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

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

^*Corresponding author for this work

Chair Engelhard

Research output: Contribution to journal › Article › Academic › peer-review

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.

Original language	English
Article number	100679
Journal	Biological Psychiatry Global Open Science
Volume	6
Issue number	2
DOIs	https://doi.org/10.1016/j.bpsgos.2025.100679
Publication status	Published - Mar 2026

Bibliographical note

Publisher Copyright:
© 2025 The Authors.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cortex
ENIGMA Consortium Gyrification
Neuroimaging
PTSD Ventromedial prefrontal cortex

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Hussain, A., Baird, C. L., Huggins, A. A., Russell, C. C., Sun, D., Rangel-Jimenez, L., Abdallah, C. G., Angstadt, M., May, G., Berg, H., Blackford, J. U., Cisler, J., Daniels, J. K., Davenport, N. D., Davidson, R. J., Densmore, M., Disner, S. G., El-Hage, W., Etkin, A., ... Morey, R. A. (2026). Lower Gyrification of the Ventromedial Prefrontal Cortex in Posttraumatic Stress Disorder: An ENIGMA-PTSD Study. Biological Psychiatry Global Open Science, 6(2), Article 100679. https://doi.org/10.1016/j.bpsgos.2025.100679

@article{66447f17a9ef4d4db00513ae170efef2,

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

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{\textquoteright}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",

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

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2026",

month = mar,

doi = "10.1016/j.bpsgos.2025.100679",

language = "English",

volume = "6",

journal = "Biological Psychiatry Global Open Science",

issn = "2667-1743",

publisher = "Elsevier Inc.",

number = "2",

}

Hussain, A, Baird, CL, Huggins, AA, Russell, CC, Sun, D, Rangel-Jimenez, L, Abdallah, CG, Angstadt, M, May, G, Berg, H, Blackford, JU, Cisler, J, Daniels, JK, Davenport, ND, Davidson, RJ, Densmore, M, Disner, SG, El-Hage, W, Etkin, A, Fani, N, Frijling, JL, Gordon, EM, Grupe, DW, Herringa, RA, Herzog, JI, Hofmann, D, Hudson, AR, Jovanovic, T, King, A, Koch, SBJ, Lanius, RA, Lazarov, A, Li, G, Liberzon, I, Lissek, S, Lu, G, Manthey, A, Maron-Katz, A, McLaughlin, KA, Mueller, SC, Nawijn, L, Nelson, SM, Neria, Y, Neufeld, RWJ, Nitschke, JB, Olatunji, BO, Olff, M, Peverill, M, Qi, R, Quidé, Y, Ravid, O, Rektor, I, Ressler, KJ, Říha, P, Ross, M, Sambrook, K, Schmahl, C, Sierk, A, Sponheim, SR, Stevens, JS, Straube, T, Suarez-Jimenez, B, Théberge, J, van der Wee, NJA, van der Werff, SJA, van Rooij, SJH, van Zuiden, M, Veltman, DJ, Vermeiren, RRJM, Walter, H, Wang, L, Zhu, X, Zhu, Y, Zilcha-Mano, S, Jahanshad, N, Thompson, PM & Morey, RA 2026, 'Lower Gyrification of the Ventromedial Prefrontal Cortex in Posttraumatic Stress Disorder: An ENIGMA-PTSD Study', Biological Psychiatry Global Open Science, vol. 6, no. 2, 100679. https://doi.org/10.1016/j.bpsgos.2025.100679

TY - JOUR

T1 - Lower Gyrification of the Ventromedial Prefrontal Cortex in Posttraumatic Stress Disorder

T2 - An ENIGMA-PTSD Study

AU - Hussain, Ahmed

AU - Baird, C. Lexi

AU - Huggins, Ashley A.

AU - Russell, Courtney C.

AU - Sun, Delin

AU - Rangel-Jimenez, Leonel

AU - Abdallah, Chadi G.

AU - Angstadt, Michael

AU - May, Geoffrey

AU - Berg, Hannah

AU - Blackford, Jennifer U.

AU - Cisler, Josh

AU - Daniels, Judith K.

AU - Davenport, Nicholas D.

AU - Davidson, Richard J.

AU - Densmore, Maria

AU - Disner, Seth G.

AU - El-Hage, Wissam

AU - Etkin, Amit

AU - Fani, Negar

AU - Frijling, Jessie L.

AU - Gordon, Evan M.

AU - Grupe, Daniel W.

AU - Herringa, Ryan A.

AU - Herzog, Julia I.

AU - Hofmann, David

AU - Hudson, Anna R.

AU - Jovanovic, Tanja

AU - King, Anthony

AU - Koch, Saskia B.J.

AU - Lanius, Ruth A.

AU - Lazarov, Amit

AU - Li, Gen

AU - Liberzon, Israel

AU - Lissek, Shmuel

AU - Lu, Guangming

AU - Manthey, Antje

AU - Maron-Katz, Adi

AU - McLaughlin, Katie A.

AU - Mueller, Sven C.

AU - Nawijn, Laura

AU - Nelson, Steven M.

AU - Neria, Yuval

AU - Neufeld, Richard W.J.

AU - Nitschke, Jack B.

AU - Olatunji, Bunmi O.

AU - Olff, Miranda

AU - Peverill, Matthew

AU - Qi, Rongfeng

AU - Quidé, Yann

AU - Ravid, Orren

AU - Rektor, Ivan

AU - Ressler, Kerry J.

AU - Říha, Pavel

AU - Ross, Marisa

AU - Sambrook, Kelly

AU - Schmahl, Christian

AU - Sierk, Anika

AU - Sponheim, Scott R.

AU - Stevens, Jennifer S.

AU - Straube, Thomas

AU - Suarez-Jimenez, Benjamin

AU - Théberge, Jean

AU - van der Wee, Nic J.A.

AU - van der Werff, Steven J.A.

AU - van Rooij, Sanne J.H.

AU - van Zuiden, Mirjam

AU - Veltman, Dick J.

AU - Vermeiren, Robert R.J.M.

AU - Walter, Henrik

AU - Wang, Li

AU - Zhu, Xi

AU - Zhu, Ye

AU - Zilcha-Mano, Sigal

AU - Jahanshad, Neda

AU - Thompson, Paul M.

AU - Morey, Rajendra A.

PY - 2026/3

Y1 - 2026/3

N2 - 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.

AB - 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.

KW - Cortex

KW - ENIGMA Consortium Gyrification

KW - Neuroimaging

KW - PTSD Ventromedial prefrontal cortex

UR - https://www.scopus.com/pages/publications/105029229157

U2 - 10.1016/j.bpsgos.2025.100679

DO - 10.1016/j.bpsgos.2025.100679

M3 - Article

AN - SCOPUS:105029229157

SN - 2667-1743

VL - 6

JO - Biological Psychiatry Global Open Science

JF - Biological Psychiatry Global Open Science

IS - 2

M1 - 100679

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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