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Objective: To evaluate a 6-week sub-symptom threshold aerobic exercise protocol (AEP) versus a stretching protocol (SP) on symptom burden and quality of life (QoL) in adults with persisting post-concussive symptoms (PPCS)., Design: The Aerobic exercise for treatment of Chronic symptoms following mild Traumatic Brain Injury (ACTBI) Trial was a randomized controlled trial with 2 groups., Setting: Outpatient brain injury, pain, and physiotherapy clinics., Participants: A total of 210 participants were screened. A consecutive sample of 52 adults with PPCS and exercise intolerance after mild traumatic brain injury were enrolled. No participants withdrew because of the adverse effects of the intervention., Interventions: Participants were randomized to a 6-week AEP (n=27) or 6-week SP (n=25)., Main Outcome and Measures: The Rivermead Post Concussion Symptoms Questionnaire was the primary outcome. Secondary outcomes included QoL using the QoL After Brain Injury Questionnaire, in addition to measures of mood, anxiety, functional impact of headache, fatigue, dizziness, exercise tolerance, and sleep., Results: Participants were a mean (SD) of 43.0 (10.9) years old (75% female) and 24.7 (14.0) months post-injury. In per-protocol analysis, between-group difference (AEP vs SP) was not significant for the Rivermead Post Concussion Symptoms Questionnaire, but QoL After Brain Injury Questionnaire between-group difference was significant (mean change=5.024; 95% Cl, 0.057-9.992; P=.047) from baseline to 6 weeks. In the intention-to-treat analysis, between-group changes in primary and secondary outcomes were not significant., Conclusions: This trial provides preliminary data to support the prescription of aerobic exercise for adults with PPCS. Despite presenting with exercise intolerance, participants were able to engage in subsymptom threshold exercise with QoL benefits., (Copyright © 2024 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: Our primary objective was to evaluate the safety and feasibility of transcranial direct current stimulation combined with exercise therapy for the treatment of cervicogenic headache. Our exploratory objectives compared symptoms of headache, mood, pain, and quality of life between active and sham transcranial direct stimulation combined with exercise therapy., Background: Cervicogenic headache arises from injury to the cervical spine or degenerative diseases impacting cervical spine structure resulting in pain, reduced quality of life, and impaired function. Current standard-of-care treatments such as radiofrequency ablation, pharmacotherapy, manual therapy, and exercise therapy lack efficacy for some patients. Transcranial direct current stimulation is a neuromodulation technique that has shown promise in treating chronic pain conditions by positively altering neuronal activity but has not been evaluated as treatment for cervicogenic headache., Methods: This double-blind, sham-controlled, randomized, feasibility trial recruited 32 participants between the ages of 18 and 65 years that met the International Classification of Headache Disorders third edition criteria for cervicogenic headache. Participants were randomized to receive either active or sham transcranial direct current stimulation both combined with daily exercise therapy over 6 weeks. Transcranial direct current stimulation was applied over the primary motor cortex ipsilateral to worse pain for 20 min at 2 mA with a 30 s ramp up/down period. Recruitment, retention, and adherence were evaluated for feasibility. Safety was assessed through serious and minor adverse events and an adverse effect questionnaire. Clinical outcome measures assessed headache, pain, quality of life, and mood symptoms at pre-treatment, post-treatment, and 6- and 12-weeks post-treatment., Results: A total of 97 participants were contacted to participate with 32 recruited, 16 randomized into each group, and 14 completing the treatment protocol in both groups. Within each group 12 (active) and nine (sham) completed treatment within the proposed 6 weeks (three sessions per week), others received 18 sessions but took longer. Exercise therapy was completed on an average of 87% of days for both groups. Transcranial direct current stimulation was safe, with no serious adverse events and one minor adverse event in the active group. Itching was a more common post-intervention complaint in the active group (64% active vs. 43% sham). Exploratory analysis revealed significant group × time interactions for average headache pain from pre- to post-treatment (β = -1.012, 95% confidence interval [CI] -1.751 to -0.273; p = 0.008), 6-weeks (β = -1.370, 95% CI -2.109 to -0.631; p < 0.001), and 12-weeks (β = -1.842, 95% CI -2.600 to -1.085; p < 0.001) post-treatment, and for neck pain from pre- to post-treatment (β = -1.184, 95% CI -2.076 to -0.292; p = 0.010) and 12-weeks (β = -1.029, 95% CI -1.944 to -0.114; p = 0.028) post-treatment favoring active vs. sham. There were no significant group × time interactions for quality of life or mood., Conclusion: The combination of transcranial direct stimulation and exercise therapy is safe and feasible for treating cervicogenic headache. While some promise has been shown for reducing headache and neck pain, larger scale trials with adequate power are needed to confirm these findings., (© 2025 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Objective . The current paper describes the creation of a simultaneous trimodal neuroimaging protocol. The authors detail their methodological design for a subsequent large-scale study, demonstrate the ability to obtain the expected physiologically induced responses across cerebrovascular domains, and describe the pitfalls experienced when developing this approach. Approach . Electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and transcranial Doppler ultrasound (TCD) were combined to provide an assessment of neuronal activity, microvascular oxygenation, and upstream artery velocity, respectively. Real-time blood pressure, capnography, and heart rate were quantified to control for the known confounding influence of cardiorespiratory variables. The EEG-fNIRS-TCD protocol was attached to a 21 year-old male who completed neurovascular coupling/functional hyperemia (finger tapping and ' Where's Waldo/Wally? '), dynamic cerebral autoregulation (squat-stand maneuvers), and cerebrovascular reactivity tasks (end-tidal clamping during hypocapnia/hypercapnia). Main results . In a pilot participant, the Waldo task produced robust hemodynamic responses within the occipital microvasculature and the posterior cerebral artery. A ∼90% decrease in alpha band power was seen in the occipital cortical region compared between the eyes closed and eyes opened protocol, compared to the frontal, central, and parietal regions (∼80% reduction). A modest increase in motor oxygenated hemoglobin was seen during the finger tapping task, with a harmonious alpha decrease of ∼15% across all cortical regions. No change in the middle or posterior cerebral arteries were noted during finger tapping. During cerebral autoregulatory challenges, sinusoidal oscillations were produced in hemodynamics at 0.05 and 0.10 Hz, while a decrease and increase in TCD and fNIRS metrics were elicited during hypocapnia and hypercapnia protocols, respectively. Significance . All neuroimaging modalities have their inherent limitations; however, these can be minimized by employing multimodal neuroimaging approaches. This EEG-fNIRS-TCD protocol enables a comprehensive assessment of cerebrovascular regulation across the association between electrical activity and cerebral hemodynamics during tasks with a mild degree of body and/or head movement., (Creative Commons Attribution license.)

