Graded Exposure Therapy for Fear Avoidance Behaviour After Concussion (GET FAB): protocol for a multisite Canadian randomised controlled trial.

INTRODUCTION: Persistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which people avoid or escape from activities or situations that they expect will exacerbate their symptoms, maybe a particularly potent and modifiable risk factor for chronic disability after mTBI. This study will evaluate the efficacy of graded exposure therapy (GET) for reducing persistent symptoms following mTBI, with two primary aims: (1) To determine whether GET is more effective than usual care; (2) to identify for whom GET is the most effective treatment option, by evaluating whether baseline fear avoidance moderates differences between GET and an active comparator (prescribed aerobic exercise). Our findings will guide evidence-based care after mTBI and enable better matching of mTBI patients to treatments. METHODS AND ANALYSIS: We will conduct a multisite randomised controlled trial with three arms. Participants (n=220) will be recruited from concussion clinics and emergency departments in three Canadian provinces and randomly assigned (1:2:2 ratio) to receive enhanced usual care, GET or prescribed aerobic exercise. The outcome assessment will occur remotely 14-18 weeks following baseline assessment, after completing the 12-week treatment phase. The primary outcome will be symptom severity (Rivermead Post-concussion Symptoms Questionnaire). ETHICS AND DISSEMINATION: Informed consent will be obtained from all participants. All study procedures were approved by the local research ethics boards (University of British Columbia Clinical Research Ethics Board, University of Calgary Conjoint Health Research Ethics Board, University Health Network Research Ethics Board-Panel D). Operational approvals were obtained for Vancouver Coastal Health Research Institute and Provincial Health Services Authority. If GET proves effective, we will disseminate the GET treatment manual and present instructional workshops for clinicians. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov #NCT05365776.

Ultrasound guided platelet rich plasma injections for post-traumatic greater occipital neuralgia following concussion: a pilot randomized controlled trial.

Background: Treatment for post-traumatic greater occipital neuralgia (GON) includes serial injections of steroid/anesthetic. While these injections can alleviate pain, effects can be transient, frequently lasting only 1 month. As a potential alternative, platelet-rich plasma (PRP) injections are an emerging biological treatment with beneficial effects in peripheral nerve disorders. We investigated the feasibility, safety, and effectiveness of a single PRP injection for post-traumatic GON in comparison to saline or steroid/anesthetic injection. Methods: In this pilot randomized, double-blinded, placebo-controlled trial, 32 adults with post-traumatic GON were allocated 1:1:1 to receive a single ultrasound-guided injection of (1) autologous PRP (2) steroid/anesthetic or (3) normal saline. Our primary outcome was feasibility (recruitment, attendance, retention) and safety (adverse events). Exploratory measures included headache intensity and frequency (daily headache diaries) and additional questionnaires (headache impact, and quality of life) assessed at pre-injection, 1 week, 1 month, and 3 months post-injection. Results: We screened 67 individuals, 55% were eligible and 95% of those participated. Over 80% of daily headache diaries were completed with 91% of participants completing the 3-month outcome questionnaires. No serious adverse events were reported. There were no significant differences between groups for headache intensity or frequency. Headache impact on function test-6 scores improved at 3 month in the PRP (ß = -9.7, 95% CI [-15.6, -3.74], p = 0.002) and saline (ß = -6.7 [-12.7, -0.57], p = 0.033) groups but not steroid/anesthetic group (p = 0.135). Conclusion: PRP is a feasible and safe method for treating post-traumatic GON with comparable results to saline and steroid/anaesthetic. Further trials with larger sample sizes are required.Clinical trial registration:https://clinicaltrials.gov/, identifier NCT04051203.

Assessment of sleep parameters in adults with persistent post-concussive symptoms.

