Traumatic brain injury (TBI) is a major health concern, with mild TBI (mTBI) being the most common type and frequently linked to long-term neurological issues. Studying mTBI is essential to improve prevention, diagnosis, and treatment strategies for affected individuals.This dissertation explores the biomechanical and biological impacts of mTBI induced by blast exposure and rapid acceleration, focusing on both experimental replication and finite element (FE) modeling. In experimental studies, using a custom-built shock tube, this study replicated blast-induced TBI (bTBI) in rats, examining the effects of single and multiple blast exposures on behavioral and histological outcomes. Behavioral evaluations using Rotarod and Open Field tasks, along with histological markers (GFAP, Iba-1, and tau protein), demonstrated that multiple blast exposures resulted in more severe motor deficits and neuroinflammatory responses than single exposures. This highlights cumulative injury risks. To address repetitive rmTBI as observed in sports and military settings, a novel Whole Body Deceleration (WBD) model, based on rapid acceleration-deceleration, was introduced. This model induced rmTBI in rats, with motor function and anxiety-like behaviors assessed alongside histological analyses of microglial activation (Iba-1) and inflammatory markers (TLR4 and TNF-α). Results indicated increased microglial activation and TLR4 expression, with notable motor impairments in the acute post-injury phase (7 days). These findings underscore the complex neuroinflammatory responses associated with rmTBI. Additionally, the long-term (21 days) effects of WBD and the impact of different injury repetition patterns were evaluated. The Novel Object Recognition task was incorporated alongside previous behavioral assessment tools to assess memory function. Over the long term, WBD led to increased impulsivity in rats, with repetition patterns influencing behavioral trends. However, no persistent memory deficits were observed over this period. Furthermore, we investigated O-1966 (CB2) as a therapeutic option for bTBI and both O-1966 and KLS for WBD. CB2 demonstrated a reduction in neuroinflammation following bTBI in the acute phase. KLS and CB2 showed no conclusive evidence of improving anxiety or memory deficits following WBD in the long term. This study developed a validated 3D FE model of a shock tube to simulate blast wave effects on a rat’s head, examining key parameters like peak overpressure and positive phase duration. The model effectively replicates blast conditions in the experiments, advancing our understanding of bTBI mechanisms. Lastly, a comparative biomechanical analysis was conducted between our blast-induced and acceleration-induced mTBI using FE simulations. Key metrics such as intracranial pressure, pressure impulse, von Mises stress, maximum principal strain, and stress power (time derivative of internal energy) revealed distinct injury patterns. The blast model centralized the energy, leading to higher shear stress and pressure, indicating a more diffuse and severe injury profile. Conversely, the acceleration model demonstrated a more symmetric distribution of energy, especially between Coup and Contrecoup regions, suggesting a localized injury effect. / Mechanical Engineering

Traumatic brain injury (TBI) affects over 1.7 million people annually in the U.S., often leading to autonomic nervous system (ANS) dysregulation and reduced heart rate variability (HRV), which may impact cognitive performance. This study investigated whether HRV biofeedback (HRV-B) improves HRV at rest and recovery after stress in individuals with TBI. Secondary aims examined links between HRV improvements and reductions in physical symptoms, enhanced emotional functioning, and better cognitive performance, as well as the role of practice adherence in moderating HRV-B effects. This randomized controlled trial compared HRV-B treatment to a sham control using a pre- and post-assessment design. Of 58 participants with TBI, 49 completed the study (HRV-B: 25, mean age 27.1 ± 9.7 years; sham: 24, mean age 26.6 ± 9.9 years). Participants underwent five weekly sessions, and assessments included cognitive, emotional, and physical measures. Heart rate variability data, encompassing both frequency-domain metrics (e.g., HF, LF, LF/HF ratio) and time-domain metrics (e.g., SDNN, RMSSD), were obtained through electrocardiogram recordings. At rest, a significant group main effect was found for the LF/HF ratio (F(1, 43) = 9.38, p = 0.004), with the HRV-B treatment group demonstrating an increase in the LF/HF ratio compared to the sham group after treatment. During stressor recovery, the LF/HF ratio differed significantly between groups (F(1, 172) = 4.27, p = 0.040), with the HRV-B group values higher than the sham group. A significant group-by-session interaction for the LF/HF ratio (F(1, 172) = 4.18, p = 0.04) further indicated an increase in the LF/HF ratio over time following a stressor in the HRV-B group compared to the sham control. For cognitive outcomes, session effects were significant for both the Fluid Cognition Composite Score and the Total Composite Score, suggesting improvement over time in both groups, although no differences were observed between the HRV-B and sham groups. Session significantly influenced anxiety and depression, with the HRV-B group showing notable improvement in depression, while no significant group effects were observed for stress and life satisfaction. Individuals with TBI who received HRV-B showed higher LF/HF ratio values at rest and during stressor recovery compared to the sham group, driven by enhanced LF components indicative of improved autonomic regulation and stress resilience. While cognitive and emotional improvements were observed across groups, the absence of condition-specific effects underscores the need for larger studies with extended interventions to clarify the unique benefits of HRV-B for TBI recovery.

