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Current methods of concussion assessment are subjective and vulnerable to error, and a missed concussion diagnosis could increase an athlete’s risk of further injury. An objective method of concussion assessment could provide valuable physiological data about injury severity and duration. The NuroChek system uses a flashing light stimulus to evoke electrophysiological activity, which is measured from occipital electrode sites and used to calculate a signal-to-noise ratio (SNR) and determine the magnitude of activity at the target location. Reductions in this activity are proposed to be associated with dysfunction or damage after concussion; in a previous study, the SNR was shown to decrease after concussion, and then return to baseline strength upon recovery. To examine the utility of the NuroChek system and SNR output in concussion assessment and management, 157 participants were assessed with the NuroChek system as rugby athletes (n = 121), combat athletes (n = 19), or non-athlete controls (n = 17). All athletes were assessed at multiple time points, while the non-athlete control group was only assessed at one time point. All participants completed two trials of the NuroChek headset and at least one cognitive measure. The first study (Chapter 4) examines the acute effects of concussion on the SNR, as well as any SNR changes after injury. Rugby athletes who sustained concussions (n = 21) were tested at multiple time points after their injuries with the NuroChek system and either the King-Devick (K-D) or the Sport Concussion Assessment Tool (SCAT-5). The post-injury and baseline SNR were compared to identify any changes within 3 days of concussion, as well as changes during the follow-up time points that might correspond with concussion recovery (up to 20 days post-injury and mid-season or end-of-season if available). No statistically significant changes were seen after concussion, W = 11.000, p = 0.612, d = -0.099, n = 8. When compared to the non-concussed male rug

Mild traumatic brain injury (mTBI) is increasingly recognized as a disconnection syndrome, due to the prevalence of disrupted long-range connections. Long-range connections refer to neural pathways that span across brain regions, allowing communication and synchronization between different brain areas. Disruption of these connections is associated with the inability to efficiently integrate local information (i.e., multiple visual attributes) into the percept of a single global shape. The aim of this thesis was to investigate whether people with a history of mTBI exhibit a reduced ability to integrate local information into meaningful context. Chapter 2 investigated whether visual integration was impaired in people with a history of mTBI, using visual illusions. Susceptibility to visual illusions demonstrates effective integration of visual information to provide a global picture, with surrounding elements automatically integrated into the perception of local elements. Results from Chapter 2 revealed that people with a history of mTBI exhibited decreased susceptibility to visual illusions, suggesting diminished automatic integration of visual information in a global manner; rather, these individuals appeared to prioritize analysis of local details within a visual stimulus. To further investigate this assumption, we employed the Navon task in Chapter 3 to assess whether people with a history of mTBI demonstrated a tendency to prioritize the processing of local details over global information when presented with multiple objects. This task was chosen as it provides a reliable measure of the extent to which individuals engage in global or local processing. The results revealed that people with a recent history of mTBI (within 12 months) had a reduced bias towards processing global elements of a figure (i.e., attending to the overall configuration of the object), indicating a reduced automatic tendency to process visual information as a coherent global percept. In contr

Neuropathic pain is caused by a dysfunction of the nervous system. It differs from normal pain sensations as it is no longer protective and can be present in the absence of a stimulus. It affects eight percent of the population worldwide and has several causes. Diabetes is the most prevalent cause, with about half of those diagnosed developing diabetic neuropathy. Other causes are genetic diseases (e.g. Charcot-Marie-Tooth disease), immune disorders or medications (e.g. chemotherapy drugs) or injury. Neuropathic pain, regardless of its cause, is often poorly managed leading to poor quality of life for those patients. The currently available analgesic options show little efficacy and are often dose-limiting due to adverse effects. Treatments that improve efficacy or offer lower adverse effects need to be investigated; one such potential treatment is medicinal cannabis. To this end, cannabis isolates and a high CBD whole extract were tested to determine efficacy to relieve neuropathic pain symptoms in a pre-clinical mouse model of neuropathy. A dose-response trial using gene expression biomarkers was completed in wildtype mice. This was to determine what doses of orally administered CBD (25 - 150 mg/kg) in an olive oil vehicle had a biological effect in the dorsal root ganglia of peripheral nerves of mice. CBD (6.25 - 100 mg/kg), a high CBD whole extract (containing CBD 12.5 mg/kg and THC 0.867 mg/kg) and a pure CBD:THC mix (at the same concentrations) were then used to determine efficacy in ameliorating neuropathic pain in a CMT2A mouse model. Finally, a single high-dose streptozotocin-induced diabetic neuropathy mouse model was characterised to determine the parameters of peripheral neuropathy and neuropathic pain symptoms in male wildtype B6:D2 mice. A pure isolate of 12.5 mg/kg CBD showed the greatest efficacy in treating thermal hyperalgesia symptoms in CMT2A mice. This paralleled a clinically relevant dose of gabapentin (40mg/kg) in efficacy for improving therma

