Cerebrospinal Fluid Flow Waveforms Research Articles

Evaluating the effect of injection protocols on intrathecal solute dispersion in non-human primates: an in vitro study using a cynomolgus cerebrospinal fluid system

BackgroundAchieving effective drug delivery to the central nervous system (CNS) remains a challenge for treating neurological disorders. Intrathecal (IT) delivery, which involves direct injection into the cerebrospinal fluid (CSF), presents a promising strategy. Large animal studies are important to assess the safety and efficacy of most drugs and treatments and translate the data to humans. An understanding of the influence of IT injection parameters on solute distribution within the CNS is essential to optimize preclinical research, which would potentially help design human clinical studies.MethodsA three-dimensional (3D) in vitro model of a cynomolgus monkey, based on MRI data, was developed to evaluate the impact of lumbar injection parameters on intrathecal solute dispersion. The parameters evaluated were (a) injection location, (b) bolus volume, (c) flush volume, (d) bolus rate, and (e) flush rate. To simulate the CSF flow within the subarachnoid space (SAS), an idealized CSF flow waveform with both cardiac and respiratory-induced components was input into the model. A solution of fluorescein drug surrogate tracer was administered in the lumbar region of the 3D in vitro model filled with deionized water. After injection of the tracer, the CSF system wide-solute dispersion was imaged using high-resolution cameras every thirty seconds for a duration of three hours. To ensure repeatability each injection protocol was repeated three times. For each protocol, the average spatial–temporal distribution over three hours post-injection, the area under the curve (AUC), and the percent injected dose (%ID) to extra-axial CSF (eaCSF) at three hours were determined.ResultsThe changes to the lumbar injection parameters led to variations in solute distribution along the neuro-axis. Specifically, injection location showed the most impact, enhancing the delivery to the eaCSF up to + 10.5%ID (p = 0.0282) at three hours post-injection. Adding a post-injection flush of 1.5 ml at 1 ml/min increased the solute delivery to the eaCSF by + 6.5%ID (p = 0.0218), while the larger bolus volume resulted in a + 2.3%ID (p = 0.1910) increase. The bolus and flush rates analyzed had minimal, statistically non-significant effects.ConclusionThese results predict the effects of lumbar injection parameters on solute distribution in the intrathecal space in NHPs. Specifically, the choice of injection location, flush, and bolus volume significantly improved solute delivery to eaCSF. The in vitro NHP CSF model and results offer a system to help predict and optimize IT delivery protocols for pre-clinical NHP studies.

SEGMENTATION OF SPINAL SUBARACHNOID LUMEN WITH 3D ATTENTION U-NET

Phase Contrast Magnetic Resonance Image (PC-MRI) is an emerging noninvasive technique that contains pulsatile information by measuring the parameters of cerebrospinal fluid (CSF) flow. As CSF flow quantities are measured from the selected region on the images, the accuracy in the identification of the interested region is the most essential, and the examination requires a lot of time and experience to analyze and for accurate CSF flow assessment. In this study, a three-dimensional (3D)-Unet architecture, including pulsatile flow data as the third dimension, is proposed to address the issue. The dataset contains 2176 phase and rephase images from 57 slabs of 39 3-tesla PC-MRI subjects collected from the lower thoracic levels of control and Idiopathic Scoliosis (IS) patients. The procedure starts with labeling the CSF containing spaces in the spinal canal. In the preprocessing step, unequal cardiac cycle images (i.e., frame) and the numbers of MRIs in cases are adjusted by interpolation to align the temporal dimension of the dataset to an equal size. The five-fold cross-validation procedure is used to evaluate the 3D Attention-U-Net model after training and achieved an average weighted performance of 97% precision, 95% recall, 98% F1 score, and 95% area under curve. The success of the model is also measured using the CSF flow waveform quantities as well. The mean flow rates through the labeled and predicted CSF lumens have a significant correlation coefficient of 0.96, and the peak CSF flow rates have a coefficient of 0.65. To our knowledge, this is the first fully automatic 3D deep learning architecture implementation to segment spinal CSF-containing spaces that utilizes both spatial and pulsatile information in PC-MRI data. We expect that our work will attract future research on the use of PC-MRI temporal information for training deep models.

