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.

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.

Factors Associated with Quality of Life in Adults with Persistent Post-Concussion Symptoms.

OBJECTIVE: To assess demographic, clinical, and injury characteristics associated with health-related quality of life (HRQOL) in adults with persistent post-concussion symptoms (PPCS). METHODS: Adults with PPCS presenting to a specialized brain injury clinic completed demographic, injury, and clinical outcome questionnaires at the initial clinic assessment. Clinical outcome measures were collected including the Rivermead Post-Concussion Symptoms Questionnaire (RPQ), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder Scale-7 (GAD-7), and the Fatigue Severity Scale (FSS). HRQOL was measured using the Quality of Life after Brain Injury (QOLIBRI) questionnaire. Stepwise hierarchical multiple regression analysis adjusting for age, sex, and months since injury was used to determine associations between quality of life and clinical outcome measures. RESULTS: Overall, 125 participants were included. The PHQ-9, FSS, and GAD-7 were significant predictors of QOLIBRI scores (R2 = 0.481, p < .001), indicating that participants with higher levels of depressive symptoms, fatigue, and anxiety reported poorer HRQOL. The PHQ-9 score was the strongest predictor, accounting for 42.0% of the variance in QOLIBRI scores. No demographic or injury characteristics significantly predicted QOLIBRI scores. There was a high prevalence of depressive symptoms with 72.8% of participants having PHQ-9 scores ≥ 10. CONCLUSION: Among patients with PPCS, mental health and fatigue are important contributors to HRQOL. As there is a high burden of mood disorders and fatigue in this population, targeted treatments for these concerns may impact the quality of life.

Feasibility of Concussion Rehabilitation Approaches Tailored to Psychological Coping Styles: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the feasibility of a clinical trial involving participants with concussion randomized to treatments designed to address fear avoidance or endurance coping, which are risk factors for disability. A secondary objective was to evaluate whether each treatment could affect selective change on targeted coping outcomes. DESIGN: Randomized controlled trial. SETTING: Outpatient concussion clinics. PARTICIPANTS: Adults (N=73, mean age=42.5y) who had persistent postconcussion symptoms and high avoidance or endurance behavior were enrolled at a mean of 12.9 weeks post injury. Ten participants did not complete treatment. INTERVENTIONS: Participants were randomized to an interdisciplinary rehabilitation program delivered via videoconferencing and tailored to avoidance coping (graded exposure therapy [GET]) or endurance coping (operant condition-based pacing strategies plus mindfulness training [Pacing+]). MAIN OUTCOME MEASURES: Feasibility outcomes included screening efficiency, accrual, credibility, treatment fidelity, adherence, and retention. Avoidance was measured with the Fear Avoidance Behavior after Traumatic Brain Injury Questionnaire and endurance behavior with the Behavioral Response to Illness Questionnaire. RESULTS: Screening efficiency, or the proportion of clinic patients who were assessed for eligibility, was 44.5% (275 of 618). A total of 65.8% (73 of 111) of eligible patients were randomized (37 to GET, 36 to Pacing+), meeting accrual targets; 91.7% (55 of 60) of participants perceived treatment as credible. Therapists covered a mean of 96.8% of essential prescribed elements, indicating excellent fidelity. The majority (71.2%; 47 of 66) of participants consistently attended treatment sessions and completed between-session homework. Retention was strong, with 65 of 73 (89%) randomized participants completing the outcome assessment. GET was associated with greater posttreatment reductions in avoidance behavior compared with Pacing+ (Cohen's drepeated measures, 0.81), whereas the treatment approach-specific effect of Pacing+ on endurance behavior was less pronounced (Cohen's drepeated measures, 0.39). CONCLUSIONS: These findings support a future efficacy-focused clinical trial. GET has the potential to selectively reduce fear avoidance behavior after concussion, and, via this mechanism, to prevent or reduce disability.

