Coupled pulsatile vascular and paravascular fluid dynamics in the human brain.

BACKGROUND: Cardiac pulsation propels blood through the cerebrovascular network to maintain cerebral homeostasis. The cerebrovascular network is uniquely surrounded by paravascular cerebrospinal fluid (pCSF), which plays a crucial role in waste removal, and its flow is suspected to be driven by arterial pulsations. Despite its importance, the relationship between vascular and paravascular fluid dynamics throughout the cardiac cycle remains poorly understood in humans. METHODS: In this study, we developed a non-invasive neuroimaging approach to investigate the coupling between pulsatile vascular and pCSF dynamics within the subarachnoid space of the human brain. Resting-state functional MRI (fMRI) and dynamic diffusion-weighted imaging (dynDWI) were retrospectively cardiac-aligned to represent cerebral hemodynamics and pCSF motion, respectively. We measured the time between peaks (∆TTP) in d d ϕ f M R I and dynDWI waveforms and measured their coupling by calculating the waveforms correlation after peak alignment (correlation at aligned peaks). We compared the ∆TTP and correlation at aligned peaks between younger [mean age: 27.9 (3.3) years, n = 9] and older adults [mean age: 70.5 (6.6) years, n = 20], and assessed their reproducibility within subjects and across different imaging protocols. RESULTS: Hemodynamic changes consistently precede pCSF motion. ∆TTP was significantly shorter in younger adults compared to older adults (-0.015 vs. -0.069, p < 0.05). The correlation at aligned peaks were high and did not differ between younger and older adults (0.833 vs. 0.776, p = 0.153). The ∆TTP and correlation at aligned peaks were robust across fMRI protocols (∆TTP: -0.15 vs. -0.053, p = 0.239; correlation at aligned peaks: 0.813 vs. 0.812, p = 0.985) and demonstrated good to excellent within-subject reproducibility (∆TTP: intraclass correlation coefficient = 0.36; correlation at aligned peaks: intraclass correlation coefficient = 0.89). CONCLUSION: This study proposes a non-invasive technique to evaluate vascular and paravascular fluid dynamics. Our findings reveal a consistent and robust cardiac pulsation-driven coupling between cerebral hemodynamics and pCSF dynamics in both younger and older adults.

Comment on, "Superb microvascular ultrasound is a promising non-invasive diagnostic tool to assess a ventriculoperitoneal shunt system function: a feasibility study".

This study by Brawanski et al. (2024) contributes significantly to neurosurgery by assessing ventriculoperitoneal shunt (VPS) function using superb microvascular ultrasound (SMI). The authors provide a thorough evaluation of SMI as a novel, non-invasive diagnostic tool, demonstrating its effectiveness in detecting cerebrospinal fluid (CSF) flow within VPS systems. By focusing on asymptomatic hydrocephalus patients, the study offers a less invasive alternative to traditional diagnostic methods, potentially reducing the need for exploratory surgeries. However, the study could have been strengthened by exploring the variability of SMI measurements under different physiological conditions and including symptomatic patients. Additionally, further analysis of the long-term reliability of SMI is needed. Future research should expand the study's scope to assess SMI's diagnostic capabilities across varied conditions and explore its integration with other non-invasive techniques, thereby enhancing its clinical utility in managing hydrocephalus and VPS functionality.

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

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Regulation of brain fluid volumes and pressures: basic principles, intracranial hypertension, ventriculomegaly and hydrocephalus.

