Non-invasive MRI quantification of cerebrospinal fluid dynamics in amyotrophic lateral sclerosis patients.

BACKGROUND: Developing novel therapeutic agents to treat amyotrophic lateral sclerosis (ALS) has been difficult due to multifactorial pathophysiologic processes at work. Intrathecal drug administration shows promise due to close proximity of cerebrospinal fluid (CSF) to affected tissues. Development of effective intrathecal pharmaceuticals will rely on accurate models of how drugs are dispersed in the CSF. Therefore, a method to quantify these dynamics and a characterization of differences across disease states is needed. METHODS: Complete intrathecal 3D CSF geometry and CSF flow velocities at six axial locations in the spinal canal were collected by T2-weighted and phase-contrast MRI, respectively. Scans were completed for eight people with ALS and ten healthy controls. Manual segmentation of the spinal subarachnoid space was performed and coupled with an interpolated model of CSF flow within the spinal canal. Geometric and hydrodynamic parameters were then generated at 1 mm slice intervals along the entire spine. Temporal analysis of the waveform spectral content and feature points was also completed. RESULTS: Comparison of ALS and control groups revealed a reduction in CSF flow magnitude and increased flow propagation velocities in the ALS cohort. Other differences in spectral harmonic content and geometric comparisons may support an overall decrease in intrathecal compliance in the ALS group. Notably, there was a high degree of variability between cases, with one ALS patient displaying nearly zero CSF flow along the entire spinal canal. CONCLUSION: While our sample size limits statistical confidence about the differences observed in this study, it was possible to measure and quantify inter-individual and cohort variability in a non-invasive manner. Our study also shows the potential for MRI based measurements of CSF geometry and flow to provide information about  the hydrodynamic environment of the spinal subarachnoid space. These dynamics may be studied further to understand the behavior of CSF solute transport in healthy and diseased states.

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.

Patient-specific cranio-spinal compliance distribution using lumped-parameter model: its relation with ICP over a wide age range.

BACKGROUND: The distribution of cranio-spinal compliance (CSC) in the brain and spinal cord is a fundamental question, as it would determine the overall role of the compartments in modulating ICP in healthy and diseased states. Invasive methods for measurement of CSC using infusion-based techniques provide overall CSC estimate, but not the individual sub-compartmental contribution. Additionally, the outcome of the infusion-based method depends on the infusion site and dynamics. This article presents a method to determine compliance distribution between the cranium and spinal canal non-invasively using data obtained from patients. We hypothesize that this CSC distribution is indicative of the ICP. METHODS: We propose a lumped-parameter model representing the hydro and hemodynamics of the cranio-spinal system. The input and output to the model are phase-contrast MRI derived volumetric transcranial blood flow measured in vivo, and CSF flow at the spinal cervical level, respectively. The novelty of the method lies in the model mathematics that predicts CSC distribution (that obeys the physical laws) from the system dc gain of the discrete-domain transfer function. 104 healthy individuals (48 males, 56 females, age 25.4 ± 14.9 years, range 3-60 years) without any history of neurological diseases, were used in the study. Non-invasive MR assisted estimate of ICP was calculated and compared with the cranial compliance to prove our hypothesis. RESULTS: A significant negative correlation was found between model-predicted cranial contribution to CSC and MR-ICP. The spinal canal provided majority of the compliance in all the age groups up to 40 years. However, no single sub-compartment provided majority of the compliance in 41-60 years age group. The cranial contribution to CSC and MR-ICP were significantly correlated with age, with gender not affecting the compliance distribution. Spinal contribution to CSC significantly positively correlated with CSF stroke volume. CONCLUSIONS: This paper describes MRI-based non-invasive way to determine the cranio-spinal compliance distribution in the brain and spinal canal sub-compartments. The proposed mathematics makes the model always stable and within the physiological range. The model-derived cranial compliance was strongly negatively correlated to non-invasive MR-ICP data from 104 patients, indicating that compliance distribution plays a major role in modulating ICP.

Deformation of dorsal root ganglion due to pressure transients of venous blood and cerebrospinal fluid in the cervical vertebral canal.

