This study looked in detail at the parental experience of having a child sustain traumatic brain injury (TBI); beginning with the child sustaining the injury, through the acute and chronic stages of rehabilitation, to the child’s return home. Mother and father dyads were interviewed in their own homes using a semi-structured interview schedule. A narrative analysis highlighted important findings through the identification and construction of several plots and subplots within parent narratives. These include that parents themselves appear to undergo trauma as a consequence of their child sustaining TBI; that parents made - and wanted to make - a major contribution throughout their child’s rehabilitation, and that all parents went - and are continuing to go - through a number of transitions in this process. Given that fathers have historically been neglected from research into child health issues, the finding here that mothers and fathers made a substantial contribution throughout the rehabilitation process is timely and important. For most parents, this event led to profound and long-lasting changes in their lives and life stories where their previous, hitherto narratives were ‘shattered’. On the child’s return home, these changes appear neither recognised nor supported by services. There seemed little if anything in service provision and coordination to meet the needs of children and parents, which resulted in parents continually fighting for services. Clinical implications are discussed as well as directions for future research.

Background: For Diffusion Tensor Imaging (DTI) to become a clinically useful tool in the detection of traumatic brain injury (TBI) and prediction of functional outcome, a reliable method enabling the identification of likely injury in individual patients needs to be developed. Objective: To explore different methods of analysing DTI measures to determine if individual TBI patients can be differentiated from a group of non-brain injured controls and if so, how these differences are associated with cognitive function. Method: 4 participants with TBI and 11 control participants were scanned using DTI and completed a battery of neuropsychological tests. The DTI measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) in the uncinate fasciculus were compared across individual TBI patients and a control group using 3 different methods of analysis. Results: The comparison of mean FA/MD from individual TBI patients with the overall mean FA/MD of the control group revealed that some TBI patients had lower values of FA whilst others had increased MD. This difference in FA may be associated with deficits in measures of attention. The histogram curves and cumulative frequency plots for individual TBI patients and the controls revealed subtle yet potentially significant differences in the distribution of FA/MD. However at this stage these differences could not be associated with cognitive function. Conclusion: Initial findings indicate that individual TBI patients can be differentiated from a control group using different methods with differing degrees of sensitivity. These differences may be related to cognitive function but further research is warranted before firm conclusions can be drawn.

