Post-concussive symptoms are frequently reported by individuals who sustain mild traumatic brain injuries (mTBIs) and subconcussive head impacts, even when evidence of intracranial pathology is lacking. Current strategies used to evaluate head injuries, which primarily rely on self-report, have a limited ability to predict the incidence, severity, and duration of post-concussive symptoms that will develop in an individual patient. In addition, these self-report measures have little association with the underlying mechanisms of pathology that may contribute to persisting symptoms, impeding advancement in precision treatment for TBI. Emerging evidence suggests that biofluid, imaging, physiological, and functional biomarkers associated with mTBI and subconcussive head impacts may address these shortcomings by providing more objective measures of injury severity and underlying pathology. Interest in the use of biomarker data has rapidly accelerated, which is reflected by the recent efforts of organizations such as the National Institute of Neurological Disorders and Stroke and the National Academies of Sciences, Engineering, and Medicine to prioritize the collection of biomarker data during TBI characterization in acute-care settings. Thus, this review aims to describe recent progress in the identification and development of biomarkers of mTBI and subconcussive head impacts and to discuss important considerations for the implementation of these biomarkers in clinical practice.

Protective factors, including psychological resilience, cognitive reserve, and brain reserve, may be positively associated with recovery after pediatric mild traumatic brain injury (mTBI) but are yet to be studied concurrently. We sought to examine these factors as moderators of post-concussive symptoms (PCS) in pediatric mTBI compared with mild orthopedic injury (OI). Participants included 967 children (633 mTBI, 334 OI) aged 8-16.99 years, recruited from 5 Canadian pediatric emergency departments as part of a prospective longitudinal cohort study. At 10 days post-injury, psychological resilience was measured using the Connor-Davidson Resilience Scale and brain reserve was measured using total brain volume derived from structural magnetic resonance imaging. Cognitive reserve was measured at 3 months post-injury using IQ scores from the Wechsler Abbreviated Scale of Intelligence-Second Edition. Cognitive and somatic PCS were measured using child and parent ratings on the Health and Behavior Inventory, completed weekly for 3 months and biweekly to 6 months. Analyses involved generalized least-squares regression models using restricted cubic splines. Covariates included age at injury, sex, racialized identity, material and social deprivation, pre-injury migraine and concussion history, and retrospective pre-injury PCS. Psychological resilience moderated group differences in parent-reported PCS. At 30 days post-injury, estimated group differences in parent-reported cognitive and somatic PCS (mTBI > OI) were larger at higher (75th percentile) resilience scores (Est = 2.25 [0.87, 3.64] and Est = 2.38 [1.76, 3.00], respectively) than at lower (25th percentile) resilience scores (Est = 1.44 [0.01, 2.86] and Est = 2.08 [1.45, 2.71], respectively). Resilience did not moderate group differences in child-reported PCS but was negatively associated with child-reported PCS in both groups (ps ≤ 0.001). Brain reserve (i.e., total brain volume [TBV]) also moderated group differences, but only for parent-reported somatic PCS (p = 0.018). Group difference (mTBI > OI) at 30 days was larger at smaller (25th percentile) TBV (Est = 2.78 [2.17, 3.38]) than at larger (75th percentile) TBV (Est = 1.95 [1.31, 2.59]). TBV was not associated with parent-reported cognitive PCS or child-reported PCS. IQ did not moderate PCS in either group but had a significant non-linear association in both groups with child-reported somatic PCS (p = 0.018) and parent-reported PCS (p < 0.001), with higher PCS scores at both lower and higher IQs. These findings suggest that higher resilience predicts fewer PCS, but less strongly after mTBI than OI; greater brain reserve may reduce the effect of mTBI on somatic PCS; and cognitive reserve has an unexpected curvilinear association with PCS across injury types. The results highlight the importance of protective factors as predictors of recovery and potential targets for intervention following pediatric mTBI.

OBJECTIVE: The aim of this study was to investigate the trajectory of parent-rated post-concussive symptoms (PCS), attentional performance and participation within 6 months in children after mild traumatic brain injury (mTBI).
METHODS: For this prospective longitudinal study, we included data on 64 children after mTBI and 57 healthy control children (age 8-16 years). Parents rated PCS using the Post-Concussion Symptom Inventory (PCSI) immediately (T0), 1 week (T1), and 3-6 months after injury (T2). Attentional performance (alertness, selective and divided attention) was measured using the Test of Attentional Performance (TAP) at T1 and T2 and participation was measured using the Child and Adolescent Scale of Participation (CASP) at T2.
RESULTS: Friedman tests showed different trajectories of PCS subscales over time: Compared to pre-injury level, the amount of somatic and cognitive PCS was still elevated at T1, while emotional PCS at T1 were already comparable to pre-injury level. The rating of sleep-related PCS at T2 was significantly elevated compared to the pre-injury rating. Quade ANCOVAs indicated group differences in PCS subscales between patients and controls at T1, but not at T2. Patients and controls showed a similar performance in tests of attention at T1 and T2, but parental rating of participation at school was significantly reduced. Although cognitive PCS and attention were not correlated, there were significantly negative Spearman correlations between participation at home and pre-injury and concurrent PCS at T2.
CONCLUSIONS: Our data imply that sleep-related PCS are still elevated weeks after injury and are thus a target for interventions after mTBI.

