficacy of treatment. and sensorineural hearing loss. Specifically in 2013 the take home message was Michael E. Hoffer, M.D. introduced the program that translation of what is known of electrophysiology to the well attended meeting. The program in 2013, of the auditory system ear and brain, can with existing “Electrophysiology and tinnitus”, was presented as the testing technologies, eg. ABR, otoacoustic emissions, fourth of a series of AAO-HNS Miniseminars, which over P 300, functional brain imaging of nuclear medicine, the past 4 years has had as its goal the providing to the single photon emission tomography, (SPECT), photon AAO HNS membership and guests of state of the art emission tomography (PET), and electrophysiology tinnitus information, both clinical and basic science, for quantitative (QEEG) provide translation by the otolaryngology practioner to the patient an objectivity for tinnitus, a subjective sensory aberrant for an increased accuracy for the tinnitus diagnosis and auditory complaint, particularly for a predominantly cen- its translation for treatment. tral type severe disabling subjective idiopathic tinnitus. The invited speakers included: Attendees were invited by Abraham Shulman, - Michael E. Hoffer, M.D. CAPT MC USN M.D. (Abe) to participate in support of the AAO-HNS - Guest of Honor: Leslie S. Prichep, PhD., Profes- International Tinnitus Miniseminar. Their participation sor , Acting Director Brain Research Labora- was requested to continue the AAO-HNS Intl Tinnitus tories, New York University School of Medicine, NY, NY Miniseminars, planned for in perpetuity beyond 2014. - Carlos A Oliveira, MD, PhD., Professor and Chair- Initially, support for the costs of the meeting had man Department Otolaryngology, Brasília University been established by the Martha Entenmann tinnitus Medical School Brasília, Brazil Research center (METRC) for the period 2010-2014. - Tobias Kleinjung, M.D., PhD. University Zurich, A contribution, large or small, short or long term, Department Otorhinolaryngology, Switzerland to defray the cost of the meeting, was requested to be - Abraham Shulman, M.D. Professor Emeritus considered by attendees, colleagues, friends and pa- Clinical Otolaryngology, SUNY/Downstate. tients, to continue to achieve the goal of the AAO-HNS, The themes of the past miniseminars, the rationale which is to provide state of the art tinnitus information to for the order in the selection of the themes since 2010 were the Otolaryngology community for continuing education reviewed. The AAO-HNS tinnitus miniseminars, started in dedicated to tinnitus to provide state of the art quality 2010, focused on tinnitus diagnosis and treatment, 2011 care to our tinnitus patients.

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 6 The AAO HNS contact is Ron Sallerson Senior The P300 brain response in neuroscience is a Director, Development and Marketing American Academy neural evoked potential component of the electroen- of Otolaryngology-Head and Neck Surgery 1650 Diagonal cephalogram (EEG). It has been clinically applied in Road|Alexandria, VA 22314. Phone: 703-535-3775|Cell: cognitive testing and in assessing progress of therapy, 301-938-3632|Fax: 703-684-4288 lie detection, computer interfacing. It can be universally elicited by varying stimuli. P300 potential is the neuronal PRESENTATIONS correlation for attention, auditory differentiation capacity, short-term memory decision-making capacity. Each of the presentations focused on a methodo- Abnormalities in P300 reported in patients with logy of ear and brain physiology and its translation for cognitive disorders and tinnitus include the following: tinnitus, e.g. how to record, analyze, and interpret the data 1. Cognitive disorders: delayed latency time of for diagnosis and treatment of severe disabling tinnitus. wave P300, more predominant on left stimu- The program was presented in two sections with lations, a reduction of amplitude, and spatial adequate time for questions. Section 1. Electrophysio- variations in the formation of the potential. This logy of ear; and Section 2. Electrophysiology of brain. A is in keeping with the pathology. In the case question and answer session followed. of cortical atrophies and Alzheimer’s disease, the temporospatial distribution of the potential I. Michael E. Hoffer, CAPT MC USN presented prevails in frontal areas. In vascular patholo- an introduction and overview of the physiology of the gical processes, temporospatial distribution peripheral and central auditory system with a focus of the potential prevails in temporoparietooc- on the P300 response and tinnitus. cipital areas1. The current diagnostics for tinnitus were re- 2. Abnormalities in P300 seen in tinnitus pa- viewed which focus on the subjective nature of the tients2. Increased latencies in individuals with tinnitus complaint. Specifically current emphasis tinnitus were reported in a controlled study is a medical audiologic team approach of otology/ of 30 individuals with tinnitus ages 29-50 and neurotology and audiology which is dependent on thirty matched individuals with no tinnitus. the subjective report by the patient of the tinnitus, its Bilateral abnormalities were identified in those clinical course and response treatment. Audiology with bilateral tinnitus3. testing focuses on the psychoacustical and psycho- In summary, the P300 results in selected tinnitus physical scaling of the tinnitus percept. Questionnaires cases have been productive, however results have not attempt to identify the characteristics of the tinnitus been universal. for quality, location, intensity, duration and masking characteristics, associated complaints of quality of life, II. Carlos A Oliveira, MD, PhD., Professor and depression, anxiety and severity. Treatment modalities, Chairman Department Otolaryngology, Brasília University pharmacologic/instrumentation are inconsistent