The principles of cerebrospinal fluid (CSF) production, circulation and outflow and regulation of fluid volumes and pressures in the normal brain are summarised. Abnormalities in these aspects in intracranial hypertension, ventriculomegaly and hydrocephalus are discussed. The brain parenchyma has a cellular framework with interstitial fluid (ISF) in the intervening spaces. Framework stress and interstitial fluid pressure (ISFP) combined provide the total stress which, after allowing for gravity, normally equals intracerebral pressure (ICP) with gradients of total stress too small to measure. Fluid pressure may differ from ICP in the parenchyma and collapsed subarachnoid spaces when the parenchyma presses against the meninges. Fluid pressure gradients determine fluid movements. In adults, restricting CSF outflow from subarachnoid spaces produces intracranial hypertension which, when CSF volumes change very little, is called idiopathic intracranial hypertension (iIH). Raised ICP in iIH is accompanied by increased venous sinus pressure, though which is cause and which effect is unclear. In infants with growing skulls, restriction in outflow leads to increased head and CSF volumes. In adults, ventriculomegaly can arise due to cerebral atrophy or, in hydrocephalus, to obstructions to intracranial CSF flow. In non-communicating hydrocephalus, flow through or out of the ventricles is somehow obstructed, whereas in communicating hydrocephalus, the obstruction is somewhere between the cisterna magna and cranial sites of outflow. When normal outflow routes are obstructed, continued CSF production in the ventricles may be partially balanced by outflow through the parenchyma via an oedematous periventricular layer and perivascular spaces. In adults, secondary hydrocephalus with raised ICP results from obvious obstructions to flow. By contrast, with the more subtly obstructed flow seen in normal pressure hydrocephalus (NPH), fluid pressure must be reduced elsewhere, e.g. in some subarachnoid spaces. In idiopathic NPH, where ventriculomegaly is accompanied by gait disturbance, dementia and/or urinary incontinence, the functional deficits can sometimes be reversed by shunting or third ventriculostomy. Parenchymal shrinkage is irreversible in late stage hydrocephalus with cellular framework loss but may not occur in early stages, whether by exclusion of fluid or otherwise. Further studies that are needed to explain the development of hydrocephalus are outlined.

Global brain activity and its coupling with cerebrospinal fluid flow is related to tau pathology.

Amyloid-ß (Aß) and tau deposition constitute Alzheimer's disease (AD) neuropathology. Cortical tau deposits first in the entorhinal cortex and hippocampus and then propagates to neocortex in an Aß-dependent manner. Tau also tends to accumulate earlier in higher-order association cortex than in lower-order primary sensory-motor cortex. While previous research has examined the production and spread of tau, little attention has been paid to its clearance. Low-frequency (<0.1 Hz) global brain activity during the resting state is coupled with cerebrospinal fluid (CSF) flow and potentially reflects glymphatic clearance. Here we report that tau deposition in subjects with evaluated Aß, accompanied by cortical thinning and cognitive decline, is strongly associated with decreased coupling between CSF flow and global brain activity. Substantial modulation of global brain activity is also manifested as propagating waves of brain activation between higher- and lower-order regions, resembling tau spreading. Together, the findings suggest an important role of resting-state global brain activity in AD tau pathology.

Correspondence between development of cytotoxic edema and cerebrospinal fluid volume and flow in the third ventricle after ischemic stroke.

OBJECTIVES: The importance of monitoring cerebrospinal fluid for the development of edema in ischemic stroke has been emphasized; however, studies on the relationship between intraventricular cerebrospinal fluid behavior and edema through longitudinal observations and analysis are rare. This study aimed to investigate the correlation between the development of cytotoxic edema and cerebrospinal fluid volume and flow in the third ventricle after ischemic stroke. MATERIALS AND METHODS: The ventricle and edema regions were obtained using apparent diffusion coefficients and T2 and subdivided into lateral/ventral 3rd ventricles and cytotoxic/vasogenic (or cyst) edema, respectively. In rat models of ischemic stroke, the volume and flow (via the pseudo-diffusion coefficient [D*]) of the ventricles and edema volumes were longitudinally monitored for up to 45 days after surgery. RESULTS: The volume of cytotoxic edema increased in the hyperacute and acute phases, whereas the volume (r = -0.49) and median D* values (r = -0.48 in the anterior-posterior direction) of the ventral 3rd ventricle both decreased, showing negative correlations with the volume of cytotoxic edema. In contrast, the volume of vasogenic edema/cyst was positively correlated with the volume (r = 0.73) and median D* values (r = 0.78 in the anterior-posterior direction) of the lateral ventricle in the subacute and chronic phases. CONCLUSIONS: This study showed that the evolution of cerebrospinal fluid volume and flow in the ventricles was associated with edema progression at different time points in the ischemic stroke brain. This provides an efficient framework for monitoring and quantifying the interplay between cerebrospinal fluid and edema.

