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Narcolepsy, cataplexy and the reward system.

Approximately 70 percent of narcoleptics struggle with cataplexy, the sudden temporary loss of skeletal muscle tone brought on by heightened emotion. A few muscles may be affected, or all skeletal muscles may be affected.

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In the latter case, a person suddenly falls to the ground, apparently unconscious. However, the person remains aware of all that is going on in the environment, but is unable to move until the episode is over. Because episodes happen suddenly and without much warning, cataplexy can be a very debilitating and, depending on the context in which it occurs, a very dangerous symptom.

Many people with narcolepsy-cataplexy find relief from the sudden episodes of cataplexy with the drug sodium oxybate, a form of gamma-hydroxybutyrate (GHB) that can be highly addictive. For this reason, people with narcolepsy-cataplexy must follow stringent rules when being treated with the drug. However, scientists have noted that people with narcolepsy-cataplexy do not seem to become addicted to GHB to the same degree as someone without the disorder.

A recent Swiss study may have found the reason: The reward system in people with narcolepsy-cataplexy processes information differently than does the reward system in a person without the disorder. The reward system in the brain involves neurons of the prefrontal cortex, nucleus accumbens, amygdala, ventral tegmental area (VTA, a region in the midbrain), the substantia nigra (a thin black layer separating the anterior and posterior portions of the midbrain) and the locus ceruleus (a small blue-hued area on both sides of the upper posterior region of the pons). These structures are connected by fibers that are part of the medial forebrain bundle (MFB).

The MFB originates in the reticular formation (a network of nerve fibers and cells in the brainstem), extends through the VTA and through the lateral hypothalamus, and finally projects into the nucleus accumbens, the amygdala and the prefrontal cortex.

When basic drives such as sex, hunger, thirst or socialization are satisfied, the reward system is activated. The VTA neurons release dopamine into the nucleus accumbens, the amygdala, and the prefrontal cortex. The increased level of dopamine results in one's sense of satiety, well-being or pleasure.

Although the VTA neurons release dopamine, they have receptors for a small protein called hypocretin. Hypocretin is produced by a group of neurons in the hypothalamus and is an excitatory neuropeptide. The hypocretinergic neurons project from the hypothalamus to the VTA, the amygdala, the nucleus accumbens, the prefrontal cortex and other reward system structures. Hypocretin may modulate the behavior of the reward system because it can bind to receptor sites on VTA neurons. When it binds to a VTA neuron, the VTA neuron fires more quickly.

Hypocretinergic neurons also send projections into brainstem areas that control various aspects of wake and rapid eye movement (REM) sleep (the locus ceruleus, raphe nuclei and reticular formation). These connections appear to play a role in a person's ability to maintain wakefulness, as indicated by the finding that people with narcolepsy-cataplexy often have insufficient amounts of hypocretin and struggle with sleepiness.

Narcolepsy is a syndrome consisting of four symptoms: excessive sleepiness, hypnagogic hallucinations, sleep paralysis, and cataplexy. A person does not have to have all four symptoms to be diagnosed with narcolepsy - only 10 to 25 percent of people diagnosed with narcolepsy have all four symptoms.

Scientists have long suspected that hypnagogic hallucinations, sleep paralysis and cataplexy in people with narcolepsy are elements of REM sleep intruding into wake. A hypnagogic hallucination is vivid, realistic imagery that occurs in the transition into or from sleep. It is thought to be dream imagery that would normally occur during REM sleep.

Sleep paralysis is the temporary inability to move in the transition into or from sleep; it is thought to result from REM sleep atonia manifesting in the transition between sleep and wake. The sudden loss of muscle tone in cataplexy is thought to be the abrupt onset of REM sleep atonia manifesting during wake. The belief that cataplexy is displaced REM sleep atonia is based on studies showing that the loss of muscle reflexes that occurs during REM sleep is similar to the loss of muscle reflexes that occurs during a cataplexy attack.

Adding credence to this view, scientists in the 1990s reported finding a group of atonia-generating neurons in the medulla that, during REM sleep, inhibit the activity of motoneurons in the spine. However, some research indicates that the muscle atonia in cataplexy may not be related to the sudden onset of REM sleep. For example, Nishino and colleagues of the Stanford University School of Medicine noted that REM sleep cyclicity occurs every 30 minutes in narcoleptic dogs with cataplexy, as well as in dogs without the disorder.

