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Objectives: A meta-analysis was conducted to determine the average effect size of internalizing and externalizing symptoms after pediatric traumatic brain injury across a range of severity (mild, moderate, and severe). Two-meta-regressions were also conducted to determine the role of age at injury at time since injury on these effect sizes.Participants and Methods: 9725 titles and abstracts were collected from PubMed, PsycInfo, and Web of Science. Of these, 63 full-text articles were examined for inclusion criteria to determine eligibility for the study. To be included, the studies needed to be published prior to March 2017 in English, needed to have a control group of either orthopedically injured or typically developing peers, and required a reliable and valuable measure of internalizing and externalizing symptoms in children. Studies were excluded for non-accidental head injuries or if the sample recruited was outside the range of 2-17 years old at the time of injury. The analysis was based on 16 studies including 1083 cases of mild TBI, 184 cases of moderate TBI, 214 cases of severe TBI, and 1605 control cases.Results: Analyses revealed a large effect size for internalizing symptoms of children with mild TBI (Hedges g = -0.624, p = 0.009), a small effect size for moderate TBI (Hedges g = -0.238, p = 0.029), and a large effect size for severe TBI (Hedges g = -0.923, p < .001). These findings indicate that parents rate childrens internalizing symptoms more severely for brain injured children than for typically developing or non-brain injured peers. These children may be experiencing more severe symptoms such as anxiety and depression regardless of injury severity. For externalizing symptoms, analyses demonstrated a moderate effect size for mild TBI (Hedges g = -0.531, p = 0.003), a small effect size for moderate TBI (Hedges g = -0.257, p = 0.007), and a large effect size for severe TBI (Hedges g = -0.909, p < .001). Thus, children who experienced a TBI demonstrated externalizing symptoms including hyperactivity and impulsivity with the largest effect size associated with severe TBI. The results of the meta-regressions indicated that only injury severity was a significant predictor of symptom severity.Conclusions: Using meta-analytic methods, we found that children who experience traumatic brain injury are rated as exhibiting more severe internalizing and externalizing symptoms across levels of severity. This effect was largest for severe injury and smallest for moderate injury. Caregivers and healthcare practitioners can use this information to better screen for and treat internalizing and externalizing symptoms in children after a traumatic brain injury.

Objectives: A meta-analysis was conducted to determine the average effect size of internalizing and externalizing symptoms after pediatric traumatic brain injury across a range of severity (mild, moderate, and severe). Two-meta-regressions were also conducted to determine the role of age at injury at time since injury on these effect sizes.Participants and Methods: 9725 titles and abstracts were collected from PubMed, PsycInfo, and Web of Science. Of these, 63 full-text articles were examined for inclusion criteria to determine eligibility for the study. To be included, the studies needed to be published prior to March 2017 in English, needed to have a control group of either orthopedically injured or typically developing peers, and required a reliable and valuable measure of internalizing and externalizing symptoms in children. Studies were excluded for non-accidental head injuries or if the sample recruited was outside the range of 2-17 years old at the time of injury. The analysis was based on 16 studies including 1083 cases of mild TBI, 184 cases of moderate TBI, 214 cases of severe TBI, and 1605 control cases.Results: Analyses revealed a large effect size for internalizing symptoms of children with mild TBI (Hedges g = -0.624, p = 0.009), a small effect size for moderate TBI (Hedges g = -0.238, p = 0.029), and a large effect size for severe TBI (Hedges g = -0.923, p <<> .001). These findings indicate that parents rate childrens internalizing symptoms more severely for brain injured children than for typically developing or non-brain injured peers. These children may be experiencing more severe symptoms such as anxiety and depression regardless of injury severity. For externalizing symptoms, analyses demonstrated a moderate effect size for mild TBI (Hedges g = -0.531, p = 0.003), a small effect size for moderate TBI (Hedges g = -0.257, p = 0.007), and a large effect size for severe TBI (Hedges g = -0.909, p <<> .001). Thus, children who experienced a TBI demonstrated externalizing symptoms including hyperactivity and impulsivity with the largest effect size associated with severe TBI. The results of the meta-regressions indicated that only injury severity was a significant predictor of symptom severity.Conclusions: Using meta-analytic methods, we found that children who experience traumatic brain injury are rated as exhibiting more severe internalizing and externalizing symptoms across levels of severity. This effect was largest for severe injury and smallest for moderate injury. Caregivers and healthcare practitioners can use this information to better screen for and treat internalizing and externalizing symptoms in children after a traumatic brain injury.

