Anxiety and depressive disorders are the most prevalent forms of mental illness and are a major public health concern. There is growing evidence that perseverative thought (PT), defined as thought that is self-focused, repetitive, and difficult-to-control, is a key mechanism of anxiety and depression. Worry and rumination are two prevalent and well-characterized forms of PT that have been experimentally and prospectively linked to increased anxiety and depression severity, higher rates of substance abuse, and poorer physical health. However, little is known about the underlying neurobiology of PT, and no studies to date have characterized the neural mechanisms that underlie the successful or unsuccessful regulation of PT. This gap in the literature is of central importance because an impaired ability to disengage from PT (i.e., an ability to stop worrying and ruminating) has been proposed as a central mechanism by which worry or rumination transitions from normative to pathological. The overarching goal of this K01 is to develop and test an ecologically-valid, clinically-informed neurobiological model of PT, with a particular emphasis on identifying the mechanisms by which PT shifts from healthy to pathological through successful and unsuccessful regulation. Using functional magnetic resonance imaging (fMRI) and ecological momentary assessment (EMA), the proposed study will 1) test specific neurobiological hypotheses about the mechanisms underlying successful and failed disengagement from PT; 2) evaluate the neurobiological plausibility of three competing clinically-derived models of PT (i.e., a bifactor vs. two-factor vs. dimensional model); and 3) link neurobiological findings to real- world experiences of pathological (dysregulated) worry and rumination. Collectively, these aims will permit the iterative refinement of a clinically meaningful neurobiological model of normative and pathological PT, which can form the basis for the development of neurobiologically informed interventions. Consistent with a transdiagnostic approach informed by the Research Domains Criteria (RDoC), N = 70 adults who represent the full spectrum of PT severity (low; moderate; pathological) will undergo fMRI while experiencing and then attempting to disengage from PT (worry and rumination). Disengagement success will be assessed via thought sampling. A subset of participants with pathological PT will then complete an EMA protocol to index real-world experiences of successful and failed disengagement from PT. A variety of data analytic approaches, including functional and effective connectivity, mixed models, and structural equation modeling will be applied to test specific hypotheses and in follow-up exploratory analyses. The training plan capitalizes on the candidate's background, mentorship team, research environment to provide the candidate with the requisite neuroimaging, EMA, and data analytic skills to conduct the proposed research and launch a successful independent research career aimed at identifying the neurocognitive mechanisms of emotion-related psychopathology (NIMH Strategic Objective 1) in service of identifying new targets for treatment (NIMH Strategic Objective 3).
/Public Health Relevance Anxiety and depressive disorders are the most common forms of mental illness and are associated with substantial public health burden. The proposed study will evaluate competing neurobiological models of perseverative thought (PT), which has been identified as a major transdiagnostic mechanism of anxiety and depression. By linking neurobiological findings to real-world experiences of psychopathology, results from this study are expected to directly inform the identification of new targets for treatment development and prevention of anxiety and depression.
