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.

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.

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.

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.

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.

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.

The Impact of Stimulation Intensity and Coil Type on Reliability and Tolerability of Cerebellar Brain Inhibition (CBI) via Dual-Coil TMS.

Cerebellar brain inhibition (CBI) describes the inhibitory tone the cerebellum exerts on the primary motor cortex (M1). CBI can be indexed via a dual-coil transcranial magnetic stimulation protocol, whereby a conditioning stimulus (CS) is delivered to the cerebellum in advance of a test stimulus (TS) to M1. The CS is typically delivered at intensities over 60% maximum stimulus output (MSO) via a double-cone coil. This is reportedly uncomfortable for participants, reducing the reliability and validity of outcomes. This feasibility study investigates the reliability and tolerability of eliciting CBI across a range of CS intensities using both a double-cone and high-powered figure-of-8 coil, the D702. It was expected that the double-cone coil would elicit CBI at intensities upwards of 60%MSO. The range for the D702 coil was exploratory. The double-cone coil was expected to be less tolerable than the D702 coil. CBI was assessed in 13 participants (25.92 ± 5.42 years, six female) using each coil (randomized) over intensities 40, 50, 60, 70, 80%MSO. Tolerability was assessed via visual analog scales. Comparisons across intensities and tolerability were assessed non-parametrically and via a linear model. The double-cone coil elicited CBI at intensities 60, 70, and 80%MSO (p < .05), with suppression elicited at 60%MSO not significantly different to that at higher intensities. CBI was not reliably elicited by the D702 coil at any intensity. The double-cone coil was significantly less tolerable than the D702. A CS of 60%MSO with a double-cone coil provides a balance between the reliability and tolerability of CBI.

Effects of acute resistance training modality on corticospinal excitability, intra-cortical and neuromuscular responses.

OBJECTIVE: Although neural adaptations from strength training are known to occur, the acute responses associated with heavy-strength (HST) and hypertrophy training (HYT) remain unclear. Therefore, we aimed to compare the acute behaviour of corticospinal responses following a single session of HST vs HYT over a 72-h period. METHODS: Fourteen participants completed a random counterbalanced, crossover study that consisted of a single HST session [5 sets × 3 repetition maximum (RM)], a HYT session (3 sets × 12 RM) of the leg extensors and a control session (CON). Single- and paired-pulse transcranial magnetic stimulation (TMS) was used to measure changes in motor-evoked potential (MEP) amplitude, corticospinal silent period (CSP), intra-cortical facilitation (ICF), short-interval intra-cortical inhibition (SICI) and long-interval intra-cortical inhibition (LICI). Additionally, maximal muscle compound wave (M MAX) of the rectus femoris (RF) and maximal voluntary isometric contraction (MVIC) of the leg extensors were taken. All measures were taken at baseline, immediately post and 2, 6, 24, 48 and 72 h post-training. RESULTS: A significant condition x time interaction was observed for MVIC (P = 0.001), M MAX (P = 0.003), MEP amplitude (P < 0.001) and CSP (P = 0.002). No differences were observed between HST and HYT for all neurophysiological measures. No changes in SICI, ICF and LICI were observed compared to baseline. CONCLUSION: Our results suggest that: (1) the acute behaviour of neurophysiological measures is similar between HST and HYT; and (2) the increase in corticospinal excitability may be a compensatory response to attenuate peripheral fatigue.

Using transcranial magnetic stimulation to quantify electrophysiological changes following concussive brain injury: a systematic review.

Mild traumatic brain injury (mTBI) and sports concussion are a growing public health concern, with increasing demands for more rigorous methods to quantify changes in the brain post-injury. Electrophysiology, and in particular, transcranial magnetic stimulation (TMS), have been demonstrated to provide prognostic value in a range of neurological conditions; however, no review has quantified the efficacy of TMS in mTBI/concussion. In the present study, we present a systematic review and critical evaluation of the scientific literature from 1990 to 2014 that has used TMS to investigate corticomotor excitability responses at short-term (< 12 months), medium-term (1-5 years), and long-term (> 5 years) post-mTBI/concussion. Thirteen studies met the selection criteria, with six studies presenting short-term changes, five studies presenting medium-term changes, and two studies presenting long-term changes. Irrespective of time post-concussion, change in intracortical inhibition was the most reported observation. Other findings included increased stimulation threshold, and slowed neurological conduction time. Although currently limited, the data suggest that TMS has prognostic value in detecting neurophysiological changes post-mTBI/concussion.

Faster VO(2) kinetics after eccentric contractions is explained by better matching of O(2) delivery to O(2) utilization.

