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Wii Fit U games utilize a Wii Balance Board™ (WBB) in a manner that can provide precise feedback contingencies similarly to some forms of balance rehabilitation, thereby potentially increasing the dose of quality therapy with or without the presence of a therapist during post-brain injury rehabilitation. Additionally, an engaging video-game could improve treatment adherence, a critical aspect of making positive functional gains, by potentially increasing the rate and quality of reinforcement embedded in therapy. The present study had three aims: (1) develop a rigorous behavioral therapy for improving balance in individuals living with chronic brain injury using a Wii Fit U game and the WBB; (2) evaluate the program's effects on balance measures using a within-subject experimental design; and (3) assess social validity of behavioral gains by evaluating the program's effects on participant's "subjective balance confidence" (i.e., their Activities-Specific Balance Confidence (ABC) scores). A reversal design is proposed for use with primary study participants, wherein the experimental gameplay condition and no intervention condition are alternated for 6 to 10 weeks. A similar design was used in a truncated fashion with pilot participants, and a multiple baseline design was used with follow-up pilot participants. It was expected that participants would exhibit greater performance in the game as well as better balance score improvement when the Wii Fit U game was administered at a high therapeutic dose, and that increased ABC scores would correlate with directly measured balance scores.

The vagus nerve is the principal pathway by which autonomic sensory information is carried from the periphery to the CNS where it influences the activity of a numerous structures including the locus coeruleus. Electrical stimulation of the vagus nerve has been demonstrated to enhance performance in a variety of memory tasks in both rats and humans and is used clinically for the control of epilepsy in humans. Electrical stimulation of the vagus nerve has also been shown to improve functional recovery following experimental brain injury in rats. The central hypothesis in these experiments is that vagus nerve stimulation exerts its beneficial effects by mediating the release of norepinephrine in the CNS. The results from Experiment I indicate that VNS results in increased extracellular NE concentration in the hippocampus at both the 0.5 and 1.0 mA stimulus intensities, and in the cortex at the 1.0 mA intensity. Increased concentrations of extracellular NE induced by VNS, regardless of structure, were transient, dissipating before the subsequent baseline recording period. Further, VNS-induced alterations in extracellular NE concentrations were observed bilaterally. Insult to the CNS by means of FPI resulted in long lasting depression of extracellular NE concentrations in the cortex of the injured controls and 1.0 mA VNS group that was partially attenuated 1.0 mA VNS. In the 0.5 mA VNS group NE concentrations remained above pre-injury levels for the majority of the post-FPI measurement period. In the hippocampus, mean NE concentrations in the period immediately following FPI were decreased in comparison to pre-FPI concentrations. Concentrations of hippocampal NE remained depressed in the injured control group throughout the 48 hr sample period. Hippocampal NE concentrations in both the 0.5 mA VNS and 1.0 mA VNS group recovered to above pre-injury levels by 14-20 hrs post-FPI and were significantly higher than that of the injured controls in the 20-26 and 26-32 hr post-FPI sampling periods. Further, hippocampal NE concentrations remained significantly higher in 0.5 mA VNS group in comparison to injured controls in the 32-38 and 38-44 hr sampling periods.

Background: Motor impairments are common sequelae of Acquired Brain Injuries (ABI). An estimated 55-75% of ABI survivors have on-going limitations in UL function. Objective measures of UL function that have established validity and reliability in the ABI population are not readily available in the literature. The Chedoke Arm and Hand Inventory (CAHAI) is an assessment used with the stroke population. There are 4 versions of this assessment; a 13 item version and 3 shortened ones. The main purpose is to assess how much the affected UL contributes to a bilateral task. The CAHAI has strong reliability and validity in this population; however, it is unknown whether this measure can be used with other clinical populations such as ABI. Purpose: The purpose of this study was to estimate the inter-rater reliability of the Chedoke Arm and Hand Activity Inventory (CAHAI) when used with persons with ABI including 3 shortened versions of the measure.   Methods: This is an observational parameter estimation study.   Participants were recruited from an in-patient ABI rehabilitation program.   The administration of the CAHAI was video recorded for 6 persons with ABI.  The videos were assessed by 6 clinicians to estimate inter-rater reliability.  A Latin square design was used to balance the order raters evaluated the videos.   Analysis:  A repeated measures ANOVA was performed and the variance components were used to calculate an intra-class correlation coefficient (ICC) and standard error of measurement (SEM) with 95% confidence intervals (CI).   Results: Inter-rater reliability was high for all versions: CAHAI-7 ICC= 0.96 (95% CL: 0.89-0.99, SEM 2.65); CAHAI-8 ICC= 0.96 (95% CL: 0.90-0.99, SEM 2.72); CAHAI-9 ICC= 0.95 (95% CL: 0.85-0.99, SEM 3.49); CAHAI -13 ICC=0.96 (95%CL: 0.88-0.99, SEM 3.35).   Conclusions: These results suggest the CAHAI is highly reliability in the ABI population. The shortened versions may be particularly useful when time constraints or patient tolerance are an issue. / Thesis / Master of Science (MSc) / It is important to measure change using reliable assessment tools. Outcome measures are designed for specific populations. If used in a different population, the reliability may be impacted. The Chedoke Arm and Hand Activity Inventory (CAHAI) is a measure of upper limb function that has been developed for use in the stroke population. It was unknown if the measure would still be reliable in the acquired brain injury (ABI) population. The goal of this thesis was to determine if the CAHAI is also reliable in ABI. Our results suggest that the CAHAI is highly reliable in this population.

