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Traumatic Brain Injury (TBI) is a risk factor for Alzheimers disease and Alzheimers disease related dementias (AD/ADRD) and otherwise classified post-traumatic neurodegeneration (PTND). Targeted research is needed to elucidate the circumstances and mechanisms through which TBI contributes to the initiation, development, and progression of AD/ADRD pathologies including multiple etiology dementia (MED). The National Institutes of Health hosts triennial ADRD summits to inform a national research agenda, and TBI was included for a second time in 2022. A multidisciplinary expert panel of TBI and dementia researchers was convened to re-evaluate the 2019 research recommendations for understanding TBI as an AD/ADRD risk factor and to assess current progress and research gaps in understanding post-TBI AD/ADRD. Refined and new recommendations were presented during the MED special topic session at the virtual ADRD Summit in March 2022. Final research recommendations incorporating broad stakeholder input are organized into four priority areas as follows: (1) Promote interdisciplinary collaboration and data harmonization to accelerate progress of rigorous, clinically meaningful research; (2) Characterize clinical and biological phenotypes of PTND associated with varied lifetime TBI histories in diverse populations to validate multimodal biomarkers; (3) Establish and enrich infrastructure to support multimodal longitudinal studies of individuals with varied TBI exposure histories and standardized methods including common data elements (CDEs) for ante-mortem and post-mortem clinical and neuropathological characterization; and (4) Support basic and translational research to elucidate mechanistic pathways, development, progression, and clinical manifestations of post-TBI AD/ADRDs. Recommendations conceptualize TBI as a contributor to MED and emphasize the unique opportunity to study AD/ADRD following known exposure, to inform disease mechanisms and treatment targets for shared common AD/ADRD pathways.

The Scandinavian NeuroTrauma Committee (SNC) guidelines recommend S100 calcium-binding protein B (S100B) as a screening tool for early detection of Traumatic brain injury (TBI) in patients presenting with an initial Glasgow Coma Scale (GCS) of 14-15. The objective of the current study was to compare S100B's diagnostic performance within the recommended 6-h window after injury, compared with glial fibrillary acidic protein (GFAP) and UCH-L1. The secondary outcome of interest was the ability of these biomarkers in detecting traumatic intracranial pathology beyond the 6-h mark. The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) core database (2014-2017) was queried for data pertaining to all TBI patients with an initial GCS of 14-15 who had a blood sample taken within 6 h of injury in which the levels of S100B, GFAP, and UCH-L1 were measured. As a subgroup analysis, data involving patients with blood samples taken within 6-9 h and 9-12 h were analyzed separately for diagnostic ability. The diagnostic ability of these biomarkers for detecting any intracranial injury was evaluated based on the area under the receiver operating characteristic curve (AUC). Each biomarker's sensitivity, specificity, and accuracy were also reported at the cutoff that maximized Youden's index. A total of 531 TBI patients with GCS 14-15 on admission had a blood sample taken within 6 h, of whom 24.9% (n = 132) had radiologically confirmed intracranial injury. The AUCs of GFAP (0.86, 95% confidence interval [CI]: 0.82-0.90) and UCH-L1 (0.81, 95% CI: 0.76-0.85) were statistically significantly higher than that of S100B (0.74, 95% CI: 0.69-0.79) during this time. There was no statistically significant difference in the predictive ability of S100B when sampled within 6 h, 6-9 h, and 9-12 h of injury, as the p values were >0.05 when comparing the AUCs. Overlapping AUC 95% CI suggests no benefit of a combined GFAP and UCH-L1 screening tool over GFAP during the time periods studied [0.87 (0.83-0.90) vs. 0.86 (0.82-0.90) when sampled within 6 h of injury, 0.83 (0.78-0.88) vs. 0.83 (0.78-0.89) within 6 to 9 h and 0.81 (0.73-0.88) vs. 0.79 (0.72-0.87) within 9-12 h]. Targeted analysis of the CENTER-TBI core database, with focus on the patient category for which biomarker testing is recommended by the SNC guidelines, revealed that GFAP and UCH-L1 perform superior to S100B in predicting CT-positive intracranial lesions within 6 h of injury. GFAP continued to exhibit superior predictive ability to S100B during the time periods studied. S100B displayed relatively unaltered screening performance beyond the diagnostic timeline provided by SNC guidelines. These findings suggest the need for a reevaluation of the current SNC TBI guidelines. [ABSTRACT FROM AUTHOR]

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (p

Cathepsin B (CatB), a lysosomal cysteine protease, is important to brain function and may have dual utility as a peripheral biomarker of moderate-severe traumatic brain injury (TBI). The present study determined levels of pro- and mature (mat) CatB protein as well as cysteine protease activity within the frontal cortex (FC; proximal injury site), hippocampus (HC; distal injury site), and cerebral spinal fluid (CSF) collected 1-7 days after craniotomy and penetrating ballistic-like brain injury (PBBI) in rats. Values were compared with naïve controls. Further, the utility of CatB protein as a translational biomarker was determined in CSF derived from patients with severe TBI. Craniotomy increased matCatB levels in the FC and HC, and led to elevation of HC activity at day 7. PBBI caused an even greater elevation in matCatB within the FC and HC within 3-7 days. After PBBI, cysteine protease activity peaked at 3 days in the FC and was elevated at 1 day and 7 days, but not 3 days, in the HC. In rat CSF, proCatB, matCatB, and cysteine protease activity peaked at 3 days after craniotomy and PBBI. Addition of CA-074, a CatB-specific inhibitor, confirmed that protease activity was due to active matCatB in rat brain tissues and CSF at all time-points. In patients, CatB protein was detectable from 6 h through 10 days after TBI. Notably, CatB levels were significantly higher in CSF collected within 3 days after TBI compared with non-TBI controls. Collectively, this work indicates that CatB and its cysteine protease activity may serve as collective molecular signatures of TBI progression that differentially vary within both proximal and distal brain regions. CatB and its protease activity may have utility as a surrogate, translational biomarker of acute-subacute TBI.

Chronic traumatic encephalopathy (CTE) is associated with pathological changes, yet detecting these changes during life has proven elusive. Positron emission tomography (PET) offers the potential for identifying such pathology. Few studies have been completed to date and their approaches and results have been diverse. It was the objective of this review to systematically examine relevant research using ligands for PET that bind to identified pathology in CTE. We focused on identification of patterns of binding and addressing gaps in knowledge of PET imaging for CTE. A comprehensive literature search was conducted. Data used were published on or before May 22, 2017. As the extant literature is limited, any peer-reviewed article assessing military, contact sports athletes, or professional fighters was considered for inclusion. The main outcomes were regional binding to brain regions identified through control comparisons or through clinical metrics (e.g., standardized uptake volume ratios). A total of 1207 papers were identified for review, of which six met inclusion criteria. Meta-analyses were planned but were deemed inappropriate given the small number of studies identified. Methodological concerns in these initial papers included small sample sizes, lack of a control comparison, use of nonstandard statistical procedures to quantify data, and interpretation of potentially off-target binding areas. Across studies, the hippocampi, amygdalae, and midbrain had reasonably consistent increased uptake. Evidence for increased uptake in cortical regions was less consistent. The evidence suggests that the field of PET imaging in those at risk for CTE remains nascent. As the field evolves to include more stringent studies, ligands for PET may prove an important tool in identifying CTE in vivo.

