Indiana University-Purdue University Indianapolis (IUPUI)

Background: People who have experienced a moderate or severe traumatic brain injury (TBI) will most likely live with motor and cognitive deficits including balance and poor mobility. These deficits may lead to limitations in activity participation, life satisfaction, and may increase the risk of falls. Improving access to rehabilitation care in the chronic phase of recovery is essential to prevent ongoing health issues. However, geographical restrictions, cost of transportation, or recently the COVID-19 pandemic restrictions may limit access to rehabilitation services. Telerehabilitation could serve as an alternative method to provide rehabilitation care while increasing access. Objectives: The overall objective of this dissertation was to understand the implementation of high-intensity telerehabilitation exercise programs for people living with a moderate or severe TBI and their family partners. This was accomplished by 1) determining the feasibility of using telerehabilitation, 2) investigating the effectiveness of high-intensity home-based telerehabilitation exercise programs on physical activity, functional mobility and dynamic balance, 3) understanding the perspectives and lived experiences of completing a telerehabilitation program, and 4) exploring how interpersonal behaviours can influence practice and be perceived in a telerehabilitation setting. Methodology: Influenced by a people-centered approach and explained by the Self-Determination Theory, this dissertation followed a mixed-method alternating single-subject design methodology. Five dyads composed of five persons living with a moderate or severe TBI and their family partners completed two high-intensity telerehabilitation programs remotely supervised, daily and weekly. The feasibility and effectiveness of the telerehabilitation programs were measured from a quantitative and qualitative perspective to replicate the clinical realities and understand all perspectives. Results: In this dissertation, the feasibility of using telerehabilitation with this population was highlighted by reporting high adherence, high usability, active engagement and safety. The effectiveness on physical activity levels, functional mobility, dynamic balance and concerns with falling was also demonstrated with no differences between the daily and weekly remote supervision schedule. The dyads described being highly satisfied, engaged, and enjoyed the remotely supervised exercise programs. The individuals with the TBI perceived more supportive behaviours than thwarting behaviours from the physiotherapist. Conclusion: This dissertation advances knowledge on telerehabilitation implementation for people living with cognitive and motor deficits following a TBI. High-intensity home-based telerehabilitation programs were shown to be feasible and effective. I introduced the importance of assessing needs-supportive and needs-thwarting interpersonal behaviours in the telerehabilitation context. Integrating these novel telerehabilitation concepts within emerging telerehabilitation models of care could significantly impact long-lasting positive health outcomes for individuals living with a moderate or severe TBI.

