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. [end of paraphrase]