Depression is the most frequent neuropsychiatric complication after traumatic brain injury (TBI) and is associated with poorer outcomes. Neuroimaging has the potential to improve our understanding of the neural correlates of depression after TBI and may improve our capacity to accurately predict and effectively treat this condition. We conducted a systematic review of structural and functional neuroimaging studies that examined the association between depression after TBI and neuroimaging measures. Electronic searches were conducted in four databases and were complemented by manual searches. In total, 2035 citations were identified and, ultimately, 38 articles were included, totaling 1793 individuals (median [25–75%] sample size of 38.5 [21.8–54.3] individuals). The most frequently used modality was structural magnetic resonance imaging (MRI) (n = 17, 45%), followed by diffusion tensor imaging (n = 11, 29%), resting-state functional MRI (n = 10, 26%), task-based functional MRI (n = 4, 8%), and positron emission tomography (n = 2, 4%). Most studies (n = 27, 71%) were cross-sectional. Overall, depression after TBI was associated with lower gray matter measures (volume, thickness, and/or density) and greater white matter damage. However, identification of specific brain areas was somewhat inconsistent. Findings that were replicated in more than one study included reduced gray matter in the rostral anterior cingulate cortex, pre-frontal cortex, and hippocampus, and damage in five white matter tracts (cingulum, internal capsule, superior longitudinal fasciculi, and anterior and posterior corona radiata). This systematic review found that the available data did not converge on a clear neuroimaging biomarker for depression after TBI. However, there are promising targets that warrant further study. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a risk factor for later-life dementia. Clinical and pre-clinical studies have elucidated multiple mechanisms through which TBI may influence or exacerbate multiple pathological processes underlying Alzheimer's disease and Alzheimer's disease–related dementias (AD/ADRD). The National Institutes of Health hosts triennial ADRD Summits to inform a national research agenda, and the 2019 ADRD Summit was the first to highlight "TBI and AD/ADRD Risk" as an emerging topic in the field. A multidisciplinary committee of TBI researchers with relevant expertise reviewed extant literature, identified research gaps and opportunities, and proposed draft research recommendations at the 2019 ADRD Summit. These research recommendations, further refined after broad stakeholder input at the Summit, cover four overall areas: 1) Encourage crosstalk and interdisciplinary collaboration between TBI and dementia researchers; 2) Establish infrastructure to study TBI as a risk factor for AD/ADRD; 3) Promote basic and clinical research examining the development and progression of TBI AD/ADRD neuropathologies and associated clinical symptoms; and 4) Characterize the clinical phenotype of progressive dementia associated with TBI and develop non-invasive diagnostic approaches. These recommendations recognize a need to strengthen communication and build frameworks to connect the complexity of TBI with rapidly evolving AD/ADRD research. Recommendations acknowledge TBI as a clinically and pathologically heterogeneous disease whose associations with AD/ADRDs remain incompletely understood. The recommendations highlight the scientific advantage of investigating AD/ADRD in the context of a known TBI exposure, the study of which can directly inform on disease mechanisms and treatment targets for AD/ADRDs with shared common pathways. [ABSTRACT FROM AUTHOR]

Traumatic acute subdural hematoma (aSDH) is associated with a high mortality rate caused by post-operative cerebral infarction. Recently, brain natriuretic peptide (BNP) was considered a reliable biomarker in the acute phase of traumatic brain injuries. We therefore aimed in this study to analyze BNP levels on admission, identify the predictors of their elevation, and assess the relationship between BNP and the risk of post-operative cerebral infarction. Patients with isolated, unilateral, traumatic aSDH who were admitted to our department between July 2017 and May 2020 were enrolled in this study. On admission, cranial computer tomography (CCT) and BNP sampling were simultaneously performed. Additionally, the time between head trauma and BNP sampling (TTS) was assessed. Admission radiographic variables included hematoma volumes, midline shift, and degree of brain edema. Cerebral infarction was detected on postoperative CCT. In total, 130 patients were included in this study. Surgical treatment was performed in 82.3% (n = 107) of cases. The multiple regression analysis showed that larger hematoma volumes (p = 0.032) and advanced age (p = 0.005) were independent predictors of elevated BNP when TTS <24 h. The binomial logistical regression analysis identified BNP with a cutoff value of <29.4 pg/mL (TTS = 3–12 h, adjusted odds ratio [aOR] = 16.5, p = 0.023) as an independent predictor of post-operative cerebral infarction. Elevated BNP levels in the first 24 h post-trauma were related to larger hematoma volumes and advanced age. Further, an increased risk of post-operative cerebral infarction was identified in patients with lower BNP levels in the post-traumatic period 3–12 h. [ABSTRACT FROM AUTHOR]

Despite multiple prior pharmacological trials in traumatic brain injury (TBI), the search for an effective, safe, and practical treatment of these patients remains ongoing. Given the ease of delivery and rapid absorption into the systemic circulation, inhalational gases that have neuroprotective properties will be an invaluable resource in the clinical management of TBI patients. In this review, we perform a systematic review of both pre-clinical and clinical reports describing inhalational gas therapy in the setting of TBI. Hyperbaric oxygen, which has been investigated for many years, and some of the newest developments are reviewed. Also, promising new therapies such as hydrogen gas, hydrogen sulfide gas, and nitric oxide are discussed. Moreover, novel therapies such as xenon and argon gases and delivery methods using microbubbles are explored. [ABSTRACT FROM AUTHOR]