Repetitive Transcranial Magnetic Stimulation for the Treatment of Post-traumatic Stress Disorder: A Systematic Review and Network Meta-analysis: La Stimulation Magnétique Transcrânienne Répétitive Pour le Traitement du Trouble de Stress Post-Traumatique : Une Revue Systématique et une Méta-Analyse en Réseau.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment modality for Post-traumatic stress disorder (PTSD). Several targets and stimulation parameters have been investigated, and while previous meta-analyses have suggested that rTMS is efficacious, these have pooled different stimulation parameters and targets, and the relative efficacy of each is unknown. METHODS: We therefore performed a systematic review and network meta-analysis of randomized controlled trials (RCTs) by searching MEDLINE, EMBASE, CENTRAL, and PsycINFO and retaining RCTs with at least 5 individuals per arm and clinician-rated PTSD symptoms (PROSPERO CRD42019134984). We adhered to PRISMA guidelines, and 2 independent reviewers screened studies for eligibility and extracted the primary outcome of clinician-rated PTSD symptoms. Dropouts were extracted as a proxy for acceptability. Random effects pairwise meta-analyses and a network meta-analysis were performed. RESULTS: We synthesize data from 10 RCTs with a total of 421 participants. Two rTMS interventions targeting the right dorsolateral prefrontal cortex (DLPFC) improved PTSD symptoms relative to sham: low-frequency stimulation (SMD = 0.70; 95% CI, 0.22 to 1.18) and high-frequency stimulation (SMD = 0.71; 95% CI, 0.11 to 1.31). Medial PFC dTMS, right DLPFC intermittent theta-burst stimulation, and left DLPFC high-frequency stimulation did not separate from sham. Dropouts as a proxy for acceptability revealed no differences between any of the active conditions or sham nor did any of the active conditions differ from each other. CONCLUSION: The current literature does not support efficacy differences between interventions; however, protocols stimulating the right DLPFC appear superior to sham. It is unclear whether this reflects heterogeneity in pathology requiring a personalized medicine approach or nonspecific mechanisms of rTMS.

Characterizing Physical Activity and Sedentary Behavior in Adults With Persistent Postconcussive Symptoms After Mild Traumatic Brain Injury.

OBJECTIVE: To evaluate physical activity (PA) and sedentary behavior and their associations with symptom and quality of life outcomes in adults with persistent postconcussive symptoms (PPCS) after mild traumatic brain injury (mTBI). DESIGN: Cross-sectional cohort study. SETTING: Outpatient brain injury clinic. PARTICIPANTS: Consecutive sample of adults (N=180) with a diagnosis of mTBI and PPCS. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: PA and sedentary behavior were assessed using the Godin Leisure-Time Exercise Questionnaire and Rapid Assessment Disuse Index, respectively. Participants were dichotomized according to whether they completed 150 minutes of moderate-to-vigorous PA per week, based on Canadian guidelines. Postinjury moderate-to-vigorous PA was also analyzed as a continuous variable. RESULTS: Prior to injury, 85% of participants reported meeting PA guidelines, compared with 28% postinjury. Individuals meeting PA guidelines postinjury reported higher quality of life (η2p=0.130; P<.001) and lower scores on measures of functional impact of headache (η2p=0.065; P=.009), fatigue (η2p=0.080; P=.004), depression (η2p=0.085; P=.001), and anxiety (η2p=0.046; P=.031), compared with those not meeting guidelines. Sedentary behavior postinjury was negatively correlated with quality of life (rs[127]=-0.252; P=.004) and positively correlated with symptom burden (rs[167]=0.227; P=.003), fatigue (rs[127]=0.288; P=.001), depression (rs[174]=0.319; P<.001), and anxiety (rs[127]=0.180; P=.042). CONCLUSIONS: PA was significantly decreased in individuals with PPCS compared to preinjury levels. Meeting PA guidelines postinjury was associated with better clinical outcomes, suggesting that returning individuals to PA should be considered in the treatment of this patient population.

Normative Data for the Fear Avoidance Behavior After Traumatic Brain Injury Questionnaire in a Clinical Sample of Adults With Mild TBI.

