Cerebrospinal Fluid Flow Research Articles

Motile cilia modulate neuronal and astroglial activity in the zebrafish larval brain.

The brain uses a specialized system to transport cerebrospinal fluid (CSF), consisting of interconnected ventricles lined by motile ciliated ependymal cells. These cells act jointly with CSF secretion and cardiac pressure gradients to regulate CSF dynamics. To date, the link between cilia-mediated CSF flow and brain function is poorly understood. Using zebrafish larvae as a model system, we identify that loss of ciliary motility does not alter progenitor proliferation, brain morphology, or spontaneous neural activity despite leading to an enlarged telencephalic ventricle. We observe altered neuronal responses to photic stimulations in the optic tectum and hindbrain and brain asymmetry defects in the habenula. Finally, we investigate astroglia since they contact CSF and regulate neuronal activity. Our analyses reveal a reduction in astroglial calcium signals during both spontaneous and light-evoked activity. Our findings highlight a role of motile cilia in regulating brain physiology through the modulation of neural and astroglial networks.

Impaired macroscopic CSF flow by sevoflurane in humans - both during and after anesthesia.

According to the model of the glymphatic system, the directed flow of cerebrospinal fluid (CSF) is a driver of waste clearance from the brain. In sleep, glymphatic transport is enhanced, but it is unclear how it is affected by anesthesia. Animal research indicates partially opposing effects of distinct anesthetics but corresponding results in humans are lacking. Thus, this study aims to investigate the effect of sevoflurane anesthesia on CSF flow in humans, both during and after anesthesia. Using data from a functional magnetic resonance imaging (fMRI) experiment in 16 healthy human subjects before, during, and 45 minutes after sevoflurane mono-anesthesia of 2vol%, we related grey matter blood-oxygenation-level dependent (BOLD) signals to CSF flow, indexed by fMRI signal fluctuations, across the basal cisternae. Specifically, CSF flow was measured by CSF fMRI signal amplitudes, global grey matter (gGM) functional connectivity by the median of inter-regional GM fMRI Spearman rank correlations, and gGM-CSF basal cisternae coupling by Spearman rank correlations of fMRI signals. Anesthesia decreased cisternal CSF peak-to-trough amplitude (median difference Mdn-diff = 1.00, 95% CI [0.17 1.83], p = .013), disrupted the global, cortical BOLD-fMRI-based connectivity (Mdn-diff = 1.5, 95% CI [0.67, 2.33], p < 0.001) and, global grey matter (gGM)-CSF coupling (Mdn-diff = 1.19, 95% CI [0.36, 2.02], p = 0.002). Remarkably, the impairments of global connectivity (Mdn-diff = 0.94, 95% CI [0.11, 1.77], p = 0.022) and gGM-CSF coupling (Mdn-diff = 1.06, 95% CI [0.23, 1.89], p = 0.008) persisted after re-emergence from anesthesia. Collectively, our data show that sevoflurane impairs macroscopic CSF flow via a disruption of coherent gGM activity. This effect persists, at least for a short time, after regaining consciousness. Future studies need to elucidate whether this contributes to the emergence of postoperative neurocognitive symptoms, especially in older patients or those with dementia.

Altered brain-ventricle coupling modes over Alzheimer's disease progression detected with fMRI.

The origins of resting-state functional MRI (rsfMRI) signal fluctuations remain debated. Recent evidence shows coupling between global cortical rsfMRI signals and cerebrospinal fluid inflow in the fourth ventricle, increasing during sleep and decreasing with Alzheimer's disease (AD) progression, potentially reflecting brain clearance mechanisms. However, the existence of more complex brain-ventricle coupling modes and their relationship to cognitive decline remains unexplored. Analyzing 599 minimally-preprocessed rsfMRI scans from 163 elderly participants across the AD spectrum, we identified distinct brain-ventricle coupling modes that differentiate across groups and correlate with cognitive scores. Beyond the known anti-phase coupling between global brain signals and ventricles -more frequent in cognitively normal controls- we discovered additional modes where specific brain areas temporarily align with ventricle signals. At the cortical level, these modes form canonical resting-state networks, such as the Default Mode Network, which occurs less in AD or the Frontoparietal Network, which correlates positively with memory scores. The direct link between ventricle and brain signals challenges the common practice of removing CSF components from rsfMRI analyses and questions the origin of cortical signal fluctuations forming functional networks, which may reflect region-specific fluid inflow patterns. These findings provide new insights into the relationship between brain clearance mechanisms and network dysfunction in neurodegenerative diseases.

Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep.

As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.

BOLD-CSF dynamics assessed using real-time phase contrast CSF flow interleaved with cortical BOLD MRI

Abstract Background Cerebrospinal fluid (CSF) motion and pulsatility has been proposed to play a crucial role in clearing brain waste. Although its driving forces remain debated, increasing evidence suggests that large amplitude vasomotion drives such CSF fluctuations. Recently, a fast blood-oxygen-level-dependent (BOLD) fMRI sequence was used to measure the coupling between CSF fluctuations and low-frequency hemodynamic oscillations in the human cortex. However, this technique is not quantitative, only captures unidirectional flow and is sensitive to B0-fluctuations. Real-time phase contrast (pcCSF) instead measures CSF flow dynamics in a fast, quantitative, bidirectional and B0-insensitive manner, but lacks information on hemodynamic brain oscillations. In this study we propose to combine the strengths of both sequences by interleaving real-time phase contrast with a cortical BOLD scan, thereby enabling the quantification of the interaction between CSF flow and cortical BOLD. Methods Two experiments were performed. First, we compared the CSF flow measured using real-time phase contrast (pcCSF) with the inflow-sensitized BOLD (iCSF) measurements by interleaving both techniques at the repetition level and planning them at the same location. Next, we compared the BOLD-CSF coupling obtained using the novel pcCSF interleaved with cortical BOLD to the coupling obtained with the original iCSF. To time-lock the CSF fluctuations, participants were instructed to perform slow, abdominal paced breathing. Results pcCSF captures bidirectional CSF dynamics with a more pronounced in- and outflow curve than the original iCSF method. With the pcCSF method, the BOLD-CSF coupling was stronger (mean cross-correlation peak increase = 0.22, p = .008) and with a 1.9 s shorter temporal lag (p = .016), as compared to using the original iCSF technique. Conclusions In this study, we introduce a new method to study the coupling of CSF flow measured in the fourth ventricle to cortical BOLD fluctuations. In contrast to the original approach, the use of phase contrast MRI to measure CSF flow provides a quantitative in- and outflow curve, and improved BOLD-CSF coupling metrics.

Recapitulation of physiologic and pathophysiologic pulsatile CSF flow in purpose-built high-throughput hydrocephalus bioreactors

