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Abstract This study compared findings from whole-brain diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) among 90 Active Duty Service Members with chronic mild traumatic brain injury (TBI; n  = 52), chronic moderate-to-severe TBI ( n  = 17), and TBI-negative controls ( n  = 21). Data were collected on a Philips Ingenia 3T MRI with DTI in 32 directions. Results demonstrated that history of TBI was associated with differences in white matter microstructure, white matter volume, and cortical thickness in both mild TBI and moderate-to-severe TBI groups relative to controls. However, the presence, pattern, and distribution of these findings varied substantially depending on the injury severity. Spatially-defined forms of DTI fractional anisotropy (FA) analyses identified altered white matter organization within the chronic moderate-to-severe TBI group, but they did not provide clear evidence of abnormalities within the chronic mild TBI group. In contrast, DTI FA "pothole" analyses identified widely distributed areas of decreased FA throughout the white matter in both the chronic mild TBI and chronic moderate-to-severe TBI groups. Additionally, decreased white matter volume was found in several brain regions for the chronic moderate-to-severe TBI group compared with the other groups. Greater number of DTI FA potholes and reduced cortical thickness were also related to greater severity of self-reported symptoms. In sum, this study expands upon a growing body of literature using advanced imaging techniques to identify potential effects of brain injury in military Service Members. These findings may differ from work in other TBI populations due to varying mechanisms and frequency of injury, as well as a potentially higher level of functioning in the current sample related to the ability to maintain continued Active Duty status after injury. In conclusion, this study provides DTI and volumetric MRI findings across the spectrum of TBI severity. These results provide support for the use of DTI and volumetric MRI to identify differences in white matter microstructure and volume related to TBI. In particular, DTI FA pothole analysis may provide greater sensitivity for detecting subtle forms of white matter injury than conventional DTI FA analyses.

Numerous studies have evaluated the efficacy of interventions to improve locomotion after acute-onset brain injury, although most focus on patients with stroke, with less attention toward traumatic brain injury (TBI). For example, a number of studies in patients post-stroke have evaluated the effects of high-intensity training (HIT) attempting to maximize stepping practice, while no studies have attempted this intervention in patients with TBI. The purpose of this blinded-assessor randomized trial was to evaluate the effects of HIT focused on stepping practice versus conventional training on walking and secondary outcomes in individuals with TBI. Using a crossover design, ambulatory participants with TBI >6-months duration performed HIT focused on stepping in variable contexts (overground, treadmill, stairs) or conventional training for up to 15 sessions over five weeks, with interventions alternated >4 weeks later. HIT focused on maximizing stepping practice while trying to achieve higher cardiovascular intensities (>70% heart rate reserve), while conventional training focused on impairment-based and functional exercises with no restrictions on intensities achieved. Greater increases in 6-min walk test and peak treadmill speed during graded exercise testing were observed after HIT versus conventional training, with moderate associations between differences in stepping practice and outcomes. Greater gains were also observed in estimates of aerobic capacity and efficiency after HIT, with additional improvements in selected cognitive assessments. The present study suggests that the amount and intensity of stepping practice may be important determinants of improved locomotor outcomes in patients with chronic TBI, with possible secondary benefits on aerobic capacity/efficiency and cognition. Clinical Trial Registration-URL : https://clinicaltrials.gov/; Unique Identifier: NCT04503473.

Objective: Memory problems are among the most frequently reported cognitive complaints by individuals with an acquired brain injury (ABI). Processing speed and working memory deficits are often the result of ABI. These cognitive deficits significantly impact the acquisition and retention of information necessary for memory formation. This study investigated the influence of processing speed and working memory on immediate and delayed recall for verbal and visual memory, as well as overall memory recall in adults living with a chronic ABI., Methods: Sixty-three participants living with a chronic ABI, who were at least one-year post-injury, were cognitively assessed with the CNS-Vital Signs (CNS-VS) computerized cognitive battery and Wechsler Test of Adult Reading., Results: The CNS-VS Processing Speed significantly predicted delayed recall for verbal memory and overall memory performance. The CNS-VS Working Memory was not a significant predictor of memory recall., Conclusions: Processing speed deficits negatively impact memory in individuals with a chronic ABI. These findings suggest the memory recall of adults with a chronic ABI is associated with poor processing speed and poor acquisition of information. Therefore, cognitive rehabilitation that improves processing speed should be the focus for individuals with ABI to improve memory performance as well as impaired processing speed.