Understanding the effects of age on longitudinal traumatic brain injury (TBI) outcomes requires attention to both chronic and evolving TBI effects and age-related changes in health and function. The present study examines the independent and interactive effects of aging and chronicity on functional outcomes after TBI. We leveraged a well-defined cohort of individuals who sustained a moderate/severe TBI and received acute inpatient rehabilitation at specialized centers with high follow up rate as part of their involvement in the TBI Model Systems longitudinal study. We selected individuals at one of two levels of TBI chronicity (either 2 or 10 years post-injury) and used an exact matching procedure to obtain balanced chronicity groups based on age and other characteristics (N = 1993). We found that both older age and greater injury chronicity were related to greater disability, reduced functional independence, and less community participation. There was a significant age by chronicity interaction, indicating that the adverse effects of greater time post-injury were most pronounced among survivors who were age 75 or older. The inflection point at roughly 75 years of age was corroborated by post hoc analyses, dividing the sample by age at 75 years and examining the interaction between age group and chronicity. These findings point to a need for provision of rehabilitation services in the chronic injury period, particularly for those who are over 75 years old. Future work should investigate the underlying mechanisms of this interaction towards the goal of developing interventions and models of care to promote healthy aging with TBI. [ABSTRACT FROM AUTHOR]

Early treatment of moderate/severe traumatic brain injury (TBI) with progesterone does not improve clinical outcomes. This is in contrast with findings from pre-clinical studies of progesterone in TBI. To understand the reasons for the negative clinical trial, we investigated whether progesterone treatment has the desired biological effect of decreasing brain cell death. We quantified brain cell death using serum levels of biomarkers of glial and neuronal cell death (glial fibrillary acidic protein [GFAP], ubiquitin carboxy-terminal hydrolase-L1 [UCH-L1], S100 calcium-binding protein B [S100B], and Alpha II Spectrin Breakdown Product 150 [SBDP]) in the Biomarkers of Injury and Outcome–Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment (BIO-ProTECT) study. Serum levels of GFAP, UCHL1, S100B, and SBDP were measured at baseline (≤4 h post-injury and before administration of study drug) and at 24 and 48 h post-injury. Serum progesterone levels were measured at 24 and 48 h post-injury. The primary outcome of ProTECT was based on the Glasgow Outcome Scale-Extended assessed at 6 months post-randomization. We found that at baseline, there were no differences in biomarker levels between subjects randomized to progesterone treatment and those randomized to placebo (p > 0.10). Similarly, at 24 and 48 h post-injury, there were no differences in biomarker levels in the progesterone versus placebo groups (p > 0.15). There was no statistically significant correlation between serum progesterone concentrations and biomarker values obtained at 24 and 48 h. When examined as a continuous variable, baseline biomarker levels did not modify the association between progesterone treatment and neurological outcome (p of interaction term >0.39 for all biomarkers). We conclude that progesterone treatment does not decrease levels of biomarkers of glial and neuronal cell death during the first 48 h post-injury. [ABSTRACT FROM AUTHOR]

Anticoagulants prevent thrombosis and death in patients with atrial fibrillation and venous thromboembolism (VTE) but also increase bleeding risk. The benefit/risk ratio favors anticoagulation in most of these patients. However, some will have a bleeding complication, such as the common trip-and-fall brain injury in elderly patients that results in traumatic intracranial hemorrhage. Clinicians must then make the difficult decision about when to restart the anticoagulant. Restarting too early risks making the bleeding worse. Restarting too late risks thrombotic events such as ischemic stroke and VTE, the indications for anticoagulation in the first place. There are more data on restarting patients with spontaneous intracranial hemorrhage, which is very different than traumatic intracranial hemorrhage. Spontaneous intracranial hemorrhage increases the risk of rebleeding because intrinsic vascular changes are widespread and irreversible. In contrast, traumatic cases are caused by a blow to the head, usually an isolated event portending less future risk. Clinicians generally agree that anticoagulation should be restarted but disagree about when. This uncertainty leads to long restart delays causing a large, potentially preventable burden of strokes and VTE, which has been unaddressed because of the absence of high quality evidence. Restart Traumatic Intracranial Hemorrhage (the "r" distinguished intracranial from intracerebral) (TICrH) is a prospective randomized open label blinded end-point response-adaptive clinical trial that will evaluate the impact of delays to restarting direct oral anticoagulation (1, 2, or 4 weeks) on the composite of thrombotic events and bleeding in patients presenting after traumatic intracranial hemorrhage. [ABSTRACT FROM AUTHOR]

Sleep disturbances are commonly reported in children with persistent post-concussion symptoms (PPCS). Melatonin treatment is often recommended, yet supporting evidence is scarce. We aimed to evaluate the efficacy of treatment with melatonin for sleep disturbance in youth with PPCS following mild traumatic brain injury (mTBI). This article is a secondary analysis of a clinical trial of melatonin compared with placebo to treat PPCS. Youth (8–18 years of age) with PPCS and significant sleep-related problems (SRPs) at 4–6 weeks post-injury were eligible. Exclusion criteria: significant medical/psychiatric history; previous concussion/mTBI within 3 months. Treatment groups were: placebo, melatonin 3 mg, or melatonin 10 mg. Primary outcome was change in SRPs measured using the Post-Concussion Symptom Inventory (PCSI) after 2 weeks of treatment. Secondary outcomes included change in actigraphy sleep efficiency, duration, onset latency, and wake-after-sleep-onset. Behavior was measured using Behaviour Assessment for Children (2nd edition). Seventy-two participants (mean age 14.0, standard deviation [SD] = 2.6) years; 60% female) with PPCS and significant sleep disturbance were included in the secondary analysis: placebo (n = 22); melatonin 3 mg (n = 25); melatonin 10 mg (n = 25). Sixty-four participants had actigraphy data. SRPs decreased across all groups over time with a significant effect of melatonin 3 mg (3.7; 95% confidence interval [CI]: 2.1, 5.4) compared with placebo (7.4; 95% CI: 4.2, 10.6) and melatonin 10 mg (6.4; 95% CI: 3.6, 9.2). Sleep duration increased in the melatonin 3 mg (43 min; 95% CI: 6, 93) and melatonin 10 mg groups (55 min; 95% CI: 5, 104) compared with placebo. A per protocol analysis demonstrated improved sleep efficiency in the melatonin 10 mg group (p = 0.029). No serious adverse events were reported. Depressive symptoms significantly decreased with melatonin 3 mg (-4.7; 95% CI: −9.2, −.2) but not with melatonin 10 mg (−1.4, 95% CI: −5.9, 3.2) treatment compared with placebo. Changes in cognition or behavior were otherwise not significantly different between treatment groups. Short-term melatonin is a well-tolerated treatment for sleep disturbance in youth with PPCS following mTBI. In this context, it may also be associated with a reduction in depressive symptoms. [ABSTRACT FROM AUTHOR]

Systemic inflammation impacts outcome after traumatic brain injury (TBI), but most TBI biomarker studies have focused on brain-specific proteins. C-reactive protein (CRP) is a widely used biomarker of inflammation with potential as a prognostic biomarker after TBI. The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study prospectively enrolled TBI patients within 24 h of injury, as well as orthopedic injury and uninjured controls; biospecimens were collected at enrollment. A subset of hospitalized participants had blood collected on day 3, day 5, and 2 weeks. High-sensitivity CRP (hsCRP) and glial fibrillary acidic protein (GFAP) were measured. Receiver operating characteristic analysis was used to evaluate the prognostic ability of hsCRP for 6-month outcome, using the Glasgow Outcome Scale-Extended (GOSE). We included 1206 TBI subjects, 122 orthopedic trauma controls (OTCs), and 209 healthy controls (HCs). Longitudinal biomarker sampling was performed in 254 hospitalized TBI subjects and 19 OTCs. hsCRP rose between days 1 and 5 for TBI and OTC subjects, and fell by 2 weeks, but remained elevated compared with HCs (p < 0.001). Longitudinally, hsCRP was significantly higher in the first 2 weeks for subjects with death/severe disability (GOSE <5) compared with those with moderate disability/good recovery (GOSE ≥5); AUC was highest at 2 weeks (AUC = 0.892). Combining hsCRP and GFAP at 2 weeks produced AUC = 0.939 for prediction of disability. Serum hsCRP measured within 2 weeks of TBI is a prognostic biomarker for disability 6 months later. hsCRP may have utility as a biomarker of target engagement for anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine if earlier age of first exposure (AFE) to football is associated with worse brain health in middle-aged men who played high school football. We assessed 123 men 35–55 years of age, who played high school football, using (1) a survey of demographic information as well as medical, sport participation, and concussion history; (2) the Patient Health Questionnaire-8 (PHQ-8); and (3) the British Columbia Post-Concussion Symptom Inventory (BC-PSI). Sixty-two (50.4%) men reported football participation starting before the age of 12 (i.e., AFE <12 years) and 61 (49.6%) reported football participation at or after the age of 12 (AFE > 12 years). Compared with those with AFE >12 years, a similar proportion of former high school football players who began playing tackle football before age 12 reported that they had been prescribed medications for mental health problems or that they had recently experienced symptoms of anxiety, depression, memory loss, chronic pain, or headaches. Moreover, there was no significant difference in their lifetime history of treatment by a mental health professional. The groups did not differ significantly on PHQ-8 (U = 1839.0, p = 0.791) or BC-PSI total scores (U = 1828.5, p = 0.751). These findings suggest that earlier AFE to football is not associated with worse brain health in middle-aged men in this sample who played high school football. [ABSTRACT FROM AUTHOR]

Brain injuries are associated with oxidative stress and a need to restore neuronal homeostasis. Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma. The aim of this study was to explore the potential role of variants in other ion channel genes in the development of such responses. We conducted whole exome sequencing (WES) on16 individuals who developed a range of neurological and concussion-related symptoms following minor or trivial head injuries. All individuals were initially tested and shown to be negative for mutations in known FHM genes. Variants identified from the WES results were filtered to identify rare variants (minor allele frequency [MAF] <0.01) in genes related to neural processes as well as genes highly expressed in the brain using a combination of in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, and Mutation Assessor). Rare (MAF <0.001) or novel heterozygous variants in 7 ion channel genes were identified in 37.5% (6/16) of the cases (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4), rare variants in neurotransmitter genes were found in 2 cases (GABRG1 and GRIK1), and rare variants in 3 ubiquitin-related genes identified in 4 cases (SQSTM1, TRIM2, and HECTD1). In this study, the largest proportion of potentially pathogenic variants in individuals with severe responses to minor head trauma were identified in genes previously implicated in migraine and seizure-related autosomal recessive neurological disorders. Together with results implicating variants in the hemiplegic migraine genes, CACNA1A and ATP1A2, in severe head trauma response, our results support a role for heterozygous deleterious mutations in genes implicated in neurological dysfunction and potentially increasing the risk of poor response to trivial head trauma. [ABSTRACT FROM AUTHOR]

There is considerable interest in the long-term brain health of retired contact and collision sport athletes; however, little is known about possible underlying changes in functional brain connectivity in this group. We evaluated whole–brain functional connectivity patterns using multi-voxel pattern analysis (MVPA) to determine whether alterations in functional connectivity distinguish retired professional athletes from a matched group of healthy community control subjects. Thirty-two retired athletes with a history of multiple self-reported sport-related concussions and 36 healthy community control subjects who were similar in age and education, completed functional magnetic resonance imaging. We identified brain regions with abnormal functional connectivity patterns using whole–brain MVPA as implemented in the Conn toolbox. First-level MVPA was performed using 64 principal component analysis (PCA) components. Second-level F test was performed using the first three MVPA components for retired athletes > controls group contrast. Post hoc seed-to-voxel analyses using the MVPA cluster results as seeds were performed to characterize functional connectivity abnormalities from brain regions identified by MVPA. MVPA revealed one cluster of abnormal functional connectivity located in cerebellar lobule V. This region of lobule V corresponded to the ventral attention network. Post hoc seed-to-voxel analysis using the cerebellar MVPA cluster as a seed revealed multiple areas of cerebral cortical hyper-connectivity and hypo-connectivity in retired athletes when compared with controls. This initial report suggests that cerebellar dysfunction might be present and clinically important in some retired athletes. [ABSTRACT FROM AUTHOR]

Increasing clinical and experimental evidence suggests that traumatic brain injury (TBI) is associated with progressive histopathological damage. The aim of the current study was to characterize the time course of motor function, memory performance, and depression-like behavior up to 1 year after experimental TBI, and to correlate these changes to histopathological outcome. Male C57BL/6N mice underwent controlled cortical impact (CCI) or sham operation, and histopathological outcome was evaluated 15 min, 24 h, 1 week, or 1, 3, 6, or 12 months thereafter (n = 12 animals per time point). Motor function, depression-like behavior, and memory function were evaluated concomitantly, and magnetic resonance imaging (MRI) was repeatedly performed. Naïve mice (n = 12) served as an unhandled control group. Injury volume almost doubled within 1 year after CCI (p = 0.008) and the ipsilateral hemisphere became increasingly atrophic (p < 0.0001). Progressive tissue loss was observed in the corpus callosum (p = 0.007) and the hippocampus (p = 0.004) together with hydrocephalus formation (p < 0.0001). Motor function recovered partially after TBI, but 6 months after injury progressive depression-like behavior (p < 0.0001) and loss of memory function (p < 0.0001) were observed. The present study demonstrates that delayed histopathological damage that occurs over months after brain injury is followed by progressive depression and memory loss, changes also observed after TBI in humans. Hence, experimental TBI models in mice replicate long-term sequelae of brain injury such as post-traumatic dementia and depression. [ABSTRACT FROM AUTHOR]

