Evidence of Ongoing Cerebral Microstructural Reorganization in Children With Persisting Symptoms Following Mild Traumatic Brain Injury: A NODDI DTI Analysis.

Approximately 300-550 children per 100,000 sustain a mild traumatic brain injury (mTBI) each year, of whom ∼25-30% have long-term cognitive problems. Following mTBI, free water (FW) accumulation occurs in white matter (WM) tracts. Diffusion tensor imaging (DTI) can be used to investigate structural integrity following mTBI. Compared with conventional DTI, neurite orientation dispersion and density imaging (NODDI) orientation dispersion index (ODI) and fraction of isolated free water (FISO) metrics may allow a more advanced insight into microstructural damage following pediatric mTBI. In this longitudinal study, we used NODDI to explore whole-brain and tract-specific differences in ODI and FISO in children with persistent symptoms after mTBI (n = 80) and in children displaying clinical recovery (n = 32) at 1 and 2-3 months post-mTBI compared with healthy controls (HCs) (n = 21). Two-way repeated measures analysis of variance (ANOVA) and voxelwise two-sample t tests were conducted to compare whole-brain and tract-specific diffusion across groups. All results were corrected at positive false discovery rate (pFDR) <0.05. We also examined the association between NODDI metrics and clinical outcomes, using logistical regression to investigate the value of NODDI metrics in predicting future recovery from mTBI. Whole-brain ODI was significantly increased in symptomatic participants compared with HCs at both 1 and 2 months post-injury, where the uncinate fasciculus (UF) and inferior fronto-occipital fasciculus (IFOF) were particularly implicated. Using region of interest (ROI) analysis in significant WM, bilateral IFOF and UF voxels, symptomatic participants had the highest ODI in all ROIs. ODI was lower in asymptomatic participants, and HCs had the lowest ODI in all ROIs. No changes in FISO were found across groups or over time. WM ODI was moderately correlated with a higher youth-reported post-concussion symptom inventory (PCSI) score. With 87% predictive power, ODI (1 month post-injury) and clinical predictors (age, sex, PCSI score, attention scores) were a more sensitive predictor of recovery at 2-3 months post-injury than fractional anisotropy (FA) and clinical predictors, or clinical predictors alone. FISO could not predict recovery at 2-3 months post-injury. Therefore, we found that ODI was significantly increased in symptomatic children following mTBI compared with HCs at 1 month post-injury, and progressively decreased over time alongside clinical recovery. We found no significant differences in FISO between groups or over time. WM ODI at 1 month was a more sensitive predictor of clinical recovery at 2-3 months post-injury than FA, FISO, or clinical measures alone. Our results show evidence of ongoing microstructural reorganization or neuroinflammation between 1 and 2-3 months post-injury, further supporting delayed return to play in children who remain symptomatic. We recommend future research examining the clinical utility of NODDI following mTBI to predict recovery or persistence of post-concussion symptoms and thereby inform management of mTBI.

Pediatric Sport-Related Concussion: Recommendations From the Amsterdam Consensus Statement 2023.

The 6th International Consensus Conference on Concussion in Sport, Amsterdam 2022, addressed sport-related concussion (SRC) in adults, adolescents, and children. We highlight the updated evidence-base and recommendations regarding SRC in children (5-12 years) and adolescents (13-18 years). Prevention strategies demonstrate lower SRC rates with mouthguard use, policy disallowing bodychecking in ice hockey, and neuromuscular training in adolescent rugby. The Sport Concussion Assessment Tools (SCAT) demonstrate robustness with the parent and child symptom scales, with the best diagnostic discrimination within the first 72 hours postinjury. Subacute evaluation (>72 hours) requires a multimodal tool incorporating symptom scales, balance measures, cognitive, oculomotor and vestibular, mental health, and sleep assessment, to which end the Sport Concussion Office Assessment Tools (SCOAT6 [13+] and Child SCOAT6 [8-12]) were developed. Rather than strict rest, early return to light physical activity and reduced screen time facilitate recovery. Cervicovestibular rehabilitation is recommended for adolescents with dizziness, neck pain, and/or headaches for greater than 10 days. Active rehabilitation and collaborative care for adolescents with persisting symptoms for more than 30 days may decrease symptoms. No tests and measures other than standardized and validated symptom rating scales are valid for diagnosing persisting symptoms after concussion. Fluid and imaging biomarkers currently have limited clinical utility in diagnosing or assessing recovery from SRC. Improved paradigms for return to school were developed. The variable nature of disability and differences in evaluating para athletes and those of diverse ethnicity, sex, and gender are discussed, as are ethical considerations and future directions in pediatric SRC research.