Loading neural stem cells on hydrogel scaffold improves cell retention rate and promotes functional recovery in traumatic brain injury.

Neural stem cell (NSC) has gained considerable attention in traumatic brain injury (TBI) treatment because of their ability to replenish dysfunctional neurons and stimulate endogenous neurorestorative processes. However, their therapeutic effects are hindered by the low cell retention rate after transplantation into the dynamic brain. In this study, we found cerebrospinal fluid (CSF) flow after TBI is an important factor associated with cell loss following NSC transplantation. Recently, several studies have shown that hydrogels could serve as a beneficial carrier for stem cell transplantation, which provides a solution to prevent CSF flow-induced cell loss after TBI. For this purpose, we evaluated three different hydrogel scaffolds and found the gelatin methacrylate (GelMA)/sodium alginate (Alg) (GelMA/Alg) hydrogel scaffold showed the best capabilities for NSC adherence, growth, and differentiation. Additionally, we detected that pre-differentiated NSCs, which were loaded on the GelMA/Alg hydrogel and cultured for 7 days in neuronal differentiation medium (NSC [7d]), had the highest cell retention rate after CSF impact. Next, the neuroprotective effects of the NSC-loaded GelMA/Alg hydrogel scaffold were evaluated in a rat model of TBI. NSC [7d]-loaded GelMA/Alg markedly decreased microglial activation and neuronal death in the acute phase, reduced tissue loss, alleviated astrogliosis, promoted neurogenesis, and improved neurological recovery in the chronic phase. In summary, we demonstrated that the integration with the GelMA/Alg and modification of NSC differentiation could inhibit the influence of CSF flow on transplanted NSCs, leading to increased number of retained NSCs and improved neuroprotective effects, providing a promising alternative for TBI treatment.

Quantitative assessment of cerebrospinal fluid flow and volume in enlargement of the subarachnoid spaces of infancy using MRI.

BACKGROUND: The etiology of enlarged subarachnoid spaces of infancy is unknown; however, there is radiologic similarity with normal pressure hydrocephalus. Adults with normal pressure hydrocephalus have been shown to have altered cerebrospinal (CSF) flow through the cerebral aqueduct. OBJECTIVE: To explore potential similarity between enlarged subarachnoid spaces of infancy and normal pressure hydrocephalus, we compared MRI-measured CSF flow through the cerebral aqueduct in infants with enlarged subarachnoid spaces of infancy to infants with normal brain MRIs. MATERIALS AND METHODS: This was an IRB approved retrospective study. Clinical brain MRI examinations including axial T2 imaging and phase contrast through the aqueduct were reviewed for infants with enlarged subarachnoid spaces of infancy and for infants with a qualitatively normal brain MRI. The brain and CSF volumes were segmented using a semi-automatic technique (Analyze 12.0) and CSF flow parameters were measured (cvi42, 5.14). All data was assessed for significant differences while controlling for age and sex using analysis of covariance (ANCOVA). RESULTS: Twenty-two patients with enlarged subarachnoid spaces (mean age 9.0 months, 19 males) and 15 patients with normal brain MRI (mean age 18.9 months, 8 females) were included. Volumes of the subarachnoid space (P < 0.001), lateral (P < 0.001), and third ventricles (P < 0.001) were significantly larger in infants with enlarged subarachnoid spaces of infancy. Aqueductal stroke volume significantly increased with age (P = 0.005), regardless of group. CONCLUSION: CSF volumes were significantly larger in infants with enlarged subarachnoid spaces of infancy versus infants with a normal MRI; however, there was no significant difference in CSF flow parameters between the two groups.

