The Daily Dose • Thursday, June 10, 2021

Convergent Rhythms: Sleep, Anesthesia and Health

Christian S. Guay, MD

For most organisms, sleep is necessary for life and a key determinant of health. From the blood brain barrier to Alzheimer disease and convergent neural circuitry, this session,  “Sleep and Health,” held May 14 at the AUA 2021 Annual Meeting, featured a multidisciplinary group of experts exploring the many interfaces of sleep, anesthesia and health.

In this combined Scientific Advisory Board and President’s Session, a chronobiologist, a sleep medicine physician and an anesthesiologist explored the multifaceted interface of sleep and health. Miriam Treggiari, MD, PhD, MPH, from Yale School of Medicine, served as the moderator for this session and introduced the speakers.

A molecular biologist by training, Amita Sehgal, PhD, from Perelman School of Medicine at University of Pennsylvania, studies circadian clocks. By driving rhythmic gene expression, these clocks influence most physiological processes, and their disruption increases susceptibility to disease. After a general discussion of circadian rhythms and sleep pressure, Dr. Sehgal focused on the rhythms regulating blood brain barrier (BBB) permeability and their relevance to health. Experiments in drosophila and mice have revealed that endocytosis and efflux transporters exhibit circadian rhythmicity. In waking states, magnesium-regulated efflux transporters actively pump small lipophilic molecules out of the brain, whereas during sleep these transporters are down-regulated by circadian clocks driving gene expression. These findings have important clinical implications for medications that rely on active transport into the brain. Dr. Sehgal’s lab has thus far focused on phenytoin, and it remains unknown whether anesthetics are susceptible to this rhythmic transport across the BBB. In contrast to efflux transporters that are up-regulated during waking states, endocytosis out of the brain is up-regulated during sleep. Interestingly, this rhythm appears to be strongly linked to homeostatic sleep pressure so that sleep-deprived organisms will exhibit increased endocytosis even if they are allowed to sleep during their usual waking hours. Dr. Sehgal and her colleagues contend that endocytosis-mediated transport out of the brain during sleep states is important for the clearance of metabolic waste in conjunction with the glymphatic system. Whether anesthetics can enhance these mechanisms remains an area of future investigation.

Building on Dr. Sehgal’s discussion of rhythmic neurometabolic processes, Yo-El Ju, MD, from Washington University in St. Louis, presented data on the circadian clearance of amyloid beta (AB), one of the central molecules in the pathogenesis of Alzheimer disease (AD). The concept of preclinical AD has recently emerged with advances in biomarker research showing that AB plaques start accumulating years before the onset of clinical signs of dementia. Furthermore, sleep appears to play a central role in this process: chronic sleep deprivation leads to increased AB concentrations in the CNS and poor sleepers identified via actigraphy exhibit a higher prevalence of preclinical AD. Dr. Ju and her colleague’s research points to slow wave sleep as a major mediator of this relationship, suggesting that slow EEG oscillations are associated with less AB release from neurons and increased clearance via the glymphatic system. If this is indeed a causal link, slow wave sleep enhancement via pharmacological and nonpharmacological means may represent a therapeutic target to delay or even prevent the onset of AD. The association of postoperative delirium and postoperative cognitive dysfunction with subsequent dementia is an active area of investigation and could lead to the early identification of patients who would benefit from interventions enhancing slow-wave sleep.

Famed anesthesiologist and neuroscientist Max Kelz, MD, PhD, from Perelman School of Medicine at University of Pennsylvania, wrapped up this multidisciplinary session with a data-driven presentation on how mechanisms of sleep and anesthesia converge in the mammalian hypothalamus. General anesthetics present a unique challenge to systems neuroscience: molecularly distinct drugs act on various receptors throughout the nervous system, and yet produce remarkably similar anesthetic states. One possible solution is that distinct primary targets of different anesthetics converge to a set of common neural circuits to produce the hallmark state of unconsciousness, amnesia and immobility. Multiple lines of evidence using neurophysiological, chemogenetic and optogenetic methods point to the ventrolateral preoptic nucleus (VLPO) and supraoptic nucleus (SON) as prime candidates for such a “final common pathway.” Neuronal ensembles in these anterior hypothalamic nuclei are reliably depolarized by mechanistically distinct general anesthetics. Furthermore, reactivation of these neurons in the absence of anesthetic promotes endogenous sleep and their modulation influences the stability of anesthetic states. Interestingly, these nuclei are also key players in the natural, circadian switch between waking and sleep states.

Sleep and general anesthesia are clearly different phenotypes; if someone tries to perform surgery on a sleeping patient, they won’t get very far. Nevertheless, they do appear to share convergent circuitry in the anterior hypothalamus. Further investigations into the key differences and common ground shared by sleep and anesthesia hold promise for discoveries that will improve human health in bedrooms, intensive care units and operating rooms.