This thesis examines the associations between substance use/ misuse and mental health outcomes among Canadians with a Traumatic Brain injury (TBI). Its primary aim is to explore whether or not individuals with a TBI have higher rates of substance use/misuse and poorer mental health than Canadians without a TBI, and to examine two competing hypothesis that help to explain these behaviours -- the impaired brain functioning and the general coping hypotheses. Drawing on data from the 2009-2010 Canadian Community Health Survey, a nationally representative cross-sectional survey, this research assessed substance use and mental health outcomes among those with a TBI, as well as two control groups: (1) individuals with a back or spinal injury; and (2) healthy non-injured controls. Analyses include descriptive statistics and multivariate regressions (logistic and multinomial) adjusting for a range of injury and socioeconomic variables. Those with a TBI demonstrated significantly elevated rates of binge drinking, illicit drug use, and having an anxiety disorder relative to non-injured Canadians, and provided partial support for both the impaired brain functioning and general coping hypotheses to substance use. These findings indicate that public health policy should increase awareness amongst healthcare and social workers on the necessity of continued follow-up of those who experience a TBI in order to reduce future health conditions and to reduce the likelihood of re-injury.

Objective: The purpose of this study was to investigate the impact of salience on the comprehension of predictive inferences in adults with traumatic brain injury (TBI), by increasing the visual salience of the predictive sentence. This study also investigated whether a relationship existed between performance on a predictive inferencing comprehension task and working memory for this population. Increasing the salience of a crucial sentence in the predictive inferencing task may lead to better memory for the inferred information within the focused portion of the text (Gernsbacher & Jescheniak, 1995; Parkhurst, Law, & Niebur, 2002). Method: Six participants with TBI and six non-brain injured peers (NBI) took part in the study. Each participant was administered an inference comprehension task which consisted of a series of 55 stories. Each story incorporated one of five conditions: 1) a Recent salient condition (inferred information immediately preceded the comprehension question and was visually salient); 2) a Recent non-salient condition (inferred information immediately preceded the comprehension question but was not visually salient); 3) a Distant salient condition (inferred information occurred early in the story and was visually salient); 4) a Distant non-salient condition (inferred information occurred early in the story and was not visually salient); and 5) a Control condition (no inferred information in the story). In addition there were 20 filler stories. The predictive sentence was bolded in half the stories in order to increase the visual salience of the stimuli. In addition, a measure of working memory span (Lehman-Blake & Tompkins, 2001) was administered. Results: A significant main effect was found for Group, F(1,11) = 7.6, p= 0.019, with adults with TBI performing more poorly than matched controls. A significant main effect was also found for Condition, F(3,33) = 3.159, p = 0.038, with all participants performing more poorly in the Distant non-salient condition. No statistically significant interaction between Group x Condition was observed, F(3,33) = 0.469, p =0.706. Post-hoc comparisons revealed that all participants performed more poorly in the non-salient condition when the storage load was high (distant non-salient condition). Significant correlations were found for working memory span and the Distant salient condition (r =0.677, p < 0.05) and Distant non-salient condition (r = 0.646, p < 0.05). Conclusion: The results have both theoretical and clinical implications. Theoretically, the role of attention in working memory is of interest in language comprehension (e.g. Montgomery, Evans, & Gillam, 2009). This study may further contribute to studies of allocation of attention using increased salience to enhance comprehension. Clinically, the use of enhancing the salience of key information is a practical strategy that can be employed.

Traumatic brain injury (TBI) is a prominent disease in developed countries, and age is an important factor in functional outcome. Although aged patients typically show diminished recovery compared to young patients, and have higher mortality and morbidity following TBI, the mechanism is not well understood. To date, there is no effective therapeutic for TBI. Previous studies indicate a secondary injury in TBI begins immediately after impact, and is likely the major contribution to delayed neuron dysfunction and loss. Studies also suggest mitochondrial dysfunction and increased free radical species (ROS) production following TBI may play a key role in the process. To evaluate oxidative damage following TBI, especially in aging, young (3 months), middle aged (12 months) and aged (22 months) Fisher-344 rats were subjected to a unilateral controlled cortical impact (CCI) injury, and tissue sparing, 4-hydroxynonenal (HNE) and acrolein levels, and antioxidant enzyme activities, and DNA oxidative damage were measured. In order to evaluate changes in mitochondria following TBI, mitochondrial protein levels were investigated using young adult animals. To evaluate a potential therapeutic for TBI, the effect of creatine on oxidative damage was evaluated. These studies show an age dependent increase of oxidative damage following TBI, demonstrated by increased levels of 4-HNE, acrolein and 8-hydroxyguanine. Middle aged and aged animals showed increased tissue loss compared to young animals 7 days post injury. Mitochondrial proteins involved in the respiratory chain, carrier proteins and channel proteins were significantly decreased 24 h post injury in ipsilateral cortex, but increased in both ipsilateral and contralateral hippocampus. To study potentially protective compounds in TBI, animals were fed with creatine two weeks before TBI and showed less oxidative damage and increased antioxidant capacity, which suggests creatine may be a potential drug for clinical treatment of TBI. The work described in this dissertation is the first to show increased oxidative damage and diminished antioxidant capacity in TBI in aging. The study of mitochondriafollowing TBI using quantitative proteomics is also the first time to show multiple mitochondrial proteins change following TBI. These data are also the first to show creatine can increase antioxidant defenses. These studies contribute to our understanding the mechanisms of secondary injury in TBI in aging.

