Cerebrospinal Fluid Flow Dynamics Research Articles

A novel minimally invasive and versatile kyphoplasty balloon-based model of porcine spinal cord injury

IntroductionSpinal cord injury (SCI) animal models often utilize an open surgical laminectomy, which results in animal morbidity and also leads to changes in spinal canal diameter, spinal cord perfusion, cerebrospinal fluid flow dynamics, and spinal stability which may confound SCI research. Moreover, the use of open surgical laminectomy for injury creation lacks realism when considering human SCI scenarios.MethodsWe developed a novel, image-guided, minimally invasive, large animal model of SCI which utilizes a kyphoplasty balloon inserted into the epidural space via an interlaminar approach without the need for open surgery.ResultsThe model was validated in 5 Yucatán pigs with imaging, neurofunctional, histologic, and electrophysiologic findings consistent with a mild compression injury.DiscussionFew large animal models exist that have the potential to reproduce the mechanisms of spinal cord injury (SCI) commonly seen in humans, which in turn limits the relevance and applicability of SCI translational research. SCI research relies heavily on animal models, which typically involve an open surgical, dorsal laminectomy which is inherently invasive and may have untoward consequences on animal morbidity and spinal physiology that limit translational impact. We developed a minimally invasive, large animal model of spinal cord injury which utilizes a kyphoplasty balloon inserted percutaneously into the spinal epidural space. Balloon inflation results in a targeted, compressive spinal cord injury with histological and electrophysiological features directly relevant to human spinal cord injury cases without the need for invasive surgery. Balloon inflation pressure, length of time that balloon remains inflated, and speed of inflation may be modified to achieve variations in injury severity and subtype.

Age related cerebrospinal fluid flow dynamics in the subarachnoid space of the optic nerve in patients with normal tension glaucoma, measured by diffusion weighted MRI.

We aimed to measure cerebrospinal fluid (CSF) flow rates in the subarachnoid space (SAS) of the optic nerve (ON) by applying non-invasive diffusion-weighted MRI in patients with normal tension glaucoma (NTG) compared to age-matched controls. In this prospective study, an analysis of diffusion-weighted images of 26 patients with NTG (49ONs) and age-matched volunteers (52ONs) was conducted. Subjects were classified into 4 groups: group I (50-59 y., n = 12 eyes), group II (60-69 y., n = 16 eyes), group III (70-79 y., n = 18 eyes) and group IV ( > 80 y., n = 6 eyes) for NTGs and healthy volunteers, respectively. The flow-range ratio (FRR) between the frontal lobe SAS and the SAS of the ON was calculated for each age category group and then compared between age-categories as well as between NTGs and controls. The mean FRR for age groups were (I) 0.54 ± 0.06 and 0.62 ± 0.03 (p < 0.05), (II) 0.56 ± 0.08 and 0.63 ± 0.03 (p < 0.05), (III) 0.54 ± 0.06 and 0.62 ± 0.02 (p < 0.001) as well as (IV) 0.61 ± 0.03 and 0.61 ± 0.04, for NTGs and controls, respectively. Using pooled data, the difference between the FRR in NTGs and controls was statistically significant (p < 0.0001). There were no statistically significant differences within the age categories of the control group. When comparing the FRR of NTGs by age categories, no statistically significant difference was found between the subgroups. FRR was significantly reduced in NTGs compared to age-matched controls without any significant differences within the age groups themselves. Given the physiological importance of CSF for the integrity of neurons, axons and glial cells, reduced CSF flow dynamics might be part of the underlying neurodegenerative process of NTG.

Cranioplasty Outcomes from a Tertiary Hospital in a Developing Country.