BackgroundHydrocephalus, an accumulation of cerebrospinal fluid (CSF) in the ventricles of the brain, is often treated via a shunt system to divert the excess CSF to a different compartment; if left untreated, it can lead to serious complications and permanent brain damage. It is estimated that one in every 500 people are born with hydrocephalus. Despite more than 60 years of concerted efforts, shunts still have the highest failure rate of any neurological device requiring follow-up shunt revision surgeries and contributing to the $2 billion cost of hydrocephalus care in the US alone. The absence of a tested and validated long-term in-vitro model that can incorporate clinically relevant parameters has limited hypothesis-driven studies and, in turn, limited our progress in understanding the mechanisms of shunt obstruction in hydrocephalus. Testing clinical parameters of flow, pressure, shear, catheter material, surface modifications, and others while optimizing for minimal protein, cellular, and blood interactions has yet to be done systematically for ventricular catheters. Several studies point to the need to not only understand how cells and tissues have occluded these shunt catheters but also how to stop the likely multi-faceted failure. For instance, studies show us that tissue occluding the ventricular catheter is primarily composed of proliferating astrocytes and cells of the macrophage lineage. Cell reactivity has been observed to follow flow gradients, with elevated levels of typically pro-inflammatory interleukin-6 produced under shear stress conditions greater than 0.5 dyne/. But also, that shear can shift cellular attachment. The Automated, In vitro Model for hydrocephalus research (AIMS), presented here, improves upon our previous long-term in vitro systems with specific goals of recapitulating bulk pulsatile cerebrospinal fluid (CSF) waveforms and steady-state flow directionality relevant to ventricular catheters used in hydrocephalus.MethodsThe AIMS setup was developed to recapitulate a wide range of physiologic and pathophysiologic CSF flow patterns with varying pulse amplitude, pulsation rate, and bulk flow rate with high throughput capabilities. These variables were specified in a custom-built user interface to match clinical CSF flow measurements. In addition to flow simulation capabilities, AIMS was developed as a modular setup for chamber testing and quality control. In this study, the capacity and consistency of single inlet resin chambers (N = 40), multidirectional resin chambers (N = 5), silicone chambers (N = 40), and PETG chambers (N = 50) were investigated. The impact of the internal geometry of the chamber types on flow vectors during pulsatile physiologic and pathophysiologic flow was visualized using Computational Fluid Dynamics (CFD). Dynamic changes in ventricular volume were investigated by combining AIMS with MRI-driven silicone model of a pediatric patient’s ventricles. Parametric data were analyzed using one-way analysis of variance (ANOVA) or repeated measures ANOVA tests. Non-parametric data were analyzed using Kruskal-Wallis test. For all tests, a confidence interval was set at 0.95 (α = 0.05). In a subset of experiments, AIMS was also tested for its capability to measure the flow of florescent microspheres through the holes of unused and explanted ventricular catheters.ResultsThe analysis of peak amplitude through chambers indicated no statistically significant differences between the chamber batches. This high throughput setup was able to reproduce clinical measurements of bulk CSF flow tested in up to 50 independent pump channels such that there was no exchange of solution or flow interference between adjacent channels. Physiologic and pathophysiologic clinical measurements of CSF flow patterns were recapitulated in all four chamber types of the AIMS setup with and without augmented compliance. The AIMS setup’s automated priming feature facilitated constant fluid contact throughout the study; no leaks or ruptures were observed during short- (up to 24 h) or long-term (30 days) experiments. Finally, qualitative microscopy long-exposure image capture revealed microsphere movement under steady-state and pulsatile flow of spheres moving into the shunt catheter.ConclusionAIMS successfully simulates clinical measurements of physiologic and pathophysiologic CSF pulsation amplitude and frequency, as exemplified using clinical data of CSF exiting an externalized ventricular drain in four distinct chamber types, as well as flow patterns from a valve. This provides a promising platform for investigating the direct interaction between CSF, immune cells, and shunt hardware under relevant flow conditions when both the source of bulk flow and pulsatility are coupled. The implementation of this system in conjunction with a previously reported three-dimensional hydrogel scaffold in future work will enhance our understanding of shunt-related complications and improve treatment strategies by reducing the obstruction rate.

Numerical study of the effects of minor structures and mean velocity fields in the cerebrospinal fluid flow

The importance of optimizing intrathecal drug delivery is highlighted by its potential to improve patient health outcomes. Findings from previous computational studies, based on an individual or a small group, may not be applicable to the wider population due to substantial geometric variability. Our study aims to circumvent this problem by evaluating an individual’s cycle-averaged Lagrangian velocity field based on the geometry of their spinal subarachnoid space. It has been shown by Lawrence et al. (J Fluid Mech 861:679–720, 2019) that dominant physical mechanisms, such as steady streaming and Stokes drift, are key to facilitating mass transport within the spinal canal. In this study, we computationally modeled pulsatile cerebrospinal fluid flow fields and Lagrangian velocity field within the spinal subarachnoid space. Our findings highlight the essential role of minor structures, such as nerve roots, denticulate ligaments, and the wavy arachnoid membrane, in modulating flow and transport dynamics within the spinal subarachnoid space. We found that these structures can enhance fluid transport. We also emphasized the need for particle tracking in computational studies of mass transport within the spinal subarachnoid space. Our research illuminates the relationship between the geometry of the spinal canal and transport dynamics, characterized by a large upward cycle-averaged Lagrangian velocity zone in the wider region of the geometry, as opposed to a downward zone in the narrower region and areas close to the wall. This highlights the potential for optimizing intrathecal injection protocols by harnessing natural flow dynamics within the spinal canal.

