Gregory A Fonzo1, Madeleine S Goodkind2, Desmond J Oathes3, Yevgeniya V Zaiko4, Meredith Harvey4, Kathy K Peng4, M Elizabeth Weiss4, Allison L Thompson5, Sanno E Zack5, Steven E Lindley6, Bruce A Arnow5, Booil Jo5, Barbara O Rothbaum7, Amit Etkin8. 1. Department of Psychiatry, University of Texas at Austin Dell Medical School, Austin, Texas. 2. New Mexico Veterans Affairs Healthcare System, Albuquerque, New Mexico. 3. Center for Neuromodulation in Depression and Stress, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania. 4. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California; Veterans Affairs Palo Alto Healthcare System and Sierra Pacific Mental Illness, Research, Education, and Clinical Center, Palo Alto, California. 5. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California. 6. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Veterans Affairs Palo Alto Healthcare System and Sierra Pacific Mental Illness, Research, Education, and Clinical Center, Palo Alto, California. 7. Trauma and Anxiety Recovery Program, Department of Psychiatry, Emory University School of Medicine, Atlanta, Georgia. 8. Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Wu Tsai Neurosciences Institute, Stanford University, Stanford, California; Alto Neuroscience, Los Altos, California. Electronic address: amitetkin@altoneuroscience.com.
Abstract
BACKGROUND: Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment-related connectivity changes and their relationship to PTSD symptom improvements. METHODS: Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level-dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings. RESULTS: The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala-frontal connectivity and insula-parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions. CONCLUSIONS: PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.
BACKGROUND: Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment-related connectivity changes and their relationship to PTSD symptom improvements. METHODS: Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level-dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings. RESULTS: The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala-frontal connectivity and insula-parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions. CONCLUSIONS: PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.
Authors: Paul S Muhle-Karbe; Jan Derrfuss; Margaret T Lynn; Franz X Neubert; Peter T Fox; Marcel Brass; Simon B Eickhoff Journal: Cereb Cortex Date: 2015-04-21 Impact factor: 5.357
Authors: Amit Etkin; Adi Maron-Katz; Wei Wu; Gregory A Fonzo; Julia Huemer; Petra E Vértes; Brian Patenaude; Jonas Richiardi; Madeleine S Goodkind; Corey J Keller; Jaime Ramos-Cejudo; Yevgeniya V Zaiko; Kathy K Peng; Emmanuel Shpigel; Parker Longwell; Russ T Toll; Allison Thompson; Sanno Zack; Bryan Gonzalez; Raleigh Edelstein; Jingyun Chen; Irene Akingbade; Elizabeth Weiss; Roland Hart; Silas Mann; Kathleen Durkin; Steven H Baete; Fernando E Boada; Afia Genfi; Jillian Autea; Jennifer Newman; Desmond J Oathes; Steven E Lindley; Duna Abu-Amara; Bruce A Arnow; Nicolas Crossley; Joachim Hallmayer; Silvia Fossati; Barbara O Rothbaum; Charles R Marmar; Edward T Bullmore; Ruth O'Hara Journal: Sci Transl Med Date: 2019-04-03 Impact factor: 17.956
Authors: Xi Zhu; Benjamin Suarez-Jimenez; Amit Lazarov; Liat Helpman; Santiago Papini; Ari Lowell; Ariel Durosky; Martin A Lindquist; John C Markowitz; Franklin Schneier; Tor D Wager; Yuval Neria Journal: Depress Anxiety Date: 2018-09-10 Impact factor: 6.505
Authors: Rajendra A Morey; Florin Dolcos; Christopher M Petty; Debra A Cooper; Jasmeet Pannu Hayes; Kevin S LaBar; Gregory McCarthy Journal: J Psychiatr Res Date: 2008-12-16 Impact factor: 4.791
Authors: Charles W Hoge; Lyndon A Riviere; Joshua E Wilk; Richard K Herrell; Frank W Weathers Journal: Lancet Psychiatry Date: 2014-08-14 Impact factor: 27.083
Authors: Brian Shiner; Jenna A Forehand; Luke Rozema; Martin Kulldorff; Bradley V Watts; Marina Trefethen; Tammy Jiang; Krista F Huybrechts; Paula P Schnurr; Matthew Vincenti; Jiang Gui; Jaimie L Gradus Journal: Biol Psychiatry Date: 2021-10-20 Impact factor: 13.382
Authors: John R Kelly; Claire M Gillan; Jack Prenderville; Clare Kelly; Andrew Harkin; Gerard Clarke; Veronica O'Keane Journal: Front Psychiatry Date: 2021-12-17 Impact factor: 4.157
Authors: Paul Zhutovsky; Jasper B Zantvoord; Judith B M Ensink; Rosanne Op den Kelder; Ramon J L Lindauer; Guido A van Wingen Journal: Neuroimage Clin Date: 2021-11-26 Impact factor: 4.881