The dorsal root ganglion (DRG) that is embedded in the foramen of the cervical vertebra can be injured during a whiplash motion. A potential cause is that whilst the neck bends in the whiplash motion, the changes of spinal canal volume induce impulsive pressure transients in the venous blood outside the dura mater (DM) and in the cerebrospinal fluid (CSF) inside the DM. The fluids can dynamically interact with the DRG and DM, which are deformable. In this work, the interaction is investigated numerically using a strong-coupling partitioned method that synchronize the computations of the fluid and structure. It is found that the interaction includes two basic processes, i.e., the pulling and pressing processes. In the pulling process, the DRG is stretched towards the spinal canal, and the venous blood is driven into the canal via the foramen. This process results from negative pressure in the fluids. In contrast, the pressing process is caused by positive pressure that leads to compression of the DRG and the outflow of the venous blood from the canal. The largest pressure gradient is observed at the foramen, where the DRG is located at. The DRG is subject to prominent von Mises stress near its end, which is fixed without motions. The negative internal pressure is more efficient to deform the DRG than the positive internal pressure. This indicates that the most hazardous condition for the DRG is the pulling process.

Respiration and the watershed of spinal CSF flow in humans.

The dynamics of human CSF in brain and upper spinal canal are regulated by inspiration and connected to the venous system through associated pressure changes. Upward CSF flow into the head during inspiration counterbalances venous flow out of the brain. Here, we investigated CSF motion along the spinal canal by real-time phase-contrast flow MRI at high spatial and temporal resolution. Results reveal a watershed of spinal CSF dynamics which divides flow behavior at about the level of the heart. While forced inspiration prompts upward surge of CSF flow volumes in the entire spinal canal, ensuing expiration leads to pronounced downward CSF flow, but only in the lower canal. The resulting pattern of net flow volumes during forced respiration yields upward CSF motion in the upper and downward flow in the lower spinal canal. These observations most likely reflect closely coupled CSF and venous systems as both large caval veins and their anastomosing vertebral plexus react to respiration-induced pressure changes.

Numerical Cerebrospinal System Modeling in Fluid-Structure Interaction.

OBJECTIVE: Cerebrospinal fluid (CSF) stroke volume in the aqueduct is widely used to evaluate CSF dynamics disorders. In a healthy population, aqueduct stroke volume represents around 10% of the spinal stroke volume while intracranial subarachnoid space stroke volume represents 90%. The amplitude of the CSF oscillations through the different compartments of the cerebrospinal system is a function of the geometry and the compliances of each compartment, but we suspect that it could also be impacted be the cardiac cycle frequency. To study this CSF distribution, we have developed a numerical model of the cerebrospinal system taking into account cerebral ventricles, intracranial subarachnoid spaces, spinal canal and brain tissue in fluid-structure interactions. MATERIALS AND METHODS: A numerical fluid-structure interaction model is implemented using a finite-element method library to model the cerebrospinal system and its interaction with the brain based on fluid mechanics equations and linear elasticity equations coupled in a monolithic formulation. The model geometry, simplified in a first approach, is designed in accordance with realistic volume ratios of the different compartments: a thin tube is used to mimic the high flow resistance of the aqueduct. CSF velocity and pressure and brain displacements are obtained as simulation results, and CSF flow and stroke volume are calculated from these results. RESULTS: Simulation results show a significant variability of aqueduct stroke volume and intracranial subarachnoid space stroke volume in the physiological range of cardiac frequencies. CONCLUSIONS: Fluid-structure interactions are numerous in the cerebrospinal system and difficult to understand in the rigid skull. The presented model highlights significant variations of stroke volumes under cardiac frequency variations only.

CNS wide simulation of flow resistance and drug transport due to spinal microanatomy.

Spinal microstructures are known to substantially affect cerebrospinal fluid patterns, yet their actual impact on flow resistance has not been quantified. Because the length scale of microanatomical aspects is below medical image resolution, their effect on flow is difficult to observe experimentally. Using a computational fluid mechanics approach, we were able to quantify the contribution of micro-anatomical aspects on cerebrospinal fluid (CSF) flow patterns and flow resistance within the entire central nervous system (CNS). Cranial and spinal CSF filled compartments were reconstructed from human imaging data; microscopic trabeculae below the image detection threshold were added artificially. Nerve roots and trabeculae were found to induce regions of microcirculation, whose location, size and vorticity along the spine were characterized. Our CFD simulations based on volumetric flow rates acquired with Cine Phase Contrast MRI in a normal human subject suggest a 2-2.5 fold increase in pressure drop mainly due to arachnoid trabeculae. The timing and phase lag of the CSF pressure and velocity waves along the spinal canal were also computed, and a complete spatio-temporal map encoding CSF volumetric flow rates and pressure was created. Micro-anatomy induced fluid patterns were found responsible for the rapid caudo-cranial spread of an intrathecally administered drug. The speed of rostral drug dispersion is drastically accelerated through pulsatile flow around microanatomy induced vortices. Exploring massive parallelization on a supercomputer, the feasibility of computational drug transport studies was demonstrated. CNS-wide simulations of intrathecal drugs administration can become a practical tool for in silico design, interspecies scaling and optimization of experimental drug trials.

