Biomarkers of Neurobiologic Recovery in Adults With Sport-Related Concussion.

Importance: Sport-related concussion (SRC), a form of mild traumatic brain injury, is a prevalent occurrence in collision sports. There are no well-established approaches for tracking neurobiologic recovery after SRC. Objective: To examine the levels of serum glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in Australian football athletes who experience SRC. Design, Setting, and Participants: A cohort study recruiting from April 10, 2021, to September 17, 2022, was conducted through the Victorian Amateur Football Association, Melbourne, Australia. Participants included adult Australian football players with or without SRC. Data analysis was performed from May 26, 2023, to March 27, 2024. Exposure: Sport-related concussion, defined as at least 1 observable sign and/or 2 or more symptoms. Main Outcomes and Measures: Primary outcomes were serum GFAP and NfL levels at 24 hours, and 1, 2, 4, 6, 8, 12, and 26 weeks. Secondary outcomes were symptoms, cognitive performance, and return to training times. Results: Eighty-one individuals with SRC (median age, 22.8 [IQR, 21.3-26.0] years; 89% male) and 56 control individuals (median age, 24.6 [IQR, 22.4-27.3] years; 96% male) completed a total of 945 of 1057 eligible testing sessions. Compared with control participants, those with SRC exhibited higher GFAP levels at 24 hours (mean difference [MD] in natural log, pg/mL, 0.66 [95% CI, 0.50-0.82]) and 4 weeks (MD, 0.17 [95% CI, 0.02-0.32]), and NfL from 1 to 12 weeks (1-week MD, 0.31 [95% CI, 0.12-0.51]; 2-week MD, 0.38 [95% CI, 0.19-0.58]; 4-week MD, 0.31 [95% CI, 0.12-0.51]; 6-week MD, 0.27 [95% CI, 0.07-0.47]; 8-week MD, 0.36 [95% CI, 0.15-0.56]; and 12-week MD, 0.25 [95% CI, 0.04-0.46]). Growth mixture modeling identified 2 GFAP subgroups: extreme prolonged (16%) and moderate transient (84%). For NfL, 3 subgroups were identified: extreme prolonged (7%), moderate prolonged (15%), and minimal or no change (78%). Individuals with SRC who reported loss of consciousness (LOC) (33% of SRC cases) had higher GFAP at 24 hours (MD, 1.01 [95% CI, 0.77-1.24]), 1 week (MD, 0.27 [95% CI, 0.06-0.49]), 2 weeks (MD, 0.21 [95% CI, 0.004-0.42]) and 4 weeks (MD, 0.34 [95% CI, 0.13-0.55]), and higher NfL from 1 week to 12 weeks (1-week MD, 0.73 [95% CI, 0.42-1.03]; 2-week MD, 0.91 [95% CI, 0.61-1.21]; 4-week MD, 0.90 [95% CI, 0.59-1.20]; 6-week MD, 0.81 [95% CI, 0.50-1.13]; 8-week MD, 0.73 [95% CI, 0.42-1.04]; and 12-week MD, 0.54 [95% CI, 0.22-0.85]) compared with SRC participants without LOC. Return to training times were longer in the GFAP extreme compared with moderate subgroup (incident rate ratio [IRR], 1.99 [95% CI, 1.69-2.34]; NfL extreme (IRR, 3.24 [95% CI, 2.63-3.97]) and moderate (IRR, 1.43 [95% CI, 1.18-1.72]) subgroups compared with the minimal subgroup, and for individuals with LOC compared with those without LOC (IRR, 1.65 [95% CI, 1.41-1.93]). Conclusions and Relevance: In this cohort study, a subset of SRC cases, particularly those with LOC, showed heightened and prolonged increases in GFAP and NfL levels, that persisted for at least 4 weeks. These findings suggest that serial biomarker measurement could identify such cases, guiding return to play decisions based on neurobiologic recovery. While further investigation is warranted, the association between prolonged biomarker elevations and LOC may support the use of more conservative return to play timelines for athletes with this clinical feature.

Improving physical movement during stroke rehabilitation: investigating associations between sleep measured by wearable actigraphy technology, fatigue, and key biomarkers.

