Veterans of the Iraqi and Afghanistan conflicts have frequently returned with injuries such as mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD). More recently, concern has been raised about the large number of returning soldiers who are diagnosed with both. Literature exists on the neuropsychological factors associated with either alone, however far less research has explored the effects when combined (PTSD+mTBI). With a sample of 206 OEF/OIF veterans, the current study employed neuropsychological and psychological measures to determine whether participants with PTSD+mTBI have poorer cognitive and psychological outcomes than participants with PTSD-o, mTBI-o, or veteran controls (VC), when groups are matched on IQ, education, and age. The PTSD+mTBI and mTBI-o groups exhibited very similar neuropsychology profiles, and both PTSD+mTBI and mTBI-o performed significantly (α=.01) worse than VC on executive functioning and processing speed measures. There were no significant differences between VC and PTSD-o on any notable neuropsychology measures. In contrast, on the psychological measures, the PTSD+mTBI and PTSD-o groups were identical to each other and more distressed than either mTBI-o or VC. These findings suggest there are lasting cognitive impairments following mTBI that are unique to the condition and cannot be attributed to known impairments associated with distress.

Traumatic brain injury (TBI) is an injury of the brain most often caused by blunt force trauma to the head and typically characterized by an increase in reactive oxygen species (ROS), inflammation, and hemorrhaging. Heme oxygenase (HO) catalyzes the breakdown of heme into carbon monoxide (CO), biliverdin which is further reduced to bilirubin, and ferrous iron. There are two active isoforms: HO-1 which is inducible and found predominantly in liver and spleen tissue; and HO-2 which is constitutive and found predominantly in the brain and testis. The metabolites of heme possess cytoprotective properties that can limit damage resulting from TBI. Our laboratory has found a selective HO-2 activator known as menadione (MD) that has been found to increase HO-2 activity by 4-fold while not affecting HO-1 in vitro. Given the higher amounts of HO-2 found in the brain and the cytoprotective properties of heme metabolites, we postulate that activation of HO-2 using menadione would mitigate further damage after TBI. The rat controlled cortical impact (CCI) model was used to simulate TBI with spontaneous locomotor activity (SLA), spontaneous alternation behaviour (SAB), and beam balance (BB) as the behavioural tasks to assess cognitive and motor function. A dose-response study (25, 50, 100, 200 μmol/kg) was performed to ascertain the effect of MD treatment on injured animals comparing to uninjured controls and injured animals treated with the vehicle (saline). We found that BB performance improved to control levels after MD treatment at 25 μmol/kg and 50 μmol/kg whereas animals treated with saline did not improve. SLA and SAB performance did not improve after treatment with MD. The findings suggest that HO-2 activation may be a viable method in mitigating further injury after TBI. / Thesis (Master, Pharmacology & Toxicology) -- Queen's University, 2014-06-27 19:33:45.645

