Association of Structural Magnetic Resonance Imaging Measures with Psychosis Onset in Individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group Mega-analysis

Maria Jalbrzikowski, Rebecca A. Hayes, Stephen J. Wood, Dorte Nordholm, Juan H. Zhou, Paolo Fusar-Poli, Peter J. Uhlhaas, Tsutomu Takahashi, Gisela Sugranyes, Yoo Bin Kwak, Daniel H. Mathalon, Naoyuki Katagiri, Christine I. Hooker, Lukasz Smigielski, Tiziano Colibazzi, Esther Via, Jinsong Tang, Shinsuke Koike, Paul E. Rasser, Chantal MichelIrina Lebedeva, Wenche Ten Velden Hegelstad, Camilo De La Fuente-Sandoval, James A. Waltz, Romina Mizrahi, Cheryl M. Corcoran, Franz Resch, Christian K. Tamnes, Shalaila S. Haas, Imke L.J. Lemmers-Jansen, Ingrid Agartz, Paul Allen, G. Paul Amminger, Ole A. Andreassen, Kimberley Atkinson, Peter Bachman, Inmaculada Baeza, Helen Baldwin, Cali F. Bartholomeusz, Stefan Borgwardt, Sabrina Catalano, Michael W.L. Chee, Xiaogang Chen, Kang Ik K. Cho, Rebecca E. Cooper, Vanessa L. Cropley, Montserrat Dolz, Bjørn H. Ebdrup, Adriana Fortea, Louise Birkedal Glenthøj, Birte Y. Glenthøj, Lieuwe De Haan, Holly K. Hamilton, Mathew A. Harris, Kristen M. Haut, Ying He, Karsten Heekeren, Andreas Heinz, Daniela Hubl, Wu Jeong Hwang, Michael Kaess, Kiyoto Kasai, Minah Kim, Jochen Kindler, Mallory J. Klaunig, Alex Koppel, Tina D. Kristensen, Jun Soo Kwon, Stephen M. Lawrie, Jimmy Lee, Pablo León-Ortiz, Ashleigh Lin, Rachel L. Loewy, Xiaoqian Ma, Patrick McGorry, Philip McGuire, Masafumi Mizuno, Paul Møller, Tomas Moncada-Habib, Daniel Muñoz-Samons, Barnaby Nelson, Takahiro Nemoto, Merete Nordentoft, Maria A. Omelchenko, Ketil Oppedal, Lijun Ouyang, Christos Pantelis, Jose C. Pariente, Jayachandra M. Raghava, Francisco Reyes-Madrigal, Brian J. Roach, Jan I. Røssberg, Wulf Rössler, Dean F. Salisbury, Daiki Sasabayashi, Ulrich Schall, Jason Schiffman, Florian Schlagenhauf, Andre Schmidt, Mikkel E. Sørensen, Michio Suzuki, Anastasia Theodoridou, Alexander S. Tomyshev, Jordina Tor, Tor G. Værnes, Dennis Velakoulis, Gloria D. Venegoni, Sophia Vinogradov, Christina Wenneberg, Lars T. Westlye, Hidenori Yamasue, Liu Yuan, Alison R. Yung, Thérèse A.M.J. Van Amelsvoort, Jessica A. Turner, Theo G.M. Van Erp, Paul M. Thompson, Dennis Hernaus

Research output: Contribution to journalArticlepeer-review

Abstract

Importance: The ENIGMA clinical high risk (CHR) for psychosis initiative, the largest pooled neuroimaging sample of individuals at CHR to date, aims to discover robust neurobiological markers of psychosis risk.

Objective: To investigate baseline structural neuroimaging differences between individuals at CHR and healthy controls as well as between participants at CHR who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-).

Design, Setting, and Participants: In this case-control study, baseline T1-weighted magnetic resonance imaging (MRI) data were pooled from 31 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group. CHR status was assessed using the Comprehensive Assessment of At-Risk Mental States or Structured Interview for Prodromal Syndromes. MRI scans were processed using harmonized protocols and analyzed within a mega-analysis and meta-analysis framework from January to October 2020.