BACKGROUND: Sleep disturbance and fatigue are common in individuals undergoing inpatient rehabilitation following stroke. Understanding the relationships between sleep, fatigue, motor performance, and key biomarkers of inflammation and neuroplasticity could provide valuable insight into stroke recovery, possibly leading to personalized rehabilitation strategies. This study aimed to investigate the influence of sleep quality on motor function following stroke utilizing wearable technology to obtain objective sleep measurements. Additionally, we aimed to determine if there were relationships between sleep, fatigue, and motor function. Lastly, the study aimed to determine if salivary biomarkers of stress, inflammation, and neuroplasticity were associated with motor function or fatigue post-stroke. METHODS: Eighteen individuals who experienced a stroke and were undergoing inpatient rehabilitation participated in a cross-sectional observational study. Following consent, participants completed questionnaires to assess sleep patterns, fatigue, and quality of life. Objective sleep was measured throughout one night using the wearable Philips Actiwatch. Upper limb motor performance was assessed on the following day and saliva was collected for biomarker analysis. Correlation analyses were performed to assess the relationships between variables. RESULTS: Participants reported poor sleep quality, frequent awakenings, and difficulties falling asleep following stroke. We identified a significant negative relationship between fatigue severity and both sleep quality (r=-0.539, p = 0.021) and participants experience of awakening from sleep (r=-0.656, p = 0.003). A significant positive relationship was found between grip strength on the non-hemiplegic limb and salivary gene expression of Brain-derived Neurotrophic Factor (r = 0.606, p = 0.028), as well as a significant negative relationship between grip strength on the hemiplegic side and salivary gene expression of C-reactive Protein (r=-0.556, p = 0.048). CONCLUSION: The findings of this study emphasize the importance of considering sleep quality, fatigue, and biomarkers in stroke rehabilitation to optimize recovery and that interventions may need to be tailored to the individual. Future longitudinal studies are required to explore these relationships over time. Integrating wearable technology for sleep and biomarker analysis can enhance monitoring and prediction of outcomes following stroke, ultimately improving rehabilitation strategies and patient outcomes.

A Preliminary Comparison of the Katrak Hand Movement Scale With the Upper Extremity Fugl Meyer Assessment Shows a Strong Correlation After Stroke.

Objective: To investigate the concurrent validity of the KHMS with the FMA-UE. Design: The FMA-UE and the KHMS were administered to 50 adults with stroke to evaluate their concurrent validity. Setting: Three tertiary rehabilitation hospitals. Participants: Participants were aged ≥18 years, receiving stroke or rehabilitation services from a participating hospital, and had a confirmed diagnosis of stroke (ischemic or hemorrhagic) with upper limb involvement. Fifty patients were recruited to the study (20 women, 30 men, N=50) with a mean age of 71 (SD 13.4, range 35-90) years. Time since stroke varied from 2 days to 187 months, with a median of 0.8 months. Interventions: Not applicable. Main Outcome Measures: Concurrent validity of the KHMS with the FMA-UE. Results: A correlation of r=0.948 was found between the 2 scales (P=.0001). Moderate floor effects were noted in our sample (16%); however, significant ceiling effects were recorded (44%). Conclusion: The KHMS demonstrated a statistically strong correlation with the FMA-UE and holds promise for use, particularly in the clinical setting, to evaluate upper limb motor impairment after stroke.