In this review, we have amalgamated the literature, taking a multimodal neuroimaging approach to quantify the relationship between neuronal firing and haemodynamics during a task paradigm (i.e., neurovascular coupling response), while considering confounding physiological influences. Original research articles that used concurrent neuronal and haemodynamic quantification in humans (n ≥ 10) during a task paradigm were included from PubMed, Scopus, Web of Science, EMBASE and PsychINFO. Articles published before 31 July 2023 were considered for eligibility. Rapid screening was completed by the first author. Two authors completed the title/abstract and full-text screening. Article quality was assessed using a modified version of the National Institutes of Health Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A total of 364 articles were included following title/abstract and full-text screening. The most common combination was EEG/functional MRI (68.7%), with cognitive (48.1%) and visual (27.5%) tasks being the most common. The majority of studies displayed an absence/minimal control of blood pressure, arterial gas concentrations and/or heart rate (92.9%), and only 1.3% monitored these factors. A minority of studies restricted or collected data pertaining to caffeine (7.4%), exercise (0.8%), food (0.5%), nicotine (2.7%), the menstrual cycle (0.3%) or cardiorespiratory fitness levels (0.5%). The cerebrovasculature is sensitive to numerous factors; thus, to understand the neurovascular coupling response fully, better control for confounding physiological influences of blood pressure and respiratory metrics is imperative during study-design formulation. Moreover, further work should continue to examine sex-based differences, the influence of sex steroid hormone concentrations and cardiorespiratory fitness., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Although guidelines support aerobic exercise in sub-acute mild traumatic brain injury (mTBI), evidence for adults with persisting post-concussive symptoms (PPCS) after mTBI is lacking. The objective was to evaluate the impact of a sub-symptom threshold aerobic exercise intervention on overall symptom burden and quality of life in adults with PPCS., Methods: This prospective cohort study was nested within the ACTBI Trial (Aerobic Exercise for treatment of Chronic symptoms following mild Traumatic Brain Injury). A total of 50 adults with a diagnosis of mTBI, PPCS and exercise intolerance completed a 12-week sub-symptom threshold aerobic exercise intervention either immediately after enrollment (i-AEP group; n  = 27) or following 6-weeks of stretching (d-AEP group; n  = 23). Data from all participants ( n  = 50) were included in the combined AEP (c-AEP) group. The primary outcome was symptom burden on the Rivermead Post Concussion Symptoms Questionnaire (RPQ). Secondary outcomes included measures of quality of life and specific post-concussive symptoms (depressive and anxiety symptoms, functional impact of headache, fatigue, sleep, dizziness and exercise tolerance). Heart rate, blood pressure and heart rate variability were also assessed to understand autonomic function response to intervention., Results: Participants were a mean (SD) of 42.6 (10.9) years old (74% female) and 25.1 (14.1) months post-mTBI. Following 12-weeks of intervention participants had a significant improvement in symptom burden on the RPQ (i-AEP: mean change = -9.415, p  < 0.001; d-AEP: mean change = -3.478, p  = 0.034; c-AEP: mean change = -6.446, p  < 0.001). Participants also had significant improvement in quality of life (i-AEP: mean change = 9.879, p  < 0.001; d-AEP: mean change = 7.994, p  < 0.001, c-AEP: mean change = 8.937, p  < 0.001), dizziness (i-AEP: mean change = -11.159, p  = 0.001; d-AEP: mean change = -6.516, p  = 0.019; c-AEP: -8.837, p  < 0.001) and exercise tolerance (i-AEP: mean change = 5.987, p  < 0.001; d-AEP: mean change = 3.421, p  < 0.001; c-AEP: mean change = 4.703, p  < 0.001). Headache (mean change = -5.522, p  < 0.001) and depressive symptoms (mean change = -3.032, p  = 0.001) improved in the i-AEP group. There was no change in measures of autonomic function., Conclusion: A 12-week aerobic exercise intervention improves overall symptom burden, quality of life and specific symptom domains in adults with PPCS. Clinicians should consider prescription of progressive, individualized, sub-symptom threshold aerobic exercise for adults with PPCS even if presenting with exercise intolerance and months-to-years of symptoms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mercier, McIntosh, Boucher, Joyce, Batycky, Galarneau, Burma, Smirl, Esser, Schneider, Dukelow, Harris and Debert.)

Background: Acquired brain injury (ABI) can result in persistent symptoms and lasting disability. Supplements are becoming more popular in patients with chronic symptoms; however, little is known about supplementation and dietary behaviors after ABI., Methods: In this cross-sectional observational study, questionnaires were collected from 211 adults with ABI presenting to outpatient brain injury clinics. The temporality of 54 unique supplements and 15 dietary behaviors were surveyed. Sources of information, reasons for use, side effects, and perceived safety were obtained., Results: After ABI, 55% of the participants increased supplement utilization by ≥1 supplement, resulting in 74% consuming supplements (3.8 ± 4.1 unique supplements daily); Vitamin D, multivitamins, magnesium, and omega 3- and/or -6 were most commonly consumed. Healthcare professionals were the main source of information, as reported by 69% of the respondents. The primary reason for supplementation was following a recommendation by a healthcare professional (63%). Supplementation was widely considered safe (83%), and most participants (76%) did not experience side effects. The majority of participants (70%) did not adhere to specific dietary behaviors.

Objective: This study explores the relationship between PTSD symptoms and cognition in patients with persistent post-concussive symptoms (PPCS)., Methods: Adults with PPCS presenting to a specialized brain injury clinic provided demographic and injury information and completed the PTSD checklist for DSM-5, Generalized Anxiety Disorder Scale-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). The Montreal Cognitive Assessment (MoCA) was used to screen for possible cognitive concerns. Multiple regression analysis (MLR) adjusting for age, sex, mechanism of injury, psychiatric history, number of previous concussions, months since most recent injury, and mental health questionnaire scores was used to determine associations between PTSD and cognition. Binomial logistic regression explored the relationship between domains of the MoCA and PCL-5 scores., Results: We found a negative correlation between MoCA scores, PCL-5 (ρ=-0.211, p  = 0.009) and PHQ-9 (ρ=-0.187, p  = 0.021) in patients with PPCS and collinearity of PCL-5 and PHQ-9 scores. Significantly higher Arousal and Reactivity cluster scores within the PCL-5 were associated with poorer scores on naming and abstract tasks on the MoCA., Conclusion: The association between specific PCL-5 clusters and lower MoCA scores may represent a viable target for psychotherapeutic and psychopharmacologic intervention in patients with cognitive changes associated with PPCS.

Background: Little is known regarding long-term consequences (≥5 years) of sport-related concussion (SRC) sustained during adolescence. Adolescent SRC has been linked to athlete considerations of sport participation and subsequent retirement from sport during this critical developmental period. Prolonged SRC symptoms can reduce ability to perform physical activity, and research suggests inactivity can extend years post-injury. Therefore, SRC may affect long-term physical activity, which may result in decreased cardiorespiratory fitness and increased adiposity., Objectives: (1) To examine cardiorespiratory fitness, adiposity and associations with physical activity between three groups: adolescent SRC 5-15 years prior; adolescent musculoskeletal injury (MSK) 5-15 years prior; and individuals who played adolescent sport but were uninjured. (2) To explore whether biological sex-modified relationships assessed by the primary objective., Methods: Young adults (16-33 years old) who sustained SRC ( n  = 54) or MSK ( n  = 52) during adolescent sport and uninjured individuals ( n  = 50) were recruited ( n  = 156) from previous Sport Injury Prevention Research Centre studies and word-of-mouth. Participants completed a cycle-ergometer maximal exertion test, dual-energy X-ray absorptiometry scanning, and wore actigraphs for 1-week post-testing. Outcome measures of cardiorespiratory fitness [peak oxygen consumption (VO 2peak [ml/min])] and adiposity [fat mass index (FMI)] were examined in relation to cohort, sex, time since injury, lean mass index and moderate-to-vigorous physical activity [daily MVPA (min)] via multiple linear regression., Results: In relation to the uninjured cohort, MSK (mean difference = 297.14 ml/min; β = 2.88; 95%CI: 0.99-4.76, p  = 0.003) and SRC (mean difference = 268.01 ml/min; β = 2.61; 95%CI: 0.77-4.44, p  = 0.006) cohorts demonstrated higher VO 2peak and this did not differ based on biological sex. FMI did not differ for MSK (mean difference= -0.10 kg/m 2 ; β= -0.02; 95%CI: -0.22-0.18, p  = 0.847) or SRC (mean difference=-0.22 kg/m 2 ; β= -0.05; 95%CI: -0.24-0.15, p  = 0.642) cohorts relative to the uninjured cohort for both males and females., Conclusions: It is possible to maintain adequate long-term cardiorespiratory fitness and adiposity following adolescent SRC relative to those who only sustained sport related MSK injuries or did not sustain significant injuries as adolescents/adults.

Background: This study explored a novel multimodal neuroimaging approach to assess neurovascular coupling (NVC) in humans using electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and transcranial Doppler ultrasound (TCD)., Methods: Fifteen participants (nine females; age 19-32) completed concurrent EEG-fNIRS-TCD imaging during motor (finger tapping) and visual ("Where's Waldo?") tasks, with synchronized monitoring of blood pressure, capnography, and heart rate. fNIRS assessed microvascular oxygenation within the frontal, motor, parietal, and occipital cortices, while the middle and posterior cerebral arteries (MCA/PCA) were insonated using TCD. A 16-channel EEG set-up was placed according to the 10-20 system. Wilcoxon signed-rank tests were used to compare physiological responses between the active and resting phases of the tasks, while cross-correlations with zero legs compared cerebral and systemic hemodynamic responses across both tasks., Results: Time-frequency analysis demonstrated a reduction in alpha and low beta band power in electrodes C3/C4 during finger tapping (p<0.045) and all electrodes during the Waldo task (all p<0.001). During Waldo, cross-correlation analysis demonstrated the change in oxygenated hemoglobin and cerebral blood velocity had a moderate-to-strong negative correlation with systemic physiological influences, highlighting the measured change resulted from neuronal input. Deoxygenated hemoglobin displayed the greatest negative cross-correlation with the MCA/PCA within the motor cortices and visual during the motor and visual tasks, respectively (range:0.54, -0.82)., Conclusions: This investigation demonstrated the feasibility of the proposed EEG-fNIRS-TCD response to comprehensively assess the NVC response within human, specifically quantifying the real-time temporal synchrony between neuronal activation (EEG), microvascular oxygenation changes (fNIRS), and conduit artery velocity alterations (TCD)., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024. Published by Elsevier Inc.)

