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.

Thesis (M.S.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / In this pilot study, 28 subjects ages 0 to 6 years who had sustained head injuries were assessed as to their functional status at one and six months post hospital discharge. The functional assessments used were the Rand Child Health Scale, the Battelle Developmental Inventory Screening Test, the Battelle Developmental Inventory Motor Domain, and the Pediatric Evaluation of Disability Inventory. Correlations between these functional measures and trauma scores reported through the National Pediatric Trauma Registry (Glasgow Coma Scale; Injury Severity Score, and Pediatric Trauma Score) were calculated to determine the predictive capacity of the trauma scores in determining functional outcome. The trauma scores were not found to be reliable predictors of functional outcome in these young children. / 2031-01-01

In the study of diseases such as chronic traumatic encephalopathy (CTE), the ability to gather retrospective estimates of an individual’s total repetitive head impacts (RHI) is paramount. Although the exact mechanism responsible for the development of CTE is still unknown, it is well accepted that RHI play a critical role. Until recently, however, the methodology used to collect retrospective estimates of RHI have been very limited. In the beginning of 2016, Montenigro et al. from the Boston University’s Alzheimer’s Disease and CTE Center published a new method of RHI estimation called the Cumulative Head Impact Index (CHII). The CHII was developed by collecting self-reported football histories (years of play, positions of play and levels of play), and using that data to extrapolate the findings of short-term helmet-accelerometer studies into career-long estimates of cumulative head impacts. In addition to publishing this new method, Montenigro et al. (2016) also determined that the CHII was very successful at predicting later-life neurobehavioral and cognitive impairment, an essential ability of any RHI estimate intended to be used in CTE research. Participants in the Montenigro et al. (2016) analysis were part of an ongoing longitudinal study where individuals take yearly surveys of their neurobehavioral and cognitive well-being in addition to answering surveys about sports participation, head injuries and overall wellbeing. Participants had played football at the high school or college level, but had not played any other contact sports. This thesis serves as an initial validation of that publication, and also tests the ability of the CHII to predict later-life impairment in a more diverse population of athletes. Participants in this thesis were selected from the same ongoing longitudinal study according to two distinct sets of inclusion and exclusion criteria. For the purposes of conducting a validation study, the first set of criteria were identical to those used by Montenigro et al. (2016). The second experimental set allowed for participants who had participated in a secondary contact sport if it was at the high school level or below. These two sets of criteria resulted in 70 “validation” participants, and 82 “experimental” participants. Using the same methods as Montenigro et al. 2016, we calculated the CHII for all participants, and examined the ability of the CHII to predict later-life impairment. Our findings validated that the CHII was indeed successful at predicting later-life impairment from cumulative head impacts among the validation group of 70 participants. In particular, the CHII successfully predicted a threshold dose-response relationship between CHI and apathy (p >0.001), depression (p >0.001), executive function dysregulation (p >0.001), and self-reported cognitive impairment (p >0.001). We then found that the CHII was much less successful at predicting impairment in the experimental group of 82, only finding significance in measures of apathy (p=0.0502) and executive function dysregulation (p=0.0277). Overall, our findings indicate that the CHII is an excellent improvement in methods of estimating RHI in people whose only contact sport is football.

Traumatic brain injury (TBI) is becoming increasingly recognized as a global health issue. Each year over 160,000 Canadians experience some form of TBI, which can be caused by sport-related injuries, motor vehicle accidents, or assault. Adolescents are especially susceptible to repeat head injury and represent an at-risk population for sustaining sports-related concussions. The hippocampus, known for its role in learning and memory, is vulnerable to this injury. Although most TBI studies exclude females, there are important sex differences in outcomes and recovery following brain injury. A greater understanding of how sex differences contribute to the heterogeneity of this disease is critical for clinical care and potential treatments. Currently, few preclinical studies have assessed sex differences in adolescents following repeated mild traumatic brain injury (rmTBI). This study uses an awake closed head injury (ACHI) paradigm in male and female adolescent rats to investigate acute injury-induced changes to the hippocampus after rmTBI. A neurological assessment protocol (NAP) administered immediately after each impact showed that the ACHI acutely alters state of consciousness, and results in deficits after each impact. Following 8 ACHIs spaced 2 hours apart, adolescent rats were injected with the thymidine analogue BrdU and perfused 2 hours later on either post injury day (PID) 1 or 3. BrdU was used to identify cells undergoing DNA synthesis, and Ki-67 - expressed during all active phases of the cell cycle - was used as an endogenous marker for proliferation. Results indicate a robust and diffuse increase in cellular proliferation in male rmTBI animals that was not present to the same extent in female rmTBI animals. Triple labeling experiments revealed a higher proportion of microglia/macrophages in the subgranular zone of rmTBI animals, indicating an immediate inflammatory response in both sexes. This study shows sex differences in the pathophysiology of rmTBI in adolescent rats. Further investigation will reveal the detrimental versus neuroprotective contributions of this effect on learning and memory. / Graduate

