A behavioral hallmark of Major Depressive Disorder (MDD) is impaired gating of negative, task-irrelevant information. In previous work we documented that people with MDD exhibit impairments in controlling the entry of irrelevant negative information into working memory (WM) and in removing no-longer-relevant information from WM. Given the high prevalence and enormous costs of MDD, it is critical that we gain a better under- standing of the neural mechanisms that underlie these cognitive difficulties. Although investigators have begun to examine neural correlates of impaired information-gating processes in MDD, we do not yet understand the functional significance of these activations or the nature of their relation to depression, or consequently, how to leverage this knowledge to develop and evaluate individualized treatments for this heterogeneous disorder. We propose to use cutting-edge neuroimaging techniques to elucidate the neural mechanisms that underlie impaired gating of negative information in MDD, conducting innovative analyses of fMRI data (multi-voxel pattern analyses [MVPA] and functional connectivity) in order to quantify on a moment-to-moment basis the degree to which negative irrelevant information is represented in WM. This approach will allow us to test hypotheses about (a) specific large-scale networks that are posited to underlie information-gating deficits in MDD; and (b) the contribution of these networks to various clinical characteristics of MDD. Specifically, in two experiments we will elucidate the cognitive and neural mechanisms that underlie impaired gating in MDD during the entry of negative stimuli into WM, and during the removal of negative information from WM. Moreover, given findings in nondepressed populations that individual differences in the ability to gate task- irrelevant information are related to variations in goal-directed behavior, we further propose to assess the relation of individual differences in information gating to specific aspects of depressive symptomatology. We hypothesize that impaired gating of negative irrelevant information in MDD is associated with anomalous functioning of dorsal frontoparietal (top-down attentional control) and subcortical (emotional appraisal) networks during both the entry of negative information into WM and the removal of negative information from WM. We further hypothesize that these abnormalities are related to the specific depressive characteristics of emotion dysregulation, rumination, and negative affect, and to the severity of depressive symptoms. Importantly, our novel quantification of neural representations of negative information will move beyond coarse group-level assays to a more fine-grained individual-subject and trial-level understanding of the dynamic nature of the neurocognitive mechanisms that underlie MDD. Together, the proposed studies promise to 1) advance understanding of mechanisms that underlie the control of affective information in MDD; 2) inform theoretical models of the interaction of attention and emotion; and 3) facilitate the ultimate development of more effective, patient-specific interventions (e.g., cognitive or neural training) for major depression.
Given the alarming prevalence and the enormous personal, social, and economic burden of Major Depressive Disorder (MDD), it is critical that we gain a more comprehensive understanding of the neural mechanisms that underlie this disorder, which will allow for improved patient-specific treatment. The innovative proposed research program will yield critical new evidence elucidating the function of neural systems that underlie difficultes in working memory, attention, and emotion in MDD. By addressing these important but under- explored issues, the proposed research promises to yield a novel quantitative brain measure that may ultimately be used to inform the development, selection, and assessment of treatment strategies for reducing emotional difficulties not only in MDD, but also in other disorders that involve attentional deficits and dysregulated emotional functioning, including bipolar disorder, attention deficit hyperactivity disorder, and schizophrenia.
