The theory on the glymphatic convection mechanism of cerebrospinal fluid holds that cardiac pulsations in part pump cerebrospinal fluid from the peri-arterial spaces through the extracellular tissue into the peri-venous spaces facilitated by aquaporin water channels. Since cardiac pulses cannot be the sole mechanism of glymphatic propulsion, we searched for additional cerebrospinal fluid pulsations in the human brain with ultra-fast magnetic resonance encephalography. We detected three types of physiological mechanisms affecting cerebral cerebrospinal fluid pulsations: cardiac, respiratory, and very low frequency pulsations. The cardiac pulsations induce a negative magnetic resonance encephalography signal change in peri-arterial regions that extends centrifugally and covers the brain in &1 Hz cycles. The respiratory &0.3 Hz pulsations are centripetal periodical pulses that occur dominantly in peri-venous areas. The third type of pulsation was very low frequency (VLF 0.001-0.023 Hz) and low frequency (LF 0.023-0.73 Hz) waves that both propagate with unique spatiotemporal patterns. Our findings using critically sampled magnetic resonance encephalography open a new view into cerebral fluid dynamics. Since glymphatic system failure may precede protein accumulations in diseases such as Alzheimer's dementia, this methodological advance offers a novel approach to image brain fluid dynamics that potentially can enable early detection and intervention in neurodegenerative diseases.

Chemotherapy aided by opening of the blood-brain barrier with intra-arterial infusion of hyperosmolar mannitol improves the outcome in primary central nervous system lymphoma. Proper opening of the blood-brain barrier is crucial for the treatment, yet there are no means available for its real-time monitoring. The intact blood-brain barrier maintains a mV-level electrical potential difference between blood and brain tissue, giving rise to a measurable electrical signal at the scalp. Therefore, we used direct-current electroencephalography (DC-EEG) to characterize the spatiotemporal behavior of scalp-recorded slow electrical signals during blood-brain barrier opening. Nine anesthetized patients receiving chemotherapy were monitored continuously during 47 blood-brain barrier openings induced by carotid or vertebral artery mannitol infusion. Left or right carotid artery mannitol infusion generated a strongly lateralized DC-EEG response that began with a 2 min negative shift of up to 2000 μV followed by a positive shift lasting up to 20 min above the infused carotid artery territory, whereas contralateral responses were of opposite polarity. Vertebral artery mannitol infusion gave rise to a minimally lateralized and more uniformly distributed slow negative response with a posterior-frontal gradient. Simultaneously performed near-infrared spectroscopy detected a multiphasic response beginning with mannitol-bolus induced dilution of blood and ending in a prolonged increase in the oxy/deoxyhemoglobin ratio. The pronounced DC-EEG shifts are readily accounted for by opening and sealing of the blood-brain barrier. These data show that DC-EEG is a promising real-time monitoring tool for blood-brain barrier disruption augmented drug delivery.

Low image sampling rates used in resting state functional magnetic resonance imaging (rs-fMRI) may cause aliasing of the cardiorespiratory pulsations over the very low frequency (VLF) BOLD signal fluctuations which reflects to functional connectivity (FC). In this study, we examine the effect of sampling rate on currently used rs-fMRI FC metrics. Ultra-fast fMRI magnetic resonance encephalography (MREG) data, sampled with TR 0.1 s, was downsampled to different subsampled repetition times (sTR, range 0.3–3 s) for comparisons. Echo planar k-space sampling (TR 2.15 s) and interleaved slice collection schemes were also compared against the 3D single shot trajectory at 2.2 s sTR. The quantified connectivity metrics included stationary spatial, time, and frequency domains, as well as dynamic analyses. Time domain methods included analyses of seed-based functional connectivity, regional homogeneity (ReHo), coefficient of variation, and spatial domain group level probabilistic independent component analysis (ICA). In frequency domain analyses, we examined fractional and amplitude of low frequency fluctuations. Aliasing effects were spatially and spectrally analyzed by comparing VLF (0.01–0.1 Hz), respiratory (0.12–0.35 Hz) and cardiac power (0.9–1.3 Hz) FFT maps at different sTRs. Quasi-periodic pattern (QPP) of VLF events were analyzed for effects on dynamic FC methods. The results in conventional time and spatial domain analyses remained virtually unchanged by the different sampling rates. In frequency domain, the aliasing occurred mainly in higher sTR (1–2 s) where cardiac power aliases over respiratory power. The VLF power maps suffered minimally from increasing sTRs. Interleaved data reconstruction induced lower ReHo compared to 3D sampling ( p < 0.001). Gradient recalled echo-planar imaging (EPI BOLD) data produced both better and worse metrics. In QPP analyses, the repeatability of the VLF pulse detection becomes linearly reduced with increasing sTR. In conclusion, the conventional resting state metrics (e.g., FC, ICA) were not markedly affected by different TRs (0.1–3 s). However, cardiorespiratory signals showed strongest aliasing in central brain regions in sTR 1–2 s. Pulsatile QPP and other dynamic analyses benefit linearly from short TR scanning.

