Thinner cortex is associated with psychosis onset in individuals at Clinical High Risk for Developing Psychosis: An ENIGMA Working Group mega-analysis
Authors: Jalbrzikowski Maria , Hayes Rebecca A. , Wood Stephen J. , Nordholm Dorte , Zhou Juan H. , Fusar-Poli Paolo , Uhlhaas Peter J. , Takahashi Tsutomu , Sugranyes Gisela , Kwak Yoo Bin , Mathalon Daniel H. , Katagiri Naoyuki , Hooker Christine I. , Smigielski Lukasz , Colibazzi Tiziano , Via Esther , Tang Jinsong , Koike Shinsuke , Rasser Paul E. , Michel Chantal , Lebedeva Irina , ten Velden Hegelstad Wenche , de la Fuente-Sandoval Camilo , Waltz James A. , Mizrahi Romina R.M. , Corcoran Cheryl , Resch Franz , Tamnes Christian K. , Haas Shalaila S. , Lemmers-Jansen Imke L.J. , Agartz Ingrid , Allen Paul , Andreassen Ole A. , Atkinson Kimberley , Bachman Peter , Baeza Inmaculada , Baldwin Helen , Bartholomeusz Cali F. , Brønnick Kolbjørn S. , Catalano Sabrina , Chee Michael W.L. , Chen Xiaogang , Cho Kang Ik K. , Cooper Rebecca E. , Cropley Vanessa L. , Dolz Montserrat , Ebdrup Bjørn H. , Fortea Adriana , Glenthøj Louise B. , Glenthøj Birte Y. , de Haan Lieuwe , Hamilton Holly K. , Harris Mathew A. , Haut Kristen M. , He Ying , Heekeren Karsten , Heinz Andreas , Hubl Daniela , Hwang Wu Jeong , Kaess Michael , Kasai Kiyoto , Kim Minah , Kindler Jochen , Klaunig Mallory J. , Kristensen Tina D. , Kwon Jun Soo , Lawrie Stephen M. , Lee Jimmy , León-Ortiz Pablo , Lin Ashleigh , Loewy Rachel L. , Ma Xiaoqian , Mathalon Daniel H. , McGorry Patrick , McGuire Philip , Mizuno Masafumi , Møller Paul , Moncada-Habib Toma , Munoz-Samons Daniel , Nelson Barnaby , Nemoto Takahiro , Nordentoft Merete , Omelchenko Maria A. , Oppedal Ketil , Ouyang Lijun , Pantelis Christos , Pariente Jose C. , Raghava Jayachandra , Reyes-Madrigal Francisco , Roach Brian J. , Røssberg Jan I. , Rössler Wulf , Salisbury Dean F. , Sasabayashi Daiki , Schall Ulrich , Schiffman Jason , Schlagenhauf Florian , Schmidt Andre , Sørensen Mikkel E. , Suzuki Michio , Theodoridou Anastasia , Tomyshev Alexander S. , Tor Jordina , Vaernes Tor G , Velakoulis Dennis , Venegoni Gloria D. , Vinogradov Sophia , Wenneberg Christina , Westlye Lars T. , Yamasue Hidenori , Yuan Liu , Yung Alison R. , van Amelsvoort Thérèse A.M.J. , Turner Jessica A. , van Erp Theo G.M. , Thompson Paul M. , Hernaus Dennis , Koppel  , Borgwardt  
Published: January 2021

Importance

The ENIGMA clinical high risk for psychosis (CHR) initiative, the largest pooled CHR-neuroimaging sample to date, aims to discover robust neurobiological markers of psychosis risk in a sample with known heterogeneous outcomes.

Objective

We investigated baseline structural neuroimaging differences between CHR subjects and healthy controls (HC), and between CHR participants who later developed a psychotic disorder (CHR-PS+) and those who did not (CHR-PS-). We assessed associations with age by group and conversion status, and similarities between the patterns of effect size maps for psychosis conversion and those found in other large-scale psychosis studies.

Design, Setting, and Participants

Baseline T1-weighted MRI data were pooled from 31 international sites participating in the ENIGMA CHR Working Group. MRI scans were processed using harmonized protocols and analyzed within a mega- and meta-analysis framework from January-October 2020.

Main Outcome(s) and Measure(s)

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

Results

The final dataset consisted of 3,169 participants (CHR=1,792, HC=1,377, age range: 9.5 to 39.8 years, 45% female). Using longitudinal clinical information, we identified CHR-PS+ (N=253) and CHR-PS- (N=1,234). CHR exhibited widespread thinner cortex compared to HC (average d=-0.125, range: -0.09 to -0.17), but not SA or subcortical volume. Thinner cortex in the fusiform, superior temporal, and paracentral regions was associated with psychosis conversion (average d=-0.22). Age showed a stronger negative association with left fusiform and left paracentral CT in HC, compared to CHR-PS+. Regional CT psychosis conversion effect sizes resembled patterns of CT alterations observed in other ENIGMA studies of psychosis.

Conclusions and Relevance

We provide evidence for widespread subtle CT reductions in CHR. The pattern of regions displaying greater CT alterations in CHR-PS+ were similar to those reported in other large-scale investigations of psychosis. Additionally, a subset of these regions displayed abnormal age associations. Widespread CT disruptions coupled with abnormal age associations in CHR may point to disruptions in postnatal brain developmental processes.

Key Points

Question

How do baseline brain morphometric features relate to later psychosis conversion in individuals at clinical high risk (CHR)?

Findings

In the largest coordinated international analysis to date, reduced baseline cortical thickness, but not cortical surface area or subcortical volume, was more pronounced in CHR, in a manner highly consistent with thinner cortex in established psychosis. Regions that displayed greater cortical thinning in future psychosis converters additionally displayed abnormal associations with age.

Meaning

CHR status and later transition to psychosis is robustly associated with reduced cortical thickness. Abnormal age associations and specificity to cortical thickness may point to aberrant postnatal brain development in CHR, including pruning and myelination.