No description available.

Despite its prevalence, there are currently zero treatments available for traumatic brain injuries (TBI). Neuroinflammation is a key aspect of the secondary injury process, but remains poorly understood. Recent work has shown that Type I Interferons, inflammatory cytokines typically produced in response to viral infection, are present in the post-mortem brains of human TBI patients. The cyclic GMP-AMP Synthase- Stimulator of Interferon Genes (cGAS-STING) pathway is one of the primary methods of producing Type I IFNs; therefore, this work sought to evaluate the role of the cGAS-STING pathway in a murine controlled cortical impact (CCI) model of TBI. Using cGAS knockout (KO) or STING KO mice, we show that global loss of either protein results in substantial neuroprotection. One day after injury, animals have reduced lesion size, cell death, and inflammatory cytokine production, as well as reduced motor deficits several days after injury. We also determined that mitochondrial DNA (mtDNA) is present in the cytosol of injured cortical cells, indicating it is available to bind cGAS, a cytosolic pattern recognition receptor. To determine whether brain-resident or peripheral immune cells are responsible for detrimental cGAS-STING signaling after TBI, we utilized bone marrow chimeric animals lacking STING in either the brain or hematopoietic cells and animals lacking STING specifically in microglia. We found that both microglia and peripheral immune cells contribute to STING signaling after neurotrauma, and that loss of STING in either cell population is beneficial. Taken together, this work demonstrates that canonical, cGAS-dependent STING signaling occurs primarily in microglia and peripheral immune cells, resulting in detrimental neuroinflammatory events after TBI. / Doctor of Philosophy / Traumatic brain injuries (TBI), including concussions and more severe injuries, are a leading cause of death and disability across the globe; yet, there are no Food and Drug Administration (FDA) approved treatments. There are two phases in the injury: primary injury, which is the immediate damage to brain cells upon impact, and secondary injury, which includes a wide range of cellular processes in the minutes to weeks after injury. Because the primary injury is so rapid, we utilize safety measures, such as helmets, to limit the severity of the TBI. The secondary injury, however, occurs over a longer period of time; therefore, this is where most research is focused for developing potential treatments. Inflammation in the brain, termed neuroinflammation, is a key part of this secondary injury. While some inflammation is useful for clearance of damaged cells, too much inflammation can cause additional damage. The goal of this work was to examine how a specific inflammatory pathway, the cGAS-STING (cyclic GMP-AMP synthase- stimulator of interferon genes) pathway, contributes to neuroinflammation after brain injury.

BACKGROUND/AIMS: Inconsistency in the use of secondary brain injury prevention guidelines among US trauma centers after severe traumatic brain injury is prevalent in many literature sources. However, this phenomenon has not been thoroughly studied. The purpose of this DNP project is to identify the key barriers and challenges in compliance to the evidence-based guidelines for secondary brain injury prevention. DESIGN: An exploratory, emergent design was used to collect descriptive qualitative data through the use of a survey. SETTING: Six Phoenix Metropolitan Level 1 trauma centers. PARTICIPANTS: All survey participants who consented to survey completion, which had greater than six months of experience and directly worked with patients suffering from a severe TBI in the clinical setting. MEASUREMENTS: Participant demographics (work experience, area of work, job title), current awareness and use of Brain Trauma Foundation guidelines, and time duration for evidence based order set implementation. Narrative responses were also used to identify barriers to current use of the BTF guidelines and factors that may promote their use in the future. RESULTS: A total of 43 participants consented to the survey study, with completion by 35 participants. RNs (n=27), Physicians (n=2), NPs or PAs (n=5), with an average work experience of 6 to 14 years (42.86%). A total of n=22 (62%) of participants were unaware of the current BTF guidelines for severe TBI and only 25% (n=9) aware that their facility has a protocol based on the BTF guidelines for severe TBI, while 51% (n=18) were unsure if their facility had a protocol. Barriers were identified in narrative form and were consistent with awareness/education, provider congruence, communication, and order set/protocol process improvement. CONCLUSION: The understanding of current patient management for severe TBI based on the BTF guidelines is sporadic among the greater Phoenix area Level 1 trauma centers. Requiring proof of BTF guidelines compliance by the ACS at time of Level 1 certification may increase the consistent recommended use of the BTF guidelines for the care of severe TBIs.

