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Traumatic brain injury (TBI) results in neurodegenerative changes that progress for months, perhaps even years post-injury. However, there is little information on the spatial distribution and the clinical significance of this late atrophy. In 24 patients who had sustained severe TBI we acquired 3D T1-weighted MRIs about 8 weeks and 12 months post-injury. For comparison, 14 healthy controls with similar distribution of age, gender and education were scanned with a similar time interval. For each subject, longitudinal atrophy was estimated using SIENA, and atrophy occurring before the first scan time point using SIENAX. Regional distribution of atrophy was evaluated using tensor-based morphometry (TBM). At the first scan time point, brain parenchymal volume was reduced by mean 8.4% in patients as compared to controls. During the scan interval, patients exhibited continued atrophy with percent brain volume change (%BVC) ranging between -0.6% and -9.4% (mean -4.0%). %BVC correlated significantly with injury severity, functional status at both scans, and with 1-year outcome. Moreover, %BVC improved prediction of long-term functional status over and above what could be predicted using functional status at approximately 8 weeks. In patients as compared to controls, TBM (permutation test, FDR 0.05) revealed a large coherent cluster of significant atrophy in the brain stem and cerebellar peduncles extending bilaterally through the thalamus, internal and external capsules, putamen, inferior and superior longitudinal fasciculus, corpus callosum and corona radiata. This indicates that the long-term atrophy is attributable to consequences of traumatic axonal injury. Despite progressive atrophy, remarkable clinical improvement occurred in most patients.

Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of rats: Sham, CCI-alone and CCI-BMMNCs (AUTO). One hundred twenty days after injury, rodents were imaged with PBR28 and their cognitive behavior assessed utilizing the Morris Water Maze. Subsequent ex vivo analysis included brain volume and immunohistochemistry. BMMNCs therapy attenuated PBR28suv in comparison to CCI alone and it improved spatial learning as measured by the Morris Water Maze. Ex vivo analysis demonstrated preservation of brain volume, a decrease in amoeboid-shaped microglia in the dentate gyrus and an increase in the ratio of ramified to amoeboid microglia in the thalamus. PBR28suv is a viable option to measure efficacy of BMMNCs therapy after TBI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) triggers progressive neurodegeneration resulting in brain atrophy that continues months‐to‐years following injury. However, a comprehensive characterization of the spatial and temporal evolution of TBI‐related brain atrophy remains incomplete. Utilizing a sensitive and unbiased morphometry analysis pipeline optimized for detecting longitudinal changes, we analyzed a sample consisting of 37 individuals with moderate‐severe TBI who had primarily high‐velocity and high‐impact injury mechanisms. They were scanned up to three times during the first year after injury (3 months, 6 months, and 12 months post‐injury) and compared with 33 demographically matched controls who were scanned once. Individuals with TBI already showed cortical thinning in frontal and temporal regions and reduced volume in the bilateral thalami at 3 months post‐injury. Longitudinally, only a subset of cortical regions in the parietal and occipital lobes showed continued atrophy from 3 to 12 months post‐injury. Additionally, cortical white matter volume and nearly all deep gray matter structures exhibited progressive atrophy over this period. Finally, we found that disproportionate atrophy of cortex along sulci relative to gyri, an emerging morphometric marker of chronic TBI, was present as early as 3 month post‐injury. In parallel, neurocognitive functioning largely recovered during this period despite this pervasive atrophy. Our findings demonstrate msTBI results in characteristic progressive neurodegeneration patterns that are divergent across regions and scale with the severity of injury. Future clinical research using atrophy during the first year of TBI as a biomarker of neurodegeneration should consider the spatiotemporal profile of atrophy described in this study. [ABSTRACT FROM AUTHOR]

Background and Purpose: We aimed to identify reliable neuroradiological features of the brainstem reflecting the neurological symptoms of patients with chronic disorders of consciousness (DOCs) due to severe traumatic brain injury (TBI). Methods: We retrospectively examined 86 patients with chronic DOCs due to severe TBI caused by automobile accidents. We studied the relationships among (1) neurological symptoms, including consciousness level, (2) integrated cognitive/physical condition, and (3) neuroradiological features of the brainstem (brainstem volume on MRI, fractional anisotropy [FA] value in the brainstem, and standardized uptake value [SUV] of 18F‐fluorodeoxyglucose [FDG] on positron emission tomography in the brainstem). Results: Brainstem volume was significantly larger and FA values were significantly higher in patients with a better level of consciousness. However, brainstem volumes were significantly decreased and the maximum SUV (SUVmax) of FDG significantly increased at 2 years following admission regardless of the level of consciousness at admission. The brainstem volume was significantly larger and the FA value and SUVmax of FDG were significantly higher in patients with better National Agency for Automotive Safety and Victims' Aid (NASVA) scores at admission. The decrease in the brainstem volume was significantly minimized and the SUVmax of FDG significantly increased in patients with more improvement in the NASVA score 2 years after admission. Conclusions: The volume, FA value, and SUVmax of FDG of the brainstem are important neuroradiological features associated with the neurological conditions of patients with chronic DOCs due to severe TBI. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) causes lifelong cognitive deficits, most often in executive function (EF). Both musical training and music‐based rehabilitation have been shown to enhance EF and neuroplasticity. Thus far, however, there is little evidence for the potential rehabilitative effects of music for TBI. Here, we review the core findings from our recent cross‐over randomized controlled trial in which a 10‐week music‐based neurological rehabilitation (MBNR) protocol was administered to 40 patients with moderate‐to‐severe TBI. Neuropsychological testing and structural/functional magnetic resonance imaging were collected at three time points (baseline, 3 months, and 6 months); one group received the MBNR between time points 1 and 2, while a second group received it between time points 2 and 3. We found that both general EF and set shifting improved after the intervention, and this effect was maintained long term. Morphometric analyses revealed therapy‐induced gray matter volume changes most consistently in the right inferior frontal gyrus, changes that correlated with better outcomes in set shifting. Finally, we found changes in the between‐ and within‐network functional connectivity of large‐scale resting‐state networks after MBNR, which also correlated with measures of EF. Taken together, the data provide evidence for concluding that MBNR improves EF in TBI; also, the data show that morphometric and resting‐state functional connectivity are sensitive markers with which to monitor the neuroplasticity induced by the MBNR intervention. [ABSTRACT FROM AUTHOR]