OBJECTIVES: The primary aim of this study was to characterize sleep in adults with persistent post-concussive symptoms (PPCS). Secondary aims explored relationships between sleep parameters, injury characteristics, and symptom questionnaires. METHODS: This case-controlled, cross-sectional study recruited adults (18-65yrs) diagnosed with PPCS and age and sex-matched controls. Participants wore a wrist-worn actigraph for 3-7 nights and completed daily sleep diaries. Participants completed questionnaires examining daytime sleepiness, fatigue, anxiety/depressive symptoms, and sedentariness. Sleep parameters were compared between groups using Mann-Whitney U tests. Secondary analyses used two-way ANOVA and Spearman's rank correlations. RESULTS: Fifty adults with PPCS (43.7 ± 10.6yrs, 78 % female) and 50 controls (43.6 ± 11.0yrs) were included in this study. Adults with PPCS had significantly longer sleep onset latency (PPCS 16.99 ± 14.51min, Controls 8.87 ± 6.44min, p < 0.001) and total sleep time (PPCS 8.3 ± 1.0hrs, Control 7.6 ± 0.9hrs, p = 0.030) compared to controls, but woke up later (PPCS 7:57:27 ± 1:36:40, Control 7:17:16 ± 0:50:08, p = 0.026) and had poorer sleep efficiency (PPCS 77.9 ± 7.5 %, Control 80.8 ± 6.0 %, p = 0.019) than controls. Adults with PPCS reported more daytime sleepiness (Epworth Sleepiness Scale: PPCS 8.70 ± 4.61, Control 4.28 ± 2.79, p < 0.001) and fatigue (Fatigue Severity Scale: PPCS 56.54 ± 12.92, Control 21.90 ± 10.38, p < 0.001). Injury characteristics did not significantly affect sleep parameters in adults with PPCS. Actigraphy parameters were not significantly correlated to questionnaire measures. CONCLUSION: Several actigraphy sleep parameters were significantly altered in adults with PPCS compared to controls, but did not correlate with sleep questionnaires, suggesting both are useful tools in characterizing sleep in PPCS. Further, this study provides potential treatment targets to improve sleep difficulties in adults with PPCS.

Unraveling Metabolic Changes following Stroke: Insights from a Urinary Metabolomics Analysis.

The neuropathological sequelae of stroke and subsequent recovery are incompletely understood. Here, we investigated the metabolic dynamics following stroke to advance the understanding of the pathophysiological mechanisms orchestrating stroke recovery. Using a nuclear magnetic resonance (NMR)-driven metabolomic profiling approach for urine samples obtained from a clinical group, the objective of this research was to (1) identify novel biomarkers indicative of severity and recovery following stroke, and (2) uncover the biochemical pathways underlying repair and functional recovery after stroke. Urine samples and clinical stroke assessments were collected during the acute (2-11 days) and chronic phases (6 months) of stroke. Using a 700 MHz 1H NMR spectrometer, metabolomic profiles were acquired followed by a combination of univariate and multivariate statistical analyses, along with biological pathway analysis and clinical correlations. The results revealed changes in phenylalanine, tyrosine, tryptophan, purine, and glycerophospholipid biosynthesis and metabolism during stroke recovery. Pseudouridine was associated with a change in post-stroke motor recovery. Thus, NMR-based metabolomics is able to provide novel insights into post-stroke cellular functions and establish a foundational framework for future investigations to develop targeted therapeutic interventions, advance stroke diagnosis and management, and enhance overall quality of life for individuals with stroke.

Blood-Derived Metabolic Signatures as Biomarkers of Injury Severity in Traumatic Brain Injury: A Pilot Study.

Metabolomic biomarkers hold promise in aiding the diagnosis and prognostication of traumatic brain injury. In Canada, over 165,000 individuals annually suffer from a traumatic brain injury (TBI), making it one of the most prevalent neurological conditions. In this pilot investigation, we examined blood-derived biomarkers as proxy measures that can provide an objective approach to TBI diagnosis and monitoring. Using a 1H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined whether (1) blood-derived metabolites change during recovery in male participants with mild to severe TBI; (2) biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery; and (3) changes in metabolites correlate to initial injury severity. Eight male participants with mild to severe TBI (with intracranial lesions) provided morning blood samples within 1-4 days and again 6 months post-TBI. Following NMR analysis, the samples were subjected to multivariate statistical and machine learning-based analyses. Statistical modelling displayed metabolic changes during recovery through group separation, and eight significant metabolic pathways were affected by TBI. Metabolic changes were correlated to injury severity. L-alanine (R= -0.63, p < 0.01) displayed a negative relationship with the Glasgow Coma Scale. This study provides pilot data to support the feasibility of using blood-derived metabolites to better understand changes in biochemistry following TBI.

Obsessive-compulsive disorder following severe traumatic brain injury.

