Sleep and Brain Health: Commentary on a New AHA Scientific Statement

Sleep may be thought of as a dynamic state of behavior and physiology whereby there is cycling of reversible states of decreased responsiveness to the environment and motor activity ¹. Sleep is divided broadly into two distinct physiologic cycles—non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Whereas quiet wakefulness with the eyes closed is characterized by alpha (8-13 Hz) brain rhythms, high muscle tone, REMs, and irregular heart and breathing rates, NREM stages of sleep generally manifest with intermediate muscle tone and regular heart and breathing rates but vary by stage in relation to electroencephalographic and eye movement patterns (e.g., N1: low voltage 4-7 Hz and slow rolling eye movements; N2: K-complexes and 11-16 Hz sleep spindles, and few or no slow eye movements; and N3: 0.5 to 2 Hz waves and mostly no eye movements) ¹. The NREM N3 stage of sleep is believed to be a restorative period. REM sleep, on the other hand, is characterized by irregular heart and breathing rates, low muscle tone or short tonic bursts of muscle activity, penile or clitoral tumescence, and REMs. A typical night may consist of 4-6 cycles of 90-110 minutes of NREM followed by minutes of REM sleep. REM cycles tend to lengthen during the night and are associated with vivid dreams recalled upon awakening. The neuroanatomical basis of sleep is driven by the ascending reticular activating system for wakefulness and a descending inhibitory system that is sleep promoting ^1,2. Simply put, the hypothalamus plays a central role with the suprachiasmatic nucleus of the anterior hypothalamus being an important regulator of circadian rhythms, and the ventral lateral pre-optic area, an inhibitor of posterior hypothalamic arousal systems ².

Whereas many would agree that sleep is essential to physical and mental well-being, it may be undervalued as presidents and prime ministers of countries have alleged that they function on only 4 or 5 hours of sleep per night, far short of the recommended 7-9-hour target for adults and 7-8-hour target for older adults ^3,4. Despite hundreds of books to teach children and their parents good sleep hygiene at an early age in life and the many children's fantasy stories about sleep (e.g., Sleeping Beauty, Rip Van Winkle), in the United States on average almost 30% of women and men sleep less than 7 hours per night ⁵. In this issue of Stroke, Gottesman et al provide a scientific statement from the American Heart Association (AHA) on disturbances of sleep primarily among persons in mid-to-late life, their relationship to brain health, and the identification of priorities for future research in the field ⁶.

10 Key Take-Away Messages about Sleep and Brain Health

The scientific statement is well-crafted, insightful and provides practicable information about sleep disorders and disturbed sleep-in relation to brain health. Here are 10 key take-away summary messages from the statement:

1. There is accumulating evidence to support a link between sleep disorders, disturbed sleep, and compromised brain health including the occurrence of heightened stroke risk, subclinical cerebrovascular disease, and compromised cognitive outcomes stemming from vascular and neurodegenerative mechanisms.
2. A wide range of sleep disorders such as sleep-disordered breathing (e.g., obstructive sleep apnea [OSA]) and other sleep-related disturbances (e.g., insomnia, sleep fragmentation, circadian rhythm disorders, and increased sleep duration) may be associated with compromised brain health.
3. The structure (i.e., architecture) of sleep varies across the lifespan and reduced sleep quality such as greater fragmentation and light sleep, substantial reductions in the NREM N3 stage of sleep (i.e., deep sleep) and REM sleep, and sleep quantity are more prevalent at older ages and among those with certain co-morbidities (e.g., obesity).
4. NREM sleep features including slow oscillations and sleep spindles and REM sleep play complementary and overlapping roles in the process of ‘memory consolidation' whereby unstable memories are relocated from the hippocampus to the neocortex where they become durable. At the cellular and molecular levels, there is experimental evidence to support that memory consolidation occurs through a process called ‘synaptic homeostasis' during the N3 phase of sleep.
5. The brain houses a deep perivascular waste removal system, the glymphatic system, which may be driven by vascular pulsatility and vasomotion, and aided by aquaporin-4 water channels on glial end-feet that facilitate perivascular cerebrospinal fluid exchange for waste removal. Glymphatic system activity is dependent on the sleep state and is enhanced during NREM N3 sleep. Disruption of sleep (especially N3 sleep) could result in accumulation of brain waste such as beta amyloid.
6. Both short and long sleep duration have been associated with greater risk of stroke. OSA is associated with greater risk of certain forms of cerebral small vessel disease (e.g., white matter hyperintensities, lacunar infarcts) and diminished cerebral blood flow, especially in the temporal regions, which may be reversed by administration of continuous positive airway pressure (CPAP). Insomnia may be associated with microstructural changes of white matter tracts connecting subcortical nuclei to the prefrontal cortex, and less NREM N3 stage sleep is associated with higher white matter hyperintensity and lower cortical gray matter volumes.
7. There is an increased risk of dementia, mild cognitive impairment, and Alzheimer's disease with OSA which may be mediated by hypoxemia and beta amyloid and tau accumulation, neuroinflammation, and hippocampal volume loss. Greater NREM N3 stage activity and sleep efficiency may protect against accumulation of beta amyloid, whereas less NREM N3 sleep may be linked to smaller brain volumes.
8. The importance of sleep and related disturbances as foundational risks for compromised cardiovascular and brain health is highlighted by the addition of sleep to the original AHA Life's Simple 7 formula for cardiovascular health, now referred to as Life's Essential 8 ³.
9. Treatment of OSA with CPAP is promising for preservation of brain health as CPAP may improve neurological function, quality of life, depression, language after stroke, and cognition. Currently, however, the quality of evidence is suboptimal, the results mixed, and the duration of follow-up has been relatively limited.
10. >Underrepresented groups have a high risk for poor sleep quality, quantity, and sleep disorder diagnoses, and there remain substantial health inequities in relation to diagnosis and access to sleep care among these groups. There is a need to improve sleep health equity.

