September 14, 2023
As a longtime scholar of the brain’s arousal states, neuroscientist and anesthesiologist Emery N. Brown is deeply aware of the science behind sleep’s importance for health and wellness, but he still starts the discussion in colloquial terms: “You realize how important it is when you can’t get it,” quipped Brown, Edward Hood Taplin Professor of Computational Neuroscience and Medical Engineering in The Picower Institute and the Institute for Medical Engineering at MIT.
Indeed, we all know the feeling when we’ve slept poorly: We’re groggy, foggy and cranky. But what Brown and other scientists can tell you based on studying the slumbering brain is that sleep does much more than just help us feel refreshed and ready in the morning.
“Sleep is linked to preserving brain health and brain function in fundamental ways,” said Laura Lewis, Athinoula A. Martinos Associate Professor and a Picower Institute affiliate faculty member who studies the neuroscience of sleep. “It’s involved in actively enhancing complex cognition, maintaining our ability to rally our attentional resources, and then also at a ‘housekeeping’ level, it maintains the physiological health of the brain.”
The structure of sleep
Sleep emerges from biochemical changes among circuit nodes or “nuclei” deep in the brain. Brown summarized one such mechanism for colleagues in a review article in The New England Journal of Medicine in 2010. During wakefulness a major arousal center of the brain, the locus coeruleus, pumps out a chemical called norepinephrine, which suppresses the activity of another region called the preoptic area (POA) of the hypothalamus .. But once we’ve been awake too long, a different chemical called adenosine builds up. When that binds to cells in the POA, it inhibits arousal circuits and promotes sleep.
Over the years, Lewis and other scientists have learned that sleep’s onset and cycles involve a “constellation” of circuit nuclei and brain chemicals. In a review in Science in 2021, she wrote that the broad-based transformation of neural circuit activity during sleep likely represents the interaction of these many components to transform neural activity brainwide.
These sweeping changes in circuit activity give sleep a signature structure, which we go through every 90 minutes. You might see reports of “deep,” “core” and “REM” sleep from your smartwatch. Scientists, however, define sleep’s phases based on the neural circuit activity evident in the oscillating patterns (or brain waves) measured in the lab with electroencephalograms (EEGs). Brain waves are produced by large networks of neurons all firing in synchronicity. This correlation indicates shared activity.
By these measures, sleep has four stages: one REM (“rapid eye movement”) phase and three non-REM phases. In non-REM sleep, waves become high in amplitude and slow in frequency. In REM sleep, which is brought about by increases of the brain chemical acetylcholine in the brain’s outer surface, or cortex, the brain exhibits relatively high-frequency, low-amplitude rhythms (but still slower and higher amplitude than during wakefulness). During different Non-REM phases, and in different regions of the brain, the big slow waves of sleep often envelop briefer patterns of activity including “sharp wave ripples,” “spindles,” and “K-complexes” that indicate specific bouts of neural activity.
This is an important point, says Sherman Fairchild Professor Matthew Wilson. The brain is not idle during sleep. Instead, it’s taking advantage of changed activity patterns to perform needed functions.
“Sleep oscillations are way of organizing activity during sleep,” Wilson said. “The brain is just as active during sleep as it is during wakefulness. It's just a different kind of activity.”
Sleep improves memory and maintenance
Wilson investigates how brain makes use of memory to function intelligently in the world. He studies sleep because that’s when the brain performs much of the needed work. As a postdoc in the early 1990s he noticed that rats who had been running mazes would while asleep replay the same patterns of activity in a brain region called the hippocampus, which forms memories of our experiences in the environment around us. The finding provided support for observations that memory improves with sleep.
Years of Wilson’s research have revealed how the mammalian brain processes its representations of experience during distinct phases of sleep. During non-REM sleep, within each new slow wave, small chunks of experience are replayed at high speed. In REM sleep, by contrast, Wilson’s team has shown that memories are replayed in real-time and sensations like motion are rekindled. In REM, animals appear to relive the memory and feeling of experience (i.e. they dream). Together these findings suggest that the brain uses the structure of sleep to build useful models of the world based on how it can manipulate representations of experience, Wilson said. Segments of experience can be represented and considered in different ways during non-REM sleep and reassembled and rehearsed (as dreams) during REM sleep.