Both individual patient-related and injury-related factors predict functional outcomes following moderate-to-severe traumatic brain injury (M/S TBI). Other than binary outcomes such as death, little is known about the role of day-of-injury neuroimaging in predicting long- term outcomes. Classification systems for assessing the severity of injury using computerized tomography (CT) scans, such as the Marshall Classification System (MCS) or Rotterdam scale, have not been systematically studied to see how they relate to long-term rehabilitation and functional outcomes following M/S TBI. The MCS consists of six categories based on information about midline shift, basal cistern compression, surgery evacuation, and lesion size. The Rotterdam scale, however, is a summed score ranging from 1-6 based on the extent of basal cistern compression, extent of midline shift, presence/absence of an epidural lesion, and presence/absence of traumatic subarachnoid hemorrhage (tSAH) or intraventricular blood. The differences between these two CT scales suggest the possibility that MCS and Rotterdam scales may differ in their ability to predict subsequent rehabilitation outcomes. Thus, we compared the relative predictive value of MCS and Rotterdam scores on long-term rehabilitation functional outcomes using the Functional Independence Measure (FIM) at rehabilitation discharge and nine-month post-discharge follow up. The study included 88 participants (25 females, mean age: 42.0 [SD: 21.3]) with M/S TBI. Day-of-injury CT images were scored using both MCS and Rotterdam criteria. Functional outcomes were measured by the cognitive and motor subscales on the FIM at discharge and after nine-month follow up, and length of stay in rehabilitation. Data were analyzed using multiple linear regression models. Neither MCS nor Rotterdam scores nor rehabilitation length of stay significantly predicted motor or cognitive outcomes at discharge or nine-month follow-up. MCS and Rotterdam scales may have limited utility in predicting long- term functional outcome in a rehabilitation setting, but instead appear to be good predictors of acute outcomes, especially regarding mortality and elevated intracranial pressure (ICP). Future research could focus on CT characteristics such as midline shift to predict long-term rehabilitation outcomes to guide treatment instead of CT rating scales.

Magnetic resonance imaging is used to assess white matter (WM) abnormalities including total WM volumes and WM hyperintensities (WMHs). Comparisons between several qualitative and quantitative methods to assess WM that are used in research and clinical settings are lacking in pediatric traumatic brain injury (TBI). This study 1) WM methods including Scheltens ratings, manual tracings, NeuroQuant®, and FreeSurfer; (2) compared total WM volumes and WMHs to assess potentially similar reporting of WM integrity; and (3) assessed the relationship between cognitive functions (intelligence, attention, processing speed, and language) and WM in pediatric TBI.Sixty participants (65% male) between ages 8-13 years old, had a complicated-mild (53%), moderate (15%), or severe TBI (32%) with a mean age of 2.6 at the time of injury. NeuroQuant® WMH volumes had poor agreement (ICC = .24), and did not correlate (r = .12, p = .21) with manually traced WMH volumes. Scheltens WMH ratings had good to excellent agreement and correlated with NeuroQuant® (ICC = .62; r = .29, p = .005) and manually traced WMH volumes (ICC = .82; r = .50, p = .000). NeuroQuant® and FreeSurfer total WM volumes had fair agreement and were correlated (ICC = .52; r = .38, p = .004). No significant difference in total WM volumes were found between complicated-mild and moderate-severe TBI groups, and in subgroups with and without WMHs. Processing speed was significantly associated with Scheltens WMH ratings: p = .004, manually traced WMHs: p = .002, and NeuroQuant® WMHs: p = .007. No other association between cognitive functions and WM volumes or hyperintensities were found. Correlations between NeuroQuant® and manual tracings with processing speed differed by sex, where males had significant correlations but females did not. Deciding when to use manual tracing and NeuroQuant® WMH volumes and Scheltens ratings in clinical or research settings will depend on available resources (e.g., time, technology, funding, and expertise) and purpose of assessing WMHs. Total WM volumes did not appear to capture WM pathology as assessed by WMHs, likely due to the sample being underpowered and that total WM volumes possibly included WMHs. Limitations include restricted range of injury severity, heterogeneity of lesions, and small sample size. Additional research is needed in a larger sample of pediatric TBI.

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Children and youth who suffer a mild traumatic brain injury or concussion are at risk for a number of negative outcomes. The symptoms of concussion and the management of these symptoms can be disruptive to the child’s everyday activities, especially if they are prolonged. Depression can result and may complicate the course of recovery. Depression has overlapping symptoms with concussion and is thought to lengthen the recovery period. There has been much research done in populations of mixed severities of brain injury but very little addresses children with concussion. Knowledge in this area is crucial due to depression’s impact on all aspects of functioning as well as the potential alteration of the child’s developmental trajectory. The purpose of this research was to examine the risks and predictors of depression following concussion in youth and to explore the experiences of a subsample of youth and their families with prolonged recovery from concussion, complicated by depression. Chapter One provides a review of the current literature setting the context for the research within what is known about concussion in youth, what is known about depression in youth and because of the early stages of this type of research, what is known about depression as an outcome of concussion in all age groups. Chapter Two presents a study highlighting the tangible risk for depression in a sample of children being followed in a tertiary care clinic (N=92). Significant predictors of depressive symptomatology were found to be the need for hospital admission and high symptom scores in the first few days and weeks after injury, which may be valuable information for prevention, early identification and treatment of youth at risk for depression after concussion. Chapter Three provides an in-depth exploration of the experiences of youth and families who have gone through prolonged recovery from concussion with significant depressive symptomatology. A phenomenological approach was used with six participants and their families who were interviewed and their responses analyzed. A trajectory of recovery was identified; common themes within each of four key stages of the trajectory were discussed and illustrated using direct quotes from the participants. Chapter Four outlines the important implications of these two studies for health care professionals; particularly in raising awareness of the mental health outcomes of concussion. Knowledge of the impact of debilitating symptoms, activity restrictions and depression can inform discussions early after a concussion to prepare and possibly prevent some of the losses experienced by youth that can lead to depression. / Thesis / Master of Science Rehabilitation Science (MSc)