OBJECTIVE: Fear avoidance behavior after a concussion or mild traumatic brain injury (mTBI) is associated with a number of adverse outcomes, such as higher symptom burden, emotional distress, and disability. The Fear Avoidance Behavior after Traumatic Brain Injury Questionnaire (FAB-TBI) is a recently developed and validated self-report measure of fear avoidance after mTBI. The objective of this study was to derive clinical normative data for the FAB-TBI. To determine whether demographic stratification was necessary and to further support clinical interpretation, we also explored associations between fear avoidance behavior and demographic and injury variables. SETTING: Five concussion clinics in Canada. PARTICIPANTS: Adults who sustained an mTBI (N = 563). DESIGN: Cross-sectional. MAIN MEASURES: Participants completed the Fear Avoidance Behavior after Traumatic Brain Injury Questionnaire (FAB-TBI) and measures of postconcussion symptom burden (Rivermead Postconcussion Symptoms Questionnaire, Sport Concussion Assessment Tool-5) at clinic intake. RESULTS: Generalized linear modeling revealed that females reported more fear avoidance than males (95% CI = 0.66 to 2.75), indicating that FAB-TBI normative data should be stratified by sex. Differences between recruitment sites on FAB-TBI scores were reduced but not eliminated by controlling for potential confounds. Loss of consciousness (95% CI =0.61 to 2.76) and higher postconcussion symptom burden (95% CI = 0.79 to 1.03) were also associated with higher FAB-TBI scores, but time since injury was not (95% = CI -0.4 to 0.03). Tables to convert FAB-TBI raw scores to Rasch scores to percentiles are presented. CONCLUSION: These findings support clinical interpretation of the FAB-TBI and further study of fear avoidance after mTBI.

Improving symptom burden in adults with persistent post-concussive symptoms: a randomized aerobic exercise trial protocol.

BACKGROUND: Persistent post-concussive symptoms (PPCS) affect up to 30% of individuals following mild traumatic brain injury. PPCS frequently includes exercise intolerance. Sub-symptom threshold aerobic exercise has been proposed as a treatment option for symptom burden and exercise intolerance in this population. The primary aim of this study is to evaluate whether a progressive, sub-symptom threshold aerobic exercise program can alleviate symptom burden in adults with PPCS. METHODS: Fifty-six adults (18-65) with PPCS (>3mos-5 yrs) will be randomized into two groups: an immediate start 12-week aerobic exercise protocol (AEP) or delayed start 6-week placebo-like stretching protocol (SP), followed by AEP. Aerobic or stretching activities will be completed 5x/week for 30 mins during the intervention. Online daily activity logs will be submitted. Exercise prescriptions for the AEP will be 70-80% of heart rate at the point of symptom exacerbation achieved on a treadmill test with heart rate monitoring. Exercise prescription will be updated every 3-weeks with a repeat treadmill test. The Rivermead Post-concussion Symptom Questionnaire will be the primary outcome measure at 6 and 12-weeks of intervention. Secondary outcomes include assessments of specific symptoms (headache, quality of life, mood, anxiety, fatigue, dizziness, sleep parameters, daytime sleepiness) in addition to blood biomarkers and magnetic resonance imaging and spectroscopy data for quantification of brain metabolites including γ-aminobutyric acid (GABA), glutathione, glutamate and N-acetyl aspartate (NAA) all measured at 6 and 12-weeks of intervention. DISCUSSION: This trial will evaluate the use of aerobic exercise as an intervention for adults with PPCS, thus expanding our knowledge of this treatment option previously studied predominantly for adolescent sport-related concussion. TRIAL REGISTRATION: ClinicalTrials.gov - NCT03895450 (registered 2019-Feb-11).

The Association of Saliva Cytokines and Pediatric Sports-Related Concussion Outcomes.