Brain atrophy induced by traumatic brain injury (TBI) progresses in parallel with epileptogenesis over time, and thus accurate placement of intracerebral electrodes to monitor seizure initiation and spread at the chronic postinjury phase is challenging. We evaluated in adult male Sprague Dawley rats whether adjusting atlas-based electrode coordinates on the basis of magnetic resonance imaging (MRI) increases electrode placement accuracy and the effect of chronic electrode implantations on TBI-induced brain atrophy. One group of rats (EEG cohort) was implanted with two intracortical (anterior and posterior) and a hippocampal electrode right after TBI to target coordinates calculated using a rat brain atlas. Another group (MRI cohort) was implanted with the same electrodes, but using T2-weighted MRI to adjust the planned atlas-based 3D coordinates of each electrode. Histological analysis revealed that the anterior cortical electrode was in the cortex in 83% (25% in targeted layer V) of the EEG cohort and 76% (31%) of the MRI cohort. The posterior cortical electrode was in the cortex in 40% of the EEG cohort and 60% of the MRI cohort. Without MRI-guided adjustment of electrode tip coordinates, 58% of the posterior cortical electrodes in the MRI cohort will be in the lesion cavity, as revealed by simulated electrode placement on histological images. The hippocampal electrode was accurately placed in 82% of the EEG cohort and 86% of the MRI cohort. Misplacement of intracortical electrodes related to their rostral shift due to TBI-induced cortical and hippocampal atrophy and caudal retraction of the brain, and was more severe ipsilaterally than contralaterally (p < 0.001). Total lesion area in cortical subfields targeted by the electrodes (primary somatosensory cortex, visual cortex) was similar between cohorts (p > 0.05). MRI-guided adjustment of coordinates for electrodes improved the success rate of intracortical electrode tip placement nearly to that at the acute postinjury phase (68% vs. 62%), particularly in the posterior brain, which exhibited the most severe postinjury atrophy. Overall, MRI-guided electrode implantation improved the quality and interpretation of the origin of EEG-recorded signals. [ABSTRACT FROM AUTHOR]

The complex pathophysiology of post-traumatic brain damage might need a polypharmacological strategy with a combination of drugs that target multiple, synergistic mechanisms. We currently tested a combination of apocynin (curtails formation of reactive oxygen species), tert-butylhydroquinone (promotes disposal of reactive oxygen species), and salubrinal (prevents endoplasmic reticulum stress) following a moderate traumatic brain injury (TBI) induced by controlled cortical impact in adult mice. Adult mice of both sexes treated with the above tri-combo showed alleviated motor and cognitive deficits, attenuated secondary lesion volume, and decreased oxidative DNA damage. Concomitantly, tri-combo treatment regulated post-TBI inflammatory response by decreasing the infiltration of T cells and neutrophils and activation of microglia in both sexes. Interestingly, sexual dimorphism was seen in the case of TBI-induced microgliosis and infiltration of macrophages in the tri-combo–treated mice. Moreover, the tri-combo treatment prevented TBI-induced white matter volume loss in both sexes. The beneficial effects of tri-combo treatment were long-lasting and were also seen in aged mice. Thus, the present study supports the tri-combo treatment to curtail oxidative stress and endoplasmic reticulum stress concomitantly as a therapeutic strategy to improve TBI outcomes. [ABSTRACT FROM AUTHOR]

Progressive cortical volumetric loss following moderate–severe traumatic brain injury (TBI) has been observed; however, regionally specific changes in the structural determinants of cortical volume, namely, cortical thickness (CT) and cortical surface area (CSA), are unknown and may inform the patterns and neural substrates of neurodegeneration and plasticity following injury. We aimed to (a) assess differences in CT and CSA between TBI participants and controls in the early chronic stage post‐injury, (b) describe longitudinal changes in cortical morphometry following TBI, and (c) examine how regional changes in CT and CSA are associated. We acquired magnetic resonance images for 67 participants with TBI at up to 4 time‐points spanning 5 months to 7 years post‐injury, and 18 controls at 2 time‐points. In the early chronic stage, TBI participants displayed thinner cortices than controls, predominantly in frontal regions, but no CSA differences. Throughout the chronic period, TBI participants showed widespread CT reductions in posterior cingulate/precuneus regions and moderate CT increase in frontal regions. Additionally, CSA showed a significant decrease in the orbitofrontal cortex and circumscribed increase in posterior regions. No changes were identified in controls. Relationships between regional cortical changes in the same morphological measure revealed coordinated patterns within participants, whereas correlations between regions with CT and CSA change yielded bi‐directional relationships. This suggests that these measures may be differentially affected by neurodegenerative mechanisms such as transneuronal degeneration following TBI and that degeneration may be localized to the depths of cortical sulci. These findings emphasize the importance of dissecting morphometric contributions to cortical volume change. [ABSTRACT FROM AUTHOR]

Objectives: Determining the volume of brain lesions after trauma is challenging. Manual delineation is observer-dependent and time-consuming and cannot therefore be used in routine practice. The study aimed to evaluate the feasibility of an automated atlas-based quantification procedure (AQP) based on the detection of abnormal mean diffusivity (MD) values computed from diffusion-weighted MR images. Methods: The performance of AQP was measured against manual delineation consensus by independent raters in two series of experiments based on: (i) realistic trauma phantoms (n = 5) where low and high MD values were assigned to healthy brain images according to the intensity, form and location of lesion observed in real TBI cases; (ii) severe TBI patients (n = 12 patients) who underwent MR imaging within 10 days after injury. Results: In realistic TBI phantoms, no statistical differences in Dice similarity coefficient, precision and brain lesion volumes were found between AQP, the rater consensus and the ground truth lesion delineations. Similar findings were obtained when comparing AQP and manual annotations for TBI patients. The intra-class correlation coefficient between AQP and manual delineation was 0.70 in realistic phantoms and 0.92 in TBI patients. The volume of brain lesions detected in TBI patients was 59 ml (19–84 ml) (median; 25–75th centiles). Conclusions: Our results support the feasibility of using an automated quantification procedure to determine, with similar accuracy to manual delineation, the volume of low and high MD brain lesions after trauma, and thus allow the determination of the type and volume of edematous brain lesions. This approach had comparable performance with manual delineation by a panel of experts. It will be tested in a large cohort of patients enrolled in the multicenter OxyTC trial (NCT02754063). [ABSTRACT FROM AUTHOR]

Neonatal brain injury may impact brain development and lead to lifelong functional impairments. Hypoxic-ischemic encephalopathy (HIE) and congenital heart disease (CHD) are two common causes of neonatal brain injury differing in timing and mechanism. Maturation of whole-brain neural networks can be quantified during development using diffusion magnetic resonance imaging (dMRI) in combination with graph theory metrics. DMRI of 35 subjects with CHD and 62 subjects with HIE were compared to understand differences in the effects of HIE and CHD on the development of network topological parameters and functional outcomes. CHD newborns had worse 12–18 month language (P<0.01) and 30 month cognitive (P<0.01), language (P = 0.05), motor outcomes (P = 0.01). Global efficiency, a metric of brain integration, was lower in CHD (P = 0.03) than in HIE, but transitivity, modularity and small-worldness were similar. After controlling for clinical factors known to affect neurodevelopmental outcomes, we observed that global efficiency was highly associated with 30 month motor outcomes (P = 0.02) in both groups. To explore neural correlates of adverse language outcomes in CHD, we used hypothesis-based and data-driven approaches to identify pathways with altered structural connectivity. We found that connectivity strength in the superior longitudinal fasciculus (SLF) tract 2 was inversely associated with expressive language. After false discovery rate correction, a whole connectome edge analysis identified 18 pathways that were hypoconnected in the CHD cohort as compared to HIE. In sum, our study shows that neonatal structural connectivity predicts early motor development after HIE or in subjects with CHD, and regional SLF connectivity is associated with language outcomes. Further research is needed to determine if and how brain networks change over time and whether those changes represent recovery or ongoing dysfunction. This knowledge will directly inform strategies to optimize neurologic functional outcomes after neonatal brain injury. [ABSTRACT FROM AUTHOR]