Imaging of mild traumatic brain injury (TBI) using conventional techniques such as CT or MRI often results in no specific imaging correlation that would explain cognitive and clinical symptoms. Molecular imaging of mild TBI suggests that secondary events after injury can be detected using PET. However, no single specific pattern emerges that can aid in diagnosing the injury or determining the prognosis of the long-term behavioral profiles, indicating the heterogeneous and diffuse nature of TBI. Chronic traumatic encephalopathy, a primary tauopathy, has been shown to be strongly associated with repetitive TBI. In vivo data on the available tau PET tracers, however, have produced mixed results and overall low retention profiles in athletes with a history of repetitive mild TBI. Here, we emphasize that the lack of a mechanistic understanding of chronic TBI has posed a challenge when interpreting the results of molecular imaging biomarkers. We advocate for better target identification, improved analysis techniques such as machine learning or artificial intelligence, and novel tracer development., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Objective: Decreased carotid arterial compliance (CAC) is associated with cerebral microvascular damage, cerebral blood flow (CBF) dysregulation, and increased risk for stroke and dementia, which are reported to be prevalent after traumatic brain injury (TBI). However, the effect of TBI on CAC has not been reported. The purposes of this pilot study were to (1) compare CAC between participants with chronic traumatic brain injury (cTBI) and age-matched healthy control (HC) subjects and (2) to examine whether CAC changed after 3 months of exercise training in those with cTBI., Setting: Community based., Participants: Nineteen participants with cTBI (6-72 months postinjury) and 19 HC matched for age and sex were tested at baseline. The same cTBI cohort was enrolled in a proof-of-concept randomized controlled exercise training program to investigate the effects of 3 months of aerobic exercise training (AET) or nonaerobic stretching and toning (SAT) on cerebrovascular parameters., Design: Cross-sectional study and randomized controlled trial., Main Measures: CAC was measured by tonometry and ultrasonography at the common carotid artery; CBF was measured by ultrasonography at the bilateral internal carotid and vertebral arteries, and pulsatile CBF was measured by transcranial Doppler ultrasonography at the middle cerebral arteries. Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by total CBF., Results: Relative to HC, the participants with cTBI had lower CAC (0.10 ± 0.03 vs 0.12 ± 0.03 mm 2 /mm Hg, P = .046) and higher CVR (0.17 ± 0.03 vs 0.15 ± 0.03 mm Hg/mL/min, P = .028). CAC tended to increase after AET compared with SAT ( P = .080). Increases in CAC were associated with decreased pulsatile CBF ( r = -0.689, P = .003)., Conclusion: These findings suggest that the individuals with cTBI have decreased CAC, which may potentially be improved by AET., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Acquired focal visuoperceptual deficits are rarely reported, and rehabilitation strategies are not well established. This is a report on visuoperceptual deficit after traumatic brain injury that initially went unnoticed. Missing visual agnosia is not unusual especially when perceptual deficits present with visual field defects, impaired insight, and inattention. This case is made more interesting because of the rarity of visual agnosia with predominant ventral pathway involvement, affecting object and face recognition. This report provides a brief discussion on visual agnosia spectrum deficits and rehabilitation measures., Competing Interests: Financial disclosure statements have been obtained, and no conflicts of interest have been reported by the authors or by any individuals in control of the content of this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Lower limb rehabilitation exoskeleton robots connect with the human body in a wearable way and control the movement of joints in the gait rehabilitation process. Among treadmill-based lower limb rehabilitation exoskeleton robots, Lokomat (Hocoma AG, Volketswil, Switzerland) has 4 actuated joints for bilateral hips and knees whereas Walkbot (P&S Mechanics, Seoul, Korea) has 6 bilateral actuated joints for bilateral hips, knees, and ankles. Lokomat and Walkbot robotic gait training systems have not been directly compared previously. The present study aimed to directly compare Lokomat and Walkbot robots in non-ambulatory chronic patients with acquired brain injury (ABI).The authors conducted a single-center, retrospective, cross-sectional study of 62 subjects with ABI who were admitted to the rehabilitation hospital. Patients were divided into 2 groups: Lokomat (n = 28) and Walkbot (n = 34). Patients were subjected to robot-assisted gait training (RAGT) combined with conventional physical therapy for a total of 14 (8-36) median (interquartile range) sessions. Baseline characteristics, including age, sex, lag time post-injury, ABI type, paralysis type, intervention sessions, lower extremity strength, spasticity, and cognitive function were assessed. Functional ambulation category (FAC) and Berg balance scale (BBS) were used for outcome measures.There were no significant differences in baseline characteristics between the groups. Baseline FAC score was 1 (0-2) in Lokomat and 1 (0-1) in Walkbot group. After the intervention, FAC scores improved significantly to 2 (1-3) in both groups (P < .05). Lokomat and Walkbot groups showed significantly enhanced BBS from 5 (2.75-24.25) and 15 (4-26.5) to 15 (4-26.5) and 22 (12-40), respectively (P < .05). Degree of improvements in both group were not significantly different with regard to balance (P = .56) and ambulatory ability (P = .74).This study indicates that both Locomat and Walkbot robotic gait training combined with conventional gait-oriented physiotherapy are promising intervention for gait rehabilitation in patients with chronic stage of ABI who are not able to walk independently., Competing Interests: HYL, JHP, and TWK declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Traumatic brain injury (TBI) is a leading cause of morbidity worldwide, for which biomarkers are needed to better understand the underlying pathophysiology. Microvascular injury represents a subset of pathological mechanisms contributing to cognitive dysfunction after TBI, which may also impair subsequent neural repair thereby inhibiting cognitive recovery. Magnetic resonance imaging (MRI)-based measurement of cerebral blood flow (CBF) by arterial spin labeling (ASL) provides an appealing means of assessing microvascular disruption in TBI; however, the relationship between CBF alterations in the early chronic post-TBI setting and cognitive dysfunction as well as subsequent cognitive recovery remain poorly understood. Structural MRI and ASL were performed in 42 TBI subjects 3 months post-injury and 35 matched healthy controls. Neuropsychological testing was performed in each subject, as well as in a subset of TBI patients ( n  = 33) at 6 and/or 12 months post-injury. TBI and control subject CBF data were compared between groups in a voxel-wise fashion while controlling for the effects of structural atrophy. A region-of-interest approach was then used to compare CBF to clinical and neuropsychological measures within the TBI group in a cross-sectional fashion, as well as to the degree of subsequent cognitive recovery among subjects with follow-up testing. At 3 months post-injury, the TBI group demonstrated lower performance in each cognitive domain ( p  < 0.05), as well as widespread reductions in gray matter CBF independent of structural atrophy ( p  < 0.05). Within the TBI group, CBF was moderately correlated with injury severity ( r  = -0.43; p  = 0.009) and executive function ( r  = 0.43; p  = 0.01). In the longitudinal analysis, there was a positive correlation between initial CBF and processing speed recovery ( r  = 0.43; p  = 0.015) independent of age, education level, and initial test score. Early chronic TBI is associated with widespread gray matter CBF deficits, which are correlated with injury severity and cognitive dysfunction. CBF may predict subsequent recovery in some cognitive domains.

Baroreflex sensitivity (BRS) and cerebral autoregulation (CA) play an important role in maintaining constant cerebral blood flow (CBF) during systemic changes in blood pressure (BP). Impaired BRS and CA have been reported in acute traumatic brain injury (TBI) which may also contribute to secondary injury and poorer recovery after acute TBI; however, their status during chronic stages remains elusive. Thus, the goal of this study is to determine whether cardiac BRS and dynamic CA (dCA) were impaired during the chronic stage in patients with single TBI and persistent neurological symptoms. Twenty-two subjects with blunt head TBI ≥ 6 months prior to the study (13 mild and 9 moderate to severe TBI) and persistent symptoms on Rivermead Post-Concussion Symptoms Questionnaire at enrollment were compared to 22 age/sex/fitness level-matched healthy control subjects. Beat-to-beat changes in heart rate, BP, and CBF velocity were measured at rest and during a repeated sit-stand maneuver. Hemodynamic variability, dCA, and cardiac BRS were calculated using spectral and transfer function analyses. We found dCA phase in low frequency (LF) range of 0.07-0.20 Hz was lower in subjects with TBI than in control subjects (0.51 ± 0.19 vs. 0.63 ± 0.26, p = 0.043) during the resting condition. Among subjects with TBI, the lower dCA phase in LF was correlated with poorer performance on measures of cognitive function (all p < 0.05). These findings suggested that subjects with chronic TBI showed impaired dCA which may contribute to persistent cognitive impairment. Cerebrovascular measures may provide a physiological measure to evaluate interventions for chronic TBI and accompanying functional deficits., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Chronic verbal retrieval deficits have been noted in traumatic brain injury (TBI), but no U.S. Food and Drug Administration-approved interventions are available. The present study investigated whether 10 sessions of 20 min of 1 mA anodal high-definition transcranial direct current stimulation (HD-tDCS) targeting pre-supplementary motor area/dorsal anterior cingulate cortex (preSMA/dACC) compared with sham HD-tDCS would improve verbal retrieval deficits in TBI patients. Improvements in verbal retrieval processes were observed up to 8 weeks post-treatment. Thus, potential dysfunction to verbal retrieval circuitry in TBI appears amenable to remediation through electromodulation with HD tDCS to the preSMA/dACC. Although further studies clarifying mechanisms by which tDCS brought about these improvements will likely inform refinements in the application of this therapeutic technique, the findings suggest the efficacy of using HD-tDCS to target other systems vulnerable to TBI to improve functioning.

Traumatic brain injury (TBI) is a major cause of acquired disability globally, and effective treatment methods are scarce. Lately, there has been increasing recognition of the devastating impact of TBI resulting from sports and other recreational activities, ranging from primarily sport-related concussions (SRC) but also more severe brain injuries requiring hospitalization. There are currently no established treatments for the underlying pathophysiology in TBI and while neuro-rehabilitation efforts are promising, there are currently is a lack of consensus regarding rehabilitation following TBI of any severity. In this narrative review, we highlight short- and long-term consequences of SRCs, and how the sideline management of these patients should be performed. We also cover the basic concepts of neuro-critical care management for more severely brain-injured patients with a focus on brain oedema and the necessity of improving intracranial conditions in terms of substrate delivery in order to facilitate recovery and improve outcome. Further, following the acute phase, promising new approaches to rehabilitation are covered for both patients with severe TBI and athletes suffering from SRC. These highlight the need for co-ordinated interdisciplinary rehabilitation, with a special focus on cognition, in order to promote recovery after TBI., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

A chronic and gradual increase in pulse pressure (PP) is associated with cognitive decline and dementia in older individuals, but the mechanisms remain ill-defined. We hypothesized that a chronic elevation of PP would cause brain microvascular endothelial mechanical stress, damage the neurovascular unit, and ultimately induce cognitive impairment in mice, potentially contributing to the progression of vascular dementia and Alzheimer disease. To test our hypothesis, male control wild-type mice and Alzheimer disease model APP/PS1 (amyloid precursor protein/presenilin 1) mice were exposed to a transverse aortic constriction for 6 weeks, creating a PP overload in the right carotid (ipsilateral). We show that the transverse aortic constriction procedure associated with high PP induces a cascade of vascular damages in the ipsilateral parenchymal microcirculation: in wild-type mice, it impairs endothelial dilatory and blood brain barrier functions and causes microbleeds, a reduction in microvascular density, microvascular cell death by apoptosis, leading to severe hypoperfusion and parenchymal cell senescence. These damages were associated with brain inflammation and a significant reduction in learning and spatial memories. In APP/PS1 mice, that endogenously display severe cerebral vascular dysfunctions, microbleeds, parenchymal inflammation and cognitive dysfunction, transverse aortic constriction-induced high PP further aggravates cerebrovascular damage, Aβ (beta-amyloid) accumulation, and prevents learning. Our study, therefore, demonstrates that brain microvessels are vulnerable to a high PP and mechanical stress associated with transverse aortic constriction, promoting severe vascular dysfunction, disruption of the neurovascular unit, and cognitive decline. Hence, chronic elevated amplitude of the PP could contribute to the development and progression of vascular dementia including Alzheimer disease.