Obsessive-compulsive disorder (OCD) as a consequence of severe traumatic brain injury (TBI) has been reported in a limited number of case studies. Informed by CARE guidelines, we present the case of a boy in his late adolescence who sustained a severe TBI from a motor vehicle crash. His injuries required a prolonged stay in the hospital, including 3 weeks in the intensive care unit and a craniotomy to evacuate a large subdural haematoma. Obsessive-compulsive behaviours were first observed on discharge from the hospital and became worse over time. Compulsive behaviours were considered in light of a neuropsychological examination, and a diagnosis of OCD was attained. Sertraline was prescribed and effectively reduced the severity of OCD symptoms. Given the challenges comorbid conditions can pose to neurorehabilitation, a better understanding of patterns in OCD symptoms and brain lesions among reported cases will help guide the diagnosis of OCD among individuals with severe TBI.

Use of Biostatistical Models to Manage Replicate Error in Concussion Biomarker Research.

Importance: Advancing research on fluid biomarkers associated with sport-related concussion (SRC) highlights the importance of detecting low concentrations using ultrasensitive platforms. However, common statistical practices may overlook replicate errors and specimen exclusion, emphasizing the need to explore robust modeling approaches that consider all available replicate data for comprehensive understanding of sample variation and statistical inferences. Objective: To evaluate the impact of replicate error and different biostatistical modeling approaches on SRC biomarker interpretation. Design, Setting, and Participants: This cross-sectional study within the Surveillance in High Schools to Reduce the Risk of Concussions and Their Consequences study used data from healthy youth athletes (ages 11-18 years) collected from 3 sites across Canada between September 2019 and November 2021. Data were analyzed from November 2022 to February 2023. Exposures: Demographic variables included age, sex, and self-reported history of previous concussion. Main Outcomes and Measures: Outcomes of interest were preinjury plasma glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament-light (NFL), total tau (t-tau) and phosphorylated-tau-181 (p-tau-181) assayed in duplicate. Bland-Altman analysis determined the 95% limits of agreement (LOAs) for each biomarker. The impact of replicate error was explored using 3 biostatistical modeling approaches assessing the associations of age, sex, and previous concussion on biomarker concentrations: multilevel regression using all available replicate data, single-level regression using the means of replicate data, and single-level regression with replicate means, excluding specimens demonstrating more than 20% coefficient variation (CV). Results: The sample included 149 healthy youth athletes (78 [52%] male; mean [SD] age, 15.74 [1.41] years; 51 participants [34%] reporting ≥1 previous concussions). Wide 95% LOAs were observed for GFAP (-17.74 to 18.20 pg/mL), UCH-L1 (-13.80 to 14.77 pg/mL), and t-tau (65.27% to 150.03%). GFAP and UCH-L1 were significantly associated with sex in multilevel regression (GFAP: effect size, 15.65%; ß = -0.17; 95% CI, -0.30 to -0.04]; P = .02; UCH-L1: effect size, 17.24%; ß = -0.19; 95% CI, -0.36 to -0.02]; P = .03) and single-level regression using the means of replicate data (GFAP: effect size, 15.56%; ß = -0.17; 95% CI, -0.30 to -0.03]; P = .02; UCH-L1: effect size, 18.02%; ß = -0.20; 95% CI, -0.37 to -0.03]; P = .02); however, there was no association for UCH-L1 after excluding specimens demonstrating more than 20% CV. Excluding specimens demonstrating more than 20% CV resulted in decreased differences associated with sex in GFAP (effect size, 12.29%; ß = -0.14; 95% CI, -0.273 to -0.004]; P = .04) and increased sex differences in UCH-L1 (effect size, 23.59%; ß = -0.27; 95% CI, -0.55 to 0.01]; P = .06), with the widest 95% CIs (ie, least precision) found in UCH-L1. Conclusions and Relevance: In this cross-sectional study of healthy youth athletes, varying levels of agreement between SRC biomarker technical replicates suggested that means of measurements may not optimize precision for population values. Multilevel regression modeling demonstrated how incorporating all available biomarker data could capture replicate variation, avoiding challenges associated with means and percentage of CV exclusion thresholds to produce more representative estimates of association.

Psychosocial Factors Associated With Time to Recovery After Concussion in Adolescent Ice Hockey Players.

