Message Board

1. What is the difference between REM and non-REM sleep?

2. They tested "The hypothesis that DQB1*0602 positivity changes the dynamics of REM sleep and leads to worse insomnia symptoms" During REM sleep, what difference did they find in the frequency bands of individuals with the DQB1 allele? Why would this activity cause them to feel less well rested than those without the allele? (even though they were getting the same amount of sleep!)

3. "95% of individuals with hypocretin (orexin)-deficient narcolepsy... carry the human leukocyte antigen (HLA) DQB1*0602 allele, as compared to 25% of the general population" Explain the role of hypocretins (AKA Orexins) in sleep regulation and REM.

4. Can you find any studies investigating this autoimmune hypothesis of narcolepsy? Please cite at least one.

REM and non-REM sleep can be readily separated and identified as two separate states thanks to a number of physiological differences. One of the most useful ways is using EEG to measure a subject?s brain waves during sleep. REM sleep will see a characteristic frequency and amplitude of activity known as Beta waves, which are relatively high frequency and low amplitude, similar to the waves present in alert, waking individuals. Non-REM sleep, on the other hand, progresses from alpha waves in stage 1, to theta and delta waves in stages 3 and 4. The progression into a deeper Non-rem State sees a decreased frequency and increased amplitude, contrary to what is observed in REM sleep. Additionally, REM sleep can be easily identified due to its defining feature ? rapid eye movements.

I thought the study presented an interesting case that individuals with the DQB1 allele were found to have an increased frequency in their EEGs. The reason this may have caused the subjects to subjectively report that they felt less well rested is because increased frequency as in beta waves is typically seen during wakefulness and alertness outside of its manifestation in REM sleep. Thus, it is possible that while the subjects slept the same as those without the DQB1 allele, their brains were more ?awake? or active during their REM sleep, preventing them from feeling as well rested.

Orexins modulate a wide array of systems in the brain; important in their role in regulating wakefulness is that they excite cholinergic, serotonergic, noradrenergic, dopaminergic, and histaminergic neurons. Due to its role in modulating these systems, it helps to promote wakefulness and also inhibit REM sleep. Thus, if orexin neurons are destroyed or orexin is, for whatever reason, not functioning correctly, there will be less inhibition on REM and less wakefulness, which is consistent with what is seen in narcolepsy. The decreased orexins found in those with narcolepsy are thought to be due to some sort of autoimmune disorder, likely involving the T-cell receptor alpha and the HLA complex causing a degeneration of the orexin neurons in the hypothalamus (Joachim Hallmayer, et. al.).
http://www.nature.com/ng/journal/v41/n6/full/ng.372.html

In REM sleep, neuron activity is very similar to that of an awake individual in that there is a lot of fast activity occurring throughout the sleep stage. This activity consists mostly of alpha and beta waves, with some desynchronous activity that is reminiscent of being awake. However, in REM, the individual is asleep and dreaming, their eyes move very rapidly (hence the name REM), and they have paralyzed muscles. This is different than non-REM sleep because in the other stages of sleep, brain activity is somewhat slower and has larger amplitude. This is also sometimes known as ?slow-wave sleep.? Theta and delta waves are predominantly observed in the non-REM stages of sleep, and muscle paralysis and rapid eye movements are not observed. Indeed, there is a striking change seen in an EMG when a person transitions from non-REM to REM sleep: muscle tone is almost completely lost upon entering REM. This, of course, is to prevent the person from acting out their dreams and possibly harming themselves or others.

In individuals with the DQB1 allele, it was found by researchers that there was an increase in the ?relative power? (a reporting of the total power generated by a particular frequency of waves) of gamma, sigma, and beta waves during REM sleep and a decrease in the relative power of alpha and theta waves. Since beta waves are most frequently observed during wakefulness, it seems like individuals with the DQB1 allele suffer from their brains being more active while they should be sleeping, and this increased activity is detracting from the sleep they should be getting, hence the feeling more sleepy even after getting a comparable amount of ?sleep? to another person. Even though beta waves are present during REM sleep, these higher frequency beta waves must be more like waking beta waves and show that the brain is more ?awake? while it should be sleeping.

Orexins in the brain, while important to feeding behaviors, also regulate sleep; specifically they are active in promoting wakefulness through their interactions with the dopaminergic, serotonergic, and cholinergic modulatory systems in the brain as well as histamine-releasing neurons. In individuals with orexin-deficient narcolepsy, it is clearly shown that orexin deficiency leads to an increase in sleep via a decrease in wakefulness. In their case, lacking orexin makes them unable to maintain wakefulness and produces less inhibition to REM sleep, resulting in the very sudden lapses into REM sleep associated with narcolepsy. In a report I found (or rather, an article that summarizes the findings of the to-be-released report), it is stated that narcolepsy has been found to involve a genetic variation pertaining to T cells, one of the many types of cells that constitute the immune system in our bodies, in which these T cells interact with human leukocyte antigen (HLA) and destroy orexigenic neurons, thereby causing narcolepsy through an autoimmune disorder.
http://www.sciencedaily.com/releases/2009/05/090503132613.htm