The brain is cleaned from waste by glymphatic clearance serving a similar purpose as the lymphatic system in the rest of the body. Impairment of the glymphatic brain clearance precedes protein accumulation and reduced cognitive function in Alzheimer's disease (AD). Cardiovascular pulsations are a primary driving force of the glymphatic brain clearance. We developed a method to quantify cardiovascular pulse propagation in the human brain with magnetic resonance encephalography (MREG). We extended a standard optical flow estimation method to three spatial dimensions, with a multi-resolution processing scheme. We added application-specific criteria for discarding inaccurate results. With the proposed method, it is now possible to estimate the propagation of cardiovascular pulse wavefronts from the whole brain MREG data sampled at 10 Hz. The results show that on average the cardiovascular pulse propagates from major arteries via cerebral spinal fluid spaces into all tissue compartments in the brain. We present an example, that cardiovascular pulsations are significantly altered in AD: coefficient of variation and sample entropy of the pulse propagation speed in the lateral ventricles change in AD. These changes are in line with the theory of glymphatic clearance impairment in AD. The proposed noninvasive method can assess a performance indicator related to the glymphatic clearance in the human brain. Index Terms-Brain, FMRI, heart, MREG, optical flow. I. INTRODUCTION R ECENTLY emerged glymphatic brain clearance mechanisms have been shown to use physiological pulsations to clear the brain tissue from metabolic waste materials such as beta-amyloid protein aggregates [1]-[3]. Glymphatic clearance pushes waste to dural lymphatic vessels and finally to cercical lymph nodes. Abnormal glymphatic clearance has been shown in [1] and [2] to cause beta-amyloid aggregation preceding the Alzheimer's disease.

IntroductionFunctional magnetic resonance imaging (fMRI) combined with simultaneous electroencephalography (EEG‐fMRI) has become a major tool in mapping epilepsy sources. In the absence of detectable epileptiform activity, the resting state fMRI may still detect changes in the blood oxygen level‐dependent signal, suggesting intrinsic alterations in the underlying brain physiology.MethodsIn this study, we used coefficient of variation (CV) of critically sampled 10 Hz ultra‐fast fMRI (magnetoencephalography, MREG) signal to compare physiological variance between healthy controls (n = 10) and patients (n = 10) with drug‐resistant epilepsy (DRE).ResultsWe showed highly significant voxel‐level (p < 0.01, TFCE‐corrected) increase in the physiological variance in DRE patients. At individual level, the elevations range over three standard deviations (σ) above the control mean (μ) CVMREG values solely in DRE patients, enabling patient‐specific mapping of elevated physiological variance. The most apparent differences in group‐level analysis are found on white matter, brainstem, and cerebellum. Respiratory (0.12–0.4 Hz) and very‐low‐frequency (VLF = 0.009–0.1 Hz) signal variances were most affected.ConclusionsThe CVMREG increase was not explained by head motion or physiological cardiorespiratory activity, that is, it seems to be linked to intrinsic physiological pulsations. We suggest that intrinsic brain pulsations play a role in DRE and that critically sampled fMRI may provide a powerful tool for their identification.

Biomarkers sensitive to prodromal or early pathophysiological changes in Alzheimer’s disease (AD) symptoms could improve disease detection and enable timely interventions. Changes in brain hemodynamics may be associated with the main clinical AD symptoms. To test this possibility, we measured the variability of blood oxygen level-dependent (BOLD) signal in individuals from three independent datasets (totaling 80 AD patients and 90 controls). We detected a replicable increase in brain BOLD signal variability in the AD populations, which constituted a robust biomarker for clearly differentiating AD cases from controls. Fast BOLD scans showed that the elevated BOLD signal variability in AD arises mainly from cardiovascular brain pulsations. Manifesting in abnormal cerebral perfusion and cerebrospinal fluid convection, present observation presents a mechanism explaining earlier observations of impaired glymphatic clearance associated with AD in humans.

Accumulation of amyloid-β is a key neuropathological feature in brain of Alzheimer's disease patients. Alterations in cerebral hemodynamics, such as arterial impulse propagation driving the (peri)vascular cerebrospinal fluid flux, predict future Alzheimer's disease progression. We now present a non-invasive method to quantify the three-dimensional propagation of cardiovascular impulses in human brain using ultrafast 10 Hz magnetic resonance encephalography. This technique revealed spatio-temporal abnormalities in impulse propagation in Alzheimer's disease. The arrival latency and propagation speed both differed in Alzheimer's disease patients. Our mapping of arterial territories revealed Alzheimer's disease-specific modifications, including reversed impulse propagation around the hippocampi and in parietal cortical areas. The findings imply that pervasive abnormality in (peri)vascular cerebrospinal fluid impulse propagation compromises vascular impulse propagation and subsequently glymphatic brain clearance of amyloid-β in Alzheimer's disease.

Oura Health Ltd.'s provided the surveillance smart rings for the study, but did not participate in the analysis. The manuscript in question is published as a preprint in bioRxiv, but we guarantee that it does not infringe any subsequent copyright or license agreement. 3We would like to thank all study subjects for their participation in the study. We also thank Tuomas Konttajärvi for assistance in measurements and preprocessing of EEG data, Jani Häkli, Annastiina Kivipää, Tarja Holtinkoski, Aleksi Rasila, Taneli Hautaniemi, Miia Lampinen and others who assisted in measurements or otherwise contributed. We are grateful for devices and data provided by Oura. We wish to acknowledge Jussi Kantola for data management and reconstruction of MREG data, the CSC -IT Center for Science Ltd.