Artificial intelligence velocimetry reveals in vivo flow rates, pressure gradients, and shear stresses in murine perivascular flows.

Quantifying the flow of cerebrospinal fluid (CSF) is crucial for understanding brain waste clearance and nutrient delivery, as well as edema in pathological conditions such as stroke. However, existing in vivo techniques are limited to sparse velocity measurements in pial perivascular spaces (PVSs) or low-resolution measurements from brain-wide imaging. Additionally, volume flow rate, pressure, and shear stress variation in PVSs are essentially impossible to measure in vivo. Here, we show that artificial intelligence velocimetry (AIV) can integrate sparse velocity measurements with physics-informed neural networks to quantify CSF flow in PVSs. With AIV, we infer three-dimensional (3D), high-resolution velocity, pressure, and shear stress. Validation comes from training with 70% of PTV measurements and demonstrating close agreement with the remaining 30%. A sensitivity analysis on the AIV inputs shows that the uncertainty in AIV inferred quantities due to uncertainties in the PVS boundary locations inherent to in vivo imaging is less than 30%, and the uncertainty from the neural net initialization is less than 1%. In PVSs of N = 4 wild-type mice we find mean flow speed 16.33 ± 11.09 µm/s, volume flow rate 2.22 ± 1.983 × 103 µm3/s, axial pressure gradient ( - 2.75 ± 2.01)×10-4 Pa/µm (-2.07 ± 1.51 mmHg/m), and wall shear stress (3.00 ± 1.45)×10-3 Pa (all mean ± SE). Pressure gradients, flow rates, and resistances agree with prior predictions. AIV infers in vivo PVS flows in remarkable detail, which will improve fluid dynamic models and potentially clarify how CSF flow changes with aging, Alzheimer's disease, and small vessel disease.

Blood and cerebrospinal fluid flow oscillations measured with real-time phase-contrast MRI: breathing mode matters.

BACKGROUND: Cervical blood and cerebrospinal fluid (CSF) flow rates can be quantified with Phase-contrast (PC) MRI, which is routinely used for clinical studies. Previous MRI studies showed that venous and CSF flow alterations are linked to various pathological conditions. Since it is well known that, besides the heart beating, the thoracic pump influences the blood and CSF dynamics, we studied the effect of different respiration modes on blood and CSF flow rates using a real-time (RT)-PC prototype. METHODS: Thirty healthy volunteers were examined with a 3 T scanner. A RT-PC sequence was acquired at the first cervical level to quantify the flow rates of internal carotid arteries, internal jugular veins (IJVs) and CSF. Each RT-PC acquisition was repeated three times, while the subjects were asked to breathe in three different ways for 60 s each: freely (F), with a constant rate (PN) and with deep and constant respiration rate (PD). The average flow rates were computed, they were removed from the respective signals and integrated in the inspiratory and expiratory phases (differential volumes). Finally, the power spectral density was computed for each detrended flow rate. High- and very-high frequency peaks were identified on the spectra while their frequencies were compared to the respiratory and cardiac frequencies estimated using a thoracic belt and a pulse oximeter. The area under the spectra was computed in four 0.5 Hz-wide ranges, centered on the high-frequency peak, on very-high frequency peak and its 2nd and 3rd harmonics, and then they were normalized by the flow rate variance. The effect of breathing patterns on average flow rates, on systolic and diastolic peaks, and on the normalized power was tested. Finally, the differential volumes of inspiration were compared to those of expiration. RESULTS: The frequencies of the high- and very-high spectral peaks corresponded to the respiratory and cardiac frequencies. The average flow rate progressively decreased from F to PN to PD breathing, and the cardiac modulations were less predominant especially for the IJVs. The respiratory modulation increased with PD breathing. The average volumes displaced in the inspiratory phases were not significantly different from those of the expiratory one. CONCLUSIONS: The spectral analyses demonstrated higher respiratory modulations in PD compared to free breathing, even prevailing the cardiac modulation in the IJVs, showing an increment of the thoracic pump affecting the flow rate shape.