OBJECTIVE: To investigate the association between psychosocial factors and physician clearance to return to play (RTP) in youth ice hockey players after sport-related concussion. DESIGN: Prospective cohort study, Safe to Play (2013-2018). SETTING: Youth hockey leagues in Alberta and British Columbia, Canada. PARTICIPANTS: Three hundred fifty-three ice hockey players (aged 11-18 years) who sustained a total of 397 physician-diagnosed concussions. INDEPENDENT VARIABLES: Psychosocial variables. MAIN OUTCOME MEASURES: Players and parents completed psychosocial questionnaires preinjury. Players with a suspected concussion were referred for a study physician visit, during which they completed the Sport Concussion Assessment Tool (SCAT3/SCAT5) and single question ratings of distress and expectations of recovery. Time to recovery (TTR) was measured as days between concussion and physician clearance to RTP. Accelerated failure time models estimated the association of psychosocial factors with TTR, summarized with time ratios (TRs). Covariates included age, sex, body checking policy, days from concussion to the initial physician visit, and symptom severity at the initial physician visit. RESULTS: Self-report of increased peer-related problems on the Strengths and Difficulties Questionnaire (TR, 1.10 [95% CI, 1.02-1.19]), higher ratings of distress about concussion outcomes by participants (TR, 1.06 [95% CI, 1.01-1.11]) and parents (TR, 1.05 [95% CI, 1.01-1.09]), and higher parent ratings of distress about their child's well-being at the time of injury (TR, 1.06 [95% CI, 1.02-1.09]) were associated with longer recovery. CONCLUSIONS: Greater pre-existing peer-related problems and acute distress about concussion outcomes and youth well-being predicted longer TTR. Treatment targeting these psychosocial factors after concussion may promote recovery.

The importance of screening for functional neurological disorders in patients with persistent post-concussion symptoms.

BACKGROUND: Functional neurological disorder (FND) may commonly co-occur with persistent symptoms following a psychological trauma or physical injury such as concussion. OBJECTIVE: To explore the occurrence of FND in a population with persistent post-concussion symptoms (PPCS) and the associations between FND and depression as well as anxiety in participants with PPCS. METHODS: Sixty-three individuals with PPCS presenting to a specialized brain injury clinic completed the following questionnaires: screening for somatoform disorder conversion disorder subscale (SOM-CD), Rivermead post-concussion symptom questionnaire (RPQ), patient health questionnaire-9 (PHQ-9), and generalized anxiety disorder questionnaire- 7 (GAD-7). Both multiple linear regression and logistic regression were conducted to evaluate the relationship between questionnaires and adjust for covariates. RESULTS: We found that total RPQ score (߈= 0.27; 95% CI = [0.16, 0.38]), GAD-7 score (߈= 0.71; 95% CI = [0.50, 0.92]) and PHQ-9 score (߈= 0.54; 95% CI = [0.32, 0.76]) were positively associated with SOM-CD score individually, after consideration of other covariates. Participants meeting the criteria for severe FND symptoms were 4.87 times more likely to have high PPCS symptom burden (95% CI = [1.57, 22.84]), 8.95 times more likely to have severe anxiety (95% CI = [3.31, 35.03]) and 4.11 times more likely to have severe depression symptom burden (95% CI = [1.77, 11.53]). CONCLUSION: The findings of this study indicate an association between FND and post-concussion symptoms as well as an association between FND and symptoms of depression and anxiety in patients with PPCS. Patients with PPCS should be screened for FND to provide a more targeted treatment approach that includes somatic-focused interventions.

Impact of averaging fNIRS regional coherence data when monitoring people with long term post-concussion symptoms.

Significance: Functional near-infrared spectroscopy (fNIRS), with its measure of delta hemoglobin concentration, has shown promise as a monitoring tool for the functional assessment of neurological disorders and brain injury. Analysis of fNIRS data often involves averaging data from several channel pairs in a region. Although this greatly reduces the processing time, it is uncertain how it affects the ability to detect changes post injury. Aim: We aimed to determine how averaging data within regions impacts the ability to differentiate between post-concussion and healthy controls. Approach: We compared interhemispheric coherence data from 16 channel pairs across the left and right dorsolateral prefrontal cortex during a task and a rest period. We compared the statistical power for differentiating groups that was obtained when undertaking no averaging, vs. averaging data from 2, 4, or 8 source detector pairs. Results: Coherence was significantly reduced in the concussion group compared with controls when no averaging was undertaken. Averaging all 8 channel pairs before undertaking the coherence analysis resulted in no group differences. Conclusions: Averaging between fiber pairs may eliminate the ability to detect group differences. It is proposed that even adjacent fiber pairs may have unique information, so averaging must be done with caution when monitoring brain disorders or injury.

