title: Treating refractory mental illness with closed-loop brain stimulation: Progress towards a patient-specific transdiagnostic approach.
abstract: Mental disorders are a leading cause of disability, morbidity, and mortality among civilian and military populations. Most available treatments have limited efficacy, particularly in disorders where symptoms vary over relatively short time scales. Targeted modulation of neural circuits, particularly through open-loop deep brain stimulation (DBS), showed initial promise but has failed in blinded clinical trials. We propose a new approach, based on targeting neural circuits linked to functional domains that cut across diagnoses. Through that framework, which includes measurement of patients using six psychophysical tasks, we seek to develop a closed-loop DBS system that corrects dysfunctional activity in brain circuits underlying those domains. We present convergent preliminary evidence from functional neuroimaging, invasive human electrophysiology, and human brain stimulation experiments suggesting that this approach is feasible. Using the Emotional Conflict Resolution (ECR) task as an example, we show that emotion-related networks can be identified and modulated in individual patients. Invasive and non-invasive methodologies both identify a network between prefrontal cortex, cingulate cortex, insula, and amygdala. Further, stimulation in cingulate and amygdala changes patients' performance in ways that are linked to the task's emotional content. We present preliminary statistical models that predict this change and allow us to track it at a single-trial level. As these diagnostic and modeling strategies are refined and embodied in an implantable device, they offer the prospect of a new approach to psychiatric treatment and its accompanying neuroscience.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States; Picower Institute for Learning & Memory, Massachusetts Institute of Technology, Cambridge, MA, United Sates. Electronic address: awidge@partners.org.
authors.forename: Alik S
authors.initials: AS
authors.lastname: Widge
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ellard
authors.affiliation: Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Angelique C
authors.initials: AC
authors.lastname: Paulk
authors.affiliation: Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Ishita
authors.initials: I
authors.lastname: Basu
authors.affiliation: Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Ali
authors.initials: A
authors.lastname: Yousefi
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
authors.forename: Samuel
authors.initials: S
authors.lastname: Zorowitz
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Gilmour
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
authors.forename: Afsana
authors.initials: A
authors.lastname: Afzal
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
authors.forename: Thilo
authors.initials: T
authors.lastname: Deckersbach
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Sydney S
authors.initials: SS
authors.lastname: Cash
authors.affiliation: Department of Mathematics & Statistics, Boston University, Boston, MA, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Kramer
authors.affiliation: Department of Mathematics & Statistics, Boston University, Boston, MA, United States.
authors.forename: Uri T
authors.initials: UT
authors.lastname: Eden
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
authors.forename: Darin D
authors.initials: DD
authors.lastname: Dougherty
authors.affiliation: Department of Neurological Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Emad N
authors.initials: EN
authors.lastname: Eskandar
mesh_terms: D000679:Amygdala / Q000502:physiology; D002540:Cerebral Cortex / Q000502:physiology; D063132:Connectome; D046690:Deep Brain Stimulation / Q000295:instrumentation / Q000379:methods*; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004644:Emotions / Q000502:physiology*; D005246:Feedback; D006179:Gyrus Cinguli / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D001523:Mental Disorders / Q000175:diagnosis / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D059906:Neuroimaging; D010641:Phenotype; D017397:Prefrontal Cortex / Q000502:physiology; D011597:Psychomotor Performance / Q000502:physiology*; D063189:Symptom Assessment
keywords: Anxiety disorders; Deep brain stimulation; Electrophysiology; Functional imaging; Local field potential; Modeling; Mood disorders; Psychiatric diagnosis; Psychiatric illness