Sulforaphane improves cognitive function administered following traumatic brain injury.

Recent studies have shown that sulforaphane, a naturally occurring compound that is found in cruciferous vegetables, offers cellular protection in several models of brain injury. When administered following traumatic brain injury (TBI), sulforaphane has been demonstrated to attenuate blood-brain barrier permeability and reduce cerebral edema. These beneficial effects of sulforaphane have been shown to involve induction of a group of cytoprotective, Nrf2-driven genes, whose protein products include free radical scavenging and detoxifying enzymes. However, the influence of sulforaphane on post-injury cognitive deficits has not been examined. In this study, we examined if sulforaphane, when administered following cortical impact injury, can improve the performance of rats tested in hippocampal- and prefrontal cortex-dependent tasks. Our results indicate that sulforaphane treatment improves performance in the Morris water maze task (as indicated by decreased latencies during learning and platform localization during a probe trial) and reduces working memory dysfunction (tested using the delayed match-to-place task). These behavioral improvements were only observed when the treatment was initiated 1h, but not 6h, post-injury. These studies support the use of sulforaphane in the treatment of TBI, and extend the previously observed protective effects to include enhanced cognition.

Progenitor cell therapies for traumatic brain injury: barriers and opportunities in translation.

Traumatic brain injury (TBI) directly affects nearly 1.5 million new patients per year in the USA, adding to the almost 6 million cases in patients who are permanently affected by the irreversible physical, cognitive and psychosocial deficits from a prior injury. Adult stem cell therapy has shown preliminary promise as an option for treatment, much of which is limited currently to supportive care. Preclinical research focused on cell therapy has grown significantly over the last decade. One of the challenges in the translation of this burgeoning field is interpretation of the promising experimental results obtained from a variety of cell types, injury models and techniques. Although these variables can become barriers to a collective understanding and to evidence-based translation, they provide crucial information that, when correctly placed, offers the opportunity for discovery. Here, we review the preclinical evidence that is currently guiding the translation of adult stem cell therapy for TBI.

Traumatic brain injury stimulates hippocampal catechol-O-methyl transferase expression in microglia.

Outcome following traumatic brain injury (TBI) is in large part determined by the combined action of multiple processes. In order to better understand the response of the central nervous system to injury, we utilized an antibody array to simultaneously screen 507 proteins for altered expression in the injured hippocampus, a structure critical for memory formation. Array analysis indicated 41 candidate proteins have altered expression levels 24h after TBI. Of particular interest was catechol-O-methyl transferase (COMT), an enzyme involved in metabolizing catecholamines released following neuronal activity. Altered catecholamine signaling has been observed after brain injury, and may contribute to the cognitive dysfunctions and behavioral deficits often experienced after TBI. Our data shows that COMT expression in the injured ipsilateral hippocampus was elevated for at least 14 d after controlled cortical impact injury. We found strong co-localization of COMT immunoreactivity with the microglia marker Iba1 near the injury site. Since dopamine transporter expression has been reported to be down-regulated after brain injury, COMT-mediated catecholamine metabolism may play a more prominent role in terminating catecholamine signaling in injured areas.

Traumatic brain injury (TBI) produces cytoskeletal protein derangements within cortical neurons that can be attenuated by protease inhibition

TBI produces a consistent and extensive loss of neurofilament 68 (NF68) and neurofilament 200 (NF200), key intermediate cytoskeletal proteins found in neurons including axons and dendrites, in cortical samples from injured brain. The presence of low molecular weight NF68 breakdown products (BDPs) strongly suggest that calpain proteolysis at least in part contributes to neurofilament (NF) protein loss following injury. Furthermore, one and two-dimensional gel electrophoresis analyses of NF BDPs obtained from in situ and in vitro tissue also implicated the involvement of calpain 2 mediated proteolysis of neurofilaments following TBI. Immunohistochemical examination of derangements in cytoskeletal proteins following traumatic brain injury in rats indicated that preferential dendritic rather than axonal damage occurs within three hours post-TBI. Although proteolysis of cytoskeletal proteins occurred concurrently with early morphological alterations, evidence of proteolysis preceded the full expression of evolutionary histopathological changes. Furthermore, cytoskeletal immunofluorescence alterations were not restricted to the site of impact. Confocal microscopic investigations of NF68 and NF200 immunofluorescence within injured cortical neurons revealed alterations in neurofilament assembly in the absence of NF derangements detectable at the light microscopic level ($<$15 minutes post-TBI). Collectively immunohistochemistry studies suggest that derangements to neuronal processes are biochemical and evolutionary in nature, and not due solely to mechanical shearing. Importantly, a systemically administered calpain inhibitor (calpain inhibitor 2) significantly reduced NF200, NF68, and spectrin protein loss as well as providing marked preservation of NF proteins in neuronal somata, dendrites, and axons at 24 hours post-TBI. ^

