Large-scale in-silico analysis of CSF dynamics within the subarachnoid space of the optic nerve.

BACKGROUND: Impaired cerebrospinal fluid (CSF) dynamics is involved in the pathophysiology of neurodegenerative diseases of the central nervous system and the optic nerve (ON), including Alzheimer's and Parkinson's disease, as well as frontotemporal dementia. The smallness and intricate architecture of the optic nerve subarachnoid space (ONSAS) hamper accurate measurements of CSF dynamics in this space, and effects of geometrical changes due to pathophysiological processes remain unclear. The aim of this study is to investigate CSF dynamics and its response to structural alterations of the ONSAS, from first principles, with supercomputers. METHODS: Large-scale in-silico investigations were performed by means of computational fluid dynamics (CFD) analysis. High-order direct numerical simulations (DNS) have been carried out on ONSAS geometry at a resolution of 1.625 µm/pixel. Morphological changes on the ONSAS microstructure have been examined in relation to CSF pressure gradient (CSFPG) and wall strain rate, a quantitative proxy for mass transfer of solutes. RESULTS: A physiological flow speed of 0.5 mm/s is achieved by imposing a hydrostatic pressure gradient of 0.37-0.67 Pa/mm across the ONSAS structure. At constant volumetric rate, the relationship between pressure gradient and CSF-accessible volume is well captured by an exponential curve. The ONSAS microstructure exhibits superior mass transfer compared to other geometrical shapes considered. An ONSAS featuring no microstructure displays a threefold smaller surface area, and a 17-fold decrease in mass transfer rate. Moreover, ONSAS trabeculae seem key players in mass transfer. CONCLUSIONS: The present analysis suggests that a pressure drop of 0.1-0.2 mmHg over 4 cm is sufficient to steadily drive CSF through the entire subarachnoid space. Despite low hydraulic resistance, great heterogeneity in flow speeds puts certain areas of the ONSAS at risk of stagnation. Alterations of the ONSAS architecture aimed at mimicking pathological conditions highlight direct relationships between CSF volume and drainage capability. Compared to the morphological manipulations considered herein, the original ONSAS architecture seems optimized towards providing maximum mass transfer across a wide range of pressure gradients and volumetric rates, with emphasis on trabecular structures. This might shed light on pathophysiological processes leading to damage associated with insufficient CSF flow in patients with optic nerve compartment syndrome.

Pulsatile cerebral paraarterial flow by peristalsis, pressure and directional resistance.

BACKGROUND: A glymphatic system has been proposed that comprises flow that enters along cerebral paraarterial channels between the artery wall and the surrounding glial layer, continues through the parenchyma, and then exits along similar paravenous channels. The mechanism driving flow through this system is unclear. The pulsatile (oscillatory plus mean) flow measured in the space surrounding the middle cerebral artery (MCA) suggests that peristalsis created by intravascular blood pressure pulses is a candidate for the paraarterial flow in the subarachnoid spaces. However, peristalsis is ineffective in driving significant mean flow when the amplitude of channel wall motion is small, as has been observed in the MCA artery wall. In this paper, peristalsis in combination with two additional mechanisms, a longitudinal pressure gradient and directional flow resistance, is evaluated to match the measured MCA paraarterial oscillatory and mean flows. METHODS: Two analytical models are used that simplify the paraarterial branched network to a long continuous channel with a traveling wave in order to maximize the potential effect of peristalsis on the mean flow. The two models have parallel-plate and annulus geometries, respectively, with and without an added longitudinal pressure gradient. The effect of directional flow resistors was also evaluated for the parallel-plate geometry. RESULTS: For these models, the measured amplitude of arterial wall motion is too large to cause the small measured amplitude of oscillatory velocity, indicating that the outer wall must also move. At a combined motion matching the measured oscillatory velocity, peristalsis is incapable of driving enough mean flow. Directional flow resistance elements augment the mean flow, but not enough to provide a match. With a steady longitudinal pressure gradient, both oscillatory and mean flows can be matched to the measurements. CONCLUSIONS: These results suggest that peristalsis drives the oscillatory flow in the subarachnoid paraarterial space, but is incapable of driving the mean flow. The effect of directional flow resistors is insufficient to produce a match, but a small longitudinal pressure gradient is capable of creating the mean flow. Additional experiments are needed to confirm whether the outer wall also moves, as well as to validate the pressure gradient.