The studies presented in this dissertation were conducted with the objective ofgaining greater understanding into the mechanisms of successful aging, the role ofmitochondria dysfunction in traumatic brain injury, and also on the mechanisms ofimproved learning and cognitive function in the aging.Aging is usually characterized by impairments in physiological functionsincreasing its susceptibility to dementia and neurodegenerative disorders. In thisdissertation, the mechanisms of dementia-free aging were investigated. The use of anantioxidant fortified diet and a program of behavioral enrichment in the canine model ofhuman aging was shown to result in a significant decrease in the levels of oxidativestress. A proteomic analysis of these brains also demonstrated a significant decrease inthe oxidative modification of key brain proteins and an increase in the expression levelsof other key brain proteins associated with energy metabolism and antioxidant systemswhich correlated with improved learning and memory.We show that following TBI key mitochondrial-related proteins undergoextensive oxidative modification, possibly contributing to the severe loss ofmitochondrial energetics and neuronal cell death previously observed in experimentalTBI.Taken together, these findings support the role of oxidative stress in thepathophysiology of aging and age-related neurodegenerative disorders and in CNS injury.These studies also show that antioxidants and a program of behavioral enrichmentprovide protection against oxidative stress-mediated cognitive impairments.

Moderate and severe pediatric traumatic brain injuries (TBI) are associated with significant familial stress and child cognitive and adaptive sequelae (Taylor et al., 1999). Research has demonstrated a relationship between familial stress and resources and child recovery of functioning following TBI (Taylor et al., 1999). We built on these findings by examining authoritarian parenting values and styles as a mediator of the relationship between parental stress and child adaptive outcomes 12-36 months following TBI or orthopedic injury (ORTHO). Participants were 21 children/adolescents with traumatic brain injuries and 23 with orthopedic injuries and one of their parents/guardians. Parents completed measures of demographics, parental stress, parenting values and styles, and child adaptive functioning. Child participants completed brief demographic questionnaires and intelligence screeners. Moderation was examined using hierarchical multiple regression. Mediation and moderated mediation were examined using bootstrapping tests of the indirect effect of parental stress on child adaptive functioning. After controlling for family insurance status, higher levels of parental stress were associated with reduced child adaptive functioning in the TBI group but not the ORTHO group. An examination of the mediational analyses revealed that higher levels of parental stress were associated with a greater reliance on authoritarian parenting styles, which was associated with reduced overall adaptive functioning and daily living skills across the two injury groups. Therefore, across groups, the relationship between parental stress and child overall adaptive functioning and daily living skills was found to be partially mediated by an authoritarian parenting style. Moderated mediation results revealed the presence of a significant interaction and 95% confidence interval on the socialization domain and indicated that the relationship between authoritarian parenting styles and child adaptive social skills differed significantly between the two groups. Our findings suggest a relationship between parental stress, authoritarian parenting styles, and child adaptive functioning in the 12-36 months following pediatric traumatic injury. Future research should explore the association among these, as well as other potentially mediating variables, both within and between the two groups with the goal of further elucidating the relationship between familial/environmental variables and child adaptive functioning following traumatic brain and orthopedic injury.

Brain injury, either surgically induced or as a result of trauma or stroke, is one of the leading causes of death and disability worldwide. Since transplantable stem cell sources are showing a great deal of promise and are actively being pursued to provide neuroprotection post-injury, in this body of work, we set out to characterize and examine the therapeutic potential of amniotic fluid derived (AF) cells as a potential cell source for cell-based therapies in mediating neuroprotection post-injury. Despite their heterogeneity, we found that AF cells are mainly epithelial in origin and express various genes involved in stem cell maintenance and neural commitment. A very small subset of AF cells also express pluripotency markers OCT4a, SOX2 and NANOG, which can be enriched for by single cell cloning. SOX2 positive clones have the capacity to give rise to a neuronal phenotype, in neural induction conditions, which can be used to examine the neural differentiation capabilities of AF cells. Subsequently, we examined the ability of AF cells to mediate a neuroprotective effect in a surgically induced brain injury model through gap junctional-mediated direct cell-cell communication and as a vehicle for GDNF delivery post-injury. AF cells express high levels of CX43 and are able to establish functional gap junctional intercellular communication (GJIC) with cortical astrocytes. We report an induction of Cx43 expression in astrocytes following injury and demonstrate, for the first time, CX43 expression at the interface between implanted AF cells and host astrocytes. In an effort to boost host endogenous neuroprotective mechanisms post-injury, via neurotrophic factor delivery, we engineered AF cells to secrete GDNF (AF-GDNF). GDNF pre-treatment significantly increased AF cell and cortical neuron survival rates following exposure to hydrogen peroxide. AF-GDNF cells, seeded on polyglycolic acid (PGA) scaffolds, survived longer in serum-free conditions and continued to secrete GDNF post-implantation activating the MAPK/ERK signaling pathway in host neural cells in the peri-lesion area. Despite some promising trends, we did not observe significant behavioural improvements following AF-GDNF/PGA implantation nor reduced lesion volume during the 7 day time-frame. In conclusion, through GJIC with cortical astrocytes and delivery of exogenous neurotrophic factors, AF cells hold great promise in mediating neuroprotection post-injury.