The cholinergic nuclei in the basal forebrain innervate frontal cortical structures regulating attention. Our aim was to investigate if cognitive test results measuring attention relate to the longitudinal volume change of cholinergically innervated structures following traumatic brain injury (TBI). During the prospective, observational TBIcare project patients with all severities of TBI (n = 114) and controls with acute orthopedic injuries (n = 17) were recruited. Head MRI was obtained in both acute (mean 2 weeks post-injury) and late (mean 8 months) time points. T1-weighted 3D MR images were analyzed with an automatic segmentation method to evaluate longitudinal, structural brain volume change. The cognitive outcome was assessed with the Cambridge Neuropsychological Test Automated Battery (CANTAB). Analyses included 16 frontal cortical structures, of which four showed a significant correlation between post-traumatic volume change and the CANTAB test results. The strongest correlation was found between the volume loss of the supplementary motor cortex and motor screening task results (R-sq 0.16, p < 0.0001), where poorer test results correlated with greater atrophy. Of the measured sum structures, greater cortical gray matter atrophy rate showed a significant correlation with the poorer CANTAB test results. TBI caused volume loss of frontal cortical structures that are heavily innervated by cholinergic neurons is associated with neuropsychological test results measuring attention. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a leading cause of death and disability. Recently, a paradigm shift in our understanding of moderate-to-severe TBI has led to its reconceptualization as a progressive neurodegenerative disorder. Widespread progressive atrophy is observed in the months and years post-injury, long after the acute effects of the injury have resolved. Some studies have begun to examine prognostic demographic, injury-related, and post-injury risk factors that contribute to these declines. A synthesis of this information, and in particular, an increased understanding of post-injury factors that may be modifiable, would improve our ability to design interventions to reduce neurodegeneration in moderate-to-severe TBI. This systematic review aims to identify prognostic factors for neural deterioration in moderate-to-severe TBI, and thereby inform future intervention research in this population. Methods: This review protocol was informed by and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) guidelines. Search strategies (designed to identify literature on prognostic factors of neurodegeneration in adults with moderate-to-severe TBI) optimized for MEDLINE, EMBASE PsychINFO, CINAHL, SportDiscus, and Cochrane Central Register of Controlled Trials will be developed with the assistance of a health sciences librarian. Retrieved studies will be screened by two team members. Studies must report on longitudinal neuroimaging (i.e., two or more scans in the same cohort) or neuroimaging in a cross-sectional study and potential prognostic factors for neurodegeneration, such as demographics (e.g., gender, age, education), injury (e.g., severity, etiology), or post-injury characteristics (e.g., type and length of therapy, activity level, mood). Discussion: By identifying prognostic factors for neurodegeneration, this systematic review can help inform injury management, as well as intervention research designed to offset the effects of modifiable prognostic factors, such as low levels of cognitive or physical activity. In turn, this systematic review can increase our understanding of how to improve outcome following moderate-to-severe TBI. Systematic review registration: PROSPERO CRD42019122389 [ABSTRACT FROM AUTHOR]

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Background: Our understanding of recovery after moderate-to-severe traumatic brain injury (TBI) has shifted. Until recently, it was presumed that following a period of acute neurological vulnerability, the brain remained stable in the chronic stages of injury. However, recent research has shown neurodegeneration in the chronic stages of moderate-to-severe TBI, challenging the assumption of neurological stability. While there is extensive evidence that neurodegeneration occurs, debate remains regarding the scale and timing. This systematic review will evaluate the scale and timelines of neurodegeneration in adult patients with moderate-to-severe TBI. Methods: Literature searches will be conducted in six electronic databases (from inception onwards), including MEDLINE, EMBASE, PsycINFO, CINAHL, SportDiscus, and Cochrane Central Register of Controlled Trials. We will include observational studies that examine neurodegenerative changes within a single sample of TBI patients or studies that compare neuroimaging outcomes between TBI patients and healthy controls. Our primary outcome is structural neuroimaging, and our secondary outcome is diffusion tensor imaging for detection of post-injury white matter changes. All screening, data extraction, and study quality appraisal will be performed independently by the same two study members. It is expected that a narrative summary of the literature will be produced. If feasible, we will conduct a random-effects meta-analysis. However, given the expected heterogeneity between studies (with respect to, for example, timing of imaging, regions imaged) we do not expect to perform a meta-analysis; rather, a narrative synthesis of our findings is expected to be performed. Discussion: Understanding the scale and timelines of neurodegeneration in moderate-to-severe TBI (as well as which brain areas are most vulnerable to chronic declines) can inform intervention research designed to offset such changes. This may help improve patient outcome following moderate-to-severe TBI and, in turn, reduce the burden of the injury. Systematic review registration: PROSPERO CRD42019117548 [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) leads to increased rates of dementia, including Alzheimer's disease. The mechanisms by which trauma can trigger neurodegeneration are increasingly understood. For example, diffuse axonal injury is implicated in disrupting microtubule function, providing the potential context for pathologies of tau and amyloid to develop. The neuropathology of post-traumatic dementias is increasingly well characterised, with recent work focusing on chronic traumatic encephalopathy (CTE). However, clinical diagnosis of post-traumatic dementia is problematic. It is often difficult to disentangle the direct effects of TBI from those produced by progressive neurodegeneration or other post-traumatic sequelae such as psychiatric impairment. CTE can only be confidently identified at postmortem and patients are often confused and anxious about the most likely cause of their post-traumatic problems. A new approach to the assessment of the long-term effects of TBI is needed. Accurate methods are available for the investigation of other neurodegenerative conditions. These should be systematically employed in TBI. MRI and positron emission tomography neuroimaging provide biomarkers of neurodegeneration which may be of particular use in the postinjury setting. Brain atrophy is a key measure of disease progression and can be used to accurately quantify neuronal loss. Fluid biomarkers such as neurofilament light can complement neuroimaging, representing sensitive potential methods to track neurodegenerative processes that develop after TBI. These biomarkers could characterise endophenotypes associated with distinct types of post-traumatic neurodegeneration. In addition, they might profitably be used in clinical trials of neuroprotective and disease-modifying treatments, improving trial design by providing precise and sensitive measures of neuronal loss. [ABSTRACT FROM AUTHOR]

Prognostic modeling in moderate to severe traumatic brain injury (TBI) has historically focused primarily on the projection of crude outcomes such as the risk of mortality and disability. Initial work in this area has perpetuated the notion that prognosis after moderate to severe TBI can be measured as a single, static, and dichotomous outcome. However, more recent conceptualizations describe moderate to severe TBI as the initiation of a chronic disease state with high levels of inter-individual variability in terms of symptom manifestation and disease progression. Unfortunately, existing prognostic models provide limited insight into the extent of chronic cognitive and neurodegenerative changes experienced by moderate to severe TBI survivors. Though prior research has identified a variety of acute factors that appear to influence post-injury cognitive and neuropathological outcomes, an empirically supported framework for prognostic modeling of these injury-distal outcomes does not exist. The current review considers the literature on an expanded array of empirically supported predictors (both premorbid and injury-related) in association with long-term sequelae of moderate to severe TBI. We also provide a theoretical framework and statistical approach for prognostic modeling in moderate to severe TBI in order to unify efforts across research groups and facilitate important progress in this research area. [ABSTRACT FROM AUTHOR]