OBJECTIVES: This study aimed to explore cytokine alterations following pediatric sports-related concussion (SRC) and whether a specific cytokine profile could predict symptom burden and time to return to sports (RTS). SETTING: Sports Medicine Clinic. PARTICIPANTS: Youth ice hockey participants (aged 12-17 years) were recruited prior to the 2013-2016 hockey season. DESIGN: Prospective exploratory cohort study. MAIN MEASURE: Following SRC, saliva samples were collected and a Sport Concussion Assessment Tool version 3 (SCAT3) was administered within 72 hours of injury and analyzed for cytokines. Additive regression of decision stumps was used to model symptom burden and length to RTS based on cytokine and clinical features. RRelieFF feature selection was used to determine the predictive value of each cytokine and clinical feature, as well as to identify the optimal cytokine profile for the symptom burden and RTS. RESULTS: Thirty-six participants provided samples post-SRC (81% male; age 14.4 ± 1.3 years). Of these, 10 features, sex, number of previous concussions, and 8 cytokines, were identified to lead to the best prediction of symptom severity (r = 0.505, P = .002), while 12 cytokines, age, and history of previous concussions predicted the number of symptoms best (r = 0.637, P < .001). The prediction of RTS led to the worst results, requiring 21 cytokines, age, sex, and number of previous concussions as features (r = -0.320, P = .076). CONCLUSIONS: In pediatric ice hockey participants following SRC, there is evidence of saliva cytokine profiles that are associated with increased symptom burden. However, further studies are needed.

The impact of traumatic brain injury on cognitive and neuropsychiatric symptoms of Parkinson's disease.

The objective was to determine whether a history of traumatic brain injury (TBI) was associated with Parkinson's Disease (PD) and specific cognitive, motor, and neuropsychiatric symptoms. A cross-sectional cohort study of 120 participants aged 60-85 years old (48 females) were recruited (69 PD and 51 healthy controls). Assessments included demographic information, neuropsychological tests, a motor evaluation, neuropsychiatric questionnaires, and the Brain Injury Screening Questionnaire. A history of TBI or number of TBIs was not significantly related to an increased risk of developing PD or poorer motor scores on the United Parkinson Disease Rating Scale part 3. There was a significant negative correlation between number of TBI's and mean z-scores of global cognition (rs(69) = -0.338, p = 0.004), executive function (rs(69) = -0.251, p = 0.038), memory (rs(69) = -0.262, p = 0.029), and language (rs(69) = -0.245, p = 0.042), and a significant positive correlation on the Beck Depression Inventory II (rs(69) = 0.285, p = 0.018) and the Patient Health Questionnaire-9 (PHQ-9) (rs(69) = 0.326, p = 0.006) in the PD group only. In conclusion, a history of TBI was negatively associated with cognition and positively associated with depressive symptoms in patients with PD, but not with motor symptoms.

Transcranial Magnetic and Direct Current Stimulation (TMS/tDCS) for the Treatment of Headache: A Systematic Review.

BACKGROUND: Headache is among the most prevalent causes of disability worldwide. Non-pharmacologic interventions, including neuromodulation therapies, have been proposed in patients who are treatment resistant or intolerant to medications. OBJECTIVE: To perform a systematic review on the use of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) for the treatment of specific headache disorders (ie, migraine, tension, cluster, posttraumatic). METHODS: Data sources: Ovid MEDLINE, Cochrane Central Register of Clinical Trials, Embase, Scopus, PsycINFO. DATA EXTRACTION: All references were reviewed by 2 independent researchers (3039 abstracts, duplicates removed). Records were selected by inclusion criteria for participants (adults 18-65 with primary or secondary headaches), interventions (TMS and tDCS applied as headache treatment), comparators (sham or alternative standard of care), and study type (cohort, case-control, and randomized controlled trials [RCT]). Studies were assessed using the Cochrane Risk of Bias Tool and overall quality determined through the GRADE Tool. A structured synthesis was performed due to heterogeneity of participants and methods. RESULTS: Thirty-four studies were included: 16 rTMS, 6 TMS (excluding rTMS), and 12 tDCS. The majority investigated treatment for migraine (19/22 TMS, 8/12 tDCS). Quality of evidence ranged from very low to high. CONCLUSION: Of all TMS and tDCS modalities, rTMS is most promising with moderate evidence that it contributes to reductions in headache frequency, duration, intensity, abortive medication use, depression, and functional impairment. However, only few studies reported changes greater than sham treatment. Further high-quality RCTs with standardized protocols are required for each specific headache disorder to validate a treatment effect. Registration Number: PROSPERO 2017 CRD42017076232.

Utility of serum IGF-1 for diagnosis of growth hormone deficiency following traumatic brain injury and sport-related concussion.

BACKGROUND: Growth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population. METHODS: We conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z-score for determining GHD by GST or ITT. RESULTS: Sixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 µg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility. CONCLUSION: Baseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve.