The adult macaque spinal cord central canal zone contains proliferative cells and closely resembles the human.

The persistence of proliferative cells, which could correspond to progenitor populations or potential cells of origin for tumors, has been extensively studied in the adult mammalian forebrain, including human and nonhuman primates. Proliferating cells have been found along the entire ventricular system, including around the central canal, of rodents, but little is known about the primate spinal cord. Here we describe the central canal cellular composition of the Old World primate Macaca fascicularis via scanning and transmission electron microscopy and immunohistochemistry and identify central canal proliferating cells with Ki67 and newly generated cells with bromodeoxyuridine incorporation 3 months after the injection. The central canal is composed of uniciliated, biciliated, and multiciliated ependymal cells, astrocytes, and neurons. Multiciliated ependymal cells show morphological characteristics similar to multiciliated ependymal cells from the lateral ventricles, and uniciliated and biciliated ependymal cells display cilia with large, star-shaped basal bodies, similar to the Ecc cells described for the rodent central canal. Here we show that ependymal cells with one or two cilia, but not multiciliated ependymal cells, proliferate and give rise to new ependymal cells that presumably remain in the macaque central canal. We found that the infant and adult human spinal cord contains ependymal cell types that resemble those present in the macaque. Interestingly, a wide hypocellular layer formed by bundles of intermediate filaments surrounded the central canal both in the monkey and in the human, being more prominent in the stenosed adult human central canal.

Evidence for altered spinal canal compliance and cerebral venous drainage in untreated idiopathic intracranial hypertension.

Idiopathic intracranial hypertension (IIH), or pseudotumor cerebri, is a debilitating neurological disorder characterized by elevated CSF pressure of unknown cause. IIH manifests as severe headaches, and visual impairments. Most typically, IIH prevails in overweight females of childbearing age and its incidence is rising in parallel with the obesity epidemic. The most accepted theory for the cause of IIH is reduced absorption of CSF due to elevated intracranial venous pressure. A comprehensive MRI study, which includes structural and physiological imaging, was applied to characterize morphological and physiological differences between a homogeneous cohort of female IIH patients and an age- and BMI-similar control group to further elucidate the underlying pathophysiology. A novel analysis of MRI measurements of blood and CSF flow to and from the cranial and spinal canal compartments employing lumped parameters modeling of the cranio-spinal biomechanics provided, for the first time, evidence for the involvement of the spinal canal compartment. The CSF space in the spinal canal is less confined by bony structures compared with the cranial CSF, thereby providing most of the craniospinal compliance. This study demonstrates that the contribution of spinal canal compliance in IIH is significantly reduced.

Conductive neuromagnetic fields in the lumbar spinal canal.

OBJECTIVE: To measure neuromagnetic evoked fields in the lumbar spinal canal. METHODS: Using a newly developed superconducting quantum interference device (SQUID) fluxmeter, neuromagnetic fields of 5 healthy male volunteers were measured at the surface of the lower back after stimulation of the tibial nerves at the ankles. For validation, we inserted a catheter-type electrode percutaneously in the lumbar epidural space in 2 of the subjects and measured cauda equina action potentials after tibial nerve stimulation. RESULTS: Neuromagnetic fields propagating from the intervertebral foramina into the spinal canal were measured, and the latencies of the magnetic fields corresponded largely with those of the cauda equina action potentials. CONCLUSIONS: We successfully measured ascending neuromagnetic fields originating at the nerve root and the cauda equina with high spatial resolution. Future studies will determine whether neuromagnetic field measurement of the lumbar spine can be a useful diagnostic method for the identification of the disordered site in spinal nerves. SIGNIFICANCE: We successfully measured neuromagnetic fields in the lumbar spinal canal, which have previously been difficult to verify. Future studies will determine whether neuromagnetic field measurement of the lumbar spine can be a useful diagnostic method for identifying disorders of spinal nerves.

