Master of Science

thesisTraumatic brain injury (TBI) is a leading cause of death and disability in the U.S.A. In mild cases, common etiologies of TBI (i.e., hemorrhage or edema) are not readily apparent during medical examination. We propose that the pia-arachnoid complex (PAC) contributes to the brain's response in TBI. The PAC is the only layer of tissue between the brain and dura (a tough membrane tightly adhered to the skull), and acts as a mechanical tether between the brain and skull. If the fine structures of the PAC are damaged during TBI, they likely go undiagnosed due to their small size and difficulty to image. To better understand the mechanics of PAC injury, several experimental and computational studies were conducted. First, a novel application of optical coherence tomography (OCT) was utilized to acquire microscale images of the in-situ porcine PAC and measure the amount of arachnoid trabeculae (AT) present. Next, two parametric studies were conducted on a microscale model of the PAC which evaluated its sensitivity to variable substructure moduli and AT volume fraction (VF). Afterwards, the microscale PAC model was paired with a macroscale head model to determine the effect of a nonuniform AT VF on whole-head mechanics. Finally, an immature porcine model of mild TBI was used to investigate PAC damage following head rotation, and identify clinically relevant MRI biomarkers indicative of PAC damage. The OCT imaging of the PAC revealed high variability of VF within each head, but low variability between brain regions and between animals. The microscale parametric studies showed high sensitivity to changes in substructure moduli and VF. The macroscale model studies showed improvement of intracranial hemorrhage prediction when variable VF was introduced into the models. Clinically relevant biomarkers of PAC damage were not able to be confidently developed, but increased sample size and improved resolution may lead to innovative biomarkers for TBI. The work presented here addresses a significant lack of data on the PAC, and presents new insights into its anatomy and biomechanics. Many of the studies presented here are the first of their kind, opening up many new paths of TBI research opportunities

Effect of changing heart rate on the ocular pulse and dynamic biomechanical behavior of the optic nerve head

Purpose: To study the effect of changing heart rate on the ocular pulse and the dynamic biomechanical behavior of the optic nerve head (ONH) using a comprehensive mathematical model. Methods: In a finite element model of a healthy eye, a biphasic choroid consisted of a solid phase with connective tissues and a fluid phase with blood, and the lamina cribrosa (LC) was viscoelastic as characterized by a stress-relaxation test. We applied arterial pressures at 18 ocular entry sites (posterior ciliary arteries), and venous pressures at four exit sites (vortex veins). In the model, the heart rate was varied from 60 to 120 bpm (increment: 20 bpm). We assessed the ocular pulse amplitude (OPA), pulse volume, ONH deformations, and the dynamic modulus of the LC at different heart rates. Results: With an increasing heart rate, the OPA decreased by 0.04 mm Hg for every 10 bpm increase in heart rate. The ocular pulse volume decreased linearly by 0.13 µL for every 10 bpm increase in heart rate. The storage modulus and the loss modulus of the LC increased by 0.014 and 0.04 MPa, respectively, for every 10 bpm increase in heart rate. Conclusions: In our model, the OPA, pulse volume, and ONH deformations decreased with an increasing heart rate, whereas the LC became stiffer. The effects of blood pressure/heart rate changes on ONH stiffening may be of interest for glaucoma pathology

Regional mechanical and biochemical properties of the porcine cortical meninges

peer-reviewedThe meninges are pivotal in protecting the brain against traumatic brain injury (TBI), an ongoing issue in most mainstream sports. Improved understanding of TBI biomechanics and pathophysiology is desirable to improve preventative measures, such as protective helmets, and advance our TBI diagnostic/prognostic capabilities. This study mechanically characterised the porcine meninges by performing uniaxial tensile testing on the dura mater (DM) tissue adjacent to the frontal, parietal, temporal, and occipital lobes of the cerebellum and superior sagittal sinus region of the DM. Mechanical characterisation revealed a significantly higher elastic modulus for the superior sagittal sinus region when compared to other regions in the DM. The superior sagittal sinus and parietal regions of the DM also displayed local mechanical anisotropy. Further, fatigue was noted in the DM following ten preconditioning cycles, which could have important implications in the context of repetitive TBI. To further understand differences in regional mechanical properties, regional variations in protein content (collagen I, collagen III, fibronectin and elastin) were examined by immunoblot analysis. The superior sagittal sinus was found to have significantly higher collagen I, elastin, and fibronectin content. The frontal region was also identified to have significantly higher collagen I and fibronectin content while the temporal region had increased elastin and fibronectin content. Regional differences in the mechanical and biochemical properties along with regional tissue thickness differences within the DM reveal that the tissue is a non-homogeneous structure. In particular, the potentially influential role of the superior sagittal sinus in TBI biomechanics warrants further investigation