Objective: Primarily, to investigate the association between informant report and objective performance on specific financial capacity (FC) tasks by adults with chronic, moderate to severe acquired brain injury, and to examine the nature of misestimates by the informants., Design: Cross-sectional design., Setting: A postacute, community-based rehabilitation center., Participants: Data were obtained from 22 chronic acquired brain injury (CABI) adults, mean age of 46.6 years (SD = 8.67), mean years of education of 13.45 years (SD = 2.15), with moderate to severe acquired brain injury (86% had traumatic brain injury), with a mean postinjury period of 17.14 years (SD = 9.5). Whereas the CABI adults completed the Financial Competence Assessment Inventory interview-a combination of self-report and performance-based assessment, 22 informants completed a specifically designed parallel version of the interview., Results: Pearson correlations and 1-sample t tests based on the discrepancy scores between informant report and CABI group's performance were used. The CABI group's performance was not associated with its informant's perceptions. One-sample t tests revealed that informants both underestimated and overestimated CABI group's performance., Conclusions: Results indicate lack of correspondence between self- and informant ratings. Further investigation revealed that misestimations by informants occurred in contrary directions with CABI adults' performance being inaccurately rated. These findings raise critical issues related to assuming that the informant report can be used as a "gold standard" for collecting functional data related to financial management, and the idea that obtaining objective data on financial tasks may represent a more valid method of assessing financial competency in adults with brain injury.

Turning is common in daily activity and requires rapid, coordinated reorientation of the head, trunk, and pelvis toward the new direction of travel. Yet, turning gait has not been well explored in populations with mild traumatic brain injury (mTBI) who may alter their turning behavior according to self-perceived symptoms or motor dysfunction. The purpose of this study was to examine turning velocities and coordination in adults with chronic mTBI (>3 months post-injury and still reporting balance complaints) during a task simulating everyday ambulation. We hypothesized that individuals with chronic mTBI would reduce their angular velocity when turning and increase the variability of head-pelvis coordination compared with controls, and that the reduction in velocity and increased variability would be associated with their self-reported symptom score. Forty-two adults (14 chronic mTBI, 28 controls) completed the Neurobehavioral Symptom Inventory before walking 12 laps around a marked course containing two 45-degree turns, four 90-degree turns, and two 135-degree turns. Inertial sensors collected angular velocities of the head and pelvis. After adjusting for covariates, participants with chronic mTBI had significantly slower lap times and peak angular velocities of the pelvis (p < 0.01) compared with the control group. The peak velocity timing (PVT) between peak velocities of the head and pelvis, and the variability of that timing was significantly greater in participants with chronic mTBI (p < 0.01). Within the chronic mTBI group, somatosensory symptoms were associated with slower angular velocities of the head and pelvis (p = 0.03) and increased PVT variability (p < 0.01). The results suggest individuals with chronic mTBI with worse somatic symptoms have impaired head stabilization during turning in situations similar to everyday life. These results encourage future research on turning gait to examine the causal relationship between symptoms and daily locomotor function in adults with chronic mTBI.

Aims and Objectives: As a first step in developing traumatic brain injury-specific nursing education, the purpose of this study was to investigate nurses' concerns about caring for patients with moderate-to-severe traumatic brain injury., Background: Patients with moderate-to-severe traumatic brain injury typically have significant immediate and chronic cognitive impairments. These cognitive impairments can negatively affect their inpatient stay after an acute traumatic brain injury and affect their health care later in life when seeking care for other acute health conditions during the chronic phase of traumatic brain injury. Nurses must be knowledgeable about modifying care to accommodate the cognitive impairments of these patients throughout the continuum of care. Yet, current guidelines focus exclusively on acute care and do not address nurses' central role in dealing with residual cognitive impairments of these patients. Thus, educational and training interventions are needed to ensure nurses have adequate knowledge to care for these patients., Design: We conducted a cross-sectional, exploratory survey of 692 nurses across hospital departments at three hospitals between October 2014-August 2015. Nurses answered the following qualitative open-ended question: "What are your primary concerns about providing care to patients with moderate-to-severe traumatic brain injury?", Methods: Conventional qualitative content analysis was used to analyse nurses' responses., Results: Findings showed nurses reported multiple concerns about caring for patients in the acute phase after traumatic brain injury, but few concerns about caring for patients in the chronic phase. Some of the concerns nurses reported included: (i) preventing physical injury; (ii) missing changes in condition; (iii) providing adequate education; (iv) providing support; and (v) promoting recovery. Barriers to providing adequate care were as follows: (i) lack of knowledge; (ii) limited staffing; and (iii) inadequate resources., Conclusions: Findings have implications for education of nurses and development of nursing guidelines for management of patients with traumatic brain injury, including providing direction for nurses on development of care plans for patients in the chronic phase after a moderate-to-severe traumatic brain injury., (© 2018 John Wiley & Sons Ltd.)

Objective: The objective of the study is to measure plasma and exosomal levels of tau, phosphorylated tau (p-tau), and amyloid beta (Aβ) in Veterans with historical mild traumatic brain injury (mTBI) and chronic neuropsychological symptoms., Methods: Tau, p-tau, Aβ40, and Aβ42 were measured by ultrasensitive immunoassay in plasma and exosomes from 195 Veterans enrolled in the Chronic Effects of Neurotrauma Consortium Multicenter Observational Study. Protein biomarkers were compared among groups with and without mTBI with loss of consciousness (LOC) or post-traumatic amnesia (PTA), and also in those with and without repetitive (≥3) mTBI (rTBI) compared to those with 0 (TBI-neg) and 1-2 mTBI., Results: There were no differences in measures of plasma and exosomal protein levels among mTBI with LOC or PTA, mTBI with alteration of consciousness only or TBI-neg. Exosomal tau and exosomal p-tau were elevated in rTBI compared to those with 2 or fewer mTBIs and TBI-neg (p < 0.05). Elevations of exosomal tau and p-tau significantly correlated with post-traumatic and post-concussive symptoms, with exosomal tau also relating specifically to cognitive, affective, and somatic post-concussive symptoms (p < 0.05)., Conclusion: rTBI is associated with elevations of exosomal p-tau and exosomal tau, suggesting that blood-based exosomes may provide a peripheral source of informative, centrally derived biomarkers in remote mTBI and that rTBI may contribute to chronic neuropsychological symptoms.