Using Robotics to Quantify Impairments in Sensorimotor Ability, Visuospatial Attention, Working Memory, and Executive Function After Traumatic Brain Injury.

OBJECTIVE: To investigate the use of a robotic assessment tool to quantify sensorimotor, visuospatial attention, and executive function impairments in individuals with traumatic brain injury (TBI). SETTING: Foothills Hospital (Calgary, Canada). PARTICIPANTS: Twenty-three subjects with first-time TBI in the subacute to chronic phase participated in this study. Normative data were collected from 275 to 494 neurologically intact control subjects for each robotic task. DESIGN: A prospective observational case series. Subjects with TBI completed brief clinical cognitive and motor assessments followed by robotic assessments of upper limb reaching, position sense, bimanual motor ability, attention, and visuospatial skills. Scores of subjects with TBI were compared with normative data. MAIN MEASURES: Robotic task performance was computed for each subject on each task, as well as performance on specific task parameters. Clinical assessments included the Montreal Cognitive Assessment, Fugl-Meyer upper extremity assessment, and Purdue Peg Board. RESULTS: Subjects with TBI demonstrated a variety of deficits on robotic tasks. The proportion of TBI subjects who were significantly different from controls ranged from 36% (dominant arm reaching) to 60% (bimanual object hitting task). CONCLUSION: Robotic measures allowed us to quantify a range of impairments specific to each subject, and offer an objective tool with which to examine these abilities after TBI.

Role of advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion: a systematic review.

OBJECTIVE: To conduct a systematic review of published literature on advanced neuroimaging, fluid biomarkers and genetic testing in the assessment of sport-related concussion (SRC). DATA SOURCES: Computerised searches of Medline, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycINFO, Scopus and Cochrane Library from 1 January 2000 to 31 December 2016 were done. There were 3222 articles identified. STUDY SELECTION: In addition to medical subject heading terms, a study was included if (1) published in English, (2) represented original research, (3) involved human research, (4) pertained to SRC and (5) involved data from neuroimaging, fluid biomarkers or genetic testing collected within 6 months of injury. Ninety-eight studies qualified for review (76 neuroimaging, 16 biomarkers and 6 genetic testing). DATA EXTRACTION: Separate reviews were conducted for neuroimaging, biomarkers and genetic testing. A standardised data extraction tool was used to document study design, population, tests employed and key findings. Reviewers used a modified quality assessment of studies of diagnostic accuracy studies (QUADAS-2) tool to rate the risk of bias, and a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to rate the overall level of evidence for each search. DATA SYNTHESIS: Results from the three respective reviews are compiled in separate tables and an interpretive summary of the findings is provided. CONCLUSIONS: Advanced neuroimaging, fluid biomarkers and genetic testing are important research tools, but require further validation to determine their ultimate clinical utility in the evaluation of SRC. Future research efforts should address current gaps that limit clinical translation. Ultimately, research on neurobiological and genetic aspects of SRC is predicted to have major translational significance to evidence-based approaches to clinical management of SRC, much like applied clinical research has had over the past 20 years.

Neuroendocrine Dysfunction in a Young Athlete With Concussion: A Case Report.

An 18-year-old female ringette and basketball player presented to our sport concussion clinic 27 months after concussion with fatigue, headache, exercise intolerance, polyuria, nocturia, and difficulties concentrating. Her history was remarkable for 4 previous concussions. Her neurologic examination was normal. Neuroendocrine screen including thyroid function, morning cortisol, glucose, and insulin-like growth factor-1 (screening test for growth hormone deficiency) were normal. Further testing for growth hormone deficiency with an insulin hypoglycemia test revealed severe growth hormone deficiency. Urine and serum electrolytes were borderline normal, suggesting partial diabetes insipidus. Treatments with growth hormone replacement lead to complete recovery. This case highlights the importance of maintaining a high index of suspicion for neuroendocrine abnormalities in athletes with persistent symptoms after sport concussion. Symptoms can be nonspecific and go undiagnosed for years, but appropriate recognition and treatment can restore function.

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.

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.

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.

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.