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Purpose: This study investigated the association between psychological resilience and resting-state network functional connectivity of three major brain networks in pediatric concussion. Methods: This was a substudy of a randomized controlled trial, recruiting children with concussion and orthopedic injury. Participants completed the Connor-Davidson Resilience 10 Scale and underwent magnetic resonance imaging at 72 h and 4-weeks postinjury. We explored associations between resilience and connectivity with the default mode network (DMN), central executive network (CEN), and salience network (SN) at both timepoints and also any change that occurred over time. We also explored associations between resilience and connectivity within each network. Results: A total of 67 children with a concussion (median age = 12.87 [IQR: 11.79-14.36]; 46% female) and 30 with orthopedic injury (median age = 12.27 [IQR: 11.19-13.94]; 40% female) were included. Seed-to-voxel analyses detected a positive correlation between 72-h resilience and CEN connectivity in the concussion group. Group moderated associations between resilience and SN connectivity at 72 h, as well as resilience and DMN connectivity over time. Regions-of-interest analyses identified group as a moderator of longitudinal resilience and within-DMN connectivity. Conclusions: These results suggest that neural recovery from concussion could be reliant on resilience. Resilience was related to functional connectivity with three of the main networks in the brain that are often impacted by concussion. Improving resilience might be investigated as a modifiable variable in children as both a protective and restorative in the context of concussion. Clinical Trial Registration Identifier: NCT05105802. PedCARE +MRI team (see Supplementary Appendix S1).

Individual differences in mindfulness may impact quality of life after concussion. In a cross-sectional analysis, the moderating effect of mindfulness was tested on the association between symptom severity and quality of life in adults with persisting postconcussion symptoms ( N  = 85). Mindfulness and symptom severity were independently associated with quality of life; however, mindfulness did not moderate this association. "Nonreactivity" was independently associated with quality of life; however, it was not a significant moderator. Taking a nonreactive stance, or allowing experiences to come and go without effort to change them, may be relevant to quality-of-life outcomes after concussion.

Objectives: Symptoms and cognition are both utilized as indicators of recovery following pediatric concussion, yet their interrelationship is not well understood. This study aimed to investigate: 1) the association of post-concussion symptom burden and cognitive outcomes (processing speed and executive functioning [EF]) at 4 and 12 weeks after pediatric concussion, and 2) the moderating effect of sex on this association., Methods: This prospective, multicenter cohort study included participants aged 5.00-17.99 years with acute concussion presenting to four Emergency Departments of the Pediatric Emergency Research Canada network. Five processing speed and EF tasks and the Post-Concussion Symptom Inventory (PCSI; symptom burden, defined as the difference between post-injury and retrospective [pre-injury] scores) were administered at 4 and 12 weeks post-concussion. Generalized least squares models were conducted with task performances as dependent variables and PCSI and PCSI*sex interaction as the main predictors, with important pre-injury demographic and injury characteristics as covariates., Results: 311 children (65.0% males; median age = 11.92 [IQR = 9.14-14.21 years]) were included in the analysis. After adjusting for covariates, higher symptom burden was associated with lower Backward Digit Span (χ 2 = 9.85, p = .043) and Verbal Fluency scores (χ 2 = 10.48, p = .033) across time points; these associations were not moderated by sex, ps ≥ .20. Symptom burden was not associated with performance on the Coding, Continuous Performance Test, and Color-Word Interference scores, ps ≥ .17., Conclusions: Higher symptom burden is associated with lower working memory and cognitive flexibility following pediatric concussion, yet these associations were not moderated by sex. Findings may inform concussion management by emphasizing the importance of multifaceted assessments of EF.

Background: The ability to cope with concussion symptoms and manage stress is an important determinant of risk for prolonged symptoms., Objective: This open-label mixed-methods pilot study assessed the acceptability and credibility of a mindfulness-based intervention delivered through a digital therapeutic (DTx; therapeutic smartphone app) for pediatric concussion., Methods: Participants aged 12 to 18 years were recruited from an emergency department within 48 hours of a concussion (acute cohort) or from a tertiary care clinic at least 1-month post-concussion (persisting symptoms cohort). Participants completed a novel 4-week mindfulness-based intervention, for 10 to 15 minutes/day, at a minimum of 4 days/week. At 2 weeks, participants completed a credibility and expectancy questionnaire. At 4 weeks, participants completed questionnaires assessing satisfaction, usability and working alliance, as well as a semi-structured phone interview., Results: Ten participants completed the study outcomes (7 acute; 3 persisting symptoms). The intervention was perceived as credible (median/max possible = 6.50/9.00 [6.83,8.75]) and DTx was usable (median/max possible = 70.00/100.00 [55.00,82.50]). Participants rated their satisfaction with the DTx (median/max possible = 27.00/32.00 [24.50,29.50]) and the working alliance with the digital mindfulness guides (median/max possible = 3.92/5.00 [3.38-4.33]) as high. Four themes were identified from the qualitative data: (a) positive attributes; (b) negative attributes; (c) ideas for modifications; and (d) technical issues., Conclusion: Results show modifications to the DTx, instructions and mindfulness intervention, and potential ways to increase adherence by leveraging positive attributes. A randomized control trial will assess the effectiveness of the DTx MBI to decrease the risk of persisting symptoms and reduce the symptom burden following pediatric concussion., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AAL reported being one of the authors of the Mindfulness-Based Intervention for Concussion protocol used in this study, she did not receive any financial benefit. AAL received funding from the Ontario Brain Institute NERD program for a separate component of the study. AAL has no other conflict of interest to disclose. BJS is the Chief Scientist and CEO of Mobio Interactive PTE LTD (Singapore), the parent company of Mobio Interactive Inc. (Toronto, Canada), and he owned approximately 22% of the company at the time of manuscript submission. BJS exclusively served as a technical liaison for the study and did not contribute to the specific study design, or select the outcome measures, nor did he directly contribute to, or have influence over, data collection or analysis. RZ is the cofounder, Scientific Director, and a minority shareholder in 360 Concussion Care, an interdisciplinary concussion clinic. RZ holds a Clinical Research Chair in Pediatric Concussion from University of Ottawa, and is on the concussion advisory board for Parachute Canada (a non-profit injury prevention charity). VS receives royalties for the publication of a book on concussion by Flammarion. The remaining authors have no conflicts of interest to report., (© The Author(s) 2024.)

Background: Concussion in children and adolescents is a significant public health concern, with 30% to 35% of patients at risk for prolonged emotional, cognitive, sleep, or physical symptoms. These symptoms negatively impact a child's quality of life while interfering with their participation in important neurodevelopmental activities such as schoolwork, socializing, and sports. Early psychological intervention following a concussion may improve the ability to regulate emotions and adapt to postinjury symptoms, resulting in the greater acceptance of change; reduced stress; and recovery of somatic, emotional, and cognitive symptoms., Objective: The primary objective of this study is to assess the feasibility of conducting a parallel-group (1:1) randomized controlled trial (RCT) to evaluate a digital therapeutics (DTx) mindfulness-based intervention (MBI) in adolescents aged 12 to <18 years. The attention-matched comparator intervention (a math game also used in previous RCTs) will be delivered on the same DTx platform. Both groups will be provided with the standard of care guidelines. The secondary objective is to examine intervention trends for quality of life; resilience; self-efficacy; cognition such as attention, working memory, and executive functioning; symptom burden; and anxiety and depression scores at 4 weeks after concussion, which will inform a more definitive RCT. A subsample will be used to examine whether those randomized to the experimental intervention group have different brain-based imaging patterns compared with those randomized to the control group., Methods: This study is a double-blind Health Canada-regulated trial. A total of 70 participants will be enrolled within 7 days of concussion and randomly assigned to receive the 4-week DTx MBI (experimental group) or comparator intervention. Feasibility will be assessed based on the recruitment rate, treatment adherence to both interventions, and retention. All outcome measures will be evaluated before the intervention (within 7 days after injury) and at 1, 2, and 4 weeks after the injury. A subset of 60 participants will undergo magnetic resonance imaging within 72 hours and at 4 weeks after recruitment to identify the neurophysiological mechanisms underlying the potential benefits from MBI training in adolescents following a concussion., Results: The recruitment began in October 2022, and the data collection is expected to be completed by September 2024. Data collection and management is still in progress; therefore, data analysis is yet to be conducted., Conclusions: This trial will confirm the feasibility and resolve uncertainties to inform a future definitive multicenter efficacy RCT. If proven effective, a smartphone-based MBI has the potential to be an accessible and low-risk preventive treatment for youth at risk of experiencing prolonged postconcussion symptoms and complications., Trial Registration: ClinicalTrials.gov NCT05105802; https://classic.clinicaltrials.gov/ct2/show/NCT05105802., International Registered Report Identifier (irrid): DERR1-10.2196/57226., (©Andrée-Anne Ledoux, Roger Zemek, Molly Cairncross, Noah Silverberg, Veronik Sicard, Nicholas Barrowman, Gary Goldfield, Clare Gray, Ashley D Harris, Natalia Jaworska, Nick Reed, Bechara J Saab, Andra Smith, Lisa Walker. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.04.2024.)

