Shape Alterations and Asymmetry in Deep Gray Matter Structures Associated with Schizophrenia and Anti-psychotics: an N=6500 Meta-analysis

Schizophrenia has been previously characterized by differences in deep gray matter structure volumes. Here, we take a detailed look at the specific morphometric differences driving these effects in a large 22-cohort meta-analysis study of 2763 patients and 3768 controls.

We use the ENIGMA-Shape package, a parametric surface-based computational tool used to measure thickness and surface area change at regional boundaries of 7 (14) bilateral regions: amygdala, nucleus accumbens, caudate nucleus, hippocampus, thalamus, putamen and pallidum. Also, we measure vertex-wise asymmetry in the context of schizophrenia. Searchlight False Discovery Rate correction is used to control for false discovery rate due to multiple testing at p=0.05. We control for age, sex, age^2, age x sex, age^2 x sex, and intracranial volume.

We report the regions affected and the 5^th/95^th percentile of the regression coefficient maps. We found a significant bilateral effect of schizophrenia on all seven structures, with effect range [0.031, 0.18] mm thickness. In addition, schizophrenia patients’ hippocampus, thalamus, putamen, caudate and nucleus accumbens were significantly less symmetric compared to controls. There were also significant reductions in sections of the hippocampus, amygdala, thalamus, caudate and nucleus accumbens associated with chlorpromazine use, effect range [7.1x10^-5, 1.4x10^-4] mm/mg.

We have for the first time analyzed subcortical shape symmetry in a large meta-study of schizophrenia. We found a widespread effect in seven subcortical regions, and data that symmetry may play a crucial role in understanding the disorder. In addition, we found concordant effects of antipsychotic medication and the disorder on deep gray matter structure morphometry.

Boris A. Gutman¹, Theo van Erp², Kathryn Alpert³, Dmitry Isaev¹, Artemis Zavaliangos-Petropulu¹, Vince Calhoun⁴ , David Glahn⁵, Ted Satterthwaite⁶, Ole Andreas Andreasen⁷, Stefan Borgwardt⁸, Fleur Howells⁹, Aristotle Voineskos¹⁰, Joaquim Radua¹¹, Steven Potkin², Benedicto Crespo Facorro¹², Li Shen¹³, Irina Lebedeva¹⁴, Gianfranco Spalletta¹⁵, Gary Donohoe¹⁶, Peter Kochunov¹⁷, N. Trung Doan⁷, Ingrid Agartz⁷, Fabienne Harrisberger⁸, Dan J. Stein⁹ , Erin W. Dickie¹⁰, Erick Jorge Canales-Rodriguez¹¹, Alexander J. Huang², Roberto Roiz-Santiañez¹², Shan Cong¹³, Alexander Tomyshev¹⁴, Fabrizio Piras¹⁵, Paul M. Thompson¹, Jessica Turner^4* and Lei Wang^3* for the ENIGMA Schizophrenia Working Group

¹Imaging Genetics Center, Keck SOM of USC, Los Angeles

²University of California, Irvine

³Psychiatry, Northwestern University, Chicago

⁴ The Mind Research Network, Albuquerque

⁵Yale University School of Medicine

⁶University of Pennsylvania

⁷University of Oslo faculty of Medicine

⁸ Department of Psychiatry, University of Basel

⁹Psychiatry, University of Cape Town, Cape Town

¹⁰Centre for Addiction and Mental Health, Toronto

¹¹FIDMAG Research Foundation, Barcelona

¹² University Hospital Marqués de Valdecilla, IDIVAL, CIBERSAM

¹³Dept. of Radiology and Imaging Sciences, Indiana University

¹⁴Mental Health Research Center, Moscow

¹⁵Neuropsychiatry Laboratory, Sta Lucia Foundation, Rome

¹⁶ School of Psychology, NUI Galway

¹⁷Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore