August 2, 2017

The case for a new sleep parameter; parasympathetic tone. (ME/CFS, POTS, and HRV)

Introduction

Classic sleep parameters involve several sleep stages. These stages are identifiable via their unique brainwave patterns. Namely, rapid eye movement sleep (REM sleep), light sleep (stage 1 and 2 sleep), and deep sleep (stage 3, previously divided into stages 3 and 4). Stages 1-3 are also grouped as non-REM sleep (NREM sleep). The time spent in, and distribution of, each sleep type during the night is known as sleep architecture (not elaborated in this paper). Sleep architecture is the classical measure of objective sleep parameters.

For the purposes of this paper, I will be writing mostly about deep sleep (stage 3). Deep sleep, also known as slow wave sleep (SWS), is characterized by slow, delta waves. These are long, lazy waves that are a result of a large number of neurons firing synchronously. Additionally, the brains waste clearance system, the glymphatic system, is active during deep sleep.

Discussion

Each sleep stage has been linked to specific cognitive functions. What's more, manipulating brainwaves can alter cognitive functions. For example, using a polysomnographic brain-computer interface to precisely time audio pulses to enhance slow wave amplitude can enhance memory consolidation compared to both no audio and mistimed audio, (1).

However, there is a sleep parameter that I think has been largely neglected; autonomic tone. The autonomic nervous system (ANS) consists of the sympathetic nervous system (SNS) and the parasympathetic nervous system (PSNS). While the SNS is characterized by "fight or flight" functions, the PSNS is characterized by "rest and digest" functions. By extension, it is reasonable to predict that the PSNS plays a role in sleep. Likewise, it would be expected that SNS activation would disrupt sleep.

Indeed, incorporating a measure of autonomic tone (namely, heart rate variability) can radically increase the predictive power of memory consolidation during sleep compared to brainwaves alone, (2). Heart rate variability (HRV) is a measure of change in heart rate from beat to beat. The heart rate changes rhythmically through the breathing cycle; increasing during inhalation and decreasing during exhalation. Since the heart rate is controlled by the ANS, heart rate and heart electrical parameters can be used as a measure of SNS and PSNS activation. High HRV indicates high parasympathetic tone.

One disease that is associated with by autonomic dysfunction and has an obvious connection to sleep is chronic fatigue syndrome (CFS). CFS is characterized by extreme fatigue, malaise (particularly post-exertional malaise), and unrefreshing sleep. What's more, CFS is associated with pain such as sore throat, headaches, and fibromyalgia (FM; translates to muscle pain). In fact, CFS is also called myalgic encephalitis (ME), which translates to muscle pain (myalgic) and brain inflammation (encephalitis). The condition is often referred to as "ME/CFS". All of these symptoms, as I will argue, can be explained by disrupted sleep. Specifically, disrupted deep sleep.

Sustained SWS disruption results in pain. Experimentally, disrupting SWS causes muscle pain, (3,4). Likewise, sensitivity to pain in general is increased, (5-8). Recovery sleep restores pain sensitivity, (5,9). Therefore, we would expect to find disrupted sleep in ME/CFS. Indeed, that is exactly what we find, (6,10-12). In particular, we find that alpha waves intrude into NREM sleep, including the delta waves of SWS, (6,10,11,13). However, this feature is not exclusive to ME/CFS. For example, it can also be found in rheumatoid arthritis and depression, (6,14,15).

Even though its possible to identify ME/CFS from brainwave patterns, it is, as I will argue, a downstream symptom of autonomic tone. ME/CFS patients can present with other sleep disorders in absence of alpha intrusions, (6,16-18). Thus, alpha intrusions are neither sufficient nor necessary for ME/CFS. Alpha intrusions can, nevertheless, be a marker. However, reduced HRV is a much better predictor, (18-22). This cardiac parameter indicates a decrease in parasympathetic tone and an increase in sympathetic tone.

The cause of reduced HRV in ME/CFS appears to be reduced blood volume and/or small heart syndrome, (23-26). On the face of it, reduced blood volume should result in the appearance of a smaller heart via reduced cardiac filling. However, the heart could still actually be smaller. In either case, the result is the same; reduced stroke volume (blood pumped per heartbeat) and reduced cardiac index. This necessitates an increase in sympathetic tone and decrease in parasympathetic tone in order to maintain blood pressure. Indeed, the absence of hypertension (high blood pressure) despite the autonomic shift in ME/CFS can, in and of itself, be used as an argument for reduced stroke volume. Stroke volume itself correlates with fatigue even in healthy subjects, (27).

The downstream effects of this results in several interesting downstream markers. For example, reduced blood pressure variability, elevated diastolic blood pressure during sleep, and hypotension (low blood pressure) during a tilt-table test, (20,28,29). Additionally, ME/CFS is associated with either orthostatic (standing upright) hypotension, or orthostatic tachycardia (accelerated heart rate), (30-32). Postural orthostatic tachycardia syndrome (POTS) is a condition where there is an excessive increase in heart rate while standing up. This is the result of reduced preload and stroke volume because blood that is attempting to return to the heart is being pulled to the lower part of the body by gravity. Naturally, the increased heart rate is for maintaining blood pressure, and failure to increase heart rate results in hypotension, (29,30). Reduced pulse pressure can also be observed, (31).

Conclusions

ME/CFS is a sleep disorder that ultimately appears to be a result of a shift towards increased sympathetic tone and decreased parasympathetic tone. This, in turn,  is the result of reduced stroke volume. Note, however, that the sympathetic nervous system increases stroke volume, so the specific claim is that ME/CFS patients have reduced stroke volume proportional to their sympathetic tone, not necessarily reduced absolute stroke volume (though absolute reductions might also be expected).

Convergent evidence indicates that autonomic activity is important in sleep. Autonomic activity is both an independent sleep parameter and a cause of disrupted sleep architecture/microarchitecture. In particular, HRV is a good independent marker of sleep quality.

Additional notes

Brain inflammation in ME/CFS is easily explained by impairment of sleep's waste clearance. However, given how recently the glymphatic system was discovered, I'm not aware of any research directly linking them. Nevertheless, anesthetics that produce slow waves also activate the glymphatic system, (33). Therefore, it is reasonable to surmise that alpha intrusions would impair glymphatic function and lead to downstream inflammation.

At least one analysis attempts to refute the relevance of alpha intrusions into delta waves, (34). It said that there is often confusion between tonic and phasic alpha frequency activity patterns. However, the remainder of their expertise is invalidated when they claim that the brain is the only organ that is affected by sleep. Given immense amounts of research, this is an absurd claim. In fact, one would be hard pressed to find an organ that isn't affected by sleep, especially if we count indirect factors. Insulin resistance, for example, is an experimentally inducible result of sleep deprivation that directly impacts muscle.

I discluded two interventional studies that are less consistent with SWS deprivation increasing pain, (35,36). One suggests an associated between SWS and sleep duration, so the results may be due to recovery sleep, (35). The other did suggest an insignificant lowered pain thresholds in the morning in the experimental group, (36). Given the short duration of these studies, the outcome will be dramatically affected by the state of the subjects coming into the study (e.g. sleep debt). Since false negatives are easier than false positives in statistics (via relatively poor controls and/or high population variability), these are not sufficient evidence against the claim.

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