Attention Please! Unravelling the Link Between Brain Network Connectivity and Cognitive Attention Following Acquired Brain Injury: A Systematic Review of Structural and Functional Measures.

Traumatic brain injury (TBI) and stroke are the most common causes of acquired brain injury (ABI), annually affecting 69 million and 15 million people, respectively. Following ABI, the relationship between brain network disruption and common cognitive issues including attention dysfunction is heterogenous. Using PRISMA guidelines, we systematically reviewed 43 studies published by February 2023 that reported correlations between attention and connectivity. Across all ages and stages of recovery, following TBI, greater attention was associated with greater structural efficiency within/between executive control network (ECN), salience network (SN), and default mode network (DMN) and greater functional connectivity (fc) within/between ECN and DMN, indicating DMN interference. Following stroke, greater attention was associated with greater structural connectivity (sc) within ECN; or greater fc within the dorsal attention network (DAN). In childhood ABI populations, decreases in structural network segregation were associated with greater attention. Longitudinal recovery from TBI was associated with normalization of DMN activity, and in stroke, normalization of DMN and DAN activity. Results improve clinical understanding of attention-related connectivity changes after ABI. Recommendations for future research include increased use of electroencephalography (EEG) and functional near-infrared spectroscopy (fNIRS) to measure connectivity at the point of care, standardized attention and connectivity outcome measures and analysis pipelines, detailed reporting of patient symptomatology, and casual analysis of attention-related connectivity using brain stimulation.

The Australian Traumatic Brain Injury Initiative: Systematic Review of Predictive Value of Biological Markers for People With Moderate-Severe Traumatic Brain Injury.

The Australian Traumatic Brain Injury Initiative (AUS-TBI) aims to co-design a data resource to predict outcomes for people with moderate-severe traumatic brain injury (TBI) across Australia. Fundamental to this resource is the data dictionary, which is an ontology of data items. Here, we report the systematic review and consensus process for inclusion of biological markers in the data dictionary. Standardized database searches were implemented from inception through April 2022. English-language studies evaluating association between a fluid, tissue, or imaging marker and any clinical outcome in at least 10 patients with moderate-severe TBI were included. Records were screened using a prioritization algorithm and saturation threshold in Research Screener. Full-length records were then screened in Covidence. A pre-defined algorithm was used to assign a judgement of predictive value to each observed association, and high-value predictors were discussed in a consensus process. Searches retrieved 106,593 records; 1,417 full-length records were screened, resulting in 546 included records. Two hundred thirty-nine individual markers were extracted, evaluated against 101 outcomes. Forty-one markers were judged to be high-value predictors of 15 outcomes. Fluid markers retained following the consensus process included ubiquitin C-terminal hydrolase L1 (UCH-L1), S100, and glial fibrillary acidic protein (GFAP). Imaging markers included computed tomography (CT) scores (e.g., Marshall scores), pathological observations (e.g., hemorrhage, midline shift), and magnetic resonance imaging (MRI) classification (e.g., diffuse axonal injury). Clinical context and time of sampling of potential predictive indicators are important considerations for utility. This systematic review and consensus process has identified fluid and imaging biomarkers with high predictive value of clinical and long-term outcomes following moderate-severe TBI.

Health care impact of implementing a clinical pathway for acute care of pediatric concussion: a stepped wedge, cluster randomised trial.