Background Traumatic brain injury (TBI) is a complex disease with a spectrum of symptoms and disabilities. Over the past decade TBI has become the focus of research due to growing epidemiological and clinical evidences that TBI incidences are strong risk factors for Alzheimer’s disease (AD). Major pathological hallmarks of AD are massive accumulations of amyloid-β peptide (Aβ) toxic oligomers and plaques. Neuroinflammation is also considered as a common denominator in AD and aging. The epidemiological and experimental studies have supported that non-steroidal anti-inflammatory drugs markedly reduce the age-related prevalence of AD and can slow amyloid deposition by mechanisms that still remain elusive. S100A9 is a multifunctional cytokine with diverse roles in the cell signaling pathways associated with inflammation and cancers. A widespread expression of S100A9 was also reported in many other ailments involving inflammatory processes, such as AD, malaria, cerebral ischemia and TBI, implying that S100A9 may be a universal biomarker of inflammation. The distinctive feature of S100A9 compared to other pro-inflammatory cytokines is its ability to self-assemble into amyloids, which may lead to the loss of its signaling functions and acquired amyloid cytotoxicity, exceeding that of Aβ. Methods S100A9 properties was studied under various ex vivo and in vitro conditions. First, human and mouse tissues with TBI and AD were subjected to microscopic, immunohistochemical and immunofluorescent techniques. Then, aged mouse treated with native, oligomeric and fibrillary S100A9 was also studied by using behavioral and neurochemical analysis. Moreover, S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ42 and tau proteins, by studying cerebrospinal fluid (CSF) samples from different stages of dementia. Finally, in vitro experiments on S100A9 amyloidogenesis, co-aggregation with Aβ40 and Aβ42, digestion and cytotoxicity were also performed by using spectroscopic, atomic force microscopy and cell biology methods. Results S100A9-driven amyloid-neuroinflammatory cascade serves as a link between TBI and AD. We have found that S100A9 contributes to the plaque formation and intraneuronal responses in AD, being a part of the amyloid-neuroinflammatory cascade. In TBI we have found that extensive S100A9 neuronal production and amyloid self-assembly is triggered immediately after injury, leading to apoptotic pathways and neuronal loss. S100A9 is an integral component of both TBI precursor-plaques, formed prior to Aβ deposition, and AD plaques, characterized by different degree of amyloid maturation, indicating that all plaques are associated with inflammation. Both intra- and extracellular amyloid-neuroinflammatory cascades are intertwined and showed similar tendencies in human and mouse tissues in TBI and AD. Ex vivo findings are further supported by in vitro experiments on S100A9 amyloidogenesis, digestion and cytotoxicity. Importantly, being highly amyloidogenic itself, S100A9 can trigger and aggravate Aβ amyloid self-assembly and significantly contribute to amyloid cytotoxicity. Moreover, the CSF dynamics of S100A9 levels matches very closely the content of Aβ42 in AD, vascular dementia and mild cognitive impairment due to AD, emphasizing the involvement of S100A9 together with Aβ in the amyloid-neuroinflammatory cascade in these ailments. Conclusions The conclusions of this thesis is that the inflammatory pathways and S100A9 specifically represent a potential target for the therapeutic interventions during various post-TBI stages and far prior AD development to halt and reverse these damaging processes. / Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury

In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury. At post-injury days (PIDs) 1, 7, and 28, brain tissue from sham and brain-injured adult, male rats was processed for Golgi, glial fibrillary acidic protein (GFAP), or silver stain and analyzed to quantify BLA dendritic branch intersections, activated astrocytes, and regional neuropathology, respectively. Compared to sham, brain-injured rats at all PIDs showed enhanced dendritic branch intersections in both pyramidal and stellate BLA neuronal types, as evidenced by Sholl analysis. GFAP staining in the BLA was significantly increased at PID1 and 7 in comparison to sham. However, the BLA was relatively spared from neuropathology, demonstrated by an absence of argyrophilic accumulation over time, in contrast to other brain regions. These data suggest an early and persistent enhancement of dendritic complexity within the BLA after a single diffuse TBI. Increased dendritic complexity would alter information processing into and through the amygdala, contributing to emotional symptoms post-TBI, including PTSD.

The ability of the brain to keep a stable and adequate cerebral blood flow (CBF) independently of fluctuations in systemic blood pressure is referred to as cerebral pressure autoregulation (CPA). When the brain is injured by trauma or hemorrhage, this ability may be impaired, leaving the brain vulnerable to events of high or low blood pressure. The aims of this thesis were to study CPA in patients with severe traumatic brain injury (TBI) or subarachnoid hemorrhage (SAH), the relation between CPA and other physiological parameters, and the influence of CPA on outcome. Four retrospective studies are included in the thesis. All patients were treated at the neurointensive care unit, Uppsala University hospital. In paper I, 58 TBI patients were studied. In patients with impaired CPA, cerebral perfusion pressure between 50-60 mm Hg was associated with favorable outcome while CPP > 70 and >80 mm Hg was associated with unfavorable outcome. In patients with intact CPA there was no association between CPP and outcome. In paper II, 107 TBI patients were studied. High CPP was associated with unfavorable outcome in patients with focal injuries. In patients with diffuse injury and impaired CPA, CPP > 70 mm Hg was associated with favorable outcome. In paper III, 47 SAH patients were studied. CBF was measured bedside with Xenon-enhance CT (Xe-CT). Patients with impaired CPA had lower CBF, both in the early (day 0-3) and late (day 4-14) acute phase of the disease. In paper IV, 64 SAH patients were studied. Optimal CPP (CPPopt) was calculated automatically as the level of CPP where CPA works best for the patient, i.e., where PRx is lowest. Patients with actual CPP below their calculated optimum had higher amounts of low-flow regions (CBF < 10 ml/100g/min). The findings in this thesis emphasize the importance of taking CPA into account in the management of TBI and SAH patients, and suggest that treatment should be individualized depending on status of autoregulation. PRx and CPPopt may be used bedside to guide management according to status of autoregulation. In the future CPA-guided management should be tested in prospective studies