A mesothelium divides the subarachnoid space into functional compartments.

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport.

Changes in intrathoracic pressure, not arterial pulsations, exert the greatest effect on tracer influx in the spinal cord.

BACKGROUND: Cerebrospinal fluid (CSF) circulation in the brain has garnered considerable attention in recent times. In contrast, there have been fewer studies focused on the spine, despite the expected importance of CSF circulation in disorders specific to the spine, including syringomyelia. The driving forces that regulate spinal CSF flow are not well defined and are likely to be different to the brain given the anatomical differences and proximity to the heart and lungs. The aims of this study were to determine the effects of heart rate, blood pressure and respiration on the distribution of CSF tracers in the spinal subarachnoid space, as well as into the spinal cord interstitium. METHODS: In Sprague Dawley rats, physiological parameters were manipulated such that the effects of spontaneous breathing (generating alternating positive and negative intrathoracic pressures), mechanical ventilation (positive intrathoracic pressure only), tachy/bradycardia, as well as hyper/hypotension were separately studied. To investigate spinal CSF hydrodynamics, in vivo near-infrared imaging of intracisternally infused indocyanine green was performed. CSF tracer transport was further characterised with in vivo two-photon intravital imaging. Tracer influx at a microscopic level was quantitatively characterised by ex vivo epifluorescence imaging of fluorescent ovalbumin. RESULTS: Compared to mechanically ventilated controls, spontaneous breathing animals had significantly greater movement of tracer in the subarachnoid space. There was also greater influx into the spinal cord interstitium. Hypertension and tachycardia had no significant effect on spinal subarachnoid spinal CSF tracer flux and exerted less effect than respiration on tracer influx into the spinal cord. CONCLUSIONS: Intrathoracic pressure changes that occur over the respiratory cycle, particularly decreased intrathoracic pressures generated during inspiration, have a profound effect on tracer movement after injection into spinal CSF and increase cord parenchymal tracer influx. Arterial pulsations likely drive fluid transport from perivascular spaces into the surrounding interstitium, but their overall impact is less than that of the respiratory cycle on net tracer influx.

Intercompartmental communication between the cerebrospinal and adjacent spaces during intrathecal infusions in an acute ovine in-vivo model.