Background: In patients with moderate and severe paediatric traumatic brain injury (TBI), we investigated the presence and severity of white matter (WM) tract damage, cortical lobar and deep grey matter (GM) atrophies, their interplay and their correlation with outcome rating scales. Methods: Diffusion tensor (DT) and 3D T1‐weighted MRI scans were obtained from 22 TBI children (13 boys; mean age at insult = 11.6 years; 72.7% in chronic condition) and 31 age‐matched healthy children. Patients were tested with outcome rating scales and the Wechsler Intelligence Scale for Children (WISC). DT MRI indices were obtained from several supra‐ and infra‐tentorial WM tracts. Cortical lobar and deep GM volumes were derived. Comparisons between patients and controls, and between patients in acute (<6 months from the event) vs. chronic (≥6 months) condition were performed. Results: Patients showed a widespread pattern of decreased WM FA and GM atrophy. Compared to acute, chronic patients showed severer atrophy in the right frontal lobe and reduced FA in the left inferior longitudinal fasciculus and corpus callosum (CC). Decreased axial diffusivity was observed in acute patients versus controls in the inferior fronto‐occipital fasciculus and CC. Chronic patients showed increased axial diffusivity in the same structures. Uncinate fasciculus DT MRI abnormalities correlated with atrophy in the frontal and temporal lobes. Hippocampal atrophy correlated with reduced WISC scores, whereas putamen atrophy correlated with lower functional independence measure scores. Conclusions: The study isolated a distributed fronto‐temporal network of structures particularly vulnerable to axonal damage and atrophy that may contribute to cognitive deficits following TBI. [ABSTRACT FROM AUTHOR]

Traumatic brain injuries (TBI) have received widespread media attention in recent years as being a risk factor for the development of dementia and chronic traumatic encephalopathy (CTE). This has sparked fears about the potential long-term effects of TBI of any severity on cognitive aging, leading to a public health concern. This article reviews the evidence surrounding TBI as a risk factor for the later development of changes in brain structure and function, and an increased risk of neurodegenerative disorders. A number of studies have shown evidence of long-term brain changes and accumulation of pathological biomarkers (e.g., amyloid and tau proteins) related to a history of moderate-to-severe TBI, and research has also demonstrated that individuals with moderate-to-severe injuries have an increased risk of dementia. While milder injuries have been found to be associated with an increased risk for dementia in some recent studies, reports on long-term brain changes have been mixed and often are complicated by factors related to injury exposure (i.e., number of injuries) and severity/complications, psychiatric conditions, and opioid use disorder. CTE, although often described as a neurodegenerative disorder, remains a neuropathological condition that is poorly understood. Future research is needed to clarify the significance of CTE pathology and determine whether that can explain any clinical symptoms. Overall, it is clear that most individuals who sustain a TBI (particularly milder injuries) do not experience worse outcomes with aging, as the incidence for dementia is found to be less than 7% across the literature. [ABSTRACT FROM AUTHOR]

This review recounts the definitions and research evidence supporting the multifaceted roles of neuroinflammation in the injured brain following trauma. We summarise the literature fluctuating from the protective and detrimental properties that cytokines, leukocytes and glial cells play in the acute and chronic stages of TBI, including the intrinsic factors that influence cytokine responses and microglial functions relative to genetics, sex, and age. We elaborate on the pros and cons that cytokines, chemokines, and microglia play in brain repair, specifically neurogenesis, and how such conflicting roles may be harnessed therapeutically to sustain the survival of new neurons. With a brief review of the clinical and experimental findings demonstrating early and chronic inflammation impacts on outcomes, we focus on the clinical conditions that may be amplified by neuroinflammation, ranging from acute seizures to chronic epilepsy, neuroendocrine dysfunction, dementia, depression, post-traumatic stress disorder and chronic traumatic encephalopathy. Finally, we provide an overview of the therapeutic agents that have been tested to reduce inflammation-driven secondary pathological cascades and speculate the future promise of alternative drugs. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is the largest cause of death and disability of persons under 45 years old, worldwide. Independent of the distribution, outcomes such as disability are associated with huge societal costs. The heterogeneity of TBI and its complicated biological response have helped clarify the limitations of current pharmacological approaches to TBI management. Five decades of effort have made some strides in reducing TBI mortality but little progress has been made to mitigate TBI-induced disability. Lessons learned from the failure of numerous randomized clinical trials and the inability to scale up results from single center clinical trials with neuroprotective agents led to the formation of organizations such as the Neurological Emergencies Treatment Trials (NETT) Network, and international collaborative comparative effectiveness research (CER) to re-orient TBI clinical research. With initiatives such as TRACK-TBI, generating rich and comprehensive human datasets with demographic, clinical, genomic, proteomic, imaging, and detailed outcome data across multiple time points has become the focus of the field in the United States (US). In addition, government institutions such as the US Department of Defense are investing in groups such as Operation Brain Trauma Therapy (OBTT), a multicenter, pre-clinical drug-screening consortium to address the barriers in translation. The consensus from such efforts including "The Lancet Neurology Commission" and current literature is that unmitigated cell death processes, incomplete debris clearance, aberrant neurotoxic immune, and glia cell response induce progressive tissue loss and spatiotemporal magnification of primary TBI. Our analysis suggests that the focus of neuroprotection research needs to shift from protecting dying and injured neurons at acute time points to modulating the aberrant glial response in sub-acute and chronic time points. One unexpected agent with neuroprotective properties that shows promise is transplantation of neural stem cells. In this review we present (i) a short survey of TBI epidemiology and summary of current care, (ii) findings of past neuroprotective clinical trials and possible reasons for failure based upon insights from human and preclinical TBI pathophysiology studies, including our group's inflammation-centered approach, (iii) the unmet need of TBI and unproven treatments and lastly, (iv) present evidence to support the rationale for sub-acute neural stem cell therapy to mediate enduring neuroprotection. [ABSTRACT FROM AUTHOR]

Background and objective: Diffuse axonal injury (DAI) induces a long-term process of brain atrophy and cognitive deficits. The goal of this study was to determine whether there are correlations between brain volume loss, microhaemorrhage load (MHL) and neuropsychological performance during the first year after DAI. Methods: Twenty-four patients with moderate or severe DAI were evaluated at 2, 6 and 12 months post-injury. MHL was evaluated at 3 months, and brain volumetry was evaluated at 3, 6 and 12 months. The trail making test (TMT) was used to evaluate executive function (EF), and the Hopkins verbal learning test (HVLT) was used to evaluate episodic verbal memory (EVM) at 6 and 12 months. Results: There were significant white matter volume (WMV), subcortical grey matter volume and total brain volume (TBV) reductions during the study period (p < 0.05). MHL was correlated only with WMV reduction. EF and EVM were not correlated with MHL but were, in part, correlated with WMV and TBV reductions. Conclusions: Our findings suggest that MHL may be a predictor of WMV reduction but cannot predict EF or EVM in DAI. Brain atrophy progresses over time, but patients showed better EF and EVM in some of the tests, which could be due to neuroplasticity. [ABSTRACT FROM AUTHOR]

Primary objective: To investigate differences in longitudinal trajectories of ventricle-brain ratio (VBR), a general measure of brain atrophy, between Veterans with and without history of mild traumatic brain injury (mTBI). Research design: Structural magnetic resonance imaging (MRI) was used to calculate VBR in 70 Veterans with a history of mTBI and 34 Veterans without such history at two time points approximately 3 and 8 years after a combat deployment. Main outcomes and results: Both groups demonstrated a quadratic relationship between VBR and age that is consistent with normal developmental trajectories. Veterans with history of mTBI had larger total brain volume, but no interaction between mTBI and age was observed for brain volume, ventricular volume, or VBR. Conclusions: In our longitudinal sample of deployed Veterans, mTBI was not associated with gross brain atrophy as reflected by abnormally high VBR or abnormal increases in VBR over time. [ABSTRACT FROM AUTHOR]