Traumatic Brain Injury (TBI) and its resulting pathophysiology have been extensively examined before. However, little is known in the area of pre-injury factors that influence vulnerability to and recovery from TBI. The current study examined the effects of pre-injury chronic nicotine exposure on Morris water maze performance, following TBI in adolescent rats. Fifteen days prior to lateral fluid percussion injury (FPI), adolescent rats (30 days old) were implanted with osmotic mini-pumps filled with nicotine (4.5mg/kg/day) or saline. Half the rats received lateral fluid percussion injury and half received sham injury. Animals were assessed for cognitive recovery in the Morris water maze on post-injury days (PID) 11 through 15. The MWM results indicated no significant differences between injured animals infused with chronic nicotine and injured animals infused with saline.

Every year an estimated 42 million people worldwide suffer a mild traumatic brain injury (MTBI) or concussion, with approximately 3.6 million sports related concussions occurring yearly in the United States alone (Bailes, 2015, Azad et al., 2015). An MTBI is an acute brain injury resulting from mechanical energy to the head from external forces (Bailes 2015). Symptoms of an MTBI include visual disturbances, dizziness, nausea and vomiting, light sensitivity, loss of balance, and a general feeling of fatigue (Bailes 2015). MTBI’s are first diagnosed through changes in ImPACT baseline scores as well as Vestibular Ocular Motor Screening (Mucha et al., 2014). Repetitive MTBI and/or repetitive sub-concussive head trauma have been tentatively linked to increased risk for a variety of neurodegenerative diseases including chronic traumatic encephalopathy (CTE) (Gardner et al., 2015). The major limitation of the link between MTBI and CTE is that CTE can only be diagnosed post-mortem (Azad et al., 2015). Due to that limitation, the prevalence of CTE is unknown and the amount of MTBI or sub-concussive trauma exposure necessary to produce CTE is unclear (Gardner et al., 2015). Newer methods of research including SNTF immunostaining and L-COSY are being further developed and studied to better diagnose MTBI and its link to CTE by exploring changes in brain protein formation and brain neurochemistry (Johnson et al., 2015, Lin et al., 2015). Through research development and case studies on professional American football players and boxers, a link between MTBI, particularly repetitive MTBI and CTE has been formed (Maroon et al., 2014).

