Normative modeling of brain morphometry in Clinical High-Risk for Psychosis
Authors: Haas Shalaila S , Ge Ruiyang , Agartz Ingrid , Amminger G. Paul , Andreassen Ole A , Bachman Peter , Baeza Inmaculada , Choi Sunah , Colibazzi Tiziano , Cropley Vanessa L , de la Fuente-Sandoval Camilo , Ebdrup Bjørn H , Fortea Adriana , Fusar-Poli Paolo , Glenthøj Birte Yding , Glenthøj Louise Birkedal , Haut Kristen M , Hayes Rebecca A , Heekeren Karsten , Hooker Christine I , Hwang Wu Jeong , Jahanshad Neda , Kaess Michael , Kasai Kiyoto , Katagiri Naoyuki , Kim Minah , Kindler Jochen , Koike Shinsuke , Kristensen Tina D , Kwon Jun Soo , Lawrie Stephen M , Lee Jimmy , Lemmers-Jansen Imke LJ , Lin Ashleigh , Ma Xiaoqian , Mathalon Daniel H , McGuire Philip , Michel Chantal , Mizrahi Romina , Mizuno Masafumi , Møller Paul , Mora-Durán Ricardo , Nelson Barnaby , Nemoto Takahiro , Nordentoft Merete , Nordholm Dorte , Omelchenko Maria A , Pantelis Christos , Pariente Jose C , Raghava Jayachandra M , Reyes-Madrigal Francisco , Røssberg Jan I , Rössler Wulf , Salisbury Dean F , Sasabayashi Daiki , Schall Ulrich , Smigielski Lukasz , Sugranyes Gisela , Suzuki Michio , Takahashi Tsutomu , Tamnes Christian K , Theodoridou Anastasia , Thomopoulos Sophia I , Thompson Paul M , Tomyshev Alexander S , Uhlhaas Peter J , Værnes Tor G , van Amelsvoort Therese AMJ , van Erp Theo GM , Waltz James A , Wenneberg Christina , Westlye Lars T , Wood Stephen J , Zhou Juan H , Hernaus Dennis , Jalbrzikowski Maria , Kahn René S , Corcoran Cheryl M , Frangou Sophia ,   the ENIGMA Clinical High Risk for Psychosis Working Group
Published: January 2023

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 the majority of 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

Clinical, IQ and FreeSurfer-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1,340 CHR-P individuals [47.09% female; mean age: 20.75 (4.74) years] and 1,237 healthy individuals [44.70% female; mean age: 22.32 (4.95) years] from 29 international sites participating in the ENIGMA Clinical High Risk for Psychosis Working Group.

Main Outcomes and Measures

For each regional morphometric measure, z-scores were computed that index the degree of deviation from the normative means of that measure in a healthy reference population (N=37,407). Average deviation scores (ADS) for CT, SA, SV, and globally across all measures (G) were generated by averaging the respective regional z-scores. Regression analyses were used to quantify the association of deviation scores with clinical severity and cognition and two-proportion z-tests to identify case-control differences in the proportion of individuals with infranormal (z<-1.96) or supranormal (z>1.96) scores.

Results

CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z-scores, and all ADS vales. The proportion of CHR-P individuals with infranormal or supranormal values in any metric was low (<12%) and similar to that of healthy individuals. CHR-P individuals who converted to psychosis compared to those who did not convert had a higher percentage of infranormal values in temporal regions (5-7% vs 0.9-1.4%). In the CHR-P group, only the ADSSAshowed significant but weak associations (|β|<0.09; PFDR<0.05) with positive symptoms and IQ.

Conclusions and Relevance

The study findings challenge the usefulness of macroscale neuromorphometric measures as diagnostic biomarkers of psychosis risk and suggest that such measures do not provide an adequate explanation for psychosis risk.

Key points

Question

Is the risk of psychosis associated with brain morphometric changes that deviate significantly from healthy variation?

Findings

In this study of 1340 individuals high-risk for psychosis (CHR-P) and 1237 healthy participants, individual-level variation in macroscale neuromorphometric measures of the CHR-P group was largely nested within healthy variation and was not associated with the severity of positive psychotic symptoms or conversion to a psychotic disorder.

Meaning

The findings suggest the macroscale neuromorphometric measures have limited utility as diagnostic biomarkers of psychosis risk.