This study examines the background and qualifications of plaintiff and defense experts using the H-Index score as quantification of expert background and qualifications. The goal is to better understand the similarities and differences among the professionals offering paid expert witness testimony in mild traumatic brain injury (mTBI) civil litigation. In this quantitative study, descriptive statistics include the mean and standard deviation scores for the data to support examining measures of central tendency and variance, respectively. The study includes the use of logistic regression and the Wilcoxon signed-rank test, and their statistical assumptions were tested to determine whether they would be used or if it was more appropriate to use a non-parametric test. The study included two research questions: How do the qualifications of plaintiff and defense expert witnesses in mild traumatic brain injury civil litigation compare? and to what extent does a higher h-index correlate with a favorable litigation outcome in a mild traumatic brain injury case? The findings for the hypothesis tests associated with the research questions led to the acceptance of the null hypothesis in each test. There was a lack of asymptotic significance in Hypothesis 1 and a lack of significance in Hypothesis 2. The findings from these tests shall support the discussion of the implications of this research and the direction of future research.

Vestibular-related problems (dizziness, vertigo, and imbalance) are common sequelae following concussion and blast exposures that result in mild traumatic brain injury (mTBI). However, the anatomical substrate connected to these dysfunctions is not well understood. To provide a better understanding of this area, we used voxel-based morphometry (VBM) as a platform for studying vestibular-related mTBI in the human brain. Briefly, VBM is a group comparison study which evaluates structural differences in magnetic resonance (MR) images between agematched groups of individuals (11 vestibular TBI patients and 10 controls). Using the VBM-8 Toolbox and statistical probability mapping (SPM), MRI images were segmented into gray matter, white matter, and cerebrospinal fluid, normalized into a standardized anatomical space, and then analyzed statistically for significant anatomical differences between groups. Based on the VBM analysis, most notable differences in brain anatomy were characterized by reductions in gray matter volume observed in the middle frontal gyrus, mesial frontal lobe, and in the insular area in the left mesial temporal lobe. These findings provide a preliminary analysis of distributed gray matter changes in key frontal and temporal areas of the brain associated with mTBI related vestibular dysfunction.

Mild traumatic brain injury (mTBI), often referred to as concussion, has become increasingly recognized as a serious health issue in the general population. The prevalence of mTBI in athletes, particularly repeated injuries in young athletes, is of great concern as injuries to the developing brain can have long-term detrimental effects. In this study we used a novel awake closed-head injury (ACHI) model in rodents to examine repeated mTBI (rmTBI), to determine if repeated injuries produced the neurological and molecular changes evident with human concussion. Animals were administered 4, 8, and 16 rmTBIs and acute neurological assessments were performed after the injuries. Changes in glial fibrillary acidic protein (GFAP) and ionized calcium-binding adapter molecule 1 (Iba-1) levels were assessed using Western blot analysis at one day following rmTBI in the ipsilateral dentate gyrus (DG) and the cornu ammonis (CA) regions of the hippocampus and the cortex (CX) indicative of astrocyte and microglial cell reactivity. Results indicated that the ACHI model produces neurological deficits immediately after the injuries, with the most deficits arising in the rmTBI16 group. Despite deficits in all injury groups, histological staining with cresyl violet revealed no significant morphological tissue damage to the brain. Western blot analysis, however, showed a significant increase in DG and CX GFAP expression in the rmTBI16 group with no changes in Iba-1 levels. This suggests an acute activation of astrocytes in response to injury, with a delay or absence of microglial activation. Our findings show that with repetitive concussions, we are able to detect acute neurological and molecular changes in the juvenile female brain. However, further investigation is necessary to determine if these are transient changes. / Graduate

BACKGROUND:Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.FINDINGS:Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI). LPA was elevated in cerebrospinal fluid (CSF) of patients with TBI compared to controls. LPA levels were also elevated in a mouse controlled cortical impact (CCI) model of TBI and B3 significantly reduced lesion volume by both histological and MRI assessments. Diminished tissue damage coincided with lower brain IL-6 levels and improvement in functional outcomes.CONCLUSIONS:This study presents a novel therapeutic approach for the treatment of TBI by blocking extracellular LPA signaling to minimize secondary brain damage and neurological dysfunction.

