The Functional Neuroanatomy of Emotion Regulation in Major Depressive Disorder (MDD)

The goal of this research is to elucidate the neurophysiological abnormalities associated with processing emotionally valenced stimuli in MDD. Neuroimaging technology has led to the identification of specific abnormalities in the amygdala, ventral striatum and medial prefrontal cortex in response to affective pictures. Much of the knowledge involving these structures in emotion processing has been elucidated through animal models including classical fear conditioning and reversal-learning paradigms. Functional magnetic resonance imaging (fMRI) studies have applied similar techniques in humans to study emotional processing. The amygdala has been shown to play a role in the learning of fear (aversive) conditioning to emotional stimuli, the ventral striatum has been shown to play a role in appetitive conditioning, and areas of the prefrontal cortex are recruited for extinction of conditioned responses. These areas have also been implicated as key structures in the abnormal expression of emotion in MDD. Dysregulation of connections between the amygdala and prefrontal cortex has been hypothesized to influence depressed subjects' tendency to ruminate on emotional events and memories, which may be associated with an inability to properly regulate emotional processing through habituation and extinction mechanisms. Research suggests that depressed individuals have an impaired ability to disengage from or habituate to emotional stimuli perceived as sad.

In addition to studying emotional processing at a conscious, cortical level, significant evidence suggests that many aspects of emotional processing occur below conscious awareness, at a preconscious level. The technique of backward masking assesses the automaticity of emotional processing and responses to affective stimuli. In MDD, backward masking serves to avoid confounding interpretation by the presence of other cognitive processing, which may result from depressed subjects perseverating on emotional stimuli. The proposed study builds on previous fMRI research to investigate neurophysiological differences in the processing of aversively conditioned emotional stimuli in depressed compared to healthy individuals. Using fMRI technology and a variation of the paradigm developed by Morris et al., subjects with MDD will be classically conditioned to the presence of an unmasked specific target face (angry or sad) and the subsequent neural responses to the stimuli will be assessed utilizing the backward masking technique. The BOLD hemodynamic response and rates of habituation and extinction to the faces will be compared between depressed subjects with MDD and healthy controls, currently depressed versus currently remitted subjects with MDD, and MDD subjects pre- and post-antidepressant therapy.

The present amendment proposes to include an additional paradigm in the testing battery. This new paradigm has been extensively examined under different pharmacological manipulations, and in healthy individuals undergoing fMRI but has yet to be examined in patient populations. The task complements the paradigms presently included by extending the research to encompass appetitive as well as aversive emotional processing.

This research will be used to evaluate neural processes involved in emotional dysregulation in MDD and may direct future research to potential therapeutic approaches for the treatment of mood and anxiety disorders with abnormalities in emotional processing.