Executive functions after pediatric mild traumatic brain injury: A prospective short-term longitudinal study

Traumatic brain injuries (TBIs) occur frequently in childhood and entail broad cognitive deficits, particularly in the domain of executive functions (EF). Concerning mild TBI (mTBI), only little empirical evidence is available on acute and postacute performance in EF. Given that EF are linked to school adaptation and achievement, even subtle deficits in performance may affect children's academic careers. The present study assessed performance in the EF components of inhibition, working memory (WM), and switching in children after mTBI. Regarding both acute and postacute consequences, performance trajectories were measured in 13 patients aged between 5 and 10 years and 13 controls who were closely matched in terms of sex, age, and education. Performance in the EF components of inhibition, switching, and WM was assessed in a short-term longitudinal design at 2, 6, and 12 weeks after the mTBI. Results indicate subtle deficits after mTBI, which became apparent in the longitudinal trajectory in the EF components of switching and WM. Compared with controls, children who sustained mTBI displayed an inferior performance enhancement across testing sessions in the first 6 weeks after the injury in switching and WM, resulting in a delayed deficit in the EF component of WM 12 weeks after the injury. Results are interpreted as mTBI-related deficits that become evident in terms of an inability to profit from previous learning opportunities, a finding that is potentially important for children's mastery of their daily lives.

Post-concussive symptoms and neuropsychological performance in the post-acute period following pediatric mild traumatic brain injury

Objective: There is evidence that children after mild traumatic brain injuries (mTBI) suffer ongoing post-concussive symptoms (PCS). However, results concerning neuropsychological outcome after mTBI are controversial. Thus, our aim was to examine group differences regarding neuropsychological outcome and PCS. Additionally, we explored the influence of current and pre-injury everyday attention problems on neuropsychological outcome in children after mTBI. Method: In a prospective short-term longitudinal study, 40 children (aged 6-16 years) after mTBI and 38 children after orthopedic injury (OI) underwent neuropsychological, socio-behavioral and PCS assessments in the acute stage and at 1 week, at 4 weeks, and 4 months after the injury. Results: Parents of children after mTBI observed significantly more PCS compared to parents of children after OI, especially in the acute stage. Our results revealed no neuropsychological or socio-behavioral differences over time between both groups. However, in children after mTBI, we found negative correlations between elevated levels of everyday attention problems and reduced neuropsychological performance. Furthermore, there was a negative influence of pre-injury everyday attention problems on neuropsychological performance in children after mTBI. Conclusion: In accordance with earlier studies, parents of children after mTBI initially observed significantly more PCS compared to parents of children after OI. There were no neuropsychological or socio-behavioral group differences between children after mTBI and OI in the post-acute period. However, our exploratory findings concerning the influence of everyday attention problems on neuropsychological outcome indicate that current and pre-injury everyday attention problems were negatively associated with neuropsychological performance in children after mTBI.

Increased sleep need and daytime sleepiness 6 months after traumatic brain injury: a prospective controlled clinical trial.