Introduction-Physical activity can reduce the risk of contracting many of the 'diseases of the sedentary', such as coronary heart disease and cancer (Blair et al., 1996). Recognition of this protective effect has led to the development of many programmes designed to promote the benefit of participation in sport and physical exercise (Hillary Commission, 1993; Nicholl et aI., 1995). With participation in sport, especially contact sport, the risk for injuries increases, including injuries to the head and neck (Wilberger, 1993; Wekesa et al., 1996; Pettersen, 2002). Mild traumatic brain injuries (MTBI) or concussion as used interchangeably in the literature (Maroon et al., 2000; Wills & Leathem, 2001) are an important public health concern, due to the high incidence and frequently persisting symptomatology (Evans, 1992). Mild traumatic brain injury is defined as a complex patho-physiological process affecting the brain induced by traumatic biomechanical forces (Aubry et al., 2002; McCrory et al., 2004). A sub-concussive injury or very mild traumatic brain injury (vMTBI) may be defined as an apparent brain insult with insufficient force to cause hallmark symptoms of concussion (Jordan, 2000; Webbe & Bath, 2003). The high incidence of sport related head injuries in South Africa is alarming, although the prevalence thereof is unknown and difficult to assess, as the seemingly trivial injuries frequently remain unreported (Roux et al., 1987). This is especially applicable in sport where a milder form of head injury is common. This is cause for concern as cumulative head injuries traditionally regarded as trivial or 'minor' may result in players running the risk of increasingly negative consequences following repetitive 'minor' head injuries. In contact sport such as rugby, players are at great risk of sustaining repetitive mild traumatic brain injuries. The negative outcome following these repetitive minor head injuries has been demonstrated by numerous studies on boxers and other athletes exposed to repeated MTBI and vMTBI (McLatchie et aI., 1987). The incidence of vMTBI has not yet been researched in school rugby and this study is the first to report the incidence of vMTBI in a secondary school rugby team. Obiectives - The objectives of this study were to determine the incidence, the neuropsychological consequences and the effect on the academic performance of repeated mild (MTBI) and very mild traumatic brain injuries (vMTBI) in a secondary school rugby team during one playing season. Methods - A cohort of 35 secondary school male rugby players divided into a vMTBI (group 1) (n=26) and a MTBI (group 2) (n=9) from a local secondary school's first and second team, was followed for a full competitive season by a trained Biokineticist, who was present at all the games and contact sessions played. All vMTBI and MTBI and the severity of these injuries were documented. A control (group 3) that consisted of 10 secondary school non-rugby players were compared with the vMTBI and MTBI groups. The incidence of repeated MTBI and vMTBI in a secondary school rugby team were gathered by questionnaires and observation next to the field by a trained Biokineticist. Pre-season and post-season neuropsychological tests were conducted on the research groups and the control group. The neuropsychological tests that were conducted on the three groups were the Colour Trial Test 1 and 2 (CTT 1 + 2), the Symbol Digit Modalities Test (SDMT), the Wechsler Memory Scale-Revised (WMS-R) and the Standardised Assessment of Concussion (SAC). After each match played throughout the season the research group also completed a SAC test. The academic results of the final examination (year 1) of the year of the specific rugby season were obtained, as well as the academic results of the final examination of the preceding two years (year 2 and 3). The programme STATISTICA (version 7.0, Stat soft, Tulsa, OK) was used to analyse the data. Descriptive statistics, one-way ANOVA's, two-way repeated measures ANOVA's, Post-hoc Tuckey HSD analysis and Pearson's product moment correlation were used for all the statistical analyses. Results - This study of a secondary school rugby team has shown 726 vMTBI's and 18 MTBI's throughout one rugby season. This relates to 1951 vMTBI's per 1000 player hours and 48 MTBI's per 1000 player hours. Reductions in delayed memory (p=O.O1)from preseason to post-season in a group of players with repetitive vMTBI's during a single rugby season were found. This was the first evidence of possible neurocognitive deficits towards delayed memory in very mild traumatic brain injuries at secondary school level. Statistically significant (p<=0.05)results of the SAC test totals between both the vMTBI and MTBI groups were documented in the different games throughout the rugby season and compared with the baseline test. No statistically significant differences (p<=0.05) between the pre-season and post-season's scores of the SAC test totals were documented. A decrease in academic performance in the subject Afrikaans (year 1 compared with year 2) with a p-value of p=O.O17(group 1) and p=O.O16(group 2) respectively was found. Conclusion - The findings of this study indicate a high incidence of vMTBI in a cohort of secondary school rugby players in one season, a statistically significant reduction (p=O.O1 )in delayed memory of the vMTBI rugby players and a statistically significant decrease in academic performance p=O.O17 (group 1) and p=O.O16 (group 2) in the subject Afrikaans from year 1 to year 2 final examinations. / Thesis (Ph.D. (Human Movement Science))--North-West University, Potchefstroom Campus, 2006.

