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Neurophysiological Aspects of RISP
As the preceding section shows, RISP is characterized by a complex ensemble of puzzling phenomena occurring simultaneously. In this section we attempt a scientific investigation of RISP by starting at the neurophysiological level: at this level, what are the mechanisms that induce the generalized muscle atonia while one is conscious or semi-conscious and that could explain some aspects of at least the first phase of a RISP episode (up to the perceived dissociation of a phantom body)?
We base our approach on the literature that has already been published on sleep paralysis in various medical journals and we attempt to show that at a fundamental physiological level, there exists a common denominator between ISP/RISP, normal Rapid Eye Movement (REM) sleep characteristic of the dream state, and other as yet not well understood conditions, mainly neuromuscular disorders. Physiologically, electrolytes such as Potassium (K+), Sodium (Na+), Calcium (Ca++) and Chloride (Cl¯ ) play an essential part in such bodily functions as nerve conduction and muscle contraction.
Maintaining an appropriate electrolyte balance between the blood serum (or plasma) and the intracellular medium of muscle cells and nerve cells is essential for muscle activity. An ensemble of different types of proteins that are imbedded inside the membrane of each cell act as channels and thus regulate the circulation of electrolytes between the inside of the cells and the blood serum. Each channel is specific to a given type of electrolyte, e.g., the Calcium channel regulates the circulation of Ca++ ions exclusively, and the cell membrane is thus semi-permeable and selectively permeable. Nerve conduction is essential to excite muscle cells into initiating muscle contraction and thus body motion. It involves mainly the K+ and Na+ ions, which are used to generate an action current and thus nerve conduction. At rest, nerve cells are said to be polarized : the Na+-K+ATPase pump maintains a difference of electrical potential between the blood serum and the intracellular medium, whith the blood serum positively charged (+) with respect to the cytoplasm (-) (usuallly, the potential difference is about -90 [mV] as measured from inside the cytoplasm). The concentration of Na+ ions is larger in the blood serum, while that of K+ ions is larger in the cytoplasm. When nerve cell excitation occurs, neuromediators (or neurotransmitters) such as acetylcholine, noradrenaline (a precursor of the hormone adrenaline) and thiamine (vitamin B1) modify the membrane permeability (e.g. the permeability to Na+ ions increases considerably, allowing Na+ ions to enter the cytoplasm via the Na+ channel), generating an action current and thus a depolarisation of the membrane (or depolarization wave), followed by a repolarisation and return to the initial state. In turn, Ca++ ions, as well as K+ and Na+ ions, play an essential part in muscle cell function, which is sensitive to even very small fluctuations in electrolyte concentration in the blood serum and in the intracellular medium.
In general, electrolyte balance is achieved via a very complex interplay of factors involving the number of different types of electrolytes, proper channel activity and Na+-K+ATPase pump activity, hormonal activity, and finally neuronal activity mediated by neurotransmitters in the brain. An electrolyte imbalance may occur due to a variety of causes: fluctuations in hormone secretion and hence levels in the blood serum, a mutation of a gene coding an electrolyte-specific channel, or a variety of toxins that inhibit channel activity or the activity of the Na+-K+ATPase pump. An electrolyte imbalance occurs when the difference of electrical potential between the blood serum and the intracellular medium is modified via an abnormal shift in electrolyte concentration : In the case of muscle cells, typically, the cells are (and may remain) partially depolarized (e.g., to -50 [mV]), but sufficiently so to prevent membrane excitation by the action current transmitted to them by the nerves. As a result, muscle contraction is compromised and partial to complete muscle atonia occurs. In the case of nerve cells, and when considering REM sleep, the neural activities producing the generalized muscle atonia that is typical of REM sleep originate mainly in the pons region of the brainstem and involve the neurotransmitter acetylcholine [2], that is, cholinergic "REM sleep-on" neurons in the brainstem are activated, while monoaminergic (serotonin or noradrenalin) "REM sleep-off" neurons cease to fire [26c]. Motoneurons in the brainstem and in the spinal cord are inhibited and a profound atonia occurs, which results in an almost complete paralysis of striated muscles. The activity of brainstem serotonin "REM sleep-off" neurons is regulated by the hormone melatonin, discovered to be the principal