Understanding the Underlying Neurobiology Behind Group Differences in Cortical Thickness Across Psychiatric Disorders

This study highlights the importance of transdiagnostic approaches to psychiatry.

Results from a large neuroimaging study published in JAMA Psychiatry reveal a set of shared neurobiologic characteristics across multiple psychiatric disorders. Greater case-control differences in cortical thickness were associated with expression of genes associated with pyramidal cells, astrocytes, and microglia. These data may serve to elucidate the pathophysiology of psychiatric disorders.  

Investigators obtained T1-weighted magnetic resonance imaging (MRI) scans from 145 cohorts registered with the ENIGMA consortium. Cortical thickness was compared between healthy controls and patients with 1 of the 6 following psychiatric conditions:  attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. Interregional profiles of group differences in cortical thickness were produced using principal component analysis. Group differences in cortical thickness were adjusted for age, sex, and study site-specific variables. Interregional profiles of cell-specific gene expression were compared with case-control differences in cortical thickness. Coexpression of genes across disorders was also assessed. 

Data were acquired from 12,721 cases and 15,600 controls. The number of cases and controls for each psychiatric disorder were as follows: ADHD (1814 cases and 1602 controls); ASD (1748 and 1770); BD (1547 and 3405); MDD (2658 and 3572); OCD (2266 and 2007); and schizophrenia (2688 and 3244). Patient ages ranged from 2 to 89 years.

Overall, regions of the cerebral cortex with greater expression of genes specific to pyramidal (CA1) cells also had greater case-control differences in cortical thickness. This trend was observed for all 6 psychiatric disorders.

Greater case-control differences in cortical thickness were also observed in regions of the brain with greater expression of genes specific to astrocytes (except for BD) and microglia (except for OCD). Gene expression profiles of specific brain regions explained between 25% and 54% of the variance in cortical thickness profiles.

The network of genes co-expressed with CA1 pyramidal genes was also assessed. Two clusters emerged: (1) a cluster of genes involved in prenatal neurodevelopment; and (2) a cluster of genes involved in postnatal synaptic activity and plasticity. Each cluster was enriched with the expression of genes specific to CA1 cells, astrocytes, and microglia, suggesting that these cells may serve as “target[s] of perturbations” that increase risk for psychiatric disorders.

The investigators hypothesized that prenatal neurodevelopment may render these cells “vulnerable”, or more likely to be involved in the etiology of psychiatric disorders. The cluster of genes related to the regulation of synaptic plasticity may also reflect the tendency of the brain to change after exposure to adverse experiences. Further study of these clusters is necessary to better understand the neurobiology of these psychiatric disorders, particularly as it relates to the prenatal and postnatal coexpression clusters.

There are several limitations to the approach used in this study. Only 2511 genes determined as having representative interregional profiles of their expression were used for virtual histology. In addition, cell data from mice were used which had shown general conservation with human data. Finally, when interpreting T1-weighted MRI, the investigators assumed that these estimates reflect true variations in brain phenotype rather than measurement error, artifacts, or other physiological sources of the T1 signal.

“There are shared neurobiologic and cellular mechanisms associated with differences in cortical thickness across multiple psychiatric disorders, implicating a common role of prenatal development and postnatal functioning of the cerebral cortex,” the investigators wrote.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Writing Committee for the Attention-Deficit/Hyperactivity Disorder; Autism Spectrum Disorder; Bipolar Disorder; Major Depressive Disorder; Obsessive-Compulsive Disorder; and Schizophrenia ENIGMA Working Groups, et al. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. JAMA Psychiatry. Published online August 26, 2020. doi: 10.1001/jamapsychiatry.2020.2694