Abstract
Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.
| Original language | English |
|---|---|
| Journal | Molecular psychiatry |
| Early online date | 2024 |
| DOIs | |
| Publication status | E-pub ahead of print - 2024 |
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In: Molecular psychiatry, 2024.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Smaller total and subregional cerebellar volumes in posttraumatic stress disorder
T2 - a mega-analysis by the ENIGMA-PGC PTSD workgroup
AU - Huggins, Ashley A.
AU - Baird, C. Lexi
AU - Briggs, Melvin
AU - Laskowitz, Sarah
AU - Hussain, Ahmed
AU - Fouda, Samar
AU - Haswell, Courtney
AU - Sun, Delin
AU - Salminen, Lauren E.
AU - Jahanshad, Neda
AU - Thomopoulos, Sophia I.
AU - Veltman, Dick J.
AU - Frijling, Jessie L.
AU - Olff, Miranda
AU - van Zuiden, Mirjam
AU - Koch, Saskia B. J.
AU - Nawjin, Laura
AU - Wang, Li
AU - Zhu, Ye
AU - Li, Gen
AU - Stein, Dan J.
AU - Ipser, Jonathan
AU - Seedat, Soraya
AU - du Plessis, Stefan
AU - van den Heuvel, Leigh L.
AU - Suarez-Jimenez, Benjamin
AU - Zhu, Xi
AU - Kim, Yoojean
AU - He, Xiaofu
AU - Zilcha-Mano, Sigal
AU - Lazarov, Amit
AU - Neria, Yuval
AU - Stevens, Jennifer S.
AU - Ressler, Kerry J.
AU - Jovanovic, Tanja
AU - van Rooij, Sanne J. H.
AU - Fani, Negar
AU - Hudson, Anna R.
AU - Mueller, Sven C.
AU - Sierk, Anika
AU - Manthey, Antje
AU - Walter, Henrik
AU - Daniels, Judith K.
AU - Schmahl, Christian
AU - Herzog, Julia I.
AU - Říha, Pavel
AU - Rektor, Ivan
AU - Lebois, Lauren A. M.
AU - Kaufman, Milissa L.
AU - Olson, Elizabeth A.
AU - Baker, Justin T.
AU - Rosso, Isabelle M.
AU - King, Anthony P.
AU - Liberzon, Isreal
AU - Angstadt, Mike
AU - Davenport, Nicholas D.
AU - Sponheim, Scott R.
AU - Disner, Seth G.
AU - Straube, Thomas
AU - Hofmann, David
AU - Qi, Rongfeng
AU - Lu, Guang Ming
AU - Baugh, Lee A.
AU - Forster, Gina L.
AU - Simons, Raluca M.
AU - Simons, Jeffrey S.
AU - Magnotta, Vincent A.
AU - Fercho, Kelene A.
AU - Maron-Katz, Adi
AU - Etkin, Amit
AU - Cotton, Andrew S.
AU - O’Leary, Erin N.
AU - Xie, Hong
AU - Wang, Xin
AU - Quidé, Yann
AU - el-Hage, Wissam
AU - Lissek, Shmuel
AU - Berg, Hannah
AU - Bruce, Steven
AU - Cisler, Josh
AU - Ross, Marisa
AU - Herringa, Ryan J.
AU - Grupe, Daniel W.
AU - Nitschke, Jack B.
AU - Davidson, Richard J.
AU - Larson, Christine L.
AU - deRoon-Cassini, Terri A.
AU - Tomas, Carissa W.
AU - Fitzgerald, Jacklynn M.
AU - Blackford, Jennifer Urbano
AU - Olatunji, Bunmi O.
AU - Kremen, William S.
AU - Lyons, Michael J.
AU - Franz, Carol E.
AU - Gordon, Evan M.
AU - May, Geoffrey
AU - Nelson, Steven M.
AU - Abdallah, Chadi G.
AU - Levy, Ifat
AU - Harpaz-Rotem, Ilan
AU - Krystal, John H.
AU - Dennis, Emily L.
AU - Tate, David F.
AU - Cifu, David X.
AU - Walker, William C.
AU - Wilde, Elizabeth A.
AU - Harding, Ian H.
AU - Kerestes, Rebecca
AU - Thompson, Paul M.