In terms of physiological characteristics of REM sleep, we see a rise in acetylcholine stimulation of the pons, which sends an inhibitory signal to your peripheral muscles, preventing movement. Norepinephrine and serotonin, on the other hand are used during non-REM sleep to promote wakefulness. However, Drew and Clementine have already done a fairly good job of elaborating on these mechanisms. During Non-REM sleep, there is an increase in activity of the parasympathetic nervous system, resulting in decreased breaths per minute, lowered heart rate, lowered kidney function, yet increased digestion. The inhibitory signal from the pons to peripheral muscles is absent during non-REM sleep, thus you are capable of moving your body. However your CNS rarely commands it to move. Also, sensation in general is decreased. REM allows intense sensations, though they are generated internally. Too state the obvious, REM sleep is also characterized by rapid eye movements. The amount of REM sleep that the average human undergoes is correlated to their age.

This adds yet another dimension to the study at hand. Newborns spend almost twice as long as adults in REM sleep, and elderly adults often experience fragmented sleep-wake cycles. Zeitzer et al. demonstrated that the lack or presence of the DQB1 allele significantly affects the ?restfulness? of sleep for the elderly while altering gamma, sigma and beta waves. However, does this allele have such an influential role in subjects of different age groups, whose REM/NREM cycle is innately different?

Orexin is a neuropeptide released by the posterior lateral hypothalamus that stimulates arousal and wakefulness in the brain. Hypocretin (at least in the hypothalamus) has been found to have highly excitatory effects with neuronal projections to a number of brain areas that are highly involved in sleep: the mesopontine tegmentum, the pontine reticular formation, and the locus coeruleus to name a few. Hence, by promoting wakefulness, orexin inhibits REM. This can be demonstrated via orexin knockout mice, which experience narcolepsy, a disorder known for increased REM sleep. A 1999 study by Thakkar et al. (http://www.ncbi.nlm.nih.gov/pubmed/11382892) built further on this knowledge by showing that REM sleep is drastically increased in rats following a microdialysis perfusion of hypocretin-II receptor antisense into the pontine reticular formation.

The difference between NREM and REM sleep can be readily described as the variation in the total neural activity. In NREM, the brain enters a lower power mode that transmits neuronal activity at lower frequencies (slower rates). This section of sleep activates the brain center by center. In contrast, REM sleep is characterized by high frequency brain waves (neural transmissions). Also, rapid movement of the eyes (hence the name) and muscle paralysis. REM stage sleep also activates many of the brains sensory centers. REM sleep causes the brain to mimic the state that it would be in while in wakefulness. Due to the activation of sensory centers and the mirror of wakeful functions, this is the state of sleep that produces dreams. This mimicking of wakefulness could be the doorway into understanding the premise of the article, the variation between total sleep time and sleep quality.

The study investigates the significance of the DQB1 allele in insomniacs. Basic insomniacs (those without disorders that feature insomnia) were tested and observed. The observations were made about their quality of sleep. People with the allele reported feeling less rested that those without. Within the group of DQB1 positives, their neural activity was observed to be higher in REM (that is, their EEG recordings showed an increase in the frequencies of the relevant brain waves) as compared to the DQB1 negative group. I believe that the increased frequency in the recordings is indicative of higher brain function. In this instance, because the brains sensory systems show some activation during REM, including the centers in the visual cortex that are associated with projecting past images or imagined images, it can be assumed that the DQB1 positive group has more vivid dream states. Thus, not only do they feel less rested because their neural centers had less time to replenish neurotransmitters, but also, they may have the experience of feeling more awake in their dreams. Since most people awake from and REM cycle, it is possible that they awaken from a dream state that they already felt awake in. They might feel like they had been awake for an hour or two already.

The role of Orexins in the regulation of sleep and REM is to promote wakefulness and as an intergrative Neurotransmitter system for metabolic and circadian cycles. Orexigenic neurons stimulate various brain nuclei, including DA, NE, ACh and Histamine centers. Each of these Neurotransmitter systems helps to regulate wake/sleep states. Thus, Orexins inhibit sleep and sleep cycles. In Orexin deficient subjects, sleep is not inhibited and thus sudden onset sleep occures (narcolepsy).

http://www.journalsleep.org/Articles/300103.pdf

Again as everyone said before, REM and non-REM sleep are distinguished by the difference in frequency and amplitude of the brain waves. REM sleep has a low amplitude and high frequency with saw tooth waves occurring randomly throughout, while non-REM sleep has a few different stages that generally have a higher amplitude and lower frequency (alpha, theta, and delta). Again, in REM sleep, the body experiences muscle atonia which prevents us from moving or acting out our dreams which may be dangerous in some cases.

