Etiology and pathogenesis
Although large pathological studies are lacking, we believe the irregular sleep-wake pattern in developmental and degenerative disorders of the brain may result from lesions in or degeneration of the endogenous circadian timing system in the hypothalamus, or its connections, or of systems mediating sleep and arousal. Reduced melatonin secretion by the pineal gland and decreased exposure to zeitgebers also play a role in the development of irregular sleep-wake rhythm disorder. Some of the developmental disorders, such as Smith-Magenis syndrome, are found to have profoundly disturbed melatonin secretion profiles. For those with advancing medical issues, inhibition of other circadian clues, such as alterations in the ability of the eyes to transmit and receive light as seen in age-related cataracts and macular disorders, can contribute to irregular sleep-wake rhythm disorder. Lack of structured physical and social activities can contribute to the loss of circadian cueing. Medications, such as beta-adrenergic blockers, may block the release of melatonin, and other medical, neurologic, or psychiatric disorders may contribute to the sleep-wake cycle disruption.
Review of circadian mechanisms. All living organisms possess an inherent circadian rhythm. This near 24-hour cycle modulates a variety of physiologic and behavioral processes, such as sleep-wake cycle, body temperature, mood, hormone secretion, and many others. The paired suprachiasmatic nuclei of the hypothalamus have been established as the “master clock” that sets the timing of the mammalian circadian system. The suprachiasmatic nuclei are composed of 10,000 anterior ventromedial hypothalamic neurons that maintain a self-sustaining daily rhythm. This cycle is achieved through a complex system of timed gene expression that creates an autoregulatory feedback loop. A variety of genes are involved in this cycle, including Clock, Per, Bmal1, and Cry. Changes in these genes or those related to proteins that regulate the core genetic clock can result in circadian rhythm disruption (17).
The biological clocks of normal humans of all ages have a natural endogenous circadian cycle of slightly more than 24 hours, generally about 24.2 hours. Therefore, the internal body clock must be adjusted on a daily basis to align with the 24-hour day, a process called entrainment. Entrainment involves using zeitgebers (German for “time givers”) to reset the internal clock slightly each day. Common zeitgebers include light, melatonin, food intake, social interaction, and exercise. Each of these factors can independently change the timing of the circadian pacemaker, thereby altering the time of all physiologic processes that are regulated on a circadian basis.
Light is the main zeitgeber for endogenous clocks in humans. The human circadian system is more sensitive to short-wave, blue-green light than to long-wave red-spectrum light. The major afferent input to the SCN consists of a melanopsin-containing subset of photosensitive retinal ganglion cells whose axons synapse on SCN cells.
This retinohypothalamic tract transmits nonvisual, light-dark information to the SCN, which is mediated through glutamate and pituitary cyclase-activating peptide. In addition to a direct pathway, retinal ganglion cells also project to the intergeniculate leaflet of the lateral geniculate body, which, in turn, projects to the SCN. Neuropeptide Y and GABA are the main neurotransmitters. Other time clues appear to influence the SCN through serotonergic input from the brainstem raphe nuclei.
The key to understanding the zeitgebers is that the response of the circadian rhythm depends on when the stimulus is delivered. For example, light delivered prior to the temperature nadir (typically 4:00 AM in normal phase individuals) will cause a delay in the body clock. Light delivered after the body temperature nadir will advance the clock. Thus, for light therapy to be appropriately used, understanding the true timing of the circadian rhythm is essential. The temperature nadir is typically 1.5 to 2 hours before the undisturbed natural wake-up time. Therefore, if a person is naturally waking at 11:00 AM without an alarm, the temperature nadir would most likely be between 9:00 and 9:30 AM.
Similar to light, melatonin also has a time-dependent effect on the phase of the circadian rhythm. Melatonin is produced during darkness periods and is suppressed by light of sufficient duration and intensity, but melatonin has its own endogenous rhythm in which the peak occurs during the evening several hours prior to the nadir of core body temperature. The melatonin circadian rhythm is highly robust, has low intra-individual but high inter-individual variability, and is appreciably masked only by light. Because melatonin is also governed by an endogenous circadian rhythm, individuals will typically have a pulse of melatonin release in the evening when it would be dark. The time of this dim light melatonin onset can be a clue to the circadian rhythm timing and is currently used as a marker of the circadian phase (19). Exogenous melatonin delivered at different times has the opposite effect of light, such that melatonin delivered in the evening causes a phase advance, whereas morning use may cause a mild phase delay. The SCN exhibit dense melatonin receptors, likely establishing a feedback mechanism for the sleep-wake cycle. Melatonin and other potential factors, such as light, help synchronize the multitude of endogenous rhythms in the brain and other organs. Synchronization of these endogenous rhythms is important to optimal body function (29).
Neurodegenerative disorders usually affect older individuals, and these individuals, even when healthy, tend to exhibit an earlier bedtime and morning awakening. Healthy elderly tend to show a circadian phase-advancement and sleep phase-advancement, as well as less consolidated sleep (26; 23). The elderly may exhibit changes in interrelationships (the phase-angle difference) between the master circadian rhythm (manifest as melatonin and core body temperature rhythms) and sleep-wake cycle, particularly the shortening of the time between core body temperature nadir and the habitual waking time. The changes in sleep consolidation and in sleep timing in the healthy elderly may be due to a reduction in the homeostatic drive for sleep and in the circadian drive that promotes sleep in the early morning (14).
The pathogenesis of irregular sleep-wake rhythm disorder is thought to be due to a reduction of exposure to zeitgebers in the face of changes of SCN functioning, whether through normal aging, developmental issues, or neurodegeneration of the circadian system (03).
The observed output of the suprachiasmatic nucleus may become affected by degenerative changes in its input sources or outflow target systems. This may cause disorganized circadian rhythms reflected in part by a disorganized sleep-wake schedule. Alzheimer dementia can cause neuropathologic changes to the circadian pacemaker in the SCN with the presence of tangles and amyloid plaques (03). Patients with Alzheimer disease may have decreased activity of the SCN through decreased vasopressin and neurotensin neurons and increased glial fibrillary acidic protein astrocytes (33). In addition, animal studies have shown age-related reduced gene expression of light stimulation–induced per1 and per2. Decreased secretion of melatonin by the pineal gland has been observed in patients with Alzheimer dementia. Similar changes have been seen in models of Huntington disease (22). Thus, the destruction of neurons of the SCN can result in alterations in circadian regulation and presence of irregular sleep-wake rhythm disorder.
At the cellular level, expression of melatonin receptors in the SCN is reduced, thus, causing a disruption of the feedback loops serving normal circadian function and circadian influence on sleep.
Decreased exposure to zeitgebers plays a pivotal role in the development of irregular sleep-wake rhythm disorder. Light is important for circadian entrainment. Light is transmitted through the lens synapsing on retinal ganglionic cells containing melanopsin, which are sensitive to blue wavelength light. The retino-hypothalamic neurons utilize glutamate and pituitary adenylate cyclase-activating peptide in transmitting light information to the SCN. Loss of these retino-hypothalamic hair-like axons may contribute to the circadian disruption in traumatic brain injury. Patients with dementia, and especially those that are institutionalized, have reduced environmental clues such as light exposure due to being inside and daytime napping. These individuals may benefit from daily light therapy to accentuate sleep-wake rhythms, which appears to reduce agitation (08). Daytime napping also limits participation in important social and physical activities that are critical inputs to the maintenance of the circadian rhythm. In addition, patients with primary eye disorders, such as cataracts and macular disorders (influencing the retinal ganglion cell layer), have decreased light input to the SCN, which can potentially result in dysfunction of the internal clock.