Resting-State Functional Connectivity of the Amygdala and Hippocampus in PTSD: Results From the PGC-ENIGMA PTSD Working Group

Cecilia A Hinojosa; Delin Sun; Courtney Russell; C Lexi Baird; Ahmed Hussain; Mohammad Sendi; Neda Jahanshad; Lauren E Salminen; Miranda Olff; Jessie L Frijling; Dick J Veltman; Saskia B J Koch; Laura Nawijn; Mirjam van Zuiden; Li Wang; Ye Zhu; Gen Li; Dan J Stein; Jonathan Ipser; Sheri-Michelle Koopowitz; Yuval Neria; Xi Zhu; Orren Ravid; Sigal Zilcha-Mano; Amit Lazarov; Benjamin Suarez-Jimenez; Ashley A Huggins; Kerry Ressler; Tanja Jovanovic; Negar Fani; Sven C Mueller; Anna R Hudson; Judith K Daniels; Anika Sierk; Antje Manthey; Henrik Walter; Nic J A van der Wee; Steven J A van der Werff; Robert R J M Vermeiren; Ivan Rektor; Pavel Říha; Milissa L Kaufman; Lauren A M Lebois; Justin T Baker; Anthony King; Israel Liberzon; Mike Angstadt; Nicholas D Davenport; Seth G Disner; Scott R Sponheim; Thomas Straube; David Hofmann; Guang Ming Lu; Rongfeng Qi; Xin Wang; Austin Kunch; Hong Xie; Yann Quidé; Wissam El-Hage; Shmuel Lissek; Hannah Berg; Josh Cisler; Marisa Ross; Ryan J Herringa; Daniel W Grupe; Jack B Nitschke; Richard J Davidson; Christine L Larson; Terri A deRoon-Cassini; Carissa W Tomas; Jacklynn M Fitzgerald; Brandee Feola; Jennifer Urbano-Blackford; Bunmi O Olatunji; Geoffrey May; Steven M Nelson; Evan M Gordon; Chadi G Abdallah; Ruth Lanius; Maria Densmore; Jean Théberge; Richard W J Neufeld; Lee A Baugh; Raluca M Simons; Jeffrey S Simons; Vincent A Magnotta; Kelene A Fercho; Jeremy Elman; Matthew Panizzon; Carol Franz; Michael J Lyons; William Kremen; Katie A McLaughin; Matthew Peverill; Kelly Sambrook; Paul M Thompson; Jennifer S Stevens; Rajendra A Morey; Sanne J H van Rooij

doi:10.1176/appi.ajp.20250062

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Resting-State Functional Connectivity of the Amygdala and Hippocampus in PTSD: Results From the PGC-ENIGMA PTSD Working Group

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Resting-State Functional Connectivity of the Amygdala and Hippocampus in PTSD: Results From the PGC-ENIGMA PTSD Working Group

Cecilia A Hinojosa, Delin Sun, Courtney Russell, C Lexi Baird, Ahmed Hussain, Mohammad Sendi, Neda Jahanshad, Lauren E Salminen, Miranda Olff, Jessie L Frijling, …

The American journal of psychiatry, Vol.183(5), pp.333-342

05/01/2026

DOI: 10.1176/appi.ajp.20250062

PMID: 41922983

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Abstract

Studies investigating resting-state functional connectivity of the amygdala and hippocampus have produced inconsistent findings. The authors' objective was to conduct the largest systematic comparison of alterations in functional connectivity of the amygdala and hippocampus in individuals with posttraumatic stress disorder (PTSD) using a multicohort mega-analysis with uniform processing steps and parameters across all cohorts. Resting-state functional MRI data from 1,017 PTSD patients and 1,702 control participants from 32 international sites were centrally preprocessed with HALFpipe and analyzed using the Image-Based Meta- and Mega-Analysis (IBMMA) package for neuroimaging processing. Group-level seed-based whole-brain analyses were completed for the right and left amygdala and hippocampus. Additional correlation analyses were conducted between PTSD norm-severity scores and resting-state functional connectivity (rs-FC). Compared to control participants, individuals with PTSD showed stronger rs-FC between the left amygdala seed and right hippocampus and amygdala and the left and right lingual gyri. Greater PTSD total norm-severity scores were significantly associated with rs-FC between the left amygdala and right hippocampus/amygdala and rs-FC between the right amygdala and left hippocampus/amygdala. Greater connectivity between subcortical threat centers involved in fear processing, memory, and extinction learning characterizes the resting state in PTSD. Future directions include investigating how different interventions, such as brain stimulation, neurofeedback, and psychotherapy, might modulate the aberrant neural networks in PTSD.

