Midnight Awakening: Exploring Its Potential Role in Brain Health
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Sleep is an essential biological process, fundamental to human life and well-being. For lasting improvements in sleep, the most effective approach is adopting proper sleep hygiene through adjustments in behavior and sleep habits. Recommendations for better sleep include aiming for 7–8 hours of rest, maintaining a consistent sleep-wake schedule, establishing a regular bedtime routine, engaging in regular physical activity, and practicing mindfulness or relaxation techniques. Additionally, avoiding certain substances later in the day, such as caffeine, alcohol, heavy meals, and excessive light exposure, can help prevent fragmented, low-quality sleep [1]. These sleep hygiene practices support improved sleep quality and duration, offering valuable health benefits.
Executive function, a cognitive domain essential for daily life activities, involves processes such as attention, problem-solving, planning, and working memory. Sleep deprivation, for instance, is associated with increased error rates in shift workers and a greater reliance on habitual rather than goal-directed decision-making. However, it was shown that excessive sleep can also negatively impact executive function. A large study of approximately 479,420 participants aged 38–73 found that 7 hours of sleep per night was associated with optimal executive function, assessed through computer-based tasks evaluating attention and working memory. Performance declined incrementally with each hour of sleep below or above this duration, suggesting an optimal sleep threshold [2].
Recent research suggests that sleep plays a crucial role in removing metabolic waste from the central nervous system. This discovery highlights a key biological purpose for sleep: the clearance of neurotoxic waste products that accumulate during wakefulness through a pathway known as the glymphatic system [3].
Sleep progresses through four stages: N1, N2, N3, and rapid eye movement (REM) sleep. Stages N1 through N3 constitute nonREM (NREM) sleep, with each stage representing a progressively deeper state. N3, also known as slow-wave sleep, is the deepest stage of NREM sleep. Typically, most deep sleep occurs in the first half of the night, while the latter part is primarily spent in lighter sleep and REM. REM periods are brief early in the night but lengthen as the night progresses, while time spent in deep NREM sleep decreases [4].
Brain activity patterns during REM sleep, as visualized by positron emission tomography scans, are notably different from those in NREM sleep. Quantification of brain glucose metabolism during REM sleep reveals a global activity level that closely resembles wakefulness [5].
Sleep is closely connected to many critical brain processes, including the function of the glymphatic system. The glymphatic system is an aquaporin-4-dependent, brain-wide perivascular network facilitating the clearance of metabolic waste from the brain. This novel pathway acts as a transit system between cerebrospinal fluid and interstitial solutes, aiding in the removal of brain waste products. Cerebrospinal fluid flows along the paraarterial spaces, reaching the capillary beds, where it enters the brain parenchyma and mixes with interstitial fluid. This mixture then collects metabolic waste, moving into the paravenous spaces and eventually draining into the cervical lymphatic vessels. Consequently, the glymphatic system functions similarly to the lymphatic system in other body organs.
The glymphatic system plays a crucial role during sleep, actively clearing potentially toxic neural waste products that accumulate while awake. One such waste product, amyloid-beta, shows circadian fluctuations, with levels in the cerebrospinal fluid rising during wakefulness, when the brain is highly active, and declining during sleep, particularly during slow-wave sleep [6], as shown in Figure 1. Amid slow-wave sleep, the glymphatic system operates at peak activity, whereas it is suppressed during REM sleep and wakefulness [7].
A schematic representation of the glymphatic flow during slow-wave sleep and wakefulness.
Sleeping uninterrupted for around 8 hours each night is not always feasible. Many people experience brief awakenings throughout the night. However, while short awakenings typically do not disrupt the sleep cycle, waking up for an extended period before returning to sleep may have an impact. Campbell [8] investigated the effects of brief awakenings on sleep structure in 10 participants. Following an uninterrupted baseline night, subjects were awakened once each night for durations ranging from 20 to 120 minutes at 2:30 AM over the course of the next five nights. During these intervals, participants sat quietly in a lit room before returning to uninterrupted sleep until morning. These awakenings resulted in prolonged durations of the first slow-wave sleep episode.
In discussing the brain’s high energy demands, it is notable that approximately 20% of the body’s energy is consumed by normal resting brain activity, despite the brain comprising only 2% of body weight. This significant metabolic requirement underscores the necessity for a robust clearance system to eliminate metabolic byproducts. The glymphatic system fulfills this essential role by continuously clearing waste generated by the brain’s metabolic activity. For instance, Alzheimer’s disease is associated with the gradual buildup of amyloid-beta in the brain, a process exacerbated by glymphatic dysfunction. Sleep deprivation, a known risk factor for Alzheimer’s, has been shown to increase amyloid-beta levels in the brain by disrupting glymphatic function [6]. Thus, maximizing sleep hygiene in individuals at risk for Alzheimer’s and other neurodegenerative diseases could potentially delay, if not prevent, the onset of these conditions.
The glymphatic system’s activity is most pronounced during the deepest stages of non-REM sleep, specifically slow-wave sleep [9], which suggests that, besides adequate sleep duration, quality is also crucial for optimal glymphatic function. Notably, as mentioned earlier, slow-wave sleep occurs predominantly in the first half of the sleep cycle and diminishes during the second half. However, an awakening followed by a return to sleep can increase slow-wave sleep in the latter half of the night [8]. This increase could extend the active period of the glymphatic system, thereby enhancing waste clearance from the brain.
These findings suggest that a well-timed midnight awakening of optimal duration within a consistent sleep schedule may help protect individuals at risk of neurodegenerative disorders like Alzheimer’s and Parkinson’s by supporting glymphatic function.
To the best of my knowledge, no clinical trials have yet explored this strategy, but the underlying mechanisms are promising and suggest that further investigation into glymphatic modulation through sleep hygiene practices is warranted.
Notes
The author has no potential conflicts of interest to disclose.
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