A sleepless night can be detrimental to every bodily function we have. Consistent sleep troubles or insomnia can precede dysfunction in endocrine, motivational, appetitive and metabolic, cardiovascular, neurological, immune, and other systems. However, it isn’t entirely known why sleep is so critical to optimal or even normal human performance, at least not from a mechanistic perspective. Most of the benefits of sleep are actually just assumed to be so because of what happens in cases of sleep deprivation, i.e. if attention and processing speed is impaired with sleep deprivation, but it is improved after sleeping, then those two functions must be maintained by sleep. Yet, sleep has no particular bent toward just improving cognitive ability during waking per se, but that’s just part of the overall process of what’s called meta-regulation. Beyond the more abstract reasoning for the purpose sleep are its more fundamental qualities that people have come to be familiar – sleep stages like deep and REM (rapid eye-movement), dreaming, and maybe even some neurochemistry like excitation/inhibition balance with glutamate and GABA. These properties are where much more of the ‘action’ is when it comes to doing things to improve or manipulate sleep variables, so that’s what I’ll spend most of the time discussing here.
~Meta-regulation refers to a mode of organismal oversight, where the primary regulatory agency prompts self-regulatory arrangements at more concrete levels of function, without interfering with the rules employed downstream ~
The primary agency (in my estimation) is the drive to maintain ‘preferred states’, such as hydration, satiety, safety, adaptive wakefulness, and other survival preferences, with the ultimate goal of maintaining physiological homeostasis. According to this view, sleep is not a distinct entity, with independent regulation and specific functions, but instead represents the process of meta-regulation, which in turn reflects an interaction between internal and external signals, preceding history, and current homeostatic needs. This overarching regulation provides a mechanism by which sleep can be evoked as a function of resource utilization, cognitive exertion and learning, physical activity, metabolic and other autonomic processes that occur during waking hours – a means of restoring cellular homeostasis that would otherwise devolve into organismal dysfunction without it.
If the combination of circadian and homeostatic processes promote the induction of sleep, then their absence should lead to a relatively sleep-devoid presentation. Indeed, when the master pacemaker for our 24-hr clock is destroyed (the suprachiasmatic nucleus, SCN), night-day entrainment is lost, which doesn’t actually impact sleep initiation but it does impair the finer balance of wake and sleep. On the other hand, reducing homeostatic drivers of sleep pressure with substances like caffeine, nicotine, amphetamines, and other stimulants can most certainly prolong the wake state and prevent sleep initiation. However, that can only go for so long before the sandman comes for rebound z’s. In fact, sleep debt and amount of sleep deprivation can be consistently calculated by the amount of slow-wave activity, or SWA, in the brain’s electrical encephalogram. This has led many researchers and sleep scientists to hypothesize that the main mechanism of sleep in restoring homeostatic balance and synaptic normalization is through the generation of SWA. Still, sleep didn’t evolve because us humans needed cognitive recovery from long days at school or the office. It is silly to attribute such a fundamental and ubiquitous process to relatively unique human activities. To summarize, a lack of sleep doesn’t cause systemic malfunction because of intrinsic qualities of sleep itself, rather cellular function requires turnover or regulatory resources that were spent during waking. Such cycling also promotes the most adaptive wake cycle, where optimal attention can be devoted to perceived goals and make them more likely to be achieved.
Sleep is divided into stages, and some of those stages have stages. We’re going to stick with the main two – Rapid Eye Movement (REM) and Non-REM, as well as the wake state.