Neuroimaging

Posttraumatic Stress Disorder (PTSD)

Details

Title: Subtitle: Resting-State Functional Connectivity of the Amygdala and Hippocampus in PTSD: Results From the PGC-ENIGMA PTSD Working Group
Creators: Cecilia A Hinojosa - Emory University
Delin Sun - Duke University
Courtney Russell - Duke University
C Lexi Baird - Pennsylvania State University
Ahmed Hussain - Duke University
Mohammad Sendi - Harvard University
Neda Jahanshad - Marina Del Rey Hospital
Lauren E Salminen - Marina Del Rey Hospital
Miranda Olff - Arq Psychotrauma Expert Group
Jessie L Frijling - Amsterdam Neuroscience
Dick J Veltman - Amsterdam Neuroscience
Saskia B J Koch - Radboud University Nijmegen
Laura Nawijn - Amsterdam Neuroscience
Mirjam van Zuiden - Utrecht University
Li Wang - Chinese Academy of Sciences
Ye Zhu - Chinese Academy of Sciences
Gen Li - Chinese Academy of Sciences
Dan J Stein - South African Medical Research Council
Jonathan Ipser - University of Cape Town
Sheri-Michelle Koopowitz - South African Medical Research Council
Yuval Neria - Columbia University Irving Medical Center
Xi Zhu - Columbia University Irving Medical Center
Orren Ravid - New York State Psychiatric Institute
Sigal Zilcha-Mano - University of Haifa
Amit Lazarov - Tel Aviv University
Benjamin Suarez-Jimenez - University of Rochester Medical Center
Ashley A Huggins - University of Arizona
Kerry Ressler - McLean Hospital
Tanja Jovanovic - Wayne State University
Negar Fani - Emory University
Sven C Mueller - Ghent University Hospital
Anna R Hudson - Ghent University Hospital
Judith K Daniels - University of Groningen
Anika Sierk - Charité - Universitätsmedizin Berlin
Antje Manthey - Charité - Universitätsmedizin Berlin
Henrik Walter - Charité - Universitätsmedizin Berlin
Nic J A van der Wee - Leiden University Medical Center
Steven J A van der Werff - Leiden University Medical Center
Robert R J M Vermeiren - Leiden University Medical Center
Ivan Rektor - Central European Institute of Technology
Pavel Říha - Masaryk University
Milissa L Kaufman - McLean Hospital
Lauren A M Lebois - Harvard University
Justin T Baker - McLean Hospital
Anthony King - University of Michigan
Israel Liberzon - Texas A&M Health Science Center
Mike Angstadt - University of Michigan
Nicholas D Davenport - Minneapolis VA Health Care System
Seth G Disner - Minneapolis VA Health Care System
Scott R Sponheim - Minneapolis VA Health Care System
Thomas Straube - University of Münster
David Hofmann - University of Münster
Guang Ming Lu - Nanjing University
Rongfeng Qi - Nanjing University
Xin Wang - University of Toledo
Austin Kunch - University of Toledo
Hong Xie - University of Toledo
Yann Quidé - UNSW Sydney
Wissam El-Hage - Université de Tours
Shmuel Lissek - University of Minnesota
Hannah Berg - University of Minnesota
Josh Cisler - The University of Texas at Austin
Marisa Ross - Northwestern University
Ryan J Herringa - University of Wisconsin–Madison
Daniel W Grupe - University of Wisconsin Health
Jack B Nitschke - University of Wisconsin–Madison
Richard J Davidson - University of Wisconsin–Madison
Christine L Larson - University of Wisconsin–Milwaukee
Terri A deRoon-Cassini - Medical College of Wisconsin
Carissa W Tomas - Medical College of Wisconsin
Jacklynn M Fitzgerald - Marquette University
Brandee Feola - Vanderbilt University Medical Center
Jennifer Urbano-Blackford - Nebraska Medical Center
Bunmi O Olatunji - Vanderbilt University
Geoffrey May - The University of Texas at Dallas
Steven M Nelson - Baylor University
Evan M Gordon - Washington University in St. Louis
Chadi G Abdallah - Baylor College of Medicine
Ruth Lanius - Western University