Limitations and Caveats

As the authors of the scientific statement point out, there are several methodologic challenges that must be considered in relation to sleep and brain health. For example, in a few studies, one cannot be certain if sleep-related symptoms occurred before the onset of disease or disease-related pathology and led to compromised brain health, or if the onset of disease and disease-related pathology was present and led to disturbances of sleep (i.e., reverse causation) ⁶. Furthermore, few studies address other study limitations include a limited number of sleep characteristics (e.g., focus on OSA or sleep duration only), issues related to disparate study methods, absence of study of biomarker panels, lack of consideration of confounding or missing information on covariates, and a focus on observational epidemiologic research but a relative absence of adequately powered randomized controlled trials ⁶.

Prospects for Screening, Prevention and Treatment

There are an estimated 50-70 million persons in the United States with chronic sleep disorders or intermittent sleep disturbances making sleep health a substantial public health challenge ¹. For example, OSA is common after stroke (70% prevalence) and in persons living at home with dementia (26% prevalence) ⁶, and the prevalence of OSA is up to 40% to 80% in persons with hypertension, heart failure, coronary artery disease, pulmonary hypertension, and atrial fibrillation ⁷. Notably, established risks for OSA include two modifiable factors, obesity and craniofacial dysmorphisms, amongst other risks ⁷. OSA stresses the body and may do so by mechanisms such as hypoxemia, autonomic dysfunction, sleep arousals and disruption, intrathoracic pressure changes, and hypercapnia. Under these adverse influences there can be inflammation, endothelial dysfunction, hypercoagulability, adverse metabolic and hemodynamic changes, and sympathetic activation culminating in cardiovascular manifestations such as hypertension, atrial fibrillation and related arrhythmias, coronary artery disease, stroke, pulmonary heart disease, and heart failure ⁷.

From a cardiovascular perspective and based on AHA guidance, it is recommended to screen for OSA in persons with resistant or poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation ⁷. For persons with New York Heart Association class II to IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment may be done, as is the case for those with tachy-brady syndrome, ventricular tachycardia or survivors of near sudden cardiac death in whom sleep apnea is suspected. Following stroke, clinical equipoise exists in relation to screening and treatment, though it is common to screen for sleep disordered breathing after stroke ⁷. Finally, people with nocturnal angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be at high risk for sleep apnea and should be considered for screening and treatment.

In an on-treatment analysis of a systematic review and meta-analysis of individual participant data of persons with cardiovascular disease and OSA, CPAP when used for >/= 4 hours/day significantly reduced the risk of recurrent cardiovascular or cerebrovascular events (hazard ratio, 0.69 [95% CI, 0.52-0.92]) ⁸. Treatment of OSA includes behavioral modifications and weight loss, if indicated, and CPAP is considered when there is severe OSA, whereas oral appliances are considered for those with mild to moderate OSA or for CPAP–intolerant patients ⁷.

In relation to prevention of cognitive impairment, it remains uncertain whether the benefits of improving sleep extend to a reduction in the risk of cognitive impairment ⁹. Whereas sleep disorders are linked to mechanisms such as hypoxemia and disruption of the brain's waste removal system, slow-wave sleep, and consolidation of memories and synaptic remodeling, the value of treatment for sleep dysfunction to improve cognitive function remains inconclusive. A meta-analysis of 16 randomized controlled trials of behavioral or medical therapy on sleep and cognition with follow-up for at least 12 weeks showed that pooled results were not indicative of a significant treatment effect for any of the primary outcomes which included the broad cognitive domains of visual processing, short- and long-term memory (and retrieval), processing speed, and reaction time ⁹. The authors concluded that there was insufficient evidence to suggest that treating sleep dysfunction improved cognitive function and that longer follow-up duration studies and those supporting biomarkers were needed ⁹. Until the veil of clinical equipoise is lifted, it is likely best for clinicians to follow standard guidance for treatment of sleep disordered breathing ⁷.