It’s provoking to think that our bodies perform almost all of our functions without us even knowing about it or having any say on how it happens. You don’t have to think to breath, and you don’t have to think in order for your guts to digest food, and luckily you don’t have to volitionally govern the processes by which you wake up or stay aroused either. The state of wakefulness is initiate and maintained by a structure called the ascending reticular activating system (ARAS). The ARAS is comprised of critically important brainstem nuclei: the raphe nuclei (produce serotonin), laterodorsal tegmental and pedunculopontine nuclei (produces acetylcholine), and the locus coeruleus (produces norepinephrine). These guys release their neurotransmitters and travel to affect areas that govern attention and arousal, like the thalamus, tuberomammillary nucleus, basal forebrain, and the hypothalamus. When those areas are stimulated, their respective action is to increase arousal and decrease sleep-promoting transmission. In response to ARAS stimulation, more arousal-promoting transmitters are released that perpetuate the wake state. Other factors outside the ARAS influence arousal also, like the suprachiasmatic nucleus (SCN), which regulates the circadian rhythm, and peripheral cues like cortisol and ascending sensory information from daily activity. Something else that is particularly interesting is the role that inhibitory GABA plays in promoting a wake state: Inhibition is still a means of excitation – just indirectly. In the brainstem and hypothalamus, GABAergic projections not only maintain inhibition of sleep promoting centers, but also the disinhibition of wake promoting centers. This provides possible mechanisms for paradoxical reactions in GABA supplementation for sleep. The next component of maintaining arousal is the lateral hypothalamus, which, oddly enough, also plays an equal and opposite role in REM sleep. The lateral hypothalamus releases a peptide called orexin (or hypocretin), which from research essentially seems like the master controller of arousal. Orexin containing neurons have massive projections across the cortex and brainstem, but more importantly it is significant to note here that they innervate and excite all of the arousal promoting centers we’ve talked about thus far, which means that it is one hell of a modulatory system. So, what induces the release of orexin? The answer is homeostasis and survival. Factors such as hunger, temperature, emotion, stress, visceral changes, and anything else that requires arousal and attention mediates the sensitivity of the orexinergic system. With the amount of people that have had trouble sleeping, how many are under significant stress? Dysglycemia? Emotional unsteadiness? Poor gut function? The list goes on for possible reasons for the inability to fall asleep, but it boils down to their body telling them it isn’t safe to fall asleep.
With all these mechanisms to stay awake, you may wonder how you manage to fall asleep at all. Well, interestingly enough there are just as many mechanisms to make you fall asleep as there are to stay awake, and much of it has to do with exogenous lighting, activity level, and self-inhibiting feedback in the arousal system. Decreased lighting leads to less photic stimulation of the retinal cells that talk to the master circadian clock. This difference in stimulation is what entrains circadian rhythm via genetic regulatory factors. When neurons in the SCN are excited they start messaging cascades that result in the phosphorylation of a certain genetic transcription factor called cAMP regulatory element binding protein (CREBp) bound to a cAMP regulatory element (CRE), which further results in the transcription of so-called “clock-genes” and “period genes” that are responsible for cellular timekeeping (Ex. CLOCK1/CLOCK2 & PER1/PER2). So, physiologically, we should be getting ready for sleep when the sun goes down – imagine that. The SCN projects to an area of the hypothalamus that is highly implicated in the generation of non-REM sleep – the ventrolateral preoptic area (VLPO) – which contains GABAergic and galaninergic neurons that project to the arousal centers in the brainstem, leading to a depression of arousal and subsequent sleep. This area also receives input from surrounding hypothalamic areas, like the median preoptic nucleus, that begin firing before sleep onset (whereas the VLPO fires primarily at onset of and during sleep), suggesting that they begin the transition out of wake that allows the VLPO to exert its effects on the arousal centers. Aside from circadian control, our day-to-day activity and metabolic workload influences the transition out of wakefulness and into sleep via a chemical called adenosine. Adenosine appears to be one of the main homeostatic regulators of sleep; it is a byproduct of energy production that accumulates in extracellular fluid as the day goes on and, as you can imagine, the amount present increases with a greater metabolic demand. The mechanism of action here is through inhibitory G-protein cell signaling in wake-promoting centers and excitatory G-protein cell signaling in sleep-promoting centers. This flip-flop of excitation and inhibition is due to receptor subtypes for adenosine; this mechanism is also the reason for caffeine’s (and any other methylxanthine) arousal promoting effects because it antagonizes adenosine receptors. On that note, studies show that methylxanthine injections into mice reverse the effects of sleep deprivation on memory consolidation and learning retention, suggesting that the build-up of too much adenosine results in too much inhibition of hippocampal neurons implicated in these processes. During non-REM sleep, ensembles of neuronal networks that were previously activated from conscious experience are replayed and re-fired. This time is also when there is the trafficking of hippocampal-dependent memory into long-term memory mediated by the neocortex, which is what gives non-REM sleep the characteristic of general memory consolidation. No sleep = less retention of previous conscious experience.