It is shown that the frequency bands of subjects with the DQB1 allele express a higher frequency when shown on the EEGs. This means that their brains are more active and using more glucose and energy when they should be in a higher state of rest. If their brains remain active all night and more energy is used while they are sleeping, it makes sense to say that they would feel more tired in the morning, after all their brains had a hard night of work!

Hypocretins stimulate wakefulness and energy expenditure as well as working with the circadian system and metabolic processes to determine if a person should be tired or awake. Orexigenic neurons excite many other neurons in the brain, causing it to be very active and awake when functioning properly. If the hypocretins are no longer present in the brain or are not working properly, one loses the ability to stay awake easily. Seeing as narcolepsy is defined as "excessive daytime sleepiness" it can be shown that the loss of orexin to keep them awake is essentially causing them to be exhausted and fall asleep throughout the day.

http://huguenard-lab.stanford.edu/205/watkins.pdf is an article that investigates the autoimmune hypothesis of narcolepsy. In this paper, they aim to identify possible autoantigens expressed by the neurons containing hypocretin in the hypothalamus. They propose that narcoleptics will have circulating antibodies and memory T cell directed against components of hypocretin producing cells, while in normal patients minimal reactivity will occur.

Sleep generally occurs in 90 minute cycles in the healthy adult. NREM is characterized by 4 progressive deepening stages of sleep defined via an EEG. Stage 1 is a major transition stage, where major changes in brain function are seen. Stage 2 is characterized by the presence of sleep spindles generated in the thalamus that prevent sensor transfer and a high amplitude K complexes both thought to promote sleep. stage 3 and 4 are deep delta sleep with lower frequency eeg waves seen with higher amplitudes. Over a 7-8 hour hour full night of sleep, all but about an hour and a half will be spent in NREM sleep. REM cycles occur during the 90 minute periods, oscillating between deep sleep and REM during the first half of the night and stage and REM in the second half of the night. REM sleep EEG waves have a low amplitude, fast frequency, and contain characteristic Saw tooth waves.

The study showed that individuals positive for the DBQ1*0602 allele had higher EEG frequencies during REM sleep. This would be consistent with them not feeling as well rested because the brain appears to be overly active during this time. So, even though the people are sleeping the same amount, the time spent in REM is not as affective as a normal persons REM sleep.

Orexins are excitatory neuropeptide hormones present in the ascending reticular activating system and more specifically in the lateral and posterior hypothalamus. As other people have said, orexins strongly excite many neurotransmitter systems that are involved in the wakefullness of the ascending nucleus including acetylcholinergic system and cortex activation. the orexin activating system works mainly opposite of the VLPO

This article discusses a DBQ1*0602 postive allele twin study involving narcolepsy and orexin levels. the levels of CSF orexin and the orexin receptor are normal, suggesting that there are other mechanisms for genetic narcolepsy as well as orexin neuron autoimmunity.
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T1B-4C46X91-D&_user=10&_coverDate=04%2F10%2F2004&_rdoc=1&_fmt=high&_orig=gateway&_origin=gateway&_sort=d&_docanchor=&view=c&_searchStrId=1680488496&_rerunOrigin=scholar.google&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=ab20c129b6e311733cfd0c99867393be&searchtype=a

Non-REM sleep and REM sleep constitute our entire sleep cycle. Non-REM sleep occurs with 4 different stages, and has decreasing EEG with increasing sleep stages. REM sleep has beta-wave activity, which is a high EEG reading that?s comparable to active waking states. Stages 3 and 4 are deep sleep, there is good evidence from sleep studies that the amount of restfulness one feels in the morning has more to do with the amount of deep sleep one gets rather than the amount of time one falls asleep. REM sleep is where our cognition is very active but our body is paralyzed. It is also when we dream.

It is interesting to see that the DBQ1 hypothesis found that with those with the same amount of sleep, ones with the DBQ1 allele felt less rested because there was an increase in EEG activity in their REM sleep. Increased beta wave activity is seen more with active wakening than in sleep stages. They also pointed out that local pockets of sleep around the cortex would be less well temporally coordinated with one another, which means that the person could be cycling out of wake and sleep in their brain activity, but still not really awake as a whole person. This could explain why individuals feel less rested even though they were asleep for the same time, when in reality; brains of individuals with the DBQ1 allele spend a longer time being actively awake.

Orexin is involved in the regulation of feeding as well as sleep behaviors. In the brain, orexin neurons are excitatory to the cholinergic, serotonergic, dopaminergic, histaminergic, and noradrenergic neurons, all of which act to keep one awake. By destroying orexin neurons, one tilts the balance of sleep and wake towards the sleep side, especially that of REM sleep. Thus, it explains why there would be sudden onset of REM sleep during times of wakefulness in narcoleptics.
Multiple Sclerosis, an autoimmune disease, has generated patients who not only has loss of motor functions, but also narcolepsy. They found that AQP4, a protein highly expressed in the hypothalamus, could be the target of our body?s own immune system.
http://archneur.ama-assn.org/cgi/content/full/66/12/1563