Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups

Ashley N. Clausen; Kelene A. Fercho; Molly Monsour; Seth Disner; Lauren Salminen; Courtney C. Haswell; Emily Clarke Rubright; Amanda A. Watts; M. Nicole Buckley; Adi Maron-Katz; Anika Sierk; Antje Manthey; Benjamin Suarez-Jimenez; Bunmi O. Olatunji; Christopher L. Averill; David Hofmann; Dick J. Veltman; Elizabeth A. Olson; Gen Li; Gina L. Forster; Henrik Walter; Jacklynn Fitzgerald; Jean Théberge; Jeffrey S. Simons; Jessica A. Bomyea; Jessie L. Frijling; John H. Krystal; Justin T. Baker; K. Luan Phan; Kerry Ressler; Laura K. M. Han; Laura Nawijn; Lauren A. M. Lebois; Lianne Schmaal; Maria Densmore; Martha E. Shenton; Mirjam van Zuiden; Murray Stein; Negar Fani; Raluca M. Simons; Richard W. J. Neufeld; Ruth Lanius; Sanne van Rooij; Saskia B. J. Koch; Serena Bonomo; Tanja Jovanovic; Terri deRoon-Cassini; Timothy D. Ely; Vincent A. Magnotta; Xiaofu He; Chadi G. Abdallah; Amit Etkin; Christian Schmahl; Christine Larson; Isabelle M. Rosso; Jennifer Urbano Blackford; Jennifer S. Stevens; Judith K. Daniels; Julia Herzog; Milissa L. Kaufman; Miranda Olff; Richard J. Davidson; Scott R. Sponheim; Sven C. Mueller; Thomas Straube; Xi Zhu; Yuval Neria; Lee A. Baugh; James H. Cole; Paul M. Thompson; Rajendra A. Morey

doi:10.1002/brb3.2413

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups

Ashley N. Clausen^*, Kelene A. Fercho, Molly Monsour, Seth Disner, Lauren Salminen, Courtney C. Haswell, Emily Clarke Rubright, Amanda A. Watts, M. Nicole Buckley, Adi Maron-Katz, Anika Sierk, Antje Manthey, Benjamin Suarez-Jimenez, Bunmi O. Olatunji, Christopher L. Averill, David Hofmann, Dick J. Veltman, Elizabeth A. Olson, Gen Li, Gina L. ForsterHenrik Walter, Jacklynn Fitzgerald, Jean Théberge, Jeffrey S. Simons, Jessica A. Bomyea, Jessie L. Frijling, John H. Krystal, Justin T. Baker, K. Luan Phan, Kerry Ressler, Laura K. M. Han, Laura Nawijn, Lauren A. M. Lebois, Lianne Schmaal, Maria Densmore, Martha E. Shenton, Mirjam van Zuiden, Murray Stein, Negar Fani, Raluca M. Simons, Richard W. J. Neufeld, Ruth Lanius, Sanne van Rooij, Saskia B. J. Koch, Serena Bonomo, Tanja Jovanovic, Terri deRoon-Cassini, Timothy D. Ely, Vincent A. Magnotta, Xiaofu He, Chadi G. Abdallah, Amit Etkin, Christian Schmahl, Christine Larson, Isabelle M. Rosso, Jennifer Urbano Blackford, Jennifer S. Stevens, Judith K. Daniels, Julia Herzog, Milissa L. Kaufman, Miranda Olff, Richard J. Davidson, Scott R. Sponheim, Sven C. Mueller, Thomas Straube, Xi Zhu, Yuval Neria, Lee A. Baugh, James H. Cole, Paul M. Thompson, Rajendra A. Morey

^*Corresponding author for this work

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

Abstract

Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method: Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

Original language	English
Journal	Brain and Behavior
Early online date	2021
DOIs	https://doi.org/10.1002/brb3.2413
Publication status	E-pub ahead of print - 2021

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Clausen, A. N., Fercho, K. A., Monsour, M., Disner, S., Salminen, L., Haswell, C. C., Rubright, E. C., Watts, A. A., Buckley, M. N., Maron-Katz, A., Sierk, A., Manthey, A., Suarez-Jimenez, B., Olatunji, B. O., Averill, C. L., Hofmann, D., Veltman, D. J., Olson, E. A., Li, G., ... Morey, R. A. (2021). Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups. Brain and Behavior. https://doi.org/10.1002/brb3.2413