hormone of the pineal gland in 1963. Qualified by Sandik [26c] as a "master hormone" involved in the control of circadian rhythms and other biological functions, melatonin reaches its lowest plasma levels during REM sleep when the serotonin neurons whose activity it regulates are inhibited, thus suggesting a causal relationship between the inhibition of melatonin secretion during REM sleep and the development of REM sleep atonia [26c]. However, still little is known about the influence of the pineal gland on motor control (recently it was suggested that not only the pineal gland, but also the suprachiasmic nuclei are involved in circadian rythms). As indicated above, REM sleep atonia is directly caused by inhibitory postsynaptic potentials in spinal motoneurons. The biochemistry of "REM-sleep on" and "REM-sleep off" neurons is still not well understood and largely under investigation, so that the exact coupling mechanisms with melatonin secretion involved during REM sleep that induce the muscle atonia are not clearly known. We may conjecture that a low concentration of melatonin in the blood serum would prevent the depolarization current to occur in the nerves and consequently prevent muscle cell excitation. But given the present state of knowledge on REM sleep, the role of melatonin in inducing the REM sleep atonia should not be overestimated. It should be mentioned that body paralysis during REM sleep is a normal, protective mechanism that prevents the sleeper from "acting out" his/her dreams.
Sleep paralysis (whether RISP or ISP) is a pathological condition in the sense that there is a marked dissociation between the level of alertness and the muscle atonia that often occurs in sleep onset REM sleep periods (SOREMPs) [2]. In other words, essentially abnormal REM sleep conditions occur in that a certain level of alertness (or awareness) is retained despite the muscle atonia characteristic of REM sleep that would be induced by a low concentration of melatonin in the blood serum. SOREMPs are characterized by vivid hypnagogic/hypnopompic hallucinations that accompany the state of sleep paralysis (the terms "hypnagogic" and "hypnopompic" refer to hallucinations that take place while drifting to sleep and during the process of waking up respectively). Both sleep paralysis and SOREMPs, which together are the basis of RISP episodes, are ancillary symptoms of a rare condition (with an estimated incidence of about 0.05% of the general population) called narcolepsy. The narcoleptic "tetrad" includes also cataplexy (a sudden and sometimes long-lasting loss of muscle tone) and as a main symptom excessive daytime sleepiness [2]. It is caused by a genetic defect, which has been localized to the short arm of chromosome 6 [2a], but the chromosomal localizations of the genetic basis for RISP, if there is one, are not known at present. It should be pointed out that although narcoleptic patients generally experience RISP episodes, RISP affects also individuals who do not have narcolepsy. As the muscular atonia of REM sleep is physiological ly and pharmacologically indistinguishable from cataplexy, it is possible that the pineal gland also influences the development of cataplexy [26c]. As stated in [2], SOREMPs may occur when some of the neural mechanisms producing wakefulness and/or "non-REM" sleep that normally inhibit the occurrence of REM sleep are abnormally weak (the activity of serotonin neurons would be abnormally decreased), or when neural mechanisms facilitating the occurrence of REM sleep are hypersensistive or hyperactive (hyperactivity of cholinergic neurons), or both. This condition might be due to an anomaly of the control mechanisms that determine the timing of REM activity and somatomotor inhibition and excitation. During normal REM sleep, the brain is highly activated, but cerebral responses to somatosensory stimulation disappear, while during sleep paralysis/SOREMPs, there is no such cerebral blocking of exteroceptive stimulation [26d]. We conjecture that sleep paralysis and SOREMPs could be caused by an inappropriate *timing* of the inhibition of melatonin secretion and consequently, of low melatonin plasma levels. At the physiological level, nerve cells could not be depolarized despite the relative level of alertness, and thus the low concentration of melatonin in the blood serum at an inappropriate time would cause a transient "imbalance" or inappropriate concentrations of the K+ and Na+ electrolytes on both sides of the nerve cell membrane during sleep paralysis accompanied (or not) by SOREMPs. At a neurological level, a somatosensory input that during normal REM sleep would be blocked by the brain may actually reach the brain during sleep paralysis/SOREMPs episodes, and may be a cause of the unusual sensory experiences (feeling of electricity throughout the body, hallucinations that would in fact be REM sleep imagery, etc...) occurring during such episodes.