Utility of Acute and Subacute Blood Biomarkers to Assist Diagnosis in CT-Negative Isolated Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) have recently been Food and Drug Administration approved as predictors of intracranial lesions on CT after mild traumatic brain injury (mTBI). However, most cases with mTBI are CT negative, and no biomarkers are approved to assist diagnosis in these individuals. In this study, we aimed to determine the optimal combination of blood biomarkers to assist mTBI diagnosis in otherwise healthy adults younger than 50 years presenting to an emergency department within 6 hours of injury. To further understand the utility of biomarkers, we assessed how biological sex, presence or absence of loss of consciousness and/or post-traumatic amnesia (LOC/PTA), and delayed presentation affected classification performance. METHODS: Blood samples, symptom questionnaires, and cognitive tests were prospectively conducted for participants with mTBI recruited from The Alfred Hospital Level 1 Emergency & Trauma Center and uninjured controls. Follow-up testing was conducted at 7 days. Simoa quantified plasma GFAP, UCH-L1, tau, neurofilament light chain (NfL), interleukin (IL)-6, and IL-1ß. Area under the receiver operating characteristic (AUC) analysis assessed classification accuracy for diagnosed mTBI, and logistic regression models identified optimal biomarker combinations. RESULTS: Plasma IL-6 (AUC 0.91, 95% CI 0.86-0.96), GFAP (AUC 0.85, 95% CI 0.78-0.93), and UCH-L1 (AUC 0.79, 95% CI 0.70-0.88) best differentiated mTBI (n = 74) from controls (n = 44) acutely (<6 hours), with NfL (AUC 0.81, 95% CI 0.72-0.90) the only marker to have such utility subacutely (7 days). Biomarker performance was similar between sexes and for participants with and without LOC/PTA, with the exception at 7 days, where GFAP and IL-6 retained some utility in female participants (GFAP: AUC 0.71, 95% CI 0.55-0.88; IL-6: AUC 0.71, 95% CI 0.55-0.87) and in those with LOC/PTA (GFAP: AUC 0.73, 95% CI 0.59-0.86; IL-6: AUC 0.71, 95% CI 0.57-0.84). Acute IL-6 (R 2 = 0.50, 95% CI 0.34-0.64) outperformed GFAP and UCH-L1 combined (R 2 = 0.35, 95% CI 0.17-0.50), with the best acute model featuring GFAP and IL-6 (R 2 = 0.54, 95% CI 0.34-0.68). DISCUSSION: These findings indicate that adding IL-6 to a panel of brain-specific proteins such as GFAP and UCH-L1 might assist in the acute diagnosis of mTBI in adults younger than 50 years. Multiple markers had high classification accuracy in participants without LOC/PTA. When compared with the best-performing acute markers, subacute measures of plasma NfL resulted in minimal reduction in classification accuracy. Future studies will investigate the optimal time frame over which plasma IL-6 might assist diagnostic decisions and how extracranial trauma affects utility.

E2730, an uncompetitive γ-aminobutyric acid transporter-1 inhibitor, suppresses epileptic seizures in a rat model of chronic mesial temporal lobe epilepsy.

OBJECTIVE: More than one third of mesial temporal lobe epilepsy (MTLE) patients are resistant to current antiseizure medications (ASMs), and half experience mild-to-moderate adverse effects of ASMs. There is therefore a strong need to develop and test novel ASMs. The objective of this work is to evaluate the pharmacokinetics and neurological toxicity of E2730, a novel uncompetitive inhibitor of γ-aminobutyric acid transporter-1, and to test its seizure suppression effects in a rat model of chronic MTLE. METHODS: We first examined plasma levels and adverse neurological effects of E2730 in healthy Wistar rats. Adult male rats were implanted with osmotic pumps delivering either 10, 20, or 100 mg/kg/day of E2730 subcutaneously for 1 week. Blood sampling and behavioral assessments were performed at several timepoints. We next examined whether E2730 suppressed seizures in rats with chronic MTLE. These rats were exposed to kainic acid-induced status epilepticus, and 9 weeks later, when chronic epilepsy was established, were assigned to receive one of the three doses of E2730 or vehicle for 1 week in a randomized crossover design. Continuous video-electroencephalographic monitoring was acquired during the treatment period to evaluate epileptic seizures. RESULTS: Plasma levels following continuous infusion of E2730 showed a clear dose-related increase in concentration. The drug was well tolerated at all doses, and any sedation or neuromotor impairment was mild and transient, resolving within 48 h of treatment initiation. Remarkably, E2730 treatment in chronically epileptic rats led to seizure suppression in a dose-dependent manner, with 65% of rats becoming seizure-free at the highest dose tested. Mean seizure class did not differ between the treatment groups. SIGNIFICANCE: This study shows that continuous subcutaneous infusion of E2730 over 7 days results in a marked, dose-dependent suppression of spontaneous recurrent seizures, with minimal adverse neurological effects, in a rat model of chronic MTLE. E2730 shows strong promise as an effective new ASM to be translated into clinical trials.

MicroRNA biomarkers for diagnosis of mild traumatic brain injury and prediction of persistent symptoms: A prospective cohort study.