Main Outcomes and Measures: Measures of regional cortical thickness (CT), surface area, and subcortical volumes were extracted from T1-weighted MRI scans. Independent variables were group (CHR group vs control group) and conversion status (CHR-PS+ group vs CHR-PS- group vs control group).

Results: Of the 3169 included participants, 1428 (45.1%) were female, and the mean (SD; range) age was 21.1 (4.9; 9.5-39.9) years. This study included 1792 individuals at CHR and 1377 healthy controls. Using longitudinal clinical information, 253 in the CHR-PS+ group, 1234 in the CHR-PS- group, and 305 at CHR without follow-up data were identified. Compared with healthy controls, individuals at CHR exhibited widespread lower CT measures (mean [range] Cohen d = -0.13 [-0.17 to -0.09]), but not surface area or subcortical volume. Lower CT measures in the fusiform, superior temporal, and paracentral regions were associated with psychosis conversion (mean Cohen d = -0.22; 95% CI, -0.35 to 0.10). Among healthy controls, compared with those in the CHR-PS+ group, age showed a stronger negative association with left fusiform CT measures (F = 9.8; P < .001; q < .001) and left paracentral CT measures (F = 5.9; P = .005; q = .02). Effect sizes representing lower CT associated with psychosis conversion resembled patterns of CT differences observed in ENIGMA studies of schizophrenia (ρ = 0.35; 95% CI, 0.12 to 0.55; P = .004) and individuals with 22q11.2 microdeletion syndrome and a psychotic disorder diagnosis (ρ = 0.43; 95% CI, 0.20 to 0.61; P = .001).

Conclusions and Relevance: This study provides evidence for widespread subtle, lower CT measures in individuals at CHR. The pattern of CT measure differences in those in the CHR-PS+ group was similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread disruptions in CT coupled with abnormal age associations in those at CHR may point to disruptions in postnatal brain developmental processes.

Original languageEnglish (US)
Pages (from-to)753-766
Number of pages14
JournalJAMA psychiatry
Volume78
Issue number7
DOIs
StatePublished - Jul 2021

Bibliographical note

Funding Information:
received grants from Lundbeck; personal fees from Angelini Pharma and Menarini Group; and nonfinancial support from Boehringer Ingelheim. Dr Uhlhaas has received grants from Lundbeck and Eli Lilly UK. Dr Takahashi has received personal fees from Toyama Hospital, Taikoyama Hospital, Saiseikai Toyama Hospital, and Greenhills Wakakusa Hospital. Dr Mathalon has served as a consultant to Boehringer Ingelheim, Cadent Therapeutics, Syndesi Therapeutics, and Recognify. Drs Via and Dolz have received personal fees from Janssen-Cilag. Dr Koike has received grants from Agency for Medical Research and Development, Japan Society for the Promotion of Science, the Naito Foundation, and Takeda Science Foundation. Dr Andreassen has received personal fees from Lundbeck and Sunovion and has served as a consultant for HealthLytix. Dr Baeza has received personal fees from Angelini Pharma, Janssen Pharmaceuticals, and Otsuka-Lundbeck. Dr Chee has served as a sleep consultant for the AIA Vitality Program. Dr Ebdrup has received personal fees for serving on advisory boards from Eli Lilly Denmark, Janssen-Cilag, Lundbeck, and Takeda and has received lecture fees from Bristol Myers Squibb, Otsuka Pharma Scandinavia, Eli Lilly and Company, Boehringer Ingelheim Denmark, and Lundbeck. Dr Fortea has received honoraria from Otsuka-Lundbeck. Dr Birte Glenthøj is the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research, which is partially funded by an independent grant from the Lundbeck Foundation and partially funded by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations. Dr Kaess has received grants from German Federal Ministry of Education and Research, Swiss National Science Foundation, German Research Foundation, Dietmar Hopp Foundation, Baden-Wuerttemberg Foundation, and National Health, Medical and Research Council. Dr Kasai has received grants from Novartis, Astellas, Merck Sharp and Dohme, Eli Lily and Company, Dainippon-Sumitomo Corporation, Eisai, Otsuka, Shionogi, Ono, Tanabe-Mitsubishi, and Takeda;

