Sleep and HD

The importance of sleep^

Experiments in animal models have suggested that sleep is necessary for the survival of a great variety of different organisms. Multiple studies have shown that rats deprived of REM sleep (see next section) die within four to six weeks, while those completely deprived of sleep only survive two to three weeks. Sleep deprivation had a marked physical effect on these rats. The animals that were not allowed to sleep exhibited increased weight loss, decreased body temperature, impaired immune systems, progressive hair discoloration, and the appearance of skin lesions. But even with these obvious signs of deterioration, scientists still were not able to pinpoint the exact cause of death in these sleep-deprived rats. Although scientists could correlate the rapid deterioration of these animals to their total sleep deprivation, they could not identify a distinct chemical or physiological abnormality that ultimately doomed these rats.

Despite the dramatic effects of sleep deprivation in rats, similar physiological symptoms under laboratory conditions have not been observed in humans, as equivalent tests cannot be run on human subjects. Regardless, sleep loss does have recognizable and measurable effects on human cognitive function, motor performance, and mood. These negative effects can be dangerous, especially when sleep deprived individuals are engaging in attention-dependent activities such as driving, medical care and similar tasks that require critical thinking and reasoning. Sleep deprivation also impairs higher brain functions, including memory formation, verbal fluency, and creativity.  The effects of sleep deprivation can be powerfully seen in fatigue-related car accidents. For example, truck drivers who have been on the road for thirteen hours straight are fifteen times more likely to have a fatal car crash in the thirteenth hour than the first hour. In fact, many researchers have suggested that the effects of driving while sleepy can be comparable to driving when drunk. Not getting enough sleep on a consistent basis can result in the buildup of a sleep “debt” that will negatively impact attention, performance, and health.

What happens during sleep^

There is a common conception that sleep is for rest, a period during which the mind and body can rejuvenate after a hard day’s work. This assumption is not unfounded—during sleep, humans are less responsive and less mobile, not dissimilar to other states of unconsciousness such as coma (but unlike comas, sleep is rapidly reversible). However, sleep is a time of significant brain activity that can be observed using a machine known as an electroencephalogram (EEG). By hooking up many different electrodes to the scalp of a patient, researchers can measure the electrical activity that takes place in the brain during sleep. Sleep is also measured by observing eye movements, which closely correlate to the type of brain waves observed in the EEG.

The two main states of sleep have been defined as non-rapid eye movement (NREM) and rapid eye movement (REM). During NREM sleep, neuronal activity in many parts of the brain is decreased, and the waves that appear on the EEG are characteristically slower than waking states. In addition, this sleep stage is accompanied by noticeable physiological changes, including the increased secretion of growth and sex hormones and decreased motor activity, heart rate, metabolic rate, breathing rate, blood pressure and intestinal mobility. Conversely, scientists have found that during REM sleep, brain waves are similar to those observed when humans are awake. This raises the interesting question: if neuronal activity is so similar in periods of both REM sleep and wakefulness, what accounts for the drastic differences between these two states? It has been suggested that a small number of neurons are responsible for differentiating between REM sleep and waking. REM sleep is characterized by pupil constriction and rapid movement of the eyes. Accompanying physiological responses include irregular heart rate, breathing and blood pressure. In addition, REM sleep is also when human dreams occur, which have been described as intense bursts of activity in certain populations of neurons. Throughout the night, the brain will alternate between periods of REM and NREM sleep every 90 minutes, repeating this cycle five to six times every night. Although both REM and NREM periods will occur during this 90 minute time window, the proportion of REM to NREM sleep increases during the night. NREM sleep dominates just after falling asleep, while periods of REM sleep dominate in the later sleep cycles.