The diagnosis of mild traumatic brain injury (mTBI) and early identification of patients who have persistent symptoms remains challenging. Symptoms are variably reported, and tests for cognitive impairment require specific expertise. The aim of this study was to assess the ability of plasma micro-ribonucleic acid (miRNA) biomarkers to distinguish between patients with mTBI and healthy controls. A secondary aim was to assess whether miRNA biomarker levels on the day of injury could predict persistent symptoms on day 7. Injured patients presented to an adult, tertiary referral hospital emergency department and were diagnosed with isolated mTBI (n = 75). Venous blood samples were collected within 6 h of injury. Symptom severity was assessed using the Rivermead Post-Concussion Symptom Questionnaire (RPQ) on the day of injury and at 7 days post-injury. The comparator group (n = 44) were healthy controls without any injury, who had bloods sampled and symptom severity assessed at the same time-point. Patients after mTBI reported higher symptom severity and had worse cognitive performance than the control group. Plasma miR423-3p levels were significantly higher among mTBI patients acutely post-injury compared to healthy controls and provided moderate discriminative ability (AUROC 0.67; 95 %CI: 0.57-0.77). None of the assessed miRNA biomarkers predicted persistent symptoms at 7 days. Plasma miR423-3p levels measured within 6 h of injury can discriminate for mTBI compared to healthy controls, with potential utility for screening after head injury or as an adjunct to the diagnosis of mTBI. Acute plasma miRNA levels did not predict patients who reported persistent symptoms at 7 days.

The role of the primary motor cortex in motor imagery: A theta burst stimulation study.

While mentally simulated actions activate similar neural structures to overt movement, the role of the primary motor cortex (PMC) in motor imagery remains disputed. The aim of the study was to use continuous theta burst stimulation (cTBS) to modulate corticospinal activity to investigate the putative role of the PMC in implicit motor imagery in young adults with typical and atypical motor ability. A randomized, double blind, sham-controlled, crossover, offline cTBS protocol was applied to 35 young adults. During three separate sessions, adults with typical and low motor ability (developmental coordination disorder [DCD]), received active cTBS to the PMC and supplementary motor area (SMA), and sham stimulation to either the PMC or SMA. Following stimulation, participants completed measures of motor imagery (i.e., hand rotation task) and visual imagery (i.e., letter number rotation task). Although active cTBS significantly reduced corticospinal excitability in adults with typical motor ability, neither task performance was altered following active cTBS to the PMC or SMA, compared to performance after sham cTBS. These results did not differ across motor status (i.e., typical motor ability and DCD). These findings are not consistent with our hypothesis that the PMC (and SMA) is directly involved in motor imagery. Instead, previous motor cortical activation observed during motor imagery may be an epiphenomenon of other neurophysiological processes and/or activity within brain regions involved in motor imagery. This study highlights the need to consider multi-session theta burst stimulation application and its neural effects when probing the putative role of motor cortices in motor imagery.

Targeting the Cerebrovascular System: Next-Generation Biomarkers and Treatment for Mild Traumatic Brain Injury.

The diagnosis, prognosis, and treatment of mild traumatic brain injuries (mTBIs), such as concussions, are significant unmet medical issues. The kinetic forces that occur in mTBI adversely affect the cerebral vasculature, making cerebrovascular injury (CVI) a pathophysiological hallmark of mTBI. Given the importance of a healthy cerebrovascular system in overall brain function, CVI is likely to contribute to neurological dysfunction after mTBI. As such, CVI and related pathomechanisms may provide objective biomarkers and therapeutic targets to improve the clinical management and outcomes of mTBI. Despite this potential, until recently, few studies have focused on the cerebral vasculature in this context. This article will begin by providing a brief overview of the cerebrovascular system followed by a review of the literature regarding how mTBI can affect the integrity and function of the cerebrovascular system, and how this may ultimately contribute to neurological dysfunction and neurodegenerative conditions. We then discuss promising avenues of research related to mTBI biomarkers and interventions that target CVI, and conclude that a clinical approach that takes CVI into account could result in substantial improvements in the care and outcomes of patients with mTBI.

Visible Signs of Concussion and Cognitive Screening in Community Sports.

Video surveillance and detection of players with visible signs of concussion by experienced medical staff facilitates rapid on-field screening of suspected concussion in professional sports. This method, however has not been validated in community sports where video footage is unavailable. This study aimed to explore the utility of visible signs of concussion to identify players with decrements in performance on concussion screening measures. In this observational prospective cohort study, personnel with basic training observed live matches across a season (60 matches) of community male and female Australian football for signs of concussion outlined in the community-based Head Injury Assessment form (HIAf). Players identified to have positive signs of concussion (CoSign+) following an impact were compared with players without signs (CoSign-). Outcome measures, the Sport Concussion Assessment Tool (SCAT3) and Cogstate, were administered at baseline and post-match. CoSign+ (n = 22) and CoSign- (n = 61) groups were similar with respect to age, sex, education, baseline mood, and medical history. CoSign+ players exhibited worse orientation, concentration, and recall, and slower reaction time in attention and working memory tasks. Comparing individual change from baseline to post-match assessment revealed 100% (95% confidence interval [CI]: 84-100%) of CoSign+ players demonstrated clinically significant deficits on SCAT3 or Cogstate tasks, compared with 59% (95% CI: 46-71%) of CoSign- players. All CoSign+ players observed to have a blank/vacant look demonstrated clinically significant decline on the Standardized Assessment of Concussion (SAC). Detection of visible signs of concussion represents a rapid, real-time method for screening players suspected of concussion in community sports where video technology and medical personnel are rarely present. Consistent with community guidelines, it is recommended that all CoSign+ players be immediately removed from play for further concussion screening.