INTRODUCTION: The treatment of hydrocephalus has been a topic of intense research ever since the first clinically successful use of a valved cerebrospinal fluid shunt 72 years ago. While ample studies elucidating different phenomena impacting this treatment exist, there are still gaps to be filled. Specifically, how intracranial, intrathecal, arterial, and venous pressures react and communicate with each other simultaneously. METHODS: An in-vivo sheep trial (n = 6) was conducted to evaluate and quantify the communication existing within the cranio-spinal, arterial, and venous systems (1 kHz sampling frequency). Standardized intrathecal infusion testing was performed using an automated infusion apparatus, including bolus and constant pressure infusions. Bolus infusions entailed six lumbar intrathecal infusions of 2 mL Ringer's solution. Constant pressure infusions were comprised of six regulated pressure steps of 3.75 mmHg for periods of 7 min each. Mean pressure reactions, pulse amplitude reactions, and outflow resistance were calculated. RESULTS: All sheep showed intracranial pressure reactions to acute increases of intrathecal pressure, with four of six sheep showing clear cranio-spinal communication. During bolus infusions, the increases of mean pressure for intrathecal, intracranial, arterial, and venous pressure were 16.6 ± 0.9, 15.4 ± 0.8, 3.9 ± 0.8, and 0.1 ± 0.2 mmHg with corresponding pulse amplitude increases of 2.4 ± 0.3, 1.3 ± 0.3, 1.3 ± 0.3, and 0.2 ± 0.1 mmHg, respectively. During constant pressure infusions, mean increases from baseline were 14.6 ± 3.8, 15.5 ± 4.2, 4.2 ± 8.2, and 3.2 ± 2.4 mmHg with the corresponding pulse amplitude increases of 2.5 ± 3.6, 2.5 ± 3.0, 7.7 ± 4.3, and 0.7 ± 2.0 mmHg for intrathecal, intracranial, arterial, and venous pulse amplitude, respectively. Outflow resistances were calculated as 51.6 ± 7.8 and 77.8 ± 14.5 mmHg/mL/min for the bolus and constant pressure infusion methods, respectively-showing deviations between the two estimation methods. CONCLUSIONS: Standardized infusion tests with multi-compartmental pressure recordings in sheep have helped capture distinct reactions between the intrathecal, intracranial, arterial, and venous systems. Volumetric pressure changes in the intrathecal space have been shown to propagate to the intraventricular and arterial systems in our sample, and to the venous side in individual cases. These results represent an important step into achieving a more complete quantitative understanding of how an acute rise in intrathecal pressure can propagate and influence other systems.

CSF dynamics as a predictor of cognitive progression.

Disproportionately enlarged subarachnoid-space hydrocephalus (DESH), characterized by tight high convexity CSF spaces, ventriculomegaly, and enlarged Sylvian fissures, is thought to be an indirect marker of a CSF dynamics disorder. The clinical significance of DESH with regard to cognitive decline in a community setting is not yet well defined. The goal of this work is to determine if DESH is associated with cognitive decline. Participants in the population-based Mayo Clinic Study of Aging (MCSA) who met the following criteria were included: age ≥ 65 years, 3T MRI, and diagnosis of cognitively unimpaired or mild cognitive impairment at enrollment as well as at least one follow-up visit with cognitive testing. A support vector machine based method to detect the DESH imaging features on T1-weighted MRI was used to calculate a "DESH score", with positive scores indicating a more DESH-like imaging pattern. For the participants who were cognitively unimpaired at enrollment, a Cox proportional hazards model was fit with time defined as years from enrollment to first diagnosis of mild cognitive impairment or dementia, or as years to last known cognitively unimpaired diagnosis for those who did not progress. Linear mixed effects models were fit among all participants to estimate annual change in cognitive z scores for each domain (memory, attention, language, and visuospatial) and a global z score. For all models, covariates included age, sex, education, APOE genotype, cortical thickness, white matter hyperintensity volume, and total intracranial volume. The hazard of progression to cognitive impairment was an estimated 12% greater for a DESH score of +1 versus -1 (HR 1.12, 95% CI 0.97-1.31, p = 0.11). Global and attention cognition declined 0.015 (95% CI 0.005-0.025) and 0.016 (95% CI 0.005-0.028) z/year more, respectively, for a DESH score of +1 vs -1 (p = 0.01 and p = 0.02), with similar, though not statistically significant DESH effects in the other cognitive domains. Imaging features of disordered CSF dynamics are an independent predictor of subsequent cognitive decline in the MCSA, among other well-known factors including age, cortical thickness, and APOE status. Therefore, since DESH contributes to cognitive decline and is present in the general population, identifying individuals with DESH features may be important clinically as well as for selection in clinical trials.

Cerebrospinal fluid flow in normal beagle dogs analyzed using magnetic resonance imaging.

