Introduction: Human adipose tissue (fat) deforms substantially under normal physiological loading and during impact. Thus, accurate data on strain-dependent stiffness of fat is essential for the creation of accurate biome-chanical models. Previous studies on ex vivo samples reported human fat to be nonlinear and viscoelastic. When static compression is combined with magnetic resonance (MR) elastography (an imaging technique used to measure viscoelasticity in vivo), the large deformation properties of tissues can be determined. Here, we use magnetic resonance elastography to quantify fat shear modulus in vivo under increasing compressive strain and compare it to the underlying passive gluteal muscle. Methods: The right buttocks of ten female participants were incrementally compressed at four levels while MR elastography (50 Hz) and mDixon images were acquired. Maps of tissue shear modulus (G*) were reconstructed from the MR elastography phase images. Tissue strain was estimated from registration of deformed and unde-formed mDixon images. Linear mixed models were fit to the natural logarithm of the compressive strain and shear modulus data for each tissue. Results: Shear modulus increased in an exponential relationship with compressive strain in fat: G* fat = 748.5 * C  1.18 yy Pa, and to a lesser extent in muscle: G*muscle = 956.4 *C yy0.36 Pa. The baseline (undeformed) stiffness of fat was significantly lower than that of muscle (mean G*fat = 752 Pa, mean G*muscle = 1000 Pa, paired samples t-test, t =  4.24, p = 0.001). However, fat exhibited a significantly higher degree of strain dependence (characterised by the exponent of the curve, t =  6.47, p = 0.0001). Conclusion: Static compression of human adipose tissue results in an increase in apparent viscoelastic shear modulus (stiffness), in an exponentially increasing relationship. The relationships defined here can be used in the development of physiologically realistic computational models for impact, injury and biomechanical modelling.

To accurately map the large deformation properties of soft tissues, accurate, in-vivo measurements of internal strain are essential. In this study, the Right Cauchy Green strain of adipose tissue was calculated from displacements generated through the non-rigid registration of mDIXON images under increasing compression. The method was validated by synthetically deforming an uncompressed image with compression. Five real-world datasets were acquired of adipose tissue under increasing compression, which resulted in significant increases in the maximum principal strain (one-way ANOVA, p<0.001). The described method provides an accurate quantification of physiological strains in adipose tissue that is essential for mapping strain-varying viscoelasticity.

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.

Chiari malformation is characterised by the herniation of the cerebellar tonsils through the foramen magnum. However, tonsillar herniation and other 2D morphometric measurements of the posterior cranial fossa (PCF) have a weak association with patients' symptoms and clinical outcomes. This study aimed to contrast current 2D metrics with a novel 3D shape analysis of the PCF and the hindbrain, to determine if 3D measurements provides further insight into the pathophysiology of Chiari. The cranium of 12 controls and 21 Chiari malformation patients with (N = 9) and without (N = 12) a syrinx were scanned. The morphology of the PCF was quantified with typical 2D measurements. Additionally, a correspondence-based shape model that normalised the PCF volume, was used to find 3D differences in the shape of the PCF, and the distance of the hindbrain from the inner surfaces of the PCF. Shape analysis showed that, compared to controls, the caudal (p = 0.007; 2.3 mm, IQR: 1.6-3.3 mm) and anterior (p = 0.027; 1.3 mm,IQR: 1.1-1.6 mm) surfaces of the hindbrain were closer to the PCF in patients with and without a syrinx, respectively. However, there were negligible differences in the shape of the PCF between patient groups (p > 0.39). Current morphometric measures should be normalised for variation in PCF volume, so that shape measures are not biased. The reduced CSF space between the hindbrain and PCF will alter CSF dynamics, which may compress cerebellar vasculature and contribute to patient symptomatology.

Elastography has become widely used clinically for characterising changes in soft tissue mechanics that are associated with altered tissue structure and composition. However, some soft tissues, such as muscle, are not isotropic as is assumed in clinical elastography implementations. This limits the ability of these methods to capture changes in anisotropic tissues associated with disease. The objective of this study was to develop and validate a novel elastography reconstruction technique suitable for estimating the linear viscoelastic mechanical properties of transversely isotropic soft tissues. We derived a divergence-free formulation of the governing equations for acoustic wave propagation through a linearly transversely isotropic viscoelastic material, and transformed this into a weak form. This was then implemented into a finite element framework, enabling the analysis of wave input data and tissue structural fibre orientations, in this case based on diffusion tensor imaging. To validate the material constants obtained with this method, numerous in silico phantom experiments were run which encompassed a range of variations in wave input directions, material properties, fibre structure and noise. The method was also tested on ex vivo muscle and in vivo human volunteer calf muscles, and compared with a previous curl-based inversion method. The new method robustly extracted the transversely isotropic shear moduli (G⊥', G∥', G″) from the in silico phantom tests with minimal bias, including in the presence of experimentally realistic levels of noise in either fibre orientation or wave data. This new method performed better than the previous method in the presence of noise. Anisotropy estimates from the ex vivo muscle phantom agreed well with rheological tests. In vivo experiments on human calf muscles were able to detect increases in muscle shear moduli with passive muscle stretch. This new reconstruction method can be applied to quantify tissue mechanical properties of anisotropic soft tissues, such as muscle, in health and disease.