Primary Objectives: To describe the association between mild traumatic brain injury (mTBI) and pain intensity and pain interference outcomes while accounting for potential confounders and mediators including environmental factors and comorbidities in a cohort of US Veterans of the Iraq and Afghanistan wars., Research Design: Cross-sectional snapshot of baseline data from a prospective, longitudinal study., Methods: Effects of mTBI on pain intensity and pain interference were compared between participants with or without mTBI exposure. Data were analysed using covariate-adjusted regression analyses as well as structural equation modelling (SEM) methods to assess the robustness of findings across different modelling assumptions. As results of the two approaches were consistent with respect to the overall association between mTBI exposure and pain, the results focus primarily on the SEM findings., Results: The mTBI exposed group reported significantly greater indices of post-traumatic stress disorder (PTSD), depression, anxiety and sleep disturbance. After accounting for other factors, mTBI exposure was significantly, but indirectly associated with the pain interference and pain intensity outcomes., Conclusions: mTBI is strongly associated with pain intensity and pain interference in this sample. However, the effect appears to be mediated by other common mTBI comorbidities: PTSD, depression, anxiety and sleep disturbance.

Background and Purpose: This case study describes a task-specific training program for gait walking and functional recovery in a young man with severe chronic traumatic brain injury., Case Description: The individual was a 26-year-old man 4 years post-traumatic brain injury with severe motor impairments who had not walked outside of therapy since his injury. He had received extensive gait training prior to initiation of services. His goal was to recover the ability to walk., Intervention: The primary focus of the interventions was the restoration of walking. A variety of interventions were used, including locomotor treadmill training, electrical stimulation, orthoses, and specialized assistive devices. A total of 79 treatments were delivered over a period of 62 weeks., Outcomes: At the conclusion of therapy, the client was able to walk independently with a gait trainer for approximately 1km (over 3000 ft) and walked in the community with the assistance of his mother using a rocker bottom crutch for distances of 100m (330 ft)., Discussion: Specific interventions were intentionally selected in the development of the treatment plan. The program emphasized structured practice of the salient task, that is, walking, with adequate intensity and frequency. Given the chronicity of this individual's injury, the magnitude of his functional improvements was unexpected.Video Abstract available for additional insights from the Authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A175).

Background: Dysarthria is an acquired speech disorder following neurological injury that reduces intelligibility of speech due to weak, imprecise, slow and/or unco-ordinated muscle control. The impact of dysarthria goes beyond communication and affects psychosocial functioning. This is an update of a review previously published in 2005. The scope has been broadened to include additional interventions, and the title amended accordingly., Objectives: To assess the effects of interventions to improve dysarthric speech following stroke and other non-progressive adult-acquired brain injury such as trauma, infection, tumour and surgery., Search Methods: We searched the Cochrane Stroke Group Trials Register (May 2016), CENTRAL (Cochrane Library 2016, Issue 4), MEDLINE, Embase, and CINAHL on 6 May 2016. We also searched Linguistics and Language Behavioral Abstracts (LLBA) (1976 to November 2016) and PsycINFO (1800 to September 2016). To identify further published, unpublished and ongoing trials, we searched major trials registers: WHO ICTRP, the ISRCTN registry, and ClinicalTrials.gov. We also handsearched the reference lists of relevant articles and contacted academic institutions and other researchers regarding other published, unpublished or ongoing trials. We did not impose any language restrictions., Selection Criteria: We selected randomised controlled trials (RCTs) comparing dysarthria interventions with 1) no intervention, 2) another intervention for dysarthria (this intervention may differ in methodology, timing of delivery, duration, frequency or theory), or 3) an attention control., Data Collection and Analysis: Three review authors selected trials for inclusion, extracted data, and assessed risk of bias. We attempted to contact study authors for clarification and missing data as required. We calculated standardised mean difference (SMD) and 95% confidence interval (CI), using a random-effects model, and performed sensitivity analyses to assess the influence of methodological quality. We planned to conduct subgroup analyses for underlying clinical conditions., Main Results: We included five small trials that randomised a total of 234 participants. Two studies were assessed as low risk of bias; none of the included studies were adequately powered. Two studies used an attention control and three studies compared to an alternative intervention, which in all cases was one intervention versus usual care intervention. The searches we carried out did not find any trials comparing an intervention with no intervention. The searches did not find any trials of an intervention that compared variations in timing, dose, or intensity of treatment using the same intervention. Four studies included only people with stroke; one included mostly people with stroke, but also those with brain injury. Three studies delivered interventions in the first few months after stroke; two recruited people with chronic dysarthria. Three studies evaluated behavioural interventions, one investigated acupuncture and another transcranial magnetic stimulation. One study included people with dysarthria within a broader trial of people with impaired communication.Our primary analysis of a persisting (three to nine months post-intervention) effect at the activity level of measurement found no evidence in favour of dysarthria intervention compared with any control (SMD 0.18, 95% CI -0.18 to 0.55; 3 trials, 116 participants, GRADE: low quality, I² = 0%). Findings from sensitivity analysis of studies at low risk of bias were similar, with a slightly wider confidence interval and low heterogeneity (SMD 0.21, 95% CI -0.30 to 0.73, I² = 32%; 2 trials, 92 participants, GRADE: low quality). Subgroup analysis results for stroke were similar to the primary analysis because few non-stroke participants had been recruited to trials (SMD 0.16, 95% CI -0.23 to 0.54, I² = 0%; 3 trials, 106 participants, GRADE: low quality).Similar results emerged from most of the secondary analyses. There was no evidence of a persisting effect at the impairment (SMD 0.07, 95% CI -0.91 to 1.06, I² = 70%; 2 trials, 56 participants, GRADE: very low quality) or participation level (SMD -0.11, 95% CI -0.56 to 0.33, I² = 0%; 2 trials, 79 participants, GRADE: low quality) but substantial heterogeneity on the former. Analyses of immediate post-intervention outcomes provided no evidence of any short-term benefit on activity (SMD 0.29, 95% CI -0.07 to 0.66, I² = 0%; 3 trials, 117 participants, GRADE: very low quality); or participation (SMD -0.24, 95% CI -0.94 to 0.45; 1 study, 32 participants) levels of measurement.There was a statistically significant effect favouring intervention at the immediate, impairment level of measurement (SMD 0.47, 95% CI 0.02 to 0.92, P = 0.04, I² = 0%; 4 trials, 99 participants, GRADE: very low quality) but only one of these four trials had a low risk of bias., Authors' Conclusions: We found no definitive, adequately powered RCTs of interventions for people with dysarthria. We found limited evidence to suggest there may be an immediate beneficial effect on impairment level measures; more, higher quality research is needed to confirm this finding.Although we evaluated five studies, the benefits and risks of interventions remain unknown and the emerging evidence justifies the need for adequately powered clinical trials into this condition.People with dysarthria after stroke or brain injury should continue to receive rehabilitation according to clinical guidelines.