Funding Information:
grant 81871057 from the National Natural Science Foundation of China. Drs Koike and Kasai have received grants JP20dm0307004 and JP20dm0207069 from the Japan Agency for Medical Research and Development. Dr Koike has received grant JP18K07550 from the Japan Society for the Promotion of Science KAKENHI. Dr Lebedeva and Mr Tomyshev were supported by grant 20-013-00748 from the Russian Foundation for Basic Research. Dr de la Fuente-Sandoval was supported by grants 182279 and 261895 from the Consejo Nacional de Ciencia y Tecnología, grants from CONACYT’s Sistema Nacional de Investigadores, and grant R21 MH117434 from the National Institutes of Health. Dr Waltz has received grant 5R01MH115031 from the National Institute of Mental Health. Dr Mizrahi has received grants R01MH100043 and R01MH113564 from the National Institute of Mental Health and grants from the Brain and Behavior Research Foundation and Canadian Institutes of Health Research. Dr Corcoran has received grant R01 MH107558 from the National Institutes of Health. Dr Tamnes has received grants 288083 and 223273 from the Research Council of Norway and grant 2019069 from the South-Eastern Norway Regional Health Authority. Dr Amminger has received Senior Research Fellowship grant 1080963 from the National Health and Medical Research Council. Dr Andreassen has received grants 223273 and 283798 from the Research Council of Norway as well as grants from K. G. Jebsen Stiftelsen and UiO: Life Science. Ms Atkinson has received grants from the University of Edinburgh. Dr Baeza has received grants INT19/00021, PI11/1349, PI15/0444, and PI180242 from the Instituto de Salud Carlos III. Ms Baldwin has received funding from the National Institute for Health Research Maudsley Biomedical Research Centre studentship. Dr Borgwardt has received grants from the SYNSCHIZ project under the ERA-NET Horizon 2020 program. Drs Chee and Lee received grant NMRC/TCR/003/2008 from the National Medical Research Council Translational and Clinical Research Flagship Programme. Dr Chee has received grant NMRC/STaR/0015/2013 from the National Medical Research Council. Dr Cropley has received investigator grant 1177370 and project grant 1065742 from the National Health and Medical Research Council. Dr Dolz has received grants PI11/02684 and PI15/00509 from the Instituto de Salud Carlos III and a grant from the Alicia Koplowitz Foundation. Dr Louise Glenthøj was supported by the Tryg Foundation and Danish Research Council. Dr Birte Glenthøj was supported by the Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research. Mr Harris has received grants from the Wellcome Trust. Dr Kasai has received grants JP18dm0207004 and JP20dm0307001 from the Japan Agency for Medical Research and Development and grants JP16H06395, JP16H06399, JP16K21720, JP16H06280, and 20H03596 from the Japan Society for the Promotion of Science KAKENHI. Dr Klaunig has received grants from the National Institute of Mental Health. Dr Kwon has received grant 2017M3C7A1029610 from the National Research Foundation of Korea. Dr Lin was supported by grant 1148793 from the Australian National Health and Medical Research Council. Dr Loewy has received grants K23MH086618 and R01MH081051 from the National Institute of Mental Health. Drs McGorry and Yung have received grant 350241 from the

Funding Information:
National Health and Medical Research Council. Dr Nelson has received Career Development Fellowship grant 1027532, Senior Research Fellowship grant 1137687, and project grant 1027741 from the National Health and Medical Research Council. Dr Oppedal has received postdoctoral scholarship grant 912152 from the Western Norway Regional Health Authority. Dr Pantelis has received Senior Principal Research Fellowship grant 1105825 and L3 Investigator grant 1196508 from the National Health and Medical Research Council as well as Distinguished Investigator Award 18722 from the Brain and Behavior Research Foundation. Dr Rössler has received grants from the Zurich Program for Sustainable Development of Mental Health Services. Dr Salisbury has received grant R01 MH113533 from the National Institute of Mental Health. Dr Sasabayashi has received grant JP18K15509 from the Japan Society for the Promotion of Science KAKENHI. Dr Schall has received grant 569259 from the National Health and Medical Research Council of Australia. Dr Schiffman has received grants from the Maryland Department of Health and Mental Hygiene, Behavioral Health Administration through the Maryland Center of Excellence on Early Intervention Program, grant 14-13717G/ M00B4400241 from the Office of Procurement and Support Services, and grant R01MH112612 from the National Institute of Mental Health. Dr Suzuki has received grant JP20H03598 from the Japan Society for the Promotion of Science KAKENHI and grant JP19dk0307069s0203 from the Japan Agency for Medical Research and Development. Ms Tor has received grants PI11/02684 and PI15/ 00509 from the Instituto de Salud Carlos III. Dr Westlye has received grant 300767 from the Research Council of Norway, grant 2019101 from the South-Eastern Norway Regional Health Authority, and European Union’s Horizon 2020 Research and Innovation Program grant 802998 from the European Research Council. Dr Yung has received Principal Research Fellowship grant GNT1136829 from the National Health and Medical Research Council and Senior Research Fellowship grant 566593 from the National Health and Medical Research Council. Dr Turner has received grant 5R01MH094524 from the National Institutes of Health.

