This revised application requests three years of funding to support a research program which employs proton magnetic resonance spectroscopic imaging (MRSI) to evaluate subjects with Bipolar I Disorder and healthy comparison subjects. In pilot studies of individuals with bipolar disorder, we have used 1H MRSI to evaluate brain cytosolic choline levels and, more recently, myo-inositol levels. Both choline and myo-inositol play critical roles in second messenger signaling cascades and recent reviews have suggested that mood stabilizes may demonstrate their clinical effects by altering signal transduction pathways within the brain. Studies will be conducted at two sites, the McLean Hospital Brain Imaging Center in Belmont, MA, and the University of Washington in Seattle, WA. Over the course of this project, a total of 72 subjects with bipolar disorder and 42 comparison subjects will be enrolled and complete repeated MRSI studies. Identical clinical assessments and MRSI protocols will be employed at both sites. Bipolar subjects will be placed on standardized formulations of lithium or valproic acid and will be followed clinically at two week intervals for the ten week duration of the study. By evaluating subjects who are receiving two alternative treatments, we will be able to assess both the shared and unique effects of these pharmacologically effective medications on brain chemistry and the relationship of these effects on mood. Patients with bipolar disorder will be scanned on three occasions at weeks 2,6, and 10 of this study. Mood at time of each scan will be assessed using the Young Mania Rating Scale and the Hamilton Depression Rating Scale. A priori regions of interest for this study will include the bilateral caudate nuclei and the anterior cingulate cortex, as pilot studies suggest that these brain regions demonstrate mood state, medication, and diagnosis dependent alteration in choline and myo-inositol resonance intensities. MRSI data from bipolar subjects will be compared to similar data from 42 healthy comparison subjects. We believe that abnormalities in brain choline and myo-inositol metabolism may, in part, mediate the pathophysiology of abnormal mood in bipolar disorder and that the therapeutic efficacy of lithium may derive from an inhibition of choline transport and/or from changes in myo-inoitol and choline metabolism within the brain. The results of these studies may provide important new insights into the neurochemical alterations which mediate the symptoms of bipolar disorder as well as information relevant to the development of novel therapeutic strategies.
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