Decompressive craniectomy (DC) is a surgical procedure to treat refractory increase in intracranial pressure. DC is frequently succeeded by cranioplasty (CP), a reconstructive procedure to protect the underlying brain and maintain cerebrospinal fluid flow dynamics. However, complications such as seizures, fluid collections, infections, and hydrocephalus can arise from CP. Our aim is to investigate these complications and their possible risk factors and to discuss whether early or late CP has any effect on the outcome. A single-center retrospective cohort study was performed, including patients who underwent CP after DC between January 2014 and January 2022. Relevant information was collected such as demographics, type of brain injury, materials used in CP, timing between DC and CP, and postoperative complications. Ultimately, 63 patients were included in our study. We also compared the complication rate between patients who underwent late CP after DC (>90 days) against patients who underwent early CP (<90 days). Most patients were male (78%). The sample median age was 29 years, with pediatric patients, accounting for 36% of the samples. Overall complication rate was 57% and they were seizure/epilepsy in 50% of the patients, fluid collection (28%), infections (25%), posttraumatic hydrocephalus (17%), and bone defect/resorption (3%). Twenty-two percent of patients with complications required reoperation and underwent a second CP. The median (interquartile range) duration between the craniotomy and the CP was 56 (27-102) days, with an early (≤3 months) percentage of 68%. We found no significant difference between early (≤3 months) and late (>3 months) CP regarding complication rates. Despite CP being a simple procedure, it has a considerable rate of complications. Therefore, it is important that surgeons possess adequate knowledge about such complications to navigate these challenges more effectively.

Is foramen magnum decompression for acquired Chiari I malformation like putting a finger in the dyke? - A simplistic overview of artificial intelligence in assessing critical upstream and downstream etiologies.

Missed diagnosis of evolving or coexisting idiopathic (IIH) and spontaneous intracranial hypotension (SIH) is often the reason for persistent or worsening symptoms after foramen magnum decompression for Chiari malformation (CM) I. We explore the role of artificial intelligence (AI)/convolutional neural networks (CNN) in Chiari I malformation in a combinatorial role for the first time in literature, exploring both upstream and downstream magnetic resonance findings as initial screening profilers in CM-1. We have also put together a review of all existing subtypes of CM and discuss the role of upright (gravity-aided) magnetic resonance imaging (MRI) in evaluating equivocal tonsillar descent on a lying-down MRI. We have formulated a workflow algorithm MaChiP 1.0 (Manjila Chiari Protocol 1.0) using upstream and downstream profilers, that cause de novo or worsening Chiari I malformation, which we plan to implement using AI. The PRISMA guidelines were used for "CM and machine learning and CNN" on PubMed database articles, and four articles specific to the topic were encountered. The radiologic criteria for IIH and SIH were applied from neurosurgical literature, and they were applied between primary and secondary (acquired) Chiari I malformations. An upstream etiology such as IIH or SIH and an isolated downstream etiology in the spine were characterized using the existing body of literature. We propose the utility of using four selected criteria for IIH and SIH each, over MRI T2 images of the brain and spine, predominantly sagittal sequences in upstream etiology in the brain and multiplanar MRI in spinal lesions. Using MaChiP 1.0 (patent/ copyright pending) concepts, we have proposed the upstream and downstream profilers implicated in progressive Chiari I malformation. The upstream profilers included findings of brain sagging, slope of the third ventricular floor, pontomesencephalic angle, mamillopontine distance, lateral ventricular angle, internal cerebral vein-vein of Galen angle, and displacement of iter, clivus length, tonsillar descent, etc., suggestive of SIH. The IIH features noted in upstream pathologies were posterior flattening of globe of the eye, partial empty sella, optic nerve sheath distortion, and optic nerve tortuosity in MRI. The downstream etiologies involved spinal cerebrospinal fluid (CSF) leak from dural tear, meningeal diverticula, CSF-venous fistulae, etc. AI would help offer predictive analysis along the spectrum of upstream and downstream etiologies, ensuring safety and efficacy in treating secondary (acquired) Chiari I malformation, especially with coexisting IIH and SIH. The MaChiP 1.0 algorithm can help document worsening of a previously diagnosed CM-1 and find the exact etiology of a secondary CM-I. However, the role of posterior fossa morphometry and cine-flow MRI data for intracranial CSF flow dynamics, along with advanced spinal CSF studies using dynamic myelo-CT scanning in the formation of secondary CM-I is still being evaluated.