Reactive oxygen species (ROS) is cytotoxic to the cell and is known to contribute to secondary cell death following primary traumatic brain injury (TBI). We described in our study that PN is the main mediator for both lipid peroxidation and protein nitration, and occurred almost immediately after injury. As a downstream factor to oxidative damage, the peak of Ca2+-dependent, calpainmediated cytoskeletal proteolysis preceded that of neurodegeneration, suggesting that calpain-mediated proteolysis is the common pathway leading to neuronal cell death. The time course study clearly elucidated the interrelationship of these cellular changes following TBI, provided window of opportunity for pharmacological intervention. Furthermore, we conducted a pharmacological study to solidify our hypothesis. First of all, we tested the potency of a membrane permeable, catalytic scavenger of PN-derived free radicals, tempol for its ability to antagonize PN-induced oxidative damage. Tempol successfully inhibited PNinduced protein nitration at dosages of 30, 100 and 300mg/kg. Moreover, early single dose of 300mg/kg was administered and isolated mitochondria were examined for respiratory function and oxidative damage level. Our data showed that tempol reduced mitochondrial oxidative damage, and maintained mitochondrial function within normal limits, which suggested that tempol is efficiently permeable to mitochondrial membrane and mitochondrial oxidative damage is essential to mitochondrial dysfunction. Next, we found that calpainmediated proteolysis is reduced at early treatment with a single dose of tempol. However, the effect of tempol on calpain is short-lived possibly due to systematic elimination. In our multiple dose study, tempol showed a significant inhibitory effect on SBDPs. Consequently, we measured neuordegeneration with the de Olmos aminocupric silver staining method at 7 days post-injury and detected a significant decrease of neuronal cell death. Together, the time course study and pharmacological study strongly support the hypothesis that PN is the upstream mediator in secondary cell death in the CCI TBI mouse model. Moreover, inhibition of PN-mediated oxidative damage with the antioxidant, tempol, is able to attenuate multiple downstream injury mechanisms. However, targeting PN alone may be clinically impractical due to its limited therapeutic window. This limitation may be overcome in future studies by a combination of multiple therapeutic strategies.