OBJECTIVES: To test the effects of actively implementing a clinical pathway for acute care of pediatric concussion on health care utilization and costs. METHODS: Stepped wedge, cluster randomized trial of a clinical pathway, conducted in 5 emergency departments (ED) in Alberta, Canada from February 1 to November 30, 2019. The clinical pathway emphasized standardized assessment of risk for persistent symptoms, provision of consistent information to patients and families, and referral for outpatient follow-up. De-identified administrative data measured 6 outcomes: ED return visits; outpatient follow-up visits; length of ED stay, including total time, time from triage to physician initial assessment, and time from physician initial assessment to disposition; and total physician claims in an episode of care. RESULTS: A total of 2878 unique patients (1164 female, 1713 male) aged 5-17 years (median 11.00, IQR 8, 14) met case criteria. They completed 3009 visits to the 5 sites and 781 follow-up visits to outpatient care, constituting 2910 episodes of care. Implementation did not alter the likelihood of an ED return visit (OR 0.77, 95% CI 0.39, 1.52), but increased the likelihood of outpatient follow-up visits (OR 1.84, 95% CI 1.19, 2.85). Total length of ED stay was unchanged, but time from physician initial assessment to disposition decreased significantly (mean change - 23.76 min, 95% CI - 37.99, - 9.52). Total physician claims increased significantly at only 1 of 5 sites. CONCLUSIONS: Implementation of a clinical pathway in the ED increased outpatient follow-up and reduced the time from physician initial assessment to disposition, without increasing physician costs. Implementation of a clinical pathway can align acute care of pediatric concussion more closely with existing clinical practice guidelines while making care more efficient. TRIAL REGISTRATION: ClinicalTrials.gov NCT05095012.

ABSTRAIT: OBJECTIFS: Mettre à l'essai les effets de la mise en œuvre active d'une voie clinique pour le traitement aigu des commotions cérébrales chez les enfants sur l'utilisation et les coûts des soins de santé. MéTHODES: Essai randomisé en grappes d'une voie clinique, échelonné, mené dans cinq services d'urgence en Alberta, au Canada, du 1 février au 30 novembre 2019. Le cheminement clinique mettait l'accent sur l'évaluation normalisée du risque de symptômes persistants, la fourniture de renseignements uniformes aux patients et aux familles, et l'aiguillage vers un suivi externe. Les données administratives dépersonnalisées ont permis de mesurer six résultats : visites de retour à l'urgence; visites de suivi en clinique externe; durée du séjour à l'urgence, y compris le temps total. le temps entre le triage et l'évaluation initiale du médecin, et le temps entre l'évaluation initiale du médecin et la décision; et le nombre total de demandes de remboursement du médecin dans un épisode de soins. RéSULTATS: Un total de 2878 patients uniques (1164 femmes, 1713 hommes) âgés de 5 à 17 ans (médiane 11,00, IQR 8, 14) répondaient aux critères de cas. Ils ont effectué 3009 visites aux 5 sites et 781 visites de suivi aux soins ambulatoires, ce qui représente 2910 épisodes de soins. La mise en œuvre n'a pas modifié la probabilité d'une visite de retour à l'urgence (RC 0,77, IC à 95 %, 0,39, 1,52), mais a augmenté la probabilité de visites de suivi en clinique externe (RC 1,84, IC à 95 %, 1,19, 2,85). La durée totale du séjour à l'urgence est demeurée inchangée, mais le temps écoulé entre l'évaluation initiale du médecin et la décision a diminué considérablement (changement moyen : -23,76 minutes, IC à 95 %, -37,99, -9,52). Le nombre total de demandes de règlement de médecins a augmenté de façon significative à seulement 1 site sur 5. CONCLUSIONS: La mise en œuvre d'un cheminement clinique à l'urgence a augmenté le suivi des patients externes et réduit le temps entre l'évaluation initiale du médecin et son élimination, sans augmenter les coûts des médecins. La mise en œuvre d'un cheminement clinique peut harmoniser davantage les soins de courte durée en cas de commotion cérébrale pédiatrique avec les lignes directrices de pratique clinique existantes tout en rendant les soins plus efficaces. ENREGISTREMENT D'ESSAI: ClinicalTrials.gov NCT05095012.

Structural brain network lateralization across childhood and adolescence.

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub-nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross-sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right-handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school-age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization.

Australian and New Zealand Guideline for Mild to Moderate Head Injuries in Children.

