This K01 proposal is designed provide the training needed to facilitate a career that (1) develops computational models that aid in our understanding of depression; (2) identifies neural circuits that contribute to depression vulnerability and severity; and (3) identifies, creates, or refines treatments that target specific neural mechanisms of depression. To realize his goals the candidate has proposed a program of training to foster expertise in applying neuroimaging and computational modeling techniques to research focused on identifying and targeting neural deficits driving rumination in depression. Rumination is a potential mechanism underlying the etiology and maintenance of depression that is not well understood or adequately targeted in existing treatments. A significant portion of depressive rumination entails a causal search for the reasons one is depressed, that typically leads a depressed individual to examine his/her most pressing problems and concerns in an attempt to understand and solve them. However, this process does not lead to the generation of solutions. Hence, the candidate has conceptualized aspects of rumination as a depressed person's failed attempts to engage in problem-solving. Neuroimaging has produced promising results in identifying mechanisms, but has focused on a restricted set of features of depression generally not involving neural mechanisms of problem-solving. In order to carry out this needed research, the candidate has formulated a detailed career development plan. This plan focuses on (1) expanding his current training in neuroimaging assessment; (2) training him in the paradigms of cognitive affective neuroscience and intervention research; and (3) enhancing his knowledge of using computational modeling to understand brain functioning in psychopathology. This training will be achieved through didactic coursework, neuroimaging workshops, tutorials in computational modeling, and training in clinical intervention research. Training will also be facilitated through ongoing supervision and consultation with experts in relevant fields. This training will be used to conduct research that specifically aims to (1) identify, validate, and understand neural circuits associated with rumination; (2) identify neural deficits that inhibit problem-solving and drive rumination; and (3) examine the potential for problem-solving training to remediate neural deficits driving rumination in depression. The proposed training and research will be conducted in the Department of Psychiatry, at the University of Pittsburgh School of Medicine. The Department of Psychiatry houses several world-renowned clinical affective neuroscientists and is affiliated with one of the premier centers for understanding the neural basis of cognition in the country. The proposed research will take place in three stages to achieve its specific aims. In stage I, depressed and healthy control participants will be induced to ruminate while undergoing functional magnetic resonance imaging (fMRI). Group differences in activation and communication between brain regions facilitating problem-solving will then be examined. Subsequently, identified neural activity will be validated by associating it with relevant behavioral constructs, for example, measures of rumination. These results will facilitate the mapping of brain regions underlying rumination and point to mechanisms driving ruminative processing. In stage II, a computational model will be created to clarify the mechanisms underlying poor problem-solving and thus rumination in depression. This model will then be used to make predictions of neural deficits in depression during problem-solving. These predictions will be evaluated by observing brain activity in depressed and healthy subjects during the completion of a problem-solving task using fMRI. Identified neural mechanisms underlying deficits in problem-solving hypothesized to drive rumination will be validated by examining the degree to which this pattern of deficits is associated with the same pattern of deficits during ruminative processing. These results will facilitate the identification of mechanisms diving rumination in depression. In stage III, a subset of depressed participants will be asked to engage in a cognitive problem-solving training protocol designed to target the identified neural deficits. Change in brain activity from the baseline assessment will be evaluated using a follow-up fMRI assessment of rumination and problem-solving. If successful these results will suggest a means of directly targeting neural mechanisms driving rumination in depression that could be fully developed as an adjunctive treatment in future research. In summary, this proposal seeks to broaden the current focus of research into the neuropathophysiology of depression beyond its current scope of examining markers and mechanisms underlying anhedonia and chronic depressed mood. The current proposal will elucidate the neural circuits underlying rumination in depression by imaging tasks which specifically activate these circuits and showing their relevance to functioning and mechanistic change. Surprisingly very little is known regarding the neural substrates of rumination. The current conceptualization of rumination in depression as a disrupted functional process has allowed for the identification of novel neural mechanisms that do not appear to be targeted in current treatments. Successfully identifying and addressing these deficits may prove in future research to provide certain depressed individuals with lasting recovery.
Existing depression treatments are inadequately targeting or fail to target key underlying mechanisms of the disorder for 30% to 60% of patients. Clarification of underlying neurobiological substrates and mechanisms of rumination in depression could facilitate: a greater understanding of depression; the development or refinement of treatments targeting these mechanisms; and the personalization of treatment.