Objectives: Most researchers have attributed observed cognitive differences between individuals with a traumatic brain injury (TBI) and ‘normal’ individuals to physiological changes to the brain. Lacking exploration has been the role of social context/environmental variables. One of the variables investigated in the social psychology literature is stereotypes. Research has shown that the presence of stereotypes in testing environments negatively interferes with test performance (called stereotype threat theory). This concept appears relevant to the TBI population given that empirical research has demonstrated that individuals tend to believe that traumatic brain injuries lead to cognitive deficits, as well as the fact that reminders of potential cognitive deficits are oftentimes present in neuropsychological testing settings (e.g., in pre-test instructions, etc.). It is argued that these cues exacerbate pre-existing negative beliefs regarding cognitive functioning for individuals with a mild-moderate TBI, thereby affecting neuropsychological test performance. Method: The sample consisted of 42 individuals who sustained a mild-to-moderate TBI at least 6 months earlier and 42 age-, gender-, and education-matched healthy adults below the age of 60. The study, similar to other stereotype threat research, consisted of ‘reduced threat’ and ‘heightened threat’ conditions. The purpose of the former condition was to reduce negative stereotypes and emphasize the notion of personal control over cognitive abilities. Questionnaires and neuropsychological tests were administered subsequent to the experimental manipulation. Results: TBI participants endorsed greater levels of anxiety, motivation, and dejection, but reduced feelings of memory self-efficacy compared to the control group. The most pivotal results to the research study revealed that the TBI heightened threat group displayed lower scores on the Initial Encoding and Attention composite variables (which were comprised of neuropsychological test measures) than the TBI reduced threat group. Furthermore, the head-injured heightened threat condition reported lower memory self-efficacy than the reduced threat condition, and the non-head-injured heightened threat group endorsed a greater degree of negative beliefs/stereotypes regarding TBI than the non-head-injured reduced threat group. The construct of memory self-efficacy was found to mediate the relation between threat condition and performance on encoding/attention measures. Conclusions: The findings highlight the role of negative stereotypes and expectations/beliefs to cognitive test performance in individuals who have sustained a mild/moderate TBI. To date, there have been few attempts to integrate social cognition with neuropsychology. Applying the information gleaned from previous stereotype threat studies to a TBI population bridges this gap and provides a prosperous avenue for future research.

The research program described in this dissertation updates the knowledge base concerning human navigation and presents new methods for investigating selection and use of cognitive navigational strategies. Four experiments were designed to answer questions about the effects of environmental and experiential factors on cognitive mapping and selection of navigation strategies. Humans are thought to navigate using two different reference frames often referred to as “world based” and “person based”. These reference frames correspond to two probable cognitive/memory systems respectively labelled “allocentric” for the formation and use of cognitive maps of the environment, and “egocentric” for navigation by stimulus response or guidance. Different navigational strategies are associated with the two systems. Allocentric strategies rely on the presence of a stable environmental structure containing a number of more distal, relational stimuli whereas egocentric strategies rely only on the presence of simple, local cues (cue-based egocentric) or on body movements (response-based egocentric). The experiments tested navigation behaviour and strategy selection using virtual environment analogues of an animal model, the Morris water maze. Adaptations included, 1) the Place maze biasing participants toward the use of an allocentric strategy, 2) the Cue maze (and Floor Cue maze) biasing participants toward the use of an egocentric strategy, and 3) the Dual-strategy maze that has no bias because participants can choose to utilize either an allocentric or egocentric strategy. Experiment 1 was a behavioural study testing 101 university students in the Place maze and Floor Cue maze, with and without the opportunity to explore the environment before testing. The experiment showed for the first time that exploration is necessary for allocentric but not for egocentric navigation, suggesting that prior exploration is important for cognitive mapping. Experiment 2 outlined a novel and reliable eye tracking method for differentiating strategy use in the Place and Cue mazes. Eye movements were measured during the first orientation second of behavioural trials to differentiate allocentric from egocentric strategy use. Experiment 3 employed the established eye tracking method to test the effects of experience on strategy selection. Participants were trained in either the Place maze or the Cue maze and then tested in the Dual-strategy maze. A strategy probe trial was introduced at the end of testing to indicate whether participants had selected an allocentric or an egocentric strategy. Training experience had a strong behavioural effect on later strategy selection at the end of testing. Furthermore the effect of experience occurred independently of the gender of participants. However, the experience effect was only briefly shown using eye tracking measures. Experiment 4 was a successful feasibility study showing that eye tracking measures can be utilized to measure navigational strategy use in survivors of traumatic brain injury. Together these experiments may indicate that strategies are not innate or within the person but rather are interactions of the person with the environment. / Graduate

