Altered Uncinate Fasciculus Microstructure in Childhood Anxiety Disorders in Boys But Not Girls

Abstract

Objective: Anxiety disorders are common, can result in lifelong suffering, and frequently begin before adolescence. Evidence from adults suggests that altered prefrontal-limbic connectivity is a pathophysiological feature of anxiety disorders. More specifically, in adults with anxiety disorders, decreased fractional anisotropy (FA), a measure of white matter integrity, has been observed in the uncinate fasciculus, the major tract that connects limbic and prefrontal regions. Because of the early onset of anxiety disorders and the increased incidence in anxiety disorders in females during their reproductive years, it is important to understand whether the reduction in uncinate fasciculus FA exists in children with anxiety disorders and the extent to which this alteration is sex related. To address these issues, the authors assessed FA in the uncinate fasciculus in unmedicated boys and girls with anxiety disorders.

Methods: FA measures were derived from diffusion tensor images that were acquired from 98 unmedicated children (ages 8-12); 52 met criteria for generalized anxiety disorder, separation anxiety disorder, social anxiety disorder, or anxiety disorder not otherwise specified, and 46 were matched control subjects.

Results: Tract-based results demonstrated that children with anxiety disorders have significant reductions in uncinate fasciculus FA. A significant sex-by-group interaction and post hoc testing revealed that this effect was evident only in boys. No other main effects or sex-by-group interactions were found for other white matter tracts.

Conclusions: These findings provide evidence of uncinate fasciculus white matter alterations in boys with anxiety disorders. The data demonstrate that anxiety disorder-related alterations in prefrontal-limbic structural connectivity are present early in life, are not related to psychotropic medication exposure, and are sex specific. Building on these findings, future research has the potential to provide insights into the genesis and sexual dimorphism of the pathophysiology that leads to anxiety disorders, as well as to identify sex-specific early-life treatment targets.

Keywords: Anxiety Disorder-Generalized; Biological Markers.

Figure 1.

Children with anxiety disorders (ADs) have reduced fractional anisotropy (FA) in the uncinate fasciculus (UF). A) Children with ADs have significantly lower FA in the UF compared to controls. Violin plot of UF FA data residualized for sex, age and site. B) Box plot of significant interaction between group and sex. Post hoc analyses indicate no significant difference between healthy girls and AD girls, but are different between healthy boys and AD boys. UF FA is residualized for age and site. C) Whole-brain voxel-based analyses confirm significant differences in UF FA between controls and AD children, test results are shown on the right UF fiber tract. The coronal view shows the extent of significant differences after TFCE correction. Cooler colors indicate lower FA values in AD patients compared to healthy controls.

Figure 2.

Group differences in tract fractional anisotropy (FA). Weighted mean FA values by tract for control and anxiety disorder (AD) subjects, with standard deviations in parentheses. Significance of the regression statistics for the main effect of group, as well as the interaction of group by sex are noted. All analyses include age, sex and site as covariates.