Key points Respiration plays a key role in the circulation of cerebrospinal fluid (CSF) around the central nervous system. During inspiration increased venous return from the cranium is believed to draw CSF rostrally. However, this mechanism does not explain why CSF has also been observed to move caudally during inspiration. We show that during inspiration decreased intrathoracic pressure draws venous blood from the cranium and lumbar spine towards the thorax. We also show that the abdominal pressure was associated with rostral CSF displacement. However, a caudal shift of cervical CSF was seen with low abdominal pressure and comparably negative intrathoracic pressures. These results suggest that the effects of epidural blood flow within the spinal canal need to be considered, as well as the cranial blood volume balance, to understand respiratory‐related CSF flow. These results may prove useful for the treatment of CSF obstructive pathology and understanding the behaviour of intrathecal drug injections. AbstractIt is accepted that during inspiration, cerebrospinal fluid (CSF) flows rostrally to compensate for decreased cranial blood volume, caused by venous drainage due to negative intrathoracic pressure. However, this mechanism does not explain observations of caudal CSF displacement during inspiration. Determining the drivers of respiratory CSF flow is crucial for understanding the pathophysiology of CSF flow disorders. To quantify the influence of respiration on CSF flow, real‐time phase‐contrast magnetic resonance imaging (MRI) was used to record CSF and blood flow, while healthy subjects (5:5 M:F, 25–50 years) performed either a brief expiratory or inspiratory effort between breaths. Transverse images were taken perpendicular to the spinal canal in the middle of the C3 and L2 vertebrae. The same manoeuvres were then performed after a nasogastric pressure catheter was used to measure the intrathoracic and abdominal pressures. During expiratory‐type manoeuvres that elevated abdominal and intrathoracic pressures, epidural blood flow into the spinal canal increased and CSF was displaced rostrally. With inspiratory manoeuvres, the negative intrathoracic pressure drew venous blood from C3 and L2 towards the thoracic spinal canal, and cervical CSF was displaced both rostrally and caudally, despite the increased venous drainage. Regression analysis showed that rostral displacement of CSF at both C3 (adjusted R2 = 0.53; P < 0.001) and L2 (adjusted R2 = 0.38; P < 0.001) were associated with the abdominal pressure. However, with low abdominal pressure and comparably negative intrathoracic pressure, cervical CSF flowed caudally. These findings suggest that changes in both the cranial and spinal pressures need to be considered to understand respiratory CSF flow.

Cerebrospinal fluid (CSF) enters nervous tissues through perivascular spaces. Flow through these pathways is important for solute transport and to prevent fluid accumulation. Syringomyelia is commonly associated with subarachnoid space obstructions such as Chiari I malformation. However, the mechanism of development of these fluid-filled cavities is unclear. Studies have suggested that changes in the arterial and CSF pressures could alter normal perivascular flow. This study uses an idealised model of the perivascular space to investigate how variation in the arterial pulse influences fluid flow. The model used simulated subarachnoid pressures from healthy controls (N = 9), Chiari patients with (N = 7) and without (N = 8) syringomyelia. A parametric analysis was conducted to determine how features of the arterial pulse altered flow. The features of interest included: the timing and magnitude of the peak displacement, and the area under the curve in the phases of uptake and decline. A secondary aim was to determine if the previously observed differences between subject groups were sensitive to variation in the arterial pulse wave. The study demonstrated that the Chiari patients without a syrinx maintained a significantly higher level of perivascular inflow over a physiologically likely range of pulse wave shapes. The analysis also suggested that age-related changes in the arterial pulse (i.e. increased late systolic pulse amplitude and faster diastolic decay), could increase resistance to perivascular inflow affecting solute transport.

OBJECTIVE:The pathogenesis of Chiari malformation type 1 (CM-1)-associated Valsalva headache is unknown, but it may be caused by abnormal cerebellar tonsil tissue strain. Advances in cardiac-gated magnetic resonance imaging (MRI) techniques such as balanced fast-field echo (bFFE) allow quantification of the motion of anatomic structures and can be used to measure tissue strain. The current study investigated the relationship between Valsalva heachache and tonsillar motion in patients with CM-1. METHODS:A retrospective review of patients with CM-1 who had undergone cardiac-gated bFFE MRI was performed. Headache symptoms were retrieved from the medical records. Anatomic landmarks were manually selected on the cine bFFE, and a validated motion-tracking software was used to assess motion over the cardiac cycle in patients at rest. For each patient, displacement, strain, and strain rate were calculated for 3 anatomic segments. Patients undergoing surgery were examined before and after surgery. RESULTS:From 88 patients, a total of 108 bFFE sequences were analyzed. Valsalva headache was present in 50% of patients. Cerebellar tonsil displacement (P = 0.003), strain (P = 0.012), and maximum strain rate (P = 0.04) were reduced after surgery (n = 20). There was no statistically significant association between tissue motion and headache symptoms. CONCLUSION:The results of this study do not support a relationship between cardiac cycle cerebellar strain and Valsalva headache in patients with CM-1. It is possible that cerebellar strain related to respiratory maneuvers is associated with headache in Chiari patients. Further investigation of tissue strain is warranted because it represents a potential biomarker for outcomes after surgery.