Head movement, an important contributor to human cerebrospinal fluid circulation

The suboccipital muscles are connected to the upper cervical spinal dura mater via the myodural bridges (MDBs). Recently, it was suggested that they might work as a pump to provide power for cerebrospinal fluid (CSF) circulation. The purpose of this study was to investigate effects of the suboccipital muscles contractions on the CSF flow. Forty healthy adult volunteers were subjected to cine phase-contrast MR imaging. Each volunteer was scanned twice, once before and once after one-minute-head-rotation period. CSF flow waveform parameters at craniocervical junction were analyzed. The results showed that, after the head rotations, the maximum and average CSF flow rates during ventricular diastole were significantly increased, and the CSF stroke volumes during diastole and during entire cardiac cycle were significantly increased. This suggested that the CSF flow was significantly promoted by head movements. Among the muscles related with head movements, only three suboccipital muscles are connected to the upper cervical spinal dura mater via MDBs. It was believed that MDBs might transform powers of the muscles to CSF. The present results suggested that the head movements served as an important contributor to CSF dynamics and the MDBs might be involved in this mechanism.

Continuous positive airway pressure alters cranial blood flow and cerebrospinal fluid dynamics at the craniovertebral junction

Abstract Purpose To investigate the impact of continuous positive airway pressure (CPAP) applied by a full-face fitted mask at 15 cmH 2 O on total cerebral blood flow (tCBF), jugular venous flow (tJVF) and cerebrospinal fluid (CSF) flow. Materials and methods Axial 2D phase-contrast MRI measurements were acquired at the C2–C3 vertebral level for 23 healthy male awake subjects at baseline (without) and with CPAP applied. CSF flow was quantified within the spinal subarachnoid space and tCBF was quantified based on the summation of blood flow within the left and right internal carotid and vertebral arteries. tJVF was quantified based on the summation of blood flow within the left and right jugular veins. Heart rate, transcutaneous carbon dioxide (PtcCO 2 ) and oxygen saturation were continuously monitored during the MR protocol. Results CPAP decreased the pulse amplitude (PtPPA) of tJVF by 21% (p = 0.004). CSF stroke volume (SV) and PtPPA also decreased by 20% (p = 0.003) and 15% (p = 0.005), respectively. Change in tCBF SV and PtPPA was not significant. However, the timing of maximum systolic tCBF occurred significantly earlier under CPAP. CSF flow and tJVF waveforms showed significant spatial and temporal differences in waveform feature points, and spectral analysis revealed a decrease in the first harmonic of tJVF under CPAP (p = 0.001). Under CPAP, a 5% decrease in PtcCO 2 (p = 0.003) and 9% increase in HR (p = 0.006) were measured. However, these HR and PtcCO 2 changes were not correlated with any changes in arterial, venous or CSF flow dynamics. Conclusion Application of CPAP via a full-fitted mask at 15 cm H 2 O was found to have a significant effect on intracranial venous outflow and spinal CSF flow at the C2 vertebral level in healthy adult-age awake volunteers. CPAP can be used to non-invasively provoke changes in intracranial and CSF flow dynamics.

A coupled hydrodynamic model of the cardiovascular and cerebrospinal fluid system

Coupling of the cardiovascular and cerebrospinal fluid (CSF) system is considered to be important to understand the pathophysiology of cerebrovascular and craniospinal disease and intrathecal drug delivery. A coupled cardiovascular and CSF system model was designed to examine the relation of spinal cord (SC) blood flow (SCBF) and CSF pulsations along the spinal subarachnoid space (SSS). A one-dimensional (1-D) cardiovascular tree model was constructed including a simplified SC arterial network. Connection between the cardiovascular and CSF system was accomplished by a transfer function based on in vivo measurements of CSF and cerebral blood flow. A 1-D tube model of the SSS was constructed based on in vivo measurements in the literature. Pressure and flow throughout the cardiovascular and CSF system were determined for different values of craniospinal compliance. SCBF results indicated that the cervical, thoracic, and lumbar SC each had a signature waveform shape. The cerebral blood flow to CSF transfer function reproduced an in vivo-like CSF flow waveform. The 1-D tube model of the SSS resulted in a distribution of CSF pressure and flow and a wave speed that were similar to those in vivo. The SCBF to CSF pulse delay was found to vary a great degree along the spine depending on craniospinal compliance and vascular anatomy. The properties and anatomy of the SC arterial network and SSS were found to have an important impact on pressure and flow and perivascular fluid movement to the SC. Overall, the coupled model provides predictions about the flow and pressure environment in the SC and SSS. More detailed measurements are needed to fully validate the model.