What tests and measures accurately diagnose persisting post-concussive symptoms in children, adolescents and adults following sport-related concussion? A systematic review.

OBJECTIVE: To determine what tests and measures accurately diagnose persisting post-concussive symptoms (PPCS) in children, adolescents and adults following sport-related concussion (SRC). DESIGN: A systematic literature review. DATA SOURCES: MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL and SPORTDiscus through March 2022. ELIGIBILITY CRITERIA: Original, empirical, peer-reviewed findings (cohort studies, case-control studies, cross-sectional studies and case series) published in English and focused on SRC. Studies needed to compare individuals with PPCS to a comparison group or their own baseline prior to concussion, on tests or measures potentially affected by concussion or associated with PPCS. RESULTS: Of 3298 records screened, 26 articles were included in the qualitative synthesis, including 1016 participants with concussion and 531 in comparison groups; 7 studies involved adults, 8 involved children and adolescents and 11 spanned both age groups. No studies focused on diagnostic accuracy. Studies were heterogeneous in participant characteristics, definitions of concussion and PPCS, timing of assessment and the tests and measures examined. Some studies found differences between individuals with PPCS and comparison groups or their own pre-injury assessments, but definitive conclusions were not possible because most studies had small convenience samples, cross-sectional designs and were rated high risk of bias. CONCLUSION: The diagnosis of PPCS continues to rely on symptom report, preferably using standardised symptom rating scales. The existing research does not indicate that any other specific tool or measure has satisfactory accuracy for clinical diagnosis. Future research drawing on prospective, longitudinal cohort studies could help inform clinical practice.

Targeted interventions and their effect on recovery in children, adolescents and adults who have sustained a sport-related concussion: a systematic review.

OBJECTIVES: We evaluated interventions to facilitate recovery in children, adolescents and adults with a sport-related concussion (SRC). DESIGN: Systematic review including risk of bias (modified Scottish Intercollegiate Guidelines Network tool). DATA SOURCES: MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, APA PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL Plus with Full Text, SPORTDiscus and Scopus searched until March 2022. STUDY ELIGIBILITY CRITERIA: (1) Original research including randomised controlled trials (RCTs), quasi-experimental designs, cohort, comparative effectiveness studies; (2) focus on SRC; (3) English; (4) peer-reviewed and (5) evaluated treatment. RESULTS: 6533 studies were screened, 154 full texts reviewed and 13 met inclusion (10 RCTs, 1 quasi-experimental and 2 cohort studies; 1 high-quality study, 7 acceptable and 5 at high risk of bias). Interventions, comparisons, timing and outcomes varied, precluding meta-analysis. For adolescents and adults with dizziness, neck pain and/or headaches >10 days following concussion, individualised cervicovestibular rehabilitation may decrease time to return to sport compared with rest followed by gradual exertion (HR 3.91 (95% CI 1.34 to 11.34)) and when compared with a subtherapeutic intervention (HR 2.91 (95% CI 1.01 to 8.43)). For adolescents with vestibular symptoms/impairments, vestibular rehabilitation may decrease time to medical clearance (vestibular rehab group 50.2 days (95% CI 39.9 to 60.4) compared with control 58.4 (95% CI 41.7 to 75.3) days). For adolescents with persisting symptoms >30 days, active rehabilitation and collaborative care may decrease symptoms. CONCLUSIONS: Cervicovestibular rehabilitation is recommended for adolescents and adults with dizziness, neck pain and/or headaches for >10 days. Vestibular rehabilitation (for adolescents with dizziness/vestibular impairments >5 days) and active rehabilitation and/or collaborative care (for adolescents with persisting symptoms >30 days) may be of benefit.

Identification of Serum Metabolites as Prognostic Biomarkers Following Spinal Cord Injury: A Pilot Study.