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A mild traumatic brain injury (mTBI), commonly referred to as a concussion, is when the brain experiences an abrupt acceleration and/or deceleration that sends shock waves through the brain tissue, upsetting its structure and function. A mTBI is a heterogeneous condition with acute and chronic outcomes for patients. The chronic form of mTBI can lead to a wide range of neurological, behavioral, and cognitive symptoms. Critically, this injury is not defined by a simple process or pathophysiological event but rather biomechanical and neurological brain damage that can trigger highly complex physiological cascades. These further lead to a wide range of cellular, molecular, and functional changes that alter genes and associated metabolites. These changes, if specifically characterized, could be used to predict a patient’s outcome and recovery timeline. Recently, genetic studies showed that specific genotypes could increase an individual’s risk of more severe injury and impaired recovery following mTBI. Consequently, an improved understanding of gene alteration and genetic changes is necessary to develop personalized diagnostic approaches which can guide the design of novel treatments. The current study proposes utilizing bioinformatic tools, biological networks, and databases to identify potential genes and microRNAs associated with the mTBI in order to aid the early diagnosis of mTBI and track recovery for individual patients. With bioinformatic techniques, we were able to identify and compare genetic and epigenetic data associated with mTBI, as well as understand the various aspects of molecular changes after brain injury. Ultimately, we analyzed and cataloged the biological pathways and networks associated with this injury. A critical search of online bioinformatics databases was performed to determine interactions between mTBI-related genes, and relevant molecular processes. The major finding was that APOE, S100B, GFAP, BDNF, AQP4, COMT, MBP, UCHL1, DRD2, ASIC1, and CACNA1A genes were significantly associated with mTBI outcome. Those genes are primarily involved in different neurological tasks and neurological pathways such as neuron projection regeneration, regulation of neuronal synaptic plasticity, cognition, memory function, neuronal cell death and the dopaminergic pathway. This study predicted specific miRNAs linked to mTBI outcomes and candidate genes (hsa-miR-204-5p, hsa-miR-16-5p, hsa-miR-10a-5p, has-miR-218-5p, has-miR-34a-5p), and RNA-seq analysis on the GSE123336 data revealed that one miRNA found (hsa-miR-10a-5p) matched our predictions related to mTBI outcomes. Pathway analysis revealed that the predicted miRNA targets were mainly engaged in nervous system signaling, neuron projection and cell differentiation. These findings may contribute to developing diagnostic procedures and treatments for mTBI patients who are still experiencing symptoms, but validation of these genetic markers for mTBI assessment requires patient participation and correlation with advanced personalized MRI methods that show concussion related changes. / Thesis / Master of Applied Science (MASc) / Traumatic brain injury (TBI) is a highly prevalent neurological injury affecting millions of individuals globally. Mild TBI (mTBI), sometimes called concussion, makes up over 85% of TBI cases. A mTBI is a heterogeneous condition with acute and chronic outcomes for patients and involves complex cascades of cellular and molecular events that can lead to functional changes in genes and associated metabolites. In recent genetic studies, it has been shown that certain genotypes are associated with a higher risk of experiencing a more serious injury and a slower recovery after mTBI. These genes can be utilized as crucial biomarkers to predict how long it will take for a person to recover from a concussion. The purpose of this study was to find potential biomarkers that could help in the early detection of mTBI and the monitoring of individual patients’ recovery. It was hypothesized that genes and miRNAs (and their associated proteins) involved in neuronal body, axonal and myelin integrity and regeneration would be identified as important markers of severity.

In an average year more than 1.7 million people will experience a traumatic brain injury (TBI) in the United States. It is known that atrophy occurs across a spectrum for TBI patients, ranging from mild to severe. Current conventional magnetic resonance imaging (MRI) methods are inconsistent in detecting this atrophy on the milder end of the spectrum. Also more contemporary imaging tools, although efficient, are too time consuming for clinical applicability. It is for these reasons that a quick and efficient measurement for detecting this atrophy is needed by clinicians. The measuring of third ventricle width had the potential to be this measurement, since it is known that ventricular dilation is an indirect measure of brain atrophy. This study used two different data sets acquired at multiple sites. A total of 152 TBI patients' MRI scans were analyzed with diagnosis ranging from mild to severe. They have been age matched with 97 orthopedic injury controls. All scans were analyzed using Freesurfer® auto-segmentation software to acquire cortical, subcortical, and ventricular volumes. These metrics were then used as a standard of efficacy which we tested the new third ventricle width protocol against. There was no statistically significant difference between the overall TBI group and OI group (Welch's F(1,238.435) = 1.091, p= .267). The complicated mild injury subgroup was significantly increased from the mild subgroup (p= .001, d= .87). The grand average third ventricle width measurement was the best prognosticator of all measures analyzed despite only predicting 35.1% of cases correctly. The findings suggest that the third ventricle width measurement is insensitive to atrophy between all groups as hypothesized.