@article{a473a5077b0d4a099dbc6a7d4a597349,

title = "Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups",

abstract = "Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method: Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.",

keywords = "aging, machine learning, mega-analysis, neuroimaging, posttraumatic stress disorder, trauma",

author = "Clausen, {Ashley N.} and Fercho, {Kelene A.} and Molly Monsour and Seth Disner and Lauren Salminen and Haswell, {Courtney C.} and Rubright, {Emily Clarke} and Watts, {Amanda A.} and Buckley, {M. Nicole} and Adi Maron-Katz and Anika Sierk and Antje Manthey and Benjamin Suarez-Jimenez and Olatunji, {Bunmi O.} and Averill, {Christopher L.} and David Hofmann and Veltman, {Dick J.} and Olson, {Elizabeth A.} and Gen Li and Forster, {Gina L.} and Henrik Walter and Jacklynn Fitzgerald and Jean Th{\'e}berge and Simons, {Jeffrey S.} and Bomyea, {Jessica A.} and Frijling, {Jessie L.} and Krystal, {John H.} and Baker, {Justin T.} and Phan, {K. Luan} and Kerry Ressler and Han, {Laura K. M.} and Laura Nawijn and Lebois, {Lauren A. M.} and Lianne Schmaal and Maria Densmore and Shenton, {Martha E.} and {van Zuiden}, Mirjam and Murray Stein and Negar Fani and Simons, {Raluca M.} and Neufeld, {Richard W. J.} and Ruth Lanius and {van Rooij}, Sanne and Koch, {Saskia B. J.} and Serena Bonomo and Tanja Jovanovic and Terri deRoon-Cassini and Ely, {Timothy D.} and Magnotta, {Vincent A.} and Xiaofu He and Abdallah, {Chadi G.} and Amit Etkin and Christian Schmahl and Christine Larson and Rosso, {Isabelle M.} and Blackford, {Jennifer Urbano} and Stevens, {Jennifer S.} and Daniels, {Judith K.} and Julia Herzog and Kaufman, {Milissa L.} and Miranda Olff and Davidson, {Richard J.} and Sponheim, {Scott R.} and Mueller, {Sven C.} and Thomas Straube and Xi Zhu and Yuval Neria and Baugh, {Lee A.} and Cole, {James H.} and Thompson, {Paul M.} and Morey, {Rajendra A.}",

note = "Funding Information: Department of Veterans Affairs via support for the National Center for PTSD; DoD W81XWH‐10‐1‐0925; Center for Brain and Behavior Research Pilot Grant; South Dakota Governor's Research Center Grant; Vanderbilt Psychiatric Genotype/Phenotype Project, and the Vanderbilt Institute for Clinical and Translational Research (through grant 1‐UL‐1‐TR000445 from the National Center for Research Resources/NIH); CX001600 VA CDA; MRC/UKRI Innovation Fellowship; German Research Foundation grant to Judith K. Daniels (numbers DA 1222/4‐1 and WA 1539/8‐2); NIMH R01‐MH043454; NIMH T32‐MH018931; VA RR&D IK2RX002922‐01A1; MH101380; National Institute of Mental Health training grant (T32MH13043); German Federal Ministry of Education and Research (BMBF RELEASE 01KR1303A); German Research Society (Deutsche Forschungsgemeinschaft, DFG; SFB/TRR 58: C06, C07); MH098212; MH071537; M01RR00039; UL1TR000454; HD071982; HD085850; R21MH112956; R01MH096987; Anonymous Women's Health Fund; Kasparian Fund; Trauma Scholars Fund; Barlow Family Fund; K01 MH118467; ZonMw, the Netherlands organization for Health Research and Development (40‐00812‐98‐10041) and a grant from the Academic Medical Center Research Council (110614) both awarded to Miranda Olff; NIAAA via support for (P50) Center for the Translational Neuroscience of Alcohol; NCATS via support of (CTSA) Yale Center for Clinical Investigation; CIHR; CIMVHR; NIH R01 MH106574; F32MH109274; VISN6 MIRECC; BOF 2–4 year project to Sven C. Mueller (01J05415); R01MH105355; National Institute of Mental Health F31 MH113271; NIMH K23MH112873; Veterans Affairs Merit Review Program (10/01/08–09/30/13); NHMRC Career Development Fellowship (1140764); DoD W81XWH08‐2‐0159 to Murray Stein; CDMRP, W81XWH‐08‐2‐0038; VA RR&D, I01RX000622; Narsad Young Investigator; German Research Society; K01 MH118428; Brain and Behavior Research Foundation Grant 07040. ENIGMA was also supported in part by NIH U54 EB020403 from the Big Data to Knowledge (BD2K) program, R56AG058854, R01MH116147, R01MH111671, and P41 EB015922. Writing of this paper was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the Durham VA Health Care System, and the Department of Veterans Affairs Mid‐Atlantic MIRECC. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the United States government, or any other funding sources listed here. Publisher Copyright: {\textcopyright} 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC",