Furthermore, they noted that the 30-minute cyclicity in REM sleep was maintained in narcoleptic dogs in whom status cataplecticus (a prolonged episode of cataplexy) had been induced. Because the atonia of the cataplexy remained despite the cyclicity of the REM sleep state, Ninshino concluded that the onset of REM sleep was not associated with muscle atonia in cataplexy, and therefore the mechanisms that induce muscle atonia in cataplexy may differ from mechanisms that induce ationia with the onset of REM sleep.

Narcolepsy-cataplexy and the reward circuits in the brain may share the same pathways, as indicated by the observation that cataplexy can be triggered by strong emotions associated with anticipating a reward such as when playing a game. Narcoleptics rarely become addicted to stimulant drugs that are prescribed to maintain wakefulness or to counteract cataplexy. This suggests impaired functioning of the reward system in narcolepsy. To understand how this is possible, Swiss researchers Aurelie Ponz and colleagues used functional magnetic resonance imaging (fMRI) in untreated narcoleptics with cataplexy to assess the brain activation while undergoing a task designed to activate structures of the reward system. The researchers also obtained fMRI scans from people without narcolepsy-cataplexy who performed the same task.

Because people with narcolepsy-cataplexy tend to have decreased amounts of hypocretin, Ponz expected that hypocretinergic neurons and the structures they project to would have altered activation in response to the expectation of reward. Based on the work of another team of scientists, Ponz also expected that the amygdala of the people with narcolepsy-cataplexy would have increased activity in response to the expectation of reward.

The subjects performed a game-like task while being scanned by fMRI. The subject was to press a button on seeing a target image. Each target image meant a potential gain or loss of one or five points. If a subject successfully pressed the button when the target image was on screen, the time before subsequent target images were displayed was incrementally shortened to increase the difficulty of the test. If a subject pushed the button after the image had been presented, the time before subsequent target images were displayed was incrementally increased. At the end of each trial, the study participants were shown whether they passed or failed and shown their overall points.

The fMRI scans showed that the controls and subjects had increased activity in the caudate nucleus and amygdala when winning the trials. In addition, the subjects with narcolepsy-cataplexy had increased activity in the putamen, which plays a role in movement and the external expression of emotion to reward.

Ponz suggests that increased activity in the putamen may explain why people with narcolepsy-cataplexy have a greater response to positive emotions. In another brain imaging study, Chabas and colleagues similarly noted increased activation of the putamen and nearby structures during status cataplecticus in a patient with narcolepsy-cataplexy who had stopped taking her medication.

Various studies indicate that neuronal activity in the VTA and nucleus accumbens increases in proportion to the magnitude of the anticipated reward. However, the people with narcolepsy-cataplexy in the Ponz study had decreased activation of the VTA when presented with greater reward. Ponz concluded that because the VTA is innervated by hypocretinergic neurons, the reduced VTA activation reflects the impact of decreased hypocretin levels in people with narcolepsy-cataplexy.

The Ponz study is the first to use fMRI to view brain activity of people with narcolepsy-cataplexy during the expectation of reward or in response to winning or losing (reward processing). Ponz is also the first to show that hypocretin may influence the reward system in humans. This interaction between hypocretinergic and dopaminergic neurons could potentially provide new avenues in treating narcolepsy.

For example, the development of drugs that directly or indirectly modulate the activity of hypocretinergic neurons that project to structures in the reward system could potentially improve alertness or counteract cataplexy. For now, more information is needed before such drugs can be developed because few studies exist concerning reduced addiction in people with narcolepsy.

Regina Patrick is a Sleep Technologist at St. Vincent Mercy Sleep Center in Toledo, OH and appears regularly in Focus journal. She can he reached at rpsgtwritr@aol.com.

by Regina Patrick RPSGT
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Title Annotation:SLEEP MEDICINE
Author:Patrick, Regina
Publication:FOCUS: Journal for Respiratory Care & Sleep Medicine
Date:May 1, 2010
Words:1476
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