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Blood-based kinetic analysis of PET data relies on an accurate estimate of the arterial plasma input function (PIF). An alternative to invasive measurements from arterial sampling is an image-derived input function (IDIF). However, an IDIF provides the whole blood radioactivity concentration, rather than the required free tracer radioactivity concentration in plasma. To estimate the tracer PIF, we corrected an IDIF from the carotid artery with estimates of plasma parent fraction (PF) and plasma-to-whole blood (PWB) ratio obtained from five venous samples. We compared the combined IDIF+venous approach to gold standard data from arterial sampling in 10 healthy volunteers undergoing [18F]GE-179 brain PET imaging of the NMDA receptor. Arterial and venous PF and PWB ratio estimates determined from 7 patients with traumatic brain injury (TBI) were also compared to assess the potential effect of medication. There was high agreement between areas under the curves of the estimates of PF (r = 0.99, p<0.001), PWB ratio (r = 0.93, p<0.001), and the PIF (r = 0.92, p<0.001) as well as total distribution volume (VT) in 11 regions across the brain (r = 0.95, p<0.001). IDIF+venous VT had a mean bias of −1.7% and a comparable regional coefficient of variation (arterial: 21.3 ± 2.5%, IDIF+venous: 21.5 ± 2.0%). Simplification of the IDIF+venous method to use only one venous sample provided less accurate VT estimates (mean bias 9.9%; r = 0.71, p<0.001). A version of the method that avoids the need for blood sampling by combining the IDIF with population-based PF and PWB ratio estimates systematically underestimated VT (mean bias −20.9%), and produced VT estimates with a poor correlation to those obtained using arterial data (r = 0.45, p<0.001). Arterial and venous blood data from 7 TBI patients showed high correlations for PF (r = 0.92, p = 0.003) and PWB ratio (r = 0.93, p = 0.003). In conclusion, the IDIF+venous method with five venous samples provides a viable alternative to arterial sampling for quantification of [18F]GE-179 VT.

Pre-clinical studies of traumatic brain injury (TBI) show that glyburide reduces edema and hemorrhagic progression of contusions. We conducted a small Phase II, three-institution, randomized placebo-controlled trial of subjects with TBI to assess the safety and efficacy of intravenous (IV) glyburide. Twenty-eight subjects were randomized and underwent a 72-h infusion of IV glyburide or placebo, beginning within 10 h of trauma. Of the 28 subjects, 25 had Glasgow Coma Scale (GCS) scores of 6–10, and 14 had contusions. There were no differences in adverse events (AEs) or severe adverse events (ASEs) between groups. The magnetic resonance imaging (MRI) percent change at 72–168 h from screening/baseline was compared between the glyburide and placebo groups. Analysis of contusions (7 per group) showed that lesion volumes (hemorrhage plus edema) increased 1036% with placebo versus 136% with glyburide (p = 0.15), and that hemorrhage volumes increased 11.6% with placebo but decreased 29.6% with glyburide (p = 0.62). Three diffusion MRI measures of edema were quantified: mean diffusivity (MD), free water (FW), and tissue MD (MDt), corresponding to overall, extracellular, and intracellular water, respectively. The percent change with time for each measure was compared in lesions (n = 14) versus uninjured white matter (n = 24) in subjects receiving placebo (n = 20) or glyburide (n = 18). For placebo, the percent change in lesions for all three measures was significantly different compared with uninjured white matter (analysis of variance [ANOVA], p < 0.02), consistent with worsening of edema in untreated contusions. In contrast, for glyburide, the percent change in lesions for all three measures was not significantly different compared with uninjured white matter. Further study of IV glyburide in contusion TBI is warranted.