Effects of the Pulsating Flow of Cerebrospinal Fluid on Spinal Pathologies

Effects of the Pulsating Flow of Cerebrospinal Fluid on Spinal Pathologies

Atlas of Cerebrospinal Fluid Immune Cells Across Neurological Diseases.

Cerebrospinal fluid (CSF) provides unique insights into the brain and neurological diseases. However, the potential of CSF flow cytometry applied on a large scale remains unknown. We used data-driven approaches to analyze paired CSF and blood flow cytometry measurements from 8,790 patients (discovery cohort) and CSF only data from 3,201 patients (validation cohort) collected across neurological diseases in a real-world setting. In somatoform controls (n = 788), activation of T cells increased with age in both CSF and blood, whereas double negative blood T cells (CD3+CD4-CD8-) decreased with age. A machine learning model of CSF and blood immune cells defined immune age, which correlated strongly with true biological age (r = 0.71). Classifying all diseases solely based on the CSF/blood parameters in 8,790 patients resulted in clusters of 4 disease categories: healthy, autoimmune, meningoencephalitis, and neurodegenerative. This clustering was validated in an analytically independent test dataset (8,790 patients) and in a temporally independent cohort (3,201 patients). Patients with multiple sclerosis were more likely to have progressive disease when assigned to the neurodegeneration cluster and to have lower disability in the autoimmune cluster. Patients with dementia in the neurodegeneration cluster showed more severe disease progression. Flow cytometry helped differentiate dementia from controls, thereby enhancing the diagnostic power of routine CSF diagnostics. Flow cytometry of CSF and blood thus identifies site-specific aging patterns and disease-overarching patterns of neurodegeneration. ANN NEUROL 2024.

Cerebrospinal Fluid Flow within Ventricles and Subarachnoid Space Evaluated by Velocity Selective Spin Labeling MRI.

This study aims to evaluate cerebrospinal fluid (CSF) flow dynamics within ventricles, and the subarachnoid space (SAS) using the velocity selective spin labeling (VSSL) MRI method with Fourier-transform-based velocity selective inversion preparation. The study included healthy volunteers who underwent MRI scanning with specific VSSL parameters optimized for CSF flow quantification. The VSSL sequence was calibrated against phase-contrast MRI (PC-MRI) to ensure accurate flow velocity measurements. The CSF flow patterns observed in the ventricles were consistent with those obtained using 3D amplified MRI and other advanced MRI techniques, verifying the reliability of the VSSL method. The VSSL method successfully measured CSF flow in the SAS along major arteries, including the middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA), with an average flow velocity of 0.339 ± 0.117 cm / s . The diffusion component was well suppressed by flow-compensated gradients, enabling comprehensive mapping of the rapid CSF flow pattern in the SAS system and ventricles. The flow pattern in the SAS system closely resembles the recently discovered perivascular subarachnoid space (PVSAS) system. CSF flow around the MCA, PCA, and ACA arteries in the SAS exhibited a weak orientation dependency. CSF flow in the ventricles was also measured, with an average flow velocity of 0.309 ± 0.116 cm / s , and the highest velocity observed along the superior-inferior direction. This study underscores the potential of VSSL MRI as a non-invasive tool for investigating CSF dynamics in both SAS and ventricles.

Inferring in vivo murine cerebrospinal fluid flow using artificial intelligence velocimetry with moving boundaries and uncertainty quantification.

Cerebrospinal fluid (CSF) flow is crucial for clearing metabolic waste from the brain, a process whose dysregulation is linked to neurodegenerative diseases like Alzheimer's. Traditional approaches like particle tracking velocimetry (PTV) are limited by their reliance on single-plane two-dimensional measurements, which fail to capture the complex dynamics of CSF flow fully. To overcome these limitations, we employ artificial intelligence velocimetry (AIV) to reconstruct three-dimensional velocities, infer pressure and wall shear stress and quantify flow rates. Given the experimental nature of the data and inherent variability in biological systems, robust uncertainty quantification (UQ) is essential. Towards this end, we have modified the baseline AIV architecture to address aleatoric uncertainty caused by noisy experimental data, enhancing our measurement refinement capabilities. We also implement UQ for the model and epistemic uncertainties arising from the governing equations and network representation. Towards this end, we test multiple governing laws, representation models and initializations. Our approach not only advances the accuracy of CSF flow quantification but also can be adapted to other applications that use physics-informed machine learning to reconstruct fields from experimental data, providing a versatile tool for inverse problems.