in Medical School Brasília, Brazil presented a summary subjective reports of efficacy. of electrophysiology clinical studies of his entitled The subjective nature and heterogeneity of the “Electrophysiology of tinnnitus in normal hearing patients complaint for etiology, tinnitus characteristics, response with”: to modalities of treatment, instrumentation/medication 1. Transient and distortion product evoked presents a dilemma to both, the tinnitus patient and oto-acoustic emissions (TEOAE/DPOAE), professional health care providers, researchers com- 2. ABR in normal hearing patients with and wi- pensation and disability organizations. thout tinnitus; In general, identification of an electrophysiologic 3. Preliminary data on the results of the mismatch correlate(s) for any diagnostic category provides objec- negativity test (MMN); and tivity for a complaint and a target for treatment. 4. The relation of anxiety and depression with The presentations of the panel of international tinnitus annoyance, otoacoustic emissions experts were charged with questions to be answered in and auditory evoked brainstem potentials. their presentations: The TEOAE and DPOAE results were compared in 1. Can electrophysiology provide us with more patients with/without tinnitus. TEOAE and DPEOAE tests objective diagnostic information? showed that normal hearing patients with tinnitus have 2. Can electrophysiology inform us about treat- significantly more abnormal results in both tests than ment modalities? normal hearing patients without tinnitus. Tinnitus without 3. Can electrophysiology methods be utilized to hearing loss is associated to abnormal function of outer treat tinnitus? hair cells (OHC) evaluated by Otoacoustic Emission

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 7 tests. Factors such as clinical history, etiologic conside- 3. Correlation of tinnitus annoyance with depres- rations, the degree of hearing loss and psychoacoustic sion levels and changes in latencies in MMN measurements have not been linked to discomfort and tests point to higher levels. In the CNS as mo- the intensity of tinnitus in patients with hearing loss4. dulators of tinnitus intensity and annoyance. No correlation was identified between annoyance and tinnitus as measured by the tinnitus handicap inven- III. Tobias Kleinjung, M.D., PhD. PD Dr. med. Leitender tory and the TEOEA or DPEOAE results. Arzt ORL Klinik University Zurich, Department Otorhi- No correlation was found between changes in the nolaryngology, Switzerland, presented “The neuronal ABR and the level of anxiety and depression in tinnitus network of tinnitus and its implication for therapy”. patients. The presentation started with the clinical profile No correlation was found between the ABR of a typical tinnitus patient, i.e. otologic examination changes and the tinnitus handicap results in the tinnitus satisfactory, associated sloping bilateral symmetrical patient group. sensorineural hearing loss, and fluctuation in the inten- A correlation was identified between with degree sity, annoyance, characteristics of the tinnitus. of anxiety and/or depression as measured by the Beck Historically, reference was made to past experien- anxiety index and depression scale (BAI/BDI). ce of persistence of the tinnitus following transection of Auditory brainstem short latency results, in pa- the auditory nerve. tients with tinnitus and normal hearing compared with The question posed was where in the brain is ABR results in normal hearing patients without tinnitus, the tinnitus located and what are its neuronal corre- demonstrated) a significantly prolonged latency of wave lates? The highlights of functional changes identified V in the study group when compared with the control for tinnitus in animal models in the central auditory group. The interpeak wave III-V latency was significantly system at levels of brainstem, mid brain and cortex (p = 0.003) enlarged in the study group when compared were presented. to control. Even though the average obtained in several 1. Increased spontaneous firing rates of neurons, analysed parameters were within normal limits the results 2. Increase in burst firing, in the study group differed from the control group sug- 3. Alteration of the tonotopic organization and gesting changes in the brain stem auditory pathways. The involvement of non auditory brain areas. significance of these changes must be further studied5. These findings provide the beginning of an Reference was made to the report of long latency understanding of a biology for tinnitus. evoked auditory potentials studied in patients with tinnitus and tinnitus was reviewed as a and/or hyperacusis who demonstrated altered latencies6. correlation of site of lesion in brain over milliseconds to The altered latencies could be caused by different days when imaging at levels of: participation of the pre-frontal cortex (attention) and/or 1. Whole brain, differences in sensibility (hyperacusis). 2. Region of interest, The mismatch negativity test (MMN) an objective 3. Neuronal population, method to quantify the central auditory process measu- 4. Single neuron and res the temporal window of integration in the auditory 5. Synapse. perception7. Of clinical interest and application for tinnitus are: Preliminary MMN testing results in patients with 1. Functional brain imaging, electroencephalo- severe disabling tinnitus (SDT) and normal hearing graphy (EEG) and quantitative electroence- were reported to demonstrate “altered pre-frontal cortex phalography (QEEG), participation in the perception of the symptom (attention 2. Nuclear medicine brain imaging (PET/SPECT). and habituation”). Further studies in this area were con- The brain wave activities, i.e. oscillations, delta sidered to be warranted since MMN seems to be able to 1-4Hz, theta 4-7Hz, Alpha 8-12 Hz Beta 13-30Hz, gamma objectively access tinnitus changes in the central auditory 30-100 + Hz were presented as the “dialectics” of the processing of sound stimulation. brain. The advantages to the tinnitus patient of EEG in- Current conclusions included: clude spatiotemporal localization of underlying neuronal 1. Tinnitus seems to be triggered in outer hair generators, i.e. source localization, by the measurement cells; of spontaneous activity. 2. Tinnitus annoyance level as measured by the Tinnitus patients demonstrate less Alpha and more tinnitus handicap index does not correlate with Delta power in temporal cortex areas as compared to the extension of lesions in the outer hair cells normal controls8. as measured with the TEOAE and DPOAE nor Tinnitus patients with high distress have been with the ABR; identified with increased alpha in subcallosal anterior