year = "2021",

doi = "10.1002/brb3.2413",

language = "English",

journal = "Brain and Behavior",

issn = "2162-3279",

publisher = "John Wiley and Sons Inc.",

}

Clausen, AN, Fercho, KA, Monsour, M, Disner, S, Salminen, L, Haswell, CC, Rubright, EC, Watts, AA, Buckley, MN, Maron-Katz, A, Sierk, A, Manthey, A, Suarez-Jimenez, B, Olatunji, BO, Averill, CL, Hofmann, D, Veltman, DJ, Olson, EA, Li, G, Forster, GL, Walter, H, Fitzgerald, J, Théberge, J, Simons, JS, Bomyea, JA, Frijling, JL, Krystal, JH, Baker, JT, Phan, KL, Ressler, K, Han, LKM , Nawijn, L, Lebois, LAM, Schmaal, L, Densmore, M, Shenton, ME, van Zuiden, M, Stein, M, Fani, N, Simons, RM, Neufeld, RWJ, Lanius, R, van Rooij, S, Koch, SBJ, Bonomo, S, Jovanovic, T, deRoon-Cassini, T, Ely, TD, Magnotta, VA, He, X, Abdallah, CG, Etkin, A, Schmahl, C, Larson, C, Rosso, IM, Blackford, JU, Stevens, JS, Daniels, JK, Herzog, J, Kaufman, ML, Olff, M, Davidson, RJ, Sponheim, SR, Mueller, SC, Straube, T, Zhu, X, Neria, Y, Baugh, LA, Cole, JH, Thompson, PM & Morey, RA 2021, 'Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups', Brain and Behavior. https://doi.org/10.1002/brb3.2413

TY - JOUR

T1 - Assessment of brain age in posttraumatic stress disorder

T2 - Findings from the ENIGMA PTSD and brain age working groups

AU - Clausen, Ashley N.

AU - Fercho, Kelene A.

AU - Monsour, Molly

AU - Disner, Seth

AU - Salminen, Lauren

AU - Haswell, Courtney C.

AU - Rubright, Emily Clarke

AU - Watts, Amanda A.

AU - Buckley, M. Nicole

AU - Maron-Katz, Adi

AU - Sierk, Anika

AU - Manthey, Antje

AU - Suarez-Jimenez, Benjamin

AU - Olatunji, Bunmi O.

AU - Averill, Christopher L.

AU - Hofmann, David

AU - Veltman, Dick J.

AU - Olson, Elizabeth A.

AU - Li, Gen

AU - Forster, Gina L.

AU - Walter, Henrik

AU - Fitzgerald, Jacklynn

AU - Théberge, Jean

AU - Simons, Jeffrey S.

AU - Bomyea, Jessica A.

AU - Frijling, Jessie L.

AU - Krystal, John H.

AU - Baker, Justin T.

AU - Phan, K. Luan

AU - Ressler, Kerry

AU - Han, Laura K. M.

AU - Nawijn, Laura

AU - Lebois, Lauren A. M.

AU - Schmaal, Lianne

AU - Densmore, Maria

AU - Shenton, Martha E.

AU - van Zuiden, Mirjam

AU - Stein, Murray

AU - Fani, Negar

AU - Simons, Raluca M.

AU - Neufeld, Richard W. J.

AU - Lanius, Ruth

AU - van Rooij, Sanne

AU - Koch, Saskia B. J.