Maria Densmore - Western University
Jean Théberge - Western University
Richard W J Neufeld - Western University
Lee A Baugh - Sioux Falls VA Health Care System
Raluca M Simons - University of South Dakota
Jeffrey S Simons - University of South Dakota
Vincent A Magnotta - University of Iowa
Kelene A Fercho - University of South Dakota
Jeremy Elman - University of California San Diego
Matthew Panizzon - University of California San Diego
Carol Franz - University of California San Diego
Michael J Lyons - Boston University
William Kremen - University of California San Diego
Katie A McLaughin - Harvard University Press
Matthew Peverill - University of Washington
Kelly Sambrook - University of Washington
Paul M Thompson - Marina Del Rey Hospital
Jennifer S Stevens - Emory University
Rajendra A Morey - Duke University
Sanne J H van Rooij - Emory University
Resource Type: Journal article
Publication Details: The American journal of psychiatry, Vol.183(5), pp.333-342
DOI: 10.1176/appi.ajp.20250062
PMID: 41922983
NLM abbreviation: Am J Psychiatry
ISSN: 1535-7228
eISSN: 1535-7228
Publisher: AMER PSYCHIATRIC PUBLISHING, INC; WASHINGTON
Grant note: NIAAA: K99AA031333, R00AA031333 NIMH: R01MH111671, R01MH129832, R01MH116147, R01MH105355-01A, K01 MH118428-01, MH098212, MH071537, MH101380, R21MH112956, R01MH119227, K01MH118467, R01MH113574, 1R01MH110483, 1R21MH098198, R01-MH043454, T32-MH018931, R01MH106574, R21MH106998, K01MH121653 VISN 6 Mental Illness Research, Education, and Clinical Center National Institute on Aging (NIA): R01AG059874 Michael J. Fox Foundation: 14848 NIA: R01ES033961, R56AG058854, R01AG050595, R01AG022381 National Institute of Environmental Health Sciences: R01ES033961 Department of Defense: W81XWH-12-2-0012, W81XWH-10-1-0925 NIH Big Data to Knowledge (BD2K) program: U54 EB020403 BD2K program: U54 EB020403 National Institute of Biomedical Imaging and Bioengineering: P41 EB015922 ZonMw (the Netherlands Organization for Health Research and Development): 40-00812-98-10041 Academic Medical Center Research Council: 110614 National Natural Science Foundation of China: U21A20364, 31971020 National Social Science Foundation of China: 20ZDA079 Key Project of Research Base of Humanities and Social Sciences of Ministry of Education: 16JJD190006 Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences: E2CX4115CX South African Medical Research Council Unit on Risk and Resilience in Mental Disorders NARSAD: 27040 NIH National Centers for Research Resources: M01RR00039 National Center for Advancing Translational Sciences: UL1TR000454 National Institute of Child Health and Human Development: HD071982, HD085850 Special Research Fund (BOF) at Ghent University: 01J05415 German Research Foundation: DA 1222/4-1, WA 1539/8-2 Ministry of Health of the Czech Republic: AZV NV18-7 04-00559 McLean Hospital Trauma Scholars Fund Julia Kasparian Fund for Neuroscience Research VA Rehabilitation Research and Development Program: 1IK2RX000709, 1K1RX002325, 1K2RX002922, I01RX000622 Congressionally Directed Medical Research Program: W81XWH-08-2-0038, 1IK2CX001680 German Research Society (Deutsche Forschungsgemeinschaft): SFB/TRR 58: C06, SFB/TRR 58: C07 Natural Science Foundation of Jiangsu Province: BK20221554 Foundation for the Social Development Project of Jiangsu: BE2022705 Programme Hospitalier de Recherche Clinique Fondation Pierre Deniker SFR: FED4226 NICHD: P30-HD003352 National Science Foundation Dana Foundation VISN17 Center of Excellence VA National Center for PTSD Beth K. and Stuart Yudofsky Chair in the Neuropsychiatry of Military Post Traumatic Stress Syndrome Canadian Institutes of Health Research Canadian Institute for Military and Veteran Health Research Center for Brain and Behavior Research South Dakota Governor's Research Center NARSAD Young Investigator Award Biogen GE Healthcare SpinTech