A vast body of literature exists showing functional and structural dysfunction within the brains of patients with disorders of consciousness. However, the function (fluorodeoxyglucose FDG-PET metabolism)-structure (MRI-diffusion-weighted images; DWI) relationship and how it is affected in severely brain injured patients remains ill-defined. FDG-PET and MRI-DWI in 25 severely brain injured patients (19 Disorders of Consciousness of which 7 unresponsive wakefulness syndrome, 12 minimally conscious; 6 emergence from minimally conscious state) and 25 healthy control subjects were acquired here. Default mode network (DMN) function-structure connectivity was assessed by fractional anisotropy (FA) and metabolic standardized uptake value (SUV). As expected, a profound decline in regional metabolism and white matter integrity was found in patients as compared with healthy subjects. Furthermore, a function-structure relationship was present in brain-damaged patients between functional metabolism of inferior-parietal, precuneus, and frontal regions and structural integrity of the frontal-inferiorparietal, precuneus-inferiorparietal, thalamo-inferioparietal, and thalamofrontal tracts. When focusing on patients, a stronger relationship between structural integrity of thalamo-inferiorparietal tracts and thalamic metabolism in patients who have emerged from the minimally conscious state as compared with patients with disorders of consciousness was found. The latter finding was in line with the mesocircuit hypothesis for the emergence of consciousness. The findings showed a positive function-structure relationship within most regions of the DMN. Hum Brain Mapp 37:3707-3720, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease, which is associated with mild repetitive traumatic brain injury (TBI). This long-term and progressive symptom due to TBI was initially called punch-drunk syndrome or dementia pugilistica, since it was believed to be associated with boxing. However, serial neuropathological studies of mild repetitive TBI in the last decade have revealed that CTE occurs not only in boxers but also in a wider population including American football players, wrestlers, and military personnel. CTE has gained large public interest owing to dramatic cases involving retired professional athletes wherein serious behavioral problems and tragic incidents were reported. Unlike mild repetitive TBI, a single episode of severe TBI can cause another type of late-onset neuropsychiatric disease including Alzheimer's disease (AD). Several epidemiological studies have shown that a single episode of severe TBI is one of the major risk factors of AD. Pathologically, both AD and CTE are characterized by abnormal accumulations of hyperphosphorylated tau proteins. However, recent neuropathological studies revealed that CTE demonstrates a unique pattern of tau pathology in neurons and astrocytes, and accumulation of other misfolded proteins such as TDP-43. Currently, no reliable biomarkers of late-onset neurodegenerative diseases following TBI are available, and a definitive diagnosis can be made only via postmortem neuropathological examination. Development in neuroimaging techniques such as tau and amyloid positron emission tomography imaging might not only enable early diagnosis of CTE, but also contribute to the interventions for prevention of late-onset neurodegenerative diseases following TBI. Further studies are necessary to elucidate the mechanisms of neurodegeneration in the living brain of patients with TBI.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with repetitive mild traumatic brain injury. In recent years, attention has focused on emerging evidence linking the development of CTE to concussive injuries in athletes and military personnel; however, the underlying molecular pathobiology of CTE remains unclear. Here, we provide evidence that the blood-brain barrier (BBB) is disrupted in regions of dense perivascular p-Tau accumulation in a case of CTE. Immunoreactivity patterns of the BBB-associated tight junction components claudin-5 and zonula occludens-1 were markedly discontinuous or absent in regions of perivascular p-Tau deposition; there was also immunohistochemical evidence of a BBB in these foci. Because the patient was diagnosed premortem clinically as having progressive supranuclear palsy (PSP), we also compromised that the CTE alterations appear to be distinct from those in the brain of a patient with PSP. This report represents the first description of BBB dysfunction in a pathologically proven CTE case and suggests a vascular component in the postconcussion cascade of events that may ultimately lead to development of a progressive degenerative disorder. BBB dysfunction may represent a correlate of neural dysfunction in live subjects suspected of being at risk for development of CTE., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Association of repetitive brain trauma with progressive neurological deterioration has been described since the 1920s. Punch drunk syndrome and dementia pugilistica (DP) were introduced first to explain symptoms in boxers, and more recently, chronic traumatic encephalopathy (CTE) has been used to describe a neurodegenerative disease in athletes and military personal with a history of multiple concussions. Although there are many similarities between DP and CTE, a number of key differences are apparent especially when comparing movement impairments. The aim of this review is to compare clinical and pathological aspects of DP and CTE with a focus on disorders of movement.

Objective: Examine sleep-wake disturbance (SWD) characteristics, factors, consequences, and management strategies from the perspective of veterans with chronic stage, moderate/severe traumatic brain injury (TBI)., Setting: VA Medical Center, Rocky Mountain., Us Participants: Nineteen male veterans with post-acute TBI and SWD in the VA Health Administration., Design: Qualitative descriptive., Measures: Semistructured interviews, Ohio State University TBI-Identification Method, Insomnia Severity Index., Results: Two main dimensions emerged: "Messed up sleep" and Surviving and Managing SWD. Sleep-wake disturbance has long-term multidimensional features, etiology, consequences, and practice implications. Although SWD may not be consistently discussed with providers, the problem appears to be pervasive in many aspects of the lives of the informants. Difficulty falling asleep, frequent awakenings, and poor sleep quality were common symptoms that were described as intrusive, isolating, and difficult to self-manage. Veterans discussed a host of physical symptoms, mental health issues, environmental, and behavioral factors that contributed to SWD. Medications, sleep apnea treatment, and self-imposed isolation were frequent management strategies. Veterans expressed a willingness to try new approaches and work with providers., Conclusion: Sleep-wake disturbance among veterans with chronic stage TBI is a multidimensional phenomenon with interplay between comorbidities, contributing factors, effects on functioning, and sleep management strategies. Implications for practice include early and routine evaluation, monitoring, and treatment of SWD. Research is needed to test interventions that address SWD and common TBI comorbidities.

Concussion is a serious health concern. Concussion in athletes is of particular interest with respect to the relationship of concussion exposure to risk of chronic traumatic encephalopathy (CTE), a neurodegenerative condition associated with altered cognitive and psychiatric functions and profound tauopathy. However, much remains to be learned about factors other than cumulative exposure that could influence concussion pathogenesis. Approximately 20% of CTE cases report a history of substance use including androgenic-anabolic steroids (AAS). How acute, chronic, or historical AAS use may affect the vulnerability of the brain to concussion is unknown. We therefore tested whether antecedent AAS exposure in young, male C57Bl/6 mice affects acute behavioral and neuropathological responses to mild traumatic brain injury (TBI) induced with the CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration) platform. Male C57Bl/6 mice received either vehicle or a cocktail of three AAS (testosterone, nandrolone and 17α-methyltestosterone) from 8-16 weeks of age. At the end of the 7th week of treatment, mice underwent two closed-head TBI or sham procedures spaced 24 h apart using CHIMERA. Post-repetitive TBI (rTBI) behavior was assessed for 7 d followed by tissue collection. AAS treatment induced the expected physiological changes including increased body weight, testicular atrophy, aggression and downregulation of brain 5-HT1B receptor expression. rTBI induced behavioral deficits, widespread axonal injury and white matter microgliosis. While AAS treatment did not worsen post-rTBI behavioral changes, AAS-treated mice exhibited significantly exacerbated axonal injury and microgliosis, indicating that AAS exposure can alter neuronal and innate immune responses to concussive TBI.

Background and Purpose: Effects of high-intensity exercise on endurance, mobility and gait speed of adults with chronic moderate-to-severe acquired brain injury (ABI) were investigated. It was hypothesized that intensive exercise would be associated with improvements in impairment and activity limitation measures., Participants: Fourteen adults with chronic ABI in supported independent living who could stand with minimal or no assist and walk with or without ambulation device were studied. Eight presented with low ambulatory status., Methods: This was a single group pre- and post-intervention study. Participants received a 6-week exercise intervention for 60-90 minutes, 3 days/week assisted by personal trainers under physical therapist supervision. Measures (6MWT, HiMAT and 10MWT) were collected at baseline, post-intervention and 6 weeks later. Repeated measures T-test and Wilcoxon Signed Ranks test were used., Results: Post-intervention improvements were achieved on average on all three measures, greater than minimal detectable change (MDC) for this population. Three participants transitioned from low-to-high ambulatory status and maintained the change 6 weeks later., Discussion and Conclusion: People with chronic ABI can improve endurance, demonstrate the ability to do advanced gait and improve ambulatory status with 6 weeks of intensive exercise. Challenges to sustainability of exercise programmes for this population remain.

Background: Mild balance deficits can be challenging to detect in individuals with long-standing traumatic brain injuries. This study compared Computerized Dynamic Posturography (CDP) scores from individuals with traumatic brain injuries (TBI) to controls to determine if CDP could differentiate between the two groups and determine if there was a learning effect associated with testing that could be used to guide evaluation of baseline balance., Methods: Ten ambulatory individuals with a history of severe TBI and 10 individuals without participated in three CDP sessions (24-72 hours apart). During each session, participants performed the Berg Balance Test, Dynamic Gait Index and three trials of a standardized balance assessment and Dynamic Movement Analysis (DMA) scores were recorded for each test., Results: Individuals with TBI scored 93% higher (i.e. reflecting poorer balance) than the control group. The group with TBI exhibited 6.6-times more variability compared to the control group, with estimated variances of 0.3407 and 0.0517, respectively. A learning effect was detected in the group with TBI on the first day of testing (βTBI F = -0.1241, p-value < 0.01)., Discussion: The CDP system detected balance differences between individuals with TBI and controls. Given the documented learning effect, the best of three trials should be used to accurately assess baseline scores.