Mild Traumatic Brain Injury (mTBI), often called concussion, has become a growing public health concern, prevalent in both athletic and military settings. In response, many researchers have explored cognitive outcomes post-mTBI, with a plethora of meta-analyses summarizing these findings; however, these meta-analyses examine solely mean performances on cognitive tasks, ignoring intra-individual variability (IIV) in cognitive performance that may elucidate neuropsychological impairment following mTBI. The current thesis involved two studies, responding to both the growing meta-analytic research and limited IIV findings. Study 1: Many meta-analyses have amalgamated individual study results on post-mTBI neuropsychological outcomes. With the abundance of meta-analyses, a systematic review of meta-analyses stands as the next logical step. Method: A systematic literature search yielded 11 meta-analyses meeting inclusion criteria (i.e., English-language systematic reviews/meta-analyses covering post-mTBI observational cognitive research on late adolescents/adults), with their findings qualitatively synthesized based on moderator variables (i.e., cognitive domain, time since injury, past head injury, participant characteristics, comparison group, assessment technique, and persistent symptoms). Results: The overall effect sizes ranged for both general (range: .07-.61) and sports-related mTBI (range: .40-.81) and differed both between and within cognitive domains, with executive functions appearing most sensitive to multiple mTBI. Cognitive domains varied in recovery rates, but overall recovery occurred by 90 days post-injury for most individuals and by seven days post-injury for athletes. Greater age/education and male gender produced smaller effects sizes, while high school athletes suffered the largest deficits post-mTBI. Control-group comparisons yielded larger effects than within-person designs, while assessment techniques had limited moderating effects. Conclusions: Overall, meta-analytic review quality remained low with few studies assessing publication or study quality bias. Meta-analyses consistently identified adverse acute mTBI-related effects and fairly rapid symptom resolution. Study 2: The long-term outcomes of executive functions and IIV following mTBI are unclear due to inconsistent and limited research, respectively. Further, the relationship between physical activity (PA) and cognitive performance at young adulthood remains almost fully unexplored. In turn, the current study aimed to (a) assess the diagnostic utility of both executive functions and IIV at predicting mTBI history and (b) evaluate the interaction between PA levels and mTBI on both of these cognitive metrics. Method: Altogether 138 self-identified athletes (Mage = 19.9 ± 1.91 years, 60.8% female, 19.6% 1 mTBI, 18.1% 2+ mTBIs) completed three executive-related cognitive tasks (i.e., N-Back, Go/No-go, Local-Global). Ordinal logistic regression analyses examined the joint effect of person-mean and IIV as predictors of mTBI status. Multi-level models examined mTBI and PA levels as predictors of trial-to-trial changes in performance. Results: Only mean response time (RT) for the Local-Global task predicted mTBI status, while no IIV variables reached unique significance. PA levels predicted subtle within-task decreases in RT across Local-Global trials. Conclusions: IIV research on mTBI remains limited; however, the preliminary results do not indicate any additional predictive value of IIV indices above mean performances. For executive functions, shifting appeared most affected, with past researchers identifying post-mTBI impairment in attentional processing. Higher PA levels minutely benefited within-task shifting and mean inhibitory performance, although these finding require cautious interpretation. / Graduate / 0622 / jkarr@uvic.ca

Children with traumatic brain injury (TBI) often experience difficulties with inhibitory control (IC), manifest in both neurocognitive function (poor performance on the stop signal task, SST) and behavior (emergence of de novo attention-deficit/hyperactivity disorder, or secondary ADHD, S-ADHD). IC allows for the regulation of thought and action, and interacts with reward to modify behaviour adaptively as environments change. Children with developmental or primary ADHD (P-ADHD) exhibit poor IC and abnormalities when responding to rewards, yet the extent to which S-ADHD is similar to and different from P-ADHD in terms of these behaviours is not well-characterized. The cancellation and restraint versions of the SST were used to examine the effects of rewards on 2 distinct forms of IC in children and adolescents divided into 4 groups (control, TBI, S-ADHD, and P-ADHD). The SST requires participants to respond to a “go signal” and inhibit their responses when encountering a “stop signal”. Rewards improved performance similarly across groups, ages, and cancellation and restraint IC tasks. Adolescents exhibited better IC and faster and less variable response execution relative to children. Significant IC deficits were found in both tasks in the P-ADHD group, with participants with S-ADHD exhibiting intermediate cancellation performance relative to the other groups. Participants with TBI without S-ADHD were not impaired on either task. The relationship between neurocognitive and behavioral IC was examined by comparing multi-informant ratings of IC across groups, and examining the relationship between ratings and IC performance on the SST. Participants in the control and TBI groups were rated within the typical range, and exhibited fewer problems than either of the ADHD groups, who differed from each other (the P-ADHD group was rated as more inattentive than the S-ADHD group). Moderate to high concordance was found between parent and teacher reports, each of which was poorly concordant with self-reports. The P-ADHD and S-ADHD groups were unaware of their own deficits. Poorer IC predicted parent and teacher classification of participants into ADHD subtypes, although IC did not predict rating concordance. Despite similar clinical presentations, S-ADHD and P-ADHD differ in the phenotypic expression of behaviour and manifestation of IC across contexts.

