Le traumatisme cranio-cérébral (TCC) est l'une des plus grandes causes de mortalité et de morbidité de ce siècle. Les études menées ces dernières années sur ce sujet, ont montré que l'hypopituitarisme est une des conséquences les plus fréquentes et les plus durables consécutives à un TCC. L'hypopituitarisme se traduit par une ou des déficience(s) hormonale(s) et notamment une diminution de la sécrétion de l'hormone de croissance (GH). Mes travaux de thèse ont consisté à mettre en place un model murin pour étudier le déficit en GH après un TCC ; et ainsi rechercher à quel niveau l'axe somatotrope est-il touché. J'ai tout d'abord participé à des études qui m'ont permis de mettre en place des pré-requis expérimentaux à l'étude du TCC sur des souris (J. Endoc. 2009 ; PNAS, 2010). Dans ce modèle animal, 10% à 20% de ces souris traumatisées présentent un défaut de sécrétion de la GH trente jours après avoir subi un TCC au niveau du cortex pariétal droit, ont un défaut de sécrétion de la GH, alors que les animaux opérés mais non traumatisés (sham) ne présentent pas ce défaut. Les souris déficientes pour la sécrétion de GH ne présentent pas de dérégulation de l'architecture vasculaire hypophysaire ou hypothalamique. Au niveau moléculaire, la transcription des ARNm de l'hormone de croissance et de la neurohormone hypothalamique GHRH (qui stimule la sécrétion de GH) ne semble pas affectée par les effets du traumatisme. En revanche, très rapidement après un traumatisme localisé au niveau du cortex, on observe l'apparition d'une cicatrice gliale. Cette cicatrice astrocytaire apparait non seulement dans la région du traumatisme, mais également au niveau de l'éminence médiane. Cette réponse inflammatoire, associée à un défaut des tanycytes bordant le 3ème ventricule, pourrait expliquer, au moins en partie, ce déficit en GH post-TCC. En résumé, cette étude nous a permis de reproduire sur le modèle murin (avec un même fond génétique) les déficits en GH que l'on observe chez des patients traumatisés. / Traumatic Brain Injury (TBI) is a major cause of mortality and morbidity. Studies on this subject in recent years have revealed that hypopituitarism is one of the most common sequelae to TBI. Since the pituitary is an endocrine tissue, hypopituitarism results in marked hormonal deficiency, including decreased serum levels of growth hormone. As such, the work contained within this thesis has focused on developing a mouse model of TBI-induced GH deficiency, with the principal aim of discovering where the deficit lies in the somatotropic axis (i.e. hypothalamaic releasing hormone vs. pituitary cell activity). By subjecting mice to a controlled impact to the right parietal cortex, we observed a GH secretory defect in 10% to 20% of cases. These defects where apparent thirty days following trauma and were not detected in animals subjected to surgery, but not TBI (sham). Mice suffering hypopituitarism secondary to TBI did not show any obvious changes to pituitary or hypothalamic vascular architecture, and at the molecular level, GH and GHRH (the major GH-secretagogue) mRNA levels were normal. However, in the acute phase following TBI, a large glial scar developed which extended to the level of the median eminence (ME). This inflammatory response could explain, at least in part, GH deficiency post-TBI if associated with dysfunction of third ventricle tanycytes known to be involved in hypothalamic neuron output. In summary, by using an isogenic, age-matched mouse model of TBI, this study has provided insights into the causes of GH deficiency, a common consequence of cranial trauma in humans.

