Functional and neurochemical brain changes in first episode

University Of Cincinnati, Cincinnati OH

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Abstract

Bipolar disorder is a dynamic condition with symptomatic fluctuations throughout its course. These[unreadable] fluctuations suggest that bipolar neurophysiology involves dysfunction of brain networks that maintain[unreadable] emotional homeostasis. Human emotional behavior appears to be modulated by ventral prefrontal cortical[unreadable] and subcortical brain regions that form the 'anterior limbic network.' Consequently, we hypothesize that the[unreadable] symptoms of bipolar disorder arise from dysfunction within this network. Specifically, functional imaging[unreadable] (fMRI) studies suggest that the anterior limbic network may be over-activated in bipolar patients, thereby[unreadable] producing the symptoms of this condition. Additionally, magnetic resonance spectroscopy (MRS) studies[unreadable] suggest that this over-activation results from anterior limbic hypermetabolism. Moreover, during mania, MRS[unreadable] studies report elevated glutamate (Glx) concentrations; excessive glutamatergic neurotransmission may[unreadable] underlie the excessive anterior limbic metabolism and activation of bipolar disorder.[unreadable] Bipolar disorder is progressive with increasing episode frequency early in the illness course, leading to[unreadable] an established, recurrent illness. Repeated increases in excitatory neurotransmission associated with manic[unreadable] episodes may cause glutamatergic neurotoxicity, thereby initiating neurophysiologic changes that produce[unreadable] progressive emotional instability. It is not known whether any of the standard treatments for bipolar disorder[unreadable] prevent these changes. Nonetheless, perhaps by decreasing excitatory glutamatergic neurotransmission,[unreadable] these medications might correct the hypothesized excessive anterior limbic activation and hypermetabolism,[unreadable] and diminish the risk of neurotoxicity, thereby preventing disease progression. Studies of early course[unreadable] patients, prior to significant disease progression, are needed to make these determinations.[unreadable] With these consideration in mind, the goals of this study are: 1) To use 1H-MRS to identify[unreadable] neurometabolic abnormalities in bipolar disorder at the time of the first manic episode, and then determine[unreadable] how these abnormalities change in response to lithium and olanzapine treatment; 2) To identify[unreadable] corresponding changes in fMRI brain activation to a cognitive probe (CRT-END) while receiving lithium and[unreadable] olanzapine therapy; and 3) To demonstrate that regional brain activation changes are associated with[unreadable] regional metabolic changes. To accomplish these aims, we will acquire integrated neurometabolic (MRS)[unreadable] and functional neuroanatomic (fMRI) measurements in first-episode manic bipolar and healthy subjects in[unreadable] order to refine neurophysiological models of bipolar disorder (Center goal 1); to identify MRS and fMRI[unreadable] markers of treatment response of acute mania to two mechanistically different medications (Center goal 2);[unreadable] and to identify potential predictors of treatment response for future studies (Center goal 3).