Neurocognitive outcome post cranioplasty: The role of cerebral hemodynamics and cerebrospinal fluid dynamics.

Cranioplasty has been useful in treating the symptoms associated with the "Sunken skin flap syndrome" post decompressive craniectomy, for which various mechanisms have been proposed. In this study, we aim to assess the changes in the cerebral blood flow and intracranial cerebrospinal fluid (CSF) dynamics post cranioplasty and correlate with the improvement in the neurocognitive status. Computed tomography perfusion and cine magnetic resonance imaging studies were done to study the changes in cerebral perfusion and CSF flow dynamics postcranioplasty. The cognitive status was assessed using Montreal cognitive assessment, mini-mental state examination, and frontal assessment battery scores in the preoperative period and at 1 and 6 months follow-up. There was a significant change in cognitive status postcranioplasty, both at 1 and 6 months follow-up, which was associated with a significant improvement in cerebral blood flow, decreased mean transit time, and improvement in the mean and peak CSF flow velocities at the foramen of Magendie and aqueduct of Sylvius. Cranioplasty leads to a marked improvement in cerebral hemodynamics, which is more significant on the ipsilateral side. It also leads to increased CSF turnover and improved CSF circulation. Improved cerebral perfusion and, more importantly, CSF dynamics may be responsible for the demonstrable improvement in the neurocognition in the postcranioplasty period.

Four-dimensional flow MRI for quantitative assessment of cerebrospinal fluid dynamics: Status and opportunities.

Neurological disorders can manifest with altered neurofluid dynamics in different compartments of the central nervous system. These include alterations in cerebral blood flow, cerebrospinal fluid (CSF) flow, and tissue biomechanics. Noninvasive quantitative assessment of neurofluid flow and tissue motion is feasible with phase contrast magnetic resonance imaging (PC MRI). While two-dimensional (2D) PC MRI is routinely utilized in research and clinical settings to assess flow dynamics through a single imaging slice, comprehensive neurofluid dynamic assessment can be limited or impractical. Recently, four-dimensional (4D) flow MRI (or time-resolved three-dimensional PC with three-directional velocity encoding) has emerged as a powerful extension of 2D PC, allowing for large volumetric coverage of fluid velocities at high spatiotemporal resolution within clinically reasonable scan times. Yet, most 4D flow studies have focused on blood flow imaging. Characterizing CSF flow dynamics with 4D flow (i.e., 4D CSF flow) is of high interest to understand normal brain and spine physiology, but also to study neurological disorders such as dysfunctional brain metabolite waste clearance, where CSF dynamics appear to play an important role. However, 4D CSF flow imaging is challenged by the long T1 time of CSF and slower velocities compared with blood flow, which can result in longer scan times from low flip angles and extended motion-sensitive gradients, hindering clinical adoption. In this work, we review the state of 4D CSF flow MRI including challenges, novel solutions from current research and ongoing needs, examples of clinical and research applications, and discuss an outlook on the future of 4D CSF flow.

Advanced cerebrospinal fluid flow MRI findings of aqueductal stenosis caused by web.

The aqueductal web (AW) is one of the causes of aqueductus stenosis (AS). Recent advances in Magnetic resonance (MR) imaging have enabled us to better reveal the cerebrospinal fluid (CSF) flow dynamics and aqueductal anatomy. The aim of this study is to evaluate the CSF flow dynamics of patients with AW with phase contrast Magnetic resonance imaging (MRI) and compare them with the imaging findings. We evaluated 23 patients under 65-year-old age. On constructive interference in steady-state (T2 CISS) images, the width of prepontine cistern (PPC) and the width of Sylvian aqueduct (SA) were measured. Localization and number of webs were evaluated. The existence of flow at the aqueduct and the presence of spontaneous third ventriculostomy (STV) were evaluated on sagittal Sampling Perfection with Application optimized Contrast (SPACE) sequences. Of the 23 patients included in the study, 11 were male and 12 were female. The mean age was 34.02 (0.5-64). A total of 31 AWs were detected in 23 patients. Six of 23 patients (26.1%) had STV and 17 of those not. Four of 23 patients (17.4%) had aqueductal flow on SPACE sequences. The PPC distance was significantly wider in patients with STV (median: 6.7-4.5, interquartile range (IQR): 1.35, p = 0.004). In the cases where artifact secondary to flow is observed in SPACE sequences in aqueduct, the Evan index (EI) was significantly lower (median: 0.2955-0.3900, IQR: 0.03-0.14, p < 0.001). In patients with a low EI, there may be flow in the SA even if there is a web. In patients with a wide PPC distance, it is necessary to consider the presence of STV and evaluate the presence of flow with the SPACE sequences.