Despite the well-characterized neurological and physiological changes that occur during sleep, scientists are still in disagreement over the actual purpose of both NREM and REM sleep in humans. Current theories include: reducing the energy consumption of the brain, consolidating memory, promoting neural plasticity (for more information on neural plasticity, click here), and increasing the body’s synthesis of important cellular building blocks such as proteins. Even though there have been many experiments showing that sleep is correlated with these various functions, scientists have found it very difficult to develop a unified theory of why we sleep. Part of this can be attributed to weaknesses in the empirical evidence—even if certain effects are statistically significant, they are not particularly notable. For example, although research has shown that exercise can improve sleep, this is only by about 10 minutes per night.  In addition, sleep research is conducted with a variety of different methods in a variety of organisms, further confounding efforts to build a unified theory of sleep. After all, the chemistry, physiology and function of sleep could very well differ significantly between similar organisms.

Sleep and circadian rhythm ^

You probably know from experience that your body responds differently depending on the time of the day. For example, you likely find it much easier to fall asleep at night than in the middle of the day. This is because darkness activates your body’s production of melatonin, a hormone that promotes sleep. Indeed, the entire human body runs on a 24-hour cycle of wakefulness and sleep. This so-called circadian rhythm (circa-, “approximately,” –diem, “day”) is driven by pacemaker cells in the hypothalamus, the part of your brain that controls a range of vital functions, including hunger, thirst, blood pressure and body temperature. Your circadian rhythm not only controls when you are alert and when you are tired, but it also coordinates your body’s countless chemical reactions. For example, during the day, when your blood sugar levels are likely to be high from eating, your body activates the chemical reactions that break down sugar into stored energy. Conversely, during the night, when your blood sugar is likely to be low, the specific processes that create sugar from stored energy are activated. The effects of the circadian pacemaker can also be seen at a whole-organism level. Human alertness and performance is highest during the day and lowest in the hours before daylight (3:00 – 6:00am), correlating with the time that humans are likely to be awake and asleep. Additionally, immediately after waking, you have probably experienced a good period of time when you were groggy and not alert. This span of time is known as sleep inertia and can last for hours after you get up. In opposition to this sleep inertia, the circadian clock sends out wake-promoting signals throughout the day, which counteracts the propensity to go back to sleep. The opposite process happens at night, with sleep-inducing signals eventually overpowering the wake-promoting ones, resulting in sleep. This natural cycle of sleep/wake signals, driven by the circadian rhythm, explains why humans tend to sleep more efficiently at night and less efficiently during the day.

It is becoming clearer that when you sleep may be just as important as how much you sleep. Deviating from your body’s circadian rhythm can lead to neurological and physical problems. Research has shown that shift workers with jobs that require them to be awake at night (e.g. police officers, fireman and health care providers) are more likely to suffer from diminished performance, sleep issues, and stress-related disorders than those who work during the day. The latter two problems can lead to more-serious conditions such as high blood pressure, stroke and heart disease. Indeed, a report by the International Agency for Research on Cancer has concluded that shift work puts individuals at a higher risk for cancer, which may be a consequence of the cellular effects of circadian rhythm disruption.

Sleep disruption and Huntington’s disease ^

Given HD’s devastating effects on many different regions of the brain, it is perhaps unsurprising that the disease would have an effect on sleep. Although the striatum, the part of the brain most visibly affected by the disease, is not currently thought to play a large role in sleep regulation, Huntington’s disease does affect several regions that have been directly implicated in controlling sleep.  For example, patients with HD have been shown to have significant atrophy of neurons in the hypothalamus, a region of the brain intimately involved in regulating metabolism and sleep/wake cycles. It is also possible that the sleep disturbances of patients with HD are secondary effects of other disease symptoms, such as depression and anxiety.

One survey on HD and sleep performed in Britain found that 87.8% of respondents suffered from sleep problems, including restless limb movements, jerky movements, waking during the nighttime, early waking, and sleepiness during the day. These harmful symptoms have been correlated with many measurable sleep abnormalities. In a study performed by an international group of scientists, individuals with HD underwent nighttime sleep monitoring and daytime wakefulness examinations. These tests used a variety of instruments to measure sleep cycle progression, eye movements, brain activity and other physical indicators of sleep. When compared to the control group, individuals with HD spent more time in the light sleep stages (stages 1-2), experienced more periodic leg movements, and generally had lower sleep efficiency, the number of minutes spent in sleep divided by the number of minutes spent in bed. In addition, individuals with HD have been shown to generally spend less time in REM sleep. Studies have shown that the long-term deprivation of REM sleep results in symptoms similar to those seen in acute sleep deprivation—impaired cognition, unstable moods and hormonal imbalances. These effects on REM sleep have been observed in individuals that were pre-symptomatic or otherwise had very mild symptoms, suggesting that problems with REM sleep are an early indicator for HD. It is noteworthy that other neurodegenerative diseases, such as Parkinson’s disease and Alzheimer’s, show similar sleep disturbances, suggesting that these illnesses may have similar effects on the neural networks that regulate sleep.

