A novel cell culture system was designed to serve as a model of neuroinflammation. Neurons, astrocytes, and microglia derived from embryonic and perinatal rat cortical tissue were combined in a three-dimensional hydrogel utilizing a method that facilitated cell maturation and viability. Chemical challenge of the cultures with a broad pro-inflammatory stimulus resulted in the production of inflammatory cytokines and other associated molecules commensurate with the response observed in vivo and in other in vitro systems. It was hypothesized that mechanical deformation of the multitypic neural cell cultures would produce a similar response and thus validate the system as an in vitro model of traumatic brain injury-induced neuroinflammation. Mechanical injury delivered using custom-manufactured culture chambers and injury devices successfully imparted a moderate level of cell death to the cultures. It was determined that a mechanically-induced inflammatory response required chemical stimulation prior to the injury. The research presented here describes the generation and characterization of a novel in vitro culture system and its implementation in experiments designed to model secondary injury mechanisms associated with injury-induced neuroinflammation. The findings of these studies, applications of the culture system, and future research avenues are discussed.

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.

The scientific problem of the study Brain concussion is the most common subtype of the post-concussion syndrome in childhood. This is a mild traumatic brain injury that accounts for 80-90℅ of all cases. Individuals who have sustained brain concussion, i.e. mild traumatic brain injury, frequently complain of various symptoms that are commonly defined as the post-concussion syndrome. Such symptoms are headache, dizziness, nausea, attention disorders, memory problems, sleep disturbances, learning problems, fatigue, emotional instability, mood changes, anxiety, fear, etc. – all of these are defined in the International Classification of Diseases. The symptoms of the post-concussion syndrome are non-specific and subjective. Some patients indicate similar symptoms even without having experienced head injury; these symptoms can occur in the presence of other health disorders, such as the fatigue syndrome, neurasthenia, hyperactivity and attention disorders, as well as in cases of anxiety, mood and emotional disorders, and depression. During the last 25 years, over 500 articles on mild traumatic brain injury have been published in psychological literature, and a similar number of publications in medical literature. The results of scientific studies are quite different, and the variety of the results is still inciting heated scientific debates. Some researchers insist that brain concussion has long-tern sequelae. On the other hand, an opinion has emerged that even if... [to full text]

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.

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.

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.

Memory and concentration problems are frequently reported long after experiencing a mild traumatic brain injury (mild TBI), though conflict with null findings of deficits on standard neuropsychological tests. Experimental research shows that these inconsistencies are, in part, due to the simplicity of neuropsychological tests. As well, past research suggests that when neuropsychological deficits are occasionally detected within this population, they could be influenced by diagnosis threat: an expectation bias for impaired performance when individuals are merely informed that cognitive problems may be experienced following a mild TBI. The main goal of this thesis was to specify the long-term cognitive effects of mild TBI, with the prediction that, while cognitive complaints may be over-reported due to diagnosis threat, significant deficits can be detected using sensitive measures in experimental paradigms. Experiment 1 sought to document whether diagnosis threat influenced self-report of everyday attention and memory problems and neuropsychological task performance in individuals with a remote history of mild TBI. We found that undergraduate students with a mild TBI were significantly more likely to report having attention and memory failures in their daily lives when exposed to diagnosis threat, compared to undergraduate students not exposed to diagnosis threat. These findings call into question the efficacy of using of self-report measures to identify long-term cognitive deficits following a mild TBI. In an attempt to further specify persistent significant cognitive deficits, we designed two different experimental paradigms that uniquely manipulated the demand place on executive processes, as past research suggested deficits emerge only when tasks require considerable cognitive resources. In Experiment 2a, we manipulated processing load on a visual working memory task, across two conditions, while also limiting the potential effect of diagnosis threat. While self-report and neuropsychological measures of attention and memory did not differentiate the groups, the mild TBI group took significantly longer to accurately detect repeated targets on our working memory task. Accuracy was comparable in the low-load condition and, unexpectedly, mild TBI performance surpassed that of controls in the high-load condition. Temporal analysis of target identification suggested a strategy difference between groups: mild TBI participants made a significantly greater number of accurate responses following the target’s offset, and significantly fewer erroneous distracter responses prior to target onset, compared to controls. In Experiment 2b we also examined whether manipulating executive processing demands would differentiate mild TBI from controls, this time on a routine action task that required participants to learn a sequence of hand movements to targets. While not significant, we found a trend such that mild TBI participants were slower to respond on trials with a large executive demand compared controls, while no differences were found on trials with relatively low executive requirements. Results from Experiments 2a and 2b provide stronger evidence for mild TBI-related slowing during a working memory task with an executive component compared to a skilled action task that also had an executive component, but placed minimal demand on memory. To more precisely identify the brain basis of this cognitive slowing, in Experiment 3 we administered a visual n-back task in which we systematically increased working memory demands from 0- to 3-item loads. We found that, compared to controls, mild TBI participants showed a reduction in P300 amplitude, conceptualized as an index of available cognitive resources for stimulus classification. While no late stage response differences were found between groups, P300 amplitude was negatively correlated with response times at higher loads in both control and mild TBI participants. Findings suggest that high functioning young adults who sustained a mild TBI in their remote past, have a reduced amount, or inefficient recruitment of, cognitive resources for target detection; a potential mechanism underlying mild TBI-related response slowing on tasks that place a heavy demand on processing resources. Similar to the effects of mild TBI, aging is also known to negatively impact cognition. In Experiment 4, we examined whether TBI-related deficits persist into older adulthood, and compound the negative effect of aging on cognition. We administered the same working memory task as in Experiment 2a, along with a variety of neuropsychological tests in order to investigate the effect of a TBI sustained an average of 50 years in the past. While no group differences emerged on our experimental working memory task, older adults with a history of 1 or 2 TBIs performed significantly worse than non head-injured older adults only on neuropsychological measures of attention that had an executive component. Such results suggest that a remote TBI sustained early in life further compounds normal age-related cognitive decline. Together, these experiments help specify the measures that best detect long lasting cognitive changes following TBI. Particularly, our findings provide a potential explanation for why long-term cognitive deficits are difficult to identify in the young mild TBI population: the majority of neuropsychological tests are insensitive to minor changes in information processing speed and, as a result, the execution of slowing strategies to maintain accuracy may go undetected. Our findings also demonstrate the importance of investigating longer-term effects of TBI, as they may be chronic and impact cognitive task performance in old age, amplifying normal age-related cognitive deficits.