OBJECTIVE: Children frequently present with head injuries to acute care settings. Although international paediatric clinical practice guidelines for head injuries exist, they do not address all considerations related to triage, imaging, observation versus admission, transfer, discharge and follow-up of mild to moderate head injuries relevant to the Australian and New Zealand context. The Paediatric Research in Emergency Departments International Collaborative (PREDICT) set out to develop an evidence-based, locally applicable, practical clinical guideline for the care of children with mild to moderate head injuries presenting to acute care settings. METHODS: A multidisciplinary Guideline Working Group (GWG) developed 33 questions in three key areas - triage, imaging and discharge of children with mild to moderate head injuries presenting to acute care settings. We identified existing high-quality guidelines and from these guidelines recommendations were mapped to clinical questions. Updated literature searches were undertaken, and key new evidence identified. Recommendations were created through either adoption, adaptation or development of de novo recommendations. The guideline was revised after a period of public consultation. RESULTS: The GWG developed 71 recommendations (evidence-informed = 35, consensus-based = 17, practice points = 19), relevant to the Australian and New Zealand setting. The guideline is presented as three documents: (i) a detailed Full Guideline summarising the evidence underlying each recommendation; (ii) a Guideline Summary; and (iii) a clinical Algorithm: Imaging and Observation Decision-making for Children with Head Injuries. CONCLUSIONS: The PREDICT Australian and New Zealand Guideline for Mild to Moderate Head Injuries in Children provides high-level evidence and practical guidance for front line clinicians.

Cerebral Blood Flow Predicts Recovery in Children with Persistent Post-Concussion Symptoms after Mild Traumatic Brain Injury.

Persistent post-concussion symptoms (PPCS) following pediatric mild traumatic brain injury (mTBI) are associated with differential changes in cerebral blood flow (CBF). Given its potential as a therapeutic target, we examined CBF changes during recovery in children with PPCS. We hypothesized that CBF would decrease and that such decreases would mirror clinical recovery. In a prospective cohort study, 61 children and adolescents (mean age 14 [standard deviation = 2.6] years; 41% male) with PPCS were imaged with three-dimensional (3D) pseudo-continuous arterial spin-labelled (pCASL) magnetic resonance imaging (MRI) at 4-6 and 8-10 weeks post-injury. Exclusion criteria included any significant past medical history and/or previous concussion within the past 3 months. Twenty-three participants had clinically recovered at the time of the second scan. We found that relative and mean absolute CBF were higher in participants with poor recovery, 44.0 (95% confidence interval [CI]: 43.32, 44.67) than in those with good recovery, 42.19 (95% CI: 41.77, 42.60) mL/min/100 g gray tissue and decreased over time (ß = -1.75; p < 0.001). The decrease was greater in those with good recovery (ß = 2.29; p < 0.001) and predicted outcome in 77% of children with PPCS (odds ratio [OR] 0.54, 95% CI: 0.36, 0.80; p = 0.002). Future studies are warranted to validate the utility of CBF as a useful predictive biomarker of outcome in PPCS.

Neural Correlates of Sleep Recovery following Melatonin Treatment for Pediatric Concussion: A Randomized Controlled Trial.

Evidence-based treatments for children with persistent post-concussion symptoms (PPCS) are few and limited. Common PPCS complaints such as sleep disturbance and fatigue could be ameliorated via the supplementation of melatonin, which has significant neuroprotective and anti-inflammatory properties. This study aims to identify neural correlates of melatonin treatment with changes in sleep disturbances and clinical recovery in a pediatric cohort with PPCS. We examined structural and functional neuroimaging (fMRI) in 62 children with PPCS in a randomized, double-blind, placebo-controlled trial of 3 mg or 10 mg of melatonin (NCT01874847). The primary outcome was the total youth self-report Post-Concussion Symptom Inventory (PCSI) score after 28 days of treatment. Secondary outcomes included the change in the sleep domain PCSI score and sleep-wake behavior (assessed using wrist-worn actigraphy). Whole-brain analyses of (1) functional connectivity (FC) of resting-state fMRI, and (2) structural gray matter volumes via voxel-based morphometry were assessed immediately before and after melatonin treatment and compared with placebo to identify neural effects of melatonin treatment. Increased FC of posterior default mode network (DMN) regions with visual, somatosensory, and dorsal networks was detected in the melatonin groups over time. The FC increases also corresponded with reduced wake periods (r = -0.27, p = 0.01). Children who did not recover (n = 39) demonstrated significant FC increases within anterior DMN and limbic regions compared with those who did recover (i.e., PCSI scores returned to pre-injury level, n = 23) over time, (p = 0.026). Increases in GM volume within the posterior cingulate cortex were found to correlate with reduced wakefulness after sleep onset (r = -0.32, p = 0.001) and sleep symptom improvement (r = 0.29, p = 0.02). Although the melatonin treatment trial was negative and did not result in PPCS recovery (with or without sleep problems), the relationship between melatonin and improvement in sleep parameters was linked to changes in function-structure within and between brain regions interacting with the DMN.