Cognitive ocular motor deficits and white matter damage chronically after sports-related concussion.

A history of concussion has been linked to long-term cognitive deficits; however, the neural underpinnings of these abnormalities are poorly understood. This study recruited 26 asymptomatic male Australian footballers with a remote history of concussion (i.e. at least six months since last concussion), and 23 non-collision sport athlete controls with no history of concussion. Participants completed three ocular motor tasks (prosaccade, antisaccade and a cognitively complex switch task) to assess processing speed, inhibitory control and cognitive flexibility, respectively. Diffusion tensor imaging data were acquired using a 3 T MRI scanner, and analysed using tract-based spatial statistics, to investigate white matter abnormalities and how they relate to ocular motor performance. Australian footballers had significantly slower adjusted antisaccade latencies compared to controls (P = 0.035). A significant switch cost (i.e. switch trial error > repeat trial error) was also found on the switch task, with Australian footballers performing increased magnitude of errors on prosaccade switch trials relative to prosaccade repeat trials (P = 0.023). Diffusion tensor imaging analysis found decreased fractional anisotropy, a marker of white matter damage, in major white matter tracts (i.e. corpus callosum, corticospinal tract) in Australian footballers relative to controls. Notably, a larger prosaccade switch cost was significantly related to reduced fractional anisotropy in anterior white matter regions found to connect to the prefrontal cortex (i.e. a key cortical ocular motor centre involved in executive functioning and task switching). Taken together, Australian footballers with a history of concussion have ocular motor deficits indicative of poorer cognitive processing speed and cognitive flexibility, which are related to reduce white matter integrity in regions projecting to important cognitive ocular motor structures. These findings provide novel insights into the neural mechanisms that may underly chronic cognitive impairments in individuals with a history of concussion.

Activation of the Protein Kinase R-Like Endoplasmic Reticulum Kinase (PERK) Pathway of the Unfolded Protein Response after Experimental Traumatic Brain Injury and Treatment with a PERK Inhibitor.

Neurodegeneration after traumatic brain injury (TBI) is increasingly recognized as a key factor contributing to poor chronic outcomes. Activation (i.e., phosphorylation) of the protein kinase R-like endoplasmic reticulum kinase (PERK) pathway has been implicated in neurodegenerative conditions with pathological similarities to TBI and may be a potential target to improve TBI outcomes. Here, we aimed to determine whether a moderate TBI would induce activation of the PERK pathway and whether treatment with the PERK inhibitor, GSK2606414, would improve TBI recovery. Male mice were administered a lateral fluid percussion injury (FPI) or sham injury and were euthanized at either 2 h, 24 h, or 1 week post-injury (n = 5 per injury group and time point) to assess changes in the PERK pathway. In the injured cortex, there was increased phosphorylated-PERK at 2 h post-FPI and increased phosphorylation of eukaryotic translation initiation factor α at 24 h post-FPI. We next examined the effect of acute treatment with GSK2606414 on pathological and behavioral outcomes at 4 weeks post-injury. Thus, there were a total of four groups: sham + VEH (n = 9); sham + GSK4606414 (n = 10); FPI + VEH (n = 9); and FPI + GSK2606414 (n = 9). GSK2606414 (50 mg/kg) or vehicle treatment was delivered by oral gavage beginning at 30 min post-injury, followed by two further treatments at 12-h increments. There were no significant effects of GSK2606414 on any of the outcomes assessed, which could be attributable to several reasons. For example, activation of PERK may not be a significant contributor to the neurological consequences 4 weeks post-FPI in mice. Further research is required to elucidate the role of the PERK pathway in TBI and whether interventions that target this pathway are beneficial.

White and Gray Matter Abnormalities in Australian Footballers With a History of Sports-Related Concussion: An MRI Study.

