Neurophysiology of Working Memory in Bipolar Disorder

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DESCRIPTION (provided by applicant): This NIMH Mentored Patient-Oriented Career Development (K23) Award application is to support Dr. Caleb M. Adler's developing expertise in neuroimaging and bipolar disorder. Bipolar disorder is a common psychiatric illness accompanied by severe morbidity and mortality. Traditionally viewed as a cyclic illness with a return to baseline function between affective episodes, evidence suggests that bipolar disorder is associated with significant deficits in specific cognitive domains, particularly working memory. Neuroimaging studies in bipolar patients suggest dysfunction of structures associated with the "network" of brain regions involved in working memory. Consistent with these observations, working memory deficits are observed in bipolar patients across the affective spectrum, suggesting that these deficits represent a "core symptom" of bipolar disorder, rising out of the neurophysiology of the illness. The specific research supported by this award will involve studying neuronal activity associated with working memory inpatients with bipolar disorder and healthy volunteers. The candidate will use fMRI to study patterns of activation in bipolar patients and healthy volunteers while they are performing a series of working memory tasks increasing parametrically in difficulty. Both medicated and unmedicated bipolar patients will be enrolled. In addition to increasing understanding of the neurophysiology underlying working memory deficits in bipolar patients, the candidate seeks to improve our understanding of the effects of medication on activation patterns. A better understanding of this "core symptom" may help clarify the underlying neurophysiologic substrates of bipolar disorder, ultimately suggesting future treatment directions. As a follow-up protocol, the candidate will compare working memory-induced activation in bipolar patients during acute mood states with the previously obtained euthymic data. Working memory deficits are exacerbated in depression and mania; these comparisons may clarify changes in the neurophysiology of bipolar disorder during acute affective episodes. During the course of this K23 award, the candidate will obtain additional training in bipolar psychopathology, functional imaging techniques, cognitive testing and statistical analysis, as well as research ethics. The candidate will integrate these skills with previous training and experience in other areas of functional imaging and clinical psychiatry in order to develop expertise in the investigation of the neurophysiology of bipolar disorder. At the conclusion of this award, the candidate will be well positioned to function as an independent investigator extending this work using other cognitive paradigms and to further examine state-related cognitive deficits in bipolar disorder.