Dr. Hinojosa received support from NIAAA grants K99AA031333 and R00AA031333. Dr. Sun, Ms. Russell, Mr. Hussain, Dr. Jahanshad, Dr. Thompson, and Dr. Morey received support from NIMH grants R01MH111671 and R01MH129832. Dr. Sun and Dr. Morey were also supported by the VISN 6 Mental Illness Research, Education, and Clinical Center. Dr. Jahanshad was also supported by National Institute on Aging (NIA) grant R01AG059874 and Michael J. Fox Foundation grant 14848. Dr. Salminen receives joint funding support from the NIA and the National Institute of Environmental Health Sciences (R01ES033961). Dr. Thompson was also supported by Department of Defense award W81XWH-12-2-0012, and ENIGMA was also supported in part by the NIH Big Data to Knowledge (BD2K) program under consortium grant U54 EB020403 and by grant U54 EB020403 from the BD2K program, NIA grant R56AG058854, NIMH grant R01MH116147, and National Institute of Biomedical Imaging and Bioengineering grant P41 EB015922. Dr. Olff received support from ZonMw (the Netherlands Organization for Health Research and Development) (40-00812-98-10041) and the Academic Medical Center Research Council (110614). Dr. Li Wang, Dr. Ye Zhu, and Dr. Gen Li received support from National Natural Science Foundation of China (U21A20364 and 31971020), the Key Project of the National Social Science Foundation of China (20ZDA079), the Key Project of Research Base of Humanities and Social Sciences of Ministry of Education (16JJD190006), and the Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences (E2CX4115CX). Dr. Stein received support from the South African Medical Research Council Unit on Risk and Resilience in Mental Disorders. Dr. Neria received support from NIMH grant R01MH105355-01A. Dr. Zhu received support from NARSAD award 27040. Dr. Suarez-Jimenez received support from NIMH grant K01 MH118428-01. Dr. Ressler, Dr. Jovanovic, and Dr. Stevens received support from NIMH grants MH098212 and MH071537, NIH National Centers for Research Resources grant M01RR00039, National Center for Advancing Translational Sciences grant UL1TR000454, and National Institute of Child Health and Human Development grants HD071982 and HD085850. Dr. Fani received support from NIMH grant MH101380. Dr. Mueller received support from grant 01J05415 from the Special Research Fund (BOF) at Ghent University. Dr. Daniels received support from German Research Foundation grants DA 1222/4-1 and WA 1539/8-2). Dr. Riha was supported by grant AZV NV18-7 04-00559 from the Ministry of Health of the Czech Republic. Dr. Kaufman received support from NIMH grants R21MH112956 and R01MH119227, the McLean Hospital Trauma Scholars Fund, and the Julia Kasparian Fund for Neuroscience Research. Dr. Lebois received support from NIMH grant K01MH118467 and the Julia Kasparian Fund for Neuroscience Research. Dr. Liberzon received support from NIMH grant R01MH113574. Dr. Davenport received support from VA Rehabilitation Research and Development Program grant 1IK2RX000709. Dr. Disner received support from VA Rehabilitation Research and Development Program grants 1K1RX002325 and 1K2RX002922. Dr. Sponheim received support from VA Rehabilitation Research and Development Program grant I01RX000622 and Congressionally Directed Medical Research Program grant W81XWH-08-2-0038. Dr. Straube and Dr. Hofmann received support from the German Research Society (Deutsche Forschungsgemeinschaft; SFB/TRR 