Cerebrospinal Fluid Oscillations in Human Sleep
Science 01 Nov 2019,:Vol. 366, Issue 6465, pp. 628-631
Coupled electrophysiological, hemodynamic, and cerebrospinal fluid
oscillations in human sleep
Nina E. Fultz, et.al.
Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA.
Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital,
Boston, MA 02129, USA.
Department of Radiology, Harvard Medical School, Boston, MA 02115, USA.
Department of Psychiatry, Beth Israel Deaconess Medical Center, Boston, MA 02215,
USA.
Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA.
[paraphrase]
Sleep is essential for both cognition and maintenance of healthy brain function. Slow waves in
neural activity contribute to memory consolidation, whereas cerebrospinal fluid (CSF) clears
metabolic waste products from the brain. Whether these two processes are related is not known.
We used accelerated neuroimaging to measure physiological and neural dynamics in the
human brain. We discovered a coherent pattern of oscillating electrophysiological,
hemodynamic, and CSF dynamics that appears during non–rapid eye movement sleep. Neural
slow waves are followed by hemodynamic oscillations, which in turn are coupled to CSF flow.
These results demonstrate that the sleeping brain exhibits waves of CSF flow on a macroscopic
scale, and these CSF dynamics are interlinked with neural and hemodynamic rhythms.
Sleep is crucial for both high-level cognitive processing and also basic maintenance and
restoration of physiological function. During human non–rapid eye movement (NREM) sleep,
the electroencephalogram (EEG) exhibits low-frequency (<4 Hz) oscillatory dynamics that
support memory and neural computation. In addition, functional magnetic resonance imaging
(fMRI) studies measuring blood oxygen level–dependent (BOLD) signals have demonstrated
widespread hemodynamic alterations during NREM sleep. Sleep is also associated with
increased interstitial fluid volume and clearance of metabolic waste products into the CSF,
and clearance is stronger in sleep with more low-frequency EEG oscillations. Why these diverse
physiological processes co-occur in this state of low arousal is not known. In particular, it remains
unclear how CSF dynamics change during sleep and how they relate to the major changes in
neural activity and hemodynamics.
We simultaneously measured BOLD fMRI dynamics, EEG, and CSF flow during human sleep.
To achieve high–temporal-resolution imaging, we acquired fMRI data at fast rates [repetition
time (TR) < 400 ms]. While fMRI is often used to detect local oxygenation changes, fast
acquisition paradigms also enable detection of fluid inflow: Fresh fluid arriving at the edge of the
imaging volume has high signal intensity because it has not yet experienced radiofrequency
pulses. By placing the boundary edge of the imaging volume at the fourth ventricle, CSF flow into
the brain was detected as increased signal in the lower slices, allowing us to measure dynamics of
CSF flow simultaneously with BOLD fMRI. We combined this imaging with simultaneous EEG
(n = 13 participants) and identified continuous segments of clear stable wake or NREM sleep
with low motion to enable analysis of continuous low-frequency dynamics.
We conclude that human sleep is associated with large coupled low-frequency oscillations in
neuronal activity, blood oxygenation, and CSF flow. Although electrophysiological slow
waves are known to play important roles in cognition, our results suggest that they may also be
linked to the physiologically restorative effects of sleep, as slow neural activity is followed by
brain-wide pulsations in blood volume and CSF flow.
These results address a key missing link in the neurophysiology of sleep. The macroscopic
changes in CSF flow that we identified are expected to alter waste clearance, as pulsatile fluid
dynamics can increase mixing and diffusion. Neurovascular coupling has been proposed to
contribute to clearance, but why it would cause higher clearance rates during sleep was not
known. Our study suggests slow neural and hemodynamic oscillations as a possible contributor
to this process, in concert with other physiological factors. Studies in animals could next test for
causal relationships between these neural and physiological rhythms.
Our identification of sleep-associated CSF fluid dynamics also suggests a potential biomarker to
be explored in clinical conditions associated with sleep disturbance. Memory impairment in
aging is associated with suppressed slow waves; our model suggests that this slow-wave loss
would, in turn, be associated with decreased CSF flow. Furthermore, our results hint at a
potential bridge between recent findings that tau CSF levels and amyloid beta depend on sleep
and neural activity and that oscillatory neural activity leads to reduced tau—coherent neural
activity might signal higher protein aggregate clearance. Taken together, our results identify
waves of CSF flow that appear during sleep and show that slow rhythms in neural activity are
interlinked with these CSF waves, with hemodynamic oscillations as an intermediate
mechanism through which these processes are coupled.
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