Lower Gyrification of the Ventromedial Prefrontal Cortex in Posttraumatic Stress Disorder: An ENIGMA-PTSD Study

Ahmed Hussain; C Lexi Baird; Ashley A Huggins; Courtney C Russell; Delin Sun; Leonel Rangel-Jimenez; Chadi G Abdallah; Michael Angstadt; Geoffrey May; Hannah Berg; Jennifer U Blackford; Josh Cisler; Judith K Daniels; Nicholas D Davenport; Richard J Davidson; Maria Densmore; Seth G Disner; Wissam El-Hage; Amit Etkin; Negar Fani; Jessie L Frijling; Evan M Gordon; Daniel W Grupe; Ryan A Herringa; Julia I Herzog; David Hofmann; Anna R Hudson; Tanja Jovanovic; Anthony King; Saskia B J Koch; Ruth A Lanius; Amit Lazarov; Gen Li; Israel Liberzon; Shmuel Lissek; Guangming Lu; Antje Manthey; Adi Maron-Katz; Katie A McLaughlin; Sven C Mueller; Laura Nawijn; Steven M Nelson; Yuval Neria; Richard W J Neufeld; Jack B Nitschke; Bunmi O Olatunji; Miranda Olff; Matthew Peverill; Rongfeng Qi; Yann Quidé; Orren Ravid; Ivan Rektor; Kerry J Ressler; Pavel Říha; Marisa Ross; Kelly Sambrook; Christian Schmahl; Anika Sierk; Scott R Sponheim; Jennifer S Stevens; Thomas Straube; Benjamin Suarez-Jimenez; Jean Théberge; Nic J A van der Wee; Steven J A van der Werff; Sanne J H van Rooij; Mirjam van Zuiden; Dick J Veltman; Robert R J M Vermeiren; Henrik Walter; Li Wang; Xi Zhu; Ye Zhu; Sigal Zilcha-Mano; Neda Jahanshad; Paul M Thompson; Rajendra A Morey

doi:10.1016/j.bpsgos.2025.100679

Lower Gyrification of the Ventromedial Prefrontal Cortex in Posttraumatic Stress Disorder: An ENIGMA-PTSD Study

Biol Psychiatry Glob Open Sci. 2025 Dec 18;6(2):100679. doi: 10.1016/j.bpsgos.2025.100679. eCollection 2026 Mar.

Authors

Ahmed Hussain^{1

2}, C Lexi Baird^{1

2

3}, Ashley A Huggins⁴, Courtney C Russell^{1

2}, Delin Sun^{1

2

5}, Leonel Rangel-Jimenez^{1

2}, Chadi G Abdallah^{6

7}, Michael Angstadt⁸, Geoffrey May^{9

10

11}, Hannah Berg¹², Jennifer U Blackford¹³, Josh Cisler¹⁴, Judith K Daniels¹⁵, Nicholas D Davenport^{16

17}, Richard J Davidson^{18

19

20}, Maria Densmore²¹, Seth G Disner^{16

17}, Wissam El-Hage^{22

23}, Amit Etkin^{24

25}, Negar Fani²⁶, Jessie L Frijling^{27

28}, Evan M Gordon²⁹, Daniel W Grupe¹⁸, Ryan A Herringa³⁰, Julia I Herzog³¹, David Hofmann³², Anna R Hudson³³, Tanja Jovanovic^{26

34}, Anthony King⁸, Saskia B J Koch^{28

35}, Ruth A Lanius^{21

36}, Amit Lazarov^{37

38}, Gen Li^{39

40}, Israel Liberzon⁴¹, Shmuel Lissek¹², Guangming Lu⁴², Antje Manthey⁴³, Adi Maron-Katz²⁴, Katie A McLaughlin⁴⁴, Sven C Mueller³³, Laura Nawijn^{28

45}, Steven M Nelson^{9

10

11

46}, Yuval Neria^{47

38}, Richard W J Neufeld²¹, Jack B Nitschke¹⁹, Bunmi O Olatunji⁴⁸, Miranda Olff^{28

49}, Matthew Peverill⁵⁰, Rongfeng Qi⁴², Yann Quidé^{51

52}, Orren Ravid⁴⁷, Ivan Rektor⁵³, Kerry J Ressler^{26

54

55}, Pavel Říha^{53

56}, Marisa Ross⁵⁷, Kelly Sambrook⁵⁸, Christian Schmahl³¹, Anika Sierk⁵⁹, Scott R Sponheim^{16

17}, Jennifer S Stevens²⁶, Thomas Straube³², Benjamin Suarez-Jimenez⁶⁰, Jean Théberge²¹, Nic J A van der Wee^{61

