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•EEG-fNIRS-TCD multimodal imaging assessed neurovascular coupling in humans.•Motor and visual tasks revealed task-dependent neurovascular responses.•Hemodynamic and neuronal activation occurred independently of systemic influences.•The \"Where's Waldo?\" task elicited robust responses across EEG, fNIRS, and TCD.•Findings demonstrated the temporal synchrony between modalities. This study explored a novel multimodal neuroimaging approach to assess neurovascular coupling (NVC) in humans using electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS), and transcranial Doppler ultrasound (TCD). Fifteen participants (nine females; age 19–32) completed concurrent EEG-fNIRS-TCD imaging during motor (finger tapping) and visual (“Where's Waldo?”) tasks, with synchronized monitoring of blood pressure, capnography, and heart rate. fNIRS assessed microvascular oxygenation within the frontal, motor, parietal, and occipital cortices, while the middle and posterior cerebral arteries (MCA/PCA) were insonated using TCD. A 16-channel EEG set-up was placed according to the 10–20 system. Wilcoxon signed-rank tests were used to compare physiological responses between the active and resting phases of the tasks, while cross-correlations with zero legs compared cerebral and systemic hemodynamic responses across both tasks. Time-frequency analysis demonstrated a reduction in alpha and low beta band power in electrodes C3/C4 during finger tapping (p<0.045) and all electrodes during the Waldo task (all p<0.001). During Waldo, cross-correlation analysis demonstrated the change in oxygenated hemoglobin and cerebral blood velocity had a moderate-to-strong negative correlation with systemic physiological influences, highlighting the measured change resulted from neuronal input. Deoxygenated hemoglobin displayed the greatest negative cross-correlation with the MCA/PCA within the motor cortices and visual during the motor and visual tasks, respectively (range:0.54, -0.82). This investigation demonstrated the feasibility of the proposed EEG-fNIRS-TCD response to comprehensively assess the NVC response within human, specifically quantifying the real-time temporal synchrony between neuronal activation (EEG), microvascular oxygenation changes (fNIRS), and conduit artery velocity alterations (TCD).

Single voxel magnetic resonance spectroscopy (MRS) quantifies metabolites within a specified volume of interest. MRS voxels are constrained to rectangular prism shapes. Therefore, they must define a small voxel contained within the anatomy of interest or include not of interest neighbouring tissue. When studying cortical regions without clearly demarcated boundaries, e.g. the dorsolateral prefrontal cortex (DLPFC), it is unclear how representative a larger voxel is of a smaller volume within it. To determine if a large voxel is representative of a small voxel placed within it, this study quantified total N-Acetylaspartate (tNAA), choline, glutamate, Glx (glutamate and glutamine combined), myo -inositol, and creatine in two overlapping MRS voxels in the DLPFC, a large (30×30x30 mm) and small (15×15x15 mm) voxel. Signal-to-noise ratio (SNR) and tissue type factors were specifically investigated. With water-referencing, only myo -inositol was significantly correlated between the two voxels, while all metabolites showed significant correlations with creatine-referencing. SNR had a minimal effect on the correspondence between voxels, