Repetitive mild traumatic brain injury-induced neurodegeneration and inflammation is attenuated by acetyl-L-carnitine in a preclinical model.

Repetitive mild traumatic brain injuries (rmTBI) may contribute to the development of neurodegenerative diseases through secondary injury pathways. Acetyl-L-carnitine (ALC) shows neuroprotection through anti-inflammatory effects and via regulation of neuronal synaptic plasticity by counteracting post-trauma excitotoxicity. This study aimed to investigate mechanisms implicated in the etiology of neurodegeneration in rmTBI mice treated with ALC. Adult male C57BL/6J mice were allocated to sham, rmTBI or ALC + rmTBI groups. 15 rmTBIs were administered across 23 days using a modified weight drop model. Neurological testing and spatial learning and memory assessments via the Morris Water Maze (MWM) were undertaken at 48 h and 3 months. RT-PCR analysis of the cortex and hippocampus was undertaken for MAPT, GFAP, AIF1, GRIA, CCL11, TDP43, and TNF genes. Gene expression in the cortex showed elevated mRNA levels of MAPT, TNF, and GFAP in the rmTBI group that were reduced by ALC treatment. In the hippocampus, mRNA expression was elevated for GRIA1 in the rmTBI group but not the ALC + rmTBI treatment group. ALC treatment showed protective effects against the deficits displayed in neurological testing and MWM assessment observed in the rmTBI group. While brain structures display differential vulnerability to insult as evidenced by location specific postimpact disruption of key genes, this study shows correlative mRNA neurodegeneration and functional impairment that was ameliorated by ALC treatment in several key genes. ALC may mitigate damage inflicted in the various secondary neurodegenerative cascades and contribute to functional protection following rmTBI.

Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points.

The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.

Minocycline improves cognition and molecular measures of inflammation and neurodegeneration following repetitive mTBI.

OBJECTIVE: To compare the neuroprotective effects of minocycline treatment in a murine model of mTBI on measures of spatial learning and memory, neuroinflammation, excitotoxicity, and neurodegeneration. DESIGN: Adult male C57BL/6 J mice were randomly assigned into vehicle control, vehicle with repetitive mTBI, minocycline without mTBI, or minocycline with repetitive mTBI groups. METHODS: A validated mouse model of repetitive impact-induced rotational acceleration was used to deliver 15 mTBIs across 23 days. Cognition was assessed via Morris water maze (MWM) testing, and mRNA analysis investigated MAPT, GFAP, AIF1, GRIA1, TARDBP, TNF, and NEFL genes. Assessment was undertaken 48 h and 3 months following final mTBI. RESULTS: In the chronic phase of recovery, MWM testing revealed impairment in the vehicle mTBI group compared to unimpacted controls (p < .01) that was not present in the minocycline mTBI group, indicating chronic neuroprotection. mRNA analysis revealed AIF1 elevation in the acute cortex (p < .01) and chronic hippocampus (p < .01) of the vehicle mTBI group, with minocycline treatment leading to improved markers of microglial activation and inflammation in the chronic stage of recovery. CONCLUSIONS: These data suggest that minocycline treatment alleviated some mTBI pathophysiology and clinical features at chronic time-points.

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy.

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker's limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.

Modeling sports-related mild traumatic brain injury in animals-A systematic review.

Sports-related head trauma has emerged as an important public health issue, as mild traumatic brain injuries (mTBIs) may result in neurodegenerative disorders such as chronic traumatic encephalopathy (CTE). Research into mTBI and CTE pathophysiology are difficult to undertake in athletes, with observational trials and post-mortem analysis the current mainstays. Thus, animal models play an important role in the study of mTBI, however, traditional animal models have focused on acute, severe injuries rather than the more typical mTBI's seen in sport injuries. Recently, a number of animal models have been developed that are both appropriately scaled and biomechanically relevant to the forces sustained by athletes. This review aimed to examine the literature for variables included in these animal models, and the resulting neurotrauma as evidenced by pathology and behavioral deficits. A systematic search of the literature was performed in multiple electronic databases. The inclusion criteria required mimicry of athlete mTBI conditions: freedom of head movement, lack of surgical alteration of the skull, and application of direct contact force. Studies were analyzed for variables including apparatus design features (impact force, change in animal head velocity, and kinetic energy transfer to the head), demonstrated pathology (phosphorylated tau, TDP-43 aggregation, diffuse axonal injury, gliosis, cytokine inflammation response, and genetic integrity), and behavioral changes. These studies suggested that appropriate animal models can assist in understanding the pathological and functional outcomes of athlete mTBI, and could be used as a platform for future studies of diagnostic/prognostic markers and in the development of treatment interventions.