Tyrimo tikslas. Palyginti eisenos atsigavimą asmenims, patyrusiems trauminį galvos smegenų sužalojimą (TGSS) ar galvos smegenų infarktą (GSI), pirmajame reabilitacijos etape taikant kineziterapiją. Tyrimo uždaviniai.1) Įvertinti asmenų, patyrusių TGSS ar GSI, protinę būklę ir mobilumą prieš ir po kineziterapijos; 2) Įvertinti asmenų, patyrusių TGSS, eiseną taikant kineziterapiją pirmojo reabilitacijos etapo pradžioje ir pabaigoje; 3) Įvertinti asmenų, patyrusių GSI, eiseną taikant kineziterapiją pirmojo reabilitacijos etapo pradžioje ir pabaigoje; 4) Įvertinti asmenų, patyrusių TGSS ar GSI, proto būklės ir mobilumo atsigavimo įtaką eisenos atsigavimui, taikant kineziterapiją. Tyrimo metodai. Tyrime dalyvavo 60 asmenų: 30 asmenų, patyrusių TGSS, ir 30 asmenų, patyrusių GSI. Visiems tiriamiesiems buvo sutrikusi eisena. Vertinome tiriamųjų proto būklę pagal Trumpą Proto Būklės Tyrimo Testą, (TPBVT), mobilumą pagal Rivermead’o mobilumo indeksą (Rivermead Mobility Index) ir eiseną pagal Dinaminį Eisenos Indeksą (Dynamic Gait Index). Rezultatai skaičiuoti atliekant matematinę statistinę analizę. Visiems tiriamiesiems buvo taikoma kineziterapija siekiant eisenos atsigavimo. Tyrimo rezultatai. Tyrimo rezultatai parodė, kad taikant kineziterapiją pagerėjo proto būklė, mobilumas ir eisena abiejose tiriamųjų grupėse. Atlikus asmenų po TGSS ar GSI proto būklės, mobilumo ir eisenos palyginamąją analizę, gavome, kad kineziterapija turi teigiamą įtaką abiejų grupių proto būklės, mobilumo... [toliau žr. visą tekstą] / The aim. To compare gait recovery of individuals after Traumatic Brain Injury (TBI) or Ischemic Brain Stroke (IBS) using Physical Therapy during first rehabilitation stage. The tasks were: 1) To evaluate individuals after TBI or IBS mental state and mobility before and after Physical Therapy. 2) To evaluate individuals gait after TBI before and after Physical Therapy during first rehabilitation state. 3) To evaluate individuals gait after IBS before and after Physical Therapy during first rehabilitation state. 4) To find correlation between mental state, mobility and gait recovery of individuals after TBI or IBS using Physical Therapy. Methods and Material. In this study there were 60 persons participated: 30 after TBI and 30 after IBS. All patients had gait disorders. We evaluated mental state using Mini Mental State Examine (MMSE), mobility using Rivermead Mobility Index (RMI) and gait using Dynamic Gait Index. The results were calculated using mathematical statistical analysis. All patients received Physical Therapy to improve their gait. Results. The results showed significant mental state, mobility and gait recovery after Physical Therapy in both groups. Comparative analysis of persons after TBI or IBS mental state, mobility and gait showed that Physical Therapy has a statistically significant influence on mental state, mobility and gait recovery in both groups. We found correlation between mental state, mobility and gait recovery for patients after TBI or IBS. Gait... [to full text]

Background: Trauma is a major cause of death and disability. Adverse events, such as prolonged prehospital time, hypoxia, hypotension and/or hyperventilation have been reported to correlate to poor outcome. Adequate cortisol levels are essential for survival after major trauma. In hypotensive critically ill patients, lack of sufficient amount of cortisol can be suspected, and a concept of critical illness related corticosteroid insufficiency has been proposed. Corticosteroid therapy has many adverse effects in critically ill patients and should only be given if life-saving. Correct measurement of serum cortisol levels is important but difficult in critically ill patients with capillary leakage. Estimation of the free and biologically active cortisol is preferable. In serum less than 10% of cortisol is free and biologically active and not possible to measure with routine laboratory methods. Salivary cortisol can be used as a surrogate for free cortisol, but salivary production is reduced in critically ill patients. Liver resection could reduce cortisol levels due to substrate deficiency. Aims: 1. Evaluate the occurrence of early adverse events in patients with traumatic brain injury and relate them to outcome. 2. Assess cortisol levels over time after trauma and correlate to severity of trauma, sedative/analgesic drugs and cardiovascular function. 3. Evaluate if saliva stimulation could be performed without interfering with salivary cortisol levels. 4. Assess cortisol levels over time after liver resection in comparison to other major surgery. Results: There was no significant correlation between prehospital time ³60 minutes, hypoxia (saturation <95%), hypotension (systolic blood pressure <90 mmHg), or hyperventilation (ETCO2 <4.5 kPa) and a poor outcome (Glasgow Outcome Scale 1-3) in patients with traumatic brain injury. Cortisol levels decreased significantly over time after trauma, but there was no correlation between low (<200 nmol/L) serum cortisol levels and severity of trauma. Infusion of sedative/analgesic drugs was the strongest predictor for a low (<200 nmol/L) serum cortisol. The odds ratio for low serum cortisol levels (<200 nmol/L) was 8.0 for patients receiving continuous infusion of sedative/analgesic drugs. There was no significant difference between unstimulated and stimulated salivary cortisol levels (p=0.06) in healthy volunteers. Liver resection was not associated with significantly lower cortisol levels compared to other major surgery. Conclusion: There was no significant correlation between early adverse events and outcome in patients with traumatic brain injury. Cortisol levels decreased significantly over time in trauma patients. Low cortisol levels (<200 nmol/L) were significantly correlated to continuous infusion of sedative/analgesic drugs. Saliva stimulation could be performed without interfering with salivary cortisol levels. Liver resection was not associated with low cortisol levels compared to other major surgery.