Movement associated reduction of spatial capacity of the equine cervical vertebral canal.

Laterolateral radiographs of equine necks are reported to be inaccurate in determining the site of spinal cord lesions even when a myelogram is carried out. The goal of this study was to assess constrictions present in the cervical vertebral canal at any time point throughout the extremes of movement. Sixteen equine cervical vertebral columns without history of cervical disease were used. After removal of the spinal cord, the dura mater was filled with polyurethane foam and during its plastic phase the cervical vertebral column was passively moved in flexion-extension, lateral bending and 30° rotated flexion and extension. Resulting moulded foam structures were scanned with a 3D laser scanner. Functional narrowing of the vertebral canal was located in the dorsolateral or ventrolateral regions, explaining its under-representation on laterolateral radiographs.

The peridural membrane of the spinal canal: a critical review.

There exists substantial evidence that a peridural membrane (PM) is present in the spinal canal of humans and, like the pleura and peritoneum, has one or more physiologic functions. Innervation of the PM suggests that it may become a source of pain if injured. Although debated, the physiology of this structure has important implications with respect to neuraxial distribution of drugs and for back and radiating pain. This review, separated into embryological, anatomic, and physiologic discussions, provides an in-depth summary of the observations of this connective tissue. The discrepancies between accounts are highlighted within each section. Focused research to clearly elucidate the true nature of the PM, especially as related to neuraxial distribution of drugs and back and radiating pain, is warranted.

Dynamic change of dural sac cross-sectional area in axial loaded magnetic resonance imaging correlates with the severity of clinical symptoms in patients with lumbar spinal canal stenosis.

STUDY DESIGN: Cross-sectional registry and imaging cohort study. OBJECTIVE.: To examine whether the dural sac cross-sectional area (DCSA) in axial loaded magnetic resonance imaging (MRI) correlates with the severity of clinical symptoms in patients with lumbar spinal canal stenosis (LSCS). SUMMARY OF BACKGROUND DATA: Many studies have analyzed the relationship between DCSA on conventional MRI and the severity of symptoms in LSCS, but the link is still uncertain. Recently, axial loaded MRI, which can stimulate the spinal canal of patients in the upright position, has been developed. Axial loaded MRI demonstrates significant reduction of DCSA and provides valuable radiologic findings in the assessment of LSCS. However, there has been no study of the correlation between DCSA in axial loaded MRI and the severity of symptoms in LSCS. METHODS: In 88 patients with LSCS, DCSA in conventional MRI, axial loaded MRI, and changes in the DCSA were determined at the single most constricted intervertebral level. The severity of symptoms was evaluated on the basis of the duration of symptoms, walking distance, visual analogue scale of leg pain/numbness, and Japanese Orthopaedic Association score. Spearman correlations of the DCSA in conventional MRI, axial loaded MRI, and changes in the DCSA with the severity of symptoms were analyzed. In addition, the severity of symptoms and DCSA in conventional and axial loaded MRI were compared, respectively, between patients with and without significant (>15 mm) changes in the DCSA. RESULTS: The DCSA in axial loaded MRI had good correlations with walking distance and Japanese Orthopaedic Association score (rs = 0.46 and 0.45, respectively; P < 0.001). In addition, the change in the DCSA significantly correlated to walking distance, visual analogue scale of leg numbness, and Japanese Orthopaedic Association score (rs = 0.59, 0.44, and 0.54, respectively; P < 0.001). Furthermore, the symptoms were significantly worse in patients with more than 15 mm change in the DCSA (P < 0.001). Axial loaded MRI, but not conventional MRI, showed a significantly smaller DCSA in patients with more than 15 mm change in the DCSA (P < 0.05). CONCLUSION: DCSA in axial loaded MRI significantly correlated with the severity of symptoms. Axial loaded MRI demonstrated that changes in the DCSA significantly correlated with the severity of symptoms, which conventional MRI could not detect. Thus, MRI with axial loading provides more valuable information than the conventional MRI for assessing patients with LSCS.

Cervical laminoplasty construct stability: an experimental and finite element investigation.