Depleting parenchymal border macrophages alleviates cerebral edema and neuroinflammation following status epilepticus

BackgroundStatus epilepticus (SE) is a common severe neurological emergency. Cerebral edema caused by SE is unavoidable and may exacerbate epilepsy. Recent studies have identified cerebrospinal fluid (CSF) as a crucial fluid source of initial cerebral edema following ischemic stroke and cardiac arrest. Moreover, synchronized neuronal firings drive CSF influx into interstitial fluid (ISF). Parenchymal border macrophages (PBMs) have been found to play a role in regulating CSF flow dynamics. However, the involvement of CSF and PBMs in cerebral edema during SE remains unclear. Here, we investigated the fluid source of cerebral edema in the initial phase of SE with the role of PBMs involved.MethodsLithium chloride-pilocarpine was used to induce SE in C57BL/6 J mice. Electroencephalogram (EEG) was acquired to assess changes in relative EEG power pre- and post-seizure onset. Apparent diffusion coefficient (ADC) maps reconstructed from diffusion-weighted imaging (DWI) were utilized to evaluate cytotoxic edema. Blood–brain barrier (BBB) permeability was examined using sodium fluorescein (NaFl). CSF tracer influx into the brain was assessed by transcranial imaging and brain slices. PBMs were depleted using clodronate liposomes. Immunohistochemistry was used to evaluate PBM depletion, severity of vasogenic edema, inflammation, and neuronal damage.ResultsDuring the initial stage of SE, relative EEG power sharply increased and ADC values significantly decreased. Concurrently, CSF tracer influx into the cortex significantly elevated, though NaFl leakage from blood to brain parenchyma did not evidently alter. Following depletion of PBM, CSF influx declined but AQP4 expression and polarization remained unaffected. Post-PBM depletion, there was no significant alteration in relative EEG power, yet CSF influx decreased substantially during the initial stage of SE. The degree of ADC decline lessened, IgG extravasation after SE decreased, activated microglia and proliferating astrocytes count fell, and neuronal damage post-SE alleviated.ConclusionsCSF appeared to contribute to cerebral edema in SE. Depletion of PBM alleviated cytotoxic edema in the initial phase of SE, and subsequent vasogenic edema, inflammatory response and neurological damage were reduced. These findings may provide potential novel strategies for treating cerebral edema following SE.

Cerebrospinal Fluid Flow Cytometry in Pediatric Acute Lymphoblastic Leukemia: A Multicenter Retrospective Study in China.

The central nervous system (CNS) is a frequent site of relapse in childhood acute lymphoblastic leukemia (ALL). This study aims to investigate the utility of cerebrospinal fluid (CSF) flow cytometry in detecting CNS infiltration and relapse. Flow cytometry was used to detect CSF leukemia cells, and patients were categorized into the CSF Flow+ and CSF Flow- groups. The primary outcome was the cumulative incidence of relapse (CIR) in the CSF Flow+ and CSF Flow- groups. A total of 1301 patients were enrolled, 159 patients (12.2%) showed positive CSF flow cytometry results. The CNS Flow+ patients exhibited significantly higher rates of any CNS relapse (22.5% vs. 0.2%, p < 0.01) and isolated CNS relapse (10.7% vs. 0%, p < 0.01) compared to CNS Flow- patients. Cox regression analysis revealed that risk factors for isolated CNS relapse included a positive result of D46 minimal residual disease (MRD) and CSF Flow+ at a non-initial diagnosis. For any CNS relapse, the significant risk factors were CSF Flow+ at the initial diagnosis and CSF Flow+ at a non-initial diagnosis. CSF flow cytometry may have clinical utility in detecting CNS infiltration among pediatric ALL patients. It could contribute to more effective risk stratification and treatment adjustments and potentially reduce the risk of CNS relapse.

Glial scarring limits recovery following decompressive surgery in rats with syringomyelia.