Few authors report comprehensive psychometric data for their acquired brain injury (ABI) outcome indices (e.g., items analyses, test-retest reliability, survivor-proxy agreement, internal consistency, convergent validity). Even fewer authors submit their indices to modern psychometric analyses, like Rasch analysis. The purpose of this dissertation was to evaluate the traditional and modern psychometric properties of a new index of brain injury outcome: the Functional Outcome Profile (FOP). One hundred and thirteen mixed (estimated mild, moderate, and severe injury) ABI survivors and 22 significant others participated in the study. Items analyses (n = 113) revealed that all items were endorsed by at least one ABI survivor, suggesting that the FOP assessed areas relevant to ABI survivors. However most items, composite scores, and the total score had distributions that were negatively skewed. One-week test-retest reliability correlations for the total score, composites, and items (n = 25) were generally in the moderate to strong range (r > 0.7), while survivor-proxy agreement correlations for the items (n = 22) were generally in the moderate range (r = 0.5 to 0.7). The internal consistency scores (n = 113) for 5 of the 8 composite scales and for the full FOP were good (Cronbach α > 0.7). Concurrent-convergent validity analyses revealed that the FOP correlated moderately well with the Mayo-Portland Adaptability Index (MPAI-4) (r = -0.75), but that it did not correlate with injury-related information (e.g., age at injury, time since injury, estimated severity). Rasch calibration of the FOP resulted in a 62-item index that fit the Rasch model well and that demonstrated good reliability and separation. Overall, the results suggest that the FOP has good traditional and modern psychometric properties when used with community-based outpatient ABI survivors. Future studies with the FOP should focus on improving the FOP’s clinical utility and further verifying its convergent and divergent validity.

The Functional Outcome Profile (FOP, Joschko & Skelton, 2003) was developed to be a broad measure of functional outcome following brain injury, unique from existing outcome measures. The purpose of this thesis was to investigate the underlying assumptions and psychometric properties of aspects of the FOP. Data from 107 brain injury survivors and 20 matched significant others were utilized. Exploratory investigations of the items, the scoring and the subscales were undertaken first, followed by investigations of the internal consistency and test-retest reliability of the outcome scores and the survivor-proxy agreement of the frequency ratings. Finally, multiple lines of evidence for the validity of the FOP were put forth based on the content, its relation to external, demographic variables and its sensitivity to change over time. In general, the FOP was found to be a reliable measure of outcome following brain injury with the subscale scores providing the most useful information. The implications for these findings are discussed.

Wayfinding is the process of determining and following a route. Survivors of acquired brain injury (ABI) may evince impaired wayfinding skills. Mobile technology offers a promising avenue for wayfinding support, but software is seldom designed for users with cognitive impairments. This research was intended to inform the design of mobile wayfinding software for survivors of ABI. Two qualitative studies were conducted to investigate wayfinding by survivors of ABI, and solicit views on a prospective mobile wayfinding aide. Data were used to generate a substantive theory of wayfinding in ABI. Participants were generally enthused by the prospect of a mobile wayfinding aide. They felt that it would be useful and bolster confidence, leading to improved community access. In conjunction with the theory and its implications, their remarks on usage and design indicate that mobile wayfinding software should: provide a simple interface; be context aware; afford an interactive user experience; integrate with calendar software; deliver [audio] notifications; and emphasize landmarks while affording map access. / Graduate

Impaired inhibition is a deficit of several psychopathological disorders, particularly attention-deficit hyperactivity disorder (ADHD). In the first study, a meta-analysis was conducted to determine whether impaired inhibition as measured by the Stop Signal Task is specific to ADHD, or whether it could be found in other psychopathological disorders. The meta-analysis found an inhibitory deficit in ADHD, but also in obsessive compulsive disorder (OCD) and schizophrenia (SCZ), suggesting that deficient inhibition is not specific to ADHD. A common neural mechanism may underlie deficient inhibition in ADHD, OCD, and SCZ. Study 2 aimed to determine the neural basis of inhibition using a lesion-deficit approach in children with traumatic brain injury (TBI). Only TBI children with white matter lesions in the superior frontal gyrus (SFG) region showed impaired inhibition compared with orthopedic injury controls. This suggests that deficient inhibition may stem from frontal lobe white matter damage, particularly in the SFG.