BACKGROUND: Diseases related to cerebrospinal fluid flow, such as hydrocephalus, syringomyelia, and Chiari malformation, are often found in small dogs. Although studies in human medicine have revealed a correlation with cerebrospinal fluid flow in these diseases by magnetic resonance imaging, there is little information and no standard data for normal dogs. OBJECTIVES: The purpose of this study was to obtain cerebrospinal fluid flow velocity data from the cerebral aqueduct and subarachnoid space at the foramen magnum in healthy beagle dogs. METHODS: Six healthy beagle dogs were used in this experimental study. The dogs underwent phase-contrast and time-spatial labeling inversion pulse magnetic resonance imaging. Flow rate variations in the cerebrospinal fluid were observed using sagittal time-spatial labeling inversion pulse images. The pattern and velocity of cerebrospinal fluid flow were assessed using phase-contrast magnetic resonance imaging within the subarachnoid space at the foramen magnum level and the cerebral aqueduct. RESULTS: In the ventral aspect of the subarachnoid space and cerebral aqueduct, the cerebrospinal fluid was characterized by a bidirectional flow throughout the cardiac cycle. The mean ± SD peak velocities through the ventral and dorsal aspects of the subarachnoid space and the cerebral aqueduct were 1.39 ± 0.13, 0.32 ± 0.12, and 0.76 ± 0.43 cm/s, respectively. CONCLUSIONS: Noninvasive visualization of cerebrospinal fluid flow movement with magnetic resonance imaging was feasible, and a reference dataset of cerebrospinal fluid flow peak velocities was obtained through the cervical subarachnoid space and cerebral aqueduct in healthy dogs.

Cerebrospinal fluid drainage kinetics across the cribriform plate are reduced with aging.

BACKGROUND: Continuous circulation and drainage of cerebrospinal fluid (CSF) are essential for the elimination of CSF-borne metabolic products and neuronal function. While multiple CSF drainage pathways have been identified, the significance of each to normal drainage and whether there are differential changes at CSF outflow regions in the aging brain are unclear. METHODS: Dynamic in vivo imaging of near infrared fluorescently-labeled albumin was used to simultaneously visualize the flow of CSF at outflow regions on the dorsal side (transcranial and -spinal) of the central nervous system. This was followed by kinetic analysis, which included the elimination rate constants for these regions. In addition, tracer distribution in ex vivo tissues were assessed, including the nasal/cribriform region, dorsal and ventral surfaces of the brain, spinal cord, cranial dura, skull base, optic and trigeminal nerves and cervical lymph nodes. RESULTS: Based on the in vivo data, there was evidence of CSF elimination, as determined by the rate of clearance, from the nasal route across the cribriform plate and spinal subarachnoid space, but not from the dorsal dural regions. Using ex vivo tissue samples, the presence of tracer was confirmed in the cribriform area and olfactory regions, around pial blood vessels, spinal subarachnoid space, spinal cord and cervical lymph nodes but not for the dorsal dura, skull base or the other cranial nerves. Also, ex vivo tissues showed retention of tracer along brain fissures and regions associated with cisterns on the brain surfaces, but not in the brain parenchyma. Aging reduced CSF elimination across the cribriform plate but not that from the spinal SAS nor retention on the brain surfaces. CONCLUSIONS: Collectively, these data show that the main CSF outflow sites were the nasal region across the cribriform plate and from the spinal regions in mice. In young adult mice, the contribution of the nasal and cribriform route to outflow was much higher than from the spinal regions. In older mice, the contribution of the nasal route to CSF outflow was reduced significantly but not for the spinal routes. This kinetic approach may have significance in determining early changes in CSF drainage in neurological disorder, age-related cognitive decline and brain diseases.

Nonreflecting Boundary Conditions for a CSF Model of Fourth Ventricle: Spinal SAS Dynamics.

In this paper, we introduce a one-dimensional model for analyzing the cerebrospinal fluid dynamics within the fourth ventricle and the spinal subarachnoid space (SSAS). The model has been derived starting from an original model of Linninger et al. and from the detailed mathematical analysis of two different reformulations. We show the steps of the modelization and the rigorous analysis of the first-order nonlinear hyperbolic system of equations which rules the new CSF model, whose conservative-law form and characteristic form are required for the boundary conditions treatment. By assuming sub-critical flows, for the particular dynamics we are dealing with, the most desirable option is to employ the nonreflecting boundary conditions, that allow the simple wave associated with the outgoing characteristic to exit the computational domain with no reflections. Finally, we carry out some numerical simulations related to different cerebral physiological conditions.