Functional magnetic resonance imaging study of working memory several years after pediatric concussion.

PRIMARY OBJECTIVE: The neurophysiological effects of pediatric concussion several years after injury remain inadequately characterized. The objective of this study was to determine if a history of concussion was associated with BOLD response differences during an n-back working memory task in youth. RESEARCH DESIGN: Observational, cross-sectional. METHODS AND PROCEDURES: Participants include 52 children and adolescents (M = 15.1 years, 95%CI = 14.4-15.8, range = 9-19) with past concussion (n = 33) or orthopedic injury (OI; n = 19). Mean time since injury was 2.5 years (95%CI = 2.0-3.0). Measures included postconcussion symptom ratings, neuropsychological testing, and blood-oxygen-dependent-level (BOLD) functional magnetic resonance imaging (fMRI) during an n-back working memory task. MAIN OUTCOMES AND RESULTS: Groups did not differ on accuracy or speed during the three n-back conditions. They also did not differ in BOLD signal change for the 1- vs. 0-back or 2- vs. 0-back contrasts (controlling for task performance). CONCLUSIONS: This study does not support group differences in BOLD response during an n-back working memory task in youth who are on average 2.5 years post-concussion. The findings are encouraging from the perspective of understanding recovery after pediatric concussion.

Efficacy of Melatonin in Children With Postconcussive Symptoms: A Randomized Clinical Trial.

BACKGROUND: Approximately 25% of children with concussion have persistent postconcussive symptoms (PPCS) with resultant significant impacts on quality of life. Melatonin has significant neuroprotective properties, and promising preclinical data suggest its potential to improve outcomes after traumatic brain injury. We hypothesized that treatment with melatonin would result in a greater decrease in PPCS symptoms when compared with a placebo. METHODS: We conducted a randomized, double-blind trial of 3 or 10 mg of melatonin compared with a placebo (NCT01874847). We included youth (ages 8-18 years) with PPCS at 4 to 6 weeks after mild traumatic brain injury. Those with significant medical or psychiatric histories or a previous concussion within the last 3 months were excluded. The primary outcome was change in the total youth self-reported Post-Concussion Symptom Inventory score measured after 28 days of treatment. Secondary outcomes included change in health-related quality of life, cognition, and sleep. RESULTS: Ninety-nine children (mean age: 13.8 years; SD = 2.6 years; 58% girls) were randomly assigned. Symptoms improved over time with a median Post-Concussion Symptom Inventory change score of -21 (95% confidence interval [CI]: -16 to -27). There was no significant effect of melatonin when compared with a placebo in the intention-to-treat analysis (3 mg melatonin, -2 [95% CI: -13 to 6]; 10 mg melatonin, 4 [95% CI: -7 to 14]). No significant group differences in secondary outcomes were observed. Side effects were mild and similar to the placebo. CONCLUSIONS: Children with PPCS had significant impairment in their quality of life. Seventy-eight percent demonstrated significant recovery between 1 and 3 months postinjury. This clinical trial does not support the use of melatonin for the treatment of pediatric PPCS.

Sleep Parameters and Overnight Urinary Melatonin Production in Children With Persistent Post-concussion Symptoms.