Background: Syringomyelia is a pathological condition in which fluid-filled cavities (syringes) form and expand in the spinal cord. Syringomyelia is often linked with obstruction of the craniocervical junction and a Chiari malformation, which is similar in both humans and animals. Some brachycephalic toy breed dogs such as Cavalier King Charles Spaniels (CKCS) are particularly predisposed. The exact mechanism of the formation of syringomyelia is undetermined and consequently with the lack of clinical explanation, engineers and mathematicians have resorted to computer models to identify possible physical mechanisms that can lead to syringes. We developed a computer model of the spinal cavity of a CKCS suffering from a large syrinx. The model was excited at the cranial end to simulate the movement of the cerebrospinal fluid (CSF) and the spinal cord due to the shift of blood volume in the cranium related to the cardiac cycle. To simulate the normal condition, the movement was prescribed to the CSF. To simulate the pathological condition, the movement of CSF was blocked. Results: For normal conditions the pressure in the SAS was approximately 400 Pa and the same applied to all stress components in the spinal cord. The stress was uniformly distributed along the length of the spinal cord. When the blockage between the cranial and spinal CSF spaces forced the cord to move with the cardiac cycle, shear and axial normal stresses in the cord increased significantly. The sites where the elevated stress was most pronounced coincided with the axial locations where the syringes typically form, but they were at the perimeter rather than in the central portion of the cord. This elevated stress originated from the bending of the cord at the locations where its curvature was high. Conclusions: The results suggest that it is possible that repetitive stressing of the spinal cord caused by its exaggerated movement could be a cause for the formation of initial syringes. Further consideration of factors such as cord tethering and the difference in mechanical properties of white and grey matter is needed to fully explore this possibility.

Syringomyelia is associated with Chiari I malformation, although the mechanistic link is unclear. Studies have suggested that cerebrospinal fluid enters the spinal cord via the perivascular spaces, and that changes in the timing of the subarachnoid pressures may increase flow into the spinal cord. This study aims to determine how Chiari malformation and syringomyelia alter the subarachnoid space pressures and hence perivascular flow. Subject-specific models of healthy controls (N = 9), Chiari patients with (N = 7) and without (N = 8) syringomyelia, were developed from magnetic resonance imaging (MRI), to simulate the subarachnoid pressures. These pressures were input to an idealised model of the perivascular space to evaluate potential differences in perivascular flow. Peak pressures in Chiari patients without a syrinx were higher than in controls (46% increase; p = .029) and arrived earlier in the cardiac cycle than both controls (2.58% earlier; p = .045) and syrinx patients (2.85% earlier; p = .045). The perivascular model predicted Chiari patients without a syrinx would have the greatest flow into the cord (p < .05) if the arterial pulse delay was between 4 and 10% of the cardiac cycle. Using phase-contrast MRI the mean arterial delay for all subjects was similar, and was estimated as 4.7 ± 0.2%. The perivascular pumping rate showed a strong positive correlation (RAdj2=0.85; p < .0001) with extended periods of high pressure that arrived earlier in the cardiac cycle, suggesting these pressure characteristics may play a role in syrinx development.

In this study, an in vitro device that mimics the oral phase of swallowing is calibrated using in vivo measurements. The oral flow behavior of different Newtonian and non-Newtonian solutions is then investigated in vitro, revealing that shear-thinning thickeners used in the treatment of dysphagia behave very similar to low-viscosity Newtonian liquids during active swallowing, but provide better control of the bolus before the swallow is initiated. A theoretical model is used to interpret the experimental results and enables the identification of two dynamical regimes for the flow of the bolus: first, an inertial regime of constant acceleration dependent on the applied force and system inertia, possibly followed by a viscous regime in which the viscosity governs the constant velocity of the bolus. This mechanistic understanding provides a plausible explanation for similarities and differences in swallowing performance of shear-thinning and Newtonian liquids. Finally, the physiological implications of the model and experimental results are discussed. In vitro and theoretical results suggest that individuals with poor tongue strength are more sensitive to overly thickened boluses. The model also suggests that while the effects of system inertia are significant, the density of the bolus itself plays a negligible role in its dynamics. This is confirmed by experiments on a high density contrast agent used for videofluoroscopy, revealing that rheologically matched contrast agents and thickener solutions flow very similarly. In vitro experiments and theoretical insights can help designing novel thickener formulations before clinical evaluations.