Preclinical studies have shown that transcranial near-infrared low-level light therapy (LLLT) administered after traumatic brain injury (TBI) confers a neuroprotective response. To assess the feasibility and safety of LLLT administered acutely after a moderate TBI and the neuroreactivity to LLLT through quantitative magnetic resonance imaging metrics and neurocognitive assessment. A randomized, single-center, prospective, double-blind, placebo-controlled parallel-group trial was conducted from November 27, 2015, through July 11, 2019. Participants included 68 men and women with acute, nonpenetrating, moderate TBI who were randomized to LLLT or sham treatment. Analysis of the response-evaluable population was conducted. Transcranial LLLT was administered using a custom-built helmet starting within 72 hours after the trauma. Magnetic resonance imaging was performed in the acute (within 72 hours), early subacute (2-3 weeks), and late subacute (approximately 3 months) stages of recovery. Clinical assessments were performed concomitantly and at 6 months via the Rivermead Post-Concussion Questionnaire (RPQ), a 16-item questionnaire with each item assessed on a 5-point scale ranging from 0 (no problem) to 4 (severe problem). The number of participants to successfully and safely complete LLLT without any adverse events within the first 7 days after the therapy was the primary outcome measure. Secondary outcomes were the differential effect of LLLT on MR brain diffusion parameters and RPQ scores compared with the sham group. Of the 68 patients who were randomized (33 to LLLT and 35 to sham therapy), 28 completed at least 1 LLLT session. No adverse events referable to LLLT were reported. Forty-three patients (22 men [51.2%]; mean [SD] age, 50.49 [17.44] years]) completed the study with at least 1 magnetic resonance imaging scan: 19 individuals in the LLLT group and 24 in the sham treatment group. Radial diffusivity (RD), mean diffusivity (MD), and fractional anisotropy (FA) showed significant time and treatment interaction at 3-month time point (RD: 0.013; 95% CI, 0.006 to 0.019; P < .001; MD: 0.008; 95% CI, 0.001 to 0.015; P = .03; FA: -0.018; 95% CI, -0.026 to -0.010; P < .001).The LLLT group had lower RPQ scores, but this effect did not reach statistical significance (time effect P = .39, treatment effect P = .61, and time × treatment effect P = .91). In this randomized clinical trial, LLLT was feasible in all patients and did not exhibit any adverse events. Light therapy altered multiple diffusion tensor parameters in a statistically significant manner in the late subacute stage. This study provides the first human evidence to date that light therapy engages neural substrates that play a role in the pathophysiologic factors of moderate TBI and also suggests diffusion imaging as the biomarker of therapeutic response. ClinicalTrials.gov Identifier: NCT02233413.

Special Weapons and Tactics (SWAT) personnel who conduct breacher exercises are at risk for blast-related head trauma. We aimed to investigate the potential impact of low-level blast exposure during breacher training on the neural functioning of working memory and auditory network connectivity. We also aimed to evaluate the effects of a jugular vein compression collar, designed to internally mitigate slosh energy absorption, preserving neural functioning and connectivity, following blast exposure. A total of 23 SWAT personnel were recruited and randomly assigned to a non-collar ( n  = 11) and collar group ( n  = 12). All participants completed a 1-day breacher training with multiple blast exposure. Prior to and following training, 18 participants (non-collar, n  = 8; collar, n  = 10) completed functional magnetic resonance imaging (fMRI) of working memory using N-Back task; 20 participants (non-collar, n  = 10; collar, n  = 12) completed resting-state fMRI. Key findings from the working memory analysis include significantly increased fMRI brain activation in the right insular, right superior temporal pole, right inferior frontal gyrus, and pars orbitalis post-training for the non-collar group ( p  < 0.05, threshold-free cluster enhancement corrected), but no changes were noted for the collar group. The elevation in fMRI activation in the non-collar group was found to correlate significantly ( n  = 7, r  = 0.943, p  = 0.001) with average peak impulse amplitude experienced during the training. In the resting-state fMRI analysis, significant pre- to post-training increase in connectivity between the auditory network and two discrete regions (left middle frontal gyrus and left superior lateral occipital/angular gyri) was found in the non-collar group, while no change was observed in the collar group. These data provided initial evidence of the impact of low-level blast on working memory and auditory network connectivity as well as the protective effect of collar on brain function following blast exposure, and is congruent with previous collar findings in sport-related traumatic brain injury.

Traumatic Brain Injury (TBI) is a frequently occurring condition and approximately 90% of TBI cases are classified as mild (mTBI). However, conventional MRI has limited diagnostic and prognostic value, thus warranting the utilization of additional imaging modalities and analysis procedures. The functional connectomic approach using resting-state functional MRI (rs-fMRI) has shown great potential and promising diagnostic capabilities across multiple clinical scenarios, including mTBI. Additionally, there is increasing recognition of a fundamental role of brain dynamics in healthy and pathological cognition. Here, we undertake an in-depth investigation of mTBI-related connectomic disturbances and their emotional and cognitive correlates. We leveraged machine learning and graph theory to combine static and dynamic functional connectivity (FC) with regional entropy values, achieving classification accuracy up to 75% (77, 74 and 76% precision, sensitivity and specificity, respectively). As compared to healthy controls, the mTBI group displayed hypoconnectivity in the temporal poles, which correlated positively with semantic (r = 0.43, p < 0.008) and phonemic verbal fluency (r = 0.46, p < 0.004), while hypoconnectivity in the right dorsal posterior cingulate correlated positively with depression symptom severity (r = 0.54, p < 0.0006). These results highlight the importance of residual FC in these regions for preserved cognitive and emotional function in mTBI. Conversely, hyperconnectivity was observed in the right precentral and supramarginal gyri, which correlated negatively with semantic verbal fluency (r=-0.47, p < 0.003), indicating a potential ineffective compensatory mechanism. These novel results are promising toward understanding the pathophysiology of mTBI and explaining some of its most lingering emotional and cognitive symptoms.