Objective: Identify patients with specific emergency department (ED) discharge diagnoses who later report symptoms associated with a mild traumatic brain injury (MTBI), compare frequency and severity of MTBI symptoms by discharge diagnoses, investigate the frequency of head injury education provided to ED patients with each diagnosis, and finally, to learn what type of changes have occurred in the lives of patients as a result of their injury. Methods: Fifty-two ED patients, aged 18 to 28 who were at least two weeks post injury, spoke English and were discharged with a diagnosis of concussion/closed head injury (CHI), head laceration, motor vehicle crash (MVC), whiplash/cervical strain, facial/jaw fractures or multiple injuries were invited to participate. Participants completed the Post Concussive Symptom Scale (PCSS), a demographic questionnaire and then a series of open-ended questions about the impact the injury had on their lives. Results: MTBI symptoms on the PCSS were reported by 84.6% (n = 44) of respondents with a range of 1 – 23 different symptoms per participant. Headache (69.2%) and fatigue (61.5%) were the most common symptoms. Males (51% of the participants) reported on average 6.76 symptoms (S.D. = 6.53) whereas females reported an average of 12.68 symptoms (S.D. = 6.32). A large percentage (83.3%, n = 10) of participants with a MVC diagnosis reported severity scores in the moderate range (mean = 3.17; S. D. = 0.27) in all four PCSS categories (physical, thinking, sleep and emotional) representing the highest severity scores reported overall. Participants diagnosed with a concussion/CHI received the most (74%) head injury education of all discharge diagnoses, but only half (51%) received written information. The most common quality of life change was that 70.3% of survey participants became more cautious. Conclusion: Participants with a discharge diagnosis not commonly associated with brain injury reported having MTBI symptoms at least two weeks post injury with females reporting twice as many symptoms as males reported. Head injury education provided in the ED was lacking for all participants and although participants involved in a MVC reported having the most severe MTBI symptoms they had the least head injury education. All health care providers, especially nurses working in the ED, need to look beyond physical complaints and recognize injuries associated with increased risk for developing MTBI symptoms. Proactive ED identification of patients with "at risk" injuries by nurses would likely promote increased MTBI education and thereby result in fewer missed MTBI diagnoses.

Working memory tasks are associated with the activation of widely distributed neural networks. The Sternberg working memory task has been used to explore the neural correlates associated with changes in memory load and the resolution of interference. Preliminary research suggests that the integrity of the anterior cingulate is correlated with resolving load adjustments but not in resolving interference demands; the opposite pattern of associations have been observed with the right middle frontal gyrus.Participants in the present study were 28 children who had sustained moderate to severe traumatic brain injuries (TBI) and 28 children who had sustained orthopedic injuries (OI). Participants were aged between 7 and 17 years at the time of injury (mean age = 13.2, s.d.=2.3). The groups were matched on age, gender, socioeconomic level, and pre-injury measures of behavioral and emotional functioning. Participants completed the Sternberg working memory task and structural MRI scans three months post injury. Automated brain parcellation software (Freesurfer) was used to calculate volumetric data for regions of interest. Regions of interest included the anterior cingulate and right middle frontal gyrus; additionally, the volume of the corpus callosum was used as an index of overall brain integrity. There were no significant differences between the groups on percent errors on the Sternberg task. Participants in the TBI group had significantly longer reaction times overall than the OI group. Interference in the Sternberg task has the potential to either help or hinder performance. Participants in the OI group displayed the anticipated effects of interference on reaction time whereas the TBI group as a whole did not display this pattern (priming effect not observed). The TBI group had significantly lower volumes in the regions of interest than the OI group. Hypothesized correlations between the regions of interest and changes in load / interference demands were partially supported. Exploratory analyses identified positive correlations between the volume of the right middle frontal gyrus and reaction time measures that warrant further exploration.

The anterior cingulate has been implicated in a number of cognitive processes that are at risk following traumatic brain injury (TBI), such as executive function and emotional processing. While the cingulate is believed to play a role in the above-mentioned cognitive processes, the relative roles of gray and white matter in functional outcomes post-TBI are not fully understood. The current study investigated various quantifiable brain properties (e.g., cortical thickness and volume, volume of underlying white matter, and white matter integrity) of the caudal anterior cingulate (CAC) gyrus and their relationships with behavioral measures of cognitive control following pediatric TBI. Parent ratings at three months post-injury indicated that TBI children demonstrated greater difficulty inhibiting inappropriate behavior and effectively transitioning between tasks. Reductions of CAC white matter integrity were observed in TBI participants, in the absence of significant morphometric group differences in this region. Neither CAC morphometrics nor fractional anisotropy (FA) were associated with experimental measures of cognitive control. The current findings indicate that DTI metrics may be more sensitive to brain changes in the region of the CAC following TBI. While strong relationships were not observed between CAC properties and measures of cognitive control, it is possible that study limitations may have obscured potential findings.