Assessing cerebrospinal fluid flow connectivity using 3D gradient echo phase contrast velocity encoded MRI

The aim of this study is to investigate the feasibility of using three-directional velocity encoded 3D gradient echo (GE) phase contrast (PC) imaging to assess cerebrospinal fluid (CSF) flow connectivity in the human brain. Five healthy volunteers were scanned using low velocity sensitivity (Venc = 0.04–0.05 m s−1). Flow–time curves were compared to standard 2D PC scans. The 3D data were used to reconstruct in vivo CSF flow volumes based on time-averaged phase-difference information, and the patency of the CSF flow pathways was assessed using nearest-neighbour connectivity. A pulsatile flow phantom was used to gauge the measurement accuracy of the CSF flow volumes at low flow velocities. Flow connectivity from the lateral ventricles down to the cisterna magna was successfully demonstrated in all volunteers. The phantom tests showed a good distinction between the flow cavities and the background noise. 3D PC imaging results in CSF flow waveforms with similar pulsatility but underestimated peak velocities compared to 2D PC data. 3D time-resolved velocity encoded GE imaging has successfully been applied to assess CSF flow connectivity in normal subjects.

Spinal Subarachnoid Space Pressure Measurements in an In Vitro Spinal Stenosis Model: Implications on Syringomyelia Theories

Full explanation for the pathogenesis of syringomyelia (SM), a neuropathology characterized by the formation of a cystic cavity (syrinx) in the spinal cord (SC), has not yet been provided. It has been hypothesized that abnormal cerebrospinal fluid (CSF) pressure, caused by subarachnoid space (SAS) flow blockage (stenosis), is an underlying cause of syrinx formation and subsequent pain in the patient. However, paucity in detailed in vivo pressure data has made theoretical explanations for the syrinx difficult to reconcile. In order to understand the complex pressure environment, four simplified in vitro models were constructed to have anatomical similarities with post-traumatic SM and Chiari malformation related SM. Experimental geometry and properties were based on in vivo data and incorporated pertinent elements such as a realistic CSF flow waveform, spinal stenosis, syrinx, flexible SC, and flexible spinal column. The presence of a spinal stenosis in the SAS caused peak-to-peak cerebrospinal fluid CSF pressure fluctuations to increase rostral to the stenosis. Pressure with both stenosis and syrinx present was complex. Overall, the interaction of the syrinx and stenosis resulted in a diastolic valve mechanism and rostral tensioning of the SC. In all experiments, the blockage was shown to increase and dissociate SAS pressure, while the axial pressure distribution in the syrinx remained uniform. These results highlight the importance of the properties of the SC and spinal SAS, such as compliance and permeability, and provide data for comparison with computational models. Further research examining the influence of stenosis size and location, and the importance of tissue properties, is warranted.

Noninvasive Intracranial Compliance From MRI-Based Measurements of Transcranial Blood and CSF Flows: Indirect Versus Direct Approach

Intracranial compliance (ICC) determines the ability of the intracranial compartment to accommodate an increase in volume without a large increase in intracranial pressure (ICP). The clinical utilization of ICC is limited by the invasiveness of current measurement. Several investigators attempted to estimate ICC noninvasively, from magnetic resonance imaging (MRI) measurements of cerebral blood and cerebral spinal fluid flows, either using indirect measures of ICC or directly by measuring the ratio of the changes in intracranial volume and pressure during the cardiac cycle. The indirect measures include the phase lag between the cerebrospinal fluid (CSF) and its driving force, either arterial inflow or net transcranial blood flow. This study compares the sensitivity of phase-based and amplitude-based measures of ICC to changes in ICC. In vivo volumetric blood and CSF flows measured by MRI phase contrast from healthy volunteers and from patients with elevated ICP were used for the comparison. An RLC circuit model of the craniospinal system was utilized to simulate the effect of a change in ICC on the CSF flow waveform. The simulations demonstrated that amplitude-based measures of ICC are considerably more sensitive than phase-based measures, and among the amplitude-based measures, the ICC index provides the most reliable estimate of ICC.

