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Pilot multimodal twin imaging study of generalized anxiety disorder


  • The authors report they have no financial relationships within the past 3 years to disclose.

  • Preliminary results from this study were presented at the 30th Annual Anxiety Disorders Association of America Conference, March 4-7, 2010, Baltimore, MD.

Correspondence to: John M. Hettema, VCU Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, P.O. Box 980126, Richmond, VA 23298-0126



Generalized anxiety disorder (GAD) is a common chronic condition that is relatively understudied compared to other psychiatric syndromes. Neuroimaging studies have begun to implicate particular neural structures and circuitry in its pathophysiology; however, no genetically informative research has examined the potential sources of reported brain differences.


We acquired spectroscopic, volumetric, and diffusion tensor magnetic resonance imaging data from a pilot study of 34 female subjects selected from monozygotic twin pairs based upon their affection status for GAD, and examined brain regions previously implicated in fear and anxiety for their relationship with affection status and genetic risk.


Lifetime GAD associated with increased creatine levels in the amygdala, smaller left hippocampal volume, and lower fractional anisotropy in the uncinate fasciculus which connects amygdala and frontal cortex. In addition, GAD genetic risk predicted increases in myo-inositol in the amygdala and, possibly, glutamate/glutamine/GABA alterations in the hippocampus. The association of lifetime GAD with smaller hippocampal volume was independent of major depression and might represent a common genetic risk marker for internalizing disorders.


These preliminary data suggest that GAD and its genetic risk factors are likely correlated with volumetric and spectroscopic changes in fear-related limbic structures and their connections with the frontal cortex. Depression and Anxiety 0:1–8, 2011. © 2011 Wiley-Liss, Inc.