Engineering choroid plexus-on-a-chip with oscillatory flow for modeling brain metastasis.

The human brain choroid plexus (ChP) is a highly organized secretory tissue with a complex vascular system and epithelial layers in the ventricles of the brain. The ChP is the body's principal source of cerebrospinal fluid (CSF); it also functions as a barrier to separate the blood from CSF, because the movement of CSF through the body is pulsatile in nature. Thus far, it has been challenging to recreate the specialized features and dynamics of the ChP in a physiologically relevant microenvironment. In this study, we recapitulated the ChP structure by developing a microfluidic chip in accordance with established design rules. Furthermore, we used image processing and analysis to mimic CSF flow dynamics within a rlcking system; we also used a hydrogel containing laminin to mimic brain extracellular matrix (ECM). Human ChP cells were cultured in the ChP-on-a-chip with in vivo-like CSF dynamic flow and an engineered ECM. The key ChP characteristics of capillaries, the epithelial layer, and secreted components were recreated in the adjusted microenvironment of our human ChP-on-a-chip. The drug screening capabilities of the device were observed through physiologically relevant drug responses from breast cancer cells that had spread in the ChP. ChP immune responses were also recapitulated in this device, as demonstrated by the motility and cytotoxic effects of macrophages, which are the most prevalent immune cells in the ChP. Our human ChP-on-a-chip will facilitate the elucidation of ChP pathophysiology and support the development of therapeutics to treat cancers that have metastasized into the ChP.

Heterozygous FOXJ1 Mutations Cause Incomplete Ependymal Cell Differentiation and Communicating Hydrocephalus

Heterozygous mutations affecting FOXJ1, a transcription factor governing multiciliated cell development, have been associated with obstructive hydrocephalus in humans. However, factors that disrupt multiciliated ependymal cell function often cause communicating hydrocephalus, raising questions about whether FOXJ1 mutations cause hydrocephalus primarily by blocking cerebrospinal fluid (CSF) flow or by different mechanisms. Here, we show that heterozygous FOXJ1 mutations are also associated with communicating hydrocephalus in humans and cause communicating hydrocephalus in mice. Disruption of one Foxj1 allele in mice leads to incomplete ependymal cell differentiation and communicating hydrocephalus. Mature ependymal cell number and motile cilia number are decreased, and 12% of motile cilia display abnormal axonemes. We observed decreased microtubule attachment to basal bodies, random localization and orientation of basal body patches, loss of planar cell polarity, and a disruption of unidirectional CSF flow. Thus, heterozygous FOXJ1 mutations impair ventricular multiciliated cell differentiation, thereby causing communicating hydrocephalus. CSF flow obstruction may develop secondarily in some patients harboring FOXJ1 mutations.Graphical Heterozygous FOXJ1 mutations impair motile cilia structure and basal body alignment, thereby disrupting CSF flow dynamics and causing communicating hydrocephalus.

Neuroendoscopy-Assisted Minimal Invasive Management of Chiari 1 Malformation.

