Psychiatric disorders can be diagnosed reliably, but how dysfunction in the brain leads to clinical symptoms is unclear. As recognized by the NIMH Strategic Plan, there is an urgent need to study multiple underlying brain circuits across diagnoses with the goal of identifying groups of patients with shared neural dysfunction. The ultimate goal of this approach is to use brain dysfunction, as an adjunct to clinical diagnosis, to guide the selection and development of treatments. Consistent with this approach, this 3-year R01 application proposes to use well-validated neurobehavioral tasks to examine multiple brain systems across three psychiatric disorders: social anxiety disorder (SAD), obsessive-compulsive disorder (OCD), and anorexia nervosa (AN). Although clinically different, these disorders share the feature of maladaptive behaviors organized around irrational fears. Moreover, the relationship between these disorders is hotly debated. Each disorder has been associated with different brain systems: cortico-amygdalar circuitry in SAD, fronto-striatal-pallidal circuitry in OCD, and cortico-mesolimbic circuitry in AN. The research team has experience using well-validated neurobehavioral tasks to assess the functioning of these different neural systems and the clinical expertise needed to recruit and evaluate all three types of patients. Specifically, this project will study 180 participants (40 with SAD, 40 with OCD, 40 with AN, and 60 healthy controls [HC]) using the following neurobehavioral tasks: 1) Fear extinction retention as a measure of "safety" learning (a probe of cortico-amygdalar functioning);2) Prepulse inhibition as a measure of sensorimotor gating (a probe of cortico-striatal-pallidal functioning);and 3) Delay discounting as a measure of capacity to delay gratification (a probe of cortical-mesolimbic functioning). All 180 participants will complete all three tasks and detailed clinical assessments. This work will be completed in three years, enabling a rapid evaluation of the success of this approach. The goals are: 1) to establish that each disorder is associated with specific abnormalities on one of these tasks, as the pilot data suggest;2) to determine whether these abnormalities are specific or shared with the other disorders;and 3) to explore whether the pattern of responses is associated with dimensional traits, clinical features, or novel groupings of cases across disorders. If task performance is associated with specific disorders as hypothesized, the data will support the role of particular neural systems in those disorders, and the use of each task as a neurobehavioral marker in that disorder. Future studies will confirm the neural correlates of these tasks, extend their specificity, and establish their clinical utility. Consistent with the RDoC initiative of NIMH, the goal is to clarify the brain dysfunction underlying these different disorders using non-invasive neurobehavioral probes. This, in turn, can be the basis for new diagnostic approaches to help guide, and perhaps develop, new treatments.
Psychiatric diagnoses based on clusters of clinical symptoms have adequate reliability but limited validity. Linking clinical disorders and symptoms to basic neurobiological components can clarify the boundaries and overlap between mental disorders and help to elucidate the causes and identify targets for novel treatments of different disorders. This three-year R01 study will use neurobehavioral tasks that have been linked to specific neural circuits to identify shared and distinct neural correlates of social anxiety disorder, obsessive-compulsive disorder, and anorexia nervosa.
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