Behavioral, Neural, and Molecular Correlates of Response Inhibition in Bipolar Disorder

Brigham And Women'S Hospital, Boston MA

Investigators

Abstract

PROJECT SUMMARY Difficulty with inhibitory control, which contributes to impulsive behavior, is a core feature of bipolar disorder (BD) and persists across mood states. Response inhibition (RI), an aspect of behavioral inhibition, is classified as a subconstruct under the domain of cognitive systems within the Research Domain Criteria (RDoC) framework. Although impaired RI has been observed in BD, there is still a limited understanding of this aspect of inhibitory control, and it has not been translated into treatment options in the clinic to date. Elucidating the role of impaired RI and its underlying neurobiology in BD is critical for identifying novel targets for interventions to reduce impulsivity and related risky behaviors. The proposed study will focus on understanding the behavioral, neural and inflammatory measures of RI in BD and employ an interdisciplinary approach to 1) characterize RI using self-report and performance based measures (Training goal 1); 2) characterize the neural circuitry underlying RI by measuring a) brain activation patterns, while performing the Parametric Go/No-Go Test (PGNG), and b) resting-state functional connectivity of cognitive control network (Training goal 2); 3) examine the association of peripheral inflammation (i.e., CRP, IL- 6, TNF-α) with behavioral and circuit-based processes that underlie RI (Training goal 3), and 4) examine the association of central inflammation (extracellular free water [FW]) with both peripheral inflammation and RI (Training goal 3). We will enroll 100 affectively stable BD patients and 50 demographically matched controls. Subjects will complete the Stop Signal Test (SST) and the PGNG outside the scanner. Inflammatory markers in blood and FW levels in the brain will be quantified. Fifty BD patients and 50 controls will undergo resting-state and task-based functional magnetic resonance imaging (fMRI), and diffusion-weighted MRI (DWI-FW). This Mentored Research Scientist Development Plan aims to assist the candidate in achieving the following goals: 1. To receive specialized training in neurocognitive testing, with a focus on inhibitory control, and gain experience in clinical symptomatology and research considerations in patients with BD, 2. To gain theoretical and applied knowledge in the collection and interpretation of brain-based measures, with a specific focus on the cognitive control network, 3. To expand knowledge in psychoneuroimmunology within the context of mental health research by integrating peripheral inflammation and a proxy measure of neuroinflammation. Training activities aligned with the proposed project will include formal coursework, hands-on training, directed readings, workshops, grant writing, and research activities. This project and related training activities will primarily take place at Brigham and Women's Hospital, Harvard Medical School. This proposed research study and training plan will prepare the candidate to become an independent scientist establishing a research program that integrates biological, behavioral and cognitive measures to identify biobehavioral mechanisms that inform intervention development, reduce disease burden and promote the quality of life of patients with mood disorders.