Charles Bonnet syndrome (CBS) describes the presence of hallucinations in patients with poor or deteriorating vision. The physician awareness of CBS is low, despite reporting of CBS hallucinations occurring in a range of ocular and central nervous system conditions. Following mild traumatic brain injury (mTBI), patients can experience visual or oculomotor dysfunction. As such, it is possible that CBS might present following mTBI. An adult male suffered an mTBI and whiplash injury following a motor vehicle accident. He developed persistent post-concussion symptoms (PPCS) including headaches and vestibular and visual disturbances. He reported experiencing visual hallucinations eight months post-mTBI and was diagnosed with CBS. Interventions for PPCS and hallucinations have persisted for five years. The treatment options for CBS are limited and the patient's PPCS made participating in visual therapy challenging. Physicians assessing patients following mTBI should be aware of CBS and should take PPCS into consideration when recommending treatments for CBS., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Dr. Ranita Manocha declare(s) a grant from McCaig Institute for Bone and Joint Health. Dr. Ranita Manocha declare(s) a grant from The Ehlers-Danlos Society. Dr. Ranita Manocha declare(s) a grant from Canadian Academy of Sport and Exercise Medicine. Dr. Chantel Debert declare(s) a grant from Hotchkiss Brain Institute. Dr. Chantel Debert declare(s) a grant from Province of Alberta. Dr. Ranita Manocha declare(s) a grant from University of Calgary. Dr. Chantel Debert declare(s) a grant from National Football League. Dr. Chantel Debert declare(s) a grant from Canadian Department of National Defense. Dr. Ranita Manocha declare(s) a grant from Alberta Health Services. Dr. Chantel Debert declare(s) a grant from Pfizer Pharmaceuticals. Dr. Ranita Manocha declare(s) a grant from Natural Sciences and Engineering Research Council of Canada. Dr. Ranita Manocha declare(s) non-financial support from Canadian Association of Physical Medicine and Rehabilitation. Dr. Chantel Debert declare(s) Expert panelist from Teva Pharmaceuticals. Dr. Chantel Debert declare(s) a grant from Canadian Institute of Health Research. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Campbell et al.)

Fear avoidance behaviour is associated with slow recovery from mild traumatic brain injury (mTBI). This study is a preliminary evaluation of graded exposure therapy (GET), which directly targets fear avoidance behaviour, for reducing post-concussion symptoms (PCS) and disability following mTBI. In a historical comparison design, we compared two groups from independent randomized trials. The GET + UC group (N = 34) received GET (delivered over 16 videoconference sessions) in addition to usual care (UC). The historical comparison group (N = 71) received UC only. PCS severity (Rivermead Post Concussion Symptoms Questionnaire; RPQ) and disability (World Health Organization Disability Assessment Schedule; WHODAS 2.0 12-item) were measured at clinic intake (M = 2.7, SD = 1.1 months after injury) and again at M = 4.9 (SD = 1.1) months after injury. Between-group differences were estimated using linear mixed effects regression, with a sensitivity analysis controlling for injury-to-assessment intervals. The estimated average change on the RPQ was -14.3 in the GET + UC group and -5.3 in the UC group. The estimated average change on the WHODAS was -5.3 in the GET + UC group and -3.2 in the UC group. Between-group differences post-treatment were -5.3 on the RPQ and -1.5 on the WHODAS. Treatment effects were larger in sensitivity analyses. Findings suggest that a randomized controlled trial is warranted.

Background: Cervicogenic headaches (CGH) are common following concussion and whiplash injuries and significantly reduce patient quality of life. Conservative therapies such as ET (ET) and physiotherapy combined with injection-based therapies are cornerstones of treatment for CGH but have shown limited efficacy. Transcranial direct current stimulation (tDCS) over the primary motor cortex (M1) has shown promise in treating other chronic pain conditions. The primary aim of this trial is to evaluate the feasibility and safety of tDCS when combined with ET for the treatment of CGH., Methods: Adults (aged 18-65), blinded to treatment arm, will be randomized into one of two groups: active tDCS followed by ET or sham tDCS followed by ET. Transcranial direct current stimulation will be applied over M1 three times per week for 6-weeks and ET will be performed daily. The primary outcomes of this trial will be the feasibility and safety of the intervention. Feasibility will be defined as greater than 30 % recruitment, 70 % protocol adherence, and 80 % retention rate. Safety will be defined as no severe adverse events. Secondary exploratory outcomes will assess improvement in pain, strength, function, and quality of life., Conclusions: This trial aims to demonstrate the safety and feasibility of tDCS in combination with ET for the treatment of CGH. Cervicogenic headaches can be difficult to treat contributing to significant impairments function and quality of life. Transcranial direct current stimulation is a potential novel treatment to improve health outcomes in these patients., Registration: ClinicalTrials.gov-NCT05582616., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Importance: Blood-based biomarkers may clarify underlying neuropathology and potentially assist in clinical management of adolescents with sport-related concussion (SRC)., Objective: To investigate the association between SRC and plasma biomarkers in adolescents., Design, Setting, and Participants: Prospective cohort study in Canadian sport and clinic settings (Surveillance in High Schools and Community Sport to Reduce Concussions and Their Consequences study; September 2019 to November 2022). Participants were a convenience sample of 849 adolescent (ages 10-18 years) sport participants with blood samples. Data were analyzed from February to September 2023., Exposures: Blood collection and clinical testing preseason (uninjured) and post-SRC follow-ups (ie, ≤72 hours, 1 week, and biweekly until medical clearance to return to play [RTP])., Main Outcomes and Measures: Plasma glial fibrillary acidic protein (GFAP), ubiquitin c-terminal hydrolase-L1 (UCH-L1), neurofilament light (NfL), and total tau (t-tau) were assayed. Group-level comparisons of biomarker levels were conducted between uninjured and post-SRC intervals (postinjury day [PID] 0-3, 4-10, 11-28, and >28) considering age and sex as modifiers. Secondary analyses explored associations between biomarker concentrations and clinical outcomes (Sport Concussion Assessment Tool, Fifth Edition [SCAT5] symptom scores and time to RTP)., Results: This study included 1023 plasma specimens from 695 uninjured participants (467 male participants [67.2%]; median [IQR] age, 15.90 [15.13-16.84] years) and 154 participants with concussion (78 male participants [51.0%]; median [IQR] age, 16.12 [15.31-17.11] years). Acute (PID 0-3) differences relative to uninjured levels were found for GFAP (female participants: 17.8% increase; β = 0.164; 95% CI, 0.064 to 0.263; P = .001; male participants: 17.1% increase; β = 0.157; 95% CI, 0.086 to 0.229; P < .001), UCH-L1 (female participants: 43.4% increase; β = 0.361; 95% CI, 0.125 to 0.596; P = .003), NfL (male participants: 19.0% increase; β = 0.174; 95% CI, 0.087 to 0.261; P < .001), and t-tau (female participants: -22.9%; β = -0.260; 95% CI, -0.391 to -0.130; P < .001; male participants: -18.4%; β = -0.203; 95% CI, -0.300 to -0.106; P < .001). Differences were observed for all biomarkers at PID 4 to 10, 11 to 28, and greater than 28 compared with uninjured groups. GFAP, NfL, and t-tau were associated with SCAT5 symptom scores across several PID intervals. Higher GFAP after 28 days post-SRC was associated with earlier clearance to RTP (hazard ratio, 4.78; 95% CI, 1.59 to 14.31; P = .01). Male participants exhibited lower GFAP (-9.7%), but higher UCH-L1 (21.3%) compared with female participants. Age was associated with lower GFAP (-5.4% per year) and t-tau (-5.3% per year)., Conclusions and Relevance: In this cohort study of 849 adolescents, plasma biomarkers differed between uninjured participants and those with concussions, supporting their continued use to understand concussion neuropathology. Age and sex are critical considerations as these biomarkers progress toward clinical validation.