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 8 cingulate, parahippocampal gyrus, amygdala, middle The title of the presentation was “Functional brain temporal gyrus. Reduced alpha was demonstrated in Imaging QEEG/LORETA and Tinnitus Present and Future”. posterior cingulate gyrus and precuneus9. Signal processing advances over the past deca- Stronger connectivity between auditory and de has exponentially expanded the information about non-auditory (frontal, ACC) regions in tinnitus patients cortical and subcortical sources of scalp recorded EEG compared to controls10. data. Such methods have enabled the pathophysiology Gamma-Band activity correlates with of neurological and neuropsychiatric disorders to be tinnitus-loudness in the contralateral auditory cortex11. studied and better understood. A correlational approach helps to identify brain Studies of QEEG in chronic patients have areas involved in tinnitus12. demonstrated significant abnormalities in regions of Neurofeedback (NF) was presented at time, as the “Pain Matrix” as identified by other neuroimaging a clinical application of QEEG for attempting tinnitus methods (e.g., fMRI, PET and SPECT), and shown a relief. NF is a type of biofeedback that has been used relationship to severity of pain reported. for attempting tinnitus relief in the past. At this time the results of a study were presented of NF, as compared Why look at QEEG in Patients with Tinnitus? to repetitive transcranial magnetic stimulation (rTMS) Quantitative electroencephalography (QEEG), a as a potential treatment for tinnitus related distress. The spectral analysis of the raw EEG data may be a signifi- technique used realtime displays of EEG to illustrate cant addition to the objective diagnosis of tinnitus and brain activity and teach self-regulation to focally increa- the optimization of treatment, including: se alpha power, found to be reduced I tinnitus patients. 1. Objective identification of the central compo- Only neurofeedback resulted in a significant decrease nent of the tinnitus complaint; in tinnitus symptoms and an increase in alpha power for 2. Identifying a potential “biomarker” of the pre- right auditory regions13. sence of the condition; Future projections included development of indi- 3. Provide an objective measure of “severity”, vidual treatment programs of a combination of NF and which can be used to evaluate efficacy of rTMS. treatment; 4. Lead to better understanding of the pathophy- IV. Guest of Honor: Leslie S. Prichep, PhD., Professor siology of tinnitus using source localization of Psychiatry, Acting Director Brain Research Laboratories, scalp recorded EEG data and New York University School of Medicine, NY. 5. Identification of heterogeneity within the Introduction diagnosis which may lead to more optimal Over the last 3 decades her academic focus treatment. has been on exploration of the pathophysiology of In this presentation the term tinnitus refers to a predo- psychiatric/neuropsychiatric disorders using quantita- minantly central type subjective idiopathic tinnitus patients tive electrophysiology. At the present time she is the of the severe disabling type. Associate Director of the Brain Research Laboratories Studies of Quantitative electroencephalography and Professor of Psychiatry (current), and a Research (QEEG) in tinnitus patients has demonstrated clear cen- Scientist at the Nathan S. Kline Institute for Psychiatric tral abnormalities in this group, and suggest both simila- Research of New York State (retired 2011). She has rities and differences from the chronic pain population. been recognized as one of the pioneers in the field of quantitative electrophysiology, lectured internationally Neurometrics - EEG Data Acquisition & Neurometric on this topic, and has published extensively in the field Analysis of human electrophysiology, clinically applied research, The technique of EEG Data Acquisition & Neurometric source and localization. Dr. Prichep is responsible for Analysis was reviewed. the Direction of the largest existing database of electro- Neurometrics is a statistical technique that eva- physiological data from normal subjects, patients with luates quantitatively the electrical activity in brain by various psychiatric/neuropsychiatric disorders, patients extracting from the different electrophysiologic pheno- with loss of consciousness (both anesthetically induced mena a common metric of relative probability14,15. and from injury), chronic pain patients, and patients with Source localization is an EEG analysis technique traumatic brain injury and post-concussive syndrome, used to identify the mathematically most probable un- and tinnitus and pain. derlying sources of the scalp recorded data, for a given Due to a personal issue Dr. Prichep was not able to at- neuropsychiatric diagnosis (using very narrow frequency tend as planned and extended her apology to the attendees. spectra), i.e. NEUROMETRIC method of EEG quantification. The following sections of her were presented by A. Shulman: NEUROMETRIC QEEG Norms have been established.