Objective The aim this study is to present the results of the minimal invasive neuroendoscopic-assisted system application as an alternative to traditional surgery in patients with Chiari malformation type 1 (CM type 1) with/without syringomyelia. Design, Setting, and Participants In the study, data of 22 symptomatic patients were prospectively collected. Before and after the operation, patient characteristics, computed tomography, magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) flow dynamics MRI, and outcome scales scores were recorded. Foramen magnum decompression and C1 total laminectomy were performed. The fibrous band at the craniocervical junction was opened and a durotomy was performed. In patients with a syrinx, the pre- and postoperative axial and sagittal lengths of the syrinx were measured and compared. Results The mean age of the patients was 32 ± 5 years. There were eight male patients. Ten patients had syrinx. The mean visual analog scale (VAS) score before and after surgery was 8 ± 1.06 and 2.18 ± 1.13, respectively. When evaluated according to the Chicago Chiari Outcome Scale, there was improvement in 20 patients, while there was no change in 2 patients. Syrinx resolved completely in 3 of 10 (13.6%) patients with syringomyelia, and the syrinx volume decreased in 3 patients (13.6%). In 4 of 10 (18.1%) patients, there was no significant change in the syrinx volume. The average operation time was 105 minutes (80-150 minutes). The average blood loss was 40 mL (20-110 mL). Conclusion Although the study was limited due to the small number of patients with a short follow-up, endoscopic decompression was a safe and effective technique for surgery in CM type 1 patients.

Cerebrospinal Fluid Flow in Patients with Huntington's Disease.

Investigations of cerebrospinal fluid (CSF) flow aberrations in Huntington's disease (HD) are of growing interest, as impaired CSF flow may contribute to mutant Huntington retention and observed heterogeneous responsiveness to intrathecally administered therapies. We assessed net cerebral aqueduct CSF flow and velocity in 29 HD participants (17 premanifest and 12 manifest) and 51 age- and sex matched non-HD control participants using 3-Tesla magnetic resonance imaging methods. Regression models were applied to test hypotheses regarding: (i) net CSF flow and cohort, (ii) net CSF flow and disease severity (CAP-score), and (iii) CSF volume after correcting for age and sex. Group-wise analyses support a decrease in net CSF flow in HD (mean 0.14 ± 0.27 mL/min) relative to control (mean 0.32 ± 0.20 mL/min) participants (p = 0.02), with lowest flow in the manifest HD cohort (mean 0.04 ± 0.25 mL/min). This finding was explained by hyperdynamic CSF movement, manifesting as higher caudal systolic CSF flow velocity and higher diastolic cranial CSF flow velocity across the cardiac cycle, in HD (caudal flow: 0.17 ± 0.07 mL/s, cranial flow: 0.14 ± 0.08 mL/s) compared to control (caudal flow: 0.13 ± 0.06 mL/s, cranial flow: 0.11 ± 0.04 mL/s) participants. A positive correlation between cranial diastolic flow and disease severity was observed (p = 0.02). Findings support aqueductal CSF flow dynamics changing with disease severity in HD. These accelerated changes are consistent with changes observed over the typical adult lifespan, and may have relevance to mutant Huntington retention and intrathecally administered therapeutics responsiveness. ANN NEUROL 2023;94:885-894.

Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure

BackgroundIt is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance.MethodsICP was monitored continuously in patients who underwent placement of an external ventricular drain (EVD) and by telemetric monitoring in experimental rats. CSF was collected via the EVD in patients and the rodent CSF secretion rate determined by in vivo experimentation. Rodent choroid plexus transporter transcripts were quantified with RNAseq and transport activity with ex vivo isotope transport assays.ResultsWe demonstrated that ICP increases by 30% in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients (12%) and CSF production rate in rats (20%), the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl- cotransporter (NKCC1), which is implicated in CSF secretion by this tissue.ConclusionCSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity in the rat. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.