Introduction: Older adults have been shown to be particularly vulnerable to the effects of mild traumatic brain injury (mTBI). However, limited research exists that examines the information and support received by older adults after a TBI, despite suggestions that input may be insufficient. We therefore aimed to evaluate the information and rehabilitative support received by individuals after mTBI, and to determine whether there were any age-related differences. Method: Adults (n = 250) who presented at the Christchurch Hospital Emergency Department over a 12 month period, with a diagnosis of mTBI were invited to participate in the study. Of these, 106 consented and 80 were able to be contacted for follow up. Participants were aged 18-85 years (M = 48) and evenly distributed into four age groups (18-30, 31-50, 51-65 and 66-85 years). Participants were interviewed over the phone using a questionnaire developed in a pilot study. Questions focussed on information and treatment received after the participants’ injury, as well as questions about cognitive and mood problems following the injury. Data was analysed both quantitatively and qualitatively. Results: There were no significant differences between age groups for the number of post-TBI symptoms reported by participants. However, as predicted, the post-injury information and assistance received were inconsistent and differed across groups: 25% of all participants did not receive any information after their TBI, and older adults were the least satisfied with the information received. Post-injury assistance was most commonly offered by friends, family and significant others, but this may not have been sufficient to encourage complete recovery. Participants made suggestions for assistance and support that they would have liked following their injury. Conclusions: The current study has significant implications for the treatment of mTBI as ill-informed and neglected patients are unlikely to return to pre-injury functioning and mental state. Furthermore, a rapidly increasing older population makes immediate attention to mTBI in older adults imperative.

Traumatic Brain Injury (TBI) accounts for 1,000,000 hospital admissions in the European Union every year and is the leading cause of death in individuals under 45 years of age in both Europe and the United States. This thesis examines the consequences to both the brain and lung following TBI using the lateral fluid percussion injury (FPI) in an in-vivo murine model. In the murine FPI model, alongside cerebral inflammation (associated with neuronal damage and the infiltration of inflammatory cells), there is significant neutrophil accumulation within the pulmonary interstitium 6 and 24 hours after TBI. This was associated with pulmonary haemorrhage and increased vascular permeability. In an attempt to reduce pulmonary injury, 17-DMAG, an HSP90 inhibitor, was applied but proved to be nonprotective. Since patients with TBI show increased susceptibility to bacterial infection, microaspiration and ventilator-induced lung injury, a double-hit model was established whereby mice first received the head injury and then received a lung injury. This demonstrated worse lung injury following intra-tracheal administration of hydrochloric acid after TBI. Depleting neutrophils with an anti-LY-6G depleting antibody improved outcome in this model, indicating increased susceptibility to damage was neutrophil dependent. To test whether neutrophil accumulation within the pulmonary interstitium was specifically related to brain injury, lung tissue following other distant organ injury such as renal ischemia-reperfusion injury (IRI) and renal transplantation were assessed. Significant pulmonary interstitial neutrophil accumulation was seen following both models and was associated with significant pulmonary haemorrhage. Inducing HSP70 activity with an HSP90 inhibitor was shown to be protective by reducing the degree of pulmonary haemorrhage in these models. In an attempt to identify the mechanisms behind neutrophil accumulation in TBI, renal IRI and renal transplantation, ICAM-1 (CD54), a marker of the reverse transmigration of neutrophils was investigated. No differences in ICAM-1 expression were seen following TBI, indicating that another mechanism must be responsible. This mechanism is the focus of on going work within the laboratory. Hypoxia is believed to contribute towards the development of secondary brain injury however little is known regarding its direct contribution. Working alongside chemists at the University of Edinburgh, a number of novel fluorescent hypoxia probes were designed and tested, but none proved to be able to detect hypoxia in-vitro. In conclusion, this thesis has demonstrated that following mild TBI, the lungs are “primed” with a massive interstitial neutrophil influx and that a subsequent micro aspiration of acid induces exaggerated lung injury. The mechanism by which this occurs is the focus of on-going investigation. Pulmonary sequestration of neutrophils is also a predominant feature of other distant organ injuries.

A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.