Anorexia nervosa--a noradrenergic dysregulation hypothesis.

Anorexia nervosa manifests a wide range of features which cannot fully be explained on the basis of socio-cultural pressures to be thin, nor by starvation, nor dehydration. Evidence is emerging of a significant neurobiological contribution to its aetiology. However there has to date been no explanation for its pathogenesis that integrates the previously identified genetic, neurobiological and socio-cultural contributing factors. In this paper we propose an empirically-based hypothesis that genetically determined noradrenergic dysregulation, interacting with epigenetic factors, leads to high levels of anxiety, impaired neuroplasticity and regional cerebral hypoperfusion. These, in combination, lead to insula dysfunction. The resulting impairment in insula homuncular representation explains the pathognomonic body image distortion. This distortion, combined with high levels of body-focused anxiety, gives rise to intense dieting, noradrenergic precursor depletion, and initial reduction in anxiety. The subsequent rebound exacerbation of anxiety leads to a vicious cycle of maintenance. Novel treatment implications based on this hypothesis are briefly considered.