Disrupted amygdalar subregion functional connectivity and evidence of a compensatory network in generalized anxiety disorder.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
Cross-sectional study.


METHODS
Academic medical center.


METHODS
Two cohorts of healthy control subjects (consisting of 17 and 31 subjects) and 16 patients with GAD.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Etkin
Amit
A
Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. amitetkin@stanford.edu
Prater
Katherine E
KE
Schatzberg
Alan F
AF
Menon
Vinod
V
Greicius
Michael D
MD
D000328:Adult; D000679:Amygdala / Q000503:physiopathology*; D001008:Anxiety Disorders / Q000175:diagnosis / Q000503:physiopathology*; D001303:Auditory Cortex / Q000503:physiopathology; D001921:Brain / Q000503:physiopathology*; D001931:Brain Mapping; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005625:Frontal Lobe / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data*; D008297:Male; D009415:Nerve Net / Q000503:physiopathology; D009434:Neural Pathways / Q000503:physiopathology*; D010296:Parietal Lobe / Q000503:physiopathology; D010555:Personality Inventory; D017397:Prefrontal Cortex / Q000503:physiopathology; D011569:Psychiatric Status Rating Scales; D011795:Surveys and Questionnaires