Biology 202
2001 Third Web Report
On Serendip

It is estimated that humans spend one-third of their lives asleep (1). With sleep appearing to be not only the ultimate pastime, but also a survival imperative, the field of sleep research is quite broad, boasting many different areas of study. By examining phenomena like sleep disorders neurobiologists can hope to understand the mechanisms of normative sleep, in addition to perfecting treatment for suffers. Narcolepsy is one such disorder that affects an estimated 250, 000 or 1 in 2000 Americans; similar numbers are estimated for Parkinson's or multiple sclerosis (2). A widespread, though often misdiagnosed disease (fewer than 50, 000 are aware of their condition), narcolepsy can be characterized by chronic daytime sleepiness, cataplexy, sleep paralysis, and hypanogic hallucinations (3 ). The latter three of the tetrad of symptoms also occur in non-narcoleptic individuals; sleep episodes are the main determinant in diagnosis. Only 20 to 25 percent of narcoleptics suffer from all four symptoms (2). This paper has several goals, all of which involve clarifying the disease and its symptoms in different contexts. In order to do this sleep will first be explained in some detail, followed by a biological and psychological treatment of narcolepsy. Research of narcolepsy and its implications for the future shows steps to be taken in order to garner a better understanding this particular brain/behavior relationship.

To start at a beginning of sorts, REM sleep and its importance should be discussed. Sleep is in fact not the passive activity it was once assumed to be. It appears that during sleep many things are going on in the brain, which are documented by electroencephalograms (EEGs) measuring neocortical neuronal activity. Sleep occurs in a cycle of distinct stages, with apparent contrasts from early sleep, deep sleep, and REM (rapid eye movement) sleep (4). During REM sleep neurons in the neocortex behave similarly to how they would when a person is awake, displaying desynchronized EEG. The first REM stage occurs 70 to 90 minutes into sleep and approximately 20% of a night's sleep is spent in this type of sleep (4). Since this stage of sleeping is associated with dreaming, it is logical that in REM sleep muscles become temporarily paralyzed, a state called muscle atonia. REM sleep is important for overall health and regulation of the nervous system. In other sleep stages, or non-REM stages, EEGs are synchronized, only partial muscle relaxation is present, and dreaming is less frequent (2). Narcolepsy alters the order and length of REM and non-REM periods. REM sleep often occurs suddenly and characteristics specific to REM sleep occur at other times (2).

Why study sleep at all? Freud said that the unconscious mind was the key all repressed desires that could not be expressed while awake. This romanticizes the idea of sleep more than I would care to argue. Why would humans spend one-third of their lives performing an activity that served little purpose? The fact that such debilitating genetic disease revolves around sleeping patterns seems to indicate that this behavior has larger implications. By understanding the symptoms of narcolepsy one can hope to pinpoint how sufferers' brains are different, and therefore create different experiences. One can speculate on the meaning of various changes in brain and behavior in an individual. It is interesting to note that no observable pathological changes in the brain are seen (5). Studying narcolepsy is a complex molecular and physiological task that does not involve noticeable variances in brain topology. It is quite startling to see narcolepsy as a disease where the root of the problem lies deeper than structure.

Narcolepsy is unique in that those who suffer from it typically fall almost instantaneously into REM sleep (5). REM sleep is an important part of the sleep cycle for normal people, beginning in an area in the base of the brain called the pons, which stimulates the thalamus and then the cerebral cortex (4). REM sleep is connected to learning, thinking, and organizing information. Other symptoms also show the close connection between sleep and wake for narcoleptics. Cataplexy is momentary paralysis without the loss of consciousness, characterized by weakness in the limbs brought on in conjunction with sudden emotional responses (2). The loss of muscle control resembles a neurological protective of REM sleep: when in REM sleep the spinal cord shuts off signals to motor neurons to prevent people from acting out their dreams. Similarly, sleep paralysis is a symptom of narcolepsy where after falling to or waking from sleep a person finds that she cannot move (2). Once again there is a resemblance between the symptom and the normal assurances of REM sleep. Sleep paralysis could be described as the body staying in REM sleep even after one is conscious. The final symptom of narcolepsy is hypnagogic hallucinations, vivid visual and auditory illusions that are similar to being in a dream while conscious (2). In the blurring of the line between sleep and wake lies the problem (and possibly the key) to narcolepsy. The lives of narcoleptic individuals are tied to worlds of both dreams and consciousness.

