Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake craniotomy Kelly R. Bijanki, … , Helen S. Mayberg, Jon T. Willie J Clin Invest. 2018. https://doi.org/10.1172/JCI120110. Clinical Medicine In-Press Preview Neuroscience Therapeutics BACKGROUND. Awake neurosurgery requires patients to converse and respond to visual or verbal prompts to identify and protect brain tissue supporting essential functions such as language, primary sensory modalities, and motor function. These procedures can be poorly tolerated due to patient anxiety, yet acute anxiolytic medications typically cause sedation and impair cortical function. METHODS. In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was discovered to reliably evoke positive affect and anxiolysis without sedation in an epilepsy patient undergoing research testing during standard, in-patient intracranial electrode monitoring. These effects were quantified using subjective and objective behavioral measures, and stimulation was found to evoke robust changes in local and distant neural activity. RESULTS. The index patient ultimately required an awake craniotomy procedure to confirm safe resection margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced positive affect and reduced the patient’s anxiety to the point that intravenous anesthetic/anxiolytic medications were discontinued and cognitive testing was completed. Behavioral responses were subsequently replicated in two patients with anatomically similar electrode placements localized to an approximately 1cm span along the anterior dorsal cingulum bundle above […] Find the latest version: https://jci.me/120110/pdf Running Head: Cingulum Stimulation Evokes Positive Affect. 1 Title: Cingulum stimulation enhances positive affect and anxiolysis to facilitate awake 2 craniotomy. 3 4 Authors: Kelly R. Bijanki1,2, Joseph R. Manns3, Cory S. Inman1, Ki Sueng Choi2, Sahar Harati4, Nigel 5 P. Pedersen5, Daniel L. Drane5, Allison C. Waters2, Rebecca E. Fasano5, Helen S. Mayberg2,5, Jon T. 6 Willie1* 7 8 Affiliations: 9 10 1 Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA. 11 2 Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, USA. 12 3 Department of Psychology, Emory University College of Arts and Sciences, Atlanta, GA 30322, USA. 13 4 Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA 30322, USA. 14 5 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA. 15 * Corresponding Author: Jon T. Willie, 1365 Clifton Rd NE, Suite B6200, Atlanta, GA 30322, USA. 16 [email protected], telephone 404-727-2354. 17 Abstract: 18 Background: Awake neurosurgery requires patients to converse and respond to visual or verbal prompts 19 to identify and protect brain tissue supporting essential functions such as language, primary sensory 20 modalities, and motor function. These procedures can be poorly tolerated due to patient anxiety, yet 21 acute anxiolytic medications typically cause sedation and impair cortical function. 22 Methods: In this study, direct electrical stimulation of the left dorsal anterior cingulum bundle was 23 discovered to reliably evoke positive affect and anxiolysis without sedation in an epilepsy patient 24 undergoing research testing during standard, in-patient intracranial electrode monitoring. These effects 25 were quantified using subjective and objective behavioral measures, and stimulation was found to evoke 26 robust changes in local and distant neural activity. 27 Results: The index patient ultimately required an awake craniotomy procedure to confirm safe resection 28 margins in the treatment of her epilepsy. During the procedure, cingulum bundle stimulation enhanced 29 positive affect and reduced the patient’s anxiety to the point that intravenous anesthetic/anxiolytic 30 medications were discontinued and cognitive testing was completed. Behavioral responses were 31 subsequently replicated in two patients with anatomically similar electrode placements localized to an 32 approximately 1cm span along the anterior dorsal cingulum bundle above genu of the corpus callosum. 33 Conclusions: The current study demonstrates a robust anxiolytic response to cingulum bundle 34 stimulation in three epilepsy patients. 35 Trial Registration: The current study was not affiliated with any formal clinical trial. 36 Funding: This project was supported by the American Foundation for Suicide Prevention and the 37 National Institutes of Health. 38 Conflicts of Interest Statement: KRB, JTW, NPP, and CSI are named inventors on a patent filing 39 based on the described work. Unrelated to the current work, HSM receives fees from licensing of 40 Intellectual Property to St. Jude Medical Inc., DLD receives grant funding from Medtronic, Inc., and 41 honoraria from Neuropace, Inc. and JTW serves as a consultant for Medtronic, Inc., MRI Interventions, 42 Inc., and Neuropace, Inc. All other authors declare no conflicts of interest exist. 