Zebrafish: an important model for understanding scoliosis.

Scoliosis is a common spinal deformity that considerably affects the physical and psychological health of patients. Studies have shown that genetic factors play an important role in scoliosis. However, its etiopathogenesis remain unclear, partially because of the genetic heterogeneity of scoliosis and the lack of appropriate model systems. Recently, the development of efficient gene editing methods and high-throughput sequencing technology has made it possible to explore the underlying pathological mechanisms of scoliosis. Owing to their susceptibility for developing scoliosis and high genetic homology with human, zebrafish are increasingly being used as a model for scoliosis in developmental biology, genetics, and clinical medicine. Here, we summarize the recent advances in scoliosis research on zebrafish and discuss the prospects of using zebrafish as a scoliosis model.

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.

Real-Time Phase-Contrast MRI to Monitor Cervical Blood and Cerebrospinal Fluid Flow Beat-by-Beat Variability.

Beat-by-beat variability (BBV) rhythms are observed in both cardiovascular (CV) and intracranial (IC) compartments, yet interactions between the two are not fully understood. Real-Time Phase-Contrast (RT-PC) MRI sequence was acquired for 30 healthy volunteers at 1st cervical level on a 3T scanner. The arterial (AF), venous (VF), and cerebrospinal fluid (CSF) flow (CSFF) were computed as velocity integrals over the internal carotid artery, internal jugular vein, and CSF. AF, VF, and CSFF signals were segmented in inspiration and expiration beats, to assess the respiration influence. Systolic and diastolic BBV, and heart period series underwent autoregressive power spectral density analysis, to evaluate the low-frequency (LF, Mayer waves) and high frequency (HF, respiratory waves) components. The diastolic VF had the largest BBV. LF power was high in the diastolic AF series, poor in all CSFF series. The pulse wave analyses revealed higher mean amplitude during inspiration. Findings suggests a possible role of LF modulation of IC resistances and propagation of HF waves from VF to AF and CCSF. PC-RT-MRI could provide new insight into the interaction between CV and IC regulation and pave the way for a detailed analysis of the cerebrovascular effects of varied respiration patterns due to exercise and rehabilitation.

Cerebrospinal Fluid Flow Detection in Post-hemorrhagic Hydrocephalus With Novel Microvascular Imaging Modality.

Cerebrospinal fluid flow dynamics serve as an important biomarker to guide medical and/or surgical intervention of hydrocephalus in infants. Imaging of cerebrospinal fluid flow can be assessed with magnetic resonance imaging, but routine evaluation is limited by practical challenges. We show for the first time that cerebrospinal fluid flow can be depicted using brain ultrasound by implementing highly sensitive ultrasound-based microvascular imaging technology (B-flow). This novel application could potentially expand the use of this technology beyond its current application in depiction of vascular flow pathologies in newborns.

D* from diffusion MRI reveals a correspondence between ventricular cerebrospinal fluid volume and flow in the ischemic rodent model.