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., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Chantel T. Debert reports financial support was provided by New Frontiers in Research. Chantel T. Debert reports financial support was provided by Physical Medicine and Rehabilitation. Chantel T. Debert reports financial support was provided by University of CalgaryHotchkiss Brain Institute. Samantha J. McIntosh reports financial support was provided by University of Calgary. Leah J. Mercier reports financial support was provided by Alberta SPOR Support Unit. Leah J. Mercier reports financial support was provided by Brain Canada Foundation. Leah J. Mercier reports financial support was provided by Integrated Concussion Research Program. Leah J. Mercier reports financial support was provided by University of Calgary. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Competing interests: AM declared a fellowship from the UBC Mental Health Institute and Department of Psychiatry. NS declared research grants from multiple granting agencies (Canada Foundation for Innovation, Canadian Institutes of Health Research, Mitacs, Ontario Brain Institute, US Department of Defense, WorkSafeBC, VGH+UBC Hospital Foundation) for research related to traumatic brain injury diagnosis, prognosis and treatment. He has received speaker fees for providing continuing medical education on these topics. KY declared grants from the Canadian Institutes of Health Research, National Institutes of Health, Brain Canada Foundation, Social Science and Humanities Research Council (Canada) and National Football League Scientific Advisory Board; royalties or licences from Guilford Press and Cambridge University Press; payments or honoraria from Northern California Neuropsychology Forum, Queensland Paediatric Rehabilitation Service (QPRS) and Queensland Children’s Hospital; support for attending Major League Soccer; participation on Independent Data Monitoring Committee (IDMC), Care for Post-Concussive Symptoms Effectiveness (CARE4PCS-2) Trial, National Institute for Child Health and Human Development; leadership or fiduciary roles as Editor (Neuropsychology), Consulting editor (Archives of Clinical Neuropsychology and Journal of Head Trauma Rehabilitation), Chair (Canadian Concussion Network), Scientific Advisory Committee (Brain Injury Canada), National Research Advisory Council, National Pediatric Rehabilitation Resource Center, Center for Pediatric Rehabilitation: Growing Research, Education, and Sharing Science (C-PROGRESS), Virginia Tech University. Other authors: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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 ( β  = -9.7, 95% CI [-15.6, -3.74], p  = 0.002) and saline ( β  = -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., Competing Interests: CD reports research grants from the Canadian Institute of Health research, Hotchkiss brain institute, Province of Alberta, National Football League, Canadian Department of National Defense, Pfizer pharmaceuticals as well fees as an expert panelist from Teva Pharmaceuticals. The Arthrex Angel System was loaned to the team for the purpose of this study by Tribe Medical Group/Arthrex Inc. The Arthrex Angel PRP kits were also provided by Tribe Medical Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Stone, Campbell, Tabor, Bonfield, Machan, Shan and Debert.)

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., Competing Interests: Brian Brooks receives royalties for the sales of the Pediatric Forensic Neuropsychology textbook (Oxford University Press), royalties for 3 pediatric neuropsychological tests [Child and Adolescent Memory Profile (ChAMP, Sherman and Brooks, 2015, PAR Inc), Memory Validity Profile (MVP, Sherman and Brooks, 2015, PAR Inc), and Multidimensional Everyday Memory Ratings for Youth (MEMRY, Sherman and Brooks, 2017, PAR Inc)], and has a private practice where he evaluates youth and professional hockey players with concussion. For the remaining authors, no conflicts of interest were noted. We acknowledge funding from the Canadian Institutes of Health Research and Hotchkiss Brain Institute., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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 1 H 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.

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 1 H 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.

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%; β = -0.17; 95% CI, -0.30 to -0.04]; P = .02; UCH-L1: effect size, 17.24%; β = -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%; β = -0.17; 95% CI, -0.30 to -0.03]; P = .02; UCH-L1: effect size, 18.02%; β = -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%; β = -0.14; 95% CI, -0.273 to -0.004]; P = .04) and increased sex differences in UCH-L1 (effect size, 23.59%; β = -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.

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 (β = -0.221, 95% confidence interval [CI; -0.396, -0.046]), 18.9% lower GFAP (β = -0.210, 95% CI [-0.352, -0.068]), and 21.8% higher P-tau-181 (β = 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 (β = -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 (β = -0.010, 95% CI [-0.018, -0.002]), whereas males had a negative age-adjusted association between UCH-L1 and testosterone (β = -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.

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., (© 2023 The Authors.)

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 mm 2 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.

