This revised resubmission of an ROl proposal (MH 61566) will test a functional neuroanatomic model of behavioral state (sleep/wake) changes in depression that are proposed to be central to the pathophysiology of depression. The investigators developed this model from several sources of information. These included EEG sleep studies in depression, preclinical studies defining brain mechanisms of behavioral state regulation, human sleep functional brain imaging studies, functional brain imaging studies in depressed subjects and evidence from our preliminary studies using the proposed experimental paradigm. The investigators propose that depressed patients suffer from two related behavioral state changes: deficits in the generation and maintenance of slow wave sleep, and increases in measures related to behavioral arousal including sleep continuity and REM sleep disturbances. The investigators further propose that these changes are related to functional alterations in two related brain systems: 1) an anterior paralimbic and prefrontal cortex system (anterior cingulate, basal forebrain, hypothalamus and prefrontal cortex); and 2) a generalized arousal system (pontine reticular formation, thalamus and amygdala). The investigators hypothesize that depressed patients suffer from functional deficits in the anterior paralimbic and prefrontal cortex systems. This leads to maladaptive behavior. In a compensatory fashion, the generalized arousal system increases its function, albeit unsuccessfully since the effector structures in the anterior paralimbic and prefrontal cortex are dysfunctional. The slow wave sleep disturbances in depression are related to 1) the cortical deficits in prefrontal cortex and anterior paralimbic structures, and 2) inhibition of slow wave sleep due to the increased function in the generalized arousal system. This inhibits the spontaneous occurrence of low frequency thalamocortical electrical oscillations characteristic of slow wave sleep. The sleep continuity and REM sleep disturbances are related to the increased function in the generalized arousal system, structures known to be important in the maintenance of wakefulness and in the generation of REM sleep. To test features of this model, we will recruit 27 depressed outpatients and 27 healthy controls into a five-day sleep brain imaging study. Measures of behavioral state include EEG sleep and regional quantitative EEG. Measures of brain function include -FDG PET relative regional glucose metabolism during waking, NREM and REM sleep. Behavioral correlates of behavioral state changes in depression will include formal assessments of mood, vigilance and performance. Repeated measures multivariate analyses of covariance and multivariate multiple regressions will test the above hypotheses. Findings from this study are expected to significantly advance our understanding of the pathophysiology of depression.
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