Background: Despite the promising benefits of self-guided digital interventions for adolescents recovering from concussion, attrition rates for such interventions are high. Evidence suggests that adults can develop therapeutic alliance with self-guided digital interventions, which is in turn associated with intervention engagement. However, no research has examined whether adolescents develop therapeutic alliance with self-guided digital interventions and what factors are important to its development. Additionally, social presence-the extent to which digital encounters feel like they are occurring in person-may be another relevant factor to understanding the nature of the connection between adolescents and a self-guided digital intervention, though this has yet to be explored., Objective: This qualitative study explored the extent to which adolescents recovering from concussion developed therapeutic alliance and social presence during their use of a self-guided digital mindfulness-based intervention. Additionally, this study aimed to determine factors important to adolescents' development of therapeutic alliance and social presence with the intervention., Methods: Adolescents aged between 12 and 17.99 years who sustained a concussion were recruited from 2 sites: a pediatric emergency department up to 48 hours after a concussion and a tertiary care clinic over 1 month following a concussion to capture adolescents who had both acute and persisting symptoms after concussion. Participants (N=10) completed a 4-week mindfulness-based intervention delivered through a smartphone app. Within the app, participants listened to audio recordings of mindfulness guides (voice actors) narrating psychoeducation and mindfulness practices. At 4 weeks, participants completed questionnaires and a semistructured interview exploring their experience of therapeutic alliance and social presence with the mindfulness guides in the intervention., Results: Themes identified within the qualitative results revealed that participants developed therapeutic alliance and social presence by "developing a genuine connection" with their mindfulness guides and "sensing real people." Particularly important to the development of therapeutic alliance and social presence were the mindfulness guides' "personal backgrounds and voices," such that participants felt more connected to the guides by knowing information about them and through the guides' calm tone of voice in audio recordings. Quantitative findings supported qualitative results; participants' average score for therapeutic alliance was far above the scale midpoint, while the mixed results for social presence measures aligned with qualitative findings that participants felt that the mindfulness guides seemed real but not quite as real as an in-person connection would., Conclusions: Our data suggest that adolescents can develop therapeutic alliance and social presence when using digital interventions with no direct human contact. Adolescents' development of therapeutic alliance and social presence with self-guided digital interventions can be bolstered by increasing human-like qualities (eg, real voices) within interventions. Maximizing therapeutic alliance and social presence may be a promising way to reduce attrition in self-guided digital interventions while providing accessible treatment., (©Kiarah M K O'Kane, Thalia Otamendi, Noah D Silverberg, Esther Choi, Veronik Sicard, Roger Zemek, Katherine Healey, Olivier Brown, Lauren Butterfield, Andra Smith, Gary Goldfield, Rachel Kardish, Bechara Saab, Andrée-Anne Ledoux, Molly Cairncross. Originally published in JMIR Formative Research (https://formative.jmir.org), 22.03.2024.)

Emerging evidence suggests that advanced neuroimaging modalities such as arterial spin labelling (ASL) might have prognostic utility for pediatric concussion. This study aimed to: 1) examine group differences in global and regional brain perfusion in youth with concussion or orthopedic injury (OI) at 72 h and 4 weeks post-injury; 2) examine patterns of abnormal brain perfusion within both groups and their recovery; 3) investigate the association between perfusion and symptom burden within concussed and OI youths at both time-points; and 4) explore perfusion between symptomatic and asymptomatic concussed and OI youths. Youths ages 10.00-17.99 years presenting to the emergency department with an acute concussion or OI were enrolled. ASL-magnetic resonance imaging scans were conducted at 72 h and 4 weeks post-injury to measure brain perfusion, along with completion of the Health Behavior Inventory (HBI) to measure symptoms. Abnormal perfusion clusters were identified using voxel-based z-score analysis at each visit. First, mixed analyses of covariance (ANCOVAs) investigated the Group*Time interaction on global and regional perfusion. Post hoc region of interest (ROI) analyses were performed on significant regions. Second, within-group generalized estimating equations investigated the recovery of abnormal perfusion at an individual level. Third, multiple regressions at each time-point examined the association between HBI and regional perfusion, and between HBI and abnormal perfusion volumes within the concussion group. Fourth, whole-brain one-way ANCOVAs explored differences in regional and abnormal perfusion based on symptomatic status (symptomatic vs. asymptomatic) and OIs at each time-point. A total of 70 youths with a concussion [median age (interquartile range; IQR) = 12.70 (11.67-14.35), 47.1% female] and 29 with an OI [median age (IQR)  =  12.05 (11.18-13.89), 41.4% female] were included. Although no Group effect was found in global perfusion, the concussion group showed greater adjusted perfusion within the anterior cingulate cortex/middle frontal gyrus (MFG) and right MFG compared with the OI group across time-points ( ps ≤ 0.004). The concussion group showed lower perfusion within the right superior temporal gyrus at both time-points and bilateral occipital gyrus at 4 weeks, ( ps ≤ 0.006). The number of hypoperfused clusters was increased at 72 h compared with 4 weeks in the concussion youths ( p  < 0.001), but not in the OIs. Moreover, Group moderated the HBI-perfusion association within the left precuneus and superior frontal gyrus at both time-points, ( ps ≤ 0.001). No association was found between HBI and abnormal perfusion volume within the concussion group at any visits. At 4 weeks, the symptomatic sub-group ( n  = 10) showed lower adjusted perfusion within the right cerebellum and lingual gyrus, while the asymptomatic sub-group ( n  = 59) showed lower adjusted perfusion within the left calcarine, but greater perfusion within the left medial orbitofrontal cortex, right middle frontal gyrus, and bilateral caudate compared with OIs. Yet, no group differences were observed in the number of abnormal perfusion clusters or volumes at any visit. The present study suggests that symptoms may be associated with changes in regional perfusion, but not abnormal perfusion levels.

Advanced magnetic resonance imaging (MRI) techniques indicate that concussion (i.e., mild traumatic brain injury) disrupts brain structure and function in children. However, the functional connectivity of brain regions within global and local networks (i.e., functional connectome) is poorly understood in pediatric concussion. This prospective, longitudinal study addressed this gap using data from the largest neuroimaging study of pediatric concussion to date to study the functional connectome longitudinally after concussion as compared with mild orthopedic injury (OI). Children and adolescents ( n  = 967) 8-16.99 years with concussion or mild OI were recruited from pediatric emergency departments within 48 h post-injury. Pre-injury and 1-month post-injury symptom ratings were used to classify concussion with or without persistent symptoms based on reliable change. Subjects completed a post-acute (2-33 days) and chronic (3 or 6 months via random assignment) MRI scan. Graph theory metrics were derived from 918 resting-state functional MRI scans in 585 children (386 concussion/199 OI). Linear mixed-effects modeling was performed to assess group differences over time, correcting for multiple comparisons. Relative to OI, the global clustering coefficient was reduced at 3 months post-injury in older children with concussion and in females with concussion and persistent symptoms. Time post-injury and sex moderated group differences in local (regional) network metrics of several brain regions, including degree centrality, efficiency, and clustering coefficient of the angular gyrus, calcarine fissure, cuneus, and inferior occipital, lingual, middle occipital, post-central, and superior occipital gyrus. Relative to OI, degree centrality and nodal efficiency were reduced post-acutely, and nodal efficiency and clustering coefficient were reduced chronically after concussion (i.e., at 3 and 6 months post-injury in females; at 6 months post-injury in males). Functional network alterations were more robust and widespread chronically as opposed to post-acutely after concussion, and varied by sex, age, and symptom recovery at 1-month post-injury. Local network segregation reductions emerged globally (across the whole brain network) in older children and in females with poor recovery chronically after concussion. Reduced functioning between neighboring regions could negatively disrupt specialized information processing. Local network metric alterations were demonstrated in several posterior regions that are involved in vision and attention after concussion relative to OI. This indicates that functioning of superior parietal and occipital regions could be particularly susceptibile to the effects of concussion. Moreover, those regional alterations were especially apparent at later time periods post-injury, emerging after post-concussive symptoms resolved in most and persisted up to 6 months post-injury, and differed by biological sex. This indicates that neurobiological changes continue to occur up to 6 months after pediatric concussion, although changes emerge earlier in females than in males. Changes could reflect neural compensation mechanisms.

