Bipolar mania is characterized by elevated and/or irritable mood symptoms, marked behavioral changes, and cognitive deficits that appears to be linked to neurofunctional changes involving the anterior limbic network (ALN), a brain network hypothesized to be involved in emotional regulation and modulation. Functional MRI (fMRI) studies suggest that increased activity in the ventrolateral prefrontal cortex (VLPFC) and other regions modulates ALN structures involved in emotional expression, such as the amygdala, to inhibit overt manifestations of mania. Bipolar mania represents a failure of these compensatory mechanisms, and is marked by decreased VLPFC activity and concomitant increases in activation of the amygdala and portions of the striatum, leading to increased affective lability and disinhibition. Complementary magnetic resonance spectroscopy (MRS) studies suggest that this increased activity in striatal-prefrontal pathways is associated with increased prefrontal glutamate, an excitotoxic neurotransmitter. Increased concentrations of glutamate may, in turn be related to decreased concentrations of prefrontal N-acetyl-aspartate (NAA), a marker of neuronal integrity in manic patients, as well as for progressive morphologic changes in the prefrontal cortex. MRS studies further suggest that ALN dysregulation is accompanied by abnormalities in neuronal metabolism and of the phosphatidylinositol cycle (Pi-cycle), a second messenger cascade with multiple downstream neuronal effects. The therapeutic effects of lithium, an effective antimanic agent, have been linked to its actions on the Pi-cycle. Concentrations of A/fyo-inositol (ml), which are normal in medicated and unmedicated euthymic bipolar patients, are significantly elevated in patients with mania. Lithium administration decreases ml, and normalizes other components of Pi-cycle dependent second messenger systems. Furthermore, lithium effects on ml concentrations precede amelioration of behavioral symptoms and may be related to the gradual resolution of functional changes. In contrast, increased glutamate and NAA persist in manic patients receiving lithium. Combining imaging modalities to study the effects of lithium will improve our understanding of treatment- related changes in neurofunctional and chemical abnormalities observed in mania, and the relationship between lithium and markers of bipolar symptomatology. Furthermore, we will explore the predictive value of early lithium-induced changes in ml. With these considerations in mind, we propose to: 1) Use fMRI and MRS to measure neurofunctional and neurochemical differences between manic and euthymic patients, and healthy controls at baseline, and: 2) Use fMRI and MRS to measure changes in neurofunctional and neurometabolic measures after 1 &8 weeks of lithium treatment, with the goal of refining neurophysiological models of bipolar mania;identifying MRS and fMRI markers and potential predictors of treatment response.
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