Unlocking Sleep's Secrets: How the Brain Clears Itself During NREM Sleep

By Ethan Sun,

Choate Rosemary Hall, CT

When faced with deadlines and impossible workloads, sleep deprivation is often dismissed as an inconvenience, but its consequences are more than just fatigue. Chronic lack of sleep has been linked to decreased cognitive capabilities, weakened immunity, and even an increased risk of neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Part of the reason behind these consequences is the brain’s inability to clear toxic waste products associated with neurodegeneration when a person is sleep-deprived. Thus, recent research efforts have focused on new ways to optimize sleep for brain health.

There are many current therapies for sleep deprivation. Cognitive Behavioral Therapy for Insomnia, or CBT-I, focuses on improving sleep hygiene and modifying sleep habits without the need for medication. Trained therapists focus on relaxation techniques or addressing anxiety related to sleep. However, this technique requires long-term commitment and trained therapists, which may not be affordable or accessible to everyone. Medications are also commonly used, like benzodiazepines or zolpidem, to induce sleep. These medications enhance the activity of neurotransmitters like GABA and help people fall asleep faster. However, they do not lead to improved sleep quality and are associated with many side effects as well as drug dependency.

Currently, strategies for preventing neurodegeneration primarily focus on maintaining healthy lifestyles. For example, regular exercise, balanced diets composed of antioxidants and omega-3 fatty acids, and engaging in cognitively stimulating activities like learning new skills. However, new research shows that sleep plays a direct role in preventing neurodegeneration by clearing toxins from the brain through the glymphatic system.

The glymphatic system is a waste-clearing system in the brain that operates primarily during sleep. It relies on cerebrospinal fluid, which occupies space inside and around the brain and the spinal cord, to flush out toxins (waste produced by the cells in the brain) from the brain, including beta-amyloid and tau proteins, both of which are associated with Alzheimer’s disease. During deep non-REM sleep, neurons shrink, allowing for increased cerebrospinal fluid flow and the enhanced removal of toxins. Thus, without enough sleep, the waste excretion process is less effective, causing the accumulation of neurotoxins and potentially worsening neurodegenerative diseases.

Using a new technique called flow fiber photometry, researchers tracked norepinephrine levels, blood, and cerebrospinal fluid flow in mice. They found that synchronized oscillations of norepinephrine drive glymphatic clearance. Norepinephrine is a neurotransmitter that plays a role in wake and arousal, and its levels fluctuate during sleep, oscillating at a frequency of 0.02 Hz or one cycle every 50 seconds. This creates waves that expand or contract blood vessels (as norepinephrine levels rise, blood vessels constrict, allowing fluids to flow into the brain tissue), acting as a pump, driving cerebrospinal fluid into the brain for waste removal. The frequency and amplitude of norepinephrine oscillations during NREM sleep were found to be strong predictors of glymphatic clearance efficiency. Therefore, sleep quality, not just duration, is crucial for brain health.

These findings suggest changes in the future of sleep therapy and neurodegenerative disease prevention.

Firstly, sleep medications may cause more harm than good. While sleep medications like zolpidem can help individuals fall asleep, they may also suppress norepinephrine oscillations, thus reducing the efficiency of the glymphatic system by interfering with the natural fluctuations needed to push cerebrospinal fluid flow. Research has shown that zolpidem not only diminishes norepinephrine oscillations but also suppresses glymphatic flow by up to 40%. This means that prolonged use of sleep medications might increase the risk of neurodegenerative diseases due to the brain’s inability to properly clear toxins using the glymphatic clearance system. It also means that sleep medications may actually cause worse sleep quality overall. Instead, research should be invested into drugs that can induce sleep without suppressing norepinephrine oscillations, leading to safer alternatives to current sleep medications.

In addition, future treatments for sleep and neurodegenerative disease prevention could also target the glymphatic system and aid norepinephrine oscillation. For example, perhaps artificial methods to constrict and relax blood vessels periodically could stimulate cerebrospinal fluid flow, enhancing glymphatic clearance. There could also be other techniques, like transcranial magnetic stimulation, that can potentially be used to enhance the glymphatic clearance system during NREM sleep. Additionally, optimizing sleep schedules and sleep hygiene to maximize NREM could be a useful strategy for maintaining cognitive health.

Lastly, there are also new insights into the prevention of neurodegenerative diseases like Alzheimer’s or Parkinson’s. The accumulation of toxic proteins may be due to an inability or impairment of the glymphatic clearance system, and this provides new targets for potential treatment and prevention options. If methods can restore drainage of neurotoxins during sleep, perhaps sleep can be used as a way to help mitigate Alzheimer's disease and other neurodegenerative diseases. Adequate, high-quality sleep may also be key to preventing the development of neurodegenerative diseases.

Sleep is a process that remains shrouded in some mystery. However, as understanding of the restorative functions of sleep evolves, it is clear that the quality of sleep is crucial to maintaining brain health. New research is creating room for new therapies, prevention methods and treatments for neurodegenerative diseases, but also showing the risks of current pharmacological interventions. Perhaps all it takes is just proper rest after all.

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