Abstract BACKGROUND An early acute marker of long-term neurological outcome would be useful to help guide clinical decision making and therapeutic effectiveness after severe traumatic brain injury (TBI). We investigated the utility of the Disability Rating Scale (DRS) as early as 1 wk after TBI as a predictor of favorable 6-mo Glasgow Outcome Scale extended (GOS-E). OBJECTIVE To determine the predictability of a favorable 6-mo GOS-E using the DRS measured during weeks 1 to 4 of injury. METHODS The study is a sub analysis of patients enrolled in the Epo Severe TBI Trial (n = 200) to train and validate L1-regularized logistic regression models. DRS was collected at weeks 1 to 4 and GOS-E at 6 mo. RESULTS The average area under the receiver operating characteristic curve was 0.82 for the model with baseline demographic and injury severity variables and week 1 DRS and increased to 0.88 when including weekly DRS until week 4. CONCLUSION This study suggests that week 1 to 4 DRS may be predictors of favorable 6-mo outcome in severe TBI patients and thus useful both for clinical prognostication as well as surrogate endpoints for adaptive clinical trials.

Introduction Prior studies have demonstrated training‐induced changes in the healthy adult brain. Yet, it remains unclear how the injured brain responds to cognitive training months‐to‐years after injury. Methods Sixty individuals with chronic traumatic brain injury (TBI) were randomized into either strategy‐based (N = 31) or knowledge‐based (N = 29) training for 8 weeks. We measured cortical thickness and resting‐state functional connectivity (rsFC) before training, immediately posttraining, and 3 months posttraining. Results Relative to the knowledge‐based training group, the cortical thickness of the strategy‐based training group showed diverse temporal patterns of changes over multiple brain regions (pvertex < .05, pcluster < .05): (1) increases followed by decreases, (2) monotonic increases, and (3) monotonic decreases. However, network‐based statistics (NBS) analysis of rsFC among these regions revealed that the strategy‐based training group induced only monotonic increases in connectivity, relative to the knowledge‐based training group (|Z| > 1.96, pNBS < 0.05). Complementing the rsFC results, the strategy‐based training group yielded monotonic improvement in scores for the trail‐making test (p < .05). Analyses of brain–behavior relationships revealed that improvement in trail‐making scores were associated with training‐induced changes in cortical thickness (pvertex < .05, pcluster < .05) and rsFC (pvertex < .05, pcluster < .005) within the strategy‐based training group. Conclusions These findings suggest that training‐induced brain plasticity continues through chronic phases of TBI and that brain connectivity and cortical thickness may serve as markers of plasticity. Although prior studies have demonstrated training‐induced changes in the healthy adult brain, it remains unclear how the injured brain responds to cognitive training months‐to‐years after injury. In this study, we determined whether cognitive training for chronic traumatic brain injury (TBI) yields changes in cortical thickness and resting‐state functional connectivity. Our findings suggest that training‐induced brain plasticity continues through chronic phases of TBI and that brain connectivity and cortical thickness may serve as markers of plasticity.