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., Competing Interests: Competing interests: VA Financial: Australian National Health and Medical Research Council and Medical Research Future fund: research grants. Royalties: Pearson Publishing (Test of Everyday Attention) Collaboration: Australian Football League (Partnership agreement to fund research—funds go to my institute) Boards: Editorship: Journal of Neuropsychology, Neuropsychology, Journal of Clinical & Experimental Neuropsychology. GAD is a member of the Scientific Committee of the 6th International Consensus Conference on Concussion in Sport; an honorary member of the AFL Concussion Scientific Committee; Section Editor, Sport and Rehabilitation, NEUROSURGERY; and has attended meetings organised by sporting organisations including the NFL, NRL, IIHF, IOC and FIFA; however, has not received any payment, research funding or other monies from these groups other than for travel costs. CTD Pharmaceutical:-2021 pharmaceutical funded invited expert panelist (Teva) for CGRP monoclonal antibody treatment in chronic migraine-2022 pharmaceutical funded grant for growth hormone deficiency following concussion Grants/Research Support: Canadian Department of National Defense, HBI, CIHR, Tri-council funding New Frontiers, Alberta Provincial government, Foundations for PMR Patents: urine metabolites diagnosis of concussion. NF International independent FIFA Concussion Advisory Group GOTS Concussion Committee Innovation and Technology Panel, UK Department for Digital, Culture, Media and SportInternational Consensus Group on Concussion in Sports (CISG), NINDSCDE Sports Concussion CDE Subacute Subgroup (National Institute of Health) IFAB Concussion Expert Group Member: Swiss Neurology Society, Swiss Society for Clinical Neurophysiology, European Neuro-Ophthalmology Society, Concussion in Sport Group (CISG) Editorial Board Member: Journal of Concussion, Journal of Science and Medicine in Football. IG has paid employment relationships with McGill University and the McGill University Health CenterI have received grants in the last 3 years from: Canadian Institutes of Health Research, Fonds de recherche du Québec—Santé, Research Institute of the McGill University Health Center, McGill University, Institut National du Sport du QuébecI have no conflicts of interest with regards to the material being presented or discussed at the conference. KMG has received grant funding from NFL for the NFL LONG study. He also serves on the NCAA Scientific Advisory Board in an unpaid capacity. KAH has nothing to disclose. SAH is co-founder and senior advisor, The Sports Institute at UW Medicine (unpaid), Centers for Disease Control and Prevention and National Center for Injury Prevention and Control Board Pediatric Mild Traumatic Brain Injury Guideline Workgroup (unpaid), Concussion in Sport Group (Travel support), NCAA Concussion Safety Advisory Group (unpaid), Team Physician, Seattle Mariners; Former Team Physician, Seattle Seahawks; occasional payment for expert travel testimony, support for professional meetings. Mr CJ has nothing to declare. MM is a sport and exercise medicine physician working in private consulting practice and is the Chief Medical Officer at the Australian Football League. Shareholder of Olympic Park Sports Medicine Centre in Melbourne. Ex-senior physician at the Hawthorn Football Club (AFL) Ex-Chief Executive Officer of the AFL Doctors Association. Research grants received from the Australian Football League, outside the submitted work.Travel support received from the Australian Football League, FIFA and the International Olympic Committee to attend and present at international conferences. Member of the Scientific Committee for the 6th International Consensus Conference on Concussion in Sport. Honorary member of the International Concussion in Sport Group. Honorary member of the Australian Rugby Union Concussion Advisory Group.Independent Concussion Consultant for World Rugby. CLM reports no financial COI Volunteer positions: Concussion team physician, Shipley School Board of Trustees, American College of Sports Medicine Board of Directors, American Medical Society for Sports Medicine Board of Directors, Pediatric Research in Sports Medicine Executive Committee, Council on Sports Medicine and Fitness, American Academy of Pediatrics Advisory Board, Untold Foundation, Pink Concussions, Headway Foundation Editorial Board, Journal of Adolescent Health, Frontiers in Neuroergonomics, Exercise, Sport and Movement. JP is Editor BJSM (honorarium), Member of World Rugby Concussion Advisory Group (unpaid), Independent Concussion Consultant for World Rugby (fee per consultation), Medical consultant to South African Rugby (unpaid), Co-chair of the Scientific Committee, 6th International Conference on Concussion in Sport (unpaid), Board member of the Concussion in Sport Group (unpaid), Scientific Board member, EyeGuideTM (unpaid). JKR-M has current or past research funding from the Centers for Disease Control and Prevention; Department of Defense—USA Medical Research Acquisition Activity, National Collegiate Athletic Association-Department of Defense Mind Matters Challenge; National Athletic Trainers’ Association Foundation; National Football League; and National Operating Committee on Standards for Athletic Equipment. She has consulted for Allied Health Education (paid) and received speaker honorarium and travel reimbursements for talks given. She is on the editorial boards (all unpaid) for Journal of Athletic Training, Journal of Sport Rehabilitation and Frontiers in Sports and Active Living. Previously she served on the editorial board for the International Journal of Athletic Training and Therapy (paid). She served previously (unpaid) on USA Football’s Football Development Council and is currently on USA Football’s Girls Football Council. She is also a member of several committees or the National Athletic Trainers’ Association and the North Carolina High School Athletic Association’s Sports Medicine Advisory Committee. PER has nothing to declare. KJS has received grant funding from the Canadian Institutes of Health Research, National Football League Scientific Advisory Board, International Olympic Committee Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary) with funds paid to her institution and not to her personally. She is an Associate Editor of BJSM (unpaid) and has received travel and accommodation support for meetings where she has presented. She is coordinating the writing of the systematic reviews that will inform the 6th International Consensus on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews. She is a member of the AFL Concussion Scientific Committee (unpaid position) and Brain Canada (unpaid positions). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass roots to professional. NDS: Employee salary from the University of British Columbia, Research grants from the Canadian Institutes of Health Research, Canada Foundation for Innovation, WorkSafeBC and the US Department of Defense (no salary contributions), Research salary support from the Michael Smith Foundation for Health Research, Editorial board member for Neuropsychology and the Journal of Head Trauma Rehabilitation (unpaid), Chair of the American Congress of Rehabilitation Medicine Mild TBI Task Force (unpaid), Member of the Scientific Advisory Committee, Brain Injury Canada (unpaid), Clinical neuropsychological consulting fees from the National Hockey League, Major League Soccer, and NDS Inc (<10% of total income). KOY: is editor-in-chief of the journal Neuropsychology and receives an editorial stipend from the American Psychological Association. He is an unpaid consulting editor for the journals Archives of Clinical Neuropsychology and Journal of Head Trauma Rehabilitation. He is an unpaid member of the Scientific Advisory Committee for Brain Injury Canada. He is the chair of the Canadian Concussion Network, which is funded by a grant from Canadian Institutes of Health Research (CIHR) to his institution; He is the principal applicant on the grant but receives no income from it. He is a principal investigator on another grant from CIHR from which he derives no income. He is a coinvestigator on research grants from CIHR, the US National Institutes of Health (NIH), Brain Canada Foundation and National Football League Scientific Advisory Board; He derives income only from the grant from NIH. He serves as a member of a CIHR grant review panel for which he receive a small honorarium. He receives book royalties from Guilford Press and Cambridge University Press. He has received travel support and honorarium for presentations to multiple organisations. He has served or serves on the following committees/boards for which I receives honorarium: 1. Independent Data Monitoring Committee (IDMC), Care for Post-Concussive Symptoms Effectiveness (CARE4PCS-2) Trial, National Institute for Child Health and Human Development 2. Observational Study Monitoring Board (OSMB), Approaches and Decisions in Acute Pediatric TBI (ADAPT) Trial, National Institute of Neurological Disorders and Stroke National Research Advisory Council, National Pediatric Rehabilitation Resource Center, Center for Pediatric Rehabilitation: Growing Research, Education, and Sharing Science (C-PROGRESS), Virginia Tech University., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Competing interests: KOY is editor-in-chief of the journal Neuropsychology for which he receives an editorial stipend from the American Psychological Association. He is an unpaid consulting editor for Archives of Clinical Neuropsychology and Journal of Head Trauma Rehabilitation. He is an unpaid member of the Scientific Advisory Committee for Brain Injury Canada. He is the chair of the Canadian Concussion Network, which is funded by a grant from Canadian Institutes of Health Research (CIHR) to the University of Calgary; he is principal applicant on the grant but receives no income from it. He is a principal investigator (PI) on another grant from CIHR from which he derives no income. He is a co-investigator on research grants from CIHR, the US National Institutes of Health (NIH), Brain Canada Foundation and National Football League Scientific Advisory Board; he derives income only from the grant from NIH. He serves as a member of a CIHR grant review panel for which he receives an honorarium. He receives book royalties from Guilford Press and Cambridge University Press. He has received travel support and honorarium for presentations to multiple organisations. He has served or serves on the following committees/boards for which he receives honorarium: Independent Data Monitoring Committee (IDMC), Care for Post-Concussive Symptoms Effectiveness (CARE4PCS-2) Trial, National Institute for Child Health and Human Development; Observational Study Monitoring Board (OSMB), Approaches and Decisions in Acute Pediatric TBI (ADAPT) Trial, National Institute of Neurological Disorders and Stroke; National Research Advisory Council, National Pediatric Rehabilitation Resource Center, Center for Pediatric Rehabilitation: Growing Research, Education, and Sharing Science (C-PROGRESS), Virginia Tech University. AMR received a stipend for the clerical and administrative aspects of the systematic review. She has received research grants from the Tonal Strength Institute and Alberta Bone and Joint Strategic Clinical Network. ZP has no disclosures. CD was a pharmaceutical funded invited expert panelist (Teva) for CGRP monoclonal antibody treatment in chronic migraine and received a pharmaceutical funded grant for growth hormone deficiency following concussion. She has grants as PI or co-investigator from the Canadian Department of National Defense, CIHR, Tri-council funding New Frontiers, Alberta Provincial government and Foundations for Physical Medicine and Rehabilitation. She holds a patent for urine metabolites in the diagnosis of concussion. PF is a co-investigator on a research grant from the NFL’s 'Play Smart. Play Safe' Initiative and an Executive committee member of the Canadian Concussion Network (financed by CIHR). He received honorarium for an expert group discussion on blood biomarkers for concussion in December 2020. SH provides client consultation services for military/veteran health, neuroscience, health, sports medicine, neurodegenerative disease, neurotrauma, nuclear medicine, molecular imaging, nuclear and radiation accidents and incidents, and health equity. Consult services includes support to Prevent Biometrics; advisor to Synaptek; advisor/consultant for the Collaborative Neuropathology Network Characterizing Outcomes of TBI (CONNECT-TBI); advisor to NanoDX; and reviewer for Peer Reviewed Alzheimer’s Disease Research Program. SH is chief of Health Equity and Deputy Medical Director for the NFL Players Association, Medical Director for the MLS Players Association. He receives grant support (no income) from the following: Co-PI, Long-term Impact of Military-relevant Brain Injury Consortium – Chronic Effects of Neurotrauma Consortium (LIMBIC-CENC); Advisory Board member to Concussion Legacy Foundation Project Enlist; Advisory Board member to the University of Michigan Concussion Center; advisor to Gryphon Bio; ad hoc reviewer for VA Brain Health Research; invited reviewer to Congressionally Directed Medical Research Programs; National Academy of Science, Engineering, and Medicine 'Accelerating Progress in TBI Research and Care'; NASEM TBI Forum committee member (currently inactive); contributor to Post-traumatic Epilepsy Former Department of Defense work: NFL Scientific Advisory Board member; NCAA-DoD CARE Medical Advisory Board Member; DoD Brain Health Research Coordinating Officer and Medical Advisor to the Principal Assistant for Research and Technology (PAR&T), United States Army Medical Research and Development Command (USAMRDC); Ex Officio National Advisory Neurological Disorders and Stroke (NANDSC) Council Member. KJS has no disclosures. KB receives funding from the Motor Accident Insurance Commission, Queensland Australia. She is a committee member on the Medical Advisory Board, Concussion Australia. She is Chief Investigator, for the first Australia and New Zealand Guidelines for the assessment and management of mild traumatic brain injury and persisting post-concussion symptoms, supported by the Medical Research Future Fund Australia. She has received travel support and honorarium for presentations to organisations. GAD is a member of the Scientific Committee of the 6th International Conference on Concussion in Sport; an honorary member of the AFL Concussion Scientific Committee; Section Editor, Sport and Rehabilitation, NEUROSURGERY; and has attended meetings organised by sporting organisations including the NFL, NRL, IIHF, IOC and FIFA; however, he has not received any payment, research funding, or other monies from these groups other than for travel costs. RJE is a paid consultant for the NHL and co-chair of the NHL/NHLPA Concussion Subcommittee. He is also a paid consultant and chair of the Major League Soccer concussion committee, and a consultant to the US Soccer Federation. He previously served as a neuropsychology consultant to Princeton University Athletic Medicine and EyeGuide. He is currently a co-PI for a grant funded by the NFL (NFL-Long) through Boston Children’s Hospital. He occasionally provides expert testimony in matters related to MTBI and sports concussion, and occasionally receives honoraria and travel support/reimbursement for professional meetings. NF-D is a member of the International independent FIFA Concussion Advisory Group; GOTS Concussion Committee Innovation and Technology Panel, UK Department for Digital, Culture, Media and Sport; Concussion in Sport Group (CISG); NINDS CDE Sports Concussion CDE Subacute Subgroup (National Institutes of Health); IFAB Concussion Expert Group; Swiss Neurology Society; Swiss Society for Clinical Neurophysiology; European NeuroOphthalmology Society; and Concussion in Sport Group (CISG). She is an Editorial Board Member for the Journal of Concussion, Journal of Science and Medicine in Football. CF is a PhD candidate at the School of Medicine & Health at University College Cork, Ireland. He is currently head of physiotherapy at the sports medicine department of the Sports Surgery Clinic (SSC), Dublin Ireland. SSC have paid the fees of his PhD and contributed towards the cost of him attending the 6th International Conference on Concussion in Sport in Amsterdam, 2022. From October 2017 to July 2020, he worked as national team lead physiotherapist for the IRFU Senior Men’s rugby team. He is a member of the Irish Society of Chartered Physiotherapists. Since 2022, he is a founder and shareholder (10%) of Fizfit Ltd., a start-up which focused on recovery and activation products for musculoskeletal health. IG has paid employment relationships with McGill University and the McGill University Health Center. She has received grants in the last 3 years from: Canadian Institutes of Health Research; Fonds de recherche du Québec – Santé; Research Institute of the McGill University Health Center; McGill University; and Institut National du Sport du Québec. CCG discloses the following grants and research support: Hit-IQ (2022-2023); NIH NINDS (R01 NS110757 2019-2024); NINDS (U54 NS121688 2021-2026); UCLA Brain Injury Research Center, UCLA Steve Tisch BrainSPORT program, Easton Clinic for Brain Health/Je os a clinical consultant (provide clinical care to athletes) for the NBA, NFL-Neurological Care Program, NHL/NHLPA, and Los Angeles Lakers. He is a member of the Advisory Board (non-compensated) for Major League Soccer, National Basketball Association, and US Soccer Federation. He is a member of the Advisory Board (Compensated) for Highmark Interactive; he occasionally serves as an expert witness in medicolegal cases. He is a shareholder in Highmark Interactive stock options. He receives book royalties from Blackwell/Wiley Publishing. GLI serves as a scientific advisor for NanoDX®, Sway Operations, LLC, and Highmark, Inc. He has a clinical and consulting practice in forensic neuropsychology, including expert testimony, involving individuals who have sustained mild TBIs (including former athletes), and on the topic of suicide. He has received past research support or funding from several test publishing companies, including ImPACT Applications, Inc., CNS Vital Signs, and Psychological Assessment Resources (PAR, Inc.). He receives royalties from the sales of one neuropsychological test (WCST-64). He has received travel support and honorariums for presentations at conferences and meetings. He has received research funding as a principal investigator from the National Football League, and subcontract grant funding as a collaborator from the Harvard Integrated Program to Protect and Improve the Health of National Football League Players Association Members. He has received research funding from the Wounded Warrior Project™. He acknowledges unrestricted philanthropic support from ImPACT Applications, Inc., the Mooney-Reed Charitable Foundation, the National Rugby League, Boston Bolts, and the Schoen Adams Research Institute at Spaulding Rehabilitation. MM is a sport and exercise medicine physician working in private consulting practice and is the Chief Medical Officer for the Australian Football League. He is a shareholder of Olympic Park Sports Medicine Centre in Melbourne, Australia. He is ex-senior physician at the Hawthorn Football Club (AFL) and ex-Chief Executive Officer of the AFL Doctors Association. He has received research grants from the Australian Football League. He has received travel support from the Australian Football League, FIFA and the International Olympic Committee to attend and present at international conferences. He is a member of the Scientific Committee for the 6th International Conference on Concussion in Sport. He is an honorary member of the International Concussion in Sport Group,and the Australian Rugby Union Concussion Advisory Group. He is an independent concussion consultant for World Rugby. KS has received grant funding from CIHR, National Football League Scientific Advisory Board, International Olympic Committee Medical and Scientific Research Fund, World Rugby, Mitacs Accelerate, University of Calgary) with funds paid to her institution and not to her personally. She is an Associate Editor of BJSM (unpaid) and has received travel and accommodation support for meetings where she has presented. She coordinated the writing of the systematic reviews that informed the 6th International Conference on Concussion in Sport, for which she has received an educational grant to assist with the administrative costs associated with the writing of the reviews. She is a member of the AFL Concussion Scientific Committee (unpaid position) and Brain Canada advisory committee (unpaid positions). She works as a physiotherapy consultant and treats athletes of all levels of sport from grass roots to professional., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