Utilization of Low Back Pain Patient Reported Outcome Measures Within Chiropractic Literature: A Descriptive Review.

OBJECTIVE: The purpose of this review was to determine the most commonly reported and utilized low back pain (LBP) Patient Reported Outcome Measures (PROMs) within the chiropractic literature and to investigate their temporal and methodological publication characteristics. METHODS: A systematic search of English-language publications in 5 electronic databases (PubMed, Cochrane [CENTRAL], CINAHL/EBSCO, PsycINFO, and Index to Chiropractic Literature) was conducted for articles published from the inception of each database through June 2016. RESULTS: One hundred forty-four articles were retrieved that utilized 75 different LBP PROMs. The 4 most commonly used LBP PROMs in the chiropractic literature were the Oswestry Disability Index, Numeric Rating Scale, Visual Analogue Scale, and Roland Morris Questionnaire. CONCLUSIONS: This research has created a unique list of the most commonly used LBP PROMs within the chiropractic literature.

A randomized double-blind placebo-controlled trial to investigate the effectiveness and safety of a novel green-lipped mussel extract -BioLex® -for managing pain in moderate to severe osteoarthritis of the hip and knee.

BACKGROUND: Extracts from perna canaliculus, the Green Lipped Mussel (GLM) are widely used as a complimentary therapy by patients with osteoarthritis (OA). The current study investigated the potential of a novel GLM formulation as a treatment for OA. A randomized double-blind placebo-controlled trial was undertaken to assess potential impacts on pain and quality of life following 12 weeks of treatment. METHODS: Eighty patients with moderate to severe OA of the hip or knee were randomized to receive either 600 mg of BioLex®-GLM daily or placebo for 12 weeks. Entry criteria included a minimum 100 mm Visual Analogue Scale pain score (VAS) of 30 mm at baseline. The primary outcome was patient reported pain, measured by the Western Ontario and McMasters OA Index (WOMAC) pain subscale and VAS pain scale. Secondary outcomes included: quality of life (OAQol), total WOMAC score, WOMAC -20 responder criteria, and change in medication use over the study period. Participants were assessed at baseline, 12 weeks (end of therapy) and 15 weeks (3-weeks post-intervention). RESULTS: At week 12, there were no significant differences in VAS or WOMAC pain subscale between active and placebo groups, nor significant improvement in the WOMAC-20 responder criteria or OAQol. Joint stiffness (measured by WOMAC-B stiffness) in the GLM group improved compared with placebo (p = 0.046). There was a significant difference in paracetamol use between the GLM treated group and the placebo group after week 12 (p = 0.001). CONCLUSIONS: BioLex® -GLM extract did not confer clinical benefit in moderate to severe OA over the intervention period, however, a significant difference in paracetamol use in the post-intervention period was observed between the BioLex® -GLM group and placebo group. Higher doses and/or longer treatment periods are worthy of future investigation. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry: no. ACTRN12611000256976 .

Does Acupressure Hit the Mark? A Three-Arm Randomized Placebo-Controlled Trial of Acupressure for Pain and Anxiety Relief in Athletes With Acute Musculoskeletal Sports Injuries.