Context: The diagnosis of chronic traumatic encephalopathy (CTE) can only be made pathologically, and there is no concordance of defined clinical criteria for premorbid diagnosis. The absence of established criteria and the insufficient imaging findings to detect this disease in a living athlete are of growing concern., Evidence Acquisition: The article is a review of the current literature on CTE. Databases searched include Medline, PubMed, JAMA evidence, and evidence-based medicine guidelines Cochrane Library, Hospital for Special Surgery, and Cornell Library databases., Study Design: Clinical review., Level of Evidence: Level 4., Results: Chronic traumatic encephalopathy cannot be diagnosed on imaging. Examples of imaging findings in common types of head trauma are discussed., Conclusion: Further study is necessary to correlate the clinical and imaging findings of repetitive head injuries with the pathologic diagnosis of CTE., (© 2015 The Author(s).)

The aim of this review was to explain the role played by pituitary hormonal deficiencies in the traumatic brain injury (TBI) disease process. Chronic dysfunction of the pituitary axis is observed in approximately 35% of individuals who sustain a moderate-to-severe TBI. The most common deficiency is that of growth hormone, followed by gonadotropin, cortisol, and thyroid. The medical, psychological, and psychiatric consequences of untreated hypopituitarism are extensive and can be devastating. Many of the consequences of a chronic symptomatic TBI have, in the past, been solely attributed to the brain injury per se. Analysis of the signs and symptoms of pituitary axis dysfunction suggests that many of these consequences can be attributed to post-traumatic hypopituitarism (PTH). PTH may well play a significant role in the progressive signs and symptoms that follow a chronic TBI.

Traumatic brain injury (TBI) is a significant clinical problem with few therapeutic interventions successfully translated to the clinic. Increased importance on the progressive, long-term consequences of TBI have been emphasized, both in the experimental and clinical literature. Thus, there is a need for a better understanding of the chronic consequences of TBI, with the ultimate goal of developing novel therapeutic interventions to treat the devastating consequences of brain injury. In models of mild, moderate, and severe TBI, histopathological and behavioral studies have emphasized the progressive nature of the initial traumatic insult and the involvement of multiple pathophysiological mechanisms, including sustained injury cascades leading to prolonged motor and cognitive deficits. Recently, the increased incidence in age-dependent neurodegenerative diseases in this patient population has also been emphasized. Pathomechanisms felt to be active in the acute and long-term consequences of TBI include excitotoxicity, apoptosis, inflammatory events, seizures, demyelination, white matter pathology, as well as decreased neurogenesis. The current article will review many of these pathophysiological mechanisms that may be important targets for limiting the chronic consequences of TBI.

Traumatic brain injury (TBI) in children, while the brain is in a state of rapid change and development, can adversely impact their development, their extended environment, and their families. The extant literature has identified several physiological, genetic, and environmental variables that predict outcomes after pediatric TBI; nonetheless, the individual course of recovery and later development of a given child is uniquely shaped by injury-related factors (e.g., nature and extent of the injury itself, the developmental status of the child) as well as a number of personal and family variables (e.g., pre-injury cognitive, genetic, and psychological status of the child, family functioning and resources, coping style). Further, the effects of a brain injury during development may or may not become evident immediately after injury depending on a number of factors. Instead, observing trajectories of development over time may allow for a better understanding of the long-term consequences in many functional domains that interest researchers, clinicians, and families. The current article reviews the chronic aspects of medical/health, cognitive/academic, emotional/behavioral, and family/social outcomes after pediatric TBI, with the goal of providing monitoring and treatment strategies for affected children and their families, as well as serving as a resource for researchers designing studies to better understand this heterogeneous population.

Background: Right brain damage (RBD) involves postural asymmetry and spatial frame disorders. In acute RBD patients, postural asymmetry is immediately reduced after one single session of prism adaptation (PA), without assessment of effects on spatial frames., Aim: To assess long-term effects of PA on posture and spatial frames in chronic RBD patients, without neglect., Method: Six chronic RBD patients without neglect (mean delay 45 months) were included. Each patient sustained 10 PA sessions of 20 min during 2 weeks. Outcome measures were: (1) posturographic analysis (mediolateral position of centre of pressure (X cop), (2) subjective straight ahead (SSA) and perception of longitudinal body axis (LBA). Each parameter was assessed by three pretests and three post-tests (+2 h, day + 3 and day + 7)., Results: In pretests, patients showed a shift of the X cop and SSA. In post-tests, results displayed (1) a significant reduction in mediolateral postural asymmetry at D + 7; (2) a significant left deviation of SSA at D + 3 and enduring at D + 7; and (3) no significant modification of LBA. The mean curves of X cop and SSA between pre- and post-tests were similar., Conclusions: PA involves persistent reduction in postural asymmetry in RBD patients without neglect. These findings were obtained at a chronic stage. This new effect cannot be explained by reduction in spatial attentional shift. Improvement may be explained by a better calibration of extra personal space frames used for posture, without effect on personal space frame. Findings argue in favour of a bottom-up effect of PA on mechanisms underlying spatial cognition.

Chronic traumatic encephalopathy (CTE) has been described in the literature as a neurodegenerative disease with: (i) localized neuronal and glial accumulations of phosphorylated tau (p-tau) involving perivascular areas of the cerebral cortex, sulcal depths, and with a preference for neurons within superficial cortical laminae; (ii) multifocal axonal varicosities and axonal loss involving deep cortex and subcortical white matter; (iii) relative absence of beta-amyloid deposits; (iv) TDP-43 immunoreactive inclusions and neurites; and (v) broad and diverse clinical features. Some of the pathological findings reported in the literature may be encountered with age and other neurodegenerative diseases. However, the focality of the p-tau cortical findings in particular, and the regional distribution, are believed to be unique to CTE. The described clinical features in recent cases are very similar to how depression manifests in middle-aged men and with frontotemporal dementia as the disease progresses. It has not been established that the described tau pathology, especially in small amounts, can cause complex changes in behavior such as depression, substance abuse, suicidality, personality changes, or cognitive impairment. Future studies will help determine the extent to which the neuropathology is causally related to the diverse clinical features., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Damage to the human ventromedial prefrontal cortex (vmPFC) leads to profound changes in everyday social interactions [1, 2]. Yet, in the lab, vmPFC patients show surprising proficiency in reasoning about other agents [3-8]. These conflicting observations suggest that what vmPFC patients lack in everyday social interactions might be the ability to guide their decisions with knowledge about a social partner [9-13], despite preserved access to that knowledge [2, 14]. Quantification of socially relevant decisions during live interaction with different partners offers the possibility of testing this hypothesis. Eight patients with vmPFC damage, eight patients with brain damage elsewhere, and 15 healthy participants were asked to communicate non-verbally with two different addressees, an adult or a child, in an experimentally controlled interactive setting [15, 16]. In reality, a confederate blindly performed the role of both adult and child addressee, with matched performance and response times, such that the two addressees differed only in terms of the communicator's beliefs. Patients with vmPFC damage were able-and motivated-to generate communicatively effective behaviors. However, unlike patient and healthy controls, vmPFC patients failed to adjust their communicative decisions to the presumed abilities of their addressee. These findings indicate that the human vmPFC is necessarily involved in social interactions, insofar as those interactions need to be tailored toward knowledge about a social partner. In this perspective, the known contribution of this region to disparate domains like value-based decision-making [17-19], schema-based memory-processing [20-22], and person-specific mentalizing [11-13] might be instances of decisions based on contingently updated conceptual knowledge., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Mild to moderate traumatic brain injury (TBI) due to blast exposure is frequently diagnosed in veterans returning from the wars in Iraq and Afghanistan. However, it is unclear whether neural damage resulting from blast TBI differs from that found in TBI due to blunt-force trauma (e.g., falls and motor vehicle crashes). Little is also known about the effects of blast TBI on neural networks, particularly over the long term. Because impairment in working memory has been linked to blunt-force TBI, the present functional magnetic resonance imaging (fMRI) study sought to investigate whether brain activation in response to a working memory task would discriminate blunt-force from blast TBI. Twenty-five veterans (mean age = 29.8 years, standard deviation = 6.01 years, 1 female) who incurred TBI due to blast an average of 4.2 years prior to enrollment and 25 civilians (mean age = 27.4 years, standard deviation = 6.68 years, 4 females) with TBI due to blunt-force trauma performed the Sternberg Item Recognition Task while undergoing fMRI. The task involved encoding 1, 3, or 5 items in working memory. A group of 25 veterans (mean age = 29.9 years, standard deviation = 5.53 years, 0 females) and a group of 25 civilians (mean age = 27.3 years, standard deviation = 5.81 years, 0 females) without history of TBI underwent identical imaging procedures and served as controls. Results indicated that the civilian TBI group and both control groups demonstrated a monotonic relationship between working memory set size and activation in the right caudate during encoding, whereas the blast TBI group did not (p < 0.05, corrected for multiple comparisons using False Discovery Rate). Blast TBI was also associated with worse performance on the Sternberg Item Recognition Task relative to the other groups, although no other group differences were found on neuropsychological measures of episodic memory, inhibition, and general processing speed. These results could not be attributed to caudate atrophy or the presence of PTSD symptoms. Our results point to a specific vulnerability of the caudate to blast injury. Changes in activation during the Sternberg Item Recognition Task, and potentially other tasks that recruit the caudate, may serve as biomarkers for blast TBI.