Sports-related concussion (SRC) is a form of mild traumatic brain injury that has been linked to long-term neurological abnormalities. Australian rules football is a collision sport with wide national participation and is growing in popularity worldwide. However, the chronic neurological consequences of SRC in Australian footballers remain poorly understood. This study investigated the presence of brain abnormalities in Australian footballers with a history of sports-related concussion (HoC) using multimodal MRI. Male Australian footballers with HoC (n = 26), as well as noncollision sport athletes with no HoC (n = 27), were recruited to the study. None of the footballers had sustained a concussion in the preceding 6 months, and all players were asymptomatic. Data were acquired using a 3T MRI scanner. White matter integrity was assessed using diffusion tensor imaging. Cortical thickness, subcortical volumes, and cavum septum pellucidum (CSP) were analyzed using structural MRI. Australian footballers had evidence of widespread microstructural white matter damage and cortical thinning. No significant differences were found regarding subcortical volumes or CSP. These novel findings provide evidence of persisting white and gray matter abnormalities in Australian footballers with HoC, and raise concerns related to the long-term neurological health of these athletes.

Diffusion Imaging Reveals Sex Differences in the White Matter Following Sports-Related Concussion.

Sports-related concussion (SRC) is a serious health concern. However, the temporal profile of neuropathophysiological changes after SRC and how these relate to biological sex are still poorly understood. This preliminary study investigated whether diffusion-weighted magnetic resonance imaging (dMRI) was sensitive to neuropathophysiological changes following SRC; whether these changes were sex-specific; and whether they persisted beyond the resolution of self-reported symptoms. Recently concussed athletes (n = 14), and age- and education-matched nonconcussed control athletes (n = 16), underwent MRI 24-48-h postinjury and again at 2-week postinjury (i.e., when cleared to return-to-play). Male athletes reported more symptoms and greater symptom severity compared with females. dMRI revealed white matter differences between athletes with SRC and their nonconcussed counterparts at 48-h postinjury. These differences were still present at 2-week postinjury, despite SRC athletes being cleared to return to play and may indicate increased cerebral vulnerability beyond the resolution of subjective symptoms. Furthermore, we identified sex-specific differences, with male SRC athletes having significantly greater white matter disruption compared with female SRC athletes. These results have important implications for the management of concussion, including guiding return-to-play decisions, and further improve our understanding regarding the role of sex in SRC outcomes.

Prolonged elevation of serum neurofilament light after concussion in male Australian football players.

BACKGROUND: Biomarkers that can objectively guide the diagnosis of sports-related concussion, and consequent return-to-play decisions, are urgently needed. In this study, we aimed to determine the temporal profile and diagnostic ability of serum levels of neurofilament light (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP), and tau in concussed male and female Australian footballers. METHODS: Blood was collected from 28 Australian rules footballers (20 males, 8 females) at 2-, 6-, and 13-days after a diagnosed concussion for comparison to their levels at baseline (i.e. pre-season), and with 27 control players (19 males, 8 females) without a diagnosis of concussion. Serum concentrations of protein markers associated with damage to neurons (UCHL1), axons (NfL, tau), and astrocytes (GFAP) were quantified using a Simoa HD-X Analyzer. Biomarker levels for concussed players were compared over time and between sex using generalised linear mixed effect models, and diagnostic performance was assessed using area under the receiver operating characteristic curve (AUROC) analysis. RESULTS: Serum NfL was increased from baseline in male footballers at 6- and 13-days post-concussion. GFAP and tau were increased in male footballers with concussion at 2- and 13-days respectively. NfL concentrations discriminated between concussed and non-concussed male footballers at all time-points (AUROC: 2d = 0.73, 6d = 0.85, 13d = 0.79), with tau also demonstrating utility at 13d (AUROC = 0.72). No biomarker differences were observed in female footballers after concussion. CONCLUSIONS: Serum NfL may be a useful biomarker for the acute and sub-acute diagnosis of concussion in males, and could inform neurobiological recovery and return-to-play decisions. Future adequately powered studies are still needed to investigate biomarker changes in concussed females.

Elevated Serum Interleukin-1ß Levels in Male, but not Female, Collision Sport Athletes with a Concussion History.