62}, Steven J A van der Werff^{61

62}, Sanne J H van Rooij²⁶, Mirjam van Zuiden^{28

63}, Dick J Veltman^{28

64}, Robert R J M Vermeiren⁶⁵, Henrik Walter⁵⁹, Li Wang^{39

40}, Xi Zhu^{38

66}, Ye Zhu^{39

40}, Sigal Zilcha-Mano⁶⁷, Neda Jahanshad⁶⁸, Paul M Thompson⁶⁸, Rajendra A Morey^{1

2}

Affiliations

¹ Brain Imaging and Analysis Center, Duke University, Durham, North Carolina.
² Department of Veteran Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center, Durham, North Carolina.
³ Department of Psychology, Pennsylvania State University, State College, Pennsylvania.
⁴ Department of Psychology, University of Arizona, Tucson, Arizona.
⁵ Department of Psychiatry and Behavioral Sciences, School of Medicine, Duke University, Durham, North Carolina.
⁶ Department of Psychiatry, Baylor College of Medicine, Houston, Texas.
⁷ Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut.
⁸ Department of Psychiatry, University of Michigan, Ann Arbor, Michigan.
⁹ Center for Vital Longevity, School of Behavioral and Brain Sciences, University of Texas at Dallas, Dallas, Texas.
¹⁰ Department of Psychology and Neuroscience, Baylor University, Waco, Texas.
¹¹ Veterans Integrated Service Network-17 Center of Excellence for Research on Returning War Veterans, Waco, Texas.
¹² Department of Psychology, University of Minnesota, Minneapolis, Minnesota.
¹³ University of Nebraska Medical Center, Munroe-Meyer Institute, Omaha, Nebraska.
¹⁴ Department of Psychiatry, University of Texas at Austin, Austin, Texas.
¹⁵ Department of Clinical Psychology, University of Groningen, Groningen, the Netherlands.
¹⁶ Minneapolis VA Health Care System, Minneapolis, Minnesota.
¹⁷ Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota.
¹⁸ Center for Healthy Minds, University of Wisconsin-Madison, Madison, Wisconsin.
¹⁹ Department of Psychiatry, University of Wisconsin-Madison, Madison, Wisconsin.
²⁰ Department of Psychology, University of Wisconsin-Madison, Madison, Wisconsin.
²¹ Department of Psychiatry, Western University, London, Ontario, Canada.
²² UMR1253, Université de Tours, Institut National de la Santé et de la Recherche Médicale (INSERM), Tours, France.
²³ CIC1415, CHRU de Tours, INSERM, Tours, France.
²⁴ Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Palo Alto, California.
²⁵ VA Palo Alto Health Care System, Palo Alto, California.
²⁶ Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia.
²⁷ De Viersprong, Netherlands Institute for Personality Disorders, Amsterdam, the Netherlands.
²⁸ Amsterdam University Medical Center (UMC) University of Amsterdam, Psychiatry, Amsterdam Neuroscience, Amsterdam, the Netherlands.
²⁹ Department of Radiology, Washington University School of Medicine, St. Louis, Missouri.
³⁰ School of Medicine and Public Health, University of Wisconsin Madison, Madison, Wisconsin.
³¹ Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany.
³² Institute of Medical Psychology and Systems Neuroscience, University of Münster, Münster, Germany.
³³ Department of Experimental Clinical and Health Psychology, Ghent University, Ghent, Belgium.
³⁴ Department of Psychiatry and Behavioral Neuroscience, Wayne State University School of Medicine, Detroit, Michigan.
³⁵ Donders Institute for Brain, Cognition and Behavior, Centre for Cognitive Neuroimaging, Radboud University Nijmegen, Nijmegen, the Netherlands.
³⁶ Department of Neuroscience, Western University, London, Ontario, Canada.
³⁷ Tel Aviv University, Tel Aviv-Yafo, Israel.
³⁸ Department of Psychiatry, Columbia University Medical Center, New York, New York.
³⁹ Laboratory for Traumatic Stress Studies, Chinese Academy of Sciences Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China.
⁴⁰ Department of Psychology, University of Chinese Academy of Sciences, Beijing, China.
⁴¹ Department of Psychiatry, Texas A&M University, Bryan, Texas.
⁴² Department of Medical Imaging, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
⁴³ Charité Universitätsmedizin Berlin, Berlin, Germany.
⁴⁴ Department of Psychology, Harvard University, Cambridge, Massachusetts.
⁴⁵ Department of Clinical Psychology, Leiden University, Leiden, the Netherlands.
⁴⁶ Department of Psychiatry and Behavioral Science, Texas A&M University Health Science Center, Bryan, Texas.
⁴⁷ New York State Psychiatric Institute, New York, New York.
⁴⁸ Department of Psychology, Vanderbilt University, Nashville, Tennessee.
⁴⁹ ARQ National Psychotrauma Centre, Diemen, the Netherlands.
⁵⁰ Department of Psychology, University of Washington, Seattle, Washington.
⁵¹ School of Psychology, University of New South Wales Sydney, Sydney, New South Wales, Australia.
⁵² Neuroscience Research Australia, Randwick, New South Wales, Australia.
⁵³ Central European Institute of Technology, Multimodal and Functional Neuroimaging Research Group, Masaryk University, Brno, Czech Republicia.
⁵⁴ Division of Depression and Anxiety Disorders, McLean Hospital, Belmont, Massachusetts.
⁵⁵ Department of Psychiatry, Harvard Medical School, Boston, Massachusetts.
⁵⁶ First Department of Neurology, St. Anne's University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republicia.
⁵⁷ Northwestern Neighborhood and Network Initiative, Northwestern University Institute for Policy Research, Evanston, Illinois.
⁵⁸ Department of Radiology, University of Washington, Seattle, Washington.
⁵⁹ University Medical Centre Charité, Berlin, Germany.
⁶⁰ Department of Neuroscience, University of Rochester Medical Center, Rochester, New York.
⁶¹ Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.
⁶² Leiden Institute for Brain and Cognition, Leiden, the Netherlands.
⁶³ Department of Clinical Psychology, Utrecht University, Utrecht, the Netherlands.
⁶⁴ Amsterdam UMC Vrije Universiteit, Psychiatry, Amsterdam Neuroscience, Amsterdam, the Netherlands.
⁶⁵ Department of Child and Adolescent Psychiatry, Leiden University Medical Center, Leiden, the Netherlands.
⁶⁶ Department of Bioengineering, University of Texas at Arlington, Arlington, Texas.
⁶⁷ Department of Psychology, University of Haifa, Haifa, Israel.
⁶⁸ Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of University of Southern California, Marina del Rey, California.