BACKGROUND: Sleep disturbance is common after a mild traumatic brain injury (mTBI) in children, yet its biology is poorly understood. We aimed to explore sleep-related problems (SRPs), sleep-activity patterns, and endogenous melatonin production in children with different recovery trajectories following mTBI. We hypothesized that children with delayed recovery would have more SRPs and abnormal sleep-activity patterns, which would correlate with lower overnight melatonin production. METHODS: In this prospective controlled cohort study, we enrolled 83 children with persistent symptoms, 26 children who had clinically recovered following mTBI, and 25 healthy controls. SRPs were evaluated using the sleep subscale of the Post-Concussion Symptom Inventory. Sleep actigraphy was performed for five to seven days at 37 (S.D. 7) days post-injury. Health-related quality of life and mood disturbance was assessed using the Child Health Questionnaire and the Behavior Assessment System for Children, respectively. Endogenous melatonin production was assessed using overnight urine collection. RESULTS: The groups were similar in age (13.9 [S.D. 2.6] years) and sex (52% female). Regression analysis demonstrated increased SRP in the symptomatic group (9.0; 95% confidence interval: 7.6, 11.1) compared with the recovered group (1.6; 95% confidence interval: 1.0, 2.4) and controls (2.0; 95% confidence intervals: 1.2, 3.2). Actigraphy parameters and urinary melatonin levels were not significantly different between groups. Neither SRPs nor actigraphy parameters correlated with anxiety and depression scores. CONCLUSIONS: Although children with persistent post-concussion symptoms reported more SRPs, this was not related to actigraphy sleep parameters or melatonin production. Further research is warranted to understand the pathophysiology of post-traumatic sleep disturbance.

A Pilot Randomized Controlled Trial of Cognitive-Behavioral Therapy for Insomnia in Adolescents With Persistent Postconcussion Symptoms.

OBJECTIVE: Cognitive-behavioral therapy for insomnia (CBT-I) is an effective insomnia treatment but has yet to be applied to adolescents with sleep disruption following concussion. This pilot study evaluated CBT-I to improve insomnia in adolescents with protracted concussion recovery. SETTING: Tertiary pediatric hospital. PARTICIPANTS: Participants (N = 24) were 12 to 18 years old (M = 15.0, SD = 1.4), 15.1 weeks (SD = 9.2) postinjury, and presenting with sleep disruption and persistent postconcussion symptoms. DESIGN: A single-blind, parallel-group randomized controlled trial (RCT) design comparing 6 weeks of CBT-I and a treatment-as-usual control group. Outcomes were measured before treatment, at treatment completion, and 4 weeks after completion. MAIN MEASURES: Primary outcome was Insomnia Severity Index. Secondary outcomes included Pittsburgh Sleep Quality Index, Dysfunctional Beliefs and Attitudes about Sleep Scale, 7-night sleep diary, PROMIS Depression, PROMIS Anxiety, and Health and Behavior Inventory. RESULTS: Adolescents who received CBT-I demonstrated large and clinically significant improvements in insomnia ratings at posttreatment that were maintained at follow-up. They also reported improved sleep quality, fewer dysfunctional beliefs about sleep, better sleep efficiency, shorter sleep-onset latency, and longer sleep time compared with those with treatment as usual. There was also a modest reduction in postconcussion symptoms. CONCLUSION: In this pilot RCT, 6 weeks of CBT-I produced significant improvement in sleep in adolescents with persistent postconcussion symptoms. A larger trial is warranted.

N-Acetyl-Aspartate in the Dorsolateral Prefrontal Cortex Long After Concussion in Youth.

OBJECTIVE: Despite increasing interest in the neurobiological effects of concussion in youth, a paucity of information is available regarding outcomes long after injury. The objective of this study was to determine the association between a history of concussion and the putative neuronal marker N-acetyl-aspartate (NAA) in the dorsolateral prefrontal cortex (DLPFC) in youth. SETTING: Outpatient clinic in a children's hospital. PARTICIPANTS: Youth with concussion (N = 35, mean = 2.63, SD = 1.07 years postinjury) and youth with a nonconcussive orthopedic injury (N = 17) participated. DESIGN: A cross-sectional proton magnetic resonance spectroscopy (H-MRS) study. MAIN MEASURES: The primary outcome measure was NAA concentration in the right and left DLPFCs. RESULTS: We observed lower levels of NAA in the right DLPFC in youth with past concussion (F = 3.31, df = 4,51, P = .018) than in orthopedic controls but not in the left DLPFC (F = 2.04, df = 4,51, P = .105). The effect of lower NAA concentrations in the right DLPFC was primarily driven by youth with a single prior concussion versus those with multiple concussions. NAA in the left DLPFC, but not in right DLPFC, was associated with worse emotional symptoms in youth with concussion. CONCLUSION: The presence of lower levels of DLPFC NAA suggests potential association of concussion in youth, although further investigation is needed, given that the result is driven by those with a single (and not multiple) concussion. Exploration of applying MRS in other brain regions is also warranted.