Mild traumatic brain injury (mTBI) occurs from biomechanical forces on the brain, leading to pathophysiological changes that cause cognitive, perceptual, and/or motor impairments. Following mTBI, individuals are likely to be concerned about preventing pain or re-injury, therefore, we asked whether they had greater propensity to consciously monitor and control their movements. We also examined whether an association exists between the propensity to consciously monitor and control movements and mTBI clinical factors (time since most recent mTBI, number of mTBI, symptom severity). 157 participants with mTBI and 188 controls completed the Movement Specific Reinvestment Scale (MSRS) to measure the propensity for conscious monitoring and control of movements (i.e., movement specific reinvestment). Multivariate analysis of variance was used to explore scores on the MSRS as a function of mTBI/control and males/females with and without history of mTBI. Compared to controls, people with mTBI scored higher on both MSRS sub-scales (conscious motor processing, movement self-consciousness). Irrespective of mTBI history, females scored higher on the movement self-consciousness sub-scale. Multiple regression analyses were conducted to examine relationships between movement specific reinvestment and mTBI clinical factors. Time since most recent mTBI was negatively associated with conscious motor processing, suggesting that during early stages of recovery, people with mTBI are more likely to consciously control their movements. No association was evident between movement specific reinvestment and number of mTBI or symptom severity. Further understanding the relationship between conscious motor processes and mTBI may help tailor rehabilitation strategies to meet individual needs of those with mTBI.

Antibodies are highly effective mediators of the adaptive immune response. Their unique structural architecture makes them ideally suited for the specific targeting of disease-causing agents and the subsequent activation of potent effector functions upon binding to immune cells. These properties have led to the extensive use of antibodies in the biomedical industry as diagnostics and therapeutics. Notably, the IgG class of human antibodies (defined by the sequence of the constant region) has dominated the pool of antibody-based therapeutics, largely due to exceptional stability and efficient immune activation. The constant region genes of human IgG harbour a surprising amount of genetic variation in the form of allelic sequences encoding nonsynonymous mutations. Many allelic sequences have only been uncovered within the last five years, yet a handful of studies have already identified links between specific amino acid polymorphisms and improved receptor binding affinities that lead to enhanced activation of effector functions. This thesis furthers our understanding of the evolutionary pressures driving this genetic diversification by investigating the influence of IgG constant region diversity on antibody structural dynamics, including stability and flexibility. To analyse the structural effects in detail, I expressed a large panel of 35 trastuzumab-formatted antibodies with unique constant region allele sequences from subclasses IgG1, IgG2, and IgG3. Purified antibodies were confirmed to be of high purity and the composition of appended glycans was characterised for each variant. In this thesis, I compare the thermal stability properties of the unique IgG antibodies, measured by red edge excitation shift (REES) spectroscopy. Striking stability differences were resolved both between and within IgG subclasses, leading to new insights about the effect of specific amino acid positions on antibody stabilisation. Following the stability analysis, I extensively evaluate t

Decreased histone acetyltransferase activity and transcriptional dysfunction have been implicated in almost all neurodegenerative conditions. Increasing net histone acetyltransferase activity through inhibition of the histone deacetylases (HDACs) has been shown to be an effective strategy to delay or halt progression of neurological disease in cellular and rodent models. These findings have provided firm rationale for Phase I and Phase II clinical trials of HDAC inhibitors in Huntington's disease, spinal muscular atrophy, and Freidreich's ataxia. In this review, we discuss the current findings and promise of HDAC inhibition as a strategy for treating neurological disorders. Despite the fact that HDAC inhibitors are in an advanced stage of development, we suggest other approaches to modulating HDAC function that may be less toxic and more efficacious than the canonical agents developed so far.