abstract: Traumatic brain injury (TBI) affects an estimated 1.7 million people in the United States each year and is a leading cause of death and disability for children and young adults in industrialized countries. Unfortunately, the molecular and cellular mechanisms of injury progression have yet to be fully elucidated. Consequently, this complexity impacts the development of accurate diagnosis and treatment options. Biomarkers, objective signatures of injury, can inform and facilitate development of sensitive and specific theranostic devices. Discovery techniques that take advantage of mining the temporal complexity of TBI are critical for the identification of high specificity biomarkers. Domain antibody fragment (dAb) phage display, a powerful screening technique to uncover protein-protein interactions, has been applied to biomarker discovery in various cancers and more recently, neurological conditions such as Alzheimer’s Disease and stroke. The small size of dAbs (12-15 kDa) and ability to screen against brain vasculature make them ideal for interacting with the neural milieu in vivo. Despite these characteristics, implementation of dAb phage display to elucidate temporal mechanisms of TBI has yet to reach its full potential. My dissertation employs a unique target identification pipeline that entails in vivo dAb phage display and next generation sequencing (NGS) analysis to screen for temporal biomarkers of TBI. Using a mouse model of controlled cortical impact (CCI) injury, targeting motifs were designed based on the heavy complementarity determining region (HCDR3) structure of dAbs with preferential binding to acute (1 day) and subacute (7 days) post-injury timepoints. Bioreactivity for these two constructs was validated via immunohistochemistry. Further, immunoprecipitation-mass spectrometry analysis identified temporally distinct candidate biological targets in brain tissue lysate. The pipeline of phage display followed by NGS analysis demonstrated a unique approach to discover motifs that are sensitive to the heterogeneous and diverse pathology caused by neural injury. This strategy successfully achieves 1) target motif identification for TBI at distinct timepoints and 2) characterization of their spatiotemporal specificity. / Dissertation/Thesis / Doctoral Dissertation Neuroscience 2020

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OBJECTIVE: This study will explore the effects that an online support group can have on traumatic brain injury (TBI) caregiver burden. BACKGROUND: TBI is a public health concern that affects the lives of both patients and their caregivers. Caregivers often take responsibility for significant elements of TBI patients’ lives and, over time, this role takes a mental and physical toll on a caregiver’s own life. To date, there is limited research on the success of interventions, such as support groups and telehealth, in mitigating caregiver burden. There is much research that remains to be done. It is crucial that new and innovative support groups and telehealth interventions, such as the one outlined in this thesis, are trialed and analyzed by participants, in order to understand what methods are most effective in supporting these caregivers. DESIGN: One-group before-after non-randomized innovative intervention study. PARTICIPANTS: Eighty-five adult primary caregivers of TBI patients, recruited through the Brain Injury Association of America (BIAA). INTERVENTION: Sixteen sessions of mindfulness-based cognitive behavioral therapy (CBT) led by trained clinical psychologists and delivered via group videoconference. MAIN OUTCOME MEASURES: Zarit Interview Burden (ZBI); Brief Symptom Inventory (BSI). DATA ANALYSIS: Descriptive demographics. Unadjusted effect size and score descriptive for ZBI and BSI. Paired t-tests to compare mean ZBI and mean BSI at pre-intervention and post-intervention. Stratify by baseline BSI score to determine if baseline BSI score predicts decrease in ZBI score over the course of the intervention. CONCLUSIONS: The proposed study provides an innovative way to reduce burden on TBI caregivers and to analyze the feasibility and acceptance of the intervention. The study does, however, present limitations and, thus, outlines areas for future research. These limitations include the lack of a control group, the use of multiple clinical psychologists as group leaders, and the recruitment of only BIAA members who are comfortable using technology.

A small subset of individuals that have experienced mild traumatic brain injury (mTBI) may experience persistent cognitive deficits more than a year following the head injury. Neuroimaging studies reveal structural and functional changes in frontal areas of the brain, exacerbated when loss of consciousness is experienced, and indicate that these changes may be progressive in nature for some people. Social support and social participation have, however, been suggested to confer cognitive reserve - neurocognitive protection against cognitive decline. Analyses were run on Canadian Longitudinal Study on Aging (CLSA) neuropsychological data, consisting of individuals who experienced mTBI with loss of consciousness (n = 536 for less than 1 minute, and n = 435 for unconsciousness between 1 and 20 minutes) more than a year prior, and 13,163 no-head injury comparisons. These same individuals were re-assessed three years later. The results presented in this thesis suggest that at a year or more after a single mTBI with loss of consciousness, a small subset of individuals are more likely to be impaired on prospective memory and other executive functioning tasks, relative to comparisons. In addition, when examined at three-year follow-up, those who experienced mTBI with longer duration of unconsciousness were more likely to exhibit cognitive decline relative to those who experienced less unconsciousness or comparisons. Moreover, greater social participation over the past year, and more perceived social support were predictive of lessened cognitive deterioration in those individuals.