Syringomyelia is a neurological disease that is difficult to cure, and treatments often have limited effectiveness. In this study, a rat model of syringomyelia induced by epidural compression was used to investigate the factors that limit the prognosis of syringomyelia. After we treated syringomyelia rats with surgical decompression alone, MRI revealed that the syringomyelia rats did not show the expected therapeutic effect. Through cerebrospinal fluid (CSF) tracing experiments, we found that the CSF flow in the subarachnoid space (SAS) of rats was restored after decompression. This shows that the poor prognosis of syringomyelia rats in this study is not caused by CSF circulation disorders, suggesting the existence of other factors. Further, immunofluorescence revealed that there were extensive glial scars characterized by increased expression of glial fibrillary acidic protein (GFAP) and chondroitin sulfate proteoglycans (CSPGs) around the syrinx in the non-improved group compared to the improved group. To verify the limiting role of glial scarring in the prognosis of syringomyelia, we intervened with the selective astrocyte inhibitor fluorocitrate (FC). Intrathecal injection of FC significantly inhibited the formation of glial scar after decompression in syringomyelia rats and promoted the reduction of syrinx. This scar-inhibiting effect significantly improved neuronal survival, promoted axonal and myelin recovery, and showed better recovery in sensory function and fine motor control functions. These findings suggest that glial scarring around syrinx is a key factor limiting recovery of syringomyelia. By inhibiting glial scar formation, the prognosis of syringomyelia can be significantly improved, which provides a new strategy for improving clinical treatment effects.

Cardiac and respiratory activities induce temporal changes in cerebral blood volume, balanced by a mirror CSF volume displacement in the spinal canal.

Understanding cerebrospinal fluid (CSF) dynamics is crucial for elucidating the pathogenesis and diagnosis of neurodegenerative diseases. The primary mechanisms driving CSF oscillations remain a topic of debate. This study investigates whether cerebral blood volume displacement (CBV), modulated by breathing and cardiac activity, is the predominant drivers of CSF oscillations. We examined 12 healthy volunteers (aged 20-34 years) using a clinical 3T MRI scanner to quantify cerebral blood flow at the intracranial level and CSF flow at the C2-C3 spinal level under free and deep breathing conditions, utilizing real-time phase-contrast sequences. We then obtained CBV and CSF volume displacement (CSFV) curves by integrating the flow rate signals. Cardiac and respiratory signals were recorded during acquisition to reconstruct cardiac-driven and breath-driven CBV and CSFV curves. During deep breathing, compared to free breathing, the total cerebral arterial flow rate decreased by 29 % (from 12.5 ml/s to 8.8 ml/s), and the duration of the cardiac cycle period shortened by 15 % (0.90 s to 0.77 s), leading to reductions of 37 % and 23 % in cardiac-driven CBV and CSFV amplitudes, respectively. Conversely, breath-driven CBV and CSFV amplitudes increased substantially by 207 % and 326 %, respectively. Notably, during free breathing, cardiac-driven CBV and CSFV were significantly greater than their breath-driven counterparts; however, during deep breathing, the amplitudes of cardiac-driven and breath-driven CBV and CSFV did not differ significantly. CBV and CSFV curves demonstrated strong coupled inverse oscillation under both breathing conditions, with consistent CSF inflow toward the intracranial compartment during inspiration. This study quantifies the contributions of cardiac and breathing activities to CBV and CSFV under varying breathing patterns, confirming that CBV changes, driven by cardiac and respiratory activities, are strongly inversely coupled with CSF oscillations. These findings enhance our understanding of CSF circulation mechanisms and offer potential diagnostic implications for neurodegenerative diseases.

Modeling of the brain movement and cerebrospinal fluid flow within porous subarachnoid space under translational impacts

Modeling of the brain movement and cerebrospinal fluid flow within porous subarachnoid space under translational impacts

Actin-based deformations of the nucleus control mouse multiciliated ependymal cell differentiation.

