Functional Alterations in Cerebellar Functional Connectivity in Anxiety Disorders

Yoon Ji Lee,Nicole Lo,Nicholas A Hubbard,Susan Whitfield-Gabrieli,Randy P Auerbach,Viviana Siless,Isabelle R Frosch,Stefan G Hofmann,Mathias Goncalves,Xavier Guell,John D.E Gabrieli,Sheeba Arnold Anteraper,Satrajit S Ghosh,Diego A Pizzagalli,Anastasia Yendiki,Atira Nair

doi:10.1007/s12311-020-01213-8

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.

Highlights

Anxiety disorders are the most common mental illnesses among adolescents, with the median age of onset at 11 years and a lifetime prevalence rate of 31.9% during adolescence [1, 2]
As the cerebellum serves a wide range of functions and is suggested to be composed of discrete regions dedicated to unique functions [24, 25], we aimed to identify whether alterations in cerebellar functional connectivity in adolescent anxiety are predominantly located within a specific functional territory within the dentate nuclei (DN) or whether these alterations are present in all aspects of the DN
We show for the first time that functional connectivity alterations between cerebellar output structures and cerebral cortical areas are associated with adolescent anxiety

Summary

Introduction

Anxiety disorders are the most common mental illnesses among adolescents, with the median age of onset at 11 years and a lifetime prevalence rate of 31.9% during adolescence [1, 2]. Adolescent anxiety disorders may lead to prolonged psychosocial problems and be a precursor to other psychiatric disorders such as major depressive disorders [4]. Neurocognitive studies on adolescent anxiety have mostly focused on amygdala and prefrontal cortex due to their roles in emotion- and cognitive control-related behaviors [5,6,7]. Anxiety disorders are associated with widespread network disruption [8]. Anxiety disorders are characterized by the exaggerated aversive response to actual or perceived threatening

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