Funding Information:
personal fees from Otsuka, Fuji-Film, Yoshitomi, Kyowa, Janssen Pharmaceuticals, Astellas, Meiji Seika Pharma, Sumitomo Dainippon Pharma, and Takeda; and serves on the funding committees of Takeda Science Foundation and Astellas. Dr Kindler has received grants from the Swiss National Science Foundation. Dr Kristensen has received grants from Lundbeck Foundation. Dr Lawrie has received personal fees from Janssen Pharmaceuticals and Sunovion. Dr León-Ortiz has received personal fees from Janssen Pharmaceuticals. Dr Loewy has received grants from National Institute of Mental Health and California Mental Health Services Authority. Dr Nemoto has received grants from Otsuka as well as personal fees from Astellas, Eisai, Janssen Pharmaceuticals, Meiji Seika Pharma, Sumitomo Dainippon Pharma, and Takeda. Dr Pantelis has received grants and personal fees from Lundbeck Foundation. Dr Reyes-Madrigal has received speaker fees from Janssen (Johnson & Johnson). Dr Rössler is supported by the Zurich Program for Sustainable Development of Mental Health Services. Dr Suzuki had received personal fees from Nakagawa Hospital. Ms Tor has received personal fees from Fundación Alicia Koplowitz. Dr Vinogradov served as a member of an advisory board for Alkermes and is an unpaid scientific collaborator for PositScience Inc. Dr Hernaus has received consulting fees from P1vital Products. No other disclosures were reported.

Funding Information:
grant K01 MH112774 from the National Institute of Mental Health. Dr Hayes has received grants from the University of Pittsburgh Medical Center. Drs Wood, Amminger, Bartholomeusz, McGorry, Nelson, and Yung have received funding from the Colonial Foundation. Drs Wood, McGorry, and Yung have received grant 566529 from the National Health and Medical Research Council. Dr Wood has received Clinical Career Development Award 359223 from the National Health and Medical Research Council. Dr Nordholm has received grants R25-A2701 and R287-2018-1485 from the Lundbeck Foundation and grants from the Mental Health Services Capital Region of Denmark. Dr Zhou has received grants from the Yong Loo Lin School of Medicine at the National University of Singapore. Drs Fusar-Poli, Allen, and McGuire and have received grant UK G0700995 from the UK Medical Research Council. Dr Uhlhaas has received grant MR/L011689/1 from the UK Medical Research Council. Dr Sugranyes has received Young Investigator Award grant 26731 from the Brain and Behavior Research Foundation, grants from the Spanish I+D+I state program, grants from the ISCIII-Subdirección General de Evaluación, grant PI18/00976 from the European Regional Development Fund, grant SLT006/17/00362 from the Government of Catalonia (Programa PERIS Salut Mental), grants from the Alicia Koplowitz Foundation, and grants from the Fundació Clínic Recerca Biomèdica (Ajut a la Recerca Pons Bartran). Dr Mathalon has received grants from the Brain and Behavior Research Foundation and grant R01 MH076989 from the National Institute of Mental Health. Dr Hooker was supported by grant R01 MH105246 from the National Institutes of Health. Dr Colibazzi has received grants 5T32MH15144 and K23 MH85063 from the National Institute of Mental Health as well as grants from the Brain and Behavior Research Foundation, Sackler Institute, Herbert Irving Scholar Award, and Columbia University Bodini Fellowship. Dr Tang has received

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