The diagnostic lesions of neurodegenerative tauopathies, such as chronic traumatic encephalopathy (CTE) and Alzheimer’s disease (AD), are located in the cortex, however, white matter pathology is a contributing factor to neurodegeneration. At all stages of disease, white matter axonal and glial morphological abnormalities are present in CTE. Similarly, white matter changes may emerge before cortical pathology in AD. White matter irregularities bear functional consequences, as they are associated to some of the most common and onerous symptoms of these diseases, like cognitive deficits and depression. Individuals with AD present with both reduced white matter integrity and cognitive symptoms starting early in disease progression. In CTE, which is triggered by repetitive head impacts (RHI), individuals are particularly vulnerable to white matter damage as RHI exposure alone is sufficient to injure white matter tracts and induce depression symptoms. In this dissertation, I investigated the cellular and molecular presentation of white matter glial cells, including astrocytes, oligodendrocytes (OLs), and microglia in CTE and AD as compared to controls. To investigate white matter pathology, I examined glial cells on a cellular level. Neuropathologically-verified CTE samples were compared to RHI-experienced controls, with both groups containing samples with and without depressed mood. CTE with depressed mood had reduced myelin and increased neuroinflammatory peripheral cells compared to non-depressed CTE and contained increased numbers of microglia compared to non-depressed CTE and control samples. Using single-nucleus transcriptomics in neuropathologically-verified CTE samples compared to matched RHI-naïve controls, OL loss, iron aggregates, OL iron trafficking dysregulation, and two distinct astrocyte subpopulations were detected in CTE white matter. AD white matter, compared to the same control samples in the same brain region, was also depleted of OLs by single-nucleus transcriptomics. However, OLs did not demonstrate iron-related transcriptional profile like those in CTE and, in further contrast, displayed increased numbers of microglia and astrocytes. Together, these findings implicate previously uncharacterized white matter glia in the neurodegenerative process of CTE and AD and further elucidate the etiology of neurodegeneration-related symptoms in CTE. These findings may aid in the development of therapeutics targeting glial contributions to the pathologic processes of both CTE and AD.

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.