BACKGROUND: In the context of managing persistent post-concussive symptoms (PPCS), existing treatments like pharmacotherapy, cognitive behavioral therapy, and physical rehabilitation show only moderate effectiveness. The emergence of neuromodulation techniques in PPCS management has led to debates regarding optimal stimulation parameters and their overall efficacy.
METHODS: this scoping review involved a comprehensive search of PubMed and ScienceDirect databases, focusing on controlled studies examining the therapeutic potential of non-invasive brain stimulation (NIBS) techniques in adults with PPCS.
RESULTS: Among the 940 abstracts screened, only five studies, encompassing 103 patients (12 to 29 per study), met the inclusion criteria. These studies assessed the efficacy of transcranial direct current stimulation (tDCS), or repetitive transcranial magnetic stimulation (rTMS), applied to specific brain regions (i.e., the left dorsolateral pre-frontal cortex (DLPFC) or left motor cortex (M1)) for addressing cognitive and psychological symptoms, headaches, and general PPCSs. The results indicated improvements in cognitive functions with tDCS. In contrast, reductions in headache intensity and depression scores were observed with rTMS, while no significant findings were noted for general symptoms with rTMS.
CONCLUSIONS: although these pilot studies suggest promise for rTMS and tDCS in PPCS management, further research with larger-scale investigations and standardized protocols is imperative to enhance treatment outcomes for PPCS patients.

Concussion may lead to persisting post-concussive symptoms affecting work ability and employment. This study examined the transitions between labour market states an individual can experience after the acute phase of concussion. The aim was to describe the incidence of favourable and adverse transitions between different labour market states (e.g., employment, sick leave) in relation to socioeconomic and health characteristics in individuals with concussion relative to matched controls.
This Danish nationwide register-based cohort study extracted 18-60-year-old individuals between 2003-2007 with concussion from the Danish National Patient Register (ICD-10 S06.0). Controls were matched on age, sex, and municipality. Patients and controls were followed for 5 years starting three months after injury. Exclusion criteria were neurological injuries and unavailability to the labour market in the inclusion period (2003-2007) and 5-years before injury (1998-2002). Labour market states were defined from transfer income data in the Danish Register for Evaluation of Marginalization. Incidence rates of transitions between these labour market states were analysed in multistate models. Transitions were bundled in favourable and adverse transitions between labour market states and the difference in incidence rates between individuals with concussion relative to matched controls were assessed with hazard ratios from Cox regression models.
Persons with concussion (n = 15.580) had a lower incidence of favourable transitions (HR 0.88, CI 0.86-0.90) and a higher incidence of adverse transitions (HR 1.30, CI 1.27-1.35), relative to matched controls (n = 16.377). The effect of concussion differed depending on health and socioeconomic characteristics. Notably, individuals between 30-39 years (HR 0.83, CI 0.79-0.87), individuals with high-income (200.000-300.000 DKK) (HR 0.83, CI 0.80-0.87), and wage earners with management experience (HR 0.60, CI 0.44-0.81) had a markedly lower incidence of favourable transitions compared to controls. Additionally, individuals with high income also had a higher incidence of adverse transitions (HR 1.46, CI 1.34-1.58) compared to controls.
Concussion was associated with enhanced risk of adverse transitions between labour market states and lower occurrence of favourable transitions, indicating work disability, potentially due to persistent post-concussive symptoms. Some age groups, individuals with high income, and employees with management experience may be more affected.

UNASSIGNED: Post-concussive symptoms (PCS) are central to the assessment and management of mild traumatic brain injury (mTBI); however, this remains poorly understood in children aged ≤5 years. The study aimed to explore individual PCS, pattern of parents\' PCS report over time, proportion of symptomatic children, and variables associated with parents\' report of PCS in their preschool child after a mTBI.
UNASSIGNED: Children aged 2-5 years with either a mTBI (n=13) or limb injury (n=6) were recruited from the emergency department (ED). Parent ratings of child PCS were assessed at ED presentation, at one month, and at three months post-injury. Injury (e.g. injury group, pain), child (e.g. pre-existing behavior, symptoms), and parent (e.g. parental stress, education) characteristics were considered when investigating variables that may be relevant to parent report of PCS.
UNASSIGNED: The number of total, physical, and sleep PCS were significantly higher after mTBI, with a significant decrease in physical and sleep PCS over time. The proportion of symptomatic children was comparable between injury groups at each time point. Acute pain and pre-injury symptoms were significantly associated with parents\' acute PCS report in the mTBI group. Further research is needed on variables that may be relevant to parents\' PCS report at follow-up.
UNASSIGNED: Preliminary findings suggest a general trauma response after a mTBI or limb injury, but acute physical and sleep PCS may help differentiate the injury groups. Injury and premorbid child variables may be relevant to parents\' report of acute PCS in their child. Additional research is needed to investigate PCS in preschoolers and variables that may predict parents\' PCS report.