Effectiveness of Tailored Exercise Protocol on Functional Independence in Post Laminectomy Induced Paraparesis – A Case Study

The compression and decompression junction are a potential site for spinal cord distortion. Cord compression could result from the changed cerebrospinal fluid flow dynamics. Para paresis will occur due to direct trauma sustained during surgery or postoperative hematomas and there is 16% of secondary disease, because of non-traumatic injuries and 84% of spinal cord injury are due to trauma and 2 to 5 times the individuals will die prematurely due to spinal cord injury. Case report of a patient, having D8-L1 wedge compression fracture undergone surgical laminectomy, for which specific exercise protocol designed to improve muscle strength, activities of daily living and reduce clonus. post-operatively patient complained of weakness in bilateral lower limb, and he was dependent on others for his daily life activities, so our aim was to make the patient independent and he should be able to transfer from bed to wheelchair and reduce clonus. Tailored protocol was designed for patient’s functional independence by bed mobility, transfer skills, muscle strengthening by using different scales, and he was trained five sessions in a week for three months. After implementing the exercise program like strengthening exercises for bilateral upper limbs, bed mobility training, stretching of bilateral lower limb muscles for clonus and transfer skills using tailored protocol for twelve weeks there was improvement in all parameters. Keywords: Paraplegia, Functional independence, Tailored exercise

Evaluation of the Cerebrospinal Fluid Flow Dynamics with Microvascular Imaging Ultrasound in Infants.

Microvascular imaging ultrasound (MVI) can detect slow blood flow in small-caliber cerebral vessels. This technology may help assess flow in other intracranial structures, such as the ventricular system. In this study, we describe the use of MVI for characterizing intraventricular cerebrospinal fluid (CSF) flow dynamics in infants. We included infants with brain ultrasound that had MVI B-Flow cine clips in the sagittal plane. Two blinded reviewers examined the images, dictated a diagnostic impression, and identified the third ventricle, cerebral aqueduct, fourth ventricle, and CSF flow direction. A third reviewer evaluated the discrepancies. We evaluated the association of visualization of CSF flow as detectable with MVI, with the diagnostic impressions. We also assessed the inter-rater reliability (IRR) for detecting CSF flow. We evaluated 101 infants, mean age 40 ± 53 days. Based on brain MVI B-Flow, a total of 49 patients had normal brain US scans, 40 had hydrocephalus, 26 had intraventricular hemorrhage (IVH), and 14 had hydrocephalus+IVH. Using spatially moving MVI signal in the third ventricle, cerebral aqueduct, and fourth ventricle as the criteria for CSF flow, CSF flow was identified in 10.9% (n = 11), 15.8% (n = 16), and 16.8% (n = 17) of cases, respectively. Flow direction was detected in 19.8% (n = 20) of cases; 70% (n = 14) was caudocranial, 15% (n = 3) was craniocaudal, and 15% (n = 3) bidirectional, with IRR = 0.662, p < 0.001. Visualization of CSF flow was significantly associated with the presence of IVH alone (OR 9.7 [3.3-29.0], p < 0.001) and IVH+hydrocephalus (OR 12.4 [3.5-440], p < 0.001), but not with hydrocephalus alone (p = 0.116). This study demonstrates that MVI can detect CSF flow dynamics in infants with a history of post-hemorrhagic hydrocephalus with a high IRR.

Hydrocephalic cerebrospinal fluid flowing rotationally with pulsatile boundaries: A mathematical simulation of the thermodynamical approach

To study the kinematics of flow rate and ventricular dilatation, an analytical perturbation approach of hydrocephalus has been devised. This research provides a comprehensive investigation of the characteristics of cerebrospinal fluid (CSF) flow and pressure in a hydrocephalic patient. The influence of hydrocephalic CSF, flowing rotationally with realistic dynamical characteristics on pulsatile boundaries of subarachnoid space, was demonstrated using a nonlinear controlling system of CSF. An analytical perturbation method of hydrocephalus has been developed to investigate the biomechanics of fluid flow rate and the ventricular enlargement. In this paper presents a detailed analysis of CSF flow and pressure dynamics in a hydrocephalic patient. It was elaborated with a nonlinear governing model of CSF to show the influence of hydrocephalic CSF, flowing rotationally with realistic dynamical behaviors on pulsatile boundaries of subarachnoid space. In accordance with the suggested model, the elasticity factor changes depending on how much a porous layer, in this case the brain parenchyma, is stretched. It was improved to include the relaxation of internal mechanical stresses for various perturbation orders, modelling the potential plasticity of brain tissue. The initial geometry that was utilised to create the framework of CSF with pathological disease hydrocephalus and indeed the output of simulations using this model were compared to the actual progression of ventricular dimensions and shapes in patients. According to this observation, the non - linear and elastic mechanical phenomena incorporated into the current model are probably true. Further modelling of ventricular dilation at a normal pressure may benefit from the existence of a valid model whose parameters approximate genuine mechanical characteristics of the cerebral cortex.

