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Neurology Today:
doi: 10.1097/01.NT.0000419607.62504.13
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Unraveling the Mechanisms of REM Sleep Paralysis — With Insights Into Other Neurodegenerative Disorders

Robinson, Richard

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ARTICLE IN BRIEF

A new study shows that REM sleep atonia requires not only glycinergic but also gamma-aminobutyric acid inhibition. The findings are important both for the fundamental insight they provide into the mechanism of sleep paralysis, and because abnormalities of REM sleep often herald Parkinson's disease or Lewy body dementia.

Rapid eye movement (REM) sleep has long been an intriguing mystery: for long stretches every night, we enter a state of complete muscle paralysis. At the same time, brain activity increases, and for part of that time, we dream. While the “why” of REM sleep is still largely mysterious, the “how” is now a little clearer, thanks to a July 18 study in the Journal of Neuroscience showing that REM sleep atonia requires not only glycinergic but also gamma-aminobutyric acid (GABA) inhibition. The findings are important both for the fundamental insight they provide into the mechanism of sleep paralysis, and because abnormalities of REM sleep often herald Parkinson's disease (PD) or Lewy body dementia.

“We've had a very incomplete understanding of the mechanisms that trigger the motor paralysis” of REM sleep, said the study's principal investigator, John Peever, PhD, associate professor of cell and systems biology at the University of Toronto. A series of experiments beginning in the 1970s implicated the neurotransmitter glycine in hyperpolarizing motor neurons during REM sleep, which, Dr. Peever said, led to the standard model of glycine “singlehandedly” being responsible for REM sleep paralysis. More recently, though, it was shown by Dr. Peever and others that the blockade of glycine receptors alone was insufficient to prevent REM paralysis, suggesting that other inhibitory systems were also at work.

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STUDY METHODS

To find out what those might be, he and coinvestigator Patricia Brooks, a PhD candidate also at the University of Toronto, implanted electroencephalography electrodes into the cortex, a microdialysis probe into the trigeminal motor pool, and electromyography electrodes into the masseter muscles of rats, allowing them to determine REM-related cortical activity and muscle paralysis during sleep in response to drugs affecting various neurotransmitter systems.

“We focused on the jaw muscle because it is clinically relevant for patients who have bruxism or obstructive sleep apnea,” Dr. Peever said, noting that relaxation of the jaw muscle contributes to airway obstruction, which is particularly significant during REM sleep.

Using the microdialysis probe, they injected bicuculline and strychnine, antagonists of ionotropic GABA-A and glycine receptors, into the trigeminal nucleus during REM sleep, but found that they did not reverse muscle paralysis. Next they applied a GABA-B receptor antagonist alone, and found that it, too, had no significant effect on muscle tone.

Based on these results, Dr. Peever said, “We hypothesized that REM motor inhibition may be driven by mechanisms that require both metabotropic GABA-B and ionotropic GABA-A and glycine receptors.” Both types of receptors respond to GABA. Ionotropic receptors react quickly, opening chloride channels, while metabotropic receptors respond more slowly, using a second messenger to open potassium channels. Both act to hyperpolarize the membrane.

When antagonists to all three receptors were applied during REM sleep, masseter muscle tone increased to the level observed during normal non-REM sleep. “It requires all three to be effective,” Dr. Peever said. But, he noted, there are almost certainly yet more systems at work, since even antagonism of these three receptors couldn't elevate muscle tone to that seen in wakefulness.

“The reality is that we're looking at two transmitters [GABA and glycine] and three receptors, and that is an incredibly incomplete picture of the commands that arrive on motor neurons every millisecond. There is excitation, and there may be other sources of inhibition. We show that blocking those inhibitory drives reverses paralysis, but that doesn't mean that other mechanisms under other circumstances aren't playing a significant role.”

Importantly, though, this work indicates that the standard view that glycine alone is responsible for REM paralysis is incorrect, he said. “I think this is a particularly important point, because neurologists and medical students learn unequivocally from medical textbooks that glycine shuts off motor neurons and triggers REM sleep paralysis. Our data do not support this.”

“GABA and glycine are almost ubiquitously packaged and released together,” he noted, which may be one reason GABA's role remained obscured. But that co-release strengthens the logic that they should be acting together, he said.

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EXPERT COMMENTARY

“These results are very exciting,” said Mark Mahowald, MD, professor of neurology at the University of Minnesota and director of the Minnesota Regional Sleep Disorders Center in Minneapolis. “I think the studies are elegantly done, and they appear to show that REM muscle atonia is very complicated and involves multiple different neurotransmitters.”

The clinical importance of the work, he said, is that REM sleep abnormalities, including REM sleep behavior disorder (RBD), occur in a variety of disorders. [See “REM Sleep Behavior Disorder: Clinical Symptoms.”] “This may help explain why REM sleep behavior disorder is seen in a number of different conditions, because different abnormalities at different levels of the neural axis involving different combinations of neurotransmitters might end up with the same clinical manifestations.”

The most obvious adaptive reason for REM sleep atonia, he noted, was to prevent us from acting out our dreams. In RBD, the loss of muscle paralysis can cause injury to the sleeping person or bed partner. Recently, RBD has been strongly linked with a later risk of PD.

“When this disorder was first identified in the 1980s, it was felt to be just a curious observation,” Dr. Mahowald said. “But as it was followed over time, it became apparent that now probably well over 50 percent of these individuals eventually go on to develop PD or dementia with Lewy bodies. The sleep disorders may be the very first manifestations of Parkinson's disease.”

About one third of PD patients report symptoms of RBD at the time of diagnosis of their Parkinson's disease, he said. “This underscores the fact that PD is much more complicated than most people think it is.”

The neuropathological connection between RBD and PD is still a matter of investigation, but the results of the current study may shed some light on that connection, Dr. Mahowald said. They are also likely to lead to better symptomatic therapies for RBD, and a better understanding of the mechanisms of current therapies, which include clonazepam and melatonin. “No one has any idea” how these therapies work, he said.

Dr. Mahowald noted that one of the most common causes of RBD is antidepressant use, particularly with selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Learning more about why these medications cause RBD, in combination with the new appreciation of the role of the GABAergic system, “is going to teach us even more about the mechanisms of sleep.”

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REM SLEEP BEHAVIOR DISORDER: CLINICAL SYMPTOMS

REM sleep behavior disorder (RBD) is characterized by loss of muscle atonia during REM sleep. Individuals experiencing RBD often “act out” their dreams, leading to movements and vocalizations that may be dramatic and even violent. These may injure both the individual experiencing them and their bed partner. RBD is diagnosed during a formal sleep study, through detection of abnormal muscle activity during REM sleep. The majority of patients are male, with onset typically in the sixth or seventh decade.

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REFERENCES:

• Brooks PL, Peever JH. Identification of the transmitter and receptor mechanisms responsible for REM sleep paralysis. J Neurosci 2012;32(29):9785–9795.

• Go to http://bit.ly/MDmVt3 for past coverage of REM sleep behavior disorder in Neurology Today.

©2012 American Academy of Neurology

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