Background: Traumatic brain injury is a significant public health problem. Heart rate variability is a potential modality to measure physiological dysfunction following traumatic brain injury to assist in determining recovery time and the relationship between traumatic brain injury severity and recovery. To date, a summary of the evidence across injury severities and the possible role of heart rate variability biofeedback in traumatic brain injury treatment is lacking but needed to determine potential clinical utility. Participants and Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematic literature searches on CINAHL, Embase, PsycINFO, SPORTDiscus, and MEDLINE were conducted in August of 2020. There were two parts to this systematic review. Part I reviewed the relationship between heart rate variability and injury severity, recovery, and cognitive and emotional functioning. Part II reviewed the relationship between heart rate variability biofeedback and traumatic brain injury. Two coders coded each article and provided quality ratings with discrepancies resolved by consensus. Results: Regarding Part I, eighty-five papers met inclusion criteria. For outcome measures, eight studies (9%) focused on HRV as a predictor of mortality following moderate-to-severe traumatic brain injury; 9 studies (10%) included a measure of post-concussive symptom improvement; 7 studies (8%) included a measure of mood disturbance/change; 3 studies (3%) assessed return to consciousness. Overall, there appears to be a positive relationship between increased heart rate variability and recovery of clinical symptoms following traumatic brain injury. For Part II, seven papers met inclusion criteria. All studies included a measure of mood; 5 studies (71%) included neuropsychological functioning as an outcome measure; 1 study (14%) included a measure of life satisfaction. On average, participants completed 14 sessions of heart rate variability biofeedback (mean = 13.5, SD = 13.5, range = 1 to 40). Biofeedback was associated with improved heart rate variability following traumatic brain injury, though the methodological quality is questionable, and more controlled studies and randomized controlled trials are needed. Conclusions: Findings to date suggest a positive relationship between increased heart rate variability and recovery of clinical symptoms, including improvements in cognitive function and physical symptoms including headaches, dizziness, and sleep problems. Literature on traumatic brain injury and heart rate variability biofeedback treatment is in the early stages, and effectiveness is unclear due to poor-to-fair study quality, though early results are promising.

Thesis (Ph.D.)--Boston University / The widespread use of Improvised Explosive Devices (IEDs) in the Wars in Iraq and Afghanistan has caused a dramatic increase in shockwave-induced mild Traumatic Brain Injury (mTBI), leading mTBI to be dubbed the 'signature injury' of modern warfare. Currently, the pathology of shockwave-induced mTBI is unknown , and it is diagnosis is based on self-reported symptoms and combat history. While the etiological mechanism has not yet been determined , it is becoming increasingly accepted that shockwaves themselves are the brain-damaging agent that emanate from IEDs. To assess how mild, sub-lethal shockwaves might damage brain tissue, we developed an in vitro assay to deliver shockwaves to neuronal cells in culture, and then assayed several properties of these cells that affect their function. This assay involved exposing rat cortical and hippocampal primary neuronal cultures to shockwaves of increasing magnitude generated with a biolistic Gene Gun. The Gene Gun produces shockwaves of sufficient overpressure to cause cognitive impairment in animal models of shockwave-induced mTBI. Our results show that overpressures of ~1.0 pound per square inch (psi) caused transient membrane permeability for molecules up to ~12 nanometers in diameter. This change in membrane permeability was accompanied by a transient decrease in cellular ATP levels and synaptic densities. This synaptic degeneration correlated with changes in the level and phosphorylation state of several synaptic proteins examined. Similar results were observed in dissected rat retinas suggesting that these shockwave-induced effects can occur in complex tissues, such as the brain. Based on these findings we propose that shockwaves damage cellular membranes, leading to a decrease in intracellular ATP, and ultimately to a reduced numbers of synapses, the part of neurons most important for learning, memory and behavior. Additional experiments in whole animals will be required to ascertain whether shockwave-induced cellular damage and synaptic degeneration plays an etiological role in shockwave-induced mTBI.