Parenchymal border macrophages regulate the flow dynamics of the cerebrospinal fluid.

Macrophages are important players in the maintenance of tissue homeostasis1. Perivascular and leptomeningeal macrophages reside near the central nervous system (CNS) parenchyma2, and their role in CNS physiology has not been sufficiently well studied. Given their continuous interaction with the cerebrospinal fluid (CSF) and strategic positioning, we refer to these cells collectively as parenchymal border macrophages (PBMs). Here we demonstrate that PBMs regulate CSF flow dynamics. We identify a subpopulation of PBMs that express high levels of CD163 and LYVE1 (scavenger receptor proteins), closely associated with the brain arterial tree, and show that LYVE1+ PBMs regulate arterial motion that drives CSF flow. Pharmacological or genetic depletion of PBMs led to accumulation of extracellular matrix proteins, obstructing CSF access to perivascular spaces and impairing CNS perfusion and clearance. Ageing-associated alterations in PBMs and impairment of CSF dynamics were restored after intracisternal injection of macrophage colony-stimulating factor. Single-nucleus RNA sequencing data obtained from patients with Alzheimer's disease (AD) and from non-AD individuals point to changes in phagocytosis, endocytosis and interferon-γ signalling on PBMs, pathways that are corroborated in a mouse model of AD. Collectively, our results identify PBMs as new cellular regulators of CSF flow dynamics, which could be targeted pharmacologically to alleviate brain clearance deficits associated with ageing and AD.

Measuring brain beats: Cardiac-aligned fast functional magnetic resonance imaging signals.

Blood and cerebrospinal fluid (CSF) pulse and flow throughout the brain, driven by the cardiac cycle. These fluid dynamics, which are essential to healthy brain function, are characterized by several noninvasive magnetic resonance imaging (MRI) methods. Recent developments in fast MRI, specifically simultaneous multislice acquisition methods, provide a new opportunity to rapidly and broadly assess cardiac-driven flow, including CSF spaces, surface vessels and parenchymal vessels. We use these techniques to assess blood and CSF flow dynamics in brief (3.5min) scans on a conventional 3T MRI scanner in five subjects. Cardiac pulses are measured with a photoplethysmography (PPG) on the index finger, along with functional MRI (fMRI) signals in the brain. We, retrospectively, align the fMRI signals to the heartbeat. Highly reliable cardiac-gated fMRI temporal signals are observed in CSF and blood on the timescale of one heartbeat (test-retest reliability within subjects R2 > 50%). In blood vessels, a local minimum is observed following systole. In CSF spaces, the ventricles and subarachnoid spaces have a local maximum following systole instead. Slower resting-state scans with slice timing, retrospectively, aligned to the cardiac pulse, reveal similar cardiac-gated responses. The cardiac-gated measurements estimate the amplitude and phase of fMRI pulsations in the CSF relative to those in the arteries, an estimate of the local intracranial impedance. Cardiac aligned fMRI signals can provide new insights about fluid dynamics or diagnostics for diseases where these dynamics are important.

Influence of the area of the aqueduct and region of interest on quantification of stroke volume in healthy volunteers using phase-contrast cine magnetic resonance imaging.