Importance: Determining the optimal volume of early moderate-to-vigorous-intensity physical activity (MVPA) after concussion and its association with subsequent symptom burden is important for early postinjury management recommendations., Objectives: To investigate the association between cumulative MVPA (cMVPA) over 2 weeks and subsequent symptom burden at 1 week, 2 weeks, and 4 weeks postinjury in children and examine the association between cMVPA and odds of persisting symptoms after concussion (PSAC) at 2 weeks and 4 weeks postinjury., Design, Setting, and Participants: This multicenter cohort study used data from a randomized clinical trial that was conducted from March 2017 to December 2019 at 3 Canadian pediatric emergency departments in participants aged 10.00 to 17.99 years with acute concussion of less than 48 hours. Data were analyzed from July 2022 to December 2023., Exposure: cMVPA postinjury was measured with accelerometers worn on the waist for 24 hours per day for 13 days postinjury, with measurements deemed valid if participants had 4 or more days of accelerometer data and 3 or fewer consecutive days of missing data. cMVPA at 1 week and 2 weeks postinjury was defined as cMVPA for 7 days and 13 days postinjury, respectively. Multiple imputations were carried out on missing MVPA days., Main Outcomes and Measures: Self-reported postconcussion symptom burden at 1 week, 2 weeks, and 4 weeks postinjury using the Health and Behavior Inventory (HBI). PSAC was defined as reliable change on the HBI. A linear mixed-effect model was used for symptom burden at 1 week, 2 weeks, and 4 weeks postinjury with a time × cMVPA interaction. Logistic regressions assessed the association between cMVPA and PSAC. All models were adjusted for prognostically important variables., Results: In this study, 267 of 456 children (119 [44.6%] female; median [IQR] age, 12.9 [11.5 to 14.4] years) were included in the analysis. Participants with greater cMVPA had significantly lower HBI scores at 1 week (75th percentile [258.5 minutes] vs 25th percentile [90.0 minutes]; difference, -5.45 [95% CI, -7.67 to -3.24]) and 2 weeks postinjury (75th percentile [565.0 minutes] vs 25th percentile [237.0 minutes]; difference, -2.85 [95% CI, -4.74 to -0.97]) but not at 4 weeks postinjury (75th percentile [565.0 minutes] vs 25th percentile [237.0 minutes]; difference, -1.24 [95% CI, -3.13 to 0.64]) (P = .20). Symptom burden was not lower beyond the 75th percentile for cMVPA at 1 week or 2 weeks postinjury (1 week, 259 minutes; 2 weeks, 565 minutes) of cMVPA. The odds ratio for the association between 75th and 25th percentile of cMVPA and PSAC was 0.48 (95% CI, 0.24 to 0.94) at 2 weeks., Conclusions and Relevance: In children and adolescents with acute concussion, 259 minutes of cMVPA during the first week postinjury and 565 minutes of cMVPA during the second week postinjury were associated with lower symptom burden at 1 week and 2 weeks postinjury. At 2 weeks postinjury, higher cMVPA volume was associated with 48% reduced odds of PSAC compared with lower cMVPA volume.

Background and Objectives: This prospective, longitudinal cohort study examined trajectories of brain gray matter macrostructure after pediatric mild traumatic brain injury (mTBI)., Methods: Children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) were recruited from 5 pediatric emergency departments. Reliable change between preinjury and 1 month postinjury symptom ratings was used to classify mTBI with or without persistent symptoms. Children completed postacute (2-33 days) and/or chronic (3 or 6 months) postinjury T1-weighted MRI, from which macrostructural metrics were derived using automated segmentation. Linear mixed-effects models were used, with multiple comparisons correction., Results: Groups ( N = 623; 407 mTBI/216 OI; 59% male; age mean = 12.03, SD = 2.38 years) did not differ in total brain, white, or gray matter volumes or regional subcortical gray matter volumes. However, time postinjury, age at injury, and biological sex-moderated differences among symptom groups in cortical thickness of the angular gyrus, basal forebrain, calcarine cortex, gyrus rectus, medial and posterior orbital gyrus, and the subcallosal area all corrected p < 0.05. Gray matter macrostructural metrics did not differ between groups postacutely. However, cortical thinning emerged chronically after mTBI relative to OI in the angular gyrus in older children ( d [95% confidence interval] = -0.61 [-1.15 to -0.08]); and in the basal forebrain (-0.47 [-0.94 to -0.01]), subcallosal area (-0.55 [-1.01 to -0.08]), and the posterior orbital gyrus (-0.55 [-1.02 to -0.08]) in females. Cortical thinning was demonstrated for frontal and occipital regions 3 months postinjury in males with mTBI with persistent symptoms vs without persistent symptoms (-0.80 [-1.55 to -0.05] to -0.83 [-1.56 to -0.10]) and 6 months postinjury in females and younger children with mTBI with persistent symptoms relative to mTBI without persistent symptoms and OI (-1.42 [-2.29 to -0.45] to -0.91 [-1.81 to -0.01])., Discussion: These findings signal little diagnostic and prognostic utility of postacute gray matter macrostructure in pediatric mTBI. However, mTBI altered the typical course of cortical gray matter thinning up to 6 months postinjury, even after symptoms typically abate in most children. Collapsing across symptom status obscured the neurobiological heterogeneity of discrete clinical outcomes after pediatric mTBI. The results illustrate the need to examine neurobiology in relation to clinical outcomes and within a neurodevelopmental framework., (© 2023 American Academy of Neurology.)