Background Tranexamic acid prevents blood clots from breaking down and reduces bleeding. However, it is uncertain whether tranexamic acid is effective in traumatic brain injury. The CRASH-3 trial is a randomised controlled trial that will examine the effect of tranexamic acid (versus placebo) on death and disability in 13,000 patients with traumatic brain injury. The CRASH-3 trial hypothesizes that tranexamic acid will reduce intracranial haemorrhage, which will reduce the risk of death. Although it is possible that tranexamic acid will reduce intracranial bleeding, there is also a potential for harm. In particular, tranexamic acid may increase the risk of cerebral thrombosis and ischaemia. The protocol detailed here is for a mechanistic sub-study nested within the CRASH-3 trial. This mechanistic sub-study aims to examine the effect of tranexamic acid (versus placebo) on intracranial bleeding and cerebral ischaemia. Methods The CRASH-3 Intracranial Bleeding Mechanistic Sub-Study (CRASH-3 IBMS) is nested within a prospective, double-blind, multi-centre, parallel-arm randomised trial called the CRASH-3 trial. The CRASH-3 IBMS will be conducted in a cohort of approximately 1000 isolated traumatic brain injury patients enrolled in the CRASH-3 trial. In the CRASH-3 IBMS, brain scans acquired before and after randomisation are examined, using validated methods, for evidence of intracranial bleeding and cerebral ischaemia. The primary outcome is the total volume of intracranial bleeding measured on computed tomography after randomisation, adjusting for baseline bleeding volume. Secondary outcomes include progression of intracranial haemorrhage (from pre- to post-randomisation scans), new intracranial haemorrhage (seen on post- but not pre-randomisation scans), intracranial haemorrhage following neurosurgery, and new focal ischaemic lesions (seen on post-but not pre-randomisation scans). A linear regression model will examine whether receipt of the trial treatment can predict haemorrhage volume. Bleeding volumes and new ischaemic lesions will be compared across treatment groups using relative risks and 95% confidence intervals. Discussion The CRASH-3 IBMS will provide an insight into the mechanism of action of tranexamic acid in traumatic brain injury, as well as information about the risks and benefits. Evidence from this trial could inform the management of patients with traumatic brain injury. Trial registration The CRASH-3 trial was prospectively registered and the CRASH-3 IBMS is an addition to the original protocol registered at the International Standard Randomised Controlled Trials registry ( ISRCTN15088122 ) 19 July 2011, and ClinicalTrials.gov on 25 July 2011 (NCT01402882).

PurposeThe CRASH-3 trial is a randomised trial of tranexamic acid (TXA) on death and disability in patients with traumatic brain injury (TBI). It is based on the hypothesis that early TXA treatment can prevent deaths from post-traumatic intracranial bleeding. The results showed that timely TXA treatment reduces head injury deaths in patients with reactive pupils and those with a mild to moderate GCS at baseline. We examined routinely collected CT scans in a sample of 1767 CRASH-3 trial patients to explore if, why, and how patients are affected by TXA.MethodsThe CRASH-3 IBMS is an explanatory study nested within the CRASH-3 trial. We measured the volume of intracranial bleeding on CT scans using established methods (e.g. ABC/2).ResultsPatients with any un-reactive pupil had a median intracranial bleeding volume of 60 ml (IQR 18–101 ml) and patients with reactive pupils had a median volume of 26 ml (IQR 1–55 ml). Patients with severe GCS had median intracranial bleeding volume of 37 ml (IQR 3–75 ml) and patients with moderate to mild GCS had a median volume of 26 ml (IQR 0.4–50 ml). For every hour increase from injury to the baseline scan, the risk of new bleeding on a further scan decreased by 12% (adjusted RR = 0.88 [95% CI 0.80–0.96], p = 0.0047).ConclusionPatients with reactive pupils and/or mild to moderate GCS may have benefited from TXA in the CRASH-3 trial because they had less intracranial bleeding at baseline. However, because bleeding occurs soon after injury, treatment delay reduces the benefit of TXA.

Objective: To investigate the effects of l-Carnitine on neuron specific enolase (NSE) as a marker of inflammation in patients with traumatic brain injury (TBI). Methods: Forty patients with severe TBI were randomized into 2 groups. The (LCA-) group received standard treatment with placebo while the (LCA+) group received l-Carnitine 2g/day for one week. NSE was measured on days 1, 3 and 7 after the initiation of the study. Neurocognitive and neurobehavioral disorders were recorded on the first and third months. Results: Neurocognitive function and NSE significantly improved within one week in both groups. Patient mortality was similar in LCA+ and LCA- groups (P value: 0.76). Brain edema was present in 7 patients in LCA+ group and 13 patients in LCA-group (P value: 0.044). While there was no difference in NSE levels between the two groups. Neurological function was preserved in the LCA+ group with an exception of attention deficit, which was frequent in the LCA+ group. Conclusion: We concluded that despite improvements in neurobehavioral function and the degree of cerebral edema, 7-days of treatment with l-Carnitine failed to reduce serum NSE levels or improve mortality rate at 90days in patients with TBI. •There is significant oxidative stress and mitochondrial dysfunction in TBI.•l-Carnitine improves mitochondrial dysfunction in animal models of cerebral ischemia.•In a randomized clinical trial, l-Carnitine was administered for 7days to TBI victims.•Despite improvements in neurobehavioral function, markers of brain injury did not change after TBI.