What happens in the brain when we fall asleep? Researchers who study this question hope to understand not only how sleep provides an interval during which the brain can repair and restore itself, but also how natural variations or dysfunction in the processes associated with the sleep/wake transition and the progression through various sleep phases may be involved in sleep-related disorders. Such investigations may also shed new light on a variety of neurological illnesses, including Alzheimer’s and Parkinson’s diseases, and perhaps some psychiatric disorders in which sleep disturbances and disorders of consciousness occur.

New research led by a recent BBRF grantee, involving the novel application of multiple brain monitoring and imaging technologies, has revealed how brain activity, energy use, and blood flow interact in a complex set of patterns during the transition from wakefulness to deep sleep.

Among other things, “our research helps explain how the brain stays responsive to the outside world, even as awareness fades during sleep,” explains Jingyuan E. Chen, Ph.D., a 2022 BBRF Young Investigator at Mass General Brigham. Dr. Chen is first author of the new paper reporting the research, appearing in Nature Communications. The team also included Dara S. Manoach, Ph.D., who received BBRF Independent Investigator grants in 2010 and 2006 and BBRF Young Investigator grants in 1999 and 1995; and Laura D. Lewis, Ph.D., a 2019 BBRF Young Investigator.

We normally cycle through two types of sleep several times each night, called REM (rapid eye movement) and NREM (non-rapid eye movement) sleep. NREM is the deep, restorative sleep state that is thought to play a key role in brain health. What happens in the brain during NREM and in the transition to it from the waking state remains unclear, in significant part due to technical limitations in monitoring different kinds of brain dynamics together in real time and relative to one another within the physical space occupied by the brain.

In their research, Dr. Chen and colleagues innovatively combined—simultaneously—three modes of brain imaging, while observing 23 healthy adults during brief afternoon sleep sessions. One mode is EEG (electroencephalography), which acquires the brain’s electrical activity with millisecond precision. A second mode is functional MRI (fMRI), which acquires images of the brain’s functional activity based on blood flow—hemodynamics. The third mode is called functional PET-FDG (fPET-FDG), which acquires images that depict changes in glucose (the brain’s chief source of fuel) and metabolism (the way in which the brain utilizes energy stores to accomplish work).

The researchers wanted to investigate brain hemodynamic and metabolic processes as they changed over short periods of time in people who were falling asleep. “Recent advances in fPET-FDG imaging have provided an opportunity for tracking rapid dynamics of glucose uptake in humans,” the team noted, with the potential to image metabolic dynamics in the brain over periods as short as one minute or less. This capability, they realized, could make fPET-FDG compatible spatially and temporally with hemodynamic changes that fMRI can measure in the brain. “With integrated PET-MR scanners, both measures can now be made simultaneously,” they explain.

Their monitoring of the 23 subjects revealed a complex series of patterns emerging in real time as the subjects progressed from wakefulness to NREM deep sleep. They found that energy use and metabolism decrease as sleep deepens, while at the same time, blood flow becomes more dynamic, especially in sensory areas that stay relatively active during sleep. Another key observation was that higher-order cognitive networks in the brain quiet down during the transition into sleep, even as flows increase of the cerebrospinal fluid (CSF) that bathes the brain and spinal cord.

Taken together, these findings support the theory that conditions during sleep support the clearing of waste from the brain, although the brain is simultaneously able to maintain a level of activity sufficient to support receptivity to sensory cues coming from the environment. These continue to be detected, and can, under a variety of conditions, trigger awakening. In other words, when sleep is performing the protective functions it has evolved to perform, it ratchets down cognitive activity while performing activities that promote the sleeper’s brain health, but it also remains active in areas and at levels that are sufficient to maintain unconscious vigilance against potential external threats.

“Our observation of temporally coordinated hemodynamic and metabolic patterns across wakefulness and light/intermediate sleep holds important clinical implications for sleep medicine,” the team wrote. “For instance: regarding the clearance and production of metabolic waste.” Recent studies have indicated that vascular responses across the brain, as seen in fMRI, are coupled to the dynamics of CSF flow. Hence, “a direct corollary” of the new findings is that CSF dynamics also couples to changes in metabolism across the sleep-wake cycle, “with higher CSF flow when metabolism is suppressed.” Why is this important? “Given that CSF dynamics may facilitate the clearance of metabolic waste during sleep, and that sleep-wake synaptic activity and metabolic dynamics play a pivotal role in waste production, including the accumulation of toxic substances such as amyloid and tau [plaques], our results may imply a temporal balance of the waste clearance and production processes” the team wrote.

Regarding their method, using fPET-fMRI together “provides an exciting opportunity to further characterize and elucidate, in humans, how disrupted coordination of these processes in sleep disorders can lead to various neurological illnesses.” Such insights could complement past studies that have investigated each mechanism in isolation, they said.

The team also suggested that their novel multi-modal method, if further validated, could demonstrate the potential of EEG-PET-fMRI to explore neural, metabolic, and blood flow-related mechanisms underlying cognition and arousal in humans—which would be a major technology-empowered step forward in understanding some of the ultimate mysteries of how the human brain works.