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Author Notes:

Meghan A. Collins, Email: meghan.collins@yale.edu

MAC and TDC conceptualized the study; JA, CEB, KSC, BAC, DHM, DOP, MTT, EFW, SWW, and TDC designed and organized the whole NAPLS3 consortium and collected the data. YC, BGG, HM, REC, MK, WSS, HT, ARP, and AA also participated in MRI data acquisition. JLJ and AA processed the MRI data; MAC, JLJ, CAL, and YAA completed MRI visual quality control; MAC analyzed the data; MAC and TDC drafted the paper with comments from all authors.

MAC, YC, CAL, YAA, JMA, CEB, TDC, KSC, BAC, DPP, MTT, and EFW have no biomedical financial interests or conflicts of interest to disclose. DHM is a consultant for Boehringer-Ingelheim, Cadent Therapeutics, Recognify, and Syndisi. SWW reports that during the last 36 months he has received sponsor-initiated research funding support from Teva, Boehringer-Ingelheim, Amarex, and SyneuRx. He has consulted to Boehringer-Ingelheim, New England Research Institute, and Takeda. He has been granted US patent no. 8492418 B2 for a method of treating prodromal schizophrenia with glycine agonists and has received royalties from Oxford University Press. JLJ previously consulted for Neumora (formerly BlackThorn Therapeutics) and is a co-inventor for the following pending patent: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioural Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No.PCT/US2119/022110, filed March 13, 2019. JLJ is an employee of Manifest Technologies. AA consults for and holds equity with Neumora (formerly BlackThorn Therapeutics), Manifest Technologies, and is a co-inventor on the following patents: Anticevic A, Murray JD, Ji JL: Systems and Methods for Neuro-Behavioural Relationships in Dimensional Geometric Embedding (N-BRIDGE), PCT International Application No. PCT/US2119/022110, filed March 13, 2019 and Murray JD, Anticevic A, Martin WJ: Methods and tools for detecting, diagnosing, predicting, prognosticating, or treating a neurobehavioral phenotype in a subject, U.S. Application No. 16/149,903 filed on October 2, 2018, U.S. Application for PCT International Application No. 18/054,009 filed on October 2, 2018.


Research Funding:

This work was supported by the National Science Foundation (NSF) (No. DGE-1752134) to Ms. Collins, by the National Institute of Mental Health grant U01MH081984 to Dr. Addington; grant U01MH081928 to Dr. Stone; grant U01MH081944 to Dr. Cadenhead; grant U01MH081902 to Drs. Cannon and Bearden; grant U01MH082004 to Dr. Perkins; grant U01MH081988 to Dr. Walker; grant U01MH082022 to Dr. Woods; grant U01MH076989 to Dr. Mathalon; grant UO1MH081857 to Dr. Cornblatt; grants 1U01MH121766, 5R01MH112189, and 5R01MH108590 to Dr. Anticevic; grant T32MH125786 to Dr. Chung.


  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemistry & Molecular Biology
  • Neurosciences
  • Psychiatry
  • Neurosciences & Neurology
  • MRI

Accelerated cortical thinning precedes and predicts conversion to psychosis: The NAPLS3 longitudinal study of youth at clinical high-risk

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Journal Title:



Volume 28, Number 3


, Pages 1182-1189

Type of Work:

Article | Final Publisher PDF


Progressive grey matter loss has been demonstrated among clinical high-risk (CHR) individuals who convert to psychosis, but it is unknown whether these changes occur prior to psychosis onset. Identifying illness-related neurobiological mechanisms that occur prior to conversion is essential for targeted early intervention. Among participants in the third wave of the North American Prodrome Longitudinal Study (NAPLS3), this report investigated if steeper cortical thinning was observable prior to psychosis onset among CHR individuals who ultimately converted (CHR-C) and assessed the shortest possible time interval in which rates of cortical thinning differ between CHR-C, CHR non-converters (CHR-NC), and health controls (HC). 338 CHR-NC, 42 CHR-C, and 62 HC participants (age 19.3±4.2, 44.8% female, 52.5% racial/ethnic minority) completed up to 5 MRI scans across 8 months. Accelerated thinning among CHR-C compared to CHR-NC and HC was observed in multiple prefrontal, temporal, and parietal cortical regions. CHR-NC also exhibited accelerated cortical thinning compared to HC in several of these areas. Greater percent decrease in cortical thickness was observed among CHR-C compared to other groups across 2.9±1.8 months, on average, in several cortical areas. ROC analyses discriminating CHR-C from CHR-NC by percent thickness change in a left hemisphere region of interest, scanner, age, age2, and sex had an AUC of 0.74, with model predictive power driven primarily by percent thickness change. Findings indicate that accelerated cortical thinning precedes psychosis onset and differentiates CHR-C from CHR-NC and HC across short time intervals. Mechanisms underlying cortical thinning may provide novel treatment targets prior to psychosis onset.

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© The Author(s) 2022

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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