The assessment, management, and prognostication of spinal cord injury (SCI) mainly rely upon observer-based ordinal scales measures. 1 H 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.

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., (© 2023. The Author(s).)

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 (βˆ= 0.27; 95% CI = [0.16, 0.38]), GAD-7 score (βˆ= 0.71; 95% CI = [0.50, 0.92]) and PHQ-9 score (βˆ= 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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Pinky, Debert, Dukelow, Benson, Harris, Yeates, Emery and Goodyear.)

Background: In response to the COVID-19 pandemic, public health measures were implemented that closed essential businesses, mandated social distancing, and imposed substantial changes to the routine care experienced by patients with mild traumatic brain injury (mTBI) and persistent postconcussive symptoms (PPCS). Patients with PPCS often rely on a comprehensive care team, requiring in-person treatments and consistent care. Little information exists regarding how access to these services have been affected by public health measures and what outcome the measures have had on the recovery of patients with PPCS., Objective: To explore the impact of the restriction of in-person treatments, shifts to virtual care, and global public health measures on the recovery and psychological well-being of patients with PPCS., Design: Qualitative interviews were recorded, transcribed, and analyzed using a reflexive thematic analysis approach to identify the main impacts of the public health measures on participants with PPCS., Setting: Participant interviews were completed remotely via telephone or video-calling software during province-wide shutdowns., Participants: 20 individuals with PPCS who attended the institution's Brain Injury Program consented to participate., Interventions: Not applicable., Results: The impacts of the public health measures emerged most prominently in three main categories: (1) day-to-day lived experiences, (2) personal health status, and (3) health service experiences and barriers., Conclusions: This in-depth investigation of the lived experiences of patients with PPCS outlines how the COVID-19 public health measures negatively affected their care and well-being. The analysis identified that through increasing social support systems, providing better access to standard or remote treatment, and developing more effective telehealth strategies, this population could be better supported in the event of future public health measures., (© 2022 American Academy of Physical Medicine and Rehabilitation.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Joyce, Debert, Chevignard, Sorek, Katz-Leurer, Gagnon and Schneider.)

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 d repeated measures , 0.81), whereas the treatment approach-specific effect of Pacing+ on endurance behavior was less pronounced (Cohen's d repeated 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., (Copyright © 2021 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Sport-related concussion (SRC) is a major concern among athletes and clinicians around the world. Research into fluid biomarkers of SRC has made significant progress in understanding the complex underlying pathophysiology of concussion. However, little headway has been made toward clinically validating any biomarkers to improve the clinical management of SRC. A major obstacle toward clinical translation of any fluid biomarker is the heterogeneity of SRC overlapping with multiple physiological systems involved in pathology and recovery. Neuroinflammation post-SRC is one such system that may confound fluid biomarker data on many fronts. Neuroinflammatory processes consist of cell mediators, both within the central nervous system and the periphery, that play vital roles in regulating the response to brain injury. Further, neuroinflammation is influenced by many biopsychosocial variables present in most athletic populations. In this commentary, we propose that future fluid biomarker research should take a systems biology approach in the context of the neuroinflammatory response to SRC. We highlight how biological variables, such as age, sex, immune challenges, and hypothalamic-pituitary-adrenal (HPA)-axis responses to stress, may alter neuroinflammation. Further, we underscore the importance of accounting for health and lifestyle variables, such as diet, exercise, sleep, and pre-morbid medical factors, when measuring inflammatory markers of SRC. To successfully move toward clinical translation, fluid biomarker research should take a more holistic approach in study design and data interpretation, collecting information on hidden variables that may be influencing the neuroinflammatory response to SRC., Competing Interests: No competing financial interests exist., (© Jason B. Tabor et al., 2022; Published by Mary Ann Liebert, Inc.)

