The arousal system involves multiple distributed neural networks working in harmony to permit normal sleep-wake cycles, satisfy internal drive states, and respond to environmental demands. Disorders of arousal involve pathology of the brainstem, thalamus, or widespread areas of both cerebral hemispheres. A parallel series of distinct neural networks using dopamine, histamine, serotonin, acetylcholine, and norepinephrine as neurotransmitters originates in the brainstem. Brain death represents the most severe disturbance of arousal, with total and irreversible cessation of any brain function. Coma is the state of neurological unconsciousness exhibited by unarousable unawareness of the external environment that is due to extensive damage to or depressed function of both cerebral hemispheres, bilateral diencephalic structures, or the ascending reticular activating system. A specific rehabilitative strategy is coma stimulation, in which structured sensory stimulation is administered for the purposes of improving sensory awareness and facilitating improvements in arousal and awareness.

This chapter focuses on the neurotransmitter and neuromodulator systems involved in the regulation of wakefulness and sleep as well as the neurochemical responses to sleep loss. Wakefulness, rapid eye movement (REM), and non-REM (NREM) states were originally defined in mammals using measures of skull surface electrical brain activity, skeletal muscle activity, and eye movements. The two primary factors that determine the degree of human vigilance and sleepiness are the duration of prior wakefulness and circadian influences. Increases in homeostatic sleep need are associated with subjective sleepiness, objective sleepiness, diminished neurocognitive function, as well as neurochemical and neurophysiological changes. The ascending reticular activating system (ARAS) is comprised of the brainstem reticular formation and its ascending projections responsible for cortical activation and wakefulness. Electrophysiological and neurochemical data indicate that highest levels of orexinergic activity occur during active wakefulness, and greatly reduced activity is seen during NREM and REM sleep.