Normative Modeling of Brain Morphometry in Clinical High Risk for Psychosis
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Findings In this case-control study of 1340 individuals at clinical high risk for psychosis and 1237 healthy participants, individual-level variation in macroscale neuromorphometric measures in the group at clinical high risk for psychosis was largely nested within healthy variation and was not associated with the severity of positive symptoms or conversion to a psychotic disorder.
Meaning The findings suggest the macroscale neuromorphometric measures have limited utility as diagnostic biomarkers of psychosis risk.
Abstract
Importance The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals.
Objective To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder.
Design, Setting, and Participants This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)–derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022.
Main Outcomes and Measures For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < −1.96) or supranormal (z > 1.96) scores.
Results Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (β = −0.08; 95% CI, −0.13 to −0.02; P = .02 for false discovery rate) and IQ (β = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate).
Conclusions and Relevance In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | JAMA Psychiatry |
| Vol/bind | 81 |
| Udgave nummer | 1 |
| Sider (fra-til) | 77-88 |
| Antal sider | 12 |
| ISSN | 2168-622X |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
Funding/Support: This study was supported by grants PI15/0444, PI18/0242, PI18/00976, and PI2100330 from the Alicia Koplowitz Foundation and the Spanish Ministry of Health (Dr Sugranyes); 30112 (Dr Kristensen) and 26731 (Dr Sugranyes) from the Brain & Behavior Research Foundation; 261895 and 320662 from the Consejo Nacional de Ciencia y Tecnología (Dr de la Fuente-Sandoval); 101057529 from the European Commission (Dr Sugranyes); 802998 from the European Research Council (Dr Westlye); INT19/00021 (Dr Baeza) and PI11/1349, PI15/0444, and PI180242 (Drs Baeza and Fortea and Mr Pariente) from the Instituto de Salud Carlos III; JP18dm0307001, JP18dm0307004, and JP19dm0207069 (Drs Kasai and Koike) and JP19dk0307069s0203 (Dr Suzuki) from the Japan Agency for Medical Research and Development; JP18K15509 and JP22K15745 (Dr Sasabayashi), JP20H03598 (Dr Suzuki), and JP18K07550 (Dr Takahashi) from the KAKENHI program of the Japan Society for the Promotion of Science; JPMJMS2021 from the Moonshot Research and Development program of the Japan Science and Technology Agency (Drs Kasai and Koike); 21-BR-03-01 (Dr Kim) and 21-BR-03-01 (Dr Kwon) from the KBRI Basic Research Program of the Korea Brain Research Institute funded by ITC and the Ministry of Science; HI19C1080 from the Korea Health Technology Research and Development Project (Dr Hwang); R25-A2701 and R287-2018-1485 from the Lundbeck Foundation (Dr Nordholm); NMRC/TCR/003/2008 from the Translational and Clinical Research Flagship Programme of the National Medical Research Council (Dr Lee); 2019R1C1C1002457 (Dr Kim) and 2020M3E5D9079910 (Dr Kwon) from the National Research Foundation of Korea; 1177370 and 1065742 (Dr Cropley), 2010063 (Dr Lin), 1137687 (Dr Nelson), 1196508 and 1150083 (Dr Pantelis), and 569259 (Dr Schall) from the NHMRC of Australia; R21 MH117434 (Dr de la Fuente-Sandoval), R01 MH105246 (Dr Hayes), R01 MH113533 (Dr Salisbury), and R01MH107558 and R01MH115332 (Dr Corcoran) from the NIH; T32MH122394 (Dr Haas), 5T32MH15144 and K23 MH85063 (Dr Colibazzi), R01MH105246 (Dr Haut), R01 MH076989 (Dr Mathalon), R01MH100043 and R01MH113564 (Dr Mizrahi), R01MH123163, R01MH121246, and R01MH116147 (Ms Thomopoulos and Dr Thompson), 5R01MH115031 (Dr Waltz), and K01MH112774 and R01MH129636 (Dr Jalbrzikowski) from the NIMH; 223272 (Dr Agartz), 223273 and 283798 (Dr Andreassen), and 223273, 288083, and 323951 (Dr Tamnes) from the Research Council of Norway; 22-15-00437 (Dr Kwon) and 22-15-00437 (Mr Tomyshev) from the Russian Science Foundation; 2019069, 2021070, 2023012, and 500189 from the South-Eastern Norway Regional Health Authority (Dr Tamnes); and MR/L011689/1 from the UK Medical Research Council (Dr Uhlhaas); and funding from the Brain & Behavior Research Foundation (Drs Colibazzi, Mathalon, and Mizrahi), the Canadian Institutes of Health Research (Dr Mizrahi), a Columbia University Bodini Fellowship (Dr Colibazzi), the Consejo Nacional de Ciencia y Tecnología Sistema Nacional de Investigadores (Drs de la Fuente-Sandoval and Reyes-Madrigal), the Danish Research Council on Independent Research (Dr L. Glenthøj), a Herbert Irving Scholar Award (Dr Colibazzi), K. G. Jebsen Stiftelsen (Dr Andreassen), the Lundbeck Foundation Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research (Drs B. Glenthøj and L. Glenthøj), the Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (Dr L. Glenthøj), Mental Health Center Copenhagen (Dr Nordentoft), the Mental Health Services Capital Region of Denmark (Drs Nordentoft and Nordholm), the NHMRC of Australia (Dr Wood), Otsuka Pharmaceutical (Dr Nemoto), the Sackler Institute (Dr Colibazzi), TrygFoundation (Dr L. Glenthøj), UiO: Life Science (Dr Andreassen), the University of Copenhagen (Dr Nordentoft), the University of Pittsburgh Medical Center (Dr Hayes), the Yong Loo Lin School of Medicine at the National University of Singapore (Dr Zhou), and the Zurich Program for Sustainable Development of Mental Health Services (Dr Rössler). Core funding for Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) was provided by grant U54 EB020403 from the NIH Big Data to Knowledge program (Dr Thompson).
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