Postmortem brains from young athletes with a history of repetitive concussive head injury and military service personnel with history of blast neurotrauma revealed evidence of parenchymal contusion, myelinated axonopathy, microvasculopathy, neuroinflammation, neurodegeneration, and phosphorylated tauopathy consistent with chronic traumatic encephalopathy (CTE) (L. E. Goldstein et al., 2012). The mechanisms by which head trauma induces acute concussion and chronic sequelae are unknown. To elucidate the mechanistic connection between traumatic brain injury (TBI), acute concussion and chronic sequelae, including CTE, require the use of animal models. This doctoral dissertation investigated the hypothesis that closed-head impact injury in mice triggers acute neurological signs associated with sport-related concussion as well as brain pathologies and functional sequelae associated with CTE. To test this hypothesis, we developed a mouse model of impact neurotrauma that utilizes a momentum transfer device to induce non-skull deforming head acceleration, triggering transient neurological signs consistent with acute concussion and traumatic brain injury (TBI) in unanesthetized C57BL/6 mice. The Boston University Concussion Scale (BUCS) was developed to assess neurological signs that are consistent with acute concussion in humans. Mice exhibited contralateral circling and limb weakness, locomotor abnormalities, and impaired gait and balance that recapitulate acute concussion in humans. Concussed mice recovered neurological function within three hours, but demonstrated persistent myelinated axonopathy, microvasculopathy, neuroinflammation, and phosphorylated tauopathy consistent with early CTE. Concussive impact injury also induced blood-brain barrier disruption, neuroinflammation (including infiltration peripheral monocytes and activation microglia), impaired hippocampal axonal conduction, and defective long-term potentiation (LTP) of synaptic transmission in medial prefrontal cortex. Kinematic analysis during impact injury revealed head acceleration of sufficient intensity to induce acute concussion, traumatic brain injury (TBI), early CTE-linked pathology, and related chronic sequelae. Surprisingly, the presence or degree of concussion measured by BUCS did not correlate with brain injury. Moreover, concussion was observed following impact injury but not blast exposure under conditions that induce comparable head kinematics. Empirical pressure measurements and dynamic modeling revealed greater pressure on the head and compression wave loading in the brain during impact compared to blast neurotrauma. These findings suggest acute concussion is triggered by focal loading of energy that transit the brain before onset of macroscopic head motion. By contrast, the forces associated with rapid head motion is sufficient to induce CTE-linked pathology. Our results indicate that while acute concussion and chronic sequelae may be triggered by the same insult, the pathophysiological responses underpinning these effects are engaged through distinct mechanisms and time domains. Our results indicate that concussion is neither necessary nor sufficient to induce acute brain injury or chronic sequelae, including CTE. / 2018-02-17T00:00:00Z

Our murine model of mild traumatic brain injury (mTBI) has shown improved survival after Pseudomonas aeruginosa (Psd) challenge as compared to controls (tail trauma or sham injury). Previous work suggests an mTBI-specific involvement of the neuro-immune axis which augments the innate immune response, increasing survival. Additional factors for the enhanced mTBI survival were explored via microarray analysis of lungs harvested 48 hours post-trauma, the point prior to Psd challenge in our model. At 48 hours post-trauma, mTBI lungs have a number of upregulated ATP synthesis and mitochondrial gene sets. Increased available energy could prime the mTBI lungs, allowing an earlier and more robust response to Psd infection, possibly contributing to the increased mTBI survival. This is supported by increased neutrophil recruitment in the bronchoalveolar lavage of mTBI mice four hours after Psd instillation. Downregulated gene sets related to cellular connections suggest that neutrophils recruited to the lung have an easier extravasation pathway into the air space of mTBI lungs compared to control. Based on genetic and neutrophil recruitment data, it is possible that mTBI creates an energetically prepared and easily accessible lung better tailored for recruiting and allowing entry of neutrophils in response to an infection compared to control.

The State of Kentucky has a high and increasing number of reported cases of traumatic brain injury (TBI), mostly attributed to motor vehicle crashes, falls, and being struck by or against an object. Young adults are among those most at-risk for experiencing a TBI through motor vehicle crashes. Using existing data from the Kentucky Post-School Outcomes Center (KyPSO), 90 youth with TBI were identified within a period of 6-years of the longitudinal study (2012-2017). The majority were males and White. Descriptive statistics, chi square, and logistic regression were used to examine the post-secondary outcomes for youth with TBI, using four demographic variables: gender, ethnicity, residence, and rural or urban status. None of these were associated with post-secondary outcomes for the sample. The results indicated that more than 50% of the youth with TBI had positive outcomes, yet they rarely used the services provided for them in the schools or at the workplace. This study suggests that, although the demographic characteristics did not predict post-secondary outcomes, other variables within education and employment yielded interesting results that could benefit rehabilitation counselors.