Intracranial pressure elevation alters CSF clearance pathways.

BACKGROUND: Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models. METHODS: We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters. RESULTS: At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route. CONCLUSIONS: The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.

The Human Visual Pathway Communicates Directly With the Subarachnoid Space.

Purpose: Explore in vivo whether there is direct communication between the cerebrospinal fluid (CSF) and extravascular compartment of human visual pathway structures. Methods: A prospective and observational study included 10 subjects who underwent intrathecal gadolinium-enhanced magnetic resonance imaging (MRI) for suspected CSF circulation disorder, but with a negative result and with no known ophthalmic diseases. After precontrast T1-weighted MRI, 0.5 mL of gadobutrol (Gadovist, 1.0 mmol/mL) was injected intrathecally. Gadobutrol distributes in the extravascular space, and served as a CSF tracer. Consecutive MRI scans were obtained throughout 24 to 48 hours. To assess gadobutrol contrast enrichment, regions of interest (ROIs) were placed at multiple locations along the visual pathway, from the primary visual cortex to the eye's vitreous body. CSF tracer dependent T1 signal was measured in each ROI. A linear mixed-model was used for statistical analyses. Results: CSF tracer enrichment was found within the optic nerve, optic chiasm, optic tract, and primary visual cortex (P < 0.001). Peak tracer enrichment in the visual pathway generally occurred after 24 hours and was preceded by peak enhancement in the prechiasmatic cistern after 4 to 6 hours. Conclusions: The results indicate direct communication between CSF of subarachnoid space and the extravascular space of the human visual pathway. Extravascular entry of the CSF tracer is a prerequisite for a glymphatic system, the present findings may suggest its presence. The existence of a glymphatic system in the human visual pathway could bring novel perspectives on the pathophysiology and treatment of ophthalmic diseases.

Subject-Specific Studies of CSF Bulk Flow Patterns in the Spinal Canal: Implications for the Dispersion of Solute Particles in Intrathecal Drug Delivery.

BACKGROUND AND PURPOSE: Recent flow dynamics studies have shown that the eccentricity of the spinal cord affects the magnitude and characteristics of the slow bulk motion of CSF in the spinal subarachnoid space, which is an important variable in solute transport along the spinal canal. The goal of this study was to investigate how anatomic differences among subjects affect this bulk flow. MATERIALS AND METHODS: T2-weighted spinal images were obtained in 4 subjects and repeated in 1 subject after repositioning. CSF velocity was calculated from phase-contrast MR images for 7 equally spaced levels along the length of the spine. This information was input into a 2-time-scale asymptotic analysis of the Navier-Stokes and concentration equations to calculate the short- and long-term CSF flow in the spinal subarachnoid space. Bulk flow streamlines were shown for each subject and position and inspected for differences in patterns. RESULTS: The 4 subjects had variable degrees of lordosis and kyphosis. Repositioning in 1 subject changed the degree of cervical lordosis and thoracic kyphosis. The streamlines of bulk flow show the existence of distinct regions where the fluid particles flow in circular patterns. The location and interconnectivity of these recirculating regions varied among individuals and different positions. CONCLUSIONS: Lordosis, kyphosis, and spinal cord eccentricity in the healthy human spine result in subject-specific patterns of bulk flow recirculating regions. The extent of the interconnectivity of the streamlines among these recirculating regions is fundamental in determining the long-term transport of solute particles along the spinal canal.

Impact of slow breathing on the blood pressure and subarachnoid space width oscillations in humans.

