Self Management of Fatal Familial Insomnia. Part 1: What Is FFI?

Joyce Schenkein, PhD; Pasquale Montagna, MD

In This Article

Sleep and Memory

Sleep has been implicated in the memory process.[20,21] However, describing its precise role is complicated by the fact that both sleep and learning consist of qualitatively different stages, each involving unique biochemistries and discrete neural loci. For example, memory, has been categorized as declarative and nondeclarative (with several subtypes), all of which involve various stages (including stabilization, enhancement, etc). Finally, determining whether learning has occurred may depend on the index of measurement.[20] Thus, conclusions regarding the role of sleep in memory sometimes differ between authors.

In rat studies, selective deprivation of either REM or slow wave sleep (SWS) interferes with long-term memory encoding.[22] A current hypothesis is that SWS is involved in clearing unusable memories and that REM sleep is necessary for the retention of newly acquired learning. Moreover, a temporal relationship has been established between the high frequency oscillations (ripple activity) of the rat hippocampus and the neocortical K complex spindles of SWS.[23] This activity is believed to underlie the learning process by strengthening connections between memory-representing cells in diverse parts of the cortex.

Some controversy exists regarding the importance of sleep in human learning.[21,24] In particular, the role of REM sleep in memory consolidation is challenged by the case of an Israeli man with a REM-abolishing shrapnel injury to the brainstem. In the 35 years since his injury, the man has prospered professionally as a lawyer, painter, and puzzle columnist.[21] He is described by others as entirely normal. Unfortunately, empirical studies using material known to depend on REM sleep have not been performed on either this (or similar types) of patients.[24]

Procedural (motor) learning improves in both speed and accuracy after sleep, although not to the extent that it replaces the need for practice.[24] At present, it is accurate to say that not all stages of sleep are required for any single form of memory consolidation. Nor is any one stage required for all forms of consolidation. Finally, some forms of memory may not require facilitation by sleep at all. Nevertheless, compelling evidence does exist for an important role of sleep in human learning.[20,21]

Human sleep deprivation studies differ from animal research in that human studies are of shorter duration than animal studies. Second, humans know why they're being kept awake and may not respond with the same degree of stress as animals.[25] Sleep deprivation may result from endogenous factors (such as aging or chronic insomnia) or exogenous prevention of sleep state (such as deliberate waking).

Total sleep deprivation stimulates the HPA axis and suppresses the growth hormone (GH) axis.[26] After a 90-hour vigil (3.7 days), human subjects show the same drop in body temperature as animals (although the circadian rhythm remains) and the same loss of sensory acuity, motor speed, and short-term memory. [15] Visual hallucinations and psychotic-like behavior have been reported.[15] As opposed to rats, who are not clinically diabetic after long-term deprivation, sleep deprivation in humans is associated with a prediabetic state.[27]

The longest period of voluntary sleep deprivation, 264 hours, was associated with irritability, incoordination, slurred speech, blurred vision, hypnagogic reveries, lapses in attention, and disturbances of short-term memory.[28] Although the vigil appeared to have no lasting deleterious effect, photographs taken during this episode show a subject with a haggard and apathetic facade.

Relative sleep deprivation in humans often occurs as a natural consequence of aging. By the fourth decade of life, both SWS and GH are reduced by 75%.[29] GH deficiency in the elderly is associated with weight gain, loss of muscle mass, and reduced exercise capacity. Increasing deep sleep triggers a proportional increase in GH secretion.[29] By the sixth decade, total sleep time is reduced by approximately 27 minutes per decade, dramatically affecting REM sleep as well. The loss of REM sleep appears to be associated with elevated evening levels of the stress-related hormone cortisol. Cortisol levels normally peakin the morning and decline during the day to very low levels in the evening, giving the body time to recover. Subjects with decreased REM sleep, however, were less able to achieve evening quiescence. Lack of hormonal "down time," a recovery period for the stress-response system, has been linked to memory deficits and insulin resistance, a risk factor for diabetes. Elevated evening cortisol levels could also cause additional sleep loss. Although the elderly person does not die of his relative insomnia, supplements that reverse sleep decay have been promoted as rejuvenating.

Chronic insomnia (CI) refers to the subjective experience of poor sleep. People differ vastly in their nightly sleep requirements from as little as 1 hour[30] to more than 10 hours. Meddis[30] described a cheerful, active, 70-year-old retired nurse who claimed to have always slept little (even in childhood) and who, upon 5 nights of testing in a sleep lab, was shown to average roughly 67 minutes of sleep per night. Approximately 3% of the population experience insomnia, particularly older people and women.[31] CI is associated with an overall rise in ACTH levels and cortisol secretion, which retains a normal circadian pattern. It is not clear whether the increased cortisol level is a cause or consequence of the insomnia.[32] Physiologic hyperarousal (eg, elevated metabolic rate; sympathetic nervous system activity) is considered to be characteristic of primary insomnia[33] and also occurs in FFI.[34]

Of interest, people who are sleep-deprived (including FFI patients) tend to be sleepy during the day. Insomniacs are not. Nevertheless, insomniacs are more likely to complain of daytime problems of mood and concentration than normal sleepers. Chronic primary insomnia is also associated with an elevated risk for major depressive and anxiety disorders (symptoms also noted in FFI).

Sustained periods of insufficient sleep (eg, 4 hours of sleep for 6 consecutive days) result in impaired glucose tolerance[35] (possibly contributing to a prediabetic state),[29] a decrease in natural killer immune cells,[25] an increase in thyrotropin and evening cortisol concentrations, and elevated sympathetic nervous system activity.[35] This degree of sleep loss also results in poorer performance on neuropsychological tests of temporal order[36] and complicated motor skills.[37]

Selective sleep deprivation restricted to specific stages (eg, REM or SWS only) results in a rebound of the deficient activity during the recovery period. During SWS deprivation, characteristic delta waves also increase during the REM portion,[38] suggesting a low-frequency homeostatic mechanism common to non-REM and REM sleep.


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