The assessment, management, and prognostication of spinal cord injury (SCI) mainly rely upon observer-based ordinal scales measures. 1H nuclear magnetic resonance (NMR) spectroscopy provides an effective approach for the discovery of objective biomarkers from biofluids. These biomarkers have the potential to aid in understanding recovery following SCI. This proof-of-principle study determined: (a) If temporal changes in blood metabolites reflect the extent of recovery following SCI; (b) whether changes in blood-derived metabolites serve as prognostic indicators of patient outcomes based on the spinal cord independence measure (SCIM); and (c) whether metabolic pathways involved in recovery processes may provide insights into mechanisms that mediate neural damage and repair. Morning blood samples were collected from male complete and incomplete SCI patients (n = 7) following injury and at 6 months post-injury. Multivariate analyses were used to identify changes in serum metabolic profiles and were correlated to clinical outcomes. Specifically, acetyl phosphate, 1,3,7-trimethyluric acid, 1,9-dimethyluric acid, and acetic acid significantly related to SCIM scores. These preliminary findings suggest that specific metabolites may serve as proxy measures of the SCI phenotype and prognostic markers of recovery. Thus, serum metabolite analysis combined with machine learning holds promise in understanding the physiology of SCI and aiding in prognosticating outcomes following injury.

Nanoporous Carbon Immunosensor for Highly Accurate and Sensitive Clinical Detection of Glial Fibrillary Acidic Protein in Traumatic Brain Injury, Stroke, and Spinal Cord Injury.

Elevated glial fibrillary acidic protein (GFAP) in the blood serum is one of the promising bodily fluid markers for the diagnosis of central nervous system (CNS) injuries, including traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). However, accurate and point-of-care (POC) quantification of GFAP in clinical blood samples has been challenging and yet to be clinically validated against gold-standard assays and outcome practices. This work engineered and characterized a novel nanoporous carbon screen-printed electrode with significantly increased surface area and conductivity, as well as preserved stability and anti-fouling properties. This nano-decorated electrode was immobilized with the target GFAP antibody to create an ultrasensitive GFAP immunosensor and quantify GFAP levels in spiked samples and the serum of CNS injury patients. The immunosensor presented a dynamic detection range of 100 fg/mL to 10 ng/mL, a limit of detection of 86.6 fg/mL, and a sensitivity of 20.3 Ω mL/pg mm2 for detecting GFAP in the serum. Its clinical utility was demonstrated by the consistent and selective quantification of GFAP comparable to the ultrasensitive single-molecule array technology in 107 serum samples collected from TBI, stroke, and SCI patients. Comparing the diagnostic and prognostic performance of the immunosensor with the existing clinical paradigms confirms the immunosensor's accuracy as a potential complement to the existing imaging diagnostic modalities and presents a potential for rapid, accurate, cost-effective, and near real-time POC diagnosis and prognosis of CNS injuries.

Characterizing Factors Influencing Baseline Plasma Biomarkers for Sport-Related Concussion in Adolescents.

Abstract Developing objective measures to diagnose sport-related concussion (SRC) is a top priority, particularly in the pediatric context, given the vulnerability of the developing brain. While advances in SRC blood biomarkers are being made in adult populations, less data are available for adolescents. Clinical validation of blood biomarkers post-SRC will first require investigation in a healthy uninjured state. Further, rapid pubertal changes during adolescence may implicate possible interactions with circulating sex hormones and the menstrual cycle for females. This cross-sectional study aimed to characterize pre-injury plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light (NF-L), ubiquitin C-terminal hydrolase-L1 (UCH-L1), total tau (T-tau), and phosphorylated tau-181 (P-tau-181), considering previous concussion, age, and sex in healthy adolescent sport participants. Possible associations with menstrual cycle phase and circulating sex hormone levels (i.e., progesterone, estradiol, testosterone) were also explored. Pre-injury blood samples were obtained from 149 healthy adolescents (48% female, ages 11-18) participating in a larger Surveillance in High Schools and Community Sports to Reduce Concussions and their Consequences (SHRed Concussions) multi-site longitudinal cohort study. Main outcomes were natural log (ln) transformed plasma GFAP, NF-L, UCH-L1, T-tau, and P-tau-181 concentrations, quantified on the Quanterix Simoa HD-X platform. Mixed-effects multi-variable linear regression was used to assess associations between biomarkers and self-reported previous concussion (yes/no), age (years), sex (male/female), objectively determined menstrual cycle phase (follicular/luteal), plasma progesterone, estradiol, and testosterone. Males had 19.8% lower UCH-L1 (ß = -0.221, 95% confidence interval [CI; -0.396, -0.046]), 18.9% lower GFAP (ß = -0.210, 95% CI [-0.352, -0.068]), and 21.8% higher P-tau-181 (ß = 0.197, 95% CI [0.048, 0.346]) compared with females, adjusting for age and previous concussion. GFAP decreased 9.5% with each 1-year increase in age, adjusting for previous concussion and sex (ß = -0.100, 95% CI [-0.152, -0.049]). No biomarkers were associated with a history of previous concussion. Exploratory investigations found no associations between biomarkers and menstrual cycle phase. Females displayed an age-adjusted negative association between T-tau and progesterone (ß = -0.010, 95% CI [-0.018, -0.002]), whereas males had a negative age-adjusted association between UCH-L1 and testosterone (ß = -0.020, 95% CI [-0.037, -0.002]). As such, age- and sex-specific reference intervals may be warranted for pediatric athlete populations prior to clinical validation of blood biomarkers for SRC. Additionally, hormonal associations highlight the need to consider puberty and development in adolescent studies. Overall, findings suggest these biomarkers are resilient to a history of previous concussion and menstrual cycle phase, supporting continued investigation in adolescent SRC.