This study investigated associations between psychological resilience and characteristics of white matter microstructure in pediatric concussion. This is a case control study and a planned substudy of a larger randomized controlled trial. Children with an acute concussion or orthopedic injury were recruited from the emergency department. Participants completed both the Connor-Davidson Resilience Scale 10 and an MRI at 72 h and 4-weeks post-injury. The association between resiliency and fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) at both timepoints were examined. We examined whether these associations were moderated by group. The association between resiliency captured at 72 h and diffusion tensor imaging metrics at 4 weeks was also investigated. Clusters were extracted using a significance threshold of threshold-free cluster enhancement corrected p < .05. A total of 66 children with concussion (median (IQR) age = 12.88 (IQR: 11.80-14.36); 47% female) and 29 children with orthopedic-injury (median (IQR) age = 12.49 (IQR: 11.18-14.01); 41% female) were included. A negative correlation was identified in the concussion group between 72 h resilience and 72 h FA. Meanwhile, positive correlations were identified in the concussion group with concussion between 72 h resilience and both 72 h MD and 72 h RD. These findings suggest that 72 h resilience is associated with white matter microstructure of the forceps minor, superior longitudinal fasciculus, and anterior thalamic radiation at 72 h post-concussion. Resilience seems to be associated with neural integrity only in the acute phase of concussion and thus may be considered when researching concussion recovery., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Advanced diffusion-weighted imaging techniques have increased understanding of the neuropathology of paediatric mild traumatic brain injury (i.e. concussion). Most studies have examined discrete white-matter pathways, which may not capture the characteristically subtle, diffuse and heterogenous effects of paediatric concussion on brain microstructure. This study compared the structural connectome of children with concussion to those with mild orthopaedic injury to determine whether network metrics and their trajectories across time post-injury differentiate paediatric concussion from mild traumatic injury more generally. Data were drawn from of a large study of outcomes in paediatric concussion. Children aged 8-16.99 years were recruited from five paediatric emergency departments within 48 h of sustaining a concussion ( n = 360; 56% male) or mild orthopaedic injury ( n = 196; 62% male). A reliable change score was used to classify children with concussion into two groups: concussion with or without persistent symptoms. Children completed 3 T MRI at post-acute (2-33 days) and/or chronic (3 or 6 months, via random assignment) post-injury follow-ups. Diffusion-weighted images were used to calculate the diffusion tensor, conduct deterministic whole-brain fibre tractography and compute connectivity matrices in native (diffusion) space for 90 supratentorial regions. Weighted adjacency matrices were constructed using average fractional anisotropy and used to calculate global and local (regional) graph theory metrics. Linear mixed effects modelling was performed to compare groups, correcting for multiple comparisons. Groups did not differ in global network metrics. However, the clustering coefficient, betweenness centrality and efficiency of the insula, cingulate, parietal, occipital and subcortical regions differed among groups, with differences moderated by time (days) post-injury, biological sex and age at time of injury. Post-acute differences were minimal, whereas more robust alterations emerged at 3 and especially 6 months in children with concussion with persistent symptoms, albeit differently by sex and age. In the largest neuroimaging study to date, post-acute regional network metrics distinguished concussion from mild orthopaedic injury and predicted symptom recovery 1-month post-injury. Regional network parameters alterations were more robust and widespread at chronic timepoints than post-acutely after concussion. Results suggest that increased regional and local subnetwork segregation (modularity) and inefficiency occurs across time after concussion, emerging after post-concussive symptom resolve in most children. These differences persist up to 6 months after concussion, especially in children who showed persistent symptoms. While prognostic, the small to modest effect size of group differences and the moderating effects of sex likely would preclude effective clinical application in individual patients., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: Determining how the timing of return to school is related to later symptom burden is important for early postinjury management recommendations., Objective: To examine the typical time to return to school after a concussion and evaluate whether an earlier return to school is associated with symptom burden 14 days postinjury., Design, Setting, and Participants: Planned secondary analysis of a prospective, multicenter observational cohort study from August 2013 to September 2014. Participants aged 5 to 18 years with an acute (<48 hours) concussion were recruited from 9 Canadian pediatric emergency departments in the Pediatric Emergency Research Canada Network., Exposure: The independent variable was the number of days of school missed. Missing fewer than 3 days after concussion was defined as an early return to school., Main Outcomes and Measures: The primary outcome was symptom burden at 14 days, measured with the Post-Concussion Symptom Inventory (PCSI). Symptom burden was defined as symptoms status at 14 days minus preinjury symptoms. Propensity score analyses applying inverse probability of treatment weighting were performed to estimate the relationship between the timing of return to school and symptom burden., Results: This cohort study examined data for 1630 children (mean age [SD] 11.8 [3.4]; 624 [38%] female). Of these children, 875 (53.7%) were classified as having an early return to school. The mean (SD) number of days missed increased across age groups (5-7 years, 2.61 [5.2]; 8-12 years, 3.26 [4.9]; 13-18 years, 4.71 [6.1]). An early return to school was associated with a lower symptom burden 14 days postinjury in the 8 to 12-year and 13 to 18-year age groups, but not in the 5 to 7-year age group. The association between early return and lower symptom burden was stronger in individuals with a higher symptom burden at the time of injury, except those aged 5 to 7 years., Conclusions and Relevance: In this cohort study of youth aged 5 to 18 years, these results supported the growing belief that prolonged absences from school and other life activities after a concussion may be detrimental to recovery. An early return to school may be associated with a lower symptom burden and, ultimately, faster recovery.

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8-16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children's pre-injury and 1-month post-injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion-weighted imaging at post-acute (2-33 days post-injury) and chronic (3 or 6 months via random assignment) post-injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, -0.58 (-1.04, -0.11), and superior longitudinal fasciculus, -0.49 (-0.90, -0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post-injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: To investigate whether preinjury physical, emotional, cognitive, and sleep symptoms on the Post-Concussion Symptoms Inventory (PCSI) are associated with persistent postconcussion symptoms (PPCS) at 4 weeks and whether any associations are moderated by sex or age., Study Setting and Participants: A total of 3063 participants with acute concussion, presenting to 9 Canadian pediatric emergency departments, were enrolled from August 2013 to June 2015., Design: A planned secondary analysis of a prospective, multicenter cohort study (Predicting Persistent Post-concussive Problems in Pediatrics or 5P). Primary outcome was PPCS at 4 weeks, defined as 3 or more new or worsening individual symptoms compared with the preinjury score at 28 days on the PCSI. The association between preinjury scores and PPCS was analyzed with a multivariable logistic regression analysis that included preinjury, sex, age, sex × preinjury, and age × preinjury interactions as predictors. Missing baseline covariates were imputed., Results: A total of 2123 (n = 844 [39.8%] girls; median [IQR] age = 12.9 [10.7, 15.0] participants were included in the analysis. Preinjury physical symptom score was associated with PPCS at 4 weeks (χ2 = 13.87, df = 6, P = .031). The preinjury emotional score also contributed to the variability in PPCS (χ2 = 11.79, df = 6, P = .067). While girls reported higher preinjury physical, emotional, and cognitive scores than boys, neither sex nor age interacted with preinjury to predict PPCS at 4 weeks. Independent of age and sex, preinjury physical symptoms were associated with PPCS at 4 weeks (OR = 1.40; 95% CI, 1.15-1.70)., Conclusion: Preinjury physical symptoms are associated with the probability of having PPCS at 4 weeks postconcussion independent of age and sex. Providers should consider preinjury symptoms to inform prognosis and recovery management., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Concussion may exacerbate existing mental health issues. Little evidence exists on whether concussion is associated with the onset of new psychopathologies or long-term mental health problems., Objective: To investigate associations between concussion and risk of subsequent mental health issues, psychiatric hospitalizations, self-harm, or suicides., Design, Setting, and Participants: This population-based retrospective cohort study including children and youths aged 5 to 18 years with a concussion or orthopedic injury incurred between April 1, 2010, and March 31, 2020, in Ontario, Canada. Participants had no previous mental health visit in the year before the index event for cohort entry and no prior concussion or traumatic brain injury 5 years before the index visit. Data were collected from provincewide health administrative databases. Participants with concussion were included in the exposed cohort, and those with an orthopedic injury were included in the comparison cohort; these groups were matched 1:2, respectively, on age and sex., Exposures: Concussion or orthopedic injury., Main Outcomes and Measures: The primary outcome was mental health problems, such as psychopathologies and psychiatric disorders, identified from health care visits in emergency departments, hospitalizations, or primary care settings. Secondary outcomes were psychiatric hospitalizations, self-harm health care visits, and death by suicide (identified in health care or vital statistics databases)., Results: A total of 152 321 children and youths with concussion (median [IQR] age, 13 [10-16] years; 86 423 [56.7%] male) and 296 482 children and youths with orthopedic injury (median [IQR] age, 13 [10-16] years; 171 563 [57.9%] male) were matched by age and sex. The incidence rates of any mental health problem were 11 141 per 100 000 person-years (exposed group) and 7960 per 100 000 person-years (unexposed group); with a difference of 3181 (95% CI, 3073-3291) per 100 000 person-years. The exposed group had an increased risk of developing a mental health issue (adjusted hazard ratio [aHR], 1.39; 95% CI, 1.37-1.40), self-harm (aHR, 1.49; 95% CI, 1.42-1.56), and psychiatric hospitalization (aHR, 1.47; 95% CI, 1.41-1.53) after a concussion. There was no statistically significant difference in death by suicide between exposed and unexposed groups (HR, 1.54; 95% CI, 0.90-2.61)., Conclusions and Relevance: Among children and youths aged 5 to 18 years, concussion was associated with an increased risk of mental health issues, psychiatric hospitalization, and self-harm compared with children and youths with an orthopedic injury.

