SECTION 3 - ENABLING TECHNOLOGY

Functional Neuroimaging of Sleep and Wake States

Background

Although the physiological and adaptive functions of sleep remain to be clarified, it is clear that sleep and wakefulness are neurologically mediated. Sleep researchers have employed behavioral observations, clinicopathologic observations, correlative studies with polysomnographic measures, and extrapolations based on invasive research in non-human subjects in order to characterize and understand the brain processes mediating and constituting sleep and wakefulness. Each of these approaches continue to yield new knowledge about sleep and the brain, and each provides a unique view, or "level of analysis" of sleep and brain functioning ranging from the behavior of single neurons to the behavior of the entire organism. The ultimate result of this multifaceted approach is likely to be a comprehensive and coherent understanding of sleep.

Functional brain imaging techniques (such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), Magnetic Resonance Spectroscopy (MRS), single photon emission computed tomography (SPECT), magnetoelectroencephalography (MEG), and near-infrared optical imaging (NIR) have enabled new and unique analyses in the study of sleep and waking. These techniques allow measurement of metabolic and neurochemical activity throughout the brain, and can discern dynamic patterns of regional cerebral activity during various brain states including stages of sleep and levels of alertness during wakefulness or during functional challenge). Furthermore, these techniques are likely to enhance identification of both normal and abnormal sleep/wake processes.

Progress In The Last 5 Years

- Functional neuroimaging techniques (primarily PET) reveal that NREM sleep is associated with deactivation of centrencephalic regions (brainstem, thalamus, basal ganglia) and multimodal association cortices (e.g., prefrontal and superior temporal/inferior parietal regions). REM sleep is characterized by reactivation of all centrencephalic regions deactivated during NREM sleep except the multimodal association areas. Thus, deactivation of the multimodal association areas has been shown to be a defining characteristic of sleep.

- PET studies during sleep-deprived wakefulness reveal regional cerebral deactivations that are especially prominent in prefrontal and inferior parietal/superior temporal cortices, and in the thalamus. These patterns are similar to that found during NREM sleep, but the deactivations are of lesser magnitude than during NREM sleep). This pattern is consistent with, and helps explain, the nature of cognitive performance deficits that occur during sleep loss. Considered together with results of sleep studies, this pattern suggests that NREM sleep initiation and sleep-deprived wakefulness in healthy individuals are manifestations of related neurobiological processes.

- Relative activation/deactivation patterns revealed by fMRI techniques during performance of cognitive tasks suggest that maintenance of performance following sleep loss may be a function of the extent to which other cortical brain regions can be recruited for task performance in the sleep-deprived state. This is one of a number of possible ways that individual differences may occur in the ability to maintain alertness and performance following sleep loss.

- PET, SPECT and fMRI studies reveal that a subset of depressed patients show initially elevated activation in anterior cingulate and medial orbital cortices. In these patients, sleep deprivation reduces this regional hyper-activation, and improvements in mood are a function of the extent to which this activity is reduced. These studies suggest possible mechanisms by which antidepressant drugs may exert their effects.

- PET scans reveal that the midbrain reticular activating system remains relatively active during stage 2 sleep-a finding that may account for the relatively heightened arousability that characterizes this stage of sleep.

- PET scans taken at 5 vs. 20 minutes after awakening suggest that re-emergence of conscious awareness upon awakening occurs as a function of centrencephalic reactivation, and reestablishment of a specific pattern of functional interconnectivity between brain regions. These data also suggest that restoration of alertness (e.g., dissipation of sleep inertia effects) occurs as a function of reactivation and reestablishment of functional interconnectivity patterns involving prefrontal cortices. These findings could constitute an important first step toward specification of the physiological basis of post-sleep waking cognitive capability.

Research Recommendations

- Perform neuroimaging studies that measure absolute as well as relative changes in brain metabolic activity and neurotransmitter levels. Such studies are needed to (1) determine the effects of sensory and cognitive demands on subsequent levels and patterns of regional brain activity during both sleep and wakefulness and as a function of state changes, and (2) to establish the functional neuroanatomy of sleep, wakefulness, alertness, and cognitive capability.

- Apply the enhanced capabilities afforded by improved functional neuroimaging, including greater temporal and spatial resolution, to study sleep and sleep disorders. These applications will help to determine the physiological correlates of phasic events like eye movements during REM, sleep-dependent changes in activity levels of specific thalamic nuclei, and brain changes subserving microsleeps and lapses of attention.

- Utilize functional neuroimaging techniques to determine the functional neuroanatomy of REM sleep, NREM sleep, and waking in patients in sleep disorders such as Narcolepsy, REM behavior disorder, and Restless Legs Syndrome. Such studies will yield insight into the pathophysiology of these disorders. Similar studies in patients with other disorders known to impact sleep processes (e.g., depression, chronic pain conditions) will yield insight into the pathophysiology of these disorders.

- The effects of sleep and alertness-promoting pharmacological agents on patterns of regional brain activation/deactivation and on occupancy/activation at specific receptor sites should be determined. Such studies will elucidate the mechanisms by which these agents impact sleep/wake processes, and will facilitate the development of new agents that might more specifically target sleep/wake-relevant sites and receptors.

- Develop new approaches to obtain polysomnographic measures and other physiological signals during MRI scanning to facilitate the study of sleep and alertness unaffected by electromagnetic interference from the MRI scanner.