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 9 Normative data exists for ages 6-90, have been controls in THETA. Maximum regions with over published and demonstrated to be culture-fair and to activation in the theta band included: Insula, have high test-retest reliability. The potential effct of age SMA, Medial Frontal cortex, S1 and hippocam- on changes observed in the EEG is removed by descri- pus. b) less activation than pain was seen in bing the individuals EEG features in terms of deviations tinnitus patients in the anterior cingulate. from age expected normal values (using z-scores). 3. EEG Source images of significance of diffe- The anatomical accuracy of QEEG source locali- rences between Tinnitus and normal controls zation has been repeatedly confirmed by coregistration in the ALPHA band. Maximum regions with with other brain imaging modalities e.g. fMRI16, PET17,18; over activation in the Alpha band included: and CT19. Insula, Anterior Cingulate, thalamus, and Included in the Neurometric normative EEG data hippocampus. b) less activation than pain in base is that different normative equations exist for EEG the left parietal lobule. across the human lifespan. The ground state of the brain is 4. EEG Source images of significance of the regulated by an anatomically extensive, genetically based differences between a) tinnitus and normal neuro-physiologic homeostatic regulating system. Distur- controls in the BETA band. Maximum regions bances in this system result in abnormal ties and must be with over activation in the Beta band inclu- considered in the evaluation of results of EEG recordings. ded: DLPFC, Insula, S1, Cingulate cortex The complexity of the pain matrix was reviewed (anterior, mid and posterior), medial frontal differentiating between neuroanatomic substrates which cortex, SMA and hippocampus. b) Differen- serve the sensory and sensory motor component of ces between Tinnitus and chronic pain: the the pain, e.g. somatosensory cortices, posterior insu- most significant differences were seen in the la, and others which may serve the affective cognitive Beta frequency band. c) maximum regions and memory (e.g. orbitofrontal cortex, anterior insula of difference showed tinnitus patents to have cortex and cingulate) components of pain. Source more activation in many regions, including: localization of EEG with functional neuroimaging, in a DLPFC, S1, Inferior Parietal Lobule, Cingu- population of 70 chronic pain patients (age range 20-92 late, Medial frontal cortex. SMA; d) in other yrs).clearly demonstrated activation in many regions of frequency bands there were many more the Pain Matrix with maximum abnormality in the theta similarities than differences, suggesting sha- frequency band. red pathophysiology of tinnitus and pain. e) one difference of note was seen in the theta Clinical research QEEG, LORETA- the tinnitus band where chronic pain had significant in- signal, tinnitus and pain - similarities, and differences- volvement of the cingulate compared to the -preliminary report. tinnitus population. The protocol and preliminary results of a Neuro- 5. EEG Source images of significance for the for metric analysis of tinnitus were presented. The study Tinnitus population for particular frequency included 124 tinnitus patients; mean age was 48.29 yrs. bands include a) 8.2 Hz sources (alpha) and Mean length of symptoms was 2 yrs. Criteria for inclusion b)15.6 Hz source (beta). in this study was identification with the medical audiologic 6. Tinnitus vs Pain in Beta band. Most significant tinnitus protocol (MATTP) of a predominantly central type differences show more activation in Tinnitus in subjective idiopathic tinnitus of the severe disabling type. superior temporal gyrus and thalamus. Exclusion criteria included a clinical history of known CNS/otologic disease. Preliminary Conclusions highlights include: Preliminary results were reported as: A) Differen- 1. Using EEG source localization clear abnorma- ces between tinnitus and normal for the delta, theta, lities can be seen in the Tinnitus population, alpha and beta bands; and B) Differences between supporting a central component of Tinnitus; tinnitus and pain: 2. QEEG features could be used to objectively 1. EEG Source images of significance of differen- measure and quantify the presence of tinnitus ces between a) tinnitus and normal controls in as part of the diagnostic process; the Delta band; b) significant differences with all 3. Future investigations will explore the QEEG showing more activation in the pain population heterogeneity of the Tinnitus population for in the delta band including: cingulate (anterior, pathophysiological subtypes, which may be mid and posterior), and parietal lobule. differentially treatment responsive; 2. EEG Source images of significance of the 4. The similarities between chronic pain and differences between Tinnitus and normal tinnitus suggest a common matrix for both

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 10 tinnitus and pain i.e a final common pathway QEEG and Tinnitus, and specifically its application with which demonstrates the integration of brain Transcranial Magnetic Stimulation: (TMS) and electri- function of sensory/affect and motor compo- cal stimulation attempting tinnitus relief was briefly nents united by the establishment of a memory reviewed. Since 1979, we have attempted to objecti- for both; vize the subjective tinnitus complaint. It is reflected in 5. EEG source localization provides an increased numerous publications which include the following: accuracy for the tinnitus diagnosis, a monito- The medical audiologic tinnitus patient protocol ring tool for objective determination efficacy (MATPP) which included cochleovestibular testing and of treatment; identification of correlates of cochleovestibular function20: 6. Memory consolidation dynamic range for pain ABR short latency responses21; exceeds that for tinnitus; Electrical Stimulation tinnitus control22,23; 7. Tinnitus is the pain of the auditory system; Transcranial magnetic stimulation24,25; 8. The resolution of electrophysiology functional Quantitative Electroencephalography (QEEG) brain imaging exceeds that of nuclear medi- 199926,27. cine, and a correlation has been established Dept Physiology NYU Tinnitus masking para- between both; digm Magnetoencephalography (MEG) 200228. 