A Comprehensive Analysis of Cerebellar Volumes in the 22q11.2 Deletion Syndrome

Abstract

Background: The presence of a 22q11.2 microdeletion (22q11.2 deletion syndrome [22q11DS]) ranks among the greatest known genetic risk factors for the development of psychotic disorders. There is emerging evidence that the cerebellum is important in the pathophysiology of psychosis. However, there is currently limited information on cerebellar neuroanatomy in 22q11DS specifically.

Methods: High-resolution 3T magnetic resonance imaging was acquired in 79 individuals with 22q11DS and 70 typically developing control subjects (N = 149). Lobar and lobule-level cerebellar volumes were estimated using validated automated segmentation algorithms, and subsequently group differences were compared. Hierarchical clustering, principal component analysis, and graph theoretical models were used to explore intercerebellar relationships. Cerebrocerebellar structural connectivity with cortical thickness was examined via linear regression models.

Results: Individuals with 22q11DS had, on average, 17.3% smaller total cerebellar volumes relative to typically developing subjects (p < .0001). The lobules of the superior posterior cerebellum (e.g., VII and VIII) were particularly affected in 22q11DS. However, all cerebellar lobules were significantly smaller, even after adjusting for total brain volumes (all cerebellar lobules p < .0002). The superior posterior lobule was disproportionately associated with cortical thickness in the frontal lobes and cingulate cortex, brain regions known be affected in 22q11DS. Exploratory analyses suggested that the superior posterior lobule, particularly Crus I, may be associated with psychotic symptoms in 22q11DS.

Conclusions: The cerebellum is a critical but understudied component of the 22q11DS neuroendophenotype.

Keywords: 22q11.2 deletion syndrome; Cerebellum; Crus I; Genetics; MRI; Psychosis; Schizophrenia.

Figure 1:

Examples of MAGeT parcellations for lobule-level cerebellar regions of interest in four representative subjects with 22q11DS. Left and right cerebellar hemispheres are measured separately (legend is for left hemisphere ROIs only, labeled in a counter-clockwise order).

Figure 2:

Decreased cerebellar volumes in 22q11DS. Panel A reports raw volumetric group differences in total cerebellar volumes between subjects with 22q11DS and a TD control group. Panel B is a scatterplot demonstrating the correlation between total brain volume and total cerebellar volumes. Panel C also quantifies group differences, but after adjusting for age, sex, race, and total brain volumes.

Figure 3:

Effect sizes (Cohen’s d) for group differences in cerebellar lobes and lobules. Negative values indicate that TD volumes are greater than 22q11DS. Cohen’s d without adjustment for TBV (purple circles) are shown, as well as TBV-adjusted values (orange squares). Error bars represent 95% confidence intervals. Lobar ROI definitions are shown both on cross-sectional images (top center) and a 3D surface (top right). Lobular-level ROI parcellations were provided in Figure 1.

Figure 4:

Results from graph theoretical models. At left (Panel A), the centroid for each ROI is projected on a coronal slice, as well as a left posterior lateral oblique surface projection; each node is color coded based on lobe. At center (B), global network statistics for a range of graph densities are plotted for each group separately. Panel C displays results of permutation tests, with standardized TD - 22q11DS difference scores at each graph density; these plots are overlaid on null distributions, with gray lines indicating 5^th, 50^th, and 95^th quantiles. Finally, panel D provides representative structural covariance graphs (density = 0.1) for each group.

Figure 5:

Group differences in cerebro-cerebellar associations for cerebellar lobes. FDR-corrected probability maps (top) show statistically significant total and lobar cerebellum x group interactions on vertex-level measures of cortical thickness. The color maps (bottom) display the standardized b-weights for the ROI x diagnosis interaction (TD dummy coded 1, 22q11DS 0). Red indicates thicker cortex in the TD group with increasing volumes (relative to 22q11DS), with areas in blue having relatively thicker cortex in 22q11DS.