The aim of the study was to assess cardiac and respiratory blood pressure (BP) and subarachnoid space (SAS) width oscillations during the resting state for slow and fast breathing and breathing against inspiratory resistance. Experiments were performed on a group of 20 healthy volunteers (8 males and 12 females; age 25.3 ± 7.9 years; BMI = 22.1 ± 3.2 kg/m2). BP and heart rate (HR) were measured using continuous finger-pulse photoplethysmography. SAS signals were recorded using an SAS monitor. Oxyhaemoglobin saturation (SaO2) and end-tidal CO2 (EtCO2) were measured using a medical monitoring system. Procedure 1 consisted of breathing spontaneously and at controlled rates of 6 breaths/minute and 6 breaths/minute with inspiratory resistance for 10 minutes. Procedure 2 consisted of breathing spontaneously and at controlled rates of 6, 12 and 18 breaths/minute for 5 minutes. Wavelet analysis with the Morlet mother wavelet was applied for delineation of BP and SAS signals cardiac and respiratory components. Slow breathing diminishes amplitude of cardiac BP and SAS oscillations. The overall increase in BP and SAS oscillations during slow breathing is driven by the respiratory component. Drop in cardiac component of BP amplitude evoked by slow-breathing may be perceived as a cardiovascular protective mechanism to avoid target organ damage. Further studies are warranted to assess long-term effects of slow breathing.

Welfare and pregnancy rate of ewes undergoing transcervical artificial insemination with ketamine subarachnoid anesthesia.

This study aimed to evaluate the impact of subarachnoid anesthesia with ketamine during transcervical artificial insemination (TCAI) on the welfare of ewes and on subsequent pregnancy rates. Ninety Suffolk adult ewes were randomized into three treatment groups: control group (CG), which underwent the TCAI procedure as established by cervical traction (CG; n = 30) and two groups that received subarachnoid anesthesia with ketamine at a dose of either 0.75 mg/kg (KE0.75; n = 30) or 1.5 mg/kg (KE1.5; n = 30) 5 min before the cervical traction procedure. Intrauterine insemination was performed using frozen semen from three males previously analyzed and approved for fertility. The use of subarachnoid anesthesia decreased ewes' vocalizations (P = 0.0001) and abdominal contraction (P = 0.0150) during cervical manipulations. The CG had more groans and vocalizations at the moment of cervix clamping and applicator passage through the cervix (P = 0.001). The cervix traction was facilitated by anesthesia. For the control group, most of the cervical traction was done just up to the middle of the vagina (P = 0.0021). Pregnancy rates increased significantly with anesthesia (P = 0.04) as shown by the rates of 40.0%, 56.7%, and 66.7% for CG, KE1.5, and KE0.75, respectively. The CG showed behaviors associated with absolute immobility, which is suggestive of distress. In brief, the use of ketamine in subarachnoid anesthesia for transcervical artificial insemination in ewes facilitated cervical traction, increased the pregnancy rate, and improved animal welfare.

Coupling of Blood Pressure and Subarachnoid Space Oscillations at Cardiac Frequency Evoked by Handgrip and Cold Tests: A Bispectral Analysis.

The aim of the study was to assess blood pressure-subarachnoid space (BP-SAS) width coupling properties using time-frequency bispectral analysis based on wavelet transforms during handgrip and cold tests. The experiments were performed on a group of 16 healthy subjects (F/M; 7/9) of the mean age 27.2 ± 6.8 years and body mass index of 23.8 ± 4.1 kg/m2. The sequence of challenges was first handgrip and then cold test. The handgrip challenge consisted of a 2-min strain, indicated by oral communication from the investigator, at 30% of maximum strength. The cold test consisted of 2 min of hand immersion to approximately wrist level in cold water of 4 °C, verified by a digital thermometer. Each test was preceded by 10 min at baseline and was followed by 10-min recovery recordings. BP and SAS were recorded simultaneously. Three 2-min stages of the procedure, baseline, test, and recovery, were analyzed. We found that BP-SAS coupling was present only at cardiac frequency, while at respiratory frequency both oscillators were uncoupled. Handgrip and cold test failed to affect BP-SAS cardiac-respiratory coupling. We showed similar handgrip and cold test cardiac bispectral coupling for individual subjects. Further studies are required to establish whether the observed intersubject variability concerning the BP-SAS coupling at cardiac frequency has any potential clinical predictive value.