9. Metabolism of each frequency band of brain Low resolution electromagnetic tomography wave activity is directly proportional to the analysis (LORETA) - 2005 - Brain Research Lab NYU degree of neuronal synchronization, i.e. beta John R, Prichep L., Pasqual R > alpha > theta > delta; • 2006 - BRL NYU Vareta-N-61 - presentation 10. EEG source localization for tinnitus, i.e. elec- • 2006 - QEEG Power analysis - presentation troencephalotinnitography (EETG/ETG) in • 2007 - BRL NYU - TMS-case report - presentation 2013-2014 is clinically considered to be ana- • 2013 - BRL NYU Identification of the tinnitus sig- logous to the EKG for cardiology in the 1930s. nal in a predominantly central type tinnitus of the severe disabling type; similarities/differences tinnitus/pain29. V. Abraham Shulman, M.D., F.A.C.S. presentation: “Electrophysiology and Tinnitus QEEG/LORETA Update C. Functional Brain Imaging and tinnitus Case Present/Future: The presentation was transcribed for Report inclusion into AAO-HNS - Academy U. Advances in functional brain imaging technology and understanding of the electrophysiology for both A. The goals included: ear and brain have been translated for the tinnitus To introduce the attendees to quantitative definition, tinnitus theory, and clinical applications for electroencephalography (QEEG) and low frequency tinnitus diagnosis and treatment. Metabolic and elec- resolution electromagnetic tomography analysis trophysiologic functional brain imaging respectively (LORETA) functional brain imaging and its applica- with PET/SPECT brain imaging and QEEG/LORETA tion for tinnitus diagnosis; and to objectively monitor analysis are establishing a neurobiology for all clinical treatment efficacy. types of tinnitus. To present a case report of a cochlear implant soft Tinnitus in the past was defined as a perception failure (CISF) to demonstrate its application for tinnitus of sound unrelated to an external auditory stimulus. The diagnosis and to monitor the clinical course of tinnitus definition reflected a sensorineural approach wit a focus and treatment efficacy; on the ear (and brain)30. To present preliminary data obtained with electro- A new and updated definition for tinnitus is a cons- encephalography (QEEG) and low frequency resolution cious, abnormal, auditory percept reflecting a dyssyn- electromagnetic tomography analysis (LORETA) func- chrony in development of, or neural transmission within, tional brain of the similarities and differences between the peripheral and central cochleovestibular system. The tinnitus and normals and tinnitus and pain; and focus is on EAR AND central BRAIN functions of percep- To recommend to attendees inclusion of functional tion, consciousness; attention, concentration, cognition, brain imaging QEEG/LORETA into the evaluation of a learning, memory, affect-behavior, and psychomotor predominantly central type subjective idiopathic tinnitus activity - all in the presence of the tinnitus signal31. of the severe disabling type. The translation of the principle of sensory phy- siology of components of sensations, i.e. sensory, B. The historical background of our initial and affect behavior and psychomotor for all clinical types ongoing experience since 1999 at SUNY/DMC De- of tinnitus provides an understanding that what is being partment Otolaryngology with Brain Electrical Activity seen with both nuclear medicine brain PET/Spect and

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 11 QEEG/LORETA functional brain imaging are respecti- The basics of the EEG technique, definition of vely metabolic alterations in neuroanatomic substrates the power spectrum and relative power in EEG and the reflective of multiple brain functions in the presence significance of Z scores was reviewed34. of the tinnitus signal, and alterations in synchronous The clinical and research applicability of functional brain wave frequency bands reflective of multiple brain brain imaging, PET and QEEG alone and/or in combi- functions activated in response to the initial dysynchro- nation was presented with a case report of CISF and nous tinnitus signal32. preliminary results of a study of similarities/differences The hypotheses of Thalamo cortical oscillation (TCO) between brain wave activity in tinnitus patients and nor- and Thalamocortical Dysrhythmia (TCD) are significant for mals, and tinnitus and pain patients. all clinical types of tinnitus. Thalamo cortical oscillation: It is a term to describe the synchronous firing and interac- D. Case report-Cochlear implant soft failure (CISF): tion that occurs between thalamic and cortical neurons at The case report was presented of a 74 yo female specific brain frequencies, delta. 5-4Hz, theta 3.5-7.5Hz, tinnitus cochlear implant patient, who in May 2008 sou- Alpha 8-12Hz, Beta 12-24Hz, and Gamma 25-39Hz. in the ght consultation for an increase in tinnitus intensity and thalamocortical system. Thalamo cortical dysrhythmia: Is reduction in hearing. a pathophysiologic model of brain wave activity of brain This case demonstrates how the application of function proposed for neurogenic pain, tinnitus, abnormal functional brain imaging, both nuclear medicine imaging movements, epilepsy, and neuropsychiatric disorders. It is brain PET and QEEG/LORETA analysis, which respectively hypothesized that a lesion results in deafferentation of exci- reflect metabolic and EEG power tomographic display of tatory inputs on thalamic relay cells which initiates tinnitus. the data, increased the accuracy of the tinnitus diagnosis, It is hypothesized for tinnitus that the sponta- provided a basis for tinnitus treatment, and a method to neous and constant gamma band of hyperactivity cau- monitor the clinical course of the tinnitus with the cochlear ses tinnitus: “In a dafferented state the thalamocortical implant On and Off - all-based on objective metabolic and columns fire in a burst mode of 4-7Hz which results in EEG power data. The clinical problem was a) diagnosis: to a decrease of lateral inhibition in adjacent areas and determine objectively if the tinnitus complaint was a “soft” a halo activity in the gamma band (> 30Hz) called the failure of the implanted cochlear implant; b) to provide edge effect33”. tinnitus relief. Functional brain imaging was explained to in- Briefly, the tinnitus was clinically diagnosed with clude different technologies each of which provides a a medical audiologic tinnitus patient protocol (MATPP) 3 dimensional display of different metrics of response. to be a predominantly central type severe disabling Specifically 1) Nuclear medicine brain positron emission tinnitus ear rt. tomography (PET) and single photon emission tomogra- Initially the integrity of the CI was confirmed with phy (SPECT) reflects alterations in brain metabolism, the manufacturer of the device. The data, metabolic direct and indirect; 2) Functional Magnetic resonance and electrophysiologic, was clinically considered to 1) imaging fMRI- blood oxygen level dependent; and 3) Support the