Objective: Investigate whether resuming physical activity (PA) at 72 hours post concussion is safe and reduces symptoms at 2 weeks, compared with resting until asymptomatic., Methods: Real-life conditions, multicentre, single-blinded randomised clinical trial, conducted in three Canadian paediatric emergency departments (ED). Children/youth aged 10-<18 years with acute concussion were recruited between March 2017 and December 2019, and randomly assigned to a 4-week stepwise return-to-PA protocol at 72 hours post concussion even if symptomatic (experimental group (EG)) or to a return-to-PA once asymptomatic protocol (control group (CG)). The primary outcome was self-reported symptoms at 2 weeks using the Health and Behaviour Inventory. Adherence was measured using accelerometers worn 24 hours/day for 14 days post injury. Adverse events (AE) (worsening of symptoms requiring unscheduled ED or primary care visit) were monitored. Multivariable intention-to-treat (ITT) and per-protocol analyses adjusting for prognostically important covariates were examined. Missing data were imputed for the ITT analysis., Results: 456 randomised participants (EG: N=227; mean (SD) age=13.3 (2.1) years; 44.5% women; CG: N=229; mean (SD) age=13.3 (2.2) years; 43.7% women) were analysed. No AE were identified. ITT analysis showed no strong evidence of a group difference at 2 weeks (adjusted mean difference=-1.3 (95% CI:-3.6 to 1.1)). In adherent participants, initiating PA 72 hours post injury significantly reduced symptoms 2 weeks post injury, compared with rest (adjusted mean difference=-4.3 (95% CI:-8.4 to -0.2))., Conclusion: Symptoms at 2 weeks did not differ significantly between children/youth randomised to initiate PA 72 hours post injury versus resting until asymptomatic; however, many were non-adherent to the intervention. Among adherent participants, early PA was associated with reduced symptoms at 2 weeks. Resumption of PA is safe and may be associated with milder symptoms at 2 weeks., Level of Evidence: 1b., Trial Registration Number: NCT02893969., Registry Name: Pediatric Concussion Assessment of Rest and Exertion (PedCARE)., Competing Interests: Competing interests: KY reported being one of the authors of the Health and Behaviour Inventory (HBI); the HBI is freely available and he receives no financial benefit for its use. There are no other conflicts of interest relevant to this article to disclose. RZ is scientific director and minority shareholder in 360 Concussion Care, an interdisciplinary concussion clinic. RZ and KY are investigators in a multicentre study funded by the National Football League (NFL) Scientific Advisory Board; they do not receive any financial benefit. There are no other conflicts of interest relevant to this article to disclose., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Concussion is a mild traumatic brain injury (mTBI) with increasing prevalence among children and adolescents. Functional connectivity (FC) within and between the default mode network (DMN), central executive network (CEN) and salience network (SN) has been shown to be altered post-concussion. Few studies have investigated connectivity within and between these 3 networks following a pediatric concussion. The present study explored whether within and between-network FC differs between a pediatric concussion and orthopedic injury (OI) group aged 10-18. Participants underwent a resting-state functional magnetic resonance imaging (rs-fMRI) scan at 4 weeks post-injury. One-way ANCOVA analyses were conducted between groups with the seed-based FC of the 3 networks. A total of 55 concussion and 27 OI participants were included in the analyses. Increased within-network FC of the CEN and decreased between-network FC of the DMN-CEN was found in the concussion group when compared to the OI group. Secondary analyses using spherical SN regions of interest revealed increased within-network FC of the SN and increased between-network FC of the DMN-SN and CEN-SN in the concussion group when compared to the OI group. This study identified differential connectivity patterns following a pediatric concussion as compared to an OI 4 weeks post-injury. These differences indicate potential adaptive brain mechanisms that may provide insight into recovery trajectories and appropriate timing of treatment within the first month following a concussion., 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. Published by Elsevier Inc.)

Context: Current evidence regarding the protective effect of mouthguard use on symptom severity in children and adolescents who sustain sport-related concussions is insufficient to make clinical recommendations., Objective: To compare the association between mouthguard use and symptoms stratified by sex in the first 4 weeks after pediatric sport-related concussion. We hypothesized that mouthguard use would be associated with less severe symptoms., Design: Prospective cohort study., Setting: Nine Canadian pediatric emergency departments (EDs)., Patients or Other Participants: Children aged 5 to 18 years who were assessed within 48 hours of concussions sustained during a collision or contact sport., Main Outcome Measure(s): Injury characteristics were collected using the Acute Concussion Evaluation. The primary outcome measure was symptom score (range = 0-6), measured using age-appropriate versions (5-7, 8-12, or 13-18 years) of the Post-Concussion Symptom Inventory. The independent variable was time postconcussion (initial assessment and 1, 2, and 4 weeks)., Results: Of 1019 children (73% male; median [interquartile range] age = 13.43 years [11.01-15.27 years]), 42% wore a mouthguard at the time of injury. No significant group-by-sex-by-time interaction was present for symptoms (\(\def\upalpha{\unicode[Times]{x3B1}}\)\(\def\upbeta{\unicode[Times]{x3B2}}\)\(\def\upgamma{\unicode[Times]{x3B3}}\)\(\def\updelta{\unicode[Times]{x3B4}}\)\(\def\upvarepsilon{\unicode[Times]{x3B5}}\)\(\def\upzeta{\unicode[Times]{x3B6}}\)\(\def\upeta{\unicode[Times]{x3B7}}\)\(\def\uptheta{\unicode[Times]{x3B8}}\)\(\def\upiota{\unicode[Times]{x3B9}}\)\(\def\upkappa{\unicode[Times]{x3BA}}\)\(\def\uplambda{\unicode[Times]{x3BB}}\)\(\def\upmu{\unicode[Times]{x3BC}}\)\(\def\upnu{\unicode[Times]{x3BD}}\)\(\def\upxi{\unicode[Times]{x3BE}}\)\(\def\upomicron{\unicode[Times]{x3BF}}\)\(\def\uppi{\unicode[Times]{x3C0}}\)\(\def\uprho{\unicode[Times]{x3C1}}\)\(\def\upsigma{\unicode[Times]{x3C3}}\)\(\def\uptau{\unicode[Times]{x3C4}}\)\(\def\upupsilon{\unicode[Times]{x3C5}}\)\(\def\upphi{\unicode[Times]{x3C6}}\)\(\def\upchi{\unicode[Times]{x3C7}}\)\(\def\uppsy{\unicode[Times]{x3C8}}\)\(\def\upomega{\unicode[Times]{x3C9}}\)\(\def\bialpha{\boldsymbol{\alpha}}\)\(\def\bibeta{\boldsymbol{\beta}}\)\(\def\bigamma{\boldsymbol{\gamma}}\)\(\def\bidelta{\boldsymbol{\delta}}\)\(\def\bivarepsilon{\boldsymbol{\varepsilon}}\)\(\def\bizeta{\boldsymbol{\zeta}}\)\(\def\bieta{\boldsymbol{\eta}}\)\(\def\bitheta{\boldsymbol{\theta}}\)\(\def\biiota{\boldsymbol{\iota}}\)\(\def\bikappa{\boldsymbol{\kappa}}\)\(\def\bilambda{\boldsymbol{\lambda}}\)\(\def\bimu{\boldsymbol{\mu}}\)\(\def\binu{\boldsymbol{\nu}}\)\(\def\bixi{\boldsymbol{\xi}}\)\(\def\biomicron{\boldsymbol{\micron}}\)\(\def\bipi{\boldsymbol{\pi}}\)\(\def\birho{\boldsymbol{\rho}}\)\(\def\bisigma{\boldsymbol{\sigma}}\)\(\def\bitau{\boldsymbol{\tau}}\)\(\def\biupsilon{\boldsymbol{\upsilon}}\)\(\def\biphi{\boldsymbol{\phi}}\)\(\def\bichi{\boldsymbol{\chi}}\)\(\def\bipsy{\boldsymbol{\psy}}\)\(\def\biomega{\boldsymbol{\omega}}\)\(\def\bupalpha{\bf{\alpha}}\)\(\def\bupbeta{\bf{\beta}}\)\(\def\bupgamma{\bf{\gamma}}\)\(\def\bupdelta{\bf{\delta}}\)\(\def\bupvarepsilon{\bf{\varepsilon}}\)\(\def\bupzeta{\bf{\zeta}}\)\(\def\bupeta{\bf{\eta}}\)\(\def\buptheta{\bf{\theta}}\)\(\def\bupiota{\bf{\iota}}\)\(\def\bupkappa{\bf{\kappa}}\)\(\def\buplambda{\bf{\lambda}}\)\(\def\bupmu{\bf{\mu}}\)\(\def\bupnu{\bf{\nu}}\)\(\def\bupxi{\bf{\xi}}\)\(\def\bupomicron{\bf{\micron}}\)\(\def\buppi{\bf{\pi}}\)\(\def\buprho{\bf{\rho}}\)\(\def\bupsigma{\bf{\sigma}}\)\(\def\buptau{\bf{\tau}}\)\(\def\bupupsilon{\bf{\upsilon}}\)\(\def\bupphi{\bf{\phi}}\)\(\def\bupchi{\bf{\chi}}\)\(\def\buppsy{\bf{\psy}}\)\(\def\bupomega{\bf{\omega}}\)\(\def\bGamma{\bf{\Gamma}}\)\(\def\bDelta{\bf{\Delta}}\)\(\def\bTheta{\bf{\Theta}}\)\(\def\bLambda{\bf{\Lambda}}\)\(\def\bXi{\bf{\Xi}}\)\(\def\bPi{\bf{\Pi}}\)\(\def\bSigma{\bf{\Sigma}}\)\(\def\bPhi{\bf{\Phi}}\)\(\def\bPsi{\bf{\Psi}}\)\(\def\bOmega{\bf{\Omega}}\)\({\rm{\chi }}&#95;3^2\) = 0.27; P = .965). Male mouthguard users reported similar symptom scores in the ED (difference in Post-Concussion Symptom Inventory Δ scores [diff] = -0.07; 95% CI = -0.23, 0.09) and at weeks 1 (diff = -0.02; 95% CI = -0.18, 0.14), 2 (diff = -0.03; 95% CI = -0.19, 0.13), and 4 (diff = -0.13; 95% CI = -0.29, 0.04) compared with males who did not wear a mouthguard. Female mouthguard users described minimally higher symptom scores at week 1 compared with non-mouthguard users (diff = 0.29; 95% CI = 0.01, 0.56). In the ED, symptom scores were not different for females who wore a mouthguard and those who did not (diff = 0.22; 95% CI = -0.04, 0.48) or at weeks 2 (diff = 0.22; 95% CI = -0.06, 0.51) or 4 (diff = 0.08; 95% CI = -0.20, 0.36)., Conclusions: Wearing a mouthguard at the time of injury was not associated with reduced acute or subacute symptoms after sport-related concussion in either males or females who were treated in the ED compared with those who did not wear a mouthguard. Athletes are still encouraged to wear mouthguards during sports because overwhelming evidence supports their use in preventing dental injuries., (© by the National Athletic Trainers' Association, Inc.)