Cerebral oxygen delivery is central to the modern intensive care of patients with severe traumatic brain injury. Low brain tissue oxygen tension (PbtO2) results from microvascular collapse and diffusion limitation and is associated with adverse outcome. A number of therapies to improve oxygen delivery are known to be effective in improving PbtO2. Their relative effectiveness and microscopic regions of hypoxia, however, may exist/persist even in the presence of normal PbtO2. Unfortunately, there are no methods currently for assessing this quantitatively. We used an in silico (computational) simulation approach to understand the effect of common interventions on the microscopic distribution of brain tissue oxygen tension. We constructed a non-linear mathematical model of cerebral oxygen supply, diffusion, and consumption for a simplified geometry. Model parameters were chosen to agree with clinical parameters. We found that it was possible to create a plausible diffusion-limited scenario with a significant hypoxic fraction by increasing the mean diffusion distance. We found that increasing cerebral blood flow/blood oxygen content or suppressing the cerebral metabolic rate were most effective at improving PbtO2 and reduced the hypoxic fraction. Within the limitations of our modeling assumptions, increasing the arterial oxygen partial pressure was less effective and only improved PbtO2 by creating a region of hyperoxic tissue with no improvement in hypoxic fraction. The in silico simulations can be useful in understanding the likely physiological effect of complex treatments for which measurement techniques do not exist. [ABSTRACT FROM AUTHOR]

Mild traumatic brain injury (mTBI) represents a serious public health concern. Although much is understood about long-term changes in cell signaling and anatomical pathologies associated with mTBI, little is known about acute changes in neuronal function. Using large scale Ca2+ imaging in vivo, we characterized the intracellular Ca2+ dynamics in thousands of individual hippocampal neurons using a repetitive mild blast injury model in which blasts were directed onto the cranium of unanesthetized mice on two consecutive days. Immediately following each blast event, neurons exhibited two types of changes in Ca2+ dynamics at different time scales. One was a reduction in slow Ca2+ dynamics that corresponded to shifts in basal intracellular Ca2+ levels at a time scale of minutes, suggesting a disruption of biochemical signaling. The second was a reduction in the rates of fast transient Ca2+ fluctuations at the sub-second time scale, which are known to be closely linked to neural activity. Interestingly, the blast-induced changes in basal Ca2+ levels were independent of the changes in the rates of fast Ca2+ transients, suggesting that blasts had heterogeneous effects on different cell populations. Both types of changes recovered after ∼1 h. Together, our results demonstrate that mTBI induced acute, heterogeneous changes in neuronal function, altering intracellular Ca2+ dynamics across different time scales, which may contribute to the initiation of longer-term pathologies. [ABSTRACT FROM AUTHOR]

The primary aim of this study was to examine the effects of valproic acid (VPA) treatment on serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NF-L) levels. To achieve this aim, we obtained serum samples from: 1) 10 Yorkshire swine subjected to controlled cortical impact traumatic brain injury (CCI TBI) + polytrauma and randomized to receive either normal saline (NS) + VPA (n = 5) or NS alone (n = 5) and 2) five additional swine subjected to CCI TBI without polytrauma and treated with VPA. GFAP and NF-L levels were measured in samples obtained from baseline until 10 days post-injury using a digital immunoassay from Quanterix Corporation. We found that elevated GFAP and NF-L levels were first detected at 2 h post-injury; and peaked at 24 h and 72 h respectively. GFAP levels returned to baseline levels by Day 10, while NF-L remained elevated at Day 10. In TBI + polytrauma swine, the magnitude and duration of biomarker elevation, quantified by the area under the biomarker-concentration-versus-time curve during the first 10 days (AUC0-10days), was higher in the NS group, compared with the VPA group. For GFAP, the AUC0-10days was 45,535 (IQR: 35,741-105,711) and 22,837 (IQR: 8,082-46,627) for the NS and NS+VPA groups, respectively. For NF-L, the AUC0-10days was 43,073 (IQR: 18,739-120,794) and 4,475 (2,868-11,157) for the NS and NS+VPA groups, respectively. Twenty-four hour GFAP and NF-L levels had the strongest correlation with lesion size and time to normalization of behavior. Accordingly, we conclude that treatment with VPA results in significantly lower serum GFAP and NF-L levels. The time-point at which GFAP and NF-L levels have the strongest correlation with outcome is 24 h post-injury. [ABSTRACT FROM AUTHOR]

The EPO-TBI study randomized 606 patients with moderate or severe traumatic brain injury (TBI) to be treated with weekly epoetin alfa (EPO) or placebo. Six month mortality was lower in EPO treated patients in an analysis adjusting for TBI severity. Knowledge of possible differential effects by TBI injury subtype and acute neurosurgical treatment as well as timing and cause of death (COD) will facilitate the design of future interventional TBI trials. We defined COD as cerebral (brain death, cerebral death with withdrawal, or death during maximal care) and non-cerebral (death following withdrawal or during maximal care, which had a non-cerebral cause). The study included 305 patients treated with EPO and 297 treated with placebo, with COD recorded in 77 (99%) out of 78 non-survivors. Median time to death in patients dying of cerebral COD was 8 days (interquartile range [IQR] 5-16) compared with 29 days (IQR 7-56) ( p = 0.01) for non-cerebral COD. When assessing subgroups by admission CT scan injury findings, we found no significant differential effects of EPO compared with placebo. However, EPO appeared more effective in patients with an injury type not requiring a neurosurgical operation prior to intensive care unit (ICU) admission (odds ratio [OR] 0.29, 95% confidence interval [CI] 0.14-0.61, p = 0.001, p for interaction = 0.003) and in this subgroup, fewer patients died of cerebral causes in the EPO than in the placebo group (5% compared with 14%, p = 0.03). In conclusion, most TBI deaths were from cerebral causes that occurred during the first 2 weeks, and were related to withdrawal of care. EPO appeared to specifically reduce cerebral deaths in the important subgroup of patients with a diffuse type of injury not requiring a neurosurgical intervention prior to randomization. [ABSTRACT FROM AUTHOR]

The present study was designed to tackle two notorious features of mild traumatic brain injury (mTBI)-heterogeneity and invisibility-by characterizing the full scope of mTBI symptoms. Mice were exposed to brain injuries of different intensities utilizing a weight-drop model (10, 30, 50, and 70 g) and subsequently subjected to a comprehensive battery of behavioral tests at different time points and immunohistochemical examination of cortical slices. Whereas the physiological, neurological, emotional, and motor function of mTBI mice (i.e., their well-being) remained largely intact, cognitive deficits were identified by the y-maze and novel object recognition. Results from these two cognitive tests were combined and a dose-response relationship was established between injury intensity and cognitive impairment, ranging from an 85% decline after a 70-g impact ( p < 0.001) to a 20% decline after a 10-g impact (essentially no effect). In addition, higher intensities of injury were accompanied by decreased expression of axonal and synaptic markers. Thus, our mTBI mice showed a clear discrepancy between performance (poor cognitive function) and appearance (healthy demeanor). This is of major concern given that diagnosis of mTBI is established on the presence of clinical symptoms and emphasizes the need for an alternative diagnostic modality. [ABSTRACT FROM AUTHOR]