In a recent paper, Wilson’s lab reported new evidence from mice that while some “place cell” neurons in the hippocampus quickly encode a basic map of an experienced space, the brain employs sleep to recruit more neurons to fill in that map with detail about the routes connecting those dots and cues encountered along the way.
Several of Wilson’s studies have shown that the hippocampus communicates with the cortex during sleep as it replays representations of experience. The lab’s most recent paper shows that during the peaks or “up states” of slow waves, the prefrontal cortex (the locus of reasoning and executive function) triggers short bursts of high-frequency activity in the hippocampus called sharp-wave ripples. That hippocampal activation then appears to precede the onset of the “down” state in the retrosplenial cortex, (which considers spatial contexts). The lab is currently working on decoding the contents of the crosstalk , Wilson said, but its participants and structure suggest the mice may be processing their experiences of the day to better understand what to do in similar situations.
As sleep’s structure enables the brain to process representations of experience, Lewis has shown that it also enables more basic brain maintenance. Studies show that poor sleep can increase people’s risk for Alzheimer’s disease later in life. After an influential study at the University of Rochester in 2013 showed that the brain clears away proteins that are hallmarks of Alzheimer’s during sleep, Lewis became interested in studying how this occurs.
Lewis earned her PhD in Brown’s MIT lab in 2014 and after a postdoc at Harvard started her own research group at Boston University and Massachusetts General Hospital (she moved her BU lab to MIT and affiliated with The Picower Institute earlier this year). In 2019 she published a study in Science that explained how sleep enables waste clearance via the cerebrospinal fluid (CSF) that pervades the brain in a circulatory system parallel to its blood vessels. Combining non-invasive measures of brain waves, blood flow, and CSF flow in sleeping human volunteers, Lewis found that during slow wave sleep the rise and fall of neural activity causes a correlated increase and decrease in blood volume. When blood flows out, CSF is drawn in. When blood flushes in, CSF is pushed out. CSF is the bath that envelops the brain, and the flow of CSF transports waste out of the brain.
“Sleep oscillations are way of organizing activity during sleep,” Wilson said. “The brain is just as active during sleep as it is during wakefulness. It's just a different kind of activity.”
At MIT, Lewis continues to study several aspects of sleep and health. In one arm of research she’s studying how the brain wakes up with astonishing quickness considering how comprehensively altered brain activity is during sleep. In a new arm, she’s studying how sleep loss undermines our capacity for attention, in health and in neurological and psychiatric disorders.
Appointed in MIT’s Department of Electrical Engineering and Computer Science, Lewis is also working to advance the fundamental capabilities of technologies such as magnetic resonance imaging (MRI) so that it can image the brain with sharper resolution and quicker timing. Improving what MRI can reveal about brain activity is critical because it’s the best technology for observing sleep’s brainwide activity non-invasively in human subjects.
Better sleep and health
After all, better understanding the dynamics of human sleep can lead to important opportunities to improve sleep and therefore health.
Getting better sleep, Wilson notes, is not merely a matter of getting more sleep. Because of how the brain exploits the structure of sleep, sleep quality requires it to be uninterrupted so that the brain can cycle through all the phases.
For many people, that can be easier said than done and so they turn to off-the-shelf sleep aids, but many of those medicines are actually not producing natural sleep states, said Brown. Instead, they are acting like sedatives, or weak anesthetics, which unnaturally induce relaxation in hope that you will then achieve natural sleep.
That’s why Brown is planning to launch new studies of the one anesthetic that actually triggers the same natural mechanism as real sleep. Dexmedetomidine acts much like adenosine to promote an arousal state that matches natural non-REM sleep in EEG. A big question is whether “dex”-induced sleep then progresses naturally through the cycle of the other phases. If it does, it would be a better sleep aid than what’s on the market. The study is one of several Brown is advancing through is efforts to establish the Brain Arousal State Control Innovation Center at MIT and MGH.
Lewis, meanwhile, is interested in learning how the uniquely structured brain state of sleep could offer a new window for therapeutic interventions more generally. Therapies are typically administered when people are awake, she notes.
“The whole brain and body are operating in a very different way during sleep,” she said. “There’s an intriguing opportunity to think about how could we possibly modulate that or enhance that to confer benefit.”
The brain naturally uses the structure of sleep to advance our health and improve our health. Maybe we can do that, too.
