Disrupted Amygdalar Subregion Functional Connectivity and Evidence of a Compensatory Network in Generalized Anxiety Disorder

TLDR

Generalized anxiety disorder’s neural underpinnings are poorly understood, and although the amygdala is implicated in other anxiety disorders, studies in GAD have been inconsistent; moreover, amygdala subregions interact with distinct brain networks, a relationship that has only been examined in animal models. This study aimed to determine whether distinct functional connectivity patterns can be reliably identified for the basolateral and centromedial subregions of the human amygdala and to assess potential compensatory connectivity in GAD. Using a cross‑sectional design at an academic medical center, resting‑state fMRI was performed on 16 GAD patients and two healthy control cohorts (17 and 31 subjects) with cytoarchitectonically defined BLA and CMA regions of interest. Reproducible subregional connectivity differences were found in controls, with BLA linked to sensory and medial prefrontal cortices and CMA to midbrain, thalamus, and cerebellum, whereas GAD patients showed less distinct BLA/CMA patterns, increased CMA gray‑matter volume, heightened connectivity to a frontoparietal executive control network, reduced connectivity to an insula‑ and cingulate‑based salience network, and evidence of a compensatory frontoparietal.

Abstract

Little is known about the neural abnormalities underlying generalized anxiety disorder (GAD). Studies in other anxiety disorders have implicated the amygdala, but work in GAD has yielded conflicting results. The amygdala is composed of distinct subregions that interact with dissociable brain networks, which have been studied only in experimental animals. A functional connectivity approach at the subregional level may therefore yield novel insights into GAD.To determine whether distinct connectivity patterns can be reliably identified for the basolateral (BLA) and centromedial (CMA) subregions of the human amygdala, and to examine subregional connectivity patterns and potential compensatory amygdalar connectivity in GAD.Cross-sectional study.Academic medical center.Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD.Functional connectivity with cytoarchitectonically determined BLA and CMA regions of interest, measured during functional magnetic resonance imaging performed while subjects were resting quietly in the scanner. Amygdalar gray matter volume was also investigated with voxel-based morphometry.Reproducible subregional differences in large-scale connectivity were identified in both cohorts of healthy controls. The BLA was differentially connected with primary and higher-order sensory and medial prefrontal cortices. The CMA was connected with the midbrain, thalamus, and cerebellum. In GAD patients, BLA and CMA connectivity patterns were significantly less distinct, and increased gray matter volume was noted primarily in the CMA. Across the subregions, GAD patients had increased connectivity with a previously characterized frontoparietal executive control network and decreased connectivity with an insula- and cingulate-based salience network.Our findings provide new insights into the functional neuroanatomy of the human amygdala and converge with connectivity studies in experimental animals. In GAD, we find evidence of an intra-amygdalar abnormality and engagement of a compensatory frontoparietal executive control network, consistent with cognitive theories of GAD.