OBJECTIVES: Injuries are a common consequence of sports and recreational activity. The optimal management of symptoms is a crucial element of sports injury management. Acupressure has previously been shown to effectively decrease symptoms of musculoskeletal injury, thus may be considered a potentially useful intervention in the management of sport-related injuries. Therefore, this study was conducted to examine the effectiveness of acupressure in decreasing pain and anxiety in acutely injured athletes. DESIGN: A prospective 3-arm randomized placebo-controlled trial. SETTING: A sports injury clinic, Dunedin, New Zealand. PATIENTS: Seventy-nine athletes who sustained a sport-related musculoskeletal injury on the day. INTERVENTION: Three minutes of either acupressure, sham acupressure, or no acupressure. MAIN OUTCOME MEASURES: The primary outcomes of pain and anxiety intensity were measured before and immediately after the intervention on a 100-mm visual analog scale (VAS). Pain and anxiety relief, satisfaction with treatment, willingness to repeat a similar treatment, and belief in the effect of acupressure were secondary outcomes measured on Likert scales after the intervention. RESULTS: The acupressure group reported 11 mm less pain (95% CI: 5-17) on average than the sham acupressure group, and 9 mm less (95% CI: 3-16) than the control group as a result of the intervention (P < 0.05). There was no difference between groups in: anxiety levels, or in any of the secondary outcome measures. CONCLUSIONS: Three minutes of acupressure was effective in decreasing pain intensity in athletes who sustained an acute musculoskeletal sports injury when measured on the VAS, but did not change anxiety levels.

Sport Concussion Management Using Facebook: A Feasibility Study of an Innovative Adjunct "iCon".

CONTEXT: Sport concussion is currently the focus of much international attention. Innovative methods to assist athletic trainers in facilitating management after this injury need to be investigated. OBJECTIVE: To investigate the feasibility of using a Facebook concussion-management program termed iCon (interactive concussion management) to facilitate the safe return to play (RTP) of young persons after sport concussion. DESIGN: Observational study. SETTING: Facebook group containing interactive elements, with moderation and support from trained health care professionals. PATIENTS OR OTHER PARTICIPANTS: Eleven participants (n = 9 men, n = 2 women; range, 18 to 28 years old) completed the study. DATA COLLECTION AND ANALYSIS: The study was conducted over a 3-month period, with participant questionnaires administered preintervention and postintervention. The primary focus was on the qualitative experiences of the participants and the effect of iCon on their RTP. Usage data were also collected. RESULTS: At the completion of the study, all participants (100%) stated that they would recommend an intervention such as iCon to others. Their supporting quotes all indicated that iCon has the potential to improve the management of concussion among this cohort. Most participants (n = 9, 82%) stated they were better informed with regard to their RTP due to participating in iCon. CONCLUSIONS: This interactive adjunct to traditional concussion management was appreciated among this participant group, which indicates the feasibility of a future, larger study of iCon. Athletic trainers should consider the role that multimedia technologies may play in assisting with the management of sport concussion.

Do Functional Movement Screen (FMS) composite scores predict subsequent injury? A systematic review with meta-analysis.

AIM: This paper aims to systematically review studies investigating the strength of association between FMS composite scores and subsequent risk of injury, taking into account both methodological quality and clinical and methodological diversity. DESIGN: Systematic review with meta-analysis. DATA SOURCES: A systematic search of electronic databases was conducted for the period between their inception and 3 March 2016 using PubMed, Medline, Google Scholar, Scopus, Academic Search Complete, AMED (Allied and Complementary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), Health Source and SPORTDiscus. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Inclusion criteria: (1) English language, (2) observational prospective cohort design, (3) original and peer-reviewed data, (4) composite FMS score, used to define exposure and non-exposure groups and (5) musculoskeletal injury, reported as the outcome. EXCLUSION CRITERIA: (1) data reported in conference abstracts or non-peer-reviewed literature, including theses, and (2) studies employing cross-sectional or retrospective study designs. RESULTS: 24 studies were appraised using the Quality of Cohort Studies assessment tool. In male military personnel, there was 'strong' evidence that the strength of association between FMS composite score (cut-point ≤14/21) and subsequent injury was 'small' (pooled risk ratio=1.47, 95% CI 1.22 to 1.77, p<0.0001, I2=57%). There was 'moderate' evidence to recommend against the use of FMS composite score as an injury prediction test in football (soccer). For other populations (including American football, college athletes, basketball, ice hockey, running, police and firefighters), the evidence was 'limited' or 'conflicting'. CONCLUSION: The strength of association between FMS composite scores and subsequent injury does not support its use as an injury prediction tool. TRIAL REGISTRATION NUMBER: PROSPERO registration number CRD42015025575.