Ependymal cells (ECs) are multiciliated cells in the brain that contribute to cerebrospinal fluid flow. ECs are specified during embryonic stages but differentiate later in development. Their differentiation depends on genes such as GEMC1 and MCIDAS in conjunction with E2F4/5 as well as on cell-cycle-related factors. In the mouse brain, we observe that nuclear deformation accompanies EC differentiation. Tampering with these deformations either by decreasing F-actin levels or by severing the link between the nucleus and the actin cytoskeleton blocks differentiation. Conversely, increasing F-actin by knocking out the Arp2/3 complex inhibitor Arpin or artificially deforming the nucleus activates differentiation. These data are consistent with actin polymerization triggering nuclear deformation and jump starting the signaling that produces ECs. A player in this process is the retinoblastoma 1 (RB1) protein, whose phosphorylation prompts MCIDAS activation. Overall, this study identifies a role for actin-based mechanical inputs to the nucleus as controlling factors in cell differentiation.

Directional ciliary beats across epithelia require Ccdc57-mediated coupling between axonemal orientation and basal body polarity

Motile cilia unify their axonemal orientations (AOs), or beat directions, across epithelia to drive liquid flows. This planar polarity results from cytoskeleton-driven swiveling of basal foot (BF), a basal body (BB) appendage coincident with the AO, in response to regulatory cues. How and when the BF-AO relationship is established, however, are unaddressed. Here, we show that the BF-AO coupling occurs during rotational polarizations of BBs and requires Ccdc57. Ccdc57 localizes on BBs as a rotationally-asymmetric punctum, which polarizes away from the BF in BBs having achieved the rotational polarity to probably fix the BF-AO relationship. Consistently, Ccdc57-deficient ependymal multicilia lack the BF-AO coupling and display directional beats at only single cell level. Ccdc57 −/− tracheal multicilia also fail to fully align their BFs. Furthermore, Ccdc57 −/− mice manifest severe hydrocephalus, due to impaired cerebrospinal fluid flow, and high mortality. These findings unravel mechanisms governing the planar polarity of epithelial motile cilia.

Attentional failures after sleep deprivation represent moments of cerebrospinal fluid flow.

Sleep deprivation rapidly disrupts cognitive function, and in the long term contributes to neurological disease. Why sleep deprivation has such profound effects on cognition is not well understood. Here, we use simultaneous fast fMRI-EEG to test how sleep deprivation modulates cognitive, neural, and fluid dynamics in the human brain. We demonstrate that after sleep deprivation, sleep-like pulsatile cerebrospinal fluid (CSF) flow events intrude into the awake state. CSF flow is coupled to attentional function, with high flow during attentional impairment. Furthermore, CSF flow is tightly orchestrated in a series of brain-body changes including broadband neuronal shifts, pupil constriction, and altered systemic physiology, pointing to a coupled system of fluid dynamics and neuromodulatory state. The timing of these dynamics is consistent with a vascular mechanism regulated by neuromodulatory state, in which CSF begins to flow outward when attention fails, and flow reverses when attention recovers. The attentional costs of sleep deprivation may thus reflect an irrepressible need for neuronal rest periods and widespread pulsatile fluid flow.

Dysregulated neurofluid coupling as a new noninvasive biomarker for primary progressive aphasia

Accumulation of pathological tau is one of the primary causes of Primary Progressive Aphasia (PPA). The glymphatic system is crucial for removing metabolite waste from the brain whereas impairments in glymphatic clearance in PPA are poorly understood. Thus, this study aims to investigate the role of dysregulated macroscopic cerebrospinal fluid (CSF) movement in PPA. Fifty-six PPA individuals and ninety-four healthy controls were included in our analysis after excluding those with excessive head motions during the scan. The coupling strength between blood-oxygen-level-dependent (BOLD) signals in the gray matter and CSF flow was calculated using Pearson correlation and compared between the groups. Its associations with clinical characteristics including scores from Clinical Dementia Rating (CDR), Mini-Mental State Exam, Geriatric Depression Scale and with morphological measures in the hippocampus and entorhinal cortex were examined. PPA subjects exhibited weaker global BOLD-CSF coupling compared to HCs, indicating impairments in glymphatic function in the patients (p = 0.01). In the PPA but not HC group, global BOLD-CSF coupling correlated with the CDR scores (p = 0.04) and hippocampal volume (p = 0.009). The observed decoupling between global brain activity and CSF flow and its association with symptomatology and brain structural changes in PPA converges with previous reports on the same measure in other neurodegenerative diseases. These findings support the potential role of global BOLD-CSF coupling as a noninvasive marker for glymphatic dysregulation in PPA.