Amygdala hyperactivation in untreated depressed individuals

Abstract

The amygdala participates in the detection and control of affective states, and has been proposed to be a site of dysfunction in affective disorders. To assess amygdala processing in individuals with unipolar depression, we applied a functional MRI (fMRI) paradigm previously shown to be sensitive to amygdala function. Fourteen individuals with untreated DSM-IV major depression and 15 healthy subjects were studied using fMRI with a standardized emotion face recognition task. Voxel-level data sets were subjected to a multiple-regression analysis, and functionally defined regions of interest (ROI), including bilateral amygdala, were analyzed with MANOVA. Pearson correlation coefficients between amygdala activation and HAM-D score also were performed. While both depressed and healthy groups showed increased amygdala activity when viewing emotive faces compared to geometric shapes, patients with unipolar depression showed relatively more activity than healthy subjects, particularly on the left. Positive Pearson correlations between amygdala activation and HAM-D score were found for both left and right ROIs in the patient group. This study provides in vivo imaging evidence to support the hypothesis of abnormal amygdala functioning in depressed individuals.

Introduction

The amygdala plays a central role in the processing of, and memory for, emotionally latent stimuli (Rolls, 2000). As part of a fronto-limbic network involved in mood regulation, the amygdala is a potential locus of dysfunction in affective disorders (Soares and Mann, 1997a, Soares and Mann, 1997b, Phillips et al., 2003). Individuals with unipolar (major) depressive disorders have difficulty discerning affective facial expressions in still photographs (Persad and Polivy, 1993), an ability linked to amygdala activity in healthy subjects (Hariri et al., 2002a). Indeed, functional neuroimaging experiments with healthy subjects have consistently demonstrated that the amygdala is selectively engaged in response to facial stimuli, particularly for negative expressions including fear (Breiter et al., 1996, Morris et al., 1996), disgust (Phillips et al., 1997), sadness (Blair et al., 1999) or anger (Hariri et al., 2002b). Patients with unipolar depression tend to over-activate the left amygdala in response to fearful or sad faces (Fu et al., 2004, Sheline et al., 2001). This over-activation normalizes with antidepressant treatment (Fu et al., 2004, Sheline et al., 2001), a finding consistent with the observation that the metabolic rate in the left amygdala of affective disorder patients normalizes with chronic treatment (Drevets et al., 1992). However, these findings are not universal (Abercrombie et al., 1998, Irwin et al., 2004), leaving questions about the specificity of left amygdala dysfunction in major depression.

Here we apply an emotional processing task previously demonstrated to be sensitive to amygdala function (Hariri et al., 2002a) in a well-characterized sample of unmedicated unipolar patients in an attempt to replicate and extend previous findings of amygdala hyperactivation in response to emotionally expressive faces. Specifically, this study assessed activation in response to faces expressing anger and fear in untreated depressed patients as well as healthy controls. We hypothesized that depressed patients would have greater amygdala activation compared with matched healthy controls.