The purpose of this study was to discover if as an expert witness, an SLP can make a significant impact on the decision made by juries in the cases of defendants with a traumatic brain injury compared to no expert witness testimony. Participants were recruited from a pool of individuals who met the requirements to be a potential juror in the state of Illinois. Participants completed a survey regarding their opinions on defendants with TBI in court cases. The survey was created with the online survey generator software, “Google Forms” in order to determine if individuals would judge a defendant differently when informed of the expert witness testimony of an SLP. Results suggest a positive correlation between exposure to SLP testimony and greater leniency or rehabilitative tendencies in legal judgment. The implications of these results shine a very important light on the issue of individuals with TBI inside the criminal justice system. If cases continue to be held in a court of law without the input of specialized SLP expert knowledge, it would be difficult to say if true justice is served for each individual. With SLP expert testimony, the number of individuals with TBI who are behind bars as a result of ill-informed jury sentencing could be significantly reduced.

Concussion is a popular clinical topic that has been the subject of unprecedented recent media coverage. As concerns about the potential short- and long-term implications of repetitive head injury in sports such as football continue to mount, the proper clinical management of concussion seems to increase in importance. The days of ignoring the ''ding'' on the sideline are definitely over. A series of updated clinical evaluation and management recommendations from international experts are highlighted in this review. The clinical presentation of an acute concussion, both the typical and more subtle variations, may be evaluated with new validated sideline evaluation tools (eg, Sports Concussion Assessment Tool 2). In addition, the role of computerized neuropsychological and balance testing in the acute and ongoing evaluation are discussed, along with how they contribute to the return-to-play decision. Same-day return to play is outdated, and the relative insensitivity of current neuroimaging modalities to demonstrate structural damage is highlighted. New therapeutic interventions such as amantadine and cognitive rest may improve recovery time. The appropriate management of concussion typically results in a normal functional and neurocognitive outcome. The recommendations in this article may guide clinicians, with varying degrees of prior experience managing concussion, to increase the likelihood of an excellent outcome.

The purpose of the current study was to explore potential differences in pre- and post-concussion performance on a computerized neurocognitive concussion test between African American and White high-school and collegiate student-athletes. A prospective case-control design was used to compare baseline and 2- and 7-day post-concussion computerized neurocognitive performance and symptoms between 48 White and 48 African American athletes matched for age, gender, and concussion history. The Immediate Post-Concussion Assessment Cognitive Test (ImPACT) version 2.0 (NeuroHealth System, LLC, Pittsburgh, PA, USA) computer software program was used to assess neurocognitive function (i.e., verbal and visual memory, motor processing speed, and reaction time) and concussion symptoms. Regardless of race/ethnicity, there were significant decrements in computerized neurocognitive performance and increased symptoms following a concussion for the entire sample. African Americans and Whites did not differ significantly on baseline or post-concussion verbal memory, visual memory, reaction time, and total reported symptoms. However, African American participants were 2.4× more likely to have at least one clinically significant cognitive decline on ImPACT at 7 days post-concussion and scored lower at 7 days post-concussion compared with baseline on processing speed than White participants. The authors concluded that the baseline ImPACT test was culturally equivalent and construct valid for use with these two racial/ethnic groups. However, in contrast, the findings support deleterious performance for the African American athletes compared with the White athletes on the ImPACT post-concussion evaluation that is of critical clinical relevance and warrants further research.

In this paper, we investigate the potential for the development of a composite score investigating population-level phenotype changes in a mouse model of traumatic brain injury. Traumatic brain injuries (TBI) are a growing concern in the United States because the number of individuals impacted by TBI and associated symptoms is increasing, leading to a growing demand for research both in the clinical and preclinical setting. However, preclinical TBI modeling is complicated by the lack of inter and intra lab consistency in the assessment of behavioral and pathologic outcomes. Indeed, it remains unclear which behavior assessments are most useful in evaluating the effects of preclinical TBI. To investigate the relative contribution of various behavior tests in the assessment of preclinical TBI, three statistical models (simple linear regression, pairwise correlation, and factor analysis) were conducted on behavioral data from the Mannix-Meehan lab at Boston Children’s Hospital in Boston, Massachusetts, U.S.A. from 2012-2018. In this paper, a composite metric was created from the computation analysis of the three statistical methods. The score revealed MWM and EPM as the most potent behavioral tests. The Open Field and Rotarod test had a small impact on the outcome, but only in one of the three statistical models assessed. Thus, to effectively analyze treatment efficiencies, injury severity and long-term impairments, MWM and EPM are the best behavioral test for a mouse model. Furthermore, this method of analysis of entire populations of mice allows for more subtle phenotypic changes resultant from injury models to be revealed, and the generalizability of this model lends to widespread use.