Résumé : Les réanimateurs ont recours à des interventions à la fois médicales et chirurgicales en contexte de choc traumatique. Le rôle des vasopresseurs dans cette prise en charge est controversé. Alors que les lignes directrices américaines considèrent que les vasopresseurs sont contre-indiqués, certains experts européens en encouragent l’utilisation pour diminuer le recours aux liquides intraveineux. Avant d’élaborer un essai clinique, il importe de comprendre la pratique actuelle à laquelle se comparera une intervention expérimentale, ainsi que de connaître le niveau d’incertitude dans la littérature entourant la question de recherche. Le Chapitre 2 de ce travail présente une étude observationnelle effectuée dans un centre régional de traumatologie québécois. Cette étude documente les pratiques de réanimation adoptées par les équipes de traumatologie en 2013, particulièrement le recours aux liquides intraveineux et aux vasopresseurs. Les résultats démontrent que les vasopresseurs ont été utilisés chez plus de 40% des patients, particulièrement les victimes de traumatismes crâniens (RC 10.2, IC 95% 2.7-38.5). De plus, les vasopresseurs ont été administrés dans les phases précoces de la réanimation, soit avant l’administration d’un volume important de liquides. Le Chapitre 3 présente une revue systématique portant sur l’utilisation précoce de vasopresseurs en traumatologie. Les bases de données MEDLINE, EMBASE, CENTRAL et ClinicalTrials.gov ont été interrogées, ainsi que les abrégés présentés dans les conférences majeures en traumatologie depuis 2005. La sélection des études et l’extraction des données ont été effectuées en duplicata. Aucune donnée interprétable n’a pu être extraite des études observationnelles et le seul essai clinique identifié n’avait pas une puissance suffisante (RR de mortalité avec vasopresseurs 1.24, IC 95 % 0.64-2.43). Cette synthèse met en lumière l’incertitude scientifique sur le rôle des vasopresseurs en traumatologie. Les vasopresseurs ont des bénéfices potentiels importants, puisqu’ils permettent entre autres de supporter étroitement l’hémodynamie des patients. En revanche, ils présentent aussi un fort potentiel de dangerosité. Ils sont utilisés fréquemment, malgré l’absence de données sur leurs risques et bénéfices. Ces trouvailles établissent clairement la pertinence clinique et le bien-fondé éthique d’un essai clinique sur le rôle des vasopresseurs dans la prise en charge précoce des victimes de traumatismes. / Abstract : Trauma teams often make use of both medical and surgical interventions in the early management of traumatic shock. Vasopressors have an important clinical potential, namely because they allow fluid restriction and narrow hemodynamic support. However, they also have the potential for significant harm. The role of vasopressors in this early phase of care is controversial. Although North American guidelines consider that vasopressors are contraindicated in this clinical setting, some European experts encourage their use in the hopes of reducing intravenous fluid administration and its inherent risks. Before designing an adequate clinical trial on vasopressor use, a number of vital questions must be answered. First, current accepted practice must be described in order to determine how it will compare with an eventual experimental intervention. Second, relevant knowledge gaps in the scientific literature must be identified in order to establish equipoise and refine the research question. Chapter 2 of this document presents an observational study conducted in a regional trauma centre in the province of Québec. This retrospective study documents current practice patterns adopted by trauma teams over the course of 2013, with particular emphasis on vasopressor and intravenous fluid use. Over this timeframe, more than 40 % of patients received vasopressors, most often in the presence of traumatic brain injury (OR 10.2, 95% CI 2.7-38.5). Moreover, these vasopressors were often administered in the very early phases of trauma care, before any significant intravenous fluid loading. Chapter 3 consists of a systematic review on the early use of vasopressors in the management of traumatic shock. MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov were searched, as well as conference proceedings from major trauma meetings since 2005. Independent reviewers completed study selection and data extraction in duplicate. Observational studies yielded no interpretable data, and the only clinical trial addressing the research question had insufficient power to inform clinical practice (RR of death with vasopressor use 1.24, 95% CI 0.64-2.43). This knowledge synthesis highlights the uncertainty surrounding the role of vasopressors in trauma. Trauma teams routinely make use of vasopressors despite the absence of data on their risks and benefits. These findings clearly establish both the clinical impetus and ethical justification for a clinical trial focusing on the early use of vasopressors in the management of traumatic shock.