A phantom for the study of positional brain shift

Positional brain shift (PBS) is the term given to the displacement of the brain which occurs upon surgical reorientation of the head and presents as one of the many sources of targeting error in high precision neurosurgery. Due to the impracticality of imaging humans in non-standard positions, however, there is currently insufficient information for surgeons to utilize in order to mitigate against PBS in surgical planning. To better characterise PBS, a novel synthetic model (phantom) of the brain-skull system was developed, comprising hydrogel brain (inc. imaging beads) with water filled ventricle cavity, elastomer dural septa, water filled subarachnoid space, and plastic skull. This phantom was validated by simulating the supine to prone PBS event and mechanically tuning the phantom’s hydrogel brain such that the general magnitude of shift (measured through CT imaging) matched that reported in human MRI studies. Using this phantom, brain shift characterisation was performed for a discrete representation of the continuous spectrum of possible positional transitions in neurosurgery. Here, brain shift was measured across eight positional transitions at 44 locations within the brain. Eight novel PBS maps were produced as a result of this study, with mean brain shift ranging between 0.39 and 0.94 mm and the standard deviation of shift within each PBS map ranging between 0.12 and 0.44 mm. The greatest shift was found upon transition from the supine to elevated right decubitus position, with a shift of 2 mm being measured in the left parietal lobe. Importantly, it was found that, a) clinically significant brain shift took place across all transitions and, b) clinically significant variability took place between the brain shift patterns of individual transitions at the local level. Together these findings further highlight the need for the consideration of PBS in surgical planning and strongly suggest that versatile parametric software are likely needed to account for the variable shifting of neurosurgical targets. The developed phantom has allowed for novel insights into an event otherwise difficult to study in humans. With further developments, it is believed that the phantom can be used to study other similarly problematic events, such as trauma

Detailed structure of the venous drainage of the brain: relevance to accidental and non-accidental traumatic head injuries

This project aimed to prove the existence of fine subdural veins hypothesised to be the source of intracranial bleeding seen in cases of accidental and non-accidental traumatic head injuries, and consequently illustrate their anatomical structure. This was important in contributing towards establishing the causal mechanism for traumatic intracranial bleeding, and was particularly applicable in unexplained traumatic head injuries in cases of possible child abuse. These issues are on-going, worldwide concerns that have been of public as well as scientific concern for many years. To illustrate the fine cerebral vessels, a unique modelling technique was recently developed involving polyurethane resin casting of the brain vasculature. Rat, marmoset, rhesus macaque and human brain tissue were all used. Tissue surrounding the resin perfused vessels were then either macerated to reveal the whole cast, or dissected to illustrate the cast as it would appear in situ. To allow analysis of these fine subdural vessels, various imaging techniques including fluorescence microscopy, light microscopy, confocal microscopy, scanning electron microscopy, transmission electron microscopy, magnetic resonance imaging, micro-computed tomography and 3D X-ray microscopy were used. The existence of subdural vessels was clearly illustrated via gross dissection of both primate and cadaveric material. Fluorescence imaging of resin-filled rat brain histological sections also showed orientation of fine vessels within the subdural space. Magnetic resonance imaging of the human head in vivo, as well as cadaveric material have shown signs of small calibre vessels that have never been previously documented, that are too fine to be bridging veins, yet seem to drain into the superior sagittal sinus. These results prove the existence of subdural vessels, present in a range of different species. Future work will further illustrate the exact morphological structure of these vessels, and biomechanical modelling will be applied to determine the exact forces required to cause them to rupture