Cerebrospinal fluid dynamics in Chiari malformation associated with syringomyelia

About 50% - 70% of patients with Chiari malformation I (CMI) presented with syringomyelia (SM), which is supposed to be related to abnormal cerebrospinal fluid (CSF) flow around the foramen magnum. The aim of this study was to investigate the cerebrospinal fluid dynamics at levels of the aqueduct and upper cervical spine in patients with CMI associated with SM, and to discuss the possible mechanism of formation of SM. From January to April 2004, we examined 10 adult patients with symptomatic CMI associated with SM and 10 healthy volunteers by phase-contrast MRI. CSF flow patterns were evaluated at seven regions of interest (ROI): the aqueduct and ventral and dorsal subarachnoid spaces of the spine at levels of the cerebellar tonsil, C2 - 3, and C5 - 6. The CSF flow waveforms were analyzed by measuring CSF circulation time, durations and maximum velocities of cranial- and caudal-directed flows, and the ratio between the two maximum velocities. Data were analyzed by t test using SPSS 11.5. We found no definite communication between the fourth ventricle and syringomyelia by MRI in the 10 patients. In both the groups, we observed cranial-directed flow of CSF in the early cardiac systolic phase, which changed the direction from cranial to caudal from the middle systolic phase to the early diastolic phase, and then turned back in cranial direction in the late diastolic phase. The CSF flow disappeared at the dorsal ROI at the level of C2 - 3 in 3 patients and 1 volunteer, and at the level of C5 - 6 in 6 patients and 3 volunteers. The durations of CSF circulation at all the ROIs were significantly shorter in the patients than those in the healthy volunteers (P = 0.014 at the midbrain aqueduct, P = 0.019 at the inferior margin of the cerebellar tonsil, P = 0.014 at the level of C2 - 3, and P = 0.022 at the level of C5 - 6). No significant difference existed between the two groups in the initial point and duration of the caudal-directed CSF flow during a cardiac cycle at all the ROIs. The maximum velocities of both cranial- and caudal-directed CSF flows were significantly higher in the patients than those in the volunteers at the aqueduct (P = 0.018 and P = 0.007) and ventral ROI at the inferior margin of the cerebellar tonsil (P < 0.001 and P = 0.002), as so did the maximum velocities of the caudal-directed flow in the ventral and dorsal ROIs at the level of C2 - 3 (P = 0.004; P = 0.007). The direction of CSF flow changes in accordance with cardiac cycle. The syringomyelia in patients with CMI may be due to the decreased circulation time and abnormal dynamics of the CSF in the upper cervical segment. The decompression of the foramen magnum with dural plasty is an alternative for patients with CMI associated with SM.

Cerebrospinal fluid flow waveforms: MR analysis in chronic adult hydrocephalus.

Henry-Feugeas MC, Idy-Peretti I, Baledent O, et al. Cerebrospinal fluid flow waveforms: MR analysis in chronic adult hydrocephalus. Invest Radiol 2001;36:146-154. To analyze changes in cerebrospinal fluid (CSF) hydrodynamics in chronic adult hydrocephalus. Phase-contrast cine-MR acquisitions were used to explore the ventricular system and the upper ventral cervical spaces of 16 patients. The aqueductal jet was explored in 32 control subjects. The duration of pulsatile caudal CSF flow (ie, CSF systole) was abnormally short in patients with active idiopathic and obstructive hydrocephalus. The duration of CSF cervical systole was normal in patients with stable hydrocephalus. The aqueductal stroke volume could be increased in stable communicating hydrocephalus. Patients who responded to shunting had shortened CSF systoles and hyperpulsatile ventricular patterns. Successful CSF diversion resulted in longer CSF systoles and CSF ventricular patterns that were no longer hyperpulsatile. Magnetic resonance analysis of CSF flow can show craniospinal dissociation and limitation of CSF outflow from the ventricles in both obstructive and communicating hydrocephalus; it should help determine the response to shunting in communicating hydrocephalus.

Cerebrospinal fluid flow dynamics study in Chiari I malformation: implications for syrinx formation