This study examined the performance of serum ubiquitin C-terminal hydrolase (UCH-L1) in detecting traumatic intracranial lesions on computed tomography (CT) scan (+CT) in children and youth with mild and moderate TBI (mmTBI) and assessed its performance in trauma control patients without head trauma. This prospective cohort study enrolled children and youth presenting to three level 1 trauma centers after blunt head trauma and a Glasgow Coma Scale (GCS) score of 9-15 as well as trauma control patients with GCS 15 that did not have blunt head trauma. The primary outcome measure was the presence of intracranial lesions on initial CT scan. Blood samples were obtained in all patients within 6 h of injury and measured by enzyme-linked immunosorbent assay ELISA for UCH-L1 (ng/mL). A total of 256 children and youth were enrolled in the study and had serum samples drawn within 6 h of injury for analysis; 196 had blunt head trauma and 60 were trauma controls. CT scan of the head was performed in 151 patients and traumatic intracranial lesions on CT scan were evident in 17 (11%), all of whom had a GCS of 13-15. The area under the receiver operating characteristic curve (AUC) for UCH-L1 in detecting children and youth with traumatic intracranial lesions on CT was 0.83 (95% confidence interval [CI], 0.73-0.93). In those presenting with a GCS of 15, the AUC for detecting lesions was 0.83 (95% CI, 0.72-0.94). Similarly, in children under 5 years of age, the AUC was 0.79 (95% CI, 0.59-1.00). Performance for detecting intracranial lesions at a UCH-L1 cut-off level of 0.18 ng/mL yielded a sensitivity of 100%, a specificity of 47%, and a negative predictive value of 100%. UCH-L1 showed good performance in infants and toddlers younger than 5 years and performed well in children and youth with a GCS score of 15. Before clinical application, further study in larger cohort of children and youth with mild TBI is warranted. [ABSTRACT FROM AUTHOR]

Recovery from concussion in childhood is poorly understood, despite its importance in decisions regarding return to normal activity. Resolution of post-concussive symptoms (PCS) is widely employed as a marker of recovery in clinical practice; however, it is unclear whether subtle impairments persist only to re-emerge in the context of increased physical or cognitive demands. This study aimed to examine the effect of strenuous exercise on clinical symptom report and neurocognition in children and adolescents after PCS resolution after concussion. We recruited children and adolescents with concussion ( n = 30) on presentation to an Emergency Department (ED). At Day 2 and Day 10 post-self-reported symptom resolution, participants completed a strenuous exercise protocol, and pre- and post-exercise assessment of PCS and neurocognition. Results demonstrated an overall reduction in PCS from Day 2 to Day 10 post-symptom resolution, with no evidence of symptom increase after strenuous exercise at either time point. Neurocognitive performance was linked to task complexity: on less cognitively demanding tasks, processing speed was slower post-exercise and, unexpectedly, slower on Day 10 than Day 2, while for more demanding tasks (new learning), Day 2 exercise resulted in faster responses, but Day 10 processing speed post-exercise was slower. In summary, we found the expected recovery pattern for PCS, regardless of exercise, while for neurocognition, recovery was dependent on the degree of cognitive demand, and there was an unexpected reduction in performance from Day 2 to Day 10. Findings provide some suggestion that premature return to normal activities (e.g., school) may slow neurocognitive recovery. [ABSTRACT FROM AUTHOR]

Internal jugular vein (IJV) compression has been shown to reduce axonal injury in pre-clinical traumatic brain injury (TBI) models and clinical concussion studies. However, this novel approach to prophylactically mitigating TBI through venous congestion raises concerns of increasing the propensity for hemorrhage and hemorrhagic propagation. This study aims to test the safety of IJV compression in a large animal controlled cortical impact (CCI) injury model and the resultant effects on hemorrhage. Twelve swine were randomized to placement of a bilateral IJV compression collar (CCI+collar) or control/no collar (CCI) prior to CCI injury. A histological grading of the extent of hemorrhage, both subarachnoid (SAH) and intraparenchymal (IPH), was conducted in a blinded manner by two neuropathologists. Other various measures of TBI histology were also analyzed including: β-amyloid precursor protein (β-APP) expression, presence of degenerating neurons, extent of cerebral edema, and inflammatory infiltrates. Euthanized 5 h after injury, the CCI+collar animals exhibited a significant reduction in total SAH ( p = 0.024-0.026) and IPH scores ( p = 0.03-0.05) compared with the CCI animals. There was no statistically significant difference in scoring for the other markers of TBI (β-APP, neuronal degeneration, cerebral edema, or inflammatory infiltration). In conclusion, IJV compression was shown to reduce hemorrhage (SAH and IPH) in the porcine CCI model when applied prior to injury. These results suggest the role of IJV compression for mitigation of not only axonal, but also hemorrhagic injury following TBI. [ABSTRACT FROM AUTHOR]

There has been a tremendous focus on the discovery and development of neuroprotective agents that might have clinical relevance following traumatic brain injury (TBI). This type of brain injury is very complex and is divided into two major components. The first component, a primary injury, occurs at the time of impact and is the result of the mechanical insult itself. This primary injury is thought to be irreversible and resistant to most treatments. A second component or secondary brain injury, is defined as cellular damage that is not immediately obvious after trauma, but that develops after a delay of minutes, hours, or even days. This injury appears to be amenable to treatment. Because of the complexity of the secondary injury, any type of therapeutic intervention needs to be multi-faceted and have the ability to simultaneously modulate different cellular changes. Because of diverse pharmaceutical interactions, combinations of different drugs do not work well in concert and result in adverse physiological conditions. Research has begun to investigate the possibility of using natural compounds as a therapeutic intervention following TBI. These compounds normally have very low toxicity and have reduced interactions with other pharmaceuticals. In addition, many natural compounds have the potential to target numerous different components of the secondary injury. Here, we review 33 different plant-derived natural compounds, phytochemicals, which have been investigated in experimental animal models of TBI. Some of these phytochemicals appear to have potential as possible therapeutic interventions to offset key components of the secondary injury cascade. However, not all studies have used the same scientific rigor, and one should be cautious in the interpretation of studies using naturally occurring phytochemical in TBI research. [ABSTRACT FROM AUTHOR]