STUDY DESIGN: Experimental and finite element investigation of cervical laminoplasty. OBJECTIVE: To determine the stability of the construct post cervical laminoplasty. SUMMARY OF BACKGROUND DATA: Cervical laminoplasty is a widely used technique to widen the spinal canal dimensions without permanently removing the dorsal elements of the cervical spine. Although various laminoplasty procedures have been developed recently, the use of mini-plates to hold the lamina open and prevent restenosis of the spinal cord is a fairly new method and has not been thoroughly investigated. METHODS: Biomechanical compression tests and finite element analyses were performed in this study. Sixteen cervical vertebrae (C3 - C6) were isolated from six cadaveric cervical spines (age at death 68 to 91 years; mean 85 years) and were used for compression tests. Out of the 16 vertebrae, four were without any surgical intervention and the remaining 12 were implanted with one of the two laminoplasty plates: open door (OD) graft. Each vertebra was randomly assigned to one of the three groups: OD plate (6), graft plate (6) or intact vertebrae (4). The intact and implanted vertebrae were potted and loaded to failure. Cross-head displacements and the corresponding reaction force throughout the test were recorded to determine the failure loads. A finite element model of the C5 cervical vertebra was created to accommodate the laminoplasty implants. Experimental loading and boundary conditions were simulated and the stress distribution in the lamina was predicted in response to the compressive loads. RESULTS: A substantial increase in the sagittal canal diameter (27%-33%) and the spinal canal area (31.2%-47%) was observed at all levels. The strength of the implanted specimens was considerably decreased (by six to eight times) as compared to the intact specimens. CONCLUSION: Experimentally obtained data can be combined with mathematical models, such as finite element models, to accurately predict the biomechanical behavior (stresses and strains) of implants and the posterior bone which may not be possible by the use of any other method.

Determination of cranio-spinal canal compliance distribution by MRI: Methodology and early application in idiopathic intracranial hypertension.

PURPOSE: To develop a method for derivation of the cranial-spinal compliance distribution, assess its reliability, and apply to obese female patients with a diagnosis of idiopathic intracranial hypertension (IIH). MATERIALS AND METHODS: Phase contrast-based measurements of blood and cerebrospinal fluid (CSF) flows to, from, and between the cranial and spinal canal compartments were used with lumped-parameter modeling to estimate systolic volume and pressure changes from which cranial and spinal compliance indices are obtained. The proposed MRI indices are analogous to pressure volume indices (PVI) currently being measured invasively with infusion-based techniques. The consistency of the proposed method was assessed using MRI data from seven aged healthy subjects. Measurement reproducibility was assessed using five repeated MR scans from one subject. The method was then applied to compare spinal canal compliance contribution in seven IIH patients and six matched healthy controls. RESULTS: In the healthy subjects, as expected, spinal canal contribution was consistently larger than the cranial contribution (average value of 69%). Measurement variability was 8%. In IIH, the spinal canal contribution is significantly smaller than normal controls (60 versus 78%, P < 0.03). CONCLUSION: An MRI-based method for derivation of compliance indices analogous to PVI has been implemented and applied to healthy subjects. The application of the method to obese IIH patients suggests a spinal canal involvement in the pathophysiology of IIH.

[Effects of short- and long-segment posterior instrumentation on spinal canal remodeling in thoracolumbar vertebra burst fractures]. / Torakolomber vertebra patlama kiriklarinda kisa ve uzun segment posterior enstrümantasyonun kanal içi düzelme üzerine etkileri.

BACKGROUND: Spinal canal remodeling results according to Magerl classification and fracture localization after short- and long-segment posterior instrumentation treatment were evaluated in patients with thoracolumbar junction burst fracture. METHODS: Eighty patients were divided into two groups: Group 1: short-segment posterior instrumentation was applied in 36 patients [9F, 27M; Median age: 42.1 (range: 19-65)] and Group 2: long-segment posterior instrumentation was applied in 44 patients [18F, 26M; Median age: 46.3 (range: 18-78)]. Twenty patients had T12, 41 patients had L1 and 19 patients had L2 fracture. According to Magerl classification, 44 patients were A3.1, 19 were A3.2 and 17 were A3.3. In both groups, spinal canal remodeling effectiveness was evaluated postoperatively with respect to all parameters. RESULTS: Median follow-up time was 35.7 months for Group 1 (12-58) and 33.1 months for Group 2 (12-58). In both groups, spinal canal remodeling was statistically significant, but a higher recovery ratio was obtained in Group 2 in comparison to Group 1. According to Magerl classification, in type A3.3 fractures, a more significant remodeling was obtained in Group 2 patients (p=0.005). A significant difference was determined in Group 2 at the T12 level according to fracture localization (p=0.018). CONCLUSION: An adequate spinal canal remodeling is obtained by posterior instrumentation, but in comminuted fractures like Magerl type A3.3, a better remodeling can be obtained by long-segment posterior instrumentation.