Consistency of frontal cortex metabolites quantified by magnetic resonance spectroscopy within overlapping small and large voxels.

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo-inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo-inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

Saliva Cortisol as a Biomarker of Injury in Youth Sport-Related Concussion.

Increasing rates of sport-related concussion (SRC) in youth impose a significant burden on public health systems and the lives of young athletes. Accurate prediction for those likely to develop persistent post-concussion symptomology (PPCS) using a fluid biomarker, reflecting both acute injury and recovery processes, would provide the opportunity for early intervention. Cortisol, a stress hormone released through the hypothalamic-pituitary-adrenal (HPA) axis following injury, may provide a missing physiological link to clinical recovery. This cohort study investigated the change in saliva cortisol following SRC and the association between cortisol and symptom burden in pediatric ice hockey players. Further, the association between cortisol levels and medical clearance to return to play was explored. In total, cortisol samples from 233 players were included; 165 athletes (23.6% female) provided pre-injury saliva and 68 athletes (19.1% female) provided post-SRC saliva samples for cortisol analysis. Quantile (median) regressions were used to compare cortisol between pre-injury and post-SRC groups, and the association between total symptoms (/22) and symptom severity scores (/132) reported on the Sport Concussion Assessment Tool (SCAT)3/SCAT5 and post-SRC cortisol (adjusting for age, sex, history of concussion, and time from injury to sample collection). Results demonstrated significantly lower saliva cortisol in post-SRC athletes compared with the pre-injury group (ß = -0.62, 95% confidence interval [CI; -1.08, -0.16], p = 0.009). Post-SRC cortisol was not significantly associated with the SCAT3/SCAT5 symptom totals or symptom severity scores; however, females were found to report more symptoms (ß = 6.95, 95% CI [0.35, 13.55], p = 0.040) and greater symptom severity (ß = 23.87, 95% CI [9.58, 38.15], p = 0.002) compared with males. Exploratory time-to-event analysis revealed a point estimate suggesting a potential association between low cortisol levels and days to medical clearance to return to play. Although preliminary, these findings suggest that the HPA axis may be dysregulated post-SRC. Further, our exploratory analysis and case presentation of post-injury outliers highlight the need to further research cortisol as a prognostic biomarker to inform individualized sex-specific care after SRC.

Multimodal magnetic resonance imaging of youth sport-related concussion reveals acute changes in the cerebellum, basal ganglia, and corpus callosum that resolve with recovery.