It is increasingly reported that a history of concussion may be associated with chronic deleterious consequences. While the pathophysiology that contributes to these consequences is not well understood, neuroinflammation is postulated to be critical. Activation of multi-protein complexes termed inflammasomes, a key component of this inflammatory response, has been reported in more severe TBIs; however, it has not been investigated in milder TBIs, such as concussion. This study investigated serum levels of interleukin (IL)-1ß and IL-18 (key proteins activated downstream of these inflammasomes) at acute, sub-acute, and chronic time-points post-concussion. We recruited 105 Australian footballers (65 male, 40 female) during the pre-season, then prospectively followed these players for the occurrence of concussion during the season. At baseline, 58 footballers reported a previous concussion history, and 47 reported no previous concussion history. Additionally, 25 players sustained a mid-season concussion and were sampled at 2, 6, and 13 days post-concussion. Serum levels of IL-1ß and IL-18 were quantified using highly sensitive Simoa HD-X Analyzer assays. At baseline, IL-1ß levels were higher in male, but not female, footballers with a previous concussion history compared with footballers with no concussion history. There was also a positive correlation between years of collision sport participation and IL-18 levels in males. No evidence was found in males or females to indicate that IL-1ß or IL-18 levels differed at 2, 6, or 13 days post-concussion. These findings provide novel insights into potential sex-specific physiological consequences of concussion, and suggest that neuroinflammation may be persistent chronically following concussion in male athletes.

Serum Protein Biomarker Findings Reflective of Oxidative Stress and Vascular Abnormalities in Male, but Not Female, Collision Sport Athletes.

Studies have indicated that concussive and sub-concussive brain injuries that are frequent during collision sports may lead to long-term neurological abnormalities, however there is a knowledge gap on how biological sex modifies outcomes. Blood-based biomarkers can help to identify the molecular pathology induced by brain injuries and to better understand how biological sex affects the molecular changes. We therefore analyzed serum protein biomarkers in male (n = 50) and female (n = 33) amateur Australian rules footballers (i.e., Australia's most participated collision sport), both with a history of concussion (HoC) and without a history of concussion (NoHoC). These profiles were compared to those of age-matched control male (n = 24) and female (n = 20) athletes with no history of neurotrauma or participation in collision sports. Serum levels of protein markers indicative of neuronal, axonal and glial injury (UCH-L1, NfL, tau, p-tau, GFAP, BLBP, PEA15), metabolic (4-HNE) and vascular changes (VEGF-A, vWF, CLDN5), and inflammation (HMGB1) were assessed using reverse phase protein microarrays. Male, but not female, footballers had increased serum levels of VEGF-A compared to controls regardless of concussion history. In addition, only male footballers who had HoC had increased serum levels of 4-HNE. These findings being restricted to males may be related to shorter collision sport career lengths for females compared to males. In summary, these findings show that male Australian rules footballers have elevated levels of serum biomarkers indicative of vascular abnormalities (VEGF-A) and oxidative stress (4-HNE) in comparison to non-collision control athletes. While future studies are required to determine how these findings relate to neurological function, serum levels of VEGF-A and 4-HNE may be useful to monitor subclinical neurological injury in males participating in collision sports.

Cerebral Cortical Activity Following Non-invasive Cerebellar Stimulation-a Systematic Review of Combined TMS and EEG Studies.

The cerebellum sends dense projections to both motor and non-motor regions of the cerebral cortex via the cerebellarthalamocortical tract. The integrity of this tract is crucial for healthy motor and cognitive function. This systematic review examines research using transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to the cerebellum with combined cortical electroencephalography (EEG) to explore the temporal features of cerebellar-cortical connectivity. A detailed discussion of the outcomes and limitations of the studies meeting review criteria is presented. Databases were searched between 1 December 2017 and 6 December 2017, with Scopus alerts current as of 23 July 2019. Of the 407 studies initially identified, 10 met review criteria. Findings suggested that cerebellar-cortical assessment is suited to combined TMS and EEG, although work is required to ensure experimental procedures are optimal for eliciting a reliable cerebellar response from stimulation. A distinct variation in methodologies and outcome measures employed across studies, and small sample sizes limited the conclusions that could be drawn regarding the electrophysiological signatures of cerebellar-cortical communication. This review highlights the need for stringent protocols and methodologies for cerebellar-cortical assessments via combined TMS and EEG. With these in place, combined TMS and EEG will provide a valuable means for exploring cerebellar connectivity with a wide range of cortical sites. Assessments have the potential to aid in the understanding of motor and cognitive function in both healthy and clinical groups, and provide insights into long-range neural communication generally.

Concussion incidence and time-loss in Australian football: A systematic review.