Background and objective: Diffuse axonal injury (DAI) induces a long-term process of brain atrophy and cognitive deficits. The goal of this study was to determine whether there are correlations between brain volume loss, microhaemorrhage load (MHL) and neuropsychological performance during the first year after DAI. Methods: Twenty-four patients with moderate or severe DAI were evaluated at 2, 6 and 12 months postinjury. MHL was evaluated at 3 months, and brain volumetry was evaluated at 3, 6 and 12 months. The trail making test (TMT) was used to evaluate executive function (EF), and the Hopkins verbal learning test (HVLT) was used to evaluate episodic verbal memory (EVM) at 6 and 12 months. Results: There were significant white matter volume (WMV), subcortical grey matter volume and total brain volume (TBV) reductions during the study period (p < 0.05). MHL was correlated only with WMV reduction. EF and EVM were not correlated with MHL but were, in part, correlated with WMV and TBV reductions. Conclusions: Our findings suggest that MHL may be a predictor of WMV reduction but cannot predict EF or EVM in DAI. Brain atrophy progresses over time, but patients showed better EF and EVM in some of the tests, which could be due to neuroplasticity. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) as a major public health problem may lead to olfactory dysfunction. However, little is known about brain responses to odors in TBI olfactory loss patients. Nineteen healthy controls and forty TBI olfactory dysfunctional patients (19 with hyposmia and 21 with anosmia) underwent a functional magnetic resonance imaging scan when two odors (peach and coffee) were presented intranasally using a computerized olfactometer. Olfactory performance was measured using the “Sniffin’ Sticks” test. TBI patients with hyposmia or anosmia showed decreased odor-induced brain activations in the primary olfactory area and insular cortex as compared to healthy controls (FWE-corrected peak p < 0.05). In addition, negative correlations were found between the time since injury (in month) and odor-induced brain responses in the right primary olfactory area for patients with hyposmia. Similar correlations were seen in the insula and orbitofrontal cortex for patients with anosmia. In conclusion, results from the current study are evidences for the impairment of central nervous processing of odor perception at all levels of the olfactory system among TBI patients with olfactory loss. In addition, the duration after the initial injury may have an impact on the severity of olfactory dysfunction. [ABSTRACT FROM AUTHOR]

Abstract: The study included 22 healthy right-handed subjects (age 25.1 ± 3.9) and 9 patients with traumatic brain injury (TBI) (age 27.9 ± 7.3) without hemiparesis and local lesions in the sensorimotor cortex. The hemodynamical brain reactions were analyzed using functional magnetic resonance imaging (fMRI) during right- and left-hand movements. It was shown that reactive changes of responses have larger interindividual variability of the main topographic activation areas during left-hand movements as compared with right-hand movements in healthy subjects. In the TBI patients, the diffuse component of reactive changes was increased and involved a larger number of brain structures, both cortex areas and subcortical formations, including areas nonspecific for the motor analyzer. These changes were most clearly expressed in the dominant hemisphere (during movement of the right hand). [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) is highly prevalent but lacks both research tools with adequate sensitivity to detect cellular alterations that accompany mild injury and pre-clinical models that are able to robustly mimic hallmark features of human TBI. To address these related challenges, high-resolution diffusion tensor MRI (DTI) analysis was performed in a model of mild TBI in the ferret – a species that, unlike rodents, share with humans a gyrencephalic cortex and high white matter (WM) volume. A set of DTI image analysis tools were optimized and implemented to explore key features of DTI alterations in ex vivo adult male ferret brains (n = 26), evaluated 1 day to 16 weeks after mild controlled cortical impact (CCI). Using template-based ROI analysis, lesion overlay mapping and DTI-driven tensor-based morphometry (D-TBM) significant differences in DTI and morphometric values were found and their dependence on time after injury evaluated. These observations were also qualitatively compared with immunohistochemistry staining of neurons, astrocytes, and microglia in the same tissue. Focal DTI abnormalities including reduced cortical diffusivity were apparent in 12/13 injured brains with greatest lesion extent found acutely following CCI by ROI overlay maps and reduced WM FA in the chronic period was observed near to the CCI site (ANOVA for FA in focal WM: time after CCI p = 0.046, brain hemisphere p = 0.0012) often in regions without other prominent MRI abnormalities. Global abnormalities were also detected, especially for WM regions, which demonstrated reduced diffusivity (ANOVA for Trace: time after CCI p = 0.007) and atrophy that appeared to become more extensive and bilateral with longer time after injury (ANOVA for D-TBM Log of the Jacobian values: time after CCI p = 0.007). The findings of this study extend earlier work in rodent models especially by evaluation of focal WM abnormalities that are not influenced by partial volume effects in the ferret. There is also substantial overlap between DTI and morphometric findings in this model and those from human studies of mTBI implying that the combination of DTI tools with a human-similar model system can provide an advantageous and informative approach for mTBI research. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a leading cause of disability and produces a wide range of cognitive, emotional, and physical consequences. The impact of TBI on cognition is among the most important questions in this field but remains incompletely understood. The immediate cognitive effects of concussion, while usually short-lived, may be profound and lasting in some individuals, and long-term sequelae of TBI may include dementia of several varieties including post-traumatic leukoencephalopathy, chronic traumatic encephalopathy, and Alzheimer's disease. Whereas the etiopathogenesis of cognitive dysfunction after TBI remains uncertain, a reasonable point to begin is a focus on the white matter of the brain, where the neuropathological lesion known as diffuse axonal injury (DAI) is routinely identified. White matter is not typically accorded the significance granted to cortical gray matter in discussions of cognitive dysfunction and dementia, but increasing evidence is accumulating to suggest that cognitive decline after TBI is a direct result of white matter injury, and that lesions in this brain component are crucial in the sequence of events leading ultimately to dementia of several types. In this review, we consider the topic of white matter and cognition in TBI, beginning with DAI and proceeding to the role of inflammation in the pathogenesis of cognitive dysfunction and dementia that can follow. A brief review of possible therapeutic options will also be offered, including the use of anti-inflammatory agents and the exploitation of white matter plasticity, to treat acute and post-acute injuries, and lower the incidence of dementia resulting from TBI. [ABSTRACT FROM AUTHOR]

Objective: To determine the prognosis of adult patients with traumatic brain injury (TBI) and diffuse axonal injury (DAI). Methods: Online search (PubMed, Embase and Ovid Science Direct) of articles providing information about outcome in (1) patients with DAI in general, (2) DAI vs. non-DAI, (3) related to magnetic resonance imaging (MRI) classification and (4) related to lesion location/load. A reference check and quality assessment were performed. Results: A total of 32 articles were included. TBI patients with DAI had a favourable outcome in 62%. The risk of unfavourable outcome in TBI with DAI was three times higher than in TBI without DAI. Odds ratio (OR) for unfavourable outcome was 2.9 per increase of DAI grade on MRI. Lesions located in the corpus callosum were associated with an unfavourable outcome. Other specific lesion locations and lesions count showed inconsistent results regarding outcome. Lesion volume was predictive for outcome only on apparent diffusion coefficient and fluid attenuation inversion recovery MRI sequences. Conclusions: Presence of DAI on MRI in patients with TBI results in a higher chance of unfavourable outcome. With MRI grading, OR for unfavourable outcome increases threefold with every grade. Lesions in the corpus callosum in particular are associated with an unfavourable outcome. [ABSTRACT FROM AUTHOR]