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Introduction 73 74 Neurosurgical procedures are performed awake when evaluation of neurological function is 75 necessary. Typical examples include deep brain stimulation (DBS) electrode placement for movement 76 disorders and awake craniotomy to resect mass lesions or seizure foci near “eloquent” cortices which, if 77 removed, can cause obvious motor, sensory, or linguistic disability. When patients are too anxious to 78 tolerate awake procedures, surgery under general anesthesia risks failure to achieve maximal safe 79 resection with minimal collateral disability. A non-sedating method that facilitates patient tolerance of 80 awake functional-anatomical correlation would be potentially transformative for neurosurgery. 81 The cingulum bundle is a white matter tract coursing longitudinally from anterior to posterior, 82 wrapping around the corpus callosum from genu to splenium. The cingulum bundle serves to connect 83 the cingulate cortices, dorsomedial prefrontal cortices, basal forebrain, parietal precunei, and temporal 84 hippocampal/parahippocampal gyri (1-3). The anterior cingulate cortex (ACC) has been ascribed 85 putative roles in a wide variety of emotional and cognitive functions, including modulation of affective 86 responses, error detection and conflict monitoring, regulation of anxiety and depression, attending to 87 physical pain and social distress, and the motivation to persevere (4-7). Electrical stimulation of dorsal 88 ACC gray matter can elicit transient euphoria and/or analgesia (8-12), and the cingulum bundle has 89 recently been suggested to mediate part of the therapeutic effects of DBS for depression (13,14). Indeed, 90 white matter stimulation is increasingly recognized as a preferred approach to therapy, especially for 91 psychiatric disorders (15-17). 92 Patients with focal medically-refractory epilepsy often undergo diagnostic intracranial 93 electroencephalography (iEEG) with temporarily implanted electrode arrays to localize seizure onsets in 94 advance of definitive surgical therapies (18). We report the case of an epilepsy patient undergoing iEEG 95 that included depth electrodes within the anterior cingulum bundle. Low amplitude stimulation induced 96 acute outward signs of mirth, subjective reports of happiness and relaxation, and persistent objective 97 behavioral features of positive affect. After characterization of acute behavioral and electrophysiological 98 responses, prolonged cingulum stimulation provided robust and effective anxiolysis without sedation 99 during awake resection for epilepsy in the language dominant posterior temporal lobe. Similarly low 100 threshold behavioral responses to stimulation were replicated in two additional epilepsy iEEG patients 101 with very similar electrode placement in the cingulum bundle. Cingulum bundle stimulation may have 102 implications for treatment of anxiety and mood disorders. 103 104 Results 105 106 Part I: Research study of affective modulation via limbic stimulation. 107 108 Case history and clinical characteristics: 109 Index Patient - A 23-year old, left-handed, English-speaking, woman with an 8-year history of 110 chronic medically-refractory focal dyscognitive seizures underwent comprehensive epilepsy evaluation 111 that included scalp EEG with poorly localized left hemispheric seizure onsets, normal MRI with left 112 hemisphere language dominance, left temporal interictal hypometabolism on 5-deoxyglucose positron 113 emission tomography, magnetoencephalogram with few poorly developed epileptiform discharges in the 114 posterior temporal region, and non-lateralizing neuropsychological findings with normal intelligence 115 (see Supplemental Materials for additional clinical characteristics). Prior intracranial electrode 116 monitoring at another institution localized seizures in part to the left posterior temporal-parietal junction 117 near sensory cortices and Wernicke’s area, but resection had not been performed. 118 In addition to epilepsy, the patient had a history of mild untreated depression which was 119 attributed to side effects of antiepileptic medications. Standard neuropsychological measures revealed 120 only minimal depression (Beck Depression Inventory = 4) but moderate anxiety (Beck Anxiety 121 Inventory = 22) at baseline, indicating a potentially clinically significant symptom burden