58: C06, C07). Dr. Qi received support from the Natural Science Foundation of Jiangsu Province (BK20221554) and the Foundation for the Social Development Project of Jiangsu (BE2022705). Dr. Xin Wang received support from NIMH grants 1R01MH110483 and 1R21MH098198. Dr. El-Hage received support from the Programme Hospitalier de Recherche Clinique, the Fondation Pierre Deniker, and SFR FED4226. Dr. Grupe, Dr. Nitschke, and Dr. Davidson received support from a core grant to the Waisman Center from NICHD (P30-HD003352). Dr. Grupe was also supported by a National Science Foundation Graduate Research Fellowship. Dr. Nitschke was also supported by the Dana Foundation. Dr. Davidson was also supported by NIMH grants R01-MH043454 and T32-MH018931. Dr. Larson and Dr. deRoon-Cassini received support from NIMH grant R01MH106574. Dr. Urbano-Blackford and Dr. Olatunji received support from NIMH grant R21MH106998. Dr. May, Dr. Nelson, and Dr. Gordon received support from Congressionally Directed Medical Research Program grant 1IK2CX001680 and VISN17 Center of Excellence Pilot funding. Dr. Abdallah received support from the VA National Center for PTSD and the Beth K. and Stuart Yudofsky Chair in the Neuropsychiatry of Military Post Traumatic Stress Syndrome. Dr. Lanius received support from the Canadian Institutes of Health Research and the Canadian Institute for Military and Veteran Health Research. Dr. Baugh, Dr. R.M. Simons, Dr. J.S. Simons, Dr. Magnotta, and Dr. Fercho received support from Department of Defense grant W81XWH-10-1-0925, a Center for Brain and Behavior Research Pilot Grant, and a South Dakota Governor's Research Center Grant. Dr. Kremen received support from NIA grants R01AG050595 and R01AG022381. Dr. van Rooij received support from a NARSAD Young Investigator Award and from NIMH grant K01MH121653. Dr. Sendi has served as a consultant for Niji Corp and is the co-founder of Vitalytic AI. Dr. Jahanshad has received research support from Biogen. Dr. Stein has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L'Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. Dr. Walter has received honoraria and loyalties from Becker Joest Volk Verlag, Hilden, Thieme Verlag Stuttgart, and Springer Verlag Heidelberg, and lecture and related travel fees from Academy of Neuroscience, Koln, Rovi-GmbH, Holzkirchen, and Psi-Fit GmbH, Wolfsburg. Dr. Lebois has served as an unpaid member of the Scientific Committee for the International Society for the Study of Trauma and Dissociation, and she reports spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals and spousal private equity in Violet Therapeutics. Dr. Baker has received consulting fees from and has an equity stake in Tetricus Labs. Dr. El-Hage has received payments from Air Liquide, Chugai, Eisai, Jazz Pharmaceuticals, Janssen, Lundbeck, Otsuka, and UCB. Dr. Herringa has served as a consultant for Jazz Pharmaceuticals. Dr. Abdallah has served as a consultant, speaker, and/or on advisory boards for Douglas Pharmaceuticals, Freedom Biosciences, FSV7, Lundbeck, Psilocybin Labs, Genentech, and Janssen; and he has filed a patent for using mTOR inhibitors to augment the effects of antidepressants. Dr. Magnotta has received research support from GE Healthcare and SpinTech. Dr. Thompson received partial research support from Biogen. The other authors report no financial relationships with commercial interests.
Language: English
Electronic publication date: 04/02/2026
Date published: 05/01/2026
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute
Record Identifier: 9985149576002771

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