PURPOSE: This study examined the impact of eccentric exercise-induced muscle damage on the rate of adjustment in muscle deoxygenation and pulmonary O2 uptake (VO(2p)) kinetics during moderate exercise. METHODS: Fourteen males (25 ± 3 year; mean ± SD) completed three step transitions to 90 % θL before (Pre), 24 h (Post24) and 48 h after (Post48) eccentric exercise (100 eccentric leg-press repetitions with a load corresponding to 110 % of the participant's concentric 1RM). Participants were separated into two groups: phase II VO(2p) time constant (τVO(2p)) ≤ 25 s (fast group; n = 7) or τVO(2p) > 25 s (slow group; n = 7). VO(2p) and [HHb] responses were modeled as a mono-exponential. RESULTS: In both groups, isometric peak torque (0°/s) at Post24 was decreased compared to Pre (p < 0.05) and remained depressed at Post48 (p < 0.05). τVO(2p) was designed to be different (p < 0.05) at Pre between the Fast (τVO(2p); 19 ± 4 s) and Slow (32 ± 6 s) groups. There were no differences among time points (τVO(2p): Pre, 19 ± 4 s; Post24, 22 ± 3 s; Post48, 20 ± 4 s) in the Fast group. In Slow, there was a speeding (p < 0.05) from the Pre (32 ± 6 s) to the Post24 (25 ± 6) but not Post48 (31 ± 6), resulting in no difference (p > 0.05) between groups at Post24. This reduction of τVO(2p) was concomitant with the abolishment (p < 0.05) of an overshoot in the [HHb]/VO(2p) ratio. CONCLUSION: We propose that the sped VO(2p) kinetics observed in the Slow group coupled with an improved [HHb]/VO(2p) ratio suggest a better matching of local muscle O2 delivery to O2 utilization following eccentric contractions.

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.

Microrna Biomarkers on Day of Injury Among Patients with Post Concussive Symptoms at 28-Days: A Prospective Cohort Study.

BACKGROUND: After mild traumatic brain injury (mTBI), some patients experience symptoms that persist for weeks to months. Recovery from mTBI is primarily assessed using selfreported symptom questionnaires. Blood biomarkers, including microRNA species, have shown promise to assist diagnosis of mTBI, however, little is known about how blood microRNA measures might predict symptom recovery. OBJECTIVE: The aim of this study was to investigate the variances in plasma microRNAs on the day of injury between individuals with mTBI who report post-concussive symptoms at the 28- day mark and those who do not. METHODS: Patients who presented to an adult, tertiary referral hospital emergency department on the day of the injury and were diagnosed with isolated mTBI (n=35) were followed up for 28 days. Venous blood samples were collected and symptom severity was assessed using the Rivermead Post-Concussion Symptom Questionnaire (RPQ) on the day of injury and at 28 days. Patients who reported ongoing symptoms of total RPQ score ≥10 or at least one symptom severity ≥2, were compared to those with lesser symptom severity or symptom resolution. RESULTS: There were 9 (25.7%; 95%CI: 12.5-43.3) patients who reported persistent symptoms. Day of injury plasma miR-223-3p levels were significantly higher in individuals with ongoing symptoms compared to those without, however, no such differences were observed for miRs 142- 3p, 423-3p, 32-5p, 144-3p, and let-7f-5p. CONCLUSION: Acute plasma miR-223-3p levels appear to detect patients who later have persistent symptoms after mTBI. The results demonstrate the potential utility for such biomarkers to assist in decisions towards early referral for therapy after mTBI.

Research priorities for diagnosis, prognosis, and rehabilitation following concussion: results from a national survey of Australian health professionals.

PURPOSE: Recently, the Concussion James Lind Alliance Priority Setting Partnership (JLAPSP) (Canada) identified serious research gaps regarding diagnosis, management, and access to effective rehabilitation for concussion/mild traumatic brain injury (mTBI). Our aim was to determine if the same research priorities are important to Australian health professionals working in the concussion/mTBI field. MATERIALS AND METHODS: A survey was distributed via professional networks, social media, professional group listservs, a research project noticeboard, and at conferences. It comprised of 25 of the highest ranked concussion research questions from the JLAPSP. We examined how professionals ranked the research questions and analyzed variation in ranking by clinical role and concussion/mTBI work experience. RESULTS: Our sample of 187 participants included medical and allied health professionals. Most participants were occupational therapists (22%), physiotherapists (18%), neuropsychologists (17%), and worked in Victoria (47%), New South Whales (18%), or Queensland (15%) in metropolitan areas. Health professionals ranked three research questions highest: identifying methods to predict prolonged recovery; effectiveness of early referral and treatment by a specialized concussion/mTBI team; and implementation studies on upskilling healthcare workers. CONCLUSIONS: The research priorities identified can guide research efforts to improve the assessment, management, and rehabilitation of individuals with concussion/mTBI in Australia.

Health professionals with experience in the assessment and rehabilitation of adults with concussions overwhelmingly agree that there is a need for further research to understand the prognosis and the effectiveness of specialized rehabilitation clinics.The role of healthcare providers in supporting recovery and the long-term health implications of suffering a concussion was identified as a priority.Both pre-clinical and clinical research are identified priorities to determine the effectiveness of biomarkers for concussion and return to activity.Health professionals also call for clinical trials testing management protocols, and implementation trials to support translation of clinical guidelines into practice to understand the role of healthcare providers in rehabilitation.

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.

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.

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.

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.

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.