Individuals recovering from mild traumatic brain injury (TBI) represent a heterogenous population that requires distinct treatment approaches. Identification of recovery trajectories improves our ability to understand the natural history of mild TBI recovery and develop targeted interventions.
To utilize group-based trajectory modeling (GBTM) to identify distinct patterns of symptom recovery following mild TBI in the first 6 months after mild TBI.
This study is comprised of 253 adults who presented to the emergency department with mild TBI and completed assessments for six-months post-injury. Patients were recruited for the prospective observational cohort study, HeadSMART. The primary outcome measure was the Rivermead Postconcussion Symptom Questionnaire. GBTM was used to identify longitudinal trajectories of recovery following mild TBI using Rivermead scores at baseline, one, three, and six months following diagnosis.
Findings identified four distinct trajectories of symptom recovery follwing mild TBI including 9% of participants who were categorized with minimal acute symptoms that decreased over time, 45% with mild acute symptoms that decreased over time, 33% with relatively higher acute symptoms that decreased over time, and 13% with relatively higher acute symptoms that increased over time.
GBTM identified four distinct trajectories of recovery following mild TBI and GBTM may be useful for research interventions that can alter recovery trajectories.

UNASSIGNED: Connective tissue disorders such as Ehlers-Danlos Syndrome (EDS) can affect collagen and elastin content and structure, including weakening of tissues and vasculature, thus contributing to multiple systemic manifestations. Prior research has successfully focused on peripheral life-threatening manifestations resulting in increased life expectancy, yet clinical observations have warranted investigation of neurological vulnerability, where little is known. Compromised brain tissues and cerebrovasculature could leave these patients vulnerable to mild traumatic brain injury (TBI), with increased severity and duration of post-concussive symptoms and delayed recovery. Clinical reports in adults indicate that higher severity of symptoms after a mild TBI, such as a concussion, can unmask connective tissues disorders leading toward diagnosis. This clinical case report is an example of a pediatric patient with presumed Ehlers-Danlos syndrome who demonstrates increased vulnerability to mild TBI/concussion.
UNASSIGNED: A pediatric female patient presents with unexplained lingering post-concussive symptoms, including trouble sleeping, nausea, frontal headaches, dizziness, visual changes, fatigue, and left-sided weakness more than 6 months post-mild concussion. Patient history of hypermobility, joint derangement, soft tissue mobility, and bruising suggests a potential diagnosis of Ehlers-Danlos syndrome, which may explain symptom severity and length of recovery.
UNASSIGNED: This case is the first documented instance of increased vulnerability to TBI in a pediatric patient with presumed Ehlers-Danlos syndrome. It highlights the need for awareness and prevention of injury in this vulnerable patient population, suggests more targeted therapeutic intervention for recovery, and demonstrates the need for preclinical research evaluating the influence of genetic mutations associated with connective tissue disorders on the central nervous system.

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.

Older age is associated with worsened outcome after mild traumatic brain injury (mTBI) and a higher risk of developing persistent post-traumatic complaints. However, the effects of mTBI sequelae on brain connectivity at older age and their association with post-traumatic complaints remain understudied.We analyzed multi-echo resting-state functional magnetic resonance imaging data from 25 older adults with mTBI (mean age: 68 years, SD: 5 years) in the subacute phase (mean injury to scan interval: 38 days, SD: 9 days) and 20 age-matched controls. Severity of complaints (e.g. fatigue, dizziness) was assessed using self-reported questionnaires. Group independent component analysis was used to identify intrinsic connectivity networks (ICNs). The effects of group and severity of complaints on ICNs were assessed using spatial maps intensity (SMI) as a measure of within-network connectivity, and (static) functional network connectivity (FNC) as a measure of between-network connectivity.Patients indicated a higher total severity of complaints than controls. Regarding SMI measures, we observed hyperconnectivity in left-mid temporal gyrus (cognitive-language network) and hypoconnectivity in the right-fusiform gyrus (visual-cerebellar network) that were associated with group. Additionally, we found interaction effects for SMI between severity of complaints and group in the visual(-cerebellar) domain. Regarding FNC measures, no significant effects were found.In older adults, changes in cognitive-language and visual(-cerebellar) networks are related to mTBI. Additionally, group-dependent associations between connectivity within visual(-cerebellar) networks and severity of complaints might indicate post-injury (mal)adaptive mechanisms, which could partly explain post-traumatic complaints (such as dizziness and balance disorders) that are common in older adults during the subacute phase.