Head injury patients not meeting the American Congress of Rehabilitation Medicine (ACRM)'s criteria for mild traumatic brain injury (mTBI), referred to hereafter as HIBRID (Head Injury BRain Injury Debatable), are often excluded from studies. The prognostic importance of HIBRID is unclear. We investigated the differences in functional and symptomatic recovery at 1 month post-injury among TBI patients classified as: HIBRID, ACRM+ cranial computed tomography (CT)-, and cranial CT+; and trauma and healthy controls. Subjects were enrolled in an ongoing prospective cohort ( Injury erum arkers for ssessing esponse to rauma; HeadSMART). Outcomes measured at 1 month post-injury include: incomplete functional recovery (Glasgow Outcome Scale Extended <8); moderate/severe post-concussive symptoms (PCS), defined according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision definition; and moderate/severe depressive symptoms (Patient Health Questionnaire 9 ≥ 10). Between April 2014 and May 2016, 500 TBI and 100 control subjects were enrolled and 376 TBI and 78 control subjects completed outcome assessment. The HIBRID group, constituting 23.9% of study population, had a lower incidence of incomplete functional recovery (36.7% [33 of 90]) than ACRM+, CT− (60.7% [125 of 206]; p < 0.01) and CT+ (78.8% [63 of 80]; p < 0.01) groups. However, the incidence of delayed functional recovery within the HIBRID group was higher than in trauma (9.3% [5 of 54]; p < 0.01) and healthy controls (0% [0 of 24]; p < 0.01). Compared to trauma/healthy controls, the HIBRID group had a higher incidence of moderate/severe depressive symptoms and a similar incidence of moderate/severe PCS. Subjects in the HIBRID group are at high risk for adverse outcomes following head injury and warrant further investigation. [ABSTRACT FROM AUTHOR]

Domestic violence is a national health crisis, which affects people of all ages, races, and socioeconomic classes. Traumatic brain injury is common in victims because of the high frequency of head and neck injuries inflicted through abuse. These recurrent injuries can lead to chronic symptoms with high morbidity. We conducted a retrospective chart review of 115 patients with a history of head trauma as a result of domestic violence. All patients were seen in a subspecialty traumatic brain injury clinic, at which time information regarding their histories and self-reported symptoms were recorded. In total, 109 females and 6 males were included in our study, with an age range of 4-68 years. Overall, 88% reported more than one injury and 81% reported a history of loss of consciousness associated with their injuries. Only 21% sought medical help at the time of injury. Whereas 85% had a history of abuse in adulthood, 22% had experienced abuse in both childhood and adulthood, and 60% of the patients abused as children went on to be abused as adults. Headache was the most common chief complaint, but on a self-reported symptom severity scale, behavioral symptoms were the most severe. Psychiatric disease was present in 84% of patients. Traumatic brain injury is a frequent sequela of domestic violence, from which many victims sustain multiple injuries without seeking medical care. Brain injuries are often sustained over many years and lead to lasting physical, behavioral, and cognitive consequences. Better understanding of these injuries will lead to improved care for this population. [ABSTRACT FROM AUTHOR]

Clinical outcome after traumatic diffuse axonal injury (DAI) is difficult to predict. In this study, three magnetic resonance imaging (MRI) sequences were used to quantify the anatomical distribution of lesions, to grade DAI according to the Adams grading system, and to evaluate the value of lesion localization in combination with clinical prognostic factors to improve outcome prediction. Thirty patients (mean 31.2 years ±14.3 standard deviation) with severe DAI (Glasgow Motor Score [GMS] <6) examined with MRI within 1 week post-injury were included. Diffusion-weighted (DW), T2*-weighted gradient echo and susceptibility-weighted (SWI) sequences were used. Extended Glasgow outcome score was assessed after 6 months. Number of DW lesions in the thalamus, basal ganglia, and internal capsule and number of SWI lesions in the mesencephalon correlated significantly with outcome in univariate analysis. Age, GMS at admission, GMS at discharge, and low proportion of good monitoring time with cerebral perfusion pressure <60 mm Hg correlated significantly with outcome in univariate analysis. Multivariate analysis revealed an independent relation with poor outcome for age (p = 0.005) and lesions in the mesencephalic region corresponding to substantia nigra and tegmentum on SWI (p = 0.008). We conclude that higher age and lesions in substantia nigra and mesencephalic tegmentum indicate poor long-term outcome in DAI. We propose an extended MRI classification system based on four stages (stage I--hemispheric lesions, stage II--corpus callosum lesions, stage III--brainstem lesions, and stage IV--substantia nigra or mesencephalic tegmentum lesions); all are subdivided by age (≥/<30 years). [ABSTRACT FROM AUTHOR]

Relying on self-reported concussion injury history is common in both clinical care and research. However, young athletes may not provide consistent medical information. To date, little is known about the reliability of self-reported concussion history in high school students. This study examined whether student athletes reported their lifetime history of concussions consistently over time. Self-reported concussion history was examined in 4792 student athletes (ages 13-18) from Maine who completed a preseason health survey on two occasions (median re-test interval = 23.7 months; standard deviation = 7.3; interquartile range = 12.4-24.5). Consistency of self-reported concussion history was determined by differences in the number of concussions reported during the second survey. Inconsistent concussion history was defined primarily by a decrease in the number of lifetime concussions reported at the second testing, compared with at the first testing. The majority of the sample (80.3%) reported no change in the number of concussions between the two baseline assessments. A minority (15.9%; n = 763) reported more concussions during the second assessment. Only 3.8% (n = 181) of student athletes provided inconsistent concussion histories, defined as fewer concussions at the second assessment. Boys provided inconsistent concussion histories a little more frequently, compared with girls (5.3% and 2.0%, respectively; p < 0.001). Similarly, athletes with self-reported attention-deficit hyperactivity disorder (ADHD) provided inconsistent concussion histories somewhat more frequently, compared with those without ADHD (7.8% and 3.5%, respectively; p < 0.001). Of the athletes with inconsistent concussion histories, greater degree of inconsistency was associated with a greater number of concussions initially reported at baseline (rs = 0.54; p < 0.001). Only a small proportion of student athletes provided inconsistent concussion histories. Male gender, ADHD, and greater number of baseline concussions were significantly associated with inconsistency in reporting. Overall, these findings suggest that student athletes are quite consistent when reporting their concussion history when surveyed twice during high school. [ABSTRACT FROM AUTHOR]