Cerebrospinal fluid (CSF) flow abnormalities are known to be present in Chiari I malformation and to underlie the origin and progression of associated syringomyelia. The incidence of syrinx formation, however, is variable for unknown reasons. The aim of this study was to investigate whether differences in CSF flow dynamics in patients with Chiari I malformation may account for the different clinical and radiological presentation. Presurgical and postsurgical phase-contrast magnetic resonance imaging investigations were prospectively conducted in 47 adult patients with symptomatic Chiari I malformation. Patients were divided into two groups according to the presence (32 cases) or absence (15 cases) of syrinx. Cerebrospinal fluid flow patterns were evaluated at four regions of interest: prebulbar cistern, foramen magnum, and the ventral and dorsal spinal subarachnoid spaces at the C-5 level. A temporal analysis of CSF flow waveforms was performed with measurement of cranial- and caudal-directed flow durations. All patients underwent a craniocervical decompressive procedure. Preoperatively, a prolonged caudal- directed (systolic) flow pattern was observed in patients with syringomyelia, as compared with normal control values obtained in 15 healthy volunteers. Conversely, a decreased systolic duration was observed in Chiari I patients who had malformation without syrinx. These trends were not statistically significant because of the considerable degree of overlap with the control values recorded in both groups. Additional comparison of the observed preoperative values obtained in patients with and those without syringomyelia indicated that the difference in systolic flow duration was significant at the ventral spinal subarachnoid space level (p = 0.003) and remarkable at the other levels, although not reaching statistical significance. Cerebrospinal fluid flow was minimal or absent at the foramen magnum (dorsal aspect) due to tonsillar herniation, precluding reliable quantitative measurement at this level. There was no evidence of communication between the fourth ventricle and syrinx in any case. Postoperatively, unobstructed CSF flow was recorded across the enlarged foramen magnum and into the artificial cisterna magna in all patients. A gradual restoration of near-normal flow patterns was observed in both groups. Inside the syrinx, fluid motion gradually tapered, no longer being detectable in 12 patients (37.5%) 1 year postsurgery. In patients with Chiari I malformation and associated syringomyelia different CSF flow patterns were demonstrated as compared with patients in whom syrinx was absent. Analysis of this study's findings supports the hypothesis that in Chiari I malformation an elongated systolic flow may prolong the condition of increased spinal subarachnoid pressure caused by the junctional obstruction, thus favoring CSF penetration into the spinal cord. It may be also proposed that a shortened systolic flow may be insufficient to maintain a hypertensive condition for enough time to induce syrinx formation.

Cerebrospinal fluid flow waveforms: effect of altered cranial venous outflow. A phase-contrast MR flow imaging study.

Our purpose was to assess the effect of alterations in the cranial venous outflow on cerebrospinal fluid (CSF) flow waveforms using phase-contrast MRI. Thirteen healthy subjects were assessed for CSF flow and cerebral vascular flow at the C2-3 level, both before and after jugular venous compression (JVC). The flow waveforms were assessed both as an aggregate, and after dividing subjects in two groups based on percent jugular venous flow (PJVF) i.e. jugular outflow expressed as percent of cerebral arterial inflow. Group 1:7 subjects with PJVF more than and including median (predominantly jugular outflow); Group 2:6 subjects with PJVF less than median (predominantly extra-jugular outflow). CSF waveforms: JVC produced rounding of contours and flattening of dicrotic waves, with the effect being greater in group 1 than group 2. In group 1, systolic upslopes of the waveforms increased. No significant aggregate amplitude changes were noted; amplitudes increased in group 1 (P = 0.001), and decreased in group 2 (P = 0.03). Temporal interval to the maximum CSF systolic flow significantly increased in group 1. Vascular flow: Arterial flow significantly decreased in group 1. Jugular flow significantly decreased in both groups. The results suggest that CSF flow waveforms are sensitive to alterations in the cranial venous outflow. Changes in group 1 are most likely because of an elevation in intracranial pressure. Analysis of CSF flow waveforms appears a promising noninvasive tool for assessment of cranial compartment.

Cerebrospinal fluid flow waveforms: analysis in patients with Chiari I malformation by means of gated phase-contrast MR imaging velocity measurements.

To determine the features of the cardiac cycle-related cerebrospinal fluid (CSF) flow pulsations in with Chiari I malformation before and after decompressive surgery. Fifteen patients and 23 healthy subjects underwent cine phase-contrast magnetic resonance imaging. Ten patients were also examined after decompressive surgery. Four regions of interest were selected in the upper cervical subarachnoid space and premedullary cistern. Velocity and fraction of the cardiac cycle waveforms were plotted, and amplitude, temporal, and CSF displacement parameters were assessed. In the Chiari I patients, impaired systolic and unaltered diastolic CSF flow pulsations immediately below the foramen magnum were identified. After surgery, the systolic flow pulsations immediately below the foramen magnum improved. Good correlation with post-surgical improvement was observed. CSF flow waveform analysis helps demonstrate abnormalities in CSF flow at the foramen magnum and the benefits of decompressive surgery in patients with the Chiari I malformation.