Objectives: To characterize symptom burden, school function, and physical activity in youth 1 year following acute concussion and those with subsequent repeat concussion., Study Design: Secondary analysis of Predicting Persistent Postconcussive Problems in Pediatrics prospective, multicenter cohort study conducted in 9 Canadian emergency departments. Participants were children between ages 5 and 18 years who presented consecutively ≤48 hours of concussion and agreed to participate in a post hoc electronic survey 1 year after injury. Outcomes were assessed using a standardized 25-question symptom scale derived from the Post-Concussion Symptom Inventory-Parent; school function and physical activity outcomes were queried. The primary outcome was total symptom score 1 year following concussion, defined as the number of symptoms experienced more than before injury., Results: Of 3052 youth enrolled in the Predicting Persistent Postconcussive Problems in Pediatrics study, 432 (median [IQR] age, 11.5 [9,14] years; 266 [62%] male) completed the 1-year survey; 34 respondents reported a repeat concussion. Following acute concussion, youth were more likely to be symptom-free than following repeat concussion (75% vs 50%; difference = 25% [95% CI 8-41]; P = .002) and to have recovered fully (90% vs 74%; difference = 17% [95% CI 5-34]; P = .002) after 1 year. Although physical symptoms were less 1 year after initial emergency department presentation for both groups (P < .001), youth with a repeat concussion reported greater headache persistence (26% vs 13%; difference = 13% [95% CI 1,31]; P = .024). Both groups returned to their normal school routine (100% vs 95%; difference = 5% [95% CI -5 to 8; P = .618). Youth without repeat concussion more frequently returned to normal physical activities (98% vs 85%; difference = 13% [95% CI 4-28]; P < .0001) and sport (95% vs 82%; difference = 13% [95% CI 3-29]; P = .009)., Conclusions: Most youth are symptom-free and fully recovered 1 year following concussion. Some children with repeat concussion have worse outcomes and have delays in returning to normal school routines and sport., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: We evaluated the association between timing of presentation and postconcussive symptoms (PCS) at 1, 4 and 12 weeks after injury., Methods: This was a secondary analysis of a prospective cohort study conducted in nine Canadian paediatric EDs in 2013-2015 (5P study). Participants were children who suffered a head injury within the preceding 48 hours and met Zurich consensus concussion diagnostic criteria. The exposure was the time between head injury and ED presentation. The primary outcome was the presence of PCS at 1 week defined by the presence of at least three symptoms on the Post-Concussion Symptom Inventory (PCSI). Secondary outcomes evaluated PCS at 4 and 12 weeks. Multivariable logistic regression analyses were adjusted for ED PCSI and other potential confounders., Results: There were 3041 patients with a concussion in which timing of the injury was known. 2287 (75%) participants sought care in the first 12 hours, 388 (13%) 12-24 hours after trauma and 366 (12%) between 24 and 48 hours. Compared with children who sought care >24 hours after trauma, children who sought care in the first 12 hours had a significantly lower incidence of PCS at 1 week (OR: 0.55 (95% CI 0.41 to 0.75)) and 4 weeks (OR: 0.74 (95% CI 0.56 to 0.99)) but not at 12 weeks (OR: 0.88 (95% CI 0.63 to 1.23))., Conclusions: Patients who present early after a concussion appear to have a shorter duration of PCS than those presenting more than 12 hours later. Patients/families should be informed of the higher probability of PCS in children with delayed presentation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Rest until symptom-free, followed by a progressive stepwise return to activities, is often prescribed in the management of paediatric concussions. Recent evidence suggests prolonged rest may hinder recovery, and early resumption of physical activity may be associated with more rapid recovery postconcussion. The primary objective is to determine whether the early reintroduction of non-contact physical activity beginning 72 hours postinjury reduces postconcussive symptoms at 2 weeks in children following an acute concussion as compared with a rest until asymptomatic protocol., Methods and Analysis: This study is a randomised clinical trial across three Canadian academic paediatric emergency departments. A total of 350 participants, aged 10-17.99 years, who present within 48 hours of an acute concussion, will be recruited and randomly assigned to either the study intervention protocol (resumption of physical activity 72 hours postconcussion even if experiencing symptoms) or physical rest until fully asymptomatic. Participants will document their daily physical and cognitive activities. Follow-up questionnaires will be completed at 1, 2 and 4 weeks postinjury. Compliance with the intervention will be measured using an accelerometer (24 hours/day for 14 days). Symptoms will be measured using the validated Health and Behaviour Inventory. A linear multivariable model, adjusting for site and prognostically important covariates, will be tested to determine differences between groups. The proposed protocol adheres to the RCT-CONSORT guidelines., Discussion: This trial will determine if early resumption of non-contact physical activity following concussion reduces the burden of concussion and will provide healthcare professionals with the evidence by which to recommend the best timing of reintroducing physical activities., Trial Registration Number: Trial identifier (Clinicaltrials.gov) NCT02893969., Competing Interests: Competing interests: RZ is supported by a clinical research chair in pediatric concussion by the University of Ottawa Brain and Mind Research Institute., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2019. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Importance: The natural progression of symptom change and recovery remains poorly defined in children after concussion., Objectives: To describe the natural progression of symptom change by age group (5-7, 8-12, and 13-18 years) and sex, as well as to develop centile curves to inform families about children after injury recovery., Design, Setting, and Participants: Planned secondary analysis of a prospective multicenter cohort study (Predicting Persistent Postconcussive Problems in Pediatrics). The setting was 9 pediatric emergency departments within the Pediatric Emergency Research Canada (PERC) network. Participants were aged 5 to 18 years with acute concussion, enrolled from August 1, 2013, to May 31, 2015, and data analyses were performed between January 2018 and March 2018., Exposures: Participants had a concussion consistent with the Zurich Consensus Statement on Concussion in Sport diagnostic criteria and 85% completeness of the Postconcussion Symptom Inventory (PCSI) at each time point., Main Outcomes and Measures: The primary outcome was symptom change, defined as current rating minus preinjury rating (delta score), at presentation and 1, 2, 4, 8, and 12 weeks after injury, measured using the PCSI. Symptoms were self-rated for ages 8 to 18 years and rated by the child and parent for ages 5 to 7 years. The secondary outcome was recovery, defined as no change in symptoms relative to current preinjury PCSI ratings (delta score = 0). Mixed-effects models incorporated the total score, adjusting for random effects (site and participant variability), fixed-effects indicators (age, sex, time, age by time interaction, and sex by time interaction), and variables associated with recovery. Recovery centile curves by age and sex were computed., Results: A total of 3063 children (median age, 12.0 years [interquartile range, 9.2-14.6 years]; 60.7% male) completed the primary outcome; 2716 were included in the primary outcome analysis. For the group aged 5 to 7 years, symptom change primarily occurred the first week after injury; by 2 weeks, 75.6% of symptoms had improved (PCSI change between 0 and 2 weeks, -5.3; 95% CI, -5.5 to -5.0). For the groups aged 8 to 12 years and 13 to 18 years, symptom change was prominent the first 2 weeks but flattened between 2 and 4 weeks. By 4 weeks, 83.6% and 86.2% of symptoms, respectively, had improved for the groups aged 8 to 12 years (PCSI change between 0 and 4 weeks, -9.0; 95% CI, -9.6 to -8.4) and 13 to 18 years (PCSI change between 0 and 4 weeks, -28.6; 95% CI, -30.8 to -26.3). Sex by time interaction was significant only for the adolescent group (β = 0.32; 95% CI, 0.21-0.43; P < .001). Most adolescent girls had not recovered by week 12., Conclusions and Relevance: Symptom improvement primarily occurs in the first 2 weeks after concussion in children and in the first 4 weeks after concussion in preadolescents and male adolescents. Female adolescents appear to have protracted recovery. The derived recovery curves may be useful for evidence-based anticipatory guidance.