Phase-contrast cine magnetic resonance imaging (PC-MRI) has been used to measure cerebrospinal fluid (CSF) flow dynamics, but the influence of the area of the aqueduct and region of interest (ROI) on quantification of stroke volume (SV) has not been assessed. To assess the influence of the area of the ROI in quantifying the aqueductal SV measured with PC-MRI within the cerebral aqueduct. Nine healthy volunteers (mean age = 29.6 years) were enrolled in the study, and brain MRI examinations were performed on a 3.0-T system. Quantitative analysis of the aqueductal CSF flow was performed using manual ROI placement. ROIs were separately drawn for each of the 12 phases of the cardiac cycle, and changes in aqueduct size during the cardiac cycle were determined. The SV was calculated using 12 different aqueductal ROIs and compared with the SV calculated using a fixed ROI size. There was variation in the size of the aqueduct during the cardiac cycle. In addition, the measured SV increased with a greater area of the ROI. A significant difference in the calculated SVs with the 12 variable ROIs was observed compared with that using a fixed ROI throughout the cardiac cycle. To establish reliable reference values for the SV in future studies, a variable ROI should be considered.

Surgical Management of Chiari Malformation Type I Associated with Syringomyelia: Outcome of Surgeries Based on the New Classification and Study of Cerebrospinal Fluid Dynamics.

Introduction: The mainstay of treatment of syringomyelia associated with Chiari malformation type I (CM-I) is the management of CM-I to normalize the cerebrospinal fluid (CSF) flow at the foramen magnum. CM-I is classified into three independent types. Surgical treatment was selected based on the mechanism of hindbrain ptosis in each CM-I type. Materials and Methods: Foramen magnum decompression (FMD: 213 cases), expansive suboccipital cranioplasty (ESCP: 87 cases), and craniocervical fixation (CCF: 30 cases) were performed. CSF flow dynamics were assessed pre- and post-surgery using cine phase contrast magnetic resonance imaging. During surgery, CSF flow dynamics were examined using color Doppler ultrasonography (CDU). Results: ESCP and FMD demonstrated high rates of improvement in neurological symptoms and signs (82.7%), whereas CCF demonstrated a high rate of improvement in neurological symptoms (89%). The pre-operative maximum flow velocity (cm/s) was significantly lower in patients than in controls and increased post-operatively. During surgery, CDU indicated that the volume of the major cistern was 8 mL, and the maximum flow velocity was >3 mL/s. Conclusions: An appropriate surgical treatment should be selected for CM-I to correct hindbrain ptosis. In addition, it is necessary to confirm the normalization of CSF flow at the foramen of Magendie.

Cerebrovascular activity is a major factor in the cerebrospinal fluid flow dynamics

Cerebrospinal fluid (CSF) provides physical protection to the central nervous system as well as an essential homeostatic environment for the normal functioning of neurons. Additionally, it has been proposed that the pulsatile movement of CSF may assist in glymphatic clearance of brain metabolic waste products implicated in neurodegeneration. In awake humans, CSF flow dynamics are thought to be driven primarily by cerebral blood volume fluctuations resulting from a number of mechanisms, including a passive vascular response to blood pressure variations associated with cardiac and respiratory cycles. Recent research has shown that mechanisms that rely on the action of vascular smooth muscle cells (“cerebrovascular activity”) such as neuronal activity, changes in intravascular CO2, and autonomic activation from the brainstem, may lead to CSF pulsations as well. Nevertheless, the relative contribution of these mechanisms to CSF flow remains unclear. To investigate this further, we developed an MRI approach capable of disentangling and quantifying CSF flow components of different time scales associated with these mechanisms. This approach was evaluated on human control subjects (n = 12) performing intermittent voluntary deep inspirations, by determining peak flow velocities and displaced volumes between these mechanisms in the fourth ventricle.We found that peak flow velocities were similar between the different mechanisms, while displaced volumes per cycle were about a magnitude larger for deep inspirations. CSF flow velocity peaked at around 10.4 s (range 7.1–14.8 s, n = 12) following deep inspiration, consistent with known cerebrovascular activation delays for this autonomic challenge. These findings point to an important role of cerebrovascular activity in the genesis of CSF pulsations. Other regulatory triggers for cerebral blood flow such as autonomic arousal and orthostatic challenges may create major CSF pulsatile movement as well. Future quantitative comparison of these and possibly additional types of CSF pulsations with the proposed approach may help clarify the conditions that affect CSF flow dynamics.