Cerebellar-Cortical Connectivity Is Linked to Social Cognition Trans-Diagnostically

Abstract

Background: Psychotic disorders are characterized by impairment in social cognitive processing, which is associated with poorer community functioning. However, the neural mechanisms of social impairment in psychosis remain unclear. Social impairment is a hallmark of other psychiatric illnesses as well, including autism spectrum disorders (ASD), and the nature and degree of social cognitive impairments across psychotic disorders and ASD are similar, suggesting that mechanisms that are known to underpin social impairments in ASD may also play a role in the impairments seen in psychosis. Specifically, in both humans and animal models of ASD, a cerebellar-parietal network has been identified that is directly related to social cognition and social functioning. In this study we examined social cognition and resting-state brain connectivity in people with psychosis and in neurotypical adults. We hypothesized that social cognition would be most strongly associated with cerebellar-parietal connectivity, even when using a whole-brain data driven approach. Methods: We examined associations between brain connectivity and social cognition in a trans-diagnostic sample of people with psychosis (n = 81) and neurotypical controls (n = 45). Social cognition was assessed using the social cognition domain score of the MATRICS Consensus Cognitive Battery. We used a multivariate pattern analysis to correlate social cognition with resting-state functional connectivity at the individual voxel level. Results: This approach identified a circuit between right cerebellar Crus I, II and left parietal cortex as the strongest correlate of social cognitive performance. This connectivity-cognition result was observed in both people with psychotic disorders and in neurotypical adults. Conclusions: Using a data-driven whole brain approach we identified a cerebellar-parietal circuit that was robustly associated with social cognitive ability, consistent with findings from people with ASD and animal models. These findings suggest that this circuit may be marker of social cognitive impairment trans-diagnostically and support cerebellar-parietal connectivity as a potential therapeutic target for enhancing social cognition.

Keywords: bipolar disorder; cerebellum; connectivity; imaging; psychosis; resting state; schizophrenia; social cognition.

Copyright © 2020 Brady, Beermann, Nye, Eack, Mesholam-Gately, Keshavan and Lewandowski.

Figures

Figure 1

Multivariate distance matrix regression identifies left parietal connectivity as the strongest correlate of social cognitive ability in a trans-diagnostic sample. MDMR procedure: (A) rsfMRI and emotional intelligence testing are collected from each participant. (B) For each participant a functional connectivity map is generated to an individual voxel. (C) Voxelwise temporal correlations between participants are used to generate a Pearson's correlation r and a distance metric d. This is repeated for all participants to generate a matrix of between subject distances. (D) The distance matrix is centered and an ANOVA-like test is used to generate an F-statistic to assess the relationship between a predictor variable (MSCEIT-ME score) and dissimilarities in functional connectivity at that voxel. (E) This process is repeated for every voxel. This results in a whole brain map of how significantly functional connectivity is related to emotional intelligence. Permutation testing then identifies whole-brain significant clusters in connectivity-MSCEIT-ME relationships. (F) In our sample of 126 participants (n = 60 with schizophrenia or schizoaffective disorder, n = 21 with bipolar disorder with psychosis, and n = 45 neurotypical participants), we identified a single region in the left parietal lobule (centered at MNI coordinates x – 24 y – 69 z + 57) whose connectivity correlated significantly with emotional intelligence. In this image, connectivity is thresholded at a voxelwise level of p < 0.001 and extent threshold of p < 0.05.

Figure 2

The strongest link between connectivity and social cognitive ability is a parietal Lobe-cerebellar Crus I, II circuit. We visualized the spatial distribution of connectivity that gave rise to the MDMR result in Figure 1. We placed a ROI in the left parietal region identified by MDMR and regressed connectivity to this region against MSCEIT-ME score. This identified the right cerebellar Crus I, II region as the region where functional connectivity correlates with social cognitive ability. Peak T-stat T = 4.99, p < 0.001, MNI x – 12, y – 90, z – 30. Cluster k = 695, pFWE < 0.001. Color bar = voxel connectivity p-value.

Figure 3

A cerebellar–parietal circuit is causally linked to social cognition both trans-diagnostically and trans-species. A series of murine and human experiments converge on a shared circuit causally linked to social cognition. (A) Imaging studies reliably identify cerebellar right Crus abnormalities in autism. Neuromodulation experiments in humans identify a circuit linking right Crus to the left parietal lobe and murine studies demonstrate this circuit is critical to normal social interaction (48). (B) We observe that, in a trans-diagnostic sample, connectivity between right cerebellar Crus and left parietal lobe connectivity is directly linked to social cognitive ability. (C) In a large (n = 461) dataset, connectivity in this cerebellar Crus–parietal circuit was the strongest link between a broad array of outcomes along a “positive–negative axis” (71). Taken together, these data are consistent with a critical role for a cerebellar–cortical circuit in complex social cognition. Murine image from the Allen Mouse Brain Atlas.