Objective: This study aimed to investigate the incidence and clinical characteristics of chronic subdural haematoma (CSDH) evolving from traumatic subdual hydroma (TSH)., Methods: The clinical characteristics of 44 patients with CSDH evolving from TSH were analysed retrospectively and the relevant literature was reviewed., Results: In 22.6% of patients, TSH evolved into CSDH. The time required for this evolution was 14-100 days after injury. All patients were cured with haematoma drainage., Conclusions: TSH is one possible origin of CSDH. The clinical characteristics of TSH evolving into CSDH include polarization of patient age and chronic small effusion. The injuries usually occur during deceleration and are accompanied by mild cerebral damage.

Background: A paucity of information is available regarding how caregivers of persons with post-traumatic disorders of consciousness (DOC) approach medical decision-making. Yet for evidence-based standards of care to be established, the onus is on caregivers' willingness to enroll their family members in clinical trials of novel tests and treatments (NTT)., Objective: To gather information regarding the beliefs and opinions of caregivers regarding NTT for DOC., Methods: Exploratory qualitative data via focus groups from N = 17 caregivers of persons in post-traumatic DOC at both the acute (N = 7) and subacute (N = 10) phases of injury recovery. Supplemental survey data about knowledge of DOC., Results: While attitudes toward NTT were generally favorable, two main themes emerged that influenced willingness to pursue NTT: patient and caregiver-specific factors, and the acquisition/use of information to guide decision-making. While survey data suggested a lack of knowledge about NTT, qualitative data revealed that this was better explained by different standards for knowledge, i.e., anecdotal versus empirical information., Conclusions: Current findings could support discussion between healthcare providers and caregivers regarding medical decision-making as well as suggestions for how to increase the likelihood of caregivers being willing to enroll their family members in clinical trials of NTT.

Objectives: To compare high-level mobility in individuals with chronic moderate-to-severe traumatic brain injury (TBI) with matched healthy controls, and to investigate whether clinical variables and magnetic resonance imaging (MRI) findings in the acute phase can predict high-level motor performance in the chronic phase., Design: A longitudinal follow-up study., Setting: A level 1 trauma center., Participants: Individuals (N=136) with chronic TBI (n=65) and healthy matched peers (n=71)., Interventions: Not applicable., Main Outcome Measures: High-Level Mobility Assessment Tool (HiMAT) and the revised version of the HiMAT performed at a mean of 2.8 years (range, 1.5-5.4y) after injury., Results: Participants with chronic TBI had a mean HiMAT score of 42.7 (95% confidence interval [CI], 40.2-45.2) compared with 47.7 (95% CI, 46.1-49.2) in the control group (P<.01). Group differences were also evident using the revised HiMAT (P<.01). Acute-phase clinical variables and MRI findings explained 58.8% of the variance in the HiMAT score (P<.001) and 59.9% in the revised HiMAT score (P<.001). Lower HiMAT scores were associated with female sex (P=.031), higher age at injury (P<.001), motor vehicle collisions (P=.030), and posttraumatic amnesia >7 days (P=.048). There was a tendency toward an association between lower scores and diffuse axonal injury in the brainstem (P=.075)., Conclusions: High-level mobility was reduced in participants with chronic, either moderate or severe TBI compared with matched peers. Clinical variables in the acute phase were significantly associated with high-level mobility performance in participants with TBI, but the role of early MRI findings needs to be further investigated. The findings of this study suggest that the clinical variables in the acute phase may be useful in predicting high-level mobility outcome in the chronic phase., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Single, severe traumatic brain injury (TBI) which elevates CNS amyloid, increases the risk of Alzheimer's disease (AD); while repetitive concussive and subconcussive events as observed in athletes and military personnel, may increase the risk of chronic traumatic encephalopathy (CTE). We describe two clinical cases, one with a history of multiple concussions during a career in the National Football League (NFL) and the second with frontotemporal dementia and a single, severe TBI. Both patients presented with cognitive decline and underwent [(18)F]-Florbetapir positron emission tomography (PET) imaging for amyloid plaques; the retired NFL player also underwent [(18)F]-T807 PET imaging, a new ligand binding to tau, the main constituent of neurofibrillary tangles (NFT). Case 1, the former NFL player, was 71 years old when he presented with memory impairment and a clinical profile highly similar to AD. [(18)F]-Florbetapir PET imaging was negative, essentially excluding AD as a diagnosis. CTE was suspected clinically, and [(18)F]-T807 PET imaging revealed striatal and nigral [(18)F]-T807 retention consistent with the presence of tauopathy. Case 2 was a 56-year-old man with personality changes and cognitive decline who had sustained a fall complicated by a subdural hematoma. At 1 year post injury, [(18)F]-Florbetapir PET imaging was negative for an AD pattern of amyloid accumulation in this subject. Focal [(18)F]-Florbetapir retention was noted at the site of impact. In case 1, amyloid imaging provided improved diagnostic accuracy where standard clinical and laboratory criteria were inadequate. In that same case, tau imaging with [(18)F]-T807 revealed a subcortical tauopathy that we interpret as a novel form of CTE with a distribution of tauopathy that mimics, to some extent, that of progressive supranuclear palsy (PSP), despite a clinical presentation of amnesia without any movement disorder complaints or signs. A key distinguishing feature is that our patient presented with hippocampal involvement, which is more frequently seen in CTE than in PSP. In case 2, focal [(18)F]-Florbetapir retention at the site of injury in an otherwise negative scan suggests focal amyloid aggregation. In each of these complex cases, a combination of [(18)F]-fluorodeoxyglucose, [(18)F]-Florbetapir and/or [(18)F]-T807 PET molecular imaging improved the accuracy of diagnosis and prevented inappropriate interventions.