Anthropomorphic Model of Intrathecal Cerebrospinal Fluid Dynamics Within the Spinal Subarachnoid Space: Spinal Cord Nerve Roots Increase Steady-Streaming.

Cerebrospinal fluid (CSF) dynamics are thought to play a vital role in central nervous system (CNS) physiology. The objective of this study was to investigate the impact of spinal cord (SC) nerve roots (NR) on CSF dynamics. A subject-specific computational fluid dynamics (CFD) model of the complete spinal subarachnoid space (SSS) with and without anatomically realistic NR and nonuniform moving dura wall deformation was constructed. This CFD model allowed detailed investigation of the impact of NR on CSF velocities that is not possible in vivo using magnetic resonance imaging (MRI) or other noninvasive imaging methods. Results showed that NR altered CSF dynamics in terms of velocity field, steady-streaming, and vortical structures. Vortices occurred in the cervical spine around NR during CSF flow reversal. The magnitude of steady-streaming CSF flow increased with NR, in particular within the cervical spine. This increase was located axially upstream and downstream of NR due to the interface of adjacent vortices that formed around NR.

Human subarachnoid space width oscillations in the resting state.

Abnormal cerebrospinal fluid (CSF) pulsatility has been implicated in patients suffering from various diseases, including multiple sclerosis and hypertension. CSF pulsatility results in subarachnoid space (SAS) width changes, which can be measured with near-infrared transillumination backscattering sounding (NIR-T/BSS). The aim of this study was to combine NIR-T/BSS and wavelet analysis methods to characterise the dynamics of the SAS width within a wide range of frequencies from 0.005 to 2 Hz, with low frequencies studied in detail for the first time. From recordings in the resting state, we also demonstrate the relationships between SAS width in both hemispheres of the brain, and investigate how the SAS width dynamics is related to the blood pressure (BP). These investigations also revealed influences of age and SAS correlation on the dynamics of SAS width and its similarity with the BP. Combination of NIR-T/BSS and time-frequency analysis may open up new frontiers in the understanding and diagnosis of various neurodegenerative and ageing related diseases to improve diagnostic procedures and patient prognosis.

Oscillations of Subarachnoid Space Width as a Potential Marker of Cerebrospinal Fluid Pulsatility.

In the cerebrospinal fluid (CSF) circulation, two components can be distinguished: bulk flow (circulation) and pulsatile flow (back and forth motion). CSF pulsatile flow is generated by both cardiac and respiratory cycles. Recent years have seen increased interest in cardiac- and respiratory-driven CSF pulsatility as an important component of cerebral homeostasis. CSF pulsatility is affected by cerebral arterial inflow and jugular outflow and potentially linked to white matter abnormalities in various diseases, such as multiple sclerosis or hypertension. In this review, we discuss the physiological mechanisms associated with CSF pulsation and its clinical significance. Finally, we explain the concept of using the oscillations of subarachnoid space width as a surrogate for CSF pulsatility.

Clinical assessment and brain findings in a cohort of mothers, fetuses and infants infected with ZIKA virus.