Quantitative measurement of cerebrospinal fluid (CSF) flow and volume and longitudinal monitoring of CSF dynamics provide insights into the compensatory characteristics of post-stroke CSF. In this study, we compared the MRI pseudo-diffusion index (D*) of live and sacrificed rat brains to confirm the effect of ventricular CSF flow on diffusion signals. We observed the relationship between the CSF peak velocities and D* through Monte Carlo (MC) simulations to further understand the source of D* contrast. We also determined the dominant CSF flow using D* in three directions. Finally, we investigated the dynamic evolutions of ventricular CSF flow and volume in a stroke rat model (n = 8) from preoperative to up to 45 days after surgery and determined the correlation between ventricular CSF volume and flow. MC simulations showed a strong positive correlation between the CSF peak velocity and D* (r = 0.99). The dominant CSF flow variations in the 3D ventricle could be measured using the maximum D* map. A longitudinal positive correlation between ventricular CSF volume and D* was observed in the lateral (r = 0.74) and ventral-third (r = 0.81) ventricles, respectively. The directional D* measurements provide quantitative CSF volume and flow information, which would provide useful insights into ischemic stroke with diffusion MRI.

Decoupling of Global Brain Activity and Cerebrospinal Fluid Flow in Parkinson's Disease Cognitive Decline.

BACKGROUND: Deposition and spreading of misfolded proteins (α-synuclein and tau) have been linked to Parkinson's disease cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow, which may reflect glymphatic function. OBJECTIVE: The objective of this current study was to determine if the decoupling of brain activity-CSF flow is linked to Parkinson's disease cognitive dysfunction. METHODS: Functional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment [MoCA]) scores were collected from 60 Parkinson's disease and 58 control subjects. Parkinson's disease patients were subgrouped into those with mild cognitive impairment (MoCA < 26), n = 31, and those without mild cognitive impairment (MoCA ≥ 26), n = 29. The coupling strength between the resting-state global blood-oxygen-level-dependent signal and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. RESULTS: Global blood-oxygen-level-dependent signal-CSF coupling decreased significantly (P < 0.006) in Parkinson's disease patients showing mild cognitive impairment, compared with those without mild cognitive impairment and controls. Reduced global blood-oxygen-level-dependent signal-CSF coupling was associated with decreased MoCA scores present in Parkinson's disease patients (P = 0.005) but not in controls (P = 0.65). Weaker global blood-oxygen-level-dependent signal-CSF coupling in Parkinson's disease patients also was associated with a thinner right entorhinal cortex (Spearman's correlation, -0.36; P = 0.012), an early structural change often seen in Alzheimer's disease. CONCLUSIONS: The decoupling between global brain activity and associated CSF flow is related to Parkinson's disease cognitive impairment. © 2021 International Parkinson and Movement Disorder Society.

Choroid Plexus and Drug Removal Mechanisms.

Timely and efficient removal of xenobiotics and metabolites from the brain is crucial in maintaining the homeostasis and normal function of the brain. The choroid plexus (CP) forms the blood-cerebrospinal fluid barrier and vitally removes drugs and wastes from the brain through several co-existing clearance mechanisms. The CP epithelial (CPE) cells synthesize and secrete the cerebrospinal fluid (CSF). As the CSF passes through the ventricular and subarachnoid spaces and eventually drains into the general circulation, it collects and removes drugs, toxins, and metabolic wastes from the brain. This bulk flow of the CSF serves as a default and non-selective pathway for the removal of solutes and macromolecules from the brain interstitium. Besides clearance by CSF bulk flow, the CPE cells express several multispecific membrane transporters to actively transport substrates from the CSF side into the blood side. In addition, several phase I and II drug-metabolizing enzymes are expressed in the CPE cells, which enzymatically inactivate a broad spectrum of reactive or toxic substances. This review summarizes our current knowledge of the functional characteristics and key contributors to the various clearance pathways in the CP-CSF system, overviewing recent developments in our understanding of CSF flow dynamics and the functional roles of CP uptake and efflux transporters in influencing CSF drug concentrations.

Cerebrospinal fluid flow driven by arterial pulsations in axisymmetric perivascular spaces: Analogy with Taylor's swimming sheet.