Connective tissue in the human optic nerve head

Purpose: This thesis aimed to characterise and analyse the 3D micro- and nanoarchitecture of connective tissue within the lamina cribrosa (LC). Methods: The microarchitecture of load-bearing connective tissue components, elastin and fibrillar collagen, of the young, elderly and glaucomatous optic nerve head (ONH) was analysed following two-photon excited fluorescence, second harmonic generation and small angle light scattering. Microfocus and conventional small angle X-ray scattering were used to analyse ONH nanoarchitecture and the potential of X-ray microtomography (XMT) as a 3D imaging technique was evaluated. Results: Fibrillar collagen and elastic fibres stretched radially across the optic nerve (ON) canal in the LC, encircled the central retinal vessels and were absent in the prelamina. In the postlaminar ON septae, collagen was perpendicular to that in the LC. Differences in young and elderly ONH tissue included; wavy collagen bundles exclusively within the young ONH and distinct elastic fibres found in the elderly ONH. Analysis of ONH reconstructions of 3D SHG datasets revealed that elderly LCs contained higher fibrillar collagen content when compared to the young LCs. Interestingly, the connective tissue beams of the inferior-temporal LC quadrant were significantly more aligned in glaucoma when compared to age-matched controls. Distinct X-ray reflections, potentially elastin in the peripapillary sclera and representative of CNS myelin in the postlaminar ON were identified. XMT enabled quantification of the regional variation in LC thickness, connective tissue content, pore area and pore count, showing potential for 3D quantification without the need for tissue sectioning. Conclusion: Differences in the young and elderly ONH microarchitecture and nanoarchitecture include fibrillar collagen content, alignment and packing and the presence of elastic fibres. These data will be important for the development of finite element models that can predict ONHs at risk of developing glaucomatous optic neuropathy

The use of 1050nm OCT to identify changes in optic nerve head pathophysiology in glaucoma

Glaucoma is a progressive optic neuropathy that causes irreversible vision loss and is the second leading cause of blindness worldwide. Glaucoma is characterised by loss of retinal ganglion cells (RGC) and the proposed site of primary damage is the lamina cribrosa (LC), where RGC axonal transport is disrupted causing subsequent RGC damage and eventual cell death. Current detection for primary open angle glaucoma (POAG) is based upon clinical measures such as intraocular pressure (IOP), visual field loss and changes to the optic nerve head (ONH). However, for there to be an indication that there is a problem using these measures, often RGC damage has already occurred. Therefore it is crucial to determine ocular parameters that alter in the earliest stage of disease, prior to vision loss occurring. In this thesis optical coherence tomography (OCT) was used to assess the optic nerve heads and maculae of control eyes and eyes with preperimetric, early and advanced glaucoma in order to characterise changes that could potentially be used as biomarkers for the earliest stages of the disease. A custom built 1050 nm research OCT was used to acquire datasets from the macula and optic nerve heads of eyes glaucomatous and control eyes in vivo. Analysis of the inner retinal layers at the macula was performed to indirectly assess RGC integrity. At the ONH the prelamina and LC volume and regional depth and thicknesses were investigated. Additionally, nerve fibre layer and Bruch’s membrane parameters were assessed. Finally, LC beam coherence and orientation were probed in order to determine whether regional or glaucomatous changes ould be detected at the LC connective tissue microstructure. Prelamina depth and thickness was shown to be an indicator of early and preperimetric glaucoma (p0.01). Border nerve fibre layer revealed significant thinning in early glaucoma compared to control, and the superior peripapillary nerve fibre layer was thinner in preperimetric glaucoma than control. The ratio of inner plexiform layer (IPL) : ganglion cell layer (GCL) showed significant differences between control eyes and preperimetric glaucoma, and as such has potential to be a useful biomarker for indicating the earliest stages of disease. Both the GCL and IPL were thinner in early glaucoma than control (p<0.01), a hypothesis that cell body shrinkage and death occurs in preperimetric glaucoma and dendritic loss occurs in early glaucoma, when vision loss is first apparent, is suggested. Additionally, LC beams showed greater coherence in the superior and inferior poles than the temporal region, indicating that the shows regional variation but that further research is required to characterise changes. In conclusion, 1050 nm OCT was used to probe microstructural parameters of the optic nerve head in vivo to characterise changes that could be used as a potential biomarker for early glaucoma. ONH and retinal parameters have been identified that, with further research, may be used to differentiate between control eyes and those with preperimetric and early glaucoma. These have the potential to help identify those ONHs at risk of glaucoma damage