Wakefulness, as shown in the Figure below, is defined by a low voltage fast frequency EEG pattern, called desynchronized or activated EEG, that consists primarily of frequencies in the beta and gamma ranges. The electrooculogram (eye movement - EOG) and electromyogram (muscle tone - EMG) recordings also show high activity during wakefulness.

In contrast to wakefulness, sleep is characterized by higher voltages and slower waves, a pattern called synchronized EEG. Non-rapid eye movement (NREM) sleep is the usual term for this state. In humans, NREM sleep is further subdivided into four Stages, 1 through 4, which depend on the extent of EEG slowing, especially in the delta frequency range ( Figure below). Stage 2 is notable for the presence of spindles, which are waxing and waning bursts of frequencies in the sigma band. Stages 3 and 4, with delta waves comprising more than 50% of the signal, are further grouped under the term slow wave sleep (SWS). During this state, the EOG can show gradual rolling eye movements and there is low or minimal muscle activity.



Slow sleep is interrupted by periods of rapid eye movement (REM, i.e., active or paradoxical) sleep, when, despite all the overt signs of continuing sleep, the activity of the brain is remarkably different. In fact, the EEG in humans during REM sleep is essentially identical to that recorded during wakefulness, but the EOG reveals rapid bursts of eye movements, hence the name of the state.

Neural activity during REM (rapid eye movement) sleep seems to originate in the brain stem, especially the pontine tegmentum and locus coeruleus. REM sleep is punctuated and immediately preceded by PGO (ponto-geniculo-occipital) waves, bursts of electrical activity originating in the brain stem. (PGO waves have long been measured directly in cats but not in humans because of constraints on experimentation; however comparable effects have been observed in humans during "phasic" events which occur during REM sleep, and the existence of similar PGO waves is thus inferred.) These waves occur in clusters about every 6 seconds for 1–2 minutes during the transition from deep to paradoxical sleep (REM phase). They exhibit their highest amplitude upon moving into the visual cortex and are a cause of the "rapid eye movements" in paradoxical sleep.

Wakefulness and EEG desynchronization require excitatory innervation of the forebrain. Being awake depends on the discharge activity in several, apparently redundant parallel ascending neurotransmitter pathways: none of these systems, which include glutamate, acetylcholine (ACh), and the monoamines (serotonin and norepinephrine), is absolutely necessary for the expression of wakefulness, but all appear to contribute (Jones, 2005). Many of the corresponding cell bodies for these systems are located in the brainstem. Two studies were critical for the discovery that this region was a principal substrate for wakefulness and hence gave rise to the important concept that wakefulness entails forebrain activation for its expression. Bremer, in a 1935 publication, noted that a complete transection above the brainstem produces a preparation that remains in a state resembling normal sleep. Subsequently, Moruzzi and Magoun in 1949 demonstrated that electrical stimulation of the reticular core of the upper brainstem produced immediate and long-lasting EEG desynchronization in a previously sleeping preparation. The latter study thus established the region as the location of an ascending reticular activating system (ARAS) that maintained wakefulness although the neurons that were responsible remained unknown.

The neurotransmitter systems that comprise the ARAS (ascending reticular activating system) were subsequently identified. However, when these transmitter systems were described individually, the term ARAS became less informative, especially as some of the cell bodies were found to lie outside the core of the reticular formation (RF). The ascending activating system (AAS) is a general term that is now more typically used. A major component of the AAS was determined by Steriade and collaborators (Steriade et al., 1990), who recorded the activity of neurons in chronic, freely moving cats. They identified thalamically projecting cells located at the pons-midbrain junction whose discharge rates increased before the first sign of the change to an EEG desynchronized state. Later studies established that many of these cells which project to the thalamus (Th) were cholinergic (relating to or denoting nerve cells in which acetylcholine acts as a neurotransmitter.) and localized them to the laterodorsal tegmentum/pedunculopontine (LDT/PPT) region.

They remain active whenever the EEG is desynchronized during wakefulness and REM sleep. Conversely these neurons have low discharge rates during NREM sleep. The LDT/PPT cholinergic system is not the exclusive substrate of EEG desynchronization. Other significant brainstem reticular neuronal projections to the thalamus, utilizing glutamatergic neurotransmission, as well as monoaminergic projections that contain norepinephrine from the locus coeruleus (LC) and serotonin from the dorsal raphe (DR) also play a role and are part of the AAS (McCormick, 1989). The monoaminergic cells send widespread projections throughout the forebrain to the cortex as well as the thalamus. Importantly, they demonstrate significant state-related changes in discharge rates, being highest during wakefulness, decreasing during NREM sleep and becoming virtually quiescent during REM sleep. A similar state-related change in discharge rate is also shown by cells that contain another monoamine, histamine. These cells are located uniquely in the tuberomammillary nucleus (TMN) of the caudolateral hypothalamus. Histaminergic cells, like the other monoaminergic components of the AAS, have been found to be a substrate of wakefulness on the basis of pharmacological, electrophysiological, lesion and stimulation studies. A second ascending cholinergic projection, originating in the nucleus basalis of Meynert in the basal forebrain (BF), sends widespread projections to the cortex and thalamus. This cholinergic system, like that from the LDT/PPT, is also important for EEG desynchronization, is a component of the AAS, and receives brainstem input. Thus, there are two major relay pathways for brainstem activation of cortex, one through the thalamus and one through the BF and nearby hypothalamus, as well as the direct projections of LC and DR to cortex. Another relatively recent addition to the list of neurotransmitters that contribute to wakefulness is the neuropeptide, orexin (also called hypocretin). Orexin-containing cell bodies are located uniquely in the lateral hypothalamus and send widespread projections throughout the neuraxis. The importance of orexin to the control of sleep and wakefulness was discovered serendipitously when narcolepsy was found to be caused by the absence of an orexin signal, either through the loss of the receptors, the neurons or the neuropeptide. Orexin supports wakefulness through excitatory projections to other components of the AAS, though its role in the regulation of sleep and wakefulness is likely to be more critical than the enhancement of general arousal and EEG desynchronization. One significant conclusion, now supported by considerable research, is that orexin is important for controlling the gate from one state to another (Lu et al., 2006; Saper et al., 2001). Hence orexin ensures the orderly transition between states and also the rapid switching that is evident when a state transition is initiated.