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Sci Transl Med. 2019 Apr 3;11(486). pii: eaal3236. doi: 10.1126/scitranslmed.aal3236.

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder.

Etkin A1,2,3,4, Maron-Katz A5,2,3,4, Wu W5,2,3,4,6, Fonzo GA5,2,3,4, Huemer J5,2,3, Vértes PE7,8,9, Patenaude B5,2,3,4, Richiardi J10,11, Goodkind MS12,13, Keller CJ5,2,3,4, Ramos-Cejudo J4,14, Zaiko YV5,2,3, Peng KK5,3, Shpigel E5,2,3,4, Longwell P5,2,3,4, Toll RT5,2,3,4, Thompson A5, Zack S5, Gonzalez B4,14, Edelstein R5,2,3,4, Chen J4,14, Akingbade I5,3,4, Weiss E5,3, Hart R4,14, Mann S4,14, Durkin K4,14, Baete SH4,12,13, Boada FE4,15,16, Genfi A4,14, Autea J5,2,3,4, Newman J4,14, Oathes DJ17, Lindley SE5,3, Abu-Amara D4,14, Arnow BA5, Crossley N18,19, Hallmayer J5,2,3, Fossati S4,14, Rothbaum BO20, Marmar CR4,14, Bullmore ET7,21,22, O'Hara R5,3.

Author information

Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94304, USA.
Wu Tsai Neurosciences Institute at Stanford, Stanford University, Stanford, CA 94304, USA.
Sierra Pacific Mental Illness Research, Education, and Clinical Center (MIRECC), Veterans Affairs Palo Alto Healthcare System, Palo Alto, CA 94394, USA.
Steven and Alexandra Cohen Veterans Center for Post-traumatic Stress and Traumatic Brain Injury, New York University Langone School of Medicine, New York, NY 10016, USA.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94304, USA.
School of Automation Science and Engineering, South China University of Technology, Guangzhou, Guangdong 510640, China.
Department of Psychiatry, Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 0SZ, UK.
School of Mathematical Sciences, Queen Mary University of London, London E1 4NS, UK.
The Alan Turing Institute, London NW1 2DB, UK.
Department of Medical Radiology, Lausanne University Hospital, Lausanne, Switzerland.
Advanced Clinical Imaging Technology, Siemens Healthcare AG, Lausanne, Switzerland.
New Mexico Veterans Affairs Healthcare System, Albuquerque, NM 87108, USA.
Department of Psychiatry and Behavioral Sciences, University of New Mexico, Albuquerque, NM 87131, USA.
Department of Psychiatry, New York University Langone School of Medicine, New York, NY 10016, USA.
Center for Advanced Imaging Innovation and Research (CAI2R), NYU School of Medicine, New York, NY 10016, USA.
Center for Biomedical Imaging, Department of Radiology, NYU School of Medicine, New York, NY 10016, USA.
Center for Neuromodulation in Depression and Stress, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Department of Psychiatry, School of Medicine, Pontificia Universidad Católica de Chile, 6513677 Santiago, Chile.
Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, UK.
Trauma and Anxiety Recovery Program, Department of Psychiatry, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cambridgeshire and Peterborough NHS Foundation Trust, Cambridge CB21 5EF, UK.
ImmunoPsychiatry, Alternative Discovery and Development, GlaxoSmithKline, Stevenage SG1 2NY, UK.


A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

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