BACKGROUND: Congenital Zika virus (ZIKV) infection can be detected in both the presence and absence of microcephaly and manifests as a number of signs and symptoms that are detected clinically and by neuroimaging. However, to date, qualitative and quantitative measures for the purpose of diagnosis and prognosis are limited. OBJECTIVES: Main objectives of this study conducted on fetuses and infants with confirmed congenital Zika virus infection and detected brain abnormalities were (1) to assess the prevalence of microcephaly and the frequency of the anomalies that include a detailed description based on ultrasound and magnetic resonance imaging in fetuses and ultrasound, magnetic resonance imaging, and computed tomography imaging postnatally, (2) to provide quantitative measures of fetal and infant brain findings by magnetic resonance imaging with the use of volumetric analyses and diffusion-weighted imaging, and (3) to obtain additional information from placental and fetal histopathologic assessments and postnatal clinical evaluations. STUDY DESIGN: This is a longitudinal cohort study of Zika virus-infected pregnancies from a single institution in Colombia. Clinical and imaging findings of patients with laboratory-confirmed Zika virus infection and fetal brain anomalies were the focus of this study. Patients underwent monthly fetal ultrasound scans, neurosonography, and a fetal magnetic resonance imaging. Postnatally, infant brain assessment was offered by the use of ultrasound imaging, magnetic resonance imaging, and/or computed tomography. Fetal head circumference measurements were compared with different reference ranges with <2 or <3 standard deviations below the mean for the diagnosis of microcephaly. Fetal and infant magnetic resonance imaging images were processed to obtain a quantitative brain volumetric assessment. Diffusion weighted imaging sequences were processed to assess brain microstructure. Anthropometric, neurologic, auditory, and visual assessments were performed postnatally. Histopathologic assessment was included if patients opted for pregnancy termination. RESULTS: All women (n=214) had been referred for Zika virus symptoms during pregnancy that affected themselves or their partners or if fetal anomalies that are compatible with congenital Zika virus syndrome were detected. A total of 12 pregnant patients with laboratory confirmation of Zika virus infection were diagnosed with fetal brain malformations. Most common findings that were assessed by prenatal and postnatal imaging were brain volume loss (92%), calcifications (92%), callosal anomalies (100%), cortical malformations (89%), and ventriculomegaly (92%). Results from fetal brain volumetric assessment by magnetic resonance imaging showed that 1 of the most common findings associated with microcephaly was reduced supratentorial brain parenchyma and increased subarachnoid cerebrospinal fluid. Diffusion weighted imaging analyses of apparent diffusion coefficient values showed microstructural changes. Microcephaly was present in 33.3-58.3% of the cases at referral and was present at delivery in 55.6-77.8% of cases. At birth, most of the affected neonates (55.6-77.8%) had head circumference measurements >3 standard deviations below the mean. Postnatal imaging studies confirmed brain malformations that were detected prenatally. Auditory screening results were normal in 2 cases that were assessed. Visual screening showed different anomalies in 2 of the 3 cases that were examined. Pathologic results that were obtained from 2 of the 3 cases who opted for termination showed similar signs of abnormalities in the central nervous system and placental analyses, including brain microcalcifications. CONCLUSION: Congenital microcephaly is not an optimal screening method for congenital Zika virus syndrome, because it may not accompany other evident and preceding brain findings; microcephaly could be an endpoint of the disease that results from progressive changes that are related to brain volume loss. Long-term studies are needed to understand the clinical and developmental relevance of these findings.

Paravascular spaces at the brain surface: Low resistance pathways for cerebrospinal fluid flow.

Clearance of waste products from the brain is of vital importance. Recent publications suggest a potential clearance mechanism via paravascular channels around blood vessels. Arterial pulsations might provide the driving force for paravascular flow, but its flow pattern remains poorly characterized. In addition, the relationship between paravascular flow around leptomeningeal vessels and penetrating vessels is unclear. In this study, we determined blood flow and diameter pulsations through a thinned-skull cranial window. We observed that microspheres moved preferentially in the paravascular space of arteries rather than in the adjacent subarachnoid space or around veins. Paravascular flow was pulsatile, generated by the cardiac cycle, with net antegrade flow. Confocal imaging showed microspheres distributed along leptomeningeal arteries, while their presence along penetrating arteries was limited to few vessels. These data suggest that paravascular spaces around leptomeningeal arteries form low resistance pathways on the surface of the brain that facilitate cerebrospinal fluid flow.