Each year in the United States, approximately 1.35 million people are a ected by mTBI (aka concussion) and subsequent cognitive impairment. Approximately 33% of mTBI cases results in persistent long-term cognitive de cits despite no abnormalities appearing on conventional neuroimaging scans. Therefore, an accurate and reliable imaging method is needed to determine injury location and extent of healing. The goal of this study was to characterize and quantify mTBI through DTI, an advanced MRI technique that encodes voxel-wise tissue water microstructural di usivity as a tensor, as well as QSM, which measures iron deposition within tissues. We hypothesized that personalizing the analysis of DTI and QSM will provide a better understanding of trauma-induced microstructural damage leading to improved diagnosis and prognosis accuracy. Through regression analysis, a preliminary comparison between DTI data to QSM measurements was performed to determine potential correlations between the two MRI techniques. Further, a large database of healthy pediatric brain DTI data was downloaded and each was warped into a standardized brain template to ultimately use for voxel-wise z-score analysis of individual mTBI patients (n=26). This allowed localization and quantitation of abnormal regions on a per-patient basis. Signi cant abnormalities were commonly observed in a number of regions including the longitudinal fasciculus, fronto-occipital fasciculus, and corticospinal tract, while unique abnormalities were localized in a host of other areas (due to the individuality of each childs injury). Further, through group-based Bonferroni corrected T-test analysis, the mTBI group was signi cantly di erent from controls in approximately 65% of regions analyzed. These results show that DTI is sensitive to the detection of microstructural changes caused by mTBI and has potential to be a useful tool for improving mTBI diagnosis accuracy / Thesis / Master of Applied Science (MASc) / Concussions affect over one million people in the United States each year. In a number of cases, these individuals must cope with persistent long-term cognitive impairment resulting from the injury. A current, significant problem is that concussion cannot be reliably diagnosed using conventional CT and MR imaging methods. Therefore, an accurate and reliable imaging method is needed to determine both injury location and severity, as well as to monitor healing. The goal of this study was to quantify concussion through MR imaging techniques known as Di ffusion Tensor Imaging and Quantitative Susceptibility Mapping, which accurately model the brain's mi- crostructure. Analysis utilizing these MRI methods found signifi cant abnormalities in a number of brain regions of concussed subjects relative to healthy individuals. These results suggest that DTI, in particular, is sensitive to microstructural changes caused by concussions and has the potential to be a useful tool for improving diagnosis accuracy.

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Military-related blast-exposure and sports-related closed-head impact-injury are associated with traumatic brain injury (TBI) and chronic traumatic encephalopathy (CTE), a tau protein neurodegenerative disease. Despite growing awareness of links between TBI and CTE, the mechanisms underpinning this association, and relationship to concussive and subconcussive head injury, are poorly understood. This dissertation addresses the hypothesis that blast-exposure and impact-injury induce traumatic acceleration of the head and injurious forces in the brain that led to structural brain damage (TBI) and chronic sequelae, including CTE. This hypothesis was addressed in five specific aims: 1) develop a blast shock tube instrument and impact instrument to deliver relevant blast-exposure and impact-injury to mice, 2) validate a mouse model of single blast-exposure that recapitulates brain pathology in blast-exposed military veterans diagnosed with CTE, 3) validate a mouse model of single-repeat closed-head impact-injury that recapitulates brain pathology in contact sport athletes diagnosed with CTE, 4) match kinematics of blast and impact models using high-speed videography, 5) deploy kinematically-matched mouse models of single blast-exposure and single-repeat closed-head impact-injury to investigate mechanisms that trigger experimental concussion and post-traumatic sequelae. Blast and impact injuries were shown to cause similar CTE-linked brain pathologies, including microvasculopathy, neuroinflammation, astrogliosis, and phosphorylated tauopathy. Despite similarities in chronic consequences, blast-exposure and impact-injury produced different acute neurological responses. Surprisingly, impact-injured mice demonstrated signs of experimental concussion, whereas blast-exposed mice with comparable head kinematics did not. Computational modeling indicated that point loading of forces during impact, as opposed to distributed loading in blast, caused ipsilateral spikes in cortical shear stress which we conclude to be responsible for experimental concussion. The blast-exposure and impact-injury models have been and will continue to be invaluable tools for elucidating the mechanisms of and relationships between concussion, TBI, and CTE. / 2019-07-09T00:00:00Z