Traumatic brain injury leads to significant loss of brain volume, which continues into the chronic stage. This can be sensitively measured using volumetric analysis of MRI. Here we: (i) investigated longitudinal patterns of brain atrophy; (ii) tested whether atrophy is greatest in sulcal cortical regions; and (iii) showed how atrophy could be used to power intervention trials aimed at slowing neurodegeneration. In 61 patients with moderate-severe traumatic brain injury (mean age = 41.55 years ± 12.77) and 32 healthy controls (mean age = 34.22 years ± 10.29), cross-sectional and longitudinal (1-year follow-up) brain structure was assessed using voxel-based morphometry on T1-weighted scans. Longitudinal brain volume changes were characterized using a novel neuroimaging analysis pipeline that generates a Jacobian determinant metric, reflecting spatial warping between baseline and follow-up scans. Jacobian determinant values were summarized regionally and compared with clinical and neuropsychological measures. Patients with traumatic brain injury showed lower grey and white matter volume in multiple brain regions compared to controls at baseline. Atrophy over 1 year was pronounced following traumatic brain injury. Patients with traumatic brain injury lost a mean (± standard deviation) of 1.55% ± 2.19 of grey matter volume per year, 1.49% ± 2.20 of white matter volume or 1.51% ± 1.60 of whole brain volume. Healthy controls lost 0.55% ± 1.13 of grey matter volume and gained 0.26% ± 1.11 of white matter volume; equating to a 0.22% ± 0.83 reduction in whole brain volume. Atrophy was greatest in white matter, where the majority (84%) of regions were affected. This effect was independent of and substantially greater than that of ageing. Increased atrophy was also seen in cortical sulci compared to gyri. There was no relationship between atrophy and time since injury or age at baseline. Atrophy rates were related to memory performance at the end of the follow-up period, as well as to changes in memory performance, prior to multiple comparison correction. In conclusion, traumatic brain injury results in progressive loss of brain tissue volume, which continues for many years post-injury. Atrophy is most prominent in the white matter, but is also more pronounced in cortical sulci compared to gyri. These findings suggest the Jacobian determinant provides a method of quantifying brain atrophy following a traumatic brain injury and is informative in determining the long-term neurodegenerative effects after injury. Power calculations indicate that Jacobian determinant images are an efficient surrogate marker in clinical trials of neuroprotective therapeutics. [ABSTRACT FROM AUTHOR]

Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = -23.30%, 95% confidence interval -40.9 to -5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury. [ABSTRACT FROM AUTHOR]

Background: The relationship between the acute clinical presentation of patients with traumatic brain injury (TBI), long-term changes in brain structure prompted by injury and chronic functional outcome is insufficiently understood. In this preliminary study, we investigate how acute Glasgow coma score (GCS) and epileptic seizure occurrence after TBIs are statistically related to functional outcome (as quantified using the Glasgow Outcome Score) and to the extent of cortical thinning observed 6 months after the traumatic event. Methods: Using multivariate linear regression, the extent to which the acute GCS and epileptic seizure occurrence (predictor variables) correlate with structural brain changes (relative cortical atrophy) was examined in a group of 33 TBI patients. The statistical significance of the correlation between relative cortical atrophy and the Glasgow Outcome Score was also investigated. Results: A statistically significant correlative relationship between cortical thinning and the predictor variables (acute GCS and seizure occurrence) was identified in the study sample. Regions where the statistical model was found to have highest statistical reliability in predicting both gray matter atrophy and neurological outcome include the frontopolar, middle frontal, postcentral, paracentral, middle temporal, angular, and lingual gyri. In addition, relative atrophy and GOS were also found to be significantly correlated over large portions of the cortex. Conclusion: This study contributes to our understanding of the relationship between clinical descriptors of acute TBI, the extent of injury-related chronic brain changes and neurological outcome. This is partly because the brain areas where cortical thinning was found to be correlated with GCS and with seizure occurrence are implicated in executive control, sensory function, motor acuity, memory, and language, all of which may be affected by TBI. Thus, our quantification suggests the existence of a statistical relationship between acute clinical presentation, on the one hand, and structural/functional brain features which are particularly susceptible to post-injury degradation, on the other hand. [ABSTRACT FROM AUTHOR]

Objective: The primary objective of this review was to examine relevant clinical and experimental literatures for information on the long-term cognitive impact of serious traumatic brain injury (TBI) with regard to the process of cognitive aging. Method: Online journal databases were queried for studies pertaining to cognitive aging in neurologically healthy populations, as well as the late cognitive effects of serious TBI. Additional studies were identified through searching bibliographies of related publications and using Google search engine. Results and Conclusions: Problems of cognition exhibited by young adults after TBI resemble many cognitive weaknesses of attention deficit and poor working memory that are usually seen in an elderly population who have no neurological history. The current state of the literature provides support for the argument that TBI can result in diminished cognitive reserve which may accelerate the normal process of cognitive decline, leading to premature aging, potentially increasing the risk of dementia. [ABSTRACT FROM PUBLISHER]

Objective: This study compared cortical and sub-cortical volumes between patients with complicated (i.e. presence of intracranial abnormality on the day-of-injury CT) and uncomplicated (i.e. absence of intracranial abnormality) mild traumatic brain injury (MTBI) 4 weeks post-injury. The study hypothesized regionally decreased brain volumes and reduced cortical thickness in patients with complicated MTBIs compared with uncomplicated MTBI. Methods: This study was part of a larger 2 years cohort study on MTBI. Baseline clinical and magnetic resonance imaging (MRI) data were compared for those with complicated and uncomplicated MTBI. It identified 168 patients with MTBI (90 uncomplicated and 78 complicated), aged 16–65 years. 3T MRI-system (Signa HDxt, GE Medical Systems, Milwaukee, WI) and cortical reconstruction and volumetric segmentation by FreeSurfer software have been used. Results: No significant differences between uncomplicated and complicated MTBIs were found in neuroanatomic volumes and cortical thickness after controlling for age, gender and education. The complicated MTBI group showed larger ventricles compared with the uncomplicated group, but this effect diluted when adjusting for potential confounders. Conclusion: The study findings suggest that the classification of complicated and uncomplicated MTBI may be too broad to differentiate volumetric and morphometric effects of injury in the early post-injury phase. [ABSTRACT FROM PUBLISHER]