A Systematic Review of Structural and Functional Imaging Correlates of Headache or Pain after Mild Traumatic Brain Injury.

Headaches and pain-related symptoms are the most disabling somatic complaints following mild traumatic brain injury (mTBI). In this study, we reviewed the existing literature examining structural differences in brain morphology and axonal connections, as well as functional differences in brain activity and connectivity associated with pain or post-traumatic headache (PTH) following mTBI. We searched MEDLINE®, Embase, PubMed, Cumulative Index of Nursing and Allied Health Literature (CINAHL), Cochrane Central Register of Controlled Trials, and Web of Science databases for: (1) TBI OR concussion OR post-concussion syndrome; (2) pain OR headache; and (3) magnetic resonance imaging OR functional MRI OR diffusion tensor imaging. Inclusion criteria were that articles be original studies written in English about participants with mTBI or concussion diagnosis with results reported about pain and/or headache. Excluded were review articles, case studies, documentaries, and studies related to moderate to severe TBI. Quality was assessed using the Newcastle-Ottawa Scale (NOS) quality assessment tool. Nineteen out of 3439 studies satisfied the inclusion and exclusion criteria. Participants with pain-related symptoms had lower cortical thickness in frontal and parietal cortical areas and spinothalamic tract volume. Differences in axonal connectivity were displayed in the corpus callosum, spinothalamic tract, fornix-septohippocampal circuit, and periaqueductal gray. Less activation in pain-related regions during a heat-pain task-based fMRI was reported in participants with PTH. In conclusion, individuals with pain following mTBI display differences in brain structure and brain function, suggesting irregularities in the descending pain modulatory system. These findings primarily provide information on neuroimaging differences in adults; there is limited research in pediatric populations.

Default mode network anatomy and function is linked to pediatric concussion recovery.

OBJECTIVE: To determine whether anatomical and functional brain features relate to key persistent post-concussion symptoms (PPCS) in children recovering from mild traumatic brain injuries (mTBI), and whether such brain indices can predict individual recovery from PPCS. METHODS: One hundred and ten children with mixed recovery following mTBI were seen at the concussion clinic at Neurology department Alberta Children's Hospital. The primary outcome was the Post-Concussion Symptom Inventory (PCSI, parent proxy). Sleep disturbance scores (PCSI subdomain) and the Neurocognition Index (CNS Vital Signs) were also measured longitudinally. PPCS was assessed at 4 weeks postinjury and 8-10 weeks postinjury. Gray matter volumes were assessed using magnetic resonance imaging (MRI) and voxel-based morphometry at 4 weeks postinjury. Functional connectivity was estimated at the same timepoint using resting-state MRI. Two complementary machine learning methods were used to assess if the combination of gray matter and functional connectivity indices carried meaningful prognostic information. RESULTS: Higher scores on a composite index of sleep disturbance, including fatigue, were associated with converging decreases in gray matter volume and local functional connectivity in two key nodes of the default mode network: the posterior cingulate cortex and the medial prefrontal cortex. Sleep-related disturbances also significantly correlated with reductions in functional connectivity between these brain regions. The combination of structural and functional brain indices associated to individual variations in the default mode network accurately predicted clinical outcomes at follow-up (area under the curve = 0.86). INTERPRETATION: These results highlight that the function-structure profile of core default mode regions underpins sleep-related problems following mTBI and carries meaningful prognostic information for pediatric concussion recovery.

Longitudinal Assessment of Cortical Excitability in Children and Adolescents With Mild Traumatic Brain Injury and Persistent Post-concussive Symptoms.