Magnetic resonance 4D flow characteristics of cerebrospinal fluid at the craniocervical junction and the cervical spinal canal.

OBJECTIVES: To evaluate the applicability of 4D phase contrast (4D PC) MR imaging in the assessment of cerebrospinal fluid dynamics in healthy volunteers and patients with lesions at the craniocervical junction or the cervical spinal canal. METHODS: Ten healthy volunteers and four patients with lesions including Chiari I malformation and cervical canal stenoses were examined by a cardiac-gated 4D PC imaging sequence on 1.5T MRI. Phase contrast images were postprocessed allowing for flow quantification and flow pathline visualisation. Velocity data were compared with conventional axial 2D phase contrast images. RESULTS: The 4D PC sequence allowed for flow quantification and visualisation in all individuals. Bland-Altman analysis showed good agreement of 2D and 4D PC velocity data. In healthy volunteers, CSF flow was homogeneously distributed in the anterior and anterolateral subarachnoid space with the flow directed caudally during systole and cranially during diastole. Flow velocities were closely related to the width of the subarachnoid space. Patients showed grossly altered CSF flow patterns with formation of flow jets with increased flow velocities. CONCLUSIONS: 4D PC MR imaging allows for a detailed assessment of CSF flow dynamics helping to distinguish physiological from complex pathological flow patterns at the craniocervical junction and the cervical spine.

Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal.

Activating mutations in FGFR3 cause the most common forms of human dwarfism: achondroplasia and thanatophoric dysplasia. In mouse models of achondroplasia, recent studies have implicated the ERK MAPK pathway, a pathway activated by FGFR3, in creating reduced bone growth. Our recent studies have indicated that increased Fgfr3 and ERK MAPK signaling in chondrocytes also causes premature synchondrosis closure in the cranial base and vertebrae, accounting for the sometimes fatal stenosis of the foramen magnum and spinal canal in achondroplasia. Conversely, whether the decrease--or inactivation--of ERK1 and ERK2 promotes bone growth and delays synchondrosis closure remains to be investigated. In this study, we inactivated ERK2 in the chondrocytes of ERK1-null mice using the Col2a1-Cre and Col2a1-CreER transgenes. We found that the genetic inactivation of ERK1 and ERK2 in chondrocytes enhances the growth of cartilaginous skeletal elements. We also found that the postnatal inactivation of ERK1 and ERK2 in chondrocytes delays synchondrosis closure and enlarges the spinal canal. These observations make ERK1 and ERK2 an attractive target for the treatment of achondroplasia and other FGFR3-related skeletal syndromes.

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs.

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier-Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system's components taken in isolation.

Effect of lumbar angular motion on central canal diameter: positional MRI study in 491 cases.

BACKGROUND: Lumbar spinal stenosis is a common problem that is receiving attention with the advent of novel treatment procedures. Prior positional MRI studies demonstrated lumbar canal diameter changes with flexion and extension. There have not been any studies to examine the amount of spinal canal diameter change relative to the amount of angular motion. The purpose of this study was to evaluate the correlation between the lumbar canal diameter change and the angular motion quantitatively. METHODS: Positional MRI (pMRI) images for 491 patients, including 310 males and 181 females (16 years-85 years of age), were obtained with the subjects in sitting flexion 40 degree, upright, and with extension of 10 degrees within a 0.6 T Positional MRI scanner. Quantitative measurements of the canal diameter and segmental angle of each level in the sagittal midline plane were obtained for each position. Then the diameter change and angular motion were examined for correlation during flexion and extension with linear regression analysis. RESULTS: The lumbar segmental angles were lordotic in all positions except L1-2 in flexion. The changes of canal diameters were statistically correlated with the segmental angular motions during flexion and extension (P < 0.001). The amount of canal diameter change correlated with the amount of angular change and was expressed as a ratio. CONCLUSIONS: Positional MRI demonstrated the amount of spinal canal diameter change that was statistically correlated with the segmental angular motion of the spine during flexion and extension. These results may be used to predict the extent of canal diameter change when interspinous devices or positional changes are used to treat spinal stenosis and the amount of increased canal space may be predicted with the amount of angular or positional change of the spine. This may correlate with symptomatic relief and allow for improved success in the treatment of spinal stenosis.