Objectives: Characterize the scale and pattern of long-term atrophy in gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) in chronic moderate-severe traumatic brain injury (TBI) and its relationship to neurocognitive outcomes. Participants: The TBI group consisted of 17 males with primary diagnosis of moderate-severe closed head injury. Participants had not received any systematic, post-acute rehabilitation and were recruited on average 8.36 years post-injury. The control group consisted of 15 males matched on age and education. Main measures: Neurocognitive battery included widely used tests of verbal memory, visual memory, executive functioning, and attention/organization. GM, WM, and CSF volumes were calculated from segmented T1-weighted anatomical MR images. Voxel-based morphometry was employed to identify brain regions with differences in GM and WM between TBI and control groups. Results: Chronic TBI results in significant neurocognitive impairments, and significant loss of GM and WM volume, and significant increase in CSF volume. Brain atrophy is not widespread, but it is rather distributed in a fronto-thalamic network. The extent of volume loss is predictive of performance on the neurocognitive tests. Conclusion: Significant brain atrophy and associated neurocognitive impairments during the chronic stages of TBI support the notion that TBI results in a chronic condition with lifelong implications. [ABSTRACT FROM AUTHOR]

A bstract We present a model hypothesis of how several types of cell therapies may target microglia as one of the principal cell types contributing to the inflammatory response after brain injury and discuss how imaging of brain inflammation could potentially be applied to develop biomarkers in patients with stroke and TBI enrolled into stem cell clinical trials. S tem C ells 2016;34:537-542 [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) has been linked to dementia and chronic neurodegeneration. Described initially in boxers and currently recognized across high contact sports, the association between repeated concussion (mild TBI) and progressive neuropsychiatric abnormalities has recently received widespread attention, and has been termed chronic traumatic encephalopathy. Less well appreciated are cognitive changes associated with neurodegeneration in the brain after isolated spinal cord injury. Also under-recognized is the role of sustained neuroinflammation after brain or spinal cord trauma, even though this relationship has been known since the 1950s and is supported by more recent preclinical and clinical studies. These pathological mechanisms, manifested by extensive microglial and astroglial activation and appropriately termed chronic traumatic brain inflammation or chronic traumatic inflammatory encephalopathy, may be among the most important causes of post-traumatic neurodegeneration in terms of prevalence. Importantly, emerging experimental work demonstrates that persistent neuroinflammation can cause progressive neurodegeneration that may be treatable even weeks after traumatic injury. [ABSTRACT FROM AUTHOR]

The human brain can adapt to overcome injury even years after an initial insult. One hypothesis states that early brain injury survivors, by taking advantage of critical periods of high plasticity during childhood, should recover more successfully than those who suffer injury later in life. This hypothesis has been challenged by recent studies showing worse cognitive outcome in individuals with early brain injury, compared with individuals with later brain injury, with working memory particularly affected. We invited individuals who suffered perinatal brain injury (PBI) for an fMRI/diffusion MRI tractography study of working memory and hypothesized that, 30 years after the initial injury, working memory deficits in the PBI group would remain, despite compensatory activation in areas outside the typical working memory network. Furthermore we hypothesized that the amount of functional reorganization would be related to the level of injury to the dorsal cingulum tract, which connects medial frontal and parietal working memory structures. We found that adults who suffered PBI did not significantly differ from controls in working memory performance. They exhibited less activation in classic fronto-parietal working memory areas and a relative overactivation of bilateral perisylvian cortex compared with controls. Structurally, the dorsal cingulum volume and hindrance-modulated orientational anisotropy was significantly reduced in the PBI group. Furthermore there was uniquely in the PBI group a significant negative correlation between the volume of this tract and activation in the bilateral perisylvian cortex and a positive correlation between this activation and task performance. This provides the first evidence of compensatory plasticity of the working memory network following PBI. [ABSTRACT FROM AUTHOR]

Purpose: Traumatic brain injury involving loss of consciousness has focal effects in the human brainstem, suggesting that it may have particular consequences for eye movement control. This hypothesis was investigated by measurements of vergence eye movement parameters. Methods: Disparity vergence eye movements were measured for a population of 123 normally sighted individuals, 26 of whom had suffered diffuse traumatic brain injury (dTBI) in the past, while the remainder served as controls. Vergence tracking responses were measured to sinusoidal disparity modulation of a random-dot field. Disparity vergence step responses were characterized in terms of their dynamic parameters separately for the convergence and divergence directions. Results: The control group showed notable differences between convergence and divergence dynamics. The dTBI group showed significantly abnormal vergence behavior on many of the dynamic parameters. Conclusion: The results support the hypothesis that occult injury to the oculomotor control system is a common residual outcome of dTBI. [ABSTRACT FROM AUTHOR]

Based on growing findings of brain volume loss and deleterious white matter alterations during the chronic stages of injury, researchers posit that moderate-severe traumatic brain injury (TBI) may act to 'age' the brain by reducing reserve capacity and inducing neurodegeneration. Evidence that these changes correlate with poorer cognitive and functional outcomes corroborates this progressive characterization of chronic TBI. Borrowing from a framework developed to explain cognitive aging (Mahncke et al., Progress in Brain Research, 157, 81-109, ; Mahncke et al., Proceedings of the National Academy of Sciences of the United States of America, 103(33), 12523-12528, ), we suggest here that environmental factors (specifically environmental impoverishment and cognitive disuse) contribute to a downward spiral of negative neuroplastic change that may modulate the brain changes described above. In this context, we review new literature supporting the original aging framework, and its extrapolation to chronic TBI. We conclude that negative neuroplasticity may be one of the mechanisms underlying cognitive and neural decline in chronic TBI, but that there are a number of points of intervention that would permit mitigation of this decline and better long-term clinical outcomes. [ABSTRACT FROM AUTHOR]

Background and purpose Visual impairments are frequent in multiple sclerosis ( MS). Optic neuritis can directly reduce retinal nerve fiber layer ( RNFL) thickness. Our objectives were to evaluate associations of the RNFL thickness ( RNFLT) of MS patients with magnetic resonance imaging ( MRI) measures of regional brain atrophy and tissue injury in the post-chiasmatic deep gray matter ( GM) section of the visual pathway. Methods Retinal nerve fiber layer thickness was measured using optical coherence tomography ( OCT) in 96 relapsing−remitting MS ( RR- MS) patients and 46 controls. MRI was obtained within ±3 months of OCT. RNFLT associations with MRI measures from diffusion tensor imaging and regional and tissue specific atrophy were assessed. Results In RR- MS, lower RNFLT was associated with lower white matter volume and lower whole brain volume. Lower RNFLT was associated with lower total deep gray matter volume and lower thalamus volume. Lower RNFLT was associated with greater mean diffusivity ( MD) in normal appearing ( NA) brain tissue and NA gray matter. Trends were found for lower RNFLT with greater MD in NA white matter and thalamus. RNFLT in controls was not associated with MD. Conclusions Lower RNFLT is associated with microscopic tissue injury in NA regions of the brain and with neurodegeneration of the deep gray matter and thalamus in RR- MS. [ABSTRACT FROM AUTHOR]

Objectives: To describe the functional level after 1 year in moderate and severe traumatic brain injury (TBI). Study design: Prospective, cross-sectional study. Setting and participants: Seventy individuals with TBI were admitted directly from acute care hospitals to a rehabilitation facility in Sawai Mansingh Medical College and Hospital, Jaipur (SMS). A follow-up of 58 patients was done up to 1 year later in the period from July 2011 to July 2012. Results: Mean change in FIM scores from admission to discharge was 51.26 and from admission to 12 months it was 85.3 in the moderate injury group. Mean change in DRS from admission to discharge was −8.19 and from admission to 12 months it was −17.76 in the moderate injury group and −8.55 and −19 in the severe injury group, respectively. The correlation coefficient ( r) between FIM and GOSE was 0.570 and between FIM and DRS was −0.8190, both of which were significant. Conclusions: All individuals improved significantly in the inpatient rehabilitation facility in the acute phase, with maximum gain in function seen from admission to discharge as assessed on FIM and DRS. The majority of the individuals continued to improve up to 6 months post-injury. [ABSTRACT FROM AUTHOR]