Introduction: Symptoms following a mild traumatic brain injury (mTBI) usually resolve quickly but may persist past 3 months in up to 15% of children. Mechanisms of mTBI recovery are poorly understood, but may involve alterations in cortical neurophysiology. Transcranial Magnetic Stimulation (TMS) can non-invasively investigate such mechanisms, but the time course of neurophysiological changes in mTBI are unknown. Objective/Hypothesis: To determine the relationship between persistent post-concussive symptoms (PPCS) and altered motor cortex neurophysiology over time. Methods: This was a prospective, longitudinal, controlled cohort study comparing children (8-18 years) with mTBI (symptomatic vs. asymptomatic) groups to controls. Cortical excitability was measured using TMS paradigms at 1 and 2 months post injury. The primary outcome was the cortical silent period (cSP). Secondary outcomes included short interval intracortical inhibition (SICI) and facilitation (SICF), and long-interval cortical inhibition (LICI). Generalized linear mixed model analyses were used to evaluate the effect of group and time on neurophysiological parameters. Results: One hundred seven participants (median age 15.1, 57% female) including 78 (73%) with symptomatic PPCS and 29 with asymptomatic mTBI, were compared to 26 controls. Cortical inhibition (cSP and SICI) was reduced in the symptomatic group compared to asymptomatic group and tended to increase over time. Measures of cortical facilitation (SICF and ICF) were increased in the asymptomatic group and decreased over time. TMS was well tolerated with no serious adverse events. Conclusions: TMS-assessed cortical excitability is altered in children following mild TBI and is dependent on recovery trajectory. Our findings support delayed return to contact sports in children even where clinical symptoms have resolved.

Relating brain connectivity with persistent symptoms in pediatric concussion.

Persistent post-concussion symptoms (PCS) in children following a mild traumatic brain injury (mTBI) are a growing public health concern. There is a pressing need to understand the neural underpinning of PCS. Here, we examined whole-brain functional connectivity from resting-state fMRI with behavioral assessments in a cohort of 110 children with mTBI. Children with mTBI and controls had similar levels of connectivity. PCS symptoms and behaviors including poor cognition and sleep were associated with connectivity within functional brain networks. The identification of a single "positive-negative" dimension linking connectivity with behaviors enables better prognosis and stratification toward personalized therapeutic interventions.

Microstructural neuroimaging of white matter tracts in persistent post-concussion syndrome: A prospective controlled cohort study.

INTRODUCTION: Children with mild traumatic brain injury (mTBI) typically recover quickly, however approximately 15% experience persistent post-concussive symptoms (PPCS) past 3 months. The microstructural pathology associated with underlying persistent symptoms is poorly understood but is suggested to involve axonal injury to white matter tracts. Diffusion tensor imaging (DTI) can be used to visualize and characterize damage to white matter microstructure of the brain. OBJECTIVE: We aimed to investigate white matter microstructure in children with persistent concussive symptoms as compared to typically developing controls, alongside evaluating differences in white matter changes over time and how this relates to symptom recovery. METHODS: The current study is a prospective, longitudinal, controlled cohort study of children with mTBI. 104 children aged 8 to 18 years with a mTBI (72 symptomatic; 32 asymptomatic) were recruited from the Alberta Children's Hospital and compared to 20 healthy controls. Microstructural evidence of white matter injury was evaluated using DTI one month post injury and repeated 4 to 6 weeks later. Primary outcomes included fractional anisotropy and mean diffusivity of the corticospinal tracts, uncinate fasciculi, and motor fibers of the corpus callosum. Post-concussive symptoms were also measured using the Post-Concussion Symptom Inventory (PCSI) taken at both time points. RESULTS: Fractional anisotropy of the left uncinate fasciculi was lower in symptomatic children compared to controls (F(2,119) = 3.582, p = 0.031). No other significant differences were observed. CONCLUSIONS: Our findings provide evidence of microstructural injury following mTBI in children with ongoing post-concussive symptoms one month post injury. The changes were persistent 4-6 weeks later. Further longitudinal studies of white matter microstructure in PPCS will be helpful to clarify whether these white matter alterations resolve over time.