This stage of sleep is also called paradoxical sleep due to its similarity in EEG recording to the wakefulness state. This is also the characteristic that is theorized to give REM sleep its domain over dreaming. While dreaming is still observed in non-REM sleep, sleep studies generally find that 80% of dream recollection occurs after being woken up from REM sleep. However, this is solely due to the increased cortical arousal present in REM sleep, not because of any intrinsic quality of REM sleep itself. Due to the high concentration of acetylcholine in the cortex and brainstem during REM sleep, the initial promoters were assumed to be the cholinergic nuclei in the brainstem and basal forebrain. As more studies were undertaken, two main nuclei were given the role of the ultimate REM modulators: the laterodorsal tegmental nucleus (LDT) and the pedunculopontine nucleus (PPT). The hypothesized responsibility for these groups is twofold, one being to activate the cortex and the other to depolarize and activate the pontine reticular formation. This activation is presumably accomplished by antagonizing the inhibiting effects of GABAergic projections from REM-off neurons, which is supported by experiments where acetylcholine and GABA are injected (separately) into REM-on regions and the effects are excitation and inhibition, respectively. Again, this phenomenon outlines a possible explanation for paradoxical effects of intervention with GABA supplements. Further studies demonstrated that a couple small groups of cells around the locus coeruleus and LDT were heavily responsible for Initiating REM sleep. These nuclei rely on non-REM sleep promoters that gradually inhibit the REM-off centers, thus allowing the transition into REM sleep. Another key player in REM sleep is the lateral hypothalamus (here’s that opposing role), which contains melanin-concentrating hormone (MCH). MCH containing neurons project to the exact same areas that orexinergic neurons do but have the opposite effects, which results in an inhibition of REM-off populations. REM sleep has been implicated in the consolidation of memories that have reward/punishment circuitry involved as well as amygdala-dependent memory. Another phenomenon that occurs during REM sleep is muscular atonia, or sleep paralysis. This process arises from glutaminergic projections to descending interneurons from the same nucleus that is proposed to be the REM-on switch. Problems here happen when there are issues with the integrity of sleep cycle, narcolepsy being one of them, where loss of the ability to maintain arousal leads to spontaneous switching of arousal state. Other disorders are associated with REM-specific malfunction and loss of atonia, which results in the acting out of dreams and random muscle twitching. Research is now finding that these REM sleep behavioral disorders have an 80% correlation with developing synucleinopathies (Lewy body dementia, Parkinson’s, multiple systems atrophy) on an average of 10 years down the road. Talk about a nice window of time for reversal and prevention.
Tools of the Trade
Now that many of the intricacies of sleep are exposed, the last frontier is to discuss the aides available to mitigate the pain of sleeplessness. In the grand scheme of things, reducing arousal is the target of therapeutic endeavors, and how that is accomplished is what differentiates the different classes of agents. It’s also worth mentioning that despite the prevalence of sleeping medications, the neurochemical approach is actually supposed to be second to cognitive behavioral therapy and changing habits around sleep.
Although good sleep hygiene is important for anyone who wants to maximize their
cognitive and physical functions during the daytime, it is the first step in treatment for people with sleep disorders including insomnia, obstructive sleep apnea and sleep disruptions caused by the side effects of drugs and medical conditions. Establishing sleep hygiene might not be the solution to all sleep problems, but it is the first step to having a healthy sleep. Many are quick to reach for some sort of sleep aid, whether prescription or over-the-counter in order to achieve that elusive good night’s sleep. This is like looking for a magic weight loss pill without putting in an effort to eat healthy and exercise. Poor sleeping choices that amass over years or even decades cause some common sleeping problems, such as insomnia. You can dramatically improve your life standards by making a few adjustments in your lifestyle and attitude. One of the most important strategies for a good night’s sleep is to get in sync with the regular sleep-wake cycle of your body. In fact, most sleep disorders surface when your sleeping schedule and your natural sleep-wake cycle sync disturbs. Melatonin is the basic substance that controls sleep-wake rhythm of the body. Having an irregular sleeping schedule will generally cause the melatonin system to throw its arms up in the air and give up. It has no idea when it should be working because your sleep and wake schedule, in addition to artificial light exposure, vary on a daily basis. Light is the primary extrinsic cue for entraining our circadian rhythm. As discussed in the section on non-REM sleep, light travels to the back of the eye where special nerve cells decipher the signal and transmit the data to the SCN. This happens even if people are visually blind. Much more could be said here regarding the effect of different wavelengths of light, intensity of light, and timing of exposure, but those are highlighted in the accompanying newsletter that focuses more on specific tactics.