Post-traumatic sleep-wake disturbances are common after acute traumatic brain injury. Increased sleep need per 24 h and excessive daytime sleepiness are among the most prevalent post-traumatic sleep disorders and impair quality of life of trauma patients. Nevertheless, the relation between traumatic brain injury and sleep outcome, but also the link between post-traumatic sleep problems and clinical measures in the acute phase after traumatic brain injury has so far not been addressed in a controlled and prospective approach. We therefore performed a prospective controlled clinical study to examine (i) sleep-wake outcome after traumatic brain injury; and (ii) to screen for clinical and laboratory predictors of poor sleep-wake outcome after acute traumatic brain injury. Forty-two of 60 included patients with first-ever traumatic brain injury were available for follow-up examinations. Six months after trauma, the average sleep need per 24 h as assessed by actigraphy was markedly increased in patients as compared to controls (8.3 ± 1.1 h versus 7.1 ± 0.8 h, P < 0.0001). Objective daytime sleepiness was found in 57% of trauma patients and 19% of healthy subjects, and the average sleep latency in patients was reduced to 8.7 ± 4.6 min (12.1 ± 4.7 min in controls, P = 0.0009). Patients, but not controls, markedly underestimated both excessive sleep need and excessive daytime sleepiness when assessed only by subjective means, emphasizing the unreliability of self-assessment of increased sleep propensity in traumatic brain injury patients. At polysomnography, slow wave sleep after traumatic brain injury was more consolidated. The most important risk factor for developing increased sleep need after traumatic brain injury was the presence of an intracranial haemorrhage. In conclusion, we provide controlled and objective evidence for a direct relation between sleep-wake disturbances and traumatic brain injury, and for clinically significant underestimation of post-traumatic sleep-wake disturbances by trauma patients.

Acute S100B in serum is associated with cognitive symptoms and memory performance 4 months after paediatric mild traumatic brain injury

OBJECTIVE This study explored whether acute serum marker S100B is related with post-concussive symptoms (PCS) and neuropsychological performance 4 months after paediatric mild traumatic brain injury (mTBI). RESEARCH DESIGN AND METHODS This prospective short-term longitudinal study investigated children (aged 6-16 years) with mTBI (n = 36, 16 males) and children with orthopaedic injuries (OI, n = 27, 18 males) as a control group. S100B in serum was measured during the acute phase and was correlated with parent-rated PCS and neuropsychological performance 4 months after the injury. MAIN OUTCOMES AND RESULTS The results revealed no between-group difference regarding acute S100B serum concentration. In children after mTBI, group-specific significant Spearman correlations were found between S100B and post-acute cognitive PCS (r = 0.54, p = 0.001) as well as S100B and verbal memory performance (r = -0.47, p = 0.006). In children after OI, there were insignificant positive relations between S100B and post-acute somatic PCS. In addition, insignificant positive correlations were found between neuropsychological outcome and S100B in children after OI. CONCLUSIONS S100B was not specific for mild brain injuries and may also be elevated after OI. The group-specific association between S100B and ongoing cognitive PCS in children after mTBI should motivate to examine further the role of S100B as a diagnostic biomarker in paediatric mTBI.

Cohort Study on the Association Between Helmet Use and Traumatic Brain Injury in Snowboarders From a Swiss Tertiary Trauma Center.

BACKGROUND Since the introduction of helmets in winter sports there is on-going debate on whether they decrease traumatic brain injuries (TBI). METHODS This cohort study included 117 adult (≥ 16 years) snowboarders with TBI admitted to a level I alpine trauma center in Switzerland between 2000/2001 and 2010/2011. The primary objective was to examine the association between helmet use and moderate-to-severe TBI. Secondary objectives were to describe the epidemiology of TBI during the past decade in relation to increased helmet use. RESULTS Of 691 injured snowboarders evaluated, 117 (17%) suffered TBI. Sixty-six percent were men (median age, 23 years). Two percent of accidents were fatal. Ninety-two percent of patients sustained minor, 1% moderate, and 7% severe TBI according to the Glasgow coma scale. Pathologic computed tomography findings were present in 16% of patients, 26% of which required surgery. Eighty-three percent of TBIs occurred while riding on-slope. There was no trend in the TBI rate during the studied period, although helmet use increased from 10% to 69%. Comparing patients with and without a helmet showed no significant difference in odds ratios for the severity of TBI. However, of the 5 patients requiring surgery only 1 was wearing a helmet. Off-piste compared with on-slope snowboarders showed an odds ratio of 26.5 (P = 0.003) for sustaining a moderate-to-severe TBI. CONCLUSIONS Despite increased helmet use we found no decrease in TBI among snowboarders. The possibility of TBI despite helmet use and the dangers of riding off-piste should be a focus of future prevention programs.