AU - Bonomo, Serena

AU - Jovanovic, Tanja

AU - deRoon-Cassini, Terri

AU - Ely, Timothy D.

AU - Magnotta, Vincent A.

AU - He, Xiaofu

AU - Abdallah, Chadi G.

AU - Etkin, Amit

AU - Schmahl, Christian

AU - Larson, Christine

AU - Rosso, Isabelle M.

AU - Blackford, Jennifer Urbano

AU - Stevens, Jennifer S.

AU - Daniels, Judith K.

AU - Herzog, Julia

AU - Kaufman, Milissa L.

AU - Olff, Miranda

AU - Davidson, Richard J.

AU - Sponheim, Scott R.

AU - Mueller, Sven C.

AU - Straube, Thomas

AU - Zhu, Xi

AU - Neria, Yuval

AU - Baugh, Lee A.

AU - Cole, James H.

AU - Thompson, Paul M.

AU - Morey, Rajendra A.

N1 - Funding Information: Department of Veterans Affairs via support for the National Center for PTSD; DoD W81XWH‐10‐1‐0925; Center for Brain and Behavior Research Pilot Grant; South Dakota Governor's Research Center Grant; Vanderbilt Psychiatric Genotype/Phenotype Project, and the Vanderbilt Institute for Clinical and Translational Research (through grant 1‐UL‐1‐TR000445 from the National Center for Research Resources/NIH); CX001600 VA CDA; MRC/UKRI Innovation Fellowship; German Research Foundation grant to Judith K. Daniels (numbers DA 1222/4‐1 and WA 1539/8‐2); NIMH R01‐MH043454; NIMH T32‐MH018931; VA RR&D IK2RX002922‐01A1; MH101380; National Institute of Mental Health training grant (T32MH13043); German Federal Ministry of Education and Research (BMBF RELEASE 01KR1303A); German Research Society (Deutsche Forschungsgemeinschaft, DFG; SFB/TRR 58: C06, C07); MH098212; MH071537; M01RR00039; UL1TR000454; HD071982; HD085850; R21MH112956; R01MH096987; Anonymous Women's Health Fund; Kasparian Fund; Trauma Scholars Fund; Barlow Family Fund; K01 MH118467; ZonMw, the Netherlands organization for Health Research and Development (40‐00812‐98‐10041) and a grant from the Academic Medical Center Research Council (110614) both awarded to Miranda Olff; NIAAA via support for (P50) Center for the Translational Neuroscience of Alcohol; NCATS via support of (CTSA) Yale Center for Clinical Investigation; CIHR; CIMVHR; NIH R01 MH106574; F32MH109274; VISN6 MIRECC; BOF 2–4 year project to Sven C. Mueller (01J05415); R01MH105355; National Institute of Mental Health F31 MH113271; NIMH K23MH112873; Veterans Affairs Merit Review Program (10/01/08–09/30/13); NHMRC Career Development Fellowship (1140764); DoD W81XWH08‐2‐0159 to Murray Stein; CDMRP, W81XWH‐08‐2‐0038; VA RR&D, I01RX000622; Narsad Young Investigator; German Research Society; K01 MH118428; Brain and Behavior Research Foundation Grant 07040. ENIGMA was also supported in part by NIH U54 EB020403 from the Big Data to Knowledge (BD2K) program, R56AG058854, R01MH116147, R01MH111671, and P41 EB015922. Writing of this paper was supported by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment, the Medical Research Service of the Durham VA Health Care System, and the Department of Veterans Affairs Mid‐Atlantic MIRECC. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs, the United States government, or any other funding sources listed here. Publisher Copyright: © 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC

PY - 2021

Y1 - 2021

N2 - Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method: Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

AB - Background: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. Method: Adult subjects (N = 2229; 56.2% male) aged 18–69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age − chronological age) controlling for chronological age, sex, and scan site. Results: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. Discussion: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

KW - aging

KW - machine learning

KW - mega-analysis

KW - neuroimaging

KW - posttraumatic stress disorder

KW - trauma

UR - http://www.scopus.com/inward/record.url?scp=85121330086&partnerID=8YFLogxK

U2 - 10.1002/brb3.2413

DO - 10.1002/brb3.2413

M3 - Article

C2 - 34907666

SN - 2162-3279

JO - Brain and Behavior

JF - Brain and Behavior

ER -

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups

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