Abstract

Background: Cortical gyrification involves the formation of folds in the cerebral cortex, coinciding with key neurodevelopmental processes. Its strong correlation with increased cortical surface area and decreased cortical thickness may improve cortical signaling efficiency by decreasing cortico-cortical distance. Differences in brain structure have been found in posttraumatic stress disorder (PTSD), yet few small studies have examined cortical gyrification.

Methods: Gyrification was quantified using FreeSurfer's Local Gyrification Index (lGI), derived from 3-dimensional T1-weighted volumetric brain magnetic resonance imaging in 1876 participants (PTSD n = 789, control n = 1087) across 24 sites from the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium) PTSD working group. Using a region of interest-based approach, we fitted a linear mixed-effects model with age (mean = 35.6, SD = 9.23, range = 8-95), sex (female = 967 [52%], male = 909 [48%]), pial surface area, PTSD, and random site effects to test associations between PTSD diagnosis/severity and regional lGI. We examined moderating effects of depression, childhood trauma, age, and sex.

Results: PTSD diagnosis and severity were both associated with lower lGI for the right medial orbitofrontal and right rostral anterior cingulate cortices. The interaction of PTSD and age was associated with lower lGI for the rostral middle frontal cortex bilaterally. Contrasting comorbid PTSD and major depressive disorder with the PTSD-only group showed that comorbidity was associated with lower lGI in the left inferior and medial temporal cortices.

Conclusions: Lower lGI, which is associated with impaired signaling efficiency, was observed in the PTSD group compared with the control group for the ventromedial prefrontal cortex, a region that has been strongly implicated in associative fear learning and extinction. It is possible that PTSD accelerates the typical age-associated decline in lGI of the rostral middle frontal cortices.

Keywords: Cortex; ENIGMA Consortium Gyrification; Neuroimaging; PTSD Ventromedial prefrontal cortex.

Plain language summary

Posttraumatic stress disorder (PTSD) involves difficulty regulating fear, but the underlying brain structure remains largely unexplored. Analyzing MRI scans from 1876 individuals worldwide, in this study, we examined cortical gyrification, which is the complex folding of the brain’s surface. We found that PTSD was associated with reduced folding in the ventromedial prefrontal cortex, a key region for emotional control. This hypogyrification was linked to greater symptom severity, independent of age or sex. These findings suggest that altered brain folding patterns may contribute to the emotional dysregulation central to PTSD, highlighting a potential structural signature of the disorder.

Abstract

Plain language summary

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