title: The neurobiology of emotion regulation in posttraumatic stress disorder: Amygdala downregulation via real-time fMRI neurofeedback.
abstract: Amygdala dysregulation has been shown to be central to the pathophysiology of posttraumatic stress disorder (PTSD) representing a critical treatment target. Here, amygdala downregulation was targeted using real-time fMRI neurofeedback (rt-fMRI-nf) in patients with PTSD, allowing us to examine further the regulation of emotional states during symptom provocation. Patients (n = 10) completed three sessions of rt-fMRI-nf with the instruction to downregulate activation in the amygdala, while viewing personalized trauma words. Amygdala downregulation was assessed by contrasting (a) regulate trials, with (b) viewing trauma words and not attempting to regulate. Training was followed by one transfer run not involving neurofeedback. Generalized psychophysiological interaction (gPPI) and dynamic causal modeling (DCM) analyses were also computed to explore task-based functional connectivity and causal structure, respectively. It was found that PTSD patients were able to successfully downregulate both right and left amygdala activation, showing sustained effects within the transfer run. Increased activation in the dorsolateral and ventrolateral prefrontal cortex (PFC), regions related to emotion regulation, was observed during regulate as compared with view conditions. Importantly, activation in the PFC, rostral anterior cingulate cortex, and the insula, were negatively correlated to PTSD dissociative symptoms in the transfer run. Increased functional connectivity between the amygdala- and both the dorsolateral and dorsomedial PFC was found during regulate, as compared with view conditions during neurofeedback training. Finally, our DCM analysis exploring directional structure suggested that amygdala downregulation involves both top-down and bottom-up information flow with regard to observed PFC-amygdala connectivity. This is the first demonstration of successful downregulation of the amygdala using rt-fMRI-nf in PTSD, which was critically sustained in a subsequent transfer run without neurofeedback, and corresponded to increased connectivity with prefrontal regions involved in emotion regulation during the intervention. Hum Brain Mapp 38:541-560, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Neuroscience, Western University, London, Ontario, Canada.|Department of Psychiatry, Western University, London, Ontario, Canada.|Department of Imaging, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Nicholson
authors.affiliation: Department of Psychiatry, Western University, London, Ontario, Canada.|Department of Imaging, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rabellino
authors.affiliation: Department of Imaging, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Maria
authors.initials: M
authors.lastname: Densmore
authors.affiliation: Department of Neuroscience, Western University, London, Ontario, Canada.|Department of Psychology, Western University, London, Ontario, Canada.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Frewen
authors.affiliation: Department of Neuroimaging, Central Institute of Mental Health Mannheim, Medical, Faculty Mannheim/Heidelberg University, Heidelberg, Germany.|Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim/Heidelberg University, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Paret
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim/Heidelberg University, Heidelberg, Germany.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Kluetsch
authors.affiliation: Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim/Heidelberg University, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schmahl
authors.affiliation: Department of Psychiatry, Western University, London, Ontario, Canada.|Department of Imaging, Lawson Health Research Institute, London, Ontario, Canada.|Department of Medical Imaging, Western University, London, Ontario, Canada.|Department of, Medial Biophysics, Western University, London, Ontario, Canada.|Department of Diagnostic Imaging, St. Joseph's Healthcare, London, Ontario, Canada.
authors.forename: Jean
authors.initials: J
authors.lastname: Théberge
authors.affiliation: Department of Neuroscience, Western University, London, Ontario, Canada.|Department of Psychiatry, Western University, London, Ontario, Canada.|Department of Psychology, Western University, London, Ontario, Canada.
authors.forename: Richard W J
authors.initials: RW
authors.lastname: Neufeld
authors.affiliation: Mood Disorders Program and Clinical Neuropsychology Service, St. Joseph's Healthcare, Hamilton, Ontario, Canada.|Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Margaret C
authors.initials: MC
authors.lastname: McKinnon
authors.affiliation: Department of Psychiatry, Western University, London, Ontario, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Reiss
authors.affiliation: Canadian Forces, Health Services, Ottawa, Ontario, Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Jetly
authors.affiliation: Department of Neuroscience, Western University, London, Ontario, Canada.|Department of Psychiatry, Western University, London, Ontario, Canada.|Department of Imaging, Lawson Health Research Institute, London, Ontario, Canada.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Lanius
mesh_terms: D000328:Adult; D000679:Amygdala / Q000000981:diagnostic imaging / Q000503:physiopathology*; D000704:Analysis of Variance; D001921:Brain / Q000000981:diagnostic imaging*; D004644:Emotions / Q000502:physiology*; D056228:Feedback, Sensory / Q000502:physiology; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D008959:Models, Neurological; D010100:Oxygen / Q000097:blood; D013313:Stress Disorders, Post-Traumatic / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*
chemical_list: D010100:Oxygen
keywords: amygdala; brain connectivity; emotion; fMRI neurofeedback; posttraumatic stress disorder