Neuroinflammation and Executive Function in Bipolar Disorder: A PET-fMRI Study

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Individuals with bipolar disorder (BD) experience severe and persistent difficulties with executive functions, such as inhibitory control. Inhibitory control difficulties in BD could be related to inflammation via its effects on brain functioning. However, direct measurement of brain inflammation markers (i.e. glial activation) in BD is limited and further understanding of how glial activation contributes to inhibitory brain dysfunction in BD is needed. The goal of this proposal is to study the neuroinflammatory basis of inhibitory control and identify novel neuroimmune treatment targets for executive dysfunction in mood disorders. To this end, the candidate proposes: (1) training objectives to establish expertise in the use of simultaneous PET-MRI as a research tool, an interdisciplinary knowledge base in psychoneuroimmunology, and full independence with fMRI methodology, which together will further career development into an expert clinical translational researcher in bipolar disorder; (2) a research objective to examine glial activation as a mechanism of inhibitory control brain dysfunction and cognitive performance in BD; (3) a team of mentors and advisors to ensure the candidate’s success, with expertise in bipolar disorder (Dr. Andrew Nierenberg), multi-modal psychiatric neuroimaging (Dr. Darin Dougherty), molecular imaging and simultaneous PET-fMRI (Dr. Jacob Hooker), psychiatric neuroimmunology (Dr. Beth Stevens), fMRI inhibitory control paradigms (Dr. Scott Langenecker), and neuroimaging statistics (Dr. Mark Vangel). The rationale for the proposed project is that despite evidence for inflammatory alterations in BD, interrogation of brain inflammatory markers in-vivo and their role in executive functioning is limited. Human imaging with novel radiopharmaceuticals to visualize glial activation and its role in inhibitory brain function is needed. The central hypothesis of the proposal is that glial activation adversely impacts frontostriatal brain circuitry and, in turn, inhibitory control in BD. The proposed specific aims are to determine the: (1) difference in glial activation between BD (n = 20) and healthy controls (HC; n = 20); (2) association between glial activation and inhibitory control neural circuitry in BD; (3) association between glial activation and inhibitory control performance on cognitive testing in BD. This proposed research is innovative for examining markers of brain inflammation as a novel mechanism of the understudied burden of executive function in BD using cutting edge simultaneous PET- fMRI technology. The proposed research is significant because it could yield novel neuroimmune treatment targets and crucial pilot data towards the use of PET-fMRI for understanding the unmet clinical problem of inhibitory dysfunction in BD. Overall, this project and training plan will promote the candidate’s career development by facilitating an independent program of program of research at the interface of psychiatric neuroimaging and neuroimmunology. This is a critical first step in furthering the candidate’s career goals to study the neuroinflammatory basis of cognition and to identify novel neuroimmune targets for future experimental therapeutics in mood disorders.