Day-to-day variability of post-concussion-like symptoms reported over time by a non-concussed cohort.

PRIMARY OBJECTIVE: To explore the change (trend) in post-concussion-like symptoms reported over time. RESEARCH DESIGN: Longitudinal study. METHODS AND PROCEDURES: University students aged 18-30 years self-reported their symptoms experienced on a daily basis. Each participant was contacted via a text message each day during one of three pre-defined time zones to complete the Sport Concussion Assessment Tool 2 (SCAT2) post-concussion symptom scale on 7 consecutive days. MAIN OUTCOMES AND RESULTS: One hundred and ten (26 males and 84 females) students completed the study on all 7 days. Only two meaningful clusters emerged and comprised of a total of 105 participants. The primary cluster included 85 participants who showed a relatively stable pattern in their symptoms reported over time. Meanwhile, a second cluster comprised of 20 participants who demonstrated a decreasing trend in the reported symptom scores. CONCLUSIONS: The data indicated that non-concussed participants exhibited considerable individual variability in the symptom scores reported over time. However, some participants showed a systematic decreasing trend in their symptom scores reported over the 7 days. Caution must be exercised in interpreting the serial symptom scores that are obtained following a concussion, given that this study was conducted in a non-concussed cohort.

The Influence of Psychological and Lifestyle Factors on the Reporting of Postconcussion-Like Symptoms.

Self-reported symptoms are an integral part of the assessment and management of a sports-related concussion. However, postconcussion-like symptoms are reported by non-concussed individuals. Moreover, the current best practice in the reporting of symptoms does not take into account the potential influence of psychological and lifestyle factors. This study aimed to explore the influence of these factors on the reporting of postconcussion-like symptoms. University students (N= 603) completed the Sport Concussion Assessment Tool 2 postconcussion symptom scale along with other predictor variables via a cross-sectional web-based survey. Linear regression analyses revealed six modifiers contributing to the total symptom score with the strongest being alcohol consumption (Estimate = 2.75, p < .001). Following these findings, clinicians need to exercise caution when interpreting the symptom scores for making decisions on the return-to-play (RTP). A failure to do so may lead the health professional to either prematurely RTP or not clear the concussed athlete to resume their sport.

How reliable are Functional Movement Screening scores? A systematic review of rater reliability.

BACKGROUND: Several physical assessment protocols to identify intrinsic risk factors for injury aetiology related to movement quality have been described. The Functional Movement Screen (FMS) is a standardised, field-expedient test battery intended to assess movement quality and has been used clinically in preparticipation screening and in sports injury research. AIM: To critically appraise and summarise research investigating the reliability of scores obtained using the FMS battery. STUDY DESIGN: Systematic literature review. METHODS: Systematic search of Google Scholar, Scopus (including ScienceDirect and PubMed), EBSCO (including Academic Search Complete, AMED, CINAHL, Health Source: Nursing/Academic Edition), MEDLINE and SPORTDiscus. Studies meeting eligibility criteria were assessed by 2 reviewers for risk of bias using the Quality Appraisal of Reliability Studies checklist. Overall quality of evidence was determined using van Tulder's levels of evidence approach. RESULTS: 12 studies were appraised. Overall, there was a 'moderate' level of evidence in favour of 'acceptable' (intraclass correlation coefficient ≥0.6) inter-rater and intra-rater reliability for composite scores derived from live scoring. For inter-rater reliability of composite scores derived from video recordings there was 'conflicting' evidence, and 'limited' evidence for intra-rater reliability. For inter-rater reliability based on live scoring of individual subtests there was 'moderate' evidence of 'acceptable' reliability (κ≥0.4) for 4 subtests (Deep Squat, Shoulder Mobility, Active Straight-leg Raise, Trunk Stability Push-up) and 'conflicting' evidence for the remaining 3 (Hurdle Step, In-line Lunge, Rotary Stability). CONCLUSIONS: This review found 'moderate' evidence that raters can achieve acceptable levels of inter-rater and intra-rater reliability of composite FMS scores when using live ratings. Overall, there were few high-quality studies, and the quality of several studies was impacted by poor study reporting particularly in relation to rater blinding.