Because of the many detrimental effects of sleep deprivation on human health, scientists believe that the sleep disturbances associated with HD can exacerbate the disease. Indeed, many of the symptoms of sleep disorders are the same as the symptoms of Huntington’s disease, including the loss of motor control, memory problems, mood changes, and impaired cognitive function. Thus, disturbed sleep may be one of the mechanisms through which the behavioral, cognitive, and motor problems associated with HD develop. It is even possible that sleep deprivation is primarily responsible for some of the symptoms of HD, a hypothesis which remains to be tested. This raises the interesting possibility that treating sleep problems can improve the lives of those with HD. Research in R6/2 mice, a transgenic mouse model for HD, has shown that regulating the sleep of affected mice significantly improves their cognitive abilities. In these studies, affected mice were given a sedative to help them fall asleep during the day, and then a wake-promoting drug to help these mice stay awake at night (normally, mice are asleep during the day and awake at night). Compared to the untreated mice, the R6/2 mice that had their sleep/wake cycles regulated by drugs showed improved performance in a series of cognitive tasks. The authors hypothesized that these beneficial effects could be due to restoration of the mice’s circadian rhythms, and that sleep therapy could one day be used to slow the progression of neurodegenerative diseases such as HD.  Another important benefit of sleep therapy could be for the caretakers of those with Huntington’s disease. Several studies have found that difficulty dealing with nocturnal sleep problems is one of the most common reasons that caretakers choose to institutionalize patients with neurodegenerative disease.

Although these mice studies are promising, the effects of sleep regulation on humans with HD have yet to be studied. However, the evidence so far indicates that sleep therapy might not only improve the symptoms of HD, but may even affect the progression of the disease. And the fact remains that we could all probably use some more sleep!

Sources^

Arnul, I. et al. (2008). Rapid eye movement sleep disturbances in Huntington disease. Archives of Neurology 65(4): 482-488.
This article presents the results of a study examining REM sleep problems in patients with HD. The introduction and comment section are quite informative and very readable.

Goodman, A. & Barker, R.A. (2010). How vital is sleep in Huntington’s disease? Journal of Neurology 257(6): 882-897.
This eminently-readable article provides an excellent review of the evidence relating disturbed sleep with Huntington’s disease.

Pallier, P. & Morton, J. (2009). Management of sleep/wake cycles improves cognitive function in a transgenic mouse model of Huntington’s disease. Brain Research 1279: 90-98.
This primary source presents the results of experiments assessing the effects of drug-induced sleep therapy on mice model of HD. The introduction and conclusion are quite interesting and generally quite understandable.

Rechtschaffen, A. (1998) Current perspectives on the function of sleep. Perspectives in Biology and Medicine 41(3): 359-391.
This article offers a comprehensive review on the function of sleep. Although the writing is slightly technical, it is still quite useful and comprehensible.

Reddy, A. & O’Neill, J. (2009). Healthy clocks, healthy body, healthy mind. Trends in Cell Biology 20(1): 36-44.
This review talks about the importance of circadian rhythms. The article is quite technical.

Siegal, J. (2005). Clues to the functions of mammalian sleep. Nature 437: 1264-1271.
This review article presents some of the current theories and analyzes some of the existing evidence regarding the importance of sleep in mammals. The writing is technical, but the main points are relatively accessible.

Zisapel, N. (2007). Sleep and sleep disturbances: biological basis and clinical implications. Cellular and Molecular Life Sciences 64: 1174-1186.
This very technical article gives a review of the many different problems associated with sleep disturbances.