Cerebrospinal fluid (CSF) flow in the perivascular space (PVS), which surrounds the arteries in the brain, is of paramount importance in the removal of metabolic waste. Despite a number of experimental and numerical studies regarding CSF flow, the underlying mechanics of CSF flow are still debated, especially regarding whether an arterial pulsation can indeed produce net CSF flow velocity. Furthermore, the relationship between CSF flow and arterial wall pulsation has not been fully defined. To clarify these questions, we numerically investigated the CSF flow in the PVS in an axisymmetric channel with a pulsating boundary, where CSF is modeled as an incompressible, Newtonian viscous fluid in non-porous space. Our numerical results show that the net CSF flow velocity driven by the arterial pulsation is consistent with that of previous animal experiments. However, the peak oscillatory velocity is two orders of magnitude larger than the net velocity. Interestingly, the net CSF flow velocity collapses on the analytical solution derived from the lubrication theory in analogy with Taylor's swimming sheet model.

Utility of True Fast Imaging with Steady-State Precession in Detecting Arachnoid Veils of the Posterior Fossa.

INTRODUCTION: Arachnoid membranes are well recognized as a cause of cerebrospinal fluid (CSF) flow impairment in disorders such as obstructive hydrocephalus and syringohydromyelia, but can be difficult to detect with standard noninvasive imaging techniques. True fast imaging with steady-state precession (TrueFISP) can exhibit brain pulsations and CSF dynamics with high spatiotemporal resolution. Here, we demonstrate the utility of this technique in the diagnosis and management of arachnoid membranes in the posterior fossa. CASE PRESENTATIONS: Three symptomatic children underwent cine TrueFISP imaging for suspicion of CSF membranous obstruction. Whereas standard imaging failed to or did not clearly visualize the site of an obstructive lesion, preoperative TrueFISP identified a membrane in all 3 cases. The membranes were confirmed intraoperatively, and postoperative TrueFISP helped verify adequate marsupialization and recommunication of CSF flow. Two out of the 3 cases showed a decrease in cerebellar tonsillar pulsatility following surgery. All children showed symptomatic improvement. CONCLUSION: TrueFISP is able to detect pulsatile arachnoid membranes responsible for CSF outflow obstruction that are otherwise difficult to visualize using standard imaging techniques. We advocate use of this technology in pre- and postsurgical decision-making as it provides a more representative image of posterior fossa pathology and contributes to our understanding of CSF flow dynamics. There is potential to use this technology to establish prognostic biomarkers for disorders of CSF hydrodynamics.

Mapping of CSF transport using high spatiotemporal resolution dynamic contrast-enhanced MRI in mice: Effect of anesthesia.

PURPOSE: Dynamic contrast-enhanced MRI (DCE-MRI) represents the only available approach for glymphatic cerebrospinal fluid (CSF) flow 3D mapping in the brain of living animals and humans. The purpose of this study was to develop a novel DCE-MRI protocol for mapping of the glymphatic system transport with improved spatiotemporal resolution, and to validate the new protocol by comparing the transport in mice anesthetized with either isoflurane or ketamine/xylazine. METHODS: The contrast agent, gadobutrol, was administered into the CSF of the cisterna magna and its transport visualized continuously on a 9.4T preclinical scanner using 3D fast-imaging with a steady-state free-precession sequence (3D-FISP), which has a spatial resolution of 0.001 mm3 and a temporal resolution of 30 s. The MR signals were measured dynamically for 60 min in multiple volumes of interest covering the entire CSF space and brain parenchyma. RESULTS: The results confirm earlier findings that glymphatic CSF influx is higher under ketamine/xylazine than with isoflurane anesthesia. This was extended to account for new details about the distinct CSF efflux pathways under the two anesthetic regimens. Dynamic contrast MR shows that CSF clearance occurs mainly along the vagus nerve near the jugular vein under isoflurane and via the olfactory bulb under ketamine/xylazine. CONCLUSION: The improved spatial and temporal sampling rates afforded by 3D-FISP shed new light on the pharmacological modulation of CSF efflux paths. The present observations may have the potential to set a new standard for future experimental DCE-MRI studies of the glymphatic system.