Objective: There is a lack of definitive pediatric literature on effective pharmacotherapy for persistent post-concussion headache symptoms. This study assessed whether acute metoclopramide treatment in the Emergency Department (ED) was associated with a reduction in persistent headache in children at 1- and 4-weeks post-concussion., Methods: Children aged 8-17years with acute concussion presenting to 9-Canadian Pediatric EDs were enrolled in a prospective cohort study, from August 2013-June 2015. Primary and secondary outcomes were persistent headache at 1- and 4-week post-injury respectively. Headache persistence was based on the one and four-week headache scores minus recalled pre-injury score using the Post-Concussion Symptom Inventory. The association between metoclopramide and headache persistence at 1- and 4-weeks were examined using unadjusted and adjusted regression and 1:4 propensity score matching model., Results: Baseline assessments were completed in 2095 participants; 65 (3.1%) received metoclopramide within 48-hours of injury. At 1- and 4-weeks, 54% (963/1808) and 26% (456/1780) of participants had persistent headache relative to baseline respectively. In unadjusted analysis, no association between metoclopramide and headache persistence at 1-week was found [treated vs. untreated: 1-week (53% vs. 53%; relative risk (RR)=1.0 (95%CI: 0.8, 1.3); 4-weeks (27.3% vs. 25.6%; RR=1.0 (95% CI: 0.9, 1.2)]. Metoclopramide was not associated with lower headache risk on propensity score matching [treated vs. untreated: 1-week, n=220 (52% vs. 59.4%; RR=0.8 (95%CI: 0.6, 1.2) and 4-weeks, n=225 (27.1% vs. 32.8%; RR=0.9 (95%CI: 0.8, 1.1)]., Conclusion: Metoclopramide administration was not associated with a reduction in headache persistence in children seeking ED care due to a concussion. Further research is necessary to determine which pharmacotherapies may be effective for acute and persistent post-concussive headache., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Childhood and adolescence are crucial periods for brain development, and the behaviours during a typical 24 h period contribute to cognitive performance. The Canadian 24-Hour Movement Guidelines for Children and Youth recommend at least 60 min physical activity per day, 2 h or less recreational screen time per day, and 9-11 h sleep per night in children aged 8-11 years. We investigated the relationship between adherence to these recommendations and global cognition., Methods: In this cross-sectional observational study, we obtained data from the first annual curated release of the Adolescent Brain Cognitive Development study, a 10-year longitudinal, observational study. Data were collected from 21 study sites across the USA between Sept 1, 2016, and Sept 15, 2017. The participants were 4524 US children aged 8-11 years from 20 study sites. Exposures of interest were adherence to the physical activity, recreational screen time, and sleep duration guideline recommendations. The primary outcome was global cognition, assessed with the NIH Toolbox (National Institutes of Health, Bethesda, MD, USA), which we analysed with multivariable linear mixed-effects models to examine the relations with movement behaviour variables., Findings: Complete movement behaviour data were available for 4520 participants. The mean number of guideline recommendations met was 1·1 (SD 0·9). Overall, 2303 (51%) participants met the sleep recommendation, 1655 (37%) met screen time, and 793 (18%) met the physical activity recommendation. 3190 (71%) participants met at least one recommendation, whereas 216 (5%) of participants met all three recommendations. Global cognition was positively associated with each additional recommendation met (β=1·44, 95% CI 0·82-2·07, p<0·0001). Compared with meeting none of the recommendations, associations with superior global cognition were found in participants who met all three recommendations (β=3·89, 95% CI 1·43 to 6·34, p=0·0019), the screen time recommendation only (β=4·25, 2·50-6·01, p<0·0001), and both the screen time and the sleep recommendations (β=5·15, 3·56-6·74, p<0·0001)., Interpretation: Meeting the 24 h movement recommendations was associated with superior global cognition. These findings highlight the importance of limiting recreational screen time and encouraging healthy sleep to improve cognition in children., Funding: National Institutes of Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

OBJECTIVE Currently, little is known about the biomechanics of head impact for concussion in youths (ages 5 to 18 years). Even less is known about the biomechanical characteristics and variables related to head impacts that may be useful in differentiating between transient and persistent postconcussion symptoms in a youth population. The purpose of this research was to examine the differences in biomechanics of youth head impact for transient postconcussion symptoms (TPCSs) and persistent postconcussion symptoms (PPCSs) by using data from a hospital population. METHODS In a laboratory setting and using physical, computational, and finite element models, the authors reconstructed falling events in a large cohort of patients who had sustained a brain injury that resulted in transient or persistent postconcussion symptoms. The falling events and resulting concussions for the TPCS and PPCS patient groups were analyzed in terms of force, energy, peak resultant linear and rotational accelerations, and maximum principal strain in the gray and white matter of the brain, as well as measurements of cumulative strain damage. RESULTS The results indicated that there were no significant differences between the groups for any of the variables analyzed. CONCLUSIONS With methods derived for use in an adult population, the magnitudes of peak linear acceleration for the youth data set were determined to be above the 50% risk of injury. The youth data set showed higher brain tissue strain responses for lower energy and impact velocities than measured in adults, suggesting that youths are at higher risk of concussive injury at lower event severities. A trend shown by some variables indicated that larger magnitudes of response were associated with PPCSs, but no single measurement variable consistently differentiated between the TPCS and PPCS groups. It is possible that using the biomechanics of head and brain responses to predict a subjective symptom load may not be appropriate. To enhance future biomechanical analyses, further investigations should include the use of quantifiable measures of brain injury linked to clinical outcomes and possible confounding factors such as history of brain injury and patient predisposition.

Importance: Although concussion treatment guidelines advocate rest in the immediate postinjury period until symptoms resolve, no clear evidence has determined that avoiding physical activity expedites recovery., Objective: To investigate the association between participation in physical activity within 7 days postinjury and incidence of persistent postconcussive symptoms (PPCS)., Design, Setting, and Participants: Prospective, multicenter cohort study (August 2013-June 2015) of 3063 children and adolescents aged 5.00-17.99 years with acute concussion from 9 Pediatric Emergency Research Canada network emergency departments (EDs)., Exposures: Early physical activity participation within 7 days postinjury., Main Outcomes and Measures: Physical activity participation and postconcussive symptom severity were rated using standardized questionnaires in the ED and at days 7 and 28 postinjury. PPCS (≥3 new or worsening symptoms on the Post-Concussion Symptom Inventory) was assessed at 28 days postenrollment. Early physical activity and PPCS relationships were examined by unadjusted analysis, 1:1 propensity score matching, and inverse probability of treatment weighting (IPTW). Sensitivity analyses examined patients (≥3 symptoms) at day 7., Results: Among 2413 participants who completed the primary outcome and exposure, (mean [SD] age, 11.77 [3.35] years; 1205 [39.3%] females), PPCS at 28 days occurred in 733 (30.4%); 1677 (69.5%) participated in early physical activity including light aerobic exercise (n = 795 [32.9%]), sport-specific exercise (n = 214 [8.9%]), noncontact drills (n = 143 [5.9%]), full-contact practice (n = 106 [4.4%]), or full competition (n = 419 [17.4%]), whereas 736 (30.5%) had no physical activity. On unadjusted analysis, early physical activity participants had lower risk of PPCS than those with no physical activity (24.6% vs 43.5%; Absolute risk difference [ARD], 18.9% [95% CI,14.7%-23.0%]). Early physical activity was associated with lower PPCS risk on propensity score matching (n = 1108 [28.7% for early physical activity vs 40.1% for no physical activity]; ARD, 11.4% [95% CI, 5.8%-16.9%]) and on inverse probability of treatment weighting analysis (n = 2099; relative risk [RR], 0.74 [95% CI, 0.65-0.84]; ARD, 9.7% [95% CI, 5.7%-13.7%]). Among only patients symptomatic at day 7 (n = 803) compared with those who reported no physical activity (n = 584; PPCS, 52.9%), PPCS rates were lower for participants of light aerobic activity (n = 494 [46.4%]; ARD, 6.5% [95% CI, 5.7%-12.5%]), moderate activity (n = 176 [38.6%]; ARD, 14.3% [95% CI, 5.9%-22.2%]), and full-contact activity (n = 133 [36.1%]; ARD, 16.8% [95% CI, 7.5%-25.5%]). No significant group difference was observed on propensity-matched analysis of this subgroup (n = 776 [47.2% vs 51.5%]; ARD, 4.4% [95% CI, -2.6% to 11.3%])., Conclusions and Relevance: Among participants aged 5 to 18 years with acute concussion, physical activity within 7 days of acute injury compared with no physical activity was associated with reduced risk of PPCS at 28 days. A well-designed randomized clinical trial is needed to determine the benefits of early physical activity following concussion.