hypotheses of TCO and TCD; 2) Neural Low frequency resolution electromagnetic tomography plasticity in brain between thalamus and frontal cortex; analysis (LORETA) EEG provides source localization and 3) increased asymmetric metabolic and brain wave of the scalp recorded brain wave activities and neuro- activity with between thalamus and cortex rt > lt, with nal connectivity. Quantitative electroencephalography the cochlear implant #1 On, and lt > rt with the CI #1 (QEEG) is a spectral analysis of the raw electrophysio- OFF. A clinical correlation was established between the logic data of the electroencephalogram. The bands of metabolic and electrophysiologic objective data, and the frequencies of response of different brain waves in brain subjective report of the tinnitus intensity increase with are displayed in multimetric topographic maps, i.e. the electrical stimulation with the CI #1 On. The patient was QEEG topographic maps are hypothesized to reflect recommended removal CI #1 and replacement with a multiple brain functions. For the QEEG raw power was new CI #2. The CI #1 was removed and replaced with transformed into a Z score against a normative databa- CI #2 6/09. The patient reported improvement in hearing se from BRL/NYU corrected for age and other factors A and tinnitus relief wit CI #2. Follow up functional brain QEEG power score with a value greater than +1.96 or imaging PET/QEEG 11/09 demonstrated thalamocortical less than -1.96 would significantly differ at the 0.05 level activation bilateral, and no excessive brain wave activity from the mean of the age adjusted norm, i.e. 2 SD -95% bilateral for the delta/theta/alpha/and beta frequency confidence level. bands. Clinically a homeostasis of auditory function was The QEEG provides an objective measure of band reestablished with the CI #2. waves of activity for display in brain of the influence of In summary, 1) Tinnitus in an implanted CI pa- modality (-ies) of treatment attempting tinnitus relief. tient may be a soft sign of CISF; 2) Serial functional

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 12 brain imaging results, metabolic and electrophysio- pharmacology, individual, specific, and per- logic, pre and post CI #1 removal and replacement sonalized for each tinnitus patient. with CI #2, provided serial objective metabolic and 5. Surgery (Non Invasive transcranial MR guided electrophysiogic data to monitor the efficacy of elec- high intensity focused ultrasound (tcMRgHIFU) trical stimulation with the CI between the time of initial utilizing source localization for tinnitus relief for consultation 5/08 and replacement with CI #2 in 6/09, a predominantly central type tinnitus35. and clinical basis for supplemental pharmacological therapy for tinnitus relief. F. Take Home messages: The PET brain and QEEG/LORETA images are The take home messages to attendees included available for review in Academy U. A publication is in the following preparation. 1. Tinnitus and the CI - its initiation and or increase This case report clinically supports the significan- - clinical consideration “soft” CI failure - Fulfills ce of both functional brain imaging, both metabolic and criteria consensus statement - “device mal- EEG power based QEEG/LORETA. It is recommended: function is suspected but cannot be proven36”. 1) Functional brain imaging, both metabolic and EEG 2. Outcomes evaluation for CI should include power based QEEG/LORETA inclusion in selected ca- objective data reflecting brain function, i.e. ses of suspected CISF; and 2) The routine inclusion in Functional brain imaging metabolic PETCT the medical audiologic evaluation of a predominantly brain, electrophysiology QEEG, central type subjective idiopathic tinnitus of the severe 3. QEEG provides an objective evaluation of low disabling type. frequency brain activity in the presence of the tinnitus signal for tinnitus diagnosis, treatment Clinical research: Similarities/Differences Tinni- and monitor of efficacy of treatment. tus normals/Pain 4. Pet Data reflects the cytoarchitecture of the Preliminary results with QEEG/LORETA were multiplicity of brain functions in the presence presented of a study of 124 patients with a diagnosis of of the tinnitus signal (e.g. frontal, temporal, a predominantly central type subjective idiopathic tinni- parietal, thalamus). tus of the severe disabling type to establish differences 5. TCO proposed as a mechanism at cortex for between: 1) Tinnitus and the Neurometric normative tinnitus perception and is supported in this database and 2) Differences between tinnitus and the case report by PET brain nuclear medicine pain matrix in brain. imaging and QEEG to improve the accuracy EEG Source images were presented of the signifi- of the tinnitus diagnosis and provide a monitor cance of differences between Tinnitus and normal controls function for treatment efficacy of the cochlear in the THETA, Alpha, Beta band. implant (CI). In other frequency bands there were many more 6. Visualization methods of neuroanatomical re- similarities than differences, suggesting shared patho- gions that are the probable source generators physiology. in brain of changes in surface EEG activity are One difference of note was seen in the theta band clinically reflective of the clinical course of the where chronic pain had significant involvement of the tinnitus and response to treatment. cingulate compared to the tinnitus population. 7. QEEG provides an objective evaluation of low frequency brain activity in the presence of the E. Future for the tinnitus patient: tinnitus signal for tinnitus diagnosis, treatment The future for tinnitus patients includes and monitor of efficacy of treatment. 1. Identification of the neurobiology, neuro bio- 8. EEG source localization analysis identified physiology, and of synaptic clear abnormalities in the tinnitus population, neurotransmission for all clinical types/subtypes supporting a central component for the tinnitus. of tinnitus. 9. QEEG/LORETA recommended to objectively 2. Molecular neuroimaging. measure and quantify the presence of tinni- 3. Source localization brain Stage 2 BRL - NYU tus as part of the diagnostic process in all - functional neuroimaging QEEG/LORETA predominantly central type subjective idiopa- - identification subtypes of a predominantly thic tinnitus of the severe disabling type. central type subjective idiopathic tinnitus of 10. QEEG/LORETA identification of the pattern of the severe disabling type. the tinnitus signal by brain wave band (s) and 4. Tinnitopharmacoproteogenomics/Tinni- frequency (ies) provide an electrophysiologic topharmacology - the development of a correlate for a predominantly central type tinnitus.