Magnetic resonance imaging (MRI) can provide a number of measurements relevant to sport-related concussion (SRC) symptoms; however, most studies to date have used a single MRI modality and whole-brain exploratory analyses in attempts to localize concussion injury. This has resulted in highly variable findings across studies due to wide ranging symptomology, severity and nature of injury within studies. A multimodal MRI, symptom-guided region-of-interest (ROI) approach is likely to yield more consistent results. The functions of the cerebellum and basal ganglia transcend many common concussion symptoms, and thus these regions, plus the white matter tracts that connect or project from them, constitute plausible ROIs for MRI analysis. We performed diffusion tensor imaging (DTI), resting-state functional MRI, quantitative susceptibility mapping (QSM), and cerebral blood flow (CBF) imaging using arterial spin labeling (ASL), in youth aged 12-18 years following SRC, with a focus on the cerebellum, basal ganglia and white matter tracts. Compared to controls similar in age, sex and sport (N = 20), recent SRC youth (N = 29; MRI at 8 ± 3 days post injury) exhibited increased susceptibility in the cerebellum (p = 0.032), decreased functional connectivity between the caudate and each of the pallidum (p = 0.035) and thalamus (p = 0.021), and decreased diffusivity in the mid-posterior corpus callosum (p < 0.038); no changes were observed in recovered asymptomatic youth (N = 16; 41 ± 16 days post injury). For recent symptomatic-only SRC youth (N = 24), symptom severity was associated with increased susceptibility in the superior cerebellar peduncles (p = 0.011) and reduced activity in the cerebellum (p = 0.013). Fewer days between injury and MRI were associated with reduced cerebellar-parietal functional connectivity (p < 0.014), reduced activity of the pallidum (p = 0.002), increased CBF in the caudate (p = 0.005), and reduced diffusivity in the central corpus callosum (p < 0.05). Youth SRC is associated with acute cerebellar inflammation accompanied by reduced cerebellar activity and cerebellar-parietal connectivity, as well as structural changes of the middle regions of the corpus callosum accompanied by functional changes of the caudate, all of which resolve with recovery. Early MRI post-injury is important to establish objective MRI-based indicators for concussion diagnosis, recovery assessment and prediction of outcome.

Determining the Agreement Between Common Measures Related to Vestibulo-ocular Reflex Function After a Mild Traumatic Brain Injury in Children and Adolescents.

Objective: To (1) determine the level of agreement between symptom provocation and performance-based tests of vestibulo-ocular reflex (VOR) function after pediatric mild traumatic brain injury (mTBI) and (2) describe the level of symptom provocation induced by a VOR task in individuals with and without cervical findings. Design: Cross-sectional. Setting: This study was conducted at a tertiary care pediatric hospital. Participants: A total of 101 participants (N=101) aged 6-18 years within 3 weeks of mTBI diagnosis were included (54.5% female; mean age, 13.92±2.63 years; mean time since injury at assessment, 18.26±6.16 days). Interventions: None. Main Outcome Measures: Symptom provocation (Vestibular/Ocular Motor Screening tool), performance (clinician-observed VOR performance, head thrust test [HTT], computerized dynamic visual acuity test, video head impulse test), and cervical impairment (cervical flexion-rotation test, range of motion test, self-reported neck pain). Agreement was evaluated using Cohen's κ statistic. Results: No outcomes demonstrated agreement with symptom provocation (κ=-0.15 to 0.14). Fair agreement demonstrated between clinician-observed VOR performance and HTT (κ=0.32), with little to no agreement demonstrated between other measures. Proportions reporting test-induced dizziness and headache were greater among individuals with cervical findings (29.1%-41.8%) than without (2.3%-6.8%). Conclusions: Findings support that symptom provocation and performance-based tests measure different constructs and thus have distinct roles when assessing VOR function. Findings suggest results from measures of symptom provocation may be influenced by coexisting cervical impairments, underlining the value of assessing for cervical injury after pediatric mTBI.

Balance impairment in patients with moderate-to-severe traumatic brain injury: Which measures are appropriate for assessment?

Left untreated, balance impairment following moderate-to-severe traumatic brain injury (TBI) can be highly debilitating and hinder activities of daily life. To detect impairments, clinicians need appropriate assessment tools. The objective of this study was to evaluate the feasibility and utility of a battery of clinical balance assessments in adults with moderate-to-severe TBI within 6-months of injury. Thirty-seven adults with TBI [Glasgow Coma Scale score ≤ 12 (33 M/4 F) age 18-50 years] participated in balance testing. Assessments included the Balance Error Scoring System (BESS), National Institutes of Health Standing Balance Test (NIH-SBT), Functional Gait Assessment (FGA), Advanced Functional Gait Assessment (FGA-A), Tandem Gait Test (TGT), Berg Balance Scale (BBS), and Walking While Talking Test (WWTT). We identified pronounced ceiling effects on the BBS and FGA, two widely used clinical balance assessments. The NIH-SBT, WWTT, and FGA used in conjunction with the FGA-A, offered versatility in their capacity to assess patients across the balance severity spectrum. This study provides evidence to support a stepwise approach to balance assessment that can be adapted to the broad range of balance ability found in moderate-to-severe TBI.