Importance: Persistent postconcussion symptoms (PPCS) pose long-term challenges and can negatively affect patients' health-related quality of life (HRQoL). To date, no large comprehensive study has addressed the association between PPCS and HRQoL., Objectives: To determine the association between HRQoL and PPCS at 4 weeks after concussion and assess the degree of impairment of HRQoL in the subsequent 12 weeks., Design, Setting, and Participants: In a prospective, multicenter cohort study (Predicting Persistent Postconcussive Problems in Pediatrics [5P]) from August 14, 2013, to September 30, 2014, children aged 5 to 18 years who presented to the emergency department within 48 hours after head injury and were considered to have an acute concussion were enrolled across 9 pediatric emergency departments within the Pediatric Emergency Research Canada Network. Persistent postconcussion symptoms were defined as 3 or more persistent symptoms on the validated Post-Concussion Symptom Inventory at 4 weeks. Linear mixed effects random coefficients models evaluated the association between PPCS and HRQoL, adjusting for potential confounders including age, sex, prior concussions, migraine, anxiety, learning disability, depression, and sleep disorder., Main Outcomes and Measures: The primary outcome was HRQoL assessed with the validated Pediatric Quality of Life Inventory version 4.0 (PedsQL-4.0) at 4, 8, and 12 weeks after head injury., Results: Of 2006 children enrolled (median age, 11.8 years [interquartile range, 8.9-14.6 years]; 1241 boys and 765 girls), 1667 (83.1%) completed the PedsQL-4.0 at all 3 time points. Of these 1667 children, the 510 with PPCS (30.6%) had lower total PedsQL-4.0 scores (mean, 70.0) than did those without PPCS (mean, 80.3; mean difference, -10.3; 95% CI, -9.4 to -11.2). Patients with PPCS also had significantly lower physical, emotional, social, and school PedsQL-4.0 subscores at 4, 8, and 12 weeks. Patients with PPCS had lower HRQoL than published healthy norms at 4 weeks (mean difference, 13.89; 95% CI, 11.55-16.23), 8 weeks (mean difference, 11.63; 95% CI, 9.34-13.93), and 12 weeks (mean difference, 9.38; 95% CI, 7.01-11.75; P < .001). Patients who recovered from concussion also had lower HRQoL than norms at 4 weeks (mean difference, 3.56; 95% CI, 1.28-5.85) and 8 weeks (mean difference, 2.75; 95% CI, 0.48-5.02; P < .05). School functioning PedsQL-4.0 subscores were significantly lower for all children regardless of PPCS status at all time points., Conclusions and Relevance: Children with PPCS have lower HRQoL compared with those who have recovered from concussion, yet deficits in HRQoL are pervasive across all domains and may persist for months even in children whose symptoms have resolved. Future interventional research should target the effect of concussion on HRQoL.

Purpose: An improved understanding of the molecular pathogenesis of brain metastases, one of the most common and devastating complications of advanced melanoma, may identify and prioritize rational therapeutic approaches for this disease. In particular, the identification of molecular differences between brain and extracranial metastases would support the need for the development of organ-specific therapeutic approaches., Experimental Design: Hotspot mutations, copy number variations (CNV), global mRNA expression patterns, and quantitative analysis of protein expression and activation by reverse-phase protein array (RPPA) analysis were evaluated in pairs of melanoma brain metastases and extracranial metastases from patients who had undergone surgical resection for both types of tumors., Results: The status of 154 previously reported hotspot mutations, including driver mutations in BRAF and NRAS, were concordant in all evaluable patient-matched pairs of tumors. Overall patterns of CNV, mRNA expression, and protein expression were largely similar between the paired samples for individual patients. However, brain metastases demonstrated increased expression of several activation-specific protein markers in the PI3K/AKT pathway compared with the extracranial metastases., Conclusions: These results add to the understanding of the molecular characteristics of melanoma brain metastases and support the rationale for additional testing of the PI3K/AKT pathway as a therapeutic target in these highly aggressive tumors., (©2014 American Association for Cancer Research.)

Episodic memory, related to the hippocampus, has been found to be impaired in schizophrenia. Further, hippocampal anomalies have also been observed in schizophrenia. This study investigated whether average hippocampal gray matter (GM) would differentiate performance on a hippocampus-dependent memory task in patients with schizophrenia and healthy controls. Twenty-one patients with schizophrenia and 22 control participants were scanned with an MRI while being tested on a wayfinding task in a virtual town (e.g., find the grocery store from the school). Regressions were performed for both groups individually and together using GM and performance on the wayfinding task. Results indicate that controls successfully completed the task more often than patients, took less time, and made fewer errors. Additionally, controls had significantly more hippocampal GM than patients. Poor performance was associated with a GM decrease in the right hippocampus for both groups. Within group regressions found an association between right hippocampi GM and performance in controls and an association between the left hippocampi GM and performance in patients. A second analysis revealed that different anatomical GM regions, known to be associated with the hippocampus, such as the parahippocampal cortex, amygdala, medial, and orbital prefrontal cortices, covaried with the hippocampus in the control group. Interestingly, the cuneus and cingulate gyrus also covaried with the hippocampus in the patient group but the orbital frontal cortex did not, supporting the hypothesis of impaired connectivity between the hippocampus and the frontal cortex in schizophrenia. These results present important implications for creating intervention programs aimed at measuring functional and structural changes in the hippocampus in schizophrenia.

Intact episodic memory requires the ability to make associations between the contextual features of an event, referred to as contextual binding. Binding processes combine different contextual elements into a complete memory representation. It has been proposed that binding errors during the encoding process are responsible for the episodic memory impairments reported in schizophrenia. Since the hippocampus is critical for contextual binding and episodic memory, it was hypothesized that patients with schizophrenia would show a deficit in information processing in the hippocampus, measured with functional magnetic resonance imaging (fMRI). In the current experiment, 21 patients with schizophrenia and 22 healthy control participants were scanned while being tested on navigating in a virtual town (i.e. find the grocery store from the school), a task that was shown to be critically dependent on the hippocampus. Between-group comparisons revealed significantly less activation among patients relative to controls in the left middle frontal gyrus, and right and left hippocampi. We propose that the context and the content are not appropriately linked, therefore affecting the formation of a cognitive map representation in the patient group and eliciting a contextual binding deficit., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Large displays and stereopsis have been shown to improve performance in several virtual navigation tasks. In the present research, we sought to determine whether wayfinding could benefit from these factors. Participants were tested in a virtual town. There were three viewing conditions: a desktop, a large screen, and a large screen on which the virtual environment was viewed in three dimensions (3-D) using polarized glasses. Participants explored the town and had to remember the location of several landmarks. Their memory of the layout of the town was tested by asking them to navigate from one landmark to another, taking the shortest route possible. All groups performed equally well in terms of the distance traveled to target locations. From this result, we concluded that large displays and 3-D perception do not significantly contribute to wayfinding. Thus, experimental paradigms and training programs that utilize wayfinding are as valuable when administered on standard desktops as on more sophisticated and costly equipment and do not induce simulator sickness as large displays tend to do.

Researchers have suggested different models to describe the feeling of presence. Most of them imply that presence is some kind of alternate state. Research conducted in our research team lead us to consider presence simply like a very powerful perceptual illusion, with the addition of challenging the meaning given to the place where the user actually is (i.e., being "there"). The aim of this study is to investigate the neural correlates of the illusion of presence in VR. Five right-handed adults were scanned in the fMRI and were immersed in two conditions: high and low presence, where the exact same stimulus was presented to participants during each condition but the context (narrative) provided differed significantly. Results show a clear, specific and statistically significant involvement of the parahippocampal area, the brain responsible for giving contextual meaning of places.