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 13 11. Significance - QEEG for otology and neuroto- by and or accompanied by an increase in delta. logy- clinically analogous to the introduction With increasing synchronization at cortex, over of the EKG in the 1930s for internal medicine time, there is a maintenance of or increase in and cardiology. delta and beta. The significance of gamma - of different frequencies - remains to be established. PRESENTATIONS EDITORIAL COMMENTS b) The underlying biophysiological process of is linked with 1. Michael E Hoffer M.D. and Neuro protection. Clinically, the P300 test may be of an increased sig- nificance when applied for a specific affective behavioral 4. Leslie S Prichep, PhD; Abraham. Shulman, M.D. characteristic of the tinnitus patient for a specific clinical QEEG provides an objective evaluation of low type of tinnitus, particularly of the severe disabling type. frequency brain activity in the presence of the tinnitus The heterogeneity of the tinnitus is one of the issues in the signal for tinnitus diagnosis, treatment and its translation results with the P300 response reported in tinnitus patients. to monitor efficacy of treatment. Correlations in brain of activity in tinnitus and pain 2. Carlos P. Oliveira M.D. patients in multiple regions of interest have been reported ABR short latency results reported are similar to between metabolic and electrophysiologic functional that reported initially in 198121. brain imaging The issue of heterogeneity of tinnitus and a need Similarities between chronic pain and tinnitus to identify the clinical type of tinnitus and parameter of suggest the hypothesis of a final common pathway for tinnitus under investigation is demonstrated in the results tinnitus, pain and all sensations-aberrant/normal. reported in this excellent presentation with TEOAE, Otolaryngology and tinnitus professionals are re- DPOAE ABR and MMN testing, i.e. clinically, a predomi- commended to introduce electrophysiologic functional nantly cochlear type tinnitus with a central component. imaging QEEG and LORETA to establish an accuracy The associated complaints of tinnitus, anxiety and for the tinnitus diagnosis, and to monitor efficacy of annoyance, are cortical brain functions. Significantly in treatment modalities recommended for a predominantly this excellent presentation, central abnormalities were central type severe disabling tinnitus. demonstrated with tests of electrophysiology of MMN and long (late) latency ABR recordings. The results provide a basis for recommendation for inclusion of these tests on The meeting was well attended until its conclusion. an individual basis to provide objective data to improve the accuracy of the tinnitus diagnosis and evaluation of the effi- We all look forward to the AAO HNS International cacy of tinnitus treatment for these associated complaints. Tinnitus Miniseminar 2014 Orlando, Fla September 21-24. Translation of the principle of sensory physio- logy of components of a sensation for tinnitus, i.e. sensory, affect and psychomotor is recommended Michael E. Hoffer, M.D. to be specified for research investigations and to be CAPT Michael Hoffer, M.D., F.A.C.S. combined with the diagnostic identification of the cli- Clinical Associate Professor nical type of tinnitus to avoid interpretation of negative Uniformed Services University of Health Sciences. results of investigations reflective in some degree to the heterogeneity of tinnitus. Selection of a particular electrophysiologic testing Barbara Goldstein, PhD. modality for tinnitus is recommended to be based on the Clinical Assistant Professor Otolaryngology electrophysiologic site of lesion of the clinical type (e) of SUNY/Downstate tinnitus and or associated complaint(s) under investigation. 450 Clarkson Ave Box 1239 Brooklyn, N.Y/11203 3. Tobias Kleinjung, M.D., PhD. To be considered in the interpretation of the brain wave activity at cortex is that they reflect not tinnitus but Abraham Shulman M.D., F.A.C.S. multiple brain functions in the presence of the tinnitus signal. Prof. Emeritus Clinical Otolaryngology a) It is hypothesized that the development of SUNY/Downstate a chronicity for tinnitus of all clinical types is 450 Clarkson Ave Box 1239 reflected in the pattern of brain wave activities. Brooklyn, N.Y/11203 Specifically an initial reduction in alpha followed

International Tinnitus Journal, Vol. 18, No 1 (2013) www.tinnitusjournal.com 14 REFERENCES 20. Shulman A. Medical audiologic tinnitus patient protocol. In: Shulman A, editor. Tinnitus diagnosis/treatment. Philadelphia: Lea 1. Bergmann JM, Bertora GO. Cognitive disorders: diagnosis and & Febiger;1991. p.319. treatment. Int Tinnitus J. 2002;8(2):104-7. 21. Shulman A, Seitz MR. Central tinnitus-diagnosis and treatment. 2. Gabr TA, El-Hay MA, Badawy A. Electrophysiological and psycho- Observations simultaneous binaural auditory brain responses logical studies in tinnitus. Auris Nasus Larynx. 2011;38(6):678-83. with monaural stimulation in the tinnitus patient. Laryngoscope. 3. Santos Filha VA, Matas CG. Late Auditory evoked potentials in in- 1981;91(12):2025-35. dividuals with tinnitus. Braz J Otorhinolaryngol. 2010;76(2):263-70. 