OBJECTIVES: Australian football is associated with a risk of concussion. However, despite the extensive and varied nature of literature devoted to this issue, concussion incidence has not been systematically evaluated. To address this, we aimed to conduct a meta-analysis of concussion incidence in Australian football. DESIGN: Systematic review. Prospero registration number: CRD42017064290. METHODS: A systematic search of 14 databases using the terms 'concussion', and 'Australian football' (and variations) was used to obtain records that reported concussion incidence per 1000 players hours across age, sex, and level-of-play. Data were grouped based on how time-loss was applied to the concussion definition. RESULTS: Forty-two studies met inclusion criteria. Incidence rates based on a possible time-loss definition per 1000 player hours, ranged from 2.24 to 17.63 at the elite level, and 0.35 to 14.77 at the community/amateur level. Return-to-play details were reported by six studies and only two studies measured head-impacts in real-time. Several limitations were identified with this literature. First, insufficient return-to-play details precluded a meta-analysis of incidence rates. Second, no longitudinal studies across levels-of-play were found. Third, concussion incidence data for junior and female players were notably scarce. CONCLUSIONS: There was limited scope to determine concussion burden (i.e., incidence and severity) and only preliminary data for player exposure to head-impacts. To address these limitations, injury surveillance should capture sufficient information to permit comparisons within and across levels-of-play. This will also help determine the influence of interventions aimed at reducing the frequency and severity of concussive-injuries.

Learning to Expect: Predicting Sounds During Movement Is Related to Sensorimotor Association During Listening.

Sensory experiences, such as sound, often result from our motor actions. Over time, repeated sound-producing performance can generate sensorimotor associations. However, it is not clear how sensory and motor information are associated. Here, we explore if sensory prediction is associated with the formation of sensorimotor associations during a learning task. We recorded event-related potentials (ERPs) while participants produced index and little finger-swipes on a bespoke device, generating novel sounds. ERPs were also obtained as participants heard those sounds played back. Peak suppression was compared to assess sensory prediction. Additionally, transcranial magnetic stimulation (TMS) was used during listening to generate finger-motor evoked potentials (MEPs). MEPs were recorded before and after training upon hearing these sounds, and then compared to reveal sensorimotor associations. Finally, we explored the relationship between these components. Results demonstrated that an increased positive-going peak (e.g., P2) and a suppressed negative-going peak (e.g., N2) were recorded during action, revealing some sensory prediction outcomes (P2: p = 0.050, η p 2 = 0.208; N2: p = 0.001, η p 2 = 0.474). Increased MEPs were also observed upon hearing congruent sounds compared with incongruent sounds (i.e., associated to a finger), demonstrating precise sensorimotor associations that were not present before learning (Index finger: p < 0.001, η p 2 = 0.614; Little finger: p < 0.001, η p 2 = 0.529). Consistent with our broad hypotheses, a negative association between the MEPs in one finger during listening and ERPs during performance of the other was observed (Index finger MEPs and Fz N1 action ERPs; r = -0.655, p = 0.003). Overall, data suggest that predictive mechanisms are associated with the fine-tuning of sensorimotor associations.

Effects of eccentric versus concentric contractions of the biceps brachii on intracortical inhibition and facilitation.

Differences in the neural mechanisms underpinning eccentric (ECC) and concentric (CON) contractions exist; however, the acute effects of fatiguing muscle contractions on intracortical and corticospinal excitability are not well understood. Therefore, we compared maximal ECC and CON contractions of the right biceps brachii (BB) muscle for changes in corticospinal excitability, short- (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF) up to 1 hour post-exercise. Fourteen right-handed adults (11 M/3F; 26.8 ± 2.9 year) undertook a single session of 3 sets of 10 maximal ECC or CON contractions (180-second rest between sets) on an isokinetic dynamometer (40°/s) separated by 1 week, in a randomized crossover study. Maximum voluntary isometric contraction torque (MVIC), maximal muscle compound waves (MMAX ), and motor-evoked potentials elicited through transcranial magnetic stimulation (TMS) were recorded via surface electromyography from the right BB. MVIC decreased (P < 0.001) immediately after ECC and CON contractions similarly, but the decrease was sustained at 1 hour post-ECC contractions only. MMAX was reduced immediately (P = 0.014) and 1 hour post-exercise (P = 0.019) only for ECC contractions. SICI and ICF increased immediately after ECC and CON contractions (P < 0.001), but LICI increased only after ECC contractions (P < 0.001), and these increases remained at 1 hour post-ECC contractions only. These findings suggest that ECC contractions induced a longer-lasting neuromodulatory effect on intracortical inhibition and facilitation, which could indicate a central compensatory response to peripheral fatigue.