Exploring volumetric abnormalities in subcortical L-HPA axis structures in pediatric generalized anxiety disorder

Abstract

Background

Pediatric generalized anxiety disorder (GAD) is debilitating and increasingly prevalent, yet its etiology remains unclear. Some believe the disorder to be propagated by chronic dysregulation of the limbic-hypothalamic-pituitary-adrenal (L-HPA) axis, but morphometric studies of implicated subcortical areas have been largely inconclusive. Recognizing that certain subcortical subdivisions are more directly involved in L-HPA axis functioning, this study aims to detect specific abnormalities in these critical areas.

Methods

Thirty-eight MRI scans of preschool children with (n = 15) and without (n = 23) GAD underwent segmentation and between-group volumetric comparisons of the basolateral amygdala (BLA), ventral hippocampal subiculum (vSC), and mediodorsal medial magnocellular (MDm) area of the thalamus.

Results

Children with GAD displayed significantly larger vSC compared to healthy peers, F(1, 31) = 6.50, p_FDR = .048. On average, children with GAD presented with larger BLA and MDm, Fs(1, 31) ≥ 4.86, ps_FDR ≤ .054. Exploratory analyses revealed right-hemispheric lateralization of all measures, most notably the MDm, F(1, 31) = 8.13, p_FDR = .024, the size of which scaled with symptom severity, r = .83, p_FDR = .033.

Conclusion

The BLA, vSC, and MDm are believed to be involved in the regulation of anxiety and stress, both individually and collectively through the excitation and inhibition of the L-HPA axis. All were found to be enlarged in children with GAD, perhaps reflecting hypertrophy related to hyperexcitability, or early neuronal overgrowth. Longitudinal studies should investigate the relationship between these early morphological differences and the long-term subcortical atrophy previously observed.

Keywords:

• Neuroimaging
• generalized anxiety disorder
• structural MRI
• hypothalamic-pituitary-adrenal axis

Acknowledgements

The present research was self-funded. Special thanks to colleagues Maya Tranter, Rubina Fray Gogulu, and Zacharias Kalle Obel for contributing with feedback during the original drafting of this manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s). Alexander Tobias Ysbæk-Nielsen works, teaches, and studies at the Department of Psychology, University of Copenhagen.

Data availability statement

The employed dataset, titled “Preschool Anxiety Disorders”, is hosted by OpenNeuro (OpenNeuro.org) and has the accession number: ds000144 (https://openneuro.org/datasets/ds000144/versions/00002). All data are freely available under the Creative Commons CC0 Universal license. For additional details, refer to the original paper in which these data appeared [47].