Characterization of cytochrome P450 4F subfamily: Response in traumatic brain injury and gene regulation

CYP4F enzymes metabolize endogenous molecules including arachidonic acid, leukotrienes and prostaglandins. The involvement of these eisosanoids in inflammation has led to the hypothesis that CYP4Fs may modulate inflammatory conditions after traumatic brain injury (TBI). In rat, TBI elicited changes in mRNA expression of CYP4Fs as a function of time in the cerebrum region. These changes in CYP4F mRNA levels inversely correlated with the cerebral leukotriene B4 (LTB4) level following injury at the same time points. TBI also resulted in changes in CYP4F protein expression and localization around the injury site, where CYP4F1 and CYP4F6 immunoreactivity increased in surrounding astrocytes and CYP4F4 immunoreactivity shifted from endothelia of cerebral vessels to astrocytes. The study with rat primary astrocytes indicated that pro-inflammatory cytokines TNFα and IL-1β could affect the transcription of CYP4Fs to a certain degree, whereas the changing pattern in the primary astrocytes appeared to be different from that in the in vivo TBI model.^ In addition, the regulation of CYP4F genes has been an unsolved issue although factors including cytokines and fatty acids appear to affect CYP4Fs expression in multiple models. In this project, HaCaT cells were used as an in vitro cellular model to define signaling pathways involved in the regulation of human CYP4F genes. Retinoic acids inhibited CYP4F11 expression, whereas cytokines TNFα and IL-1β induced transcription of CYP4F11 in HaCaT cells. The induction of CYP4F11 by both cytokines could be blocked by a JNK specific inhibitor, indicating the involvement of the JNK pathway in the up-regulation of CYP4F11. Retinoic acids are known to function in gene regulation through nuclear receptors RARs and RXRs. The RXR agonist LG268 greatly induced transcription of CYP4F11, whereas RAR agonist TTNPB obviously inhibited CYP4F11 transcription, indicating that the down-regulation of CYP4F11 by retinoic acid was mediated by RARs, and that inhibition of CYP4F11 by retinoic acid may also be related to the competition for RXR receptors. Thus, the CYP4F11 gene is regulated by signaling pathways including the RXR pathway and the JNK pathway. In contrast, the regulation mechanism of other CYP4Fs by retinoic acids appears to be different from that of CYP4F11.^

MedVir: an interactive representation system of multidimensional medical data applied to Traumatic Brain Injury's rehabilitation prediction

Clinicians could model the brain injury of a patient through his brain activity. However, how this model is defined and how it changes when the patient is recovering are questions yet unanswered. In this paper, the use of MedVir framework is proposed with the aim of answering these questions. Based on complex data mining techniques, this provides not only the differentiation between TBI patients and control subjects (with a 72% of accuracy using 0.632 Bootstrap validation), but also the ability to detect whether a patient may recover or not, and all of that in a quick and easy way through a visualization technique which allows interaction.

The Utility of the CVLT-C as an Embedded Validity Indicator After Pediatric Mild Traumatic Brain Injury.

Results of neuropsychological examinations depend on valid data. Whereas clinicians previously believed that clinical skill was sufficient to identify non-credible performance by examinees on standard tests, research demonstrates otherwise. Consequently, studies on measures to detect suspect effort in adults have received tremendous attention in the previous twenty years, and incorporation of validity indicators into neuropsychological examinations is now seen as integral. Few studies exist that validate methods appropriate for the measurement of effort in pediatric populations. Of extant studies, most evaluate standalone measures originally developed for use with adults. The present study examined the utility of indices from the California Verbal Learning Test – Children's Version (CVLT-C) as embedded validity indicators in a pediatric sample. Participants were 225 outpatients aged 8 to 16 years old referred for clinical assessment after mild traumatic brain injury (mTBI). Non-credible performance (n = 39) was defined as failure of the Medical Symptom Validity Test (MSVT). Logistic regression demonstrated that only the Recognition Discriminability index was predictive of MSVT failure (OR = 2.88, p < .001). A cutoff of z ≤ -1.0 was associated with sensitivity of 51% and specificity of 91%. In the current study, CVLT-C Recognition Discriminability was useful in the identification of non-credible performance in a sample of relatively high-functioning pediatric outpatients with mTBI. Thus, this index can be added to the short list of embedded validity indicators appropriate for pediatric neuropsychological assessment.