By understanding narcolepsy researchers can seek some insight into sleep generation, which is not well understood on a molecular level. As neurobiologists learn more and more about sleep by studying its disorders, the effects and purpose of it for the human body are clarified. Sleep has a measurable influence on concepts like mood, behavior, and learning. Compare the life of a narcoleptic to someone who experiences normal sleeping patterns. Those who suffer from narcolepsy do lead fairly normal lives once diagnosed, but often face personal and social problems because of their condition. Many narcoleptics find it difficult to maintain jobs and relationships with the demands of excessive sleep and potential cataplectic occurrences (6). Since the onset of narcolepsy is often during adolescence (14 years being the average), sufferers face problems with staying awake in class. Students' grades often decline dramatically. Those who were once bright learners as children have trouble with even remembering a lecture. A physical phenomenon in the brain has an acute effect on behavior; the case of waking up on the "wrong side of the bed" is taken to a whole new extreme. Narcolepsy shows how heavily sleep (an almost autonomous brain function) dictates how humans interact with the world around them. Brain equaling behavior, though without an extensive knowledge of molecular mechanisms.

The purpose of REM sleep in day-to-day behavior is not totally understood. Returning to Freud, the acting out of repressed desires in dreams can be very cathartic. Where else is there a venue for someone to safely fly like a bird or slay dragons? Dreams allow human beings to experience things that they would normally not have an opportunity to do; and not only that, they can experience them without being in any real danger. A stricter biological interpretation is that dreams are the cerebral cortex's attempt to make sense out of the random signals that are created in the brain during REM sleep (4). Dreams are the "stories" the cortex pieces together out of these signals. Regardless of the true nature of dreams, narcoleptics spend the majority of their sleep states in REM, and thus are likely to be dreaming much more than a normal person. If a narcoleptic dreams more than a normal person, do they feel more fulfilled? Are narcoleptics' lists of experiences lengthier than everyone else's? Most narcoleptics find that their sleep often feels "unproductive"; they are often tired and they appear to others as "lazy" (6). REM sleep, an obviously positive part of the nervous system, is manifested in a pathological way in those with narcolepsy. The questions that remain are the effects of narcolepsy as a disease, what can be learned from those who have the disease, and the implications this has on the meaning of REM sleep. It is in studying the degenerative that better understanding of the way sleep works can be reached.

In 1999 researchers identified that canine narcolepsy is caused by a mutation in the hypocretin receptor 2 gene (Hcrtr2) (1). Canine narcolepsy is phenotypically similar to human narcolepsy, so this discovery was an important breakthrough in sleep research. Cells bodies that contain hypocretins, a novel neuropeptide which possess excitatory effects, are found in the hypothalamus, an area of the brain responsible for regulation (7). These neurons project into many other areas of the brain, like the brainstem (where the pons is located), responsible for REM sleep. It is hypothesized that hypocretins may play a role in modulating neurons involved in REM sleep, helping in the interaction between two chemical systems in the brain, the aminergic and the cholinergic (1). Researchers also hypothesized that when the Hcrtr2 is stimulated that administration of hypocretins promotes wakefulness and represses REM sleep in normal, but not narcoleptic animals (1). Though the defect that causes narcolepsy in humans is unknown, understanding canine narcolepsy is an important step. The next question to ask is whether or not Hcrtr2 mutations are present in human narcolepsy. Again, an understanding of the biological basis of narcolepsy could provide insight into sleep and wake stages, mechanisms of REM sleep, as well as other sleep pathologies (7).

Narcolepsy remains the only sleep disorder than affects the how we sleep: how we get to sleep and how this sleep is organized (1). Narcolepsy appears to be more environmentally influenced than genetic, though familial patterns of the disease have been reported. Narcolepsy has also been touted as an autoimmune disease, which would support the notion that sleep is a healthful activity and that narcolepsy disrupts this activity. In all likelihood, the disease is a combination of factors to create the token physiological and biochemical disturbances (1). Narcoleptics achieve REM sleep quickly and spend more time in REM sleep (2). It is possible that this state of dreams and processing random signals is not therapeutic when done to any extreme. Regardless of this, individuals with narcolepsy do have a somewhat positive prognosis. Drug treatment, behavioral therapy, and support can help narcoleptics lead near-normal, productive lives. To combat the excessive daytime sleepiness narcoleptics are often prescribed stimulant drugs or Modafinil, which was approved by the FDA in 1999. Cataplexy can be treated with anti-depressants (5). A biological problem that dictates external responses like emotions or interactions with others, narcolepsy is a good tie between brain and behavior.

WWW Sources

2)Facts about Narcolepsy, Helpful pamphlet published by the National Institute of Health containing lots of helpful information on the disease.

3)Ce nter for Narcolepsy, Stanford's Center for Narcolepsy is the leading researcher of the disease. This site provides updated information and links on the disease, as well as basic information like symptoms.

4)Brain Basics: Understanding Sleep, Another NIH site that discusses sleep: what it is, why we need it, plus more interesting topics, including sleep disorders like narcolepsy.

5)The Merck Manual: Sleep Disorders, Part of the Merck Manual, this site provides basic information on narcolepsy, diagnosis and treatment.

6)A Classic Case of Narcolepsy, One man's story of living with narcolepsy. Provides some interesting personal insights into the disease.

7)Narcolepsy and the Hypocretin Receptor 2 Gene, A review of the "Cell" article cited earlier. This site gives a condensed version of information presented there.

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