Table 1: Components of sleep hygiene
Central Nervous System Depressants
Mechanistically, agonizing the GABA receptor has been the primary target since it has the role of being the primary inhibitory driver in the brain. In that space, the barbiturates are the classical hypnotic agents, although they became a victim to their own effectiveness – as one would imagine, potently reducing consciousness can become problematic. Following in the wake of barbiturates, the benzodiazepines came into the picture, offering a moderately less-potent solution to the problem of anxiety and insomnia, although still problematic with abuse, tolerance, and dependency. Next came the “Z” drugs, the non-benzodiazepine hypnotics (zolpidem, zopiclone, zaleplon), which seemed to displace risk for some of the deadlier aspects with mere insidious sleep behaviors. With some differences in pharmacology, both of these drug classes act mainly by enhancing GABAergic activity, which, broadly speaking, inhibits neuronal activity across the brain and voila! Lights out. On the nutraceutical side, several of the most common also target the GABAergic system: phenibut, GABA (duh), L-theanine, passion flower, lemon balm, and honokiol.
Questions regarding the benefits and risks of sleeping aides in this class have been prevalent, and there has been a good deal of reporting in the media regarding the dangers of these medications. From the acute incidences of overdose, sleep walking and other odd behaviors to long term risk of cognitive decline and Alzheimer’s disease. However, as with most other mainstream reporting, the truth is often exaggerated. While benzodiazepines like alprazolam, lorazepam, temazepam, and diazepam have consistently been shown to increase risk of cognitive decline, the Z drugs have maintained a relatively neutral ground. When push comes to shove, the absence of slow wave sleep with insomnia turns out to be a much greater problem when considering risk for cognitive decline.
Histamine isn’t typically thought of when it comes to wakefulness, but anyone that’s taken a dose of Benadryl for allergies knows of the drowsiness that can ensue. As mentioned in the section on wakefulness, histamine is made in the tuberomammillary nucleus in the hypothalamus. The activity of the TMN follows wakefulness, with high activity throughout the day, reduced activity in states of relaxation and rest, and nearly no activity during non-REM and REM sleep. The medications that target histamine are antagonists, meaning the block the activity of histamine in the brain. Beside the obvious ones like doxylamine (Unisom), hydroxyzine (Vistaril), diphenhydramine (Benadryl), there are other agents in the anti-depressant class that are used at lower doses because of their anti-histamine activity, like trazodone and doxepin.
The anti-histamine method of promoting sleep has its pros and cons. Generally, anti-histamines cause rebound wakefulness and distort sleep architecture, not to mention a decent incidence of residual drowsiness the morning after. That being said, there are quite a few people for whom this class really works wonders, and it is worth acknowledging its place in the toolbox. The problem really lies with using agents that are promiscuous across multiple neurotransmitter systems, so there is great individual variability in how they work to achieve the goal and minimize off target effects.
The most recently developed tools for sleep are the orexin receptor antagonists, Belsomra and Dayvigo (Quviviq to join the club soon). As noted in the wake section, orexin is as close to a conductor of this whole wake-show as we can get, and it’s a wonder why it took so long to consider this approach. To further emphasize importance of orexin, loss of orexigenic neurons in the lateral hypothalamus is the cause of narcolepsy in a majority of cases (~90%). As it turns out, reducing activity in the primary arousal generator is a homerun with insomnia. There are so many reasons for poor sleep, but a major one is racing thoughts and what I like to call “hamster-wheeling”. What keeps people awake when they actually feel tired? Why can’t they just turn off? Assuming that there isn’t a legitimate threat, it’s the inability for the homeostatic drivers of sleep to influence physiology to wind down. Enter in the orexin receptor antagonists. By reducing the wake-drive, these agents allow the natural sleep pressure to flip the non-REM sleep switch on, without forcing an inhibitory cascade to reduce consciousness outright.