Background: Approximately one-third of all concussions lead to persistent postconcussion syndrome (PPCS). Repetitive transcranial magnetic stimulation (rTMS) is a form of noninvasive brain stimulation that has been extensively used to treat refractory major depressive disorder and has a strong potential to be used as a treatment for patients with PPCS. Functional near-infrared spectroscopy (fNIRS) has already been used as a tool to assess patients with PPCS and may provide insight into the pathophysiology of rTMS treatment in patients with PPCS., Objective: The primary objective of this research is to determine whether rTMS treatment improves symptom burden in patients with PPCS compared to sham treatment using the Rivermead postconcussion symptom questionnaire. The secondary objective is to explore the neuropathophysiological changes that occur following rTMS in participants with PPCS using fNIRS. Exploratory objectives include determining whether rTMS treatment in participants with PPCS will also improve quality of life, anxiety, depressive symptoms, cognition, posttraumatic stress, and function secondary to headaches., Methods: A total of 44 adults (18-65 years old) with PPCS (>3 months to 5 years) will participate in a double-blind, sham-controlled, concealed allocation, randomized clinical trial. The participants will engage in either a 4-week rTMS treatment protocol or sham rTMS protocol (20 treatments). The left dorsolateral prefrontal cortex will be located through Montreal Neurologic Institute coordinates. The intensity of the rTMS treatment over the left dorsolateral prefrontal cortex will be 120% of resting motor threshold, with a frequency of 10 Hz, 10 trains of 60 pulses per train (total of 600 pulses), and intertrain interval of 45 seconds. Prior to starting the rTMS treatment, participant and injury characteristics, questionnaires (symptom burden, quality of life, depression, anxiety, cognition, and headache), and fNIRS assessment will be collected. Repeat questionnaires and fNIRS will occur immediately after rTMS treatment and at 1 month and 3 months post rTMS. Outcome parameters will be analyzed by a 2-way (treatment × time) mixed analysis of variance., Results: As of May 6, 2021, 5 participants have been recruited for the study, and 3 have completed the rTMS protocol. The estimated completion date of the trial is May 2022., Conclusions: This trial will expand our knowledge of how rTMS can be used as a treatment option of PPCS and will explore the neuropathophysiological response of rTMS through fNIRS analysis., Trial Registration: ClinicalTrials.gov NCT04568369; https://clinicaltrials.gov/ct2/show/NCT04568369., International Registered Report Identifier (irrid): DERR1-10.2196/31308., (©Sané du Plessis, Ibukunoluwa K Oni, Andrew P Lapointe, Christina Campbell, Jeff F Dunn, Chantel T Debert. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.03.2022.)

To date, sport-related concussion diagnosis and management is primarily based on subjective clinical tests in the absence of validated biomarkers. A major obstacle to clinical validation and application is a lack of studies exploring potential biomarkers in non-injured populations. This cross-sectional study examined the associations between saliva telomere length (TL) and multiple confounding variables in a healthy university athlete population. One hundred eighty-three (108 male and 75 female) uninjured varsity athletes were recruited to the study and provided saliva samples at either pre- or mid-season, for TL analysis. Multiple linear regression was used to determine the associations between saliva TL and history of concussion, sport contact type, time in season (pre vs. mid-season collection), age, and sex. Results showed no significant associations between TL and history of concussion, age, or sport contact type. However, TL from samples collected mid-season were longer than those collected pre-season [β = 231.4, 95% CI (61.9, 401.0), p = 0.008], and males had longer TL than females [β = 284.8, 95% CI (111.5, 458.2), p = 0.001] when adjusting for all other variables in the model. These findings population suggest that multiple variables may influence TL. Future studies should consider these confounders when evaluating saliva TL as a plausible fluid biomarker for SRC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Machan, Tabor, Wang, Sutter, Wiley, Mychasiuk and Debert.)

Persistent post-concussive symptoms (PPCS) are debilitating and endure beyond the usual recovery period after mild traumatic brain injury (mTBI). Altered neurotransmission, impaired energy metabolism and oxidative stress have been examined acutely post-injury but have not been explored extensively in those with persistent symptoms. Specifically, the antioxidant glutathione (GSH) and the excitatory and inhibitory metabolites, glutamate (Glu) and γ-aminobutyric acid (GABA), are seldom studied together in the clinical mTBI literature. While Glu can be measured using conventional magnetic resonance spectroscopy (MRS) methods at 3 Tesla, GABA and GSH require the use of advanced MRS methods. Here, we used the recently established Hadamard Encoding and Reconstruction of MEGA-Edited Spectroscopy (HERMES) to simultaneously measure GSH and GABA and short-echo time point resolved spectroscopy (PRESS) to measure Glu to gain new insight into the pathophysiology of PPCS. Twenty-nine adults with PPCS (mean age: 45.69 years, s.d.: 10.73, 22 females, 7 males) and 29 age- and sex-matched controls (mean age: 43.69 years, s.d.: 11.00) completed magnetic resonance spectroscopy scans with voxels placed in the anterior cingulate and right sensorimotor cortex. Relative to controls, anterior cingulate Glu was significantly reduced in PPCS. Higher anterior cingulate GABA was significantly associated with a higher number of lifetime mTBIs, suggesting GABA may be upregulated with repeated incidence of mTBI. Furthermore, GSH in both regions of interest was positively associated with symptoms of sleepiness and headache burden. Collectively, our findings suggest that the antioxidant defense system is active in participants with PPCS, however this may be at the expense of other glutamatergic functions such as cortical excitation and energy metabolism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Increasing evidence suggests autonomic nervous system (ANS) dysfunction may occur following mild traumatic brain injury (mTBI). Measures of heart rate, heart rate variability, blood pressure and baroreceptor sensitivity can be used to evaluate ANS dysfunction following mTBI., Objective: Summarize the evidence for ANS dysfunction in adults following mTBI., Methods: A search of Embase, MEDLINE, Cochrane Central Register, PsycINFO, CINAHL and SPORTDiscus databases was conducted. Search topics included: mTBI and ANS. Identified abstracts were independently reviewed by 2 reviewers followed by full text screening. Risk of bias was assessed using a modified SIGN checklist. A structured synthesis was performed., Results: Thirty-nine studies (combined 1,467 participants diagnosed with mTBI) evaluating ANS function were included. ANS function was evaluated under various conditions including: rest, during exertion, cold pressor test, Valsalva maneuver, using face cooling and eyeball pressure paradigms. Short-term or ultra-short-term recordings were most common. The majority of studies (28/39) were rated as "unacceptable" for quality of evidence., Conclusions: Altered parameters of ANS function have been reported in multiple conditions following mTBI, both acutely and in the post-acute/chronic stages of recovery. However, due to methodological limitations, conclusions regarding the severity and timing of ANS dysfunction following mTBI cannot be drawn.

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.

Objective: Reporting of unexpected symptoms after concussion might, in some people, reflect a Functional Neurological Disorder (FND), Somatic Symptom Disorder (SSD), or exaggeration (feigning). This study aimed to determine whether reporting unexpected symptoms after concussion was associated with risk factors for FND/SSD, exaggeration, or both., Method: Adults with persistent symptoms following concussion (N = 77; 61% women) rated the presence and severity of unexpected neurological symptoms (from the Screening for Somatoform Symptoms scale, e.g., paralysis) and somatic symptoms (from the Patient Health Questionnaire-15, e.g., stomach pain) that did not overlap with post-concussion symptom scale items. The independent variables were risk factors for exaggeration (neuropsychological performance validity test failure and personal injury litigation) and predisposing and perpetuating factors for developing FND and/or SSD (e.g., fear avoidance behavior)., Results: When adjusting for all covariates, fear avoidance behavior was most strongly related to unexpected neurological symptoms (B = 0.11, 95% confidence interval = 0.05-0.18, p < .001), while current anxiety scores were most strongly related to unexpected somatic symptoms (B = 0.34, 95% confidence interval = 0.15-0.52, p < .001). Performance validity test failure and litigation were not significant predictors in either model., Conclusion: Unexpected neurological and other somatic symptoms after concussion should not be dismissed as exaggeration. Psychological factors thought to perpetuate FND and SSD (e.g., fear avoidance behavior) may contribute to unexpected symptoms following concussion. More research is needed at the intersection of FND, SSD, and persistent post-concussive symptoms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Analysis of fluid metabolites has the potential to provide insight into the neuropathophysiology of injury in patients with traumatic brain injury (TBI)., Objective: Using a 1 H nuclear magnetic resonance (NMR)-based quantitative metabolic profiling approach, this study determined (1) if urinary metabolites change during recovery in patients with mild to severe TBI; (2) whether changes in urinary metabolites correlate to injury severity; (3) whether biological pathway analysis reflects mechanisms that mediate neural damage/repair throughout TBI recovery., Methods: Urine samples were collected within 7 days and at 6-months post-injury in male participants (n = 8) with mild-severe TBI. Samples were analyzed with NMR-based quantitative spectroscopy for metabolomic profiles and analyzed with multivariate statistical and machine learning-based analyses., Results: Lower levels of homovanillate (R = -0.74, p  ≤ 0.001), L-methionine (R = -0.78, p  < 0.001), and thymine (R = -0.85, p  < 0.001) negatively correlated to injury severity. Pathway analysis revealed purine metabolism to be a primary pathway ( p  < 0.01) impacted by TBI., Conclusion: This study provides pilot data to support the use of urinary metabolites in clinical practice to better interpret biochemical changes underlying TBI severity and recovery. The discovery of urinary metabolites as biomarkers may assist in objective and rapid identification of TBI severity and prognosis. Thus, 1 H NMR metabolomics has the potential to facilitate the adaptation of treatment programs that are personalized to the patient's needs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 The Authors.)