Individuals with a history of traumatic brain injury (TBI) are at increased risk for a number of disorders, including Alzheimer's disease, Parkinson's disease, and chronic traumatic encephalopathy. However, mediators of the long-term morbidity are uncertain. We conducted a multi-site, prospective trial in chronic TBI patients (~18 years post-TBI) living in long-term 24-h care environments and local controls without a history of head injury. Inability to give informed consent was exclusionary for participation. A total of 41 individuals (17 moderate-severe TBI, 24 controls) were studied before and after consumption of a standardized breakfast to determine if concentrations of amino acids, cytokines, C-reactive protein, and insulin are potential mediators of long-term TBI morbidity. Analyte concentrations were measured in serum drawn before (fasting) and 1 h after meal consumption. Mean ages were 44 ± 15 and 49 ± 11 years for controls and chronic TBI patients, respectively. Chronic TBI patients had significantly lower circulating concentrations of numerous individual amino acids, as well as essential amino acids ( p = 0.03) and large neutral amino acids ( p = 0.003) considered as groups, and displayed fundamentally altered cytokine-amino acid relationships. Many years after injury, TBI patients exhibit abnormal metabolic responses and altered relationships between circulating amino acids, cytokines, and hormones. This pattern is consistent with TBI, inducing a chronic disease state in patients. Understanding the mechanisms causing the chronic disease state could lead to new treatments for its prevention. [ABSTRACT FROM AUTHOR]

Current thinking views mild head impact (i.e., subconcussion) as an underrecognized phenomenon that has the ability to cause significant current and future detrimental neurological effects. Repeated mild impacts to the head, however, often display no observable behavioral deficits based on standard clinical tests, which may lack sensitivity. The current study investigates the effects of subconcussive impacts from soccer heading with innovative measures of vestibular function and walking stability in a pre- 0-2 h, post- 24 h post-heading repeated measures design. The heading group ( n = 10) executed 10 headers with soccer balls projected at a velocity of 25 mph (11.2 m/sec) over 10 min. Subjects were evaluated 24 h before, immediately after, and 24 h after soccer heading with: the modified Balance Error Scoring System (mBESS); a walking stability task with visual feedback of trunk movement; and galvanic vestibular stimulation (GVS) while standing with eyes closed on foam. A control group ( n = 10) followed the same protocol with no heading. The results showed significant decrease in trunk angle, leg angle gain, and center of mass gain relative to GVS for the heading group compared with controls. Medial-lateral trunk orientation displacement and velocity during treadmill walking increased immediately after mild head impact for the heading group compared with controls. Controls showed an improvement in mBESS scores over time, indicating a learning effect, which was not observed with the heading group. These results suggest that mild head impact leads to a transient dysfunction in vestibular processing, which deters walking stability during task performance. [ABSTRACT FROM AUTHOR]

A Phase III, double-blind, placebo-controlled trial (ProTECT III) found that administration of progesterone did not reduce mortality or improve functional outcome as measured by the Glasgow Outcome Scale Extended (GOSE) in subjects with moderate to severe traumatic brain injury. We conducted a secondary analysis of neuropsychological outcomes to evaluate whether progesterone is associated with improved recovery of cognitive and motor functioning. ProTECT III was conducted at 49 level I trauma centers in the United States. Adults with moderate to severe TBI were randomized to receive intravenous progesterone or placebo within 4 h of injury for a total of 4 days. At 6 months, subjects underwent evaluation of memory, attention, executive functioning, language, and fine motor coordination/dexterity. Chi-square analysis revealed no significant difference in the proportion of subjects (263/280 progesterone, 283/295 placebo) with Galveston Orientation and Amnesia Test scores ≥75. Analyses of covariance did not reveal significant treatment effects for memory (Buschke immediate recall, p = 0.53; delayed recall, p = 0.94), attention (Trails A speed, p = 0.81 and errors, p = 0.22; Digit Span Forward length, p = 0.66), executive functioning (Trails B speed, p = 0.97 and errors, p = 0.93; Digit Span Backward length, p = 0.60), language (timed phonemic fluency, p = 0.05), and fine motor coordination/dexterity (Grooved Pegboard dominant hand time, p = 0.75 and peg drops, p = 0.59; nondominant hand time, p = 0.74 and peg drops, p = 0.61). Pearson Product Moment Correlations demonstrated significant ( p < 0.001) associations between better neuropsychological performance and higher GOSE scores. Similar to the ProTECT III trial's results of the primary outcome, the secondary outcomes do not provide evidence of a neuroprotective effect of progesterone. [ABSTRACT FROM AUTHOR]

As concerns about head impact in American football have grown, similar concerns have started to extend to other sports thought to experience less head impact, such as soccer and lacrosse. However, the amount of head impact experienced in soccer and lacrosse is relatively unknown, particularly compared with the substantial amount of data from football. This pilot study quantifies and compares head impact from four different types of sports teams: college football, high school football, college soccer, and college lacrosse. During the 2013 and 2014 seasons, 61 players wore mastoid patch accelerometers to quantify head impact during official athletic events (i.e., practices and games). In both practices and games, college football players experienced the most or second-most impacts per athletic event, highest average peak resultant linear and rotational acceleration per impact, and highest cumulative linear and rotational acceleration per athletic event. For average peak resultant linear and rotational acceleration per individual impact, college football was followed by high school football, then college lacrosse, and then college soccer, with similar trends in both practices and games. In the four teams under study, college football players experienced a categorically higher burden of head impact. However, for cumulative impact burden, the high school football cohort was not significantly different from the college soccer cohort. The results suggest that head impact in sport substantially varies by both the type of sport (football vs. soccer vs. lacrosse) and level of play (college vs. high school). [ABSTRACT FROM AUTHOR]

The objective of this systematic review and meta-analysis is to evaluate whether the pre-injury use of antiplatelet therapy (APT) is associated with increased risk of traumatic intracranial hemorrhage (tICH) on CT scan. PubMed, Medline, Embase, Cochrane Central, reference lists, and national guidelines on traumatic brain injury were used as data sources. Eligible studies were cohort studies and case-control studies that assessed the relationship between APT and tICH. Studies without control group were not included. The primary outcome of interest was tICH on CT. Two reviewers independently selected studies, assessed methodological quality, and extracted outcome data. This search resulted in 10 eligible studies with 20,247 patients with head injury that were included in the meta-analysis. The use of APT in patients with head injury was associated with significant increased risk of tICH compared with control (odds ratio [OR] 1.87, 95% confidence interval [CI]1.27-2.74). There was significant heterogeneity in the studies (I2 84%), although almost all showed an association between APT use and tICH. This association could not be established for patients receiving aspirin monotherapy. When considering only patients with mild traumatic brain injury (mTBI), the OR is 2.72 (95% CI 1.92-3.85). The results were robust to sensitivity analysis on study quality. In summary, APT in patients with head injury is associated with increased risk of tICH; this association is most relevant in patients with mTBI. Whether this association is the result of a causal relationship and whether this relationship also exists for patients receiving aspirin monotherapy cannot be established with the current review and meta-analysis. [ABSTRACT FROM AUTHOR]