Objective: To examine sleep and wake disorders following traumatic brain injury (TBI) and their impact on recovery of cognition, communication and mood. Research Design: This three-manuscript thesis comprises an introduction to sleep in the context of human function and development. It is followed by a systematic review of the literature pertaining to sleep and wake disorders following TBI, and then explores the relationship between sleep and arousal disturbance and functional recovery of cognitive-communication through a single case study, pre–post intervention. Finally, a larger study longitudinally explores the impact of treatment to optimize sleep and wakefulness on recovery of cognition, communication and mood through objective and subjective measures, pre-post intervention. The thesis concludes with a chapter that addresses the implications of findings for rehabilitation from the perspective of the International Classification of Functioning, Disability and Health (ICF), and a presentation of future research directions for the field Methods: The first manuscript involved a systematic review and rating of the quality of evidence. The second manuscript involved the evaluation of sleep and wakefulness by objective measures, and longitudinally by self-report through the Daily Cognitive-Communication and Sleep Profile (DCCASP, © Wiseman-Hakes 2008, see Appendix S). Cognitive-communication abilities were also measured by the DCCASP. The third manuscript utilized a single case series and cohort design to evaluate sleep and wakefulness, and to examine cognition, communication and mood at baseline and following optimization of sleep and wakefulness. Results: For Manuscript One, 43 articles were reviewed for levels and quality of evidence across 5 domains: epidemiology, pathophysiology, neuropsychological implications, intervention and paediatrics. In Manuscript Two, we showed that there was a statistically and functionally significant relationship between perceived quality of sleep and language processing, attention and memory, seen across the phases of the intervention. In Manuscript Three, we showed that there were statistically and functionally significant improvements across several domains of cognition, communication and mood in response to treatment. Conclusions: Sleep and wake disorders after TBI are pervasive, and can negatively impact rehabilitation and recovery. There is a need for systematic evaluation and intervention for these disorders in all persons with TBI.

This thesis investigates head injuries (HIs) occurring in sports and recreation (SR) that presented to emergency departments (EDs) in Edmonton, Alberta, from April 1st, 1997 to March 31st, 2008. There were 4,950 SR HIs identified over the 11 years (5.13 HIs per 1,000 ED injury visits). Individuals less than 18 years old were 3.4 times more likely, and males were 1.25 times more likely to present with a head injury from SR (p < 0.0001). A history of one or two previous SR HIs increased the odds of subsequent HI by 2.62 and 5.94 times, respectively, while children aged 7 13 and 14 17 were more than four times more likely to sustain a HIs from SR (p < 0.001). The effects of multiple HIs occurring in children participating in SR activities needs to be addressed, due to the chronic neurobehavioral effects of HIs. / Epidemiology

Traumatic Brain Injury (TBI) mainly affects young persons in traffic accidents and the elderly in fall accidents. Improvements in the clinical management have significantly improved the outcome following TBI but survivors still suffer from depression, memory problems, personality changes, epilepsy and fatigue. The initial injury starts a series of events that give rise to a secondary injury process and despite several clinical trials there is no drug available for clinical use that targets secondary brain injury mechanisms. Some recovery of function is seen during the first months following injury but is usually limited and there are no drugs that stimulate the recovery of lost function. Some of the recovery is attributed to plasticity, the brains ability to adapt to new circumstances, and enhancing plasticity via increased axonal growth has the potential to partly restore lost function. In this thesis mice were subjected to the controlled cortical impact model of TBI and functional outcome was evaluated using Morris water maze, the cylinder test and the rotarod. Brain tissue loss was measured in all Papers but the additional histological analyses differ among the Papers. Attempts to increase axonal growth were made by interfering with Nogo receptor function in Paper I and by conditional knockout of ephA4 in Paper II. Contrary to the hypothesis cognition was impaired in Paper I but otherwise no effects of treatment were detected in Paper I and II. Much is still unknown about plasticity and despite the discouraging results of Papers I and II this treatment approach is still worth further exploration. It is firmly established that TBI results in an inflammatory response and some aspects of it may damage brain tissue. In Papers III and IV the inflammatory response was attenuated using an IL-1β directed antibody which resulted in reduced tissue loss and edema while improving cognitive function. The results from Papers III and IV are encouraging and the possibility to find a treatment based on IL-1β inhibition appears promising.