So far, these agents have been without the significant side effects associated with the other sleeping aid classes. From the trials, mild headache, drowsiness, and fatigue have been the most common, but even they are not substantially different than what was seen in the placebo groups. Sleep maintenance and latency were the two major improvements, which make sense given the overall reduction in ability to stay awake. There was no dependency noted after a year of use, and although there was a return to baseline sleep metrics, there was no rebound insomnia where it was even harder to sleep. My personal experience with this class is exceedingly favorable.
Sleep hygiene methods are generally geared toward addressing the maintenance of circadian rhythm, which again, is the physiologic sleep-wake timing system. It is a externally guided process, influenced by light, sound, temperature, and other stimuli to direct organ activity according to how those signals convey time of day. Internally, though, this message is carried and contrasted by the levels of melatonin and cortisol.
Derived from serotonin, melatonin is primarily synthesized in the pineal gland after sampling the circadian cues and also the homeostatic cues for sleep onset. Melatonin then promotes sleep in two ways: first, by promoting the SCN and VLPO to increase their firing rates and enhance the ‘nighttime’ shift, and secondly by serving as a homeostatic signal to maintain sleep, with higher levels allowing greater ability to stay asleep. Methods used to increase melatonin synthesis and release typically involve practicing good sleep hygiene – optimizing lighting, sound, smell, and temperature in the sleep environment. However, as everyone probably knows melatonin is sold over the counter as a sleep aid. Effectiveness varies on the individual, but most people do find it to be effective, at least part of the time. Another round-about way of increasing melatonin comes from taking the amino acid precursor 5HTP, which becomes serotonin and melatonin. There are also two melatonin agonist medications, one of which (agomelatine) is not approved in the US but has a better profile for general insomnia. The other, ramelteon, has relatively good data for sleep onset insomnia with hardly any negative off target effects, rebound insomnia, or hangover.
In contrast to melatonin, cortisol promotes wakefulness and follows the inverse circadian pattern. Levels of cortisol are lowest when melatonin is highest, and highest when melatonin is lowest. This balance is critical because of the stress-related nature of cortisol. When people have chronically elevated cortisol, that is a message that essentially conveys that it is dangerous to sleep. Even when the person isn’t conscious of having anxious thoughts or the perception that they are stressed, cortisol can be high in the background, leading to excessive frustration and even more arousal. Stress management techniques like meditation, mindfulness, breathing techniques, and therapy can all promote a reduction and stress-induced arousal and should not be overlooked in cases of insomnia. Getting to the root of fear and anxiety is the most fundamental solution here, which of course takes a lot of work and emotional chaos. Aside from these techniques, the adaptogenic class of nutraceuticals can make a profound impact in attenuating the stress response. Herbs like ashwagandha, rhodiola, ginseng, kava, and others work on the arousal networks to modulate vigilance and reduce the intensity of perceived threats.
Well that was a lot. I hope that his blog provides insight and stimulates interest in the complex phenomenon that sleep is and how to integrate some of these tools in your own sleep life. Sleep is a difficult thing to integrate in society today. There's always so much going on personally, socially, familially, and professionally that taking ourselves off the playing field for a third of the day seems almost irresponsible. Deadlines, commitments, promises, obligations - who has time for sleep? The brain is amazing at justifying thoughts and behaviors that support its equipped predictions of how to make sure needs are met. If you're running programs deep down that prioritize proximal gratification or even conscientious future goals, then you will believe that sleep is less necessary for you than what you know is true for the rest of humanity. We time-crunch ourselves into sleep debt, push back the tides of sleep pressure with caffeine and other stimulants, and compromise long term function for relative short-term success. It really isn't worth it, but hey at least we have some tools to help us figure out how to strategically pay the piper and restore balance to the excitation/inhibition story.