Abstract
Pathological anxiety typically emerges during preadolescence and has been linked to alterations in white matter (WM) pathways. Because myelination is critical for efficient neuronal communication, characterizing associations between WM microstructure and symptoms may provide insights into pathophysiological mechanisms associated with childhood pathological anxiety. This longitudinal study examined 182 girls enrolled between the ages of 9–11 that were treatment-naïve at study entry: healthy controls (n = 49), subthreshold-anxiety disorders (AD) (n = 82), or meeting DSM-5 criteria for generalized, social, and/or separation ADs (n = 51), as determined through structured clinical interview. Anxiety severity was assessed with the Clinical Global Impression Scale and Screen for Child Anxiety and Related Emotional Disorders (SCARED). Participants (n = 182) underwent clinical, behavioral, and diffusion tensor imaging (DTI) assessments at study entry, and those with pathological anxiety (subthreshold-AD and AD, n = 133) were followed longitudinally for up to 3 additional years. Cross-sectional ANCOVAs (182 scans) examining control, subthreshold-AD, and AD participants found no significant relations between anxiety and DTI measurements. However, in longitudinal analyses of girls with pathological anxiety (343 scans), linear mixed-effects models demonstrated that increases in anxiety symptoms (SCARED scores) were associated with reductions in whole-brain fractional anisotropy, independent of age (Std. β (95% CI) = −0.06 (−0.09 to −0.03), F(1, 46.24) = 11.90, P = 0.001). Using a longitudinal approach, this study identified a dynamic, within-participant relation between whole-brain WM microstructural integrity and anxiety in girls with pathological anxiety. Given the importance of WM microstructure in modulating neural communication, this finding suggests the possibility that WM development could be a viable target in the treatment of anxiety-related psychopathology.
Highlights
Anxiety is dimensional and, when extreme, becomes maladaptive and is pathological
Bayesian analyses support the interpretation of these null effects as the absence of a relation between anxiety and fractional anisotropy (FA) in the corpus callosum (CC), cingulum bundle (CING), internal capsule (IC), inferior fronto-occipital fasciculus (IFO), STRIA/FX, and uncinate fasciculus (UF) (BFsH1 < 0.33), and a lack of evidence for anxiety-FA relations in the superior longitudinal fasciculus (SLF) and whole-brain white matter (WM) (0.33 < BFsH1 < 3)
Age was associated with FA at the whole-brain level, as well as in the CING, IC, IFO, and UF, but not in the CC, SLF, or STRIA/FX (Supplementary Fig. 3 and Supplementary Table 1)
Summary
Anxiety is dimensional and, when extreme, becomes maladaptive and is pathological. Numerous children have subclinical and persistent anxiety symptoms that do not meet DSM-5 criteria [2, 3]. Because anxiety is dimensional in nature, studying the full range of anxiety may provide insights into the factors that contribute to the varying degrees of distress and disability experienced by children with pathological anxiety. Understanding the factors underlying the development and expression of anxiety in young girls is of particular interest because after the transition to adolescence there is a two-fold increase in the prevalence of ADs in adolescent girls compared to boys that persists throughout the reproductive years [6,7,8]
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