22. Shulman A. External electrical stimulation in tinnitus control. Am J 4. Granjeiro RC, Kehrle HM, Bezerra RL, Almeida VF, Sampaio AL, Otol. 1985;6(1):110-5. Oliveira CA. Transient and distortion product evoked oto-acoustic 23. Punte AK, Vermeire K, Hofkens A, De Bodt M, De Ridder D, Van de emissions in normal hearing patients with and without tinnitus. Heyning P. Cochlear implantation as a durable tinnitus treatment Otolaryngol Head Neck Surg. 2008;138(4):502-6. in single-sided deafness. Cochlear Implants Int. 2011;12 Suppl 5. Kehrle HM, Granjeiro RC, Sampaio AL, Bezerra R, Almeida VF, 1:S26-9. Oliveira CA. Comparison of auditory brainstem response results in 24. Kleinjung T, Eichhammer P, Langguth B, Jacob P, Marienhagen J, normal-hearing patients with and without tinnitus. Arch Otolaryngol Hajak G, et al. Long-term effects of repetitive transcranial magnetic Head Neck Surg. 2008;134(6):647-51. stimulation (rTMS) in patients with chronic tinnitus. Otolaryngol 6. Norena A, Cransac H, Chery-Croze S. Towards an objectification Head Neck Surg. 2005;132(4):566-9. by classification of tinnitus. Clin Neuropjhysiol.1999:110(4):666-75. 25. Shulman A. Transcranial magnetic stimulation: summary of the 7. Näätänen R. Mismatch negativity: clinical research and possible proceedings of the Twenty-Sixth Annual Meeting of the International applications. Int J Psychophysiol. 2003;48(2):179-88. Tinnitus Forum. Int Tinnitus J. 2009;15(1):62-78. 8. Weisz N, Moratti S, Meinzer M, Dohrmann K, Elbert T. Tinnitus 26. Weiler EW, Brill K, Tachiki KH, Wiegand R. Electroencephalography perception and distress is related to abnormal spontaneous brain correlates in tinnitus. Int Tinnitus J. 2000;6(1):21-4. activity as measured by magnetoencephalography. PLoS Med. 27. Shulman A, Avitable MJ, Goldstein B. Quantitative electroencepha- 2005;2(6):e153. lography power analysis in subjective idiopathic tinnitus patients: 9. Vanneste S, Plazier M, der Loo Ev, de Heyning PV, Congedo M, a clinical paradigm shift in the understanding of tinnitus, an elec- De Ridder D. The neural correlates of tinnitus-related distress. trophysiological correlate. Int Tinnitus J. 2006;12(2):121-31. Neuroimage. 2010;52(2):470-80. 28. van Marle HJF, Kronberg E, Schulman JJ, Ribary U, Llinas R, Shul- 10. Schlee W, Hartmann T, Langguth B, Weisz N. Abnormal resting-state man A, et al. Magnetoencephalographic Recordings from Tinnitus cortical coupling in chronic tinnitus. BMC Neurosci. 2009;10:11. Patients During Masking Procedures. Presented at the Thirteenth 11. van der Loo E, Gais S, Congedo M, Vanneste S, Plazier M, Meno- International Meeting on Biomagnetism; 2002; Berlin, Germany. vsky T, et al. Tinnitus intensity dependent gamma oscillations of 29. Prichep LS, Shulman A. Identification of the tinnitus signal ina the contralateral auditory cortex. PLoS One. 2009;4(10):e7396. predominantly central type tinnitus of the severe disabling type. 12. De Ridder D, Elgoyhen AB, Romo R, Langguth B. Phantom per- N-124. (Stage 1 -completed; in preparation for publication). cepts: tinnitus and pain as persisting aversive memory networks. 30. Shulman A. Tinnitus: Diagnosis/Treatment. San Diego: Singular Proc Natl Acad Sci U S A. 2011;108(20):8075-80. Publishing Group; 1979;32-4 13. Hartmann T, Lorenz I, Müller N, Langguth B, Weisz N. The effects 31. Shulman A, Goldstein B. Quantitative electroencephalography: of neurofeedback on oscillatory processes related to tinnitus. Brain preliminary report-tinnitus. Int Tinnitus J. 2002;8(2):77-86. Topogr. 2014;27(1):149-57. 32. Shulman A, Goldstein B. Tinnitus dyssynchrony-synchrony theory: 14. John ER, Karmel BZ, Corning WC, Easton P, Brown D, Ahn H, et a translational concept for diagnosis and treatment. Int Tinnitus J. al. Neurometrics. Science. 1977;196(4297):1393-410. 2006;12(2):101-14. 15. John ER, Prichep LS, Fridman J, Easton P. Neurometrics: computer- 33. Llinás RR, Ribary U, Jeanmonod D, Kronberg E, Mitra PP. Tha- -assisted differential diagnosis of brain dysfunctions. Science. lamocortical dysrhythmia: A neurological and neuropsychiatric 1988;239(4836):162-9. syndrome characterized by magnetoencephalography. Proc Natl 16. Mulert C, Jäger L, Schmitt R, Bussfeld P, Pogarell O, Möller HJ, Acad Sci U S A. 1999;96(26):15222-7. et al. Integration of fMRI and simultaneous EEG: towards a com- 34. Lopes da Silva FH. EEG Analysis. Theory and Practice. In: Nieder- prehensive understanding of localization and time-course of brain meyer E, Lopes da Silva FH, eds. Electroencephalography: Basic activity in target detection. Neuroimage. 2004;22(1):83-94. Principles, Clinical Applications and Related Fields. 4th Edition. 17. Zumsteg D, Wennberg RA, Treyer V, Buck A, Wieser HG. H2(15)O Baltimore: Lippincott Williams & Wilkens; 1999. p.1138-45. or 13NH3 PET and electromagnetic tomography (LORETA) during 35. Jeanmonod D, Werner B, Morel A, Michels L, Zadicario E, Schiff partial status epilepticus. . 2005;65(10):1657-60. G, et al. Transcranial magnetic resonance imaging-guided focused 18. Bolwig TG, Hansen ES, Hansen A, Merkin H, Prichep LS. Toward ultrasound: noninvasive central lateral thalamotomy for chronic a better understanding of the pathophysiology of OCD SSRI neuropathic pain. Neurosurg Focus. 2012;32(1):E1. responders: QEEG source localization. Acta Psychiatr Scand. 36. Balkany TJ, Hodges AV, Buchman CA, Luxford WM, Pillsbury 2007;115(3):237-42. CH, Roland PS, et al. Cochlear implant soft failures consensus 19. Prichep LS, John ER, Tom ML. Localization of deep white matter development conference statement. Otol Neurotol. 2005;26(4):815-8. lymphoma using VARETA: a case study. Clin Electroencephalogr. 2001;32(2):62-6.

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