Understanding the neuronal basis of learning and memory is a fundamental problem in neuroscience. A leading theory, the origins of which date back to the beginning of the twentieth century, is that the neural basis for memory resides in engrams (also called memory traces), ensembles of cells that are activated during learning and reactivated during memory retrieval. Recent genetic tools have allowed researchers to visualize and manipulate memory traces in small brain regions; however, the ultimate goal is to analyze memory traces across the entire brain in order to better understand how memories are stored in neural networks and how multiple memories may coexist. In order to do so, methods and technologies need to be developed that allow labeling of engram cells throughout the brain, visualization of these cells, and automated quantification of cells in an anatomically precise manner. The first of these challenges has been addressed through the development over the past several years of different mouse models that permit the labeling of active cells throughout the brain at multiple time points. One of the most powerful models, the ArcCreERT2 mouse line, uses drug-induced genetic recombination to indelibly label cells throughout the brain in an activity-dependent manner. In this thesis, I present our work utilizing this model to solve the second and third challenges: imaging of brain-wide memory traces and automated quantification of labeled cells, as well as the application of these novel methods to understanding the engram network changes following fear extinction. Intact tissue clearing and imaging is a new and rapidly growing area of focus that holds great promise for enabling the brain-wide visualization of memory traces. We utilized the leading protocols for whole-brain clearing and applied them to the ArcCreERT2 mice. We found that CLARITY and passive clarity technique (PACT) greatly distorted the tissue, and immunolabeling-enabled three-dimensional imaging of solvent-cleared organs (iDISCO) quenched enhanced yellow fluorescent protein (eYFP) fluorescence and hindered immunolabeling. Alternative clearing solutions, such as tert-Butanol, circumvented these harmful effects, but still did not permit whole-brain immunolabeling. Clear unobstructed brain imaging cocktails and computational analysis (CUBIC) and CUBIC with Reagent 1A produced improved antibody penetration and preserved eYFP fluorescence, but also did not allow for whole-brain memory trace visualization. We developed CUBIC with Reagent-1A*, a modified CUBIC protocol that resulted in eYFP fluorescence preservation and immunolabeling of the immediate early gene (IEG) Arc in deep brain areas; however, optimized memory trace labeling still required tissue slicing into mm-thick tissue sections. Nonetheless, our data show that CUBIC with Reagent-1A* is the ideal method for reproducible clearing and immunolabeling for the visualization of memory traces in mm-thick tissue sections from ArcCreERT2 brains. Recent developments in brain-wide engram tagging strategies, primarily through the use of transgenic mouse models such as the ArcCreERT2 line, and whole brain imaging strategies, such as CLARITY, CUBIC, and iDISCO, have created the circumstances to, for the first time, be able to visualize throughout the brain neuronal activity that is directly linked to behavior. However, as noted above, quantifying and analyzing these brain-wide memory traces presents its own challenge, and widely applicable, readily accessible solutions to this problem have thus far been limited. Although a handful of freely available programs and suites do exist, such as CellProfiler and ClearMap, these are generally tailored to specific approaches, and in particular, no currently available solution exists for quantifying multi-labeled engram cells imaged in three dimensions along the coronal plane, a relatively common scenario that is sure to become even more prominent as greater adoption of the underlying technologies progresses. Using ImageJ and R, we developed an image analysis pipeline to solve precisely this problem. Our strategy allows for the segmentation of both the encoding and retrieval populations, including identification of the reactivated cells, and registration of segmented cells to an anatomical atlas in order to analyze cell activity in a region- and layer-specific manner. Post-traumatic stress disorder (PTSD) can develop following a traumatic event and results in heightened, inappropriate fear and anxiety. Approximately 8% of the US population suffers from PTSD, the main treatment for which is repeated exposure to triggering stimuli under controlled conditions. A better understanding of the neural circuits modified during this process would help advance therapeutic treatment for PTSD. We sought to determine the brain-wide neuronal activity changes underlying fear extinction, the best laboratory model of exposure therapy, by using the ArcCreERT2 x eYFP mice and our newly developed brain-wide segmentation and registration pipeline. ArcCreERT2 x eYFP mice were administered a 4-shock contextual fear conditioning (CFC) paradigm followed by either a 10-day extinction protocol or re-exposure to the aversive context without extinction. Following the final exposure session, mice were euthanized, and active cells were quantified throughout the brain using the pipeline. We found that fear learning leads to increased functional connectivity of amygdalar and hypothalamic regions, and extinction leads to a decentralization of the fear memory network and disengages the thalamus and striatal amygdala. Additionally, coordinated reactivation of the basomedial amygdala and secondary somatosensory cortex with frontal association regions are differentially modulated following extinction, and we identified the temporal association area and medial habenula as novel brain regions involved in modulating freezing behavior. In summary, in this thesis, we have developed a novel engram analysis pipeline and shown its potential for quantifying brain-wide memory traces. This is the first study to analyze brain-wide functional connectivity following fear learning and extinction of a recent fear memory, as well as the first study to analyze fear memory trace reactivation patterns across the brain and relate all three measures to behavioral output. This work both greatly enhances our understanding of the neural underpinnings of fear extinction and provides a toolset for readily exploring the neural underpinnings of other behaviors and types of associative memory.

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.