This is a revised submission of the Mentored Clinical Scientist Development Award application 1 K08 MH 01414-01. The biological basis of mood disorders has been clarified through alterations in REM and delta sleep across the clinical course of depression. Questions remain, however, regarding the pathophysiologic mechanisms of these EEG sleep alterations as well as regarding the specificity of these findings. Advances in the neurobiology of sleep suggest that the neuropharmacologic modulation of REM/NREM sleep states as well as regions of the brain found to be metabolically active during REM/NREM sleep have parallels with pathophysiologic mechanisms hypothesized for mood disorder patients. These include monoaminergic/cholinergic interactions involving the prefrontal cortex,and limbic and paralimbic cortical regions. Therefore, paradigms utilizing functional brain imaging during REM/NREM sleep states may clarify specific neuropathologic mechanisms in mood disorder patients. Within this background, this K08 Mentored Clinical Scientist Development Award proposal outlines: 1) the candidate's background in mood disorders, sleep disorders and psychiatric EEG sleep research; 2) a career development path describing new research training in the neurosciences and in PET imaging necessary for the successful completion of functional imaging studies of sleep; 3) a research paradigm combining EEG sleep and PET imaging methodologies to study waking, NREM, and REM sleep in 20 unipolar depressed patients and 20 age- and sex-matched healthy controls; and 4) directions for future proposals using similar methodologies in conjunction with longitudinal clinical trials and utilizing pharmacologic probes in limbic and paralimbic cortex in mood disorder patients over the course of illness. PET sleep pilot data in six unipolar depressed women and six age-matched healthy women demonstrate the feasibility of these methods. Preliminary data suggest that there are fundamental differences in relative and absolute cerebral glucose metabolism during REM sleep between depressed and control subjects. These changes involve neural systems which regulate affective and adaptive behavior. Mentors for this work include: Dr. Robert Moore (neurosciences), Dr. Wayne Drevets (PET), and Dr. Charles Reynolds, III (psychobiology and clinical trials), Drs. J. Christian Gillin and Richard Frackowiak will provide additional training in the neuropharmacology of sleep in mood disorders and in the design of PET studies utilizing pharmacologic modulation of cognitive activation, respectively.
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