30722 Sleep 5.qxd

SLEEP DEPRIVATION HAS LONG BEEN USED AS A TOOL TO STUDY THE FUNCTION OF SLEEP. It has been well documented that sleep deprivation results in significant consequences, including daytime sleepiness and substantial functional impairment.1 Numerous studies have shown that slow wave sleep (SWS) increases during recovery sleep after partial or total sleep deprivation. The amount of both conventionally scored SWS and spectral analysis measures of slow wave activity (SWA) is enhanced as a function of prior wakefulness.2-6 However, the precise function of SWA is not clearly understood. It often has been assumed to play a role in recovery or restoration because it has been shown to increase after exercise,7 external heat stress,8,9 and sleep deprivation. The SWA may be a reflection of the sleep-regulating mechanism that serves to maintain the equilibrium of the sleep-wake system in response to the stress of sleep deprivation. The mechanism of sleep homeostasis and the neurophysiologic and neurochemical substrates that underlie it have yet to be clarified. Adenosine is believed to play a role in the production of SWA because caffeine is known to block adenosine receptors10 and adenosine analogs can increase SWS, while this increase can be prevented by caffeine.11,12 Adenosine can be found within specific neurons but also can exist in the extracellular space as a degradation product of adenosine triphosphate (ATP), which is released and transported throughout the central nervous system in response to increased metabolic demand, such as during wakefulness.12 It has been suggested that adenosine promotes slow electroencephalogram (EEG) potentials and that there may be changes in EEG in specific populations of neurons in response to increased metabolic demand during wakefulness or prolonged wakefulness.13 In animals, increases in extracellular adenosine have been observed in the basal forebrain, in particular, during prolonged wakefulness (ie, sleep deprivation).14,15 Such chemical changes are difficult to measure in humans and are undetectable by traditional means of assessment that measure blood flow and glucose metabolism. Phosphorous (31P) magnetic resonance spectroscopy (MRS) is a technique that allows the noninvasive detection of high-energy phosphates, phospholipid metabolites, pH, and magnesium levels. The high-energy phosphates phosphocreatine (PCr) and β-nucleoside triphosphate (βNTP) and inorganic phosphate (Pi) can be measured with 31P MRS. Nucleoside triphosphate is largely reflective of ATP; approximately 80% of the β-NTP resonance is comprised of ATP. The 31P MRS allows measurement only of phosphorous and compounds that contain phosphorous. It does not provide a direct measurement of adenosine. However, while adenosine, per se, does not contribute directly to the NTP resonance, since we can detect adenosine only when it is attached to a phosphorous atom or phosphate group, it is possible that changes in NTP are related to changes in intracellular or extracellular adenosine in addition to changes in ATP. Adenosine triphosphate is produced primarily by the enzyme creatine kinase (CK), which transfers high-energy phosphate equivalents, stored as the phosphate moiety of PCr; the CK equilibrium largely favors production of ATP. Accordingly, metabolic stress typically induces an early reduction of PCr levels, while prolonged metabolic stress can induce a reduction of both PCr and ATP. The PCr/β-NTP ratio, which can be determined with 31P MRS, is a measure that reflects the