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 (η 2 p =0.130; P<.001) and lower scores on measures of functional impact of headache (η 2 p =0.065; P=.009), fatigue (η 2 p =0.080; P=.004), depression (η 2 p =0.085; P=.001), and anxiety (η 2 p =0.046; P=.031), compared with those not meeting guidelines. Sedentary behavior postinjury was negatively correlated with quality of life (r s [127]=-0.252; P=.004) and positively correlated with symptom burden (r s [167]=0.227; P=.003), fatigue (r s [127]=0.288; P=.001), depression (r s [174]=0.319; P<.001), and anxiety (r s [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., (Copyright © 2021 The American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

Objective: Millions of sport-related concussions (SRC) occur annually in North America, and current diagnosis of concussion is based largely on clinical evaluations. The objective of this study was to determine whether urinary metabolites are significantly altered post-SRC compared to pre-injury. Setting: Outpatient sports medicine clinic. Participants: Twenty-six male youth sport participants. Methods: Urine was analyzed pre-injury and after SRC by 1 H NMR spectroscopy. Data were analyzed using multivariate statistics, pairwise t -test, and metabolic pathway analysis. Variable importance analysis based on random variable combination (VIAVC) was applied to the entire data set and resulted in a panel of 18 features. Partial least square discriminant analysis was performed exploring the separation between pre-injury and post-SRC groups. Pathway topography analysis was completed to identify biological pathway involvement. Spearman correlations provide support for the relationships between symptom burden and length of return to play and quantifiable metabolic changes in the human urinary metabolome. Results: Phenylalanine and 3-indoxysulfate were upregulated, while citrate, propylene glycol, 1-methylhistidine, 3-methylhistidine, anserine, and carnosine were downregulated following SRC. A receiver operator curve (ROC) tool constructed using the 18-feature classifier had an area under the curve (AUC) of 0.887. A pairwise t -test found an additional 19 altered features, 7 of which overlapped with the VIAVC analysis. Pathway topology analysis indicated that aminoacyl-tRNA biosynthesis and beta-alanine metabolism were the two pathways most significantly changed. There was a significant positive correlation between post-SRC 2-hydroxybutyrate and the length of return to play (ρ = 0.482, p = 0.02) as well as the number of symptoms and post-SRC lactose (ρ = 0.422, p = 0.036). Conclusion: We found that 1 H NMR metabolomic urinary analysis can identify a set of metabolites that can correctly classify SRC with an accuracy of 81.6%, suggesting potential for a more objective method of characterizing SRC. Correlations to both the number of symptoms and length of return to play indicated that 2-hydroxybutyrate and lactose may have potential applications as biomarkers for sport-related concussion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wanner, Southam, Sanghavi, Boora, Paxman, Dukelow, Benson, Montina, Metz and Debert.)

Background: Post-traumatic headaches (PTH) are a common sequelae of traumatic brain injury (TBI) and greatly impact patient function and quality of life. Post-traumatic greater occipital neuralgia (GON) is a type of post-traumatic headache. Conventional treatment includes steroid/anesthetic injections which typically alleviate pain but have a short duration of effect. Platelet-rich plasma (PRP) is an emerging biological treatment for numerous degenerative disorders, including peripheral nerve disorders. The primary aim of this pilot study is to evaluate whether a randomized control trial of PRP for the treatment of GON in patients with post-traumatic headaches is feasible in regard to recruitment, adherence, retention, and adherence and adverse events. Exploratory aims include improvement in pain, function, and quality of life in patients with post-traumatic GON receiving PRP compared to steroid/anesthetic and normal saline injections., Methods: Thirty adults (over 18 years of age) with post-traumatic GON will be randomized into one of three groups: (1) autologous PRP injection, (2) steroid/anesthetic injection (standard care), or (3) placebo injection with normal saline. Injections will be performed to the greater occipital nerve under ultrasound guidance by a trained physician. Daily headache intensity and frequency data will be collected pre-injection and for the duration of the study period. Feasibility will be defined as greater than 30% recruitment, 70% completion of intervention, 70% retention, and less than 2 minor adverse events. Exploratory outcomes will be explored using the Headache Impact Test-6 (HIT-6, a valid and reliable 6-item questionnaire for assessment of the impact of headaches across different diagnostic groups of headaches) and the quality of life in following brain injury questionnaire (QOILIBRI)., Discussion: This pilot study will be the first to evaluate the feasibility of PRP as a potential treatment of GON in patients with post-traumatic headache., Trial Registration: ClinicalTrials.gov - NCT04051203 (registered August 9, 2019).

Pituitary dysfunction, specifically growth hormone (GH) deficiency, can occur following traumatic brain injury. Our objective was to characterize the prevalence of GH deficiency (GHD) testing and response to recombinant human GH (rhGH) treatment in adults with persistent symptoms following mild traumatic brain injury (mTBI) referred for assessment of pituitary dysfunction. A retrospective chart review was conducted of patients seen at an outpatient brain injury clinic with a diagnosis of mTBI and persistent post-concussive symptoms who were referred to endocrinology. Clinical assessments of symptoms were collected. Investigations and results of GHD were collected, including initiation of rhGH treatment and treatment response. Of the 253 patients seen in both brain injury and endocrinology clinics, 97 with mTBI were referred for investigation of pituitary dysfunction and 73 (75%) had dynamic testing for assessment of GHD. Of the 26 individuals diagnosed with GHD, 23 (88%) started rhGH. GH therapy was inconsistently offered based on interpretation of GH dynamic testing results. Of those who started rhGH, 18 (78%) had a useful treatment response. This study suggests that clinical management of these patients is varied, highlighting a need for clear guidelines for the diagnosis and management of GHD following mTBI.

Current assessments of recovery following spinal cord injury (SCI) focus on clinical outcome measures. These assessments bear an inherent risk of bias, emphasizing the need for more reliable prognostic biomarkers to measure SCI severity. This study evaluated fluid biomarkers as an objective tool to aid with prognosticating outcomes following SCI. Using a 1 H nuclear magnetic resonance (NMR)-based quantitative metabolomics approach of urine samples, the objectives were to determine (a) if alterations in metabolic profiles reflect the extent of recovery of individual SCI patients, (b) whether changes in urine metabolites correlate to patient outcomes, and (c) whether biological pathway analysis reflects mechanisms of neural damage and repair. An inception cohort exploratory pilot study collected morning urine samples from male SCI patients (n=6) following injury and again at 6-months post-injury. A 700 MHz Bruker Avance III HD NMR spectrometer was used to acquire the metabolic signatures of urine samples, which were used to derive metabolic pathways. Multivariate statistical analyses were used to identify changes in metabolic signatures, which were correlated to clinical outcomes in the Spinal Cord Independence Measure (SCIM). Among SCI-induced metabolic changes, biomarkers which significantly correlated to patient SCIM scores included caffeine (R = -0.76, p < 0.01), 3-hydroxymandelic acid (R= -0.85, p < 0.001), L-valine (R = 0.90, p < 0.001; R = -0.64, p < 0.05), and N-methylhydantoin (R = -0.90, p < 0.001). The most affected pathway was purine metabolism. These findings indicate that urinary metabolites reflect SCI lesion severity and recovery and provide potentially prognostic biomarkers of SCI outcome in precision medicine approaches., (© 2021 The Authors.)