Two notable findings emerged from this preliminary investigation that contribute to clinical neuroscience research on depression. First, the relatively consistent pattern of hypoactivation seen in the MDD/GAD group in medial and middle frontal regions as well as in the anterior cingulate, cingulate and insula is generally consistent with prior findings demonstrating frontal-limbic dysfunction in depression [
2-
4]. Reduced activation in MDD/GAD patients was found in the insula and right cingulate gyrus for both negative visual stimuli but not the positive stimulus, suggesting a decrease in somato-affective [
9] and cognitive-attentional interactions [
10]. One interpretation of the hypoactivation observed in medial/middle frontal regions is that it reflects reduced engagement with provocative, emotional stimuli. The middle frontal gyrus has been associated with sustained attention, working memory and language [
11], thus the reduced activation suggests a decrease in executive functioning [
12]. Presentations of individualized autobiographic statements were also associated with attenuated responses in the dorsal anterior cingulate cortex, an area associated with cognitive-emotional responses [
13]. These results demonstrate comorbid anxiety may not work in opposition to depressive symptoms in ways that minimize between group differences commonly reported. It should be noted that we did not observe activation in the ventromedial and subgenual cingulate cortex or amygdala [
2,
4] during presentation of standardized visual stimuli. Whether this difference reflects a procedural difference or the effects of a prolonged period of GAD is unclear.
The second notable finding of this investigation concerns modulation of activation by anxiety level during emotional information processing. In regions that showed hypoactivation, increased anxiety was correlated with increased activation in middle frontal regions and the insula but only during presentation of faces expressing anger and autobiographical sentences describing happy personal events, suggesting that anxiety effects do not generalize across all types of emotional information. The area of insula activation observed was more posterior in our study compared with other anxiety studies [
14]. The positive correlation between insula activation and anxiety level suggests that the posterior part of the insula also may be involved in the neurobiology of anxiety. One implication of these findings for research on depression is that anxiety level may serve as an important individual difference variable [
1]. Complicating matters is that anxiety level does not equally modulate activation to all types of emotional information. The important implication is that divergent findings reported in the imaging literature on depression could reflect modulation of activation by anxiety level in response to different emotional information.
While our findings suggest frontal and limbic dysfunction in patients with depression and comorbid anxiety and modulation of activation by anxiety level, additional research including larger samples of patients with major depression alone and with comorbid generalized anxiety is needed to replicate findings and clarify the effects of anxiety. Future research is needed that refines the assessment of manifestations of anxiety in novel ways that extend beyond DSM categorizations, such as considering measures of negative forecasting, avoidance frequency, level of experiential avoidance and sustained levels of activation, The integration of alternative measures of anxiety with neuroimaging technology may provide additional novel insights into the brain abnormalities underlying depression.
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