In spite of many studies and published reports on REM sleep, as well as on sleep paralysis and SOREMPs, we are still far from a complete understanding of the pathophysiological mechanisms of ISP/RISP, let alone of the physiological mechanisms producing muscle atonia in REM sleep, though it is apparent that these mechanisms are closely related. The conjectures presented in the last two paragraphs cannot possibly, only by themselves, account for the complexity of a full-blown RISP episode such as the typical episode whose profile was described in Section 2. However, there seems to be a clear relationship between RISP and narcolepsy in terms of symptomology, and future advances at the molecular, genetic and neurophysiological levels might not only provide a more comprehensive picture of narcolepsy but also help to better understand the mechanisms and the causes specific to RISP. Also, the study of the possible connections between ISP/RISP and other specific (mainly neuromuscular) conditions might help in the future to better understand some processes inherent to ISP/RISP.
First, the so-called "Periodic Paralyses", that include, but are not limited to, (familial) Hypokalemic Periodic paralysis (HypoKPP), (familial) Hyperkalemic periodic paralysis (HyperKPP) and Hypokalemic Thyrotoxic Periodic Paralysis (HypoKTPP) (linked to an overactivity of the thyroid gland that induces the hypokalemia) are generally considered by the scientific community to have no relationship to sleep paralysis and RISP, yet they are known to closely mimic sleep paralysis. HypoKPP is an autosomal dominant muscle disorder caused by at least three different possible genetic mutations of the gene coding the Ca++ voltage-gated channel in muscle cell membranes, which is characterized by episodic attacks of muscle weakness and/or rigid or flaccid paralysis associated with an abnormal decrease in blood serum K+ levels [26e]. HyperKPP is also an autosomal dominant muscle disorder, caused by several different possible genetic mutations of the gene coding the Na+ channel, also in muscle cell membranes, and which produces episodes of generalized flaccid weakness and/or paralysis in response to abnormally elevated levels of blood serum K+ [26f]. Both are part of a spectrum of rare muscular disorders (with an estimated average incidence of 0.001%) called "channelopathies" [10]. At the physiological level, it is, as we mentioned above, an intrinsic partial depolarization of muscle cells probably due to the abnormally low/high K+ levels in the blood serum that inhibits their excitability by the nerves and leads to attacks of muscle weakness or of paralysis. In this sense, these forms of periodic paralysis are caused by an intrinsic electrolyte imbalance. Concerning HypoKPP, the only medical information we could find in terms of differential diagnosis in relation with sleep paralysis is that, according to "The International Classification of Sleep Disorders: Diagnostic and Coding Manual," Rochester, MN: American Sleep Disorders Association, The Diagnostic Classification Steering Committee (Thorpy, 1990)", hypokalemic periodic paralysis has to be excluded in order to diagnose sleep paralysis. However, more recently, the first case of a patient associating HyperKPP with multiple SOREMPs was medically documented, by Iranzo et al. in [10a], who conclude that in this case, "SOREMPs may be explained by an increased extracellular potassium conductance related to HyperKPP." Could two conditions with a seemingly different etiology (namely, HyperKPP and RISP, or intrinsic muscle cell unexcitability due to HyperKPP and the polarization of nerve cells due to low levels of melatonin in the blood during SOREMPs or RISP respectively) both generate a similar symptomoly in terms of SOREMPs ? Such a question begs for more research in the possible -but not necessarily probable- connections between some forms of the PPs and RISP. Sleep paralysis/SOREMPs (or RISP) may indeed be a symptom of a variety of different pathophysiological phenomena.More research also on the coupling between nerve conduction and the process of muscle contraction could help to understand such possible connections. Of course, one can experience sleep paralysis and SOREMPs without having any of the periodic paralyses, and periodic paralysis patients may not experience sleep paralysis or SOREMPs; moreoever, the case presented by Iranzo et al. is isolated and therefore, it is not statistically significant. However, a recent survey conducted by G. Buzzi [26g] on a population of 35 adults having being diagnosed with either HypoKPP or HyperKPP and who are members of an electronic mailing list specifically dedicated