Clinical tests to diagnose lumbar spondylolysis and spondylolisthesis: A systematic review.

The aim of this paper was to systematically review the diagnostic ability of clinical tests to detect lumbar spondylolysis and spondylolisthesis. A systematic literature search of six databases, with no language restrictions, from 1950 to 2014 was concluded on February 1, 2014. Clinical tests were required to be compared against imaging reference standards and report, or allow computation, of common diagnostic values. The systematic search yielded a total of 5164 articles with 57 retained for full-text examination, from which 4 met the full inclusion criteria for the review. Study heterogeneity precluded a meta-analysis of included studies. Fifteen different clinical tests were evaluated for their ability to diagnose lumbar spondylolisthesis and one test for its ability to diagnose lumbar spondylolysis. The one-legged hyperextension test demonstrated low to moderate sensitivity (50%-73%) and low specificity (17%-32%) to diagnose lumbar spondylolysis, while the lumbar spinous process palpation test was the optimal diagnostic test for lumbar spondylolisthesis; returning high specificity (87%-100%) and moderate to high sensitivity (60-88) values. Lumbar spondylolysis and spondylolisthesis are identifiable causes of LBP in athletes. There appears to be utility to lumbar spinous process palpation for the diagnosis of lumbar spondylolisthesis, however the one-legged hyperextension test has virtually no value in diagnosing patients with spondylolysis.

Smartphone and tablet apps for concussion road warriors (team clinicians): a systematic review for practical users.

BACKGROUND: Mobile technologies are steadily replacing traditional assessment approaches for the recognition and assessment of a sports concussion. Their ease of access, while facilitating the early identification of a concussion, also raises issues regarding the content of the applications (apps) and their suitability for different user groups. AIM: To locate and review apps that assist in the recognition and assessment of a sports concussion and to assess their content with respect to that of internationally accepted best-practice instruments. METHODS: A search of international app stores and of the web using key terms such as 'concussion', 'sports concussion' and variants was conducted. For those apps meeting the inclusion criteria, data were extracted on the platform, intended users and price. The content of each app was benchmarked to the Sport Concussion Assessment Tool 2 (SCAT2) and Pocket SCAT2 using a custom scoring scheme to generate a percentage compliance statistic. RESULTS: 18 of the 155 apps identified met the inclusion criteria. Almost all (16/18) were available on an iOS platform and only five required a payment to purchase. The apps were marketed for a wide range of intended users from medical professionals to the general public. The content of the apps varied from 0% to 100% compliance with the selected standard, and 'symptom evaluation' components demonstrated the highest level of compliance. CONCLUSIONS: The surge in availability of apps in an unregulated market raises concerns as to the appropriateness of their content for different groups of end users. The consolidation of best-practice concussion instruments now provides a framework to inform the development of future apps.

Does a standardised exercise protocol incorporating a cognitive task provoke postconcussion-like symptoms in healthy individuals?

OBJECTIVES: To explore whether an exercise protocol, alone and in combination with two selected cognitive tasks related to working memory, provokes postconcussion-like symptoms in healthy individuals. DESIGN: Prospective single cohort semi-randomised crossover repeated measures (time×condition) design. METHODS: 36 healthy individuals completed three submaximal exercise protocol conditions, namely: exercise alone, exercise with the paced auditory serial addition task, and exercise with Tetris. Self-reported symptoms were measured before exercise and 1-min and 15-min after the cessation of each exercise protocol using the Sports Concussion Assessment Tool 2-Postconcussion symptoms scale. RESULTS: Analysis of variance indicated a significant increase in symptom scores over time (p<0.001), but no effect between conditions (p=0.371) or a significant time×condition interaction (p=0.444). CONCLUSIONS: The combination of working memory tasks and a symptom provoking submaximal exercise protocol did not have an additional effect on the provocation of self-reported symptoms in healthy individuals. Furthermore, the two distinct methods of cognitive load delivery, controlled (paced auditory serial addition task) and pragmatic (Tetris), did not lead to a differential symptom response. These findings provide an initial insight into the scientific foundations for the symptom provocation model that is integral to the currently accepted clinical postconcussion return-to-play protocol.