Cerebellar metabolism, neural circuits, and symptoms in bipolar disorder

Bipolar disorder (BD) is a frequently devastating psychiatric illness that is challenging to diagnose and treat. In our prior work, we have shown that metabolism, function, and morphology of the cerebellum is different in participants with BD as compared to controls. Furthermore, we have observed a relationship between mood and cerebellar metabolism as well as function in a cross-sectional design. These findings support the growing body of literature that the cerebellum is involved with BD. However, there has been a sparsity of studies undertaken that have attempted to follow participants with BD and observe changes in brain metabolism and function associated with fluctuations in mood. We are proposing to conduct a two-year longitudinal study of 170 participants with a diagnosis of BD type I as well as 90 matched controls to study changes in cerebellar metabolism and function associated with mood fluctuations. The participants with BD will receive a brief weekly mood assessment to identify changes in mood where subjects will be assessed using neuroimaging. Brain imaging will include metabolic, functional, and anatomical imaging with the data used address the following aims. Aim 1) Does cerebellar metabolism change with mood in BD? We hypothesize that the cerebellum plays a significant role in maintaining the euthymic mood state (i.e. plays a compensatory role) and when the cerebellum is no longer able to serve this compensatory role depressive or manic mood states develop. To test this hypothesis, we will assess changes in cerebellar metabolism (31P, 1H MRS, and T1ρ) associated with mood changes. Aim 2) Does cerebellar function and connectivity vary with mood in BD? To test the function of the cerebellar vermis, we plan to perform two task-based fMRI studies (backward masking emotional faces and go/no-go). In addition, resting state functional connectivity will allow us to explore connectivity of the cerebellum with the emotional control network. We hypothesize that connectivity between the vermis and nodes of the emotional control network will vary with mood state and expect increased connectivity in the euthymic state and decreased connectivity during exaggerated mood states (depression/mania). Furthermore, we expect that as mood ratings for depression and mania increase subjects with BD will exhibit a greater number of incorrect responses and failure to activate the cerebellum. These results would provide further evidence that the cerebellum is playing a compensatory role to maintain mood. In addition, this study may provide information leading to novel therapy trials in the future.