Significant attention has recently been drawn to the potential link between head trauma and the development of neurodegenerative disease, namely chronic traumatic encephalopathy (CTE). The acute neurotrauma associated with sports-related concussions in athletes and blast-induced traumatic brain injury in soldiers elevates the risk for future development of chronic neurodegenerative diseases such as CTE. CTE is a progressive disease distinguished by characteristic tau neurofibrillary tangles (NFTs) and, occasionally, transactive response DNA binding protein 43 (TDP43) oligomers, both of which have a predilection for perivascular and subcortical areas near reactive astrocytes and microglia. The disease is currently only diagnosed postmortem by neuropathological identification of NFTs. A recent workshop sponsored by National Institute of Neurological Disorders and Stroke emphasized the need for premortem diagnosis, to better understand disease pathophysiology and to develop targeted treatments. In order to accomplish this objective, it is necessary to discover the mechanistic link between acute neurotrauma and the development of chronic neurodegenerative and neuropsychiatric disorders such as CTE. In this review, we briefly summarize what is currently known about CTE development and pathophysiology, and subsequently discuss injury-induced pathways that warrant further investigation. Understanding the mechanistic link between acute brain injury and chronic neurodegeneration will facilitate the development of appropriate diagnostic and therapeutic options for CTE and other related disorders.

There has been an increased focus on the neurological sequelae of repetitive mild traumatic brain injury (TBI), particularly neurodegenerative syndromes, such as chronic traumatic encephalopathy (CTE); however, no animal model exists that captures the behavioral spectrum of this phenomenon. We sought to develop an animal model of CTE. Our novel model is a modification and fusion of two of the most popular models of TBI and allows for controlled closed-head impacts to unanesthetized mice. Two-hundred and eighty 12-week-old mice were divided into control, single mild TBI (mTBI), and repetitive mTBI groups. Repetitive mTBI mice received six concussive impacts daily for 7 days. Behavior was assessed at various time points. Neurological Severity Score (NSS) was computed and vestibulomotor function tested with the wire grip test (WGT). Cognitive function was assessed with the Morris water maze (MWM), anxiety/risk-taking behavior with the elevated plus maze, and depression-like behavior with the forced swim/tail suspension tests. Sleep electroencephalogram/electromyography studies were performed at 1 month. NSS was elevated, compared to controls, in both TBI groups and improved over time. Repetitive mTBI mice demonstrated transient vestibulomotor deficits on WGT. Repetitive mTBI mice also demonstrated deficits in MWM testing. Both mTBI groups demonstrated increased anxiety at 2 weeks, but repetitive mTBI mice developed increased risk-taking behaviors at 1 month that persist at 6 months. Repetitive mTBI mice exhibit depression-like behavior at 1 month. Both groups demonstrate sleep disturbances. We describe the neurological sequelae of repetitive mTBI in a novel mouse model, which resemble several of the neuropsychiatric behaviors observed clinically in patients sustaining repetitive mild head injury.

Mild traumatic brain injury (mTBI) includes concussion, subconcussion, and most exposures to explosive blast from improvised explosive devices. mTBI is the most common traumatic brain injury affecting military personnel; however, it is the most difficult to diagnose and the least well understood. It is also recognized that some mTBIs have persistent, and sometimes progressive, long-term debilitating effects. Increasing evidence suggests that a single traumatic brain injury can produce long-term gray and white matter atrophy, precipitate or accelerate age-related neurodegeneration, and increase the risk of developing Alzheimer's disease, Parkinson's disease, and motor neuron disease. In addition, repetitive mTBIs can provoke the development of a tauopathy, chronic traumatic encephalopathy. We found early changes of chronic traumatic encephalopathy in four young veterans of the Iraq and Afghanistan conflict who were exposed to explosive blast and in another young veteran who was repetitively concussed. Four of the five veterans with early-stage chronic traumatic encephalopathy were also diagnosed with posttraumatic stress disorder. Advanced chronic traumatic encephalopathy has been found in veterans who experienced repetitive neurotrauma while in service and in others who were accomplished athletes. Clinically, chronic traumatic encephalopathy is associated with behavioral changes, executive dysfunction, memory loss, and cognitive impairments that begin insidiously and progress slowly over decades. Pathologically, chronic traumatic encephalopathy produces atrophy of the frontal and temporal lobes, thalamus, and hypothalamus; septal abnormalities; and abnormal deposits of hyperphosphorylated tau as neurofibrillary tangles and disordered neurites throughout the brain. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently unknown. Chronic traumatic encephalopathy has clinical and pathological features that overlap with postconcussion syndrome and posttraumatic stress disorder, suggesting that the three disorders might share some biological underpinnings., (Copyright © 2014. Published by Elsevier Inc.)

Chronic traumatic encephalopathy (CTE) formerly known as dementia pugilistica is a long-term neurodegenerative disorder associated with repeated subconcussive head injuries in high-contact sports. We reviewed the existing literature on CTE and examined epidemiological trends, risk factors, and its temporal progression, and proposed the underlying pathophysiological mechanisms that may provide unique insights to clinicians with an in-depth understanding of the disease to aid in the diagnosis and prevention, and provide future perspectives for research via search of Medline and Cochrane databases as well as manual review of bibliographies from selected articles and monographs. The prevalence of CTE in recent years is on the rise and almost exclusively affects men, with pathologic signs characterized by progressive memory loss, behavioral changes, and violent tendencies with some patients demonstrating Parkinsonian-like symptoms and signs. Many patients with CTE die following suicide, accident, or complications of drug or alcohol use. Postmortem pathologic analysis is characterized by neurofibrillary tangles and Aβ plaques in 50 % of cases. Currently, there are no ante-mortem diagnostic criteria, but modern imaging techniques such as functional magnetic resonance (MR) imaging, MR spectroscopy, and diffusion tension imaging hold promise for delineating the future diagnostic criteria. Further long-term longitudinal studies are warranted to investigate risk factors that will enhance understanding of the disease progression and its pathogenesis.

We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60's followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed.

Chronic traumatic encephalopathy (CTE, previously called punch drunk and dementia pugilistica) has a rich history in the medical literature in association with boxing, but has only recently been recognized with other contact sports, such as football and ice hockey, as well as with military blast injuries. CTE is thought to be a neurodegenerative disease associated with repeated concussive and subconcussive blows to the head. There is characteristic gross and microscopic pathology found in the brain, including frontal and temporal atrophy, axonal degeneration, and hyperphosphorylated tau and TAR DNA-binding protein 43 pathology. Clinically, there are characteristic progressive deficits in cognition (memory, executive dysfunction), behavior (explosivity, aggression), mood (depression, suicidality), and motor function (parkinsonism), which correlate with the anatomic distribution of brain pathology. While CTE shares clinical and neuropathological traits with other neurodegenerative diseases, the clinical syndrome and the neuropathology as a whole are distinct from other neurodegenerative diseases. Here we review the CTE literature to date. We also draw on the literature from mild traumatic brain injury and other neurodegenerative dementias, particularly when these studies provide guidance for future CTE research. We conclude by suggesting seven essential areas for future CTE research.

Recent scientific reports and popular press describing chronic traumatic encephalopathy (CTE) collectively link this condition to a broad array of neuropsychiatric symptoms, including extremely rare and multi-determined behaviors such as murder-suicide. These reports are difficult to reconcile with several decades of research on the science of traumatic brain injury (TBI) and its consequences, especially the natural history and prognosis of mild TBI. This article attempts to reconcile these sources by reviewing the state of the science on CTE, with particular attention to case definitions and neuropathological criteria for this diagnosis. The evidence for links between TBI, CTE, and catastrophic clinical events is explored, and the complexity of attributing rare frequency behavioral events to CTE is highlighted. The clinical and medicolegal implications of the best available evidence are discussed, concluding with a cautionary note against prematurely generalizing current findings on CTE to entire populations of persons with, or at risk for, concussion exposures., (Copyright © 2013 John Wiley & Sons, Ltd.)