AU - Morey, Rajendra
N1 - Funding Information: NJ received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the content of this manuscript. PMT received partial research support from Biogen, Inc. (Boston, USA) for research unrelated to the topic of this manuscript. CS is consultant for Boehringer Ingelheim International GmbH. LAML reports unpaid membership on the Scientific Committee for the International Society for the Study of Trauma and Dissociation (ISSTD), grant support from the National Institute of Mental Health, K01 MH118467, and spousal IP payments from Vanderbilt University for technology licensed to Acadia Pharmaceuticals unrelated to the present work. ISSTD and NIMH were not involved in the analysis or preparation of the manuscript. WEH is affiliated with Air Liquide, Boehringer Ingelheim, CHUGAI, EISAI, Jazz Pharmaceuticals, Janssen, Lundbeck, Novartis, Otsuka, UCB but nothing related to this work. RJD is the founder and president of, and serves on the board of directors for, the non-profit organization Healthy Minds Innovations, Inc. CGA has served as a consultant, speaker and/or on advisory boards for FSV7, Lundbeck, Psilocybin Labs, Genentech, Janssen and Aptinyx; served as editor of Chronic Stress for Sage Publications, Inc; and filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). JHK is a consultant for AbbVie, Inc., Amgen, Astellas Pharma Global Development, Inc., AstraZeneca Pharmaceuticals, Biomedisyn Corporation, Bristol-Myers Squibb, Eli Lilly and Company, Euthymics Bioscience, Inc., Neurovance, Inc., FORUM Pharmaceuticals, Janssen Research & Development, Lundbeck Research USA, Novartis Pharma AG, Otsuka America Pharmaceutical, Inc., Sage Therapeutics, Inc., Sunovion Pharmaceuticals, Inc., and Takeda Industries; is on the Scientific Advisory Board for Lohocla Research Corporation, Mnemosyne Pharmaceuticals, Inc., Naurex, Inc., and Pfizer; is a stockholder in Biohaven Pharmaceuticals; holds stock options in Mnemosyne Pharmaceuticals, Inc.; holds patents for Dopamine and Noradrenergic Reuptake Inhibitors in Treatment of Schizophrenia, US Patent No. 5,447,948 (issued September 5, 1995), and Glutamate Modulating Agents in the Treatment of Mental Disorders, U.S. Patent No. 8,778,979 (issued July 15, 2014); and filed a patent for Intranasal Administration of Ketamine to Treat Depression. U.S. Application No. 14/197,767 (filed on March 5, 2014); US application or Patent Cooperation Treaty international application No. 14/306,382 (filed on June 17, 2014). Filed a patent for using mTOR inhibitors to augment the effects of antidepressants (filed on August 20, 2018). A version of this manuscript was uploaded to the biorxiv.org preprint server ( https://doi.org/10.1101/2022.10.13.512111 ). Funding Information: This study was funded by the Department of Defense (Grants Nos. R01MH111671, R01MH117601, R01AG059874, MJFF 14848 [to NJ], W81XWH-12-2-0012 [to SIT & PMT]; ENIGMA was also supported in part by NIH U54 EB020403 from the Big Data to Knowledge (BD2K) program (Grant Nos. R56AG058854, R01MH116147, R01MH111671, and P41 EB015922 [to PMT, SIT]); ZonMw, the Netherlands organization for Health Research and Development (Grant No. 40-00812-98-10041), and by a grant from the Academic Medical Center Research Council (Grant No. 110614) both awarded [to MO, DJV, JLF, MVZ, SBJK, LN]; The National Natural Science Foundation of China (No. U21A20364 and No. 31971020), the Key Project of the National Social Science Foundation of China (No. 20ZDA079), the Key Project of Research Base of Humanities and Social Sciences of Ministry of Education (No.16JJD190006), and the Scientific Foundation of Institute of Psychology, Chinese Academy of Sciences (No. E2CX4115CX) [to LW, YZ]; The SAMRC Unit on Risk & Resilience in Mental Disorders [to DJS]; The South African Medical Research Council for the “Shared Roots” Flagship Project, (Grant no. MRC-RFA-IFSP-01-2013 [to SS, SDP, LLVDH)/SHARED ROOTS” through funding received from the South African National Treasury under its Economic Competitiveness and Support Package. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the South African Medical Research Council. [SS] is supported by the South African Research Chairs Initiative in Posttraumatic Stress Disorder through the Department of Science and Innovation and the National Research Foundation. The work by [LLVDH] reported herein was made possible through funding by the South African Medical Research Council through its Division of Research Capacity Development under the SAMRC CLINICIAN RESEARCHER (M.D PHD) SCHOLARSHIP PROGRAMME from funding received from the South African National Treasury. The content hereof is the sole responsibility of the authors and do not necessarily represent the official views of the SAMRC or the funders; National Institute of Mental Health (Grant No. NIMH K01 MH118428 [to BSJ]), NARSAD Young Investigator Award [to BSJ]; NARSAD (Grant No. 27040) and K01MH122774 to [ZX]; R01MH105355-01A to [YN]; The National Institutes of Health (Grant No. RO1 MH111671) & VA Mid-Atlantic MIRECC [to CLB, AAH, CCH, RM, DS, MB, SF, SL]; The National Institute of Mental Health (Grants Nos. MH098212, MH071537 [to JSS, KSR, TJ, SJHVR] & MH101380 [to NF]), the National Center for Advancing Translational Sciences (Grant No. UL1TR000454 [to JSS, KSR, TJ, SJHVR]), National Center for Research Resources (Grant Nos. M01RR00039 [to JSS, KSR, TJ, SJHVR]); Eunice Kennedy Shriver National Institute of Child Health and Human Development (Grant Nos. HD071982 and HD085850 [to JSS, KRJ, TJ, SJHVR]); BOF 2–4 year project (Grant No. 01J05415 [to SCM]); German Research Foundation (Grant Nos. DA 1222/4-1 and WA 1539/8-2 [to AS, AM, HW, JKD]); The Ministry of Health of the Czech Republic (Grant no. AZV NV18-7 04-00559 [to PŘ]); K01MH118467 [to LAML]; Julia Kasparian Fund for Neuroscience Research [to LAML, MLK]; R21MH112956 & R01MH119227 [to MLK], McLean Hospital Trauma Scholars Fund [to MLK], Barlow Family Fund [to MLK]; R01 MH096987 [to IMR]; R01MH113574 [to IL]; VA Rehabilitation Research and Development (RR&D) (Grant Nos. 1IK2RX000709 [to NDD], 1K2RX002922 [to SGD], and I01RX000622 [to SRS]); Congressionally Directed Medical Research Programs Grant No. W81XWH-08–2–0038 (to SRS); German Research Society - Deutsche Forschungsgemeinschaft, DFG; (Grant No. SFB/TRR 58: C06, C07 [to DH, TS]); The Natural Science Foundation of Jiangsu Province (Grant No. BK20221554 [to RQ]), and the Foundation for the Social Development Project of Jiangsu (Grant No. BE2022705 [to RQ]); The Department of Defense (Grant Nos. W81XWH-10-1-0925), Center for Brain and Behavior Research Pilot Grant, and South Dakota Governor’s Research Center Grant [to LAB, GLF, RMS, JSS, VAM, KAF]; The Fondation Pierre Deniker and Neuroimagerie Fonctionnelle (Grant No. SFR FED4226 [to WEH]; R01MH107382-02 [to SL]; K23 MH090366-01 [to SB]; Dana Foundation [to JBN]; the University of Wisconsin Institute for Clinical and Translational Research; a National Science Foundation Graduate Research Fellowship [to DWG]; the National Institute of Mental Health (NIMH) (Grant Nos. R01-MH043454 and T32-MH018931 [to RJD]; and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant No. P30-HD003352); R01 MH106574 [to CL, TADC]; NIMH R21MH106998; NIMH (Grant No. R21MH106998 [to JUB, BOO]; The National Institute on Aging (Grant Nos. R01 AG050595, R01 AG022381 [to WSK, MJL]; VA Clinical Science Research and Development (Grant No. 1IK2CX001680 [to EG]); VISN17 Center of Excellence pilot funding [to EMG, GM, SMN]; VA National Center for PTSD and the Beth K and Stuart Yudofsky Chair in the Neuropsychiatry of Military Post Traumatic Stress Syndrome [to CGA]; 1R21MH102634 [to IL]; R01MH105535 [to IHR]; Department of Veterans Affairs via support for the National Center for PTSD, National Institute on Alcohol Abuse and Alcoholism via its support for (P50) Center for the Translational Neuroscience of Alcohol, and NCATS via its support of (Clinical and Translational Science Awards) Yale Center for Clinical Investigation [to JHK]; R61NS120249 [to ELD, DFT, EAW]; The Assistant Secretary of Defense for Health Affairs endorsed by the Department of Defense, through the Psychological Health/Traumatic Brain Injury Research Program Long-Term Impact of Military-Relevant Brain Injury Consortium (LIMBIC) Award/W81XWH-18-PH/TBIRP-LIMBIC under (Grant Nos. W81XWH1920067 and W81XWH-13-2-00950 [to WCW], and by the U.S. Department of Veterans Affairs (Grant Nos. I01 CX002097, I01 CX002096, I01 CX001820, I01 HX003155, I01 RX003444, I01 RX003443, I01 RX003442, I01 CX001135, I01 CX001246, I01 RX001774, I01 RX 001135, I01 RX 002076, I01 RX 001880, I01 RX 002172, I01 RX 002173, I01 RX 002171, I01 RX 002174, and I01 RX 002170 [to WCW]), The U.S. Army Medical Research Acquisition Activity, 839 Chandler Street, Fort Detrick MD 21702-5014 is the awarding and administering acquisition office [to WCW]; HFP90-020 [to EAW]; NHMRC Ideas (Grant No. 1184403 [to IHH]. Publisher Copyright: © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2024
Y1 - 2024
N2 - Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.
AB - Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p -FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.
UR - http://www.scopus.com/inward/record.url?scp=85181942750&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41380-023-02352-0
DO - https://doi.org/10.1038/s41380-023-02352-0
M3 - Article
C2 - 38195980
SN - 1359-4184
JO - Molecular psychiatry
JF - Molecular psychiatry
ER -