to patients affected with various forms of periodic paralysis [26h] lends some credence to the possibility that a REM sleep disorder such as RISP is present in some patients with HypoKPP or HyperKPP : 31.4% of the respondents to the survey have sleep paralysis "at least sometimes" (8.6% "often or always"), 65.7% of the respondents have hypnogogic/hypnopompic hallucinations characteristic of SOREMPs "at least sometimes" (25.7% "often or always") [26i]; moreover, 97.1% of the respondents complain of excessive daytime sleepiness "at least sometimes" (45.7% "often or always") [26h], which, as we mentioned before, is the main symptom of narcolepsy. According to G. Buzzi, there are no statistically significant differences between respondents with HypoKPP and those with HyperKPP. The percentages for sleep paralysis, and especially for SOREMPs are significantly higher than those for the general population, thus warranting further research. Finally, a majority of the respondents also have recurrent migraines. Interestingly, migraines (with or without headaches) are believed to result from a genetic mutation of a (brain-specific) Ca++ channel-coding gene and hence may also be a channelopathy, involving auditory and vestibular symptoms [13a-13c].
Secondly, there seems to be a significant relationship between ISP/RISP and anxiety disorders [27]: as reported in [8], in the case of anxiety disorders with agoraphobia, it was found that the percentage of patients with sleep paralysis was 40% higher than that obtained in a control group not suffering from an anxiety disorder (20%). Anxiety is a neurocognitive event involving both psychological processes and physical processes, or some might prefer to call these somatic processes. Anxiety or panic, being somewhere near the extreme end of the emotional scale results in the release of potent signal molecules that trigger all kinds of physical events. It is well known that a variety of neurological and cognitive events may be induced by transient fluctuations of electrolytes.
This leads us to conjecture that a genetic basis, in addition to environmental factors, may thus predispose to RISP and that is is not impossible that the occurrence of RISP may be linked to some channelopathies. These hypotheses may be supported by the fact that RISP is generally familial [1], [20].
We conclude that a possible common denominator between ISP/RISP and those other conditions at the physiological level may well be at least transient fluctuations of electrolytes (or inappropriate concentrations of electrolytes on either sides of nerve or muscle cell membranes), and that it is possible for an individual to have a cluster of disorders rather than a single disorder, with associated genetic defects (or mutations). Finally, we hypothesize that a condition known as Sudden Unexplained Nocturnal Death Syndrome (SUNDS) might be an extreme case of sleep paralysis [11-13]. SUNDS is a very rare condition that is prevalent in southeast Asia (mainly in northeast Thailand and in Laos), interestingly in populations where HypoKPP is endemic (but generally induced by environmental factors), and which affects mostly young adult males. The death is a result of a myocardial infarction, the sleepers are lying in a supine position (on their back), experience strong breathing difficulties [28] and there appears to be little or no movement or struggle in the dying process of SUNDS. Many cases are reported to have a fixed and "terrified" expression on their face. One explanation could be that the muscle atonia during a sleep paralysis episode would become so severe that potentially lethal cardiac arrhythmias and respiratory failure would occur. Such muscle atonia would originate from a severe hypokalemia occurring in the middle of the night, as speculated in [11]. Once again, one can see possible relationships at a physiological level between sleep paralysis (ISP/RISP), some of the periodic paralyses and SUNDS in terms of electrolytes.
To conclude this section, we have attempted to investigate the relationship between the generalized muscle atonia and the first phase of a RISP episode from a neurophysiological viewpoint. It is however very difficult to determine the relationship between the muscle atonia, the awareness and the REM-like "hallucinations" that are characteristic of a RISP episode since so little research has been conducted on this specific subject until now. In the next section we attempt to describe some neurocognitive processes involved in the hallucinations and the possible relationships between the second phase of a RISP episode and lucid dreaming.
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