Recent research on traumatic brain injury (TBI) has shown that impairments in cognitive and executive control functions are accompanied by a disrupted neural connectivity characterized by white matter damage. We constructed binary and weighted brain structural networks in 21 patients with chronic TBI and 17 healthy young adults utilizing diffusion tensor tractography and calculated topological properties of the networks using a graph theoretical method. Executive function was assessed with the local global task and the trail making task, requiring inhibition, updating, and switching. The results revealed that TBI patients were less successful than controls on the executive tasks, as shown by the higher reaction times, higher switch costs, and lower accuracy rates. Moreover, both TBI patients and controls exhibited a small world topology in their white matter networks. More importantly, the TBI patients demonstrated increased shortest path length and decreased global efficiency of the structural network. These findings suggest that TBI patients have a weaker globally integrated structural brain network, resulting in a limited capacity to integrate information across brain regions. Furthermore, we showed that the white matter networks of both groups contained highly connected hub regions that were predominately located in the parietal cortex, frontal cortex, and basal ganglia. Finally, we showed significant correlations between switching performance and network property metrics within the TBI group. Specifically, lower scores on the switching tasks corresponded to a lower global efficiency. We conclude that analyzing the structural brain network connectivity provides new insights into understanding cognitive control changes following brain injury. [ABSTRACT FROM AUTHOR]

This study investigated whether deferoxamine (DFO), an iron chelator attenuates iron-induced toxicity in rats with traumatic brain injury. In this study, three groups of Sprague-Dawley rats (sham, injury and DFO groups) were examined. Rats were killed on day 28 after Morris water maze testing and brains perfused for either non-heme brain binding or hemosiderin staining. Western blotting was used to measure protein levels of ferritin, transferrin and transient receptor potential canonical channel 6 (TRPC6). In TBI rats, there was a significant increase in brain iron on day 28, ferritin L, ferritin H, transferrin and TRPC6 levels were all significantly elevated post-TB1. There were also deficits in spatial learning and memory; however, DFO administration attenuated these effects in TBI rats supporting the notion that DFO may reduce brain injury accentuated by iron overload. [ABSTRACT FROM AUTHOR]

After traumatic injury, the brain undergoes a prolonged period of degenerative change that is paradoxically accompanied by cognitive recovery. The spatiotemporal pattern of atrophy and the specific relationships of atrophy to cognitive changes are ill understood. The present study used tensor-based morphometry and neuropsychological testing to examine brain volume loss in 17 traumatic brain injury (TBI) patients and 13 controls over a 4-year period. Patients were scanned at 2 months, 1 year, and 4 years post-injury. High-dimensional warping procedures were used to create change maps of each subject's brain for each of the two intervals. TBI patients experienced volume loss in both cortical areas and white matter regions during the first interval. We also observed continuing volume loss in extensive regions of white matter during the second interval. Neuropsychological correlations indicated that cognitive tasks were associated with subsequent volume loss in task-relevant regions. The extensive volume loss in brain white matter observed well beyond the first year post-injury suggests that the injured brain remains malleable for an extended period, and the neuropsychological relationships suggest that this volume loss may be associated with subtle cognitive improvements. [ABSTRACT FROM AUTHOR]

Comprehensive clinical ( MMSE, FIM and MPAI-3 and Berg scales) and stabilographic evaluation was carried out in 14 patients (with a mean age of 25.7 ± 4.7 years) with consequences of traumatic brain injury (TBI) in comparison with the data on 40 healthy subjects (with a mean age of 29.8 ± 2.5 years) performing separate and dual tasks, including voluntary postural control and calculation. According to the clinical evaluation, all the patients were divided into two groups: group 1 with a moderate deficit (eight patients) and group 2 with a marked functional deficit (six patents). The parameters of the quality of motor and, especially, cognitive subtask performance in both separate and dual tasks were lower than the normative values in all the patients, especially in group 2 patients. Types of dual tasks where the quality of the motor subtask performance was higher than in separate tasks were revealed in healthy subjects and some group 1 patients. The stabilographic parameters characterizing the quality of subtask performance by TBI patients were revealed. Dual tasks could be used for diagnostic purposes such as an additional method for evaluating the adaptive capacity of TBI patients, and certain types of dual tasks could become a promising approach for the recovery of TBI patients at the late stages of rehabilitation. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) often involves focal cortical injury and white matter (WM) damage that can be measured shortly after injury. Additionally, slowly evolving WM change can be observed but there is a paucity of research on the duration and spatial pattern of long-term changes several years post-injury. The current study utilized diffusion tensor imaging to identify regional WM changes in 12 TBI patients and nine healthy controls at three time points over a four year period. Neuropsychological testing was also administered to each participant at each time point. Results indicate that TBI patients exhibit longitudinal changes to WM indexed by reductions in fractional anisotropy (FA) in the corpus callosum, as well as FA increases in bilateral regions of the superior longitudinal fasciculus (SLF) and portions of the optic radiation (OR). FA changes appear to be driven by changes in radial (not axial) diffusivity, suggesting that observed longitudinal FA changes may be related to changes in myelin rather than to axons. Neuropsychological correlations indicate that regional FA values in the corpus callosum and sagittal stratum (SS) correlate with performance on finger tapping and visuomotor speed tasks (respectively) in TBI patients, and that longitudinal increases in FA in the SS, SLF, and OR correlate with improved performance on the visuomotor speed (SS) task as well as a derived measure of cognitive control (SLF, OR). The results of this study showing progressive WM deterioration for several years post-injury contribute to a growing literature supporting the hypothesis that TBI should be viewed not as an isolated incident but as a prolonged disease state. The observations of long-term neurological and functional improvement provide evidence that some ameliorative change may be occurring concurrently with progressive degeneration. [ABSTRACT FROM AUTHOR]

It is important for clinicians to recognize major depression following traumatic brain injury (TBI) because of its association with poor global and psychosocial outcome, posteoncussive symptoms and cognitive deficits. The purpose cf this review is to provide an up-to-date selective review of the current understanding of epidemiology, risk factors and management of major deçression following TBI. Many studies of prevalence of depression following TB! have not used accepted structured criteria for the diagnoses, but those that did found wide ranges of rates, from 17% to 61%. The risk factors for development of depression following TBI are poorly understood, but past psychiatric history, frontal lesions and atrophy, and family dys- function have been shown in more than one study to play important roles. There are few controlled trials of the treatment of major depression in patients with TBI using accepted diagnostic criteria for major depression, as well as defined criteria for response and remission. As such, it is important for clinicians 10 use best practice guidelines for the treatment of major depression in the absence of TBI. [ABSTRACT FROM AUTHOR]

The article presents information on a study conducted to examine whether metabotropic glutamate receptor 5 (mGluR5) activation by (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) reduces chronic neuroinflammation and neurodegeneration after traumatic brain injury in mice. The study found that delayed CHPG treatment reduced expression of reactive microglia expressing NADPH oxidase subunits; decreased hippocampal neuronal loss; and limited lesion progression.