Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders

Abstract

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R² = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

Keywords: Anxiety; Cerebellum; Dentate nucleus; Motor network; Salience network.

Fig. 1

Structural location and FTs of the dentate nuclei as reported in [26]). Red, FT1 = default-mode network FT. Blue, FT2 = salience-motor FT. Green, FT3 = visual FT

Fig. 2

Top: Within-group results (overlaid on surface maps in CONN) using functional connectivity calculated from the salience-motor FT of the DN (FT2), at voxel-level height threshold of p < 0.001 (two-sided) and cluster size FDR correction of p < 0.05. Bottom: Between-group results after controlling for medication use (Anx > HC) at voxel-level height threshold of p < 0.001 (two-sided) and cluster size FDR correction of p < 0.05, T = 5.15. Bar plots provide data for the significant cluster (precentral and postcentral cerebral cortex) in Anx and HC

Fig. 3

Whole-brain correlation between STAI-trait scores in healthy controls and salience-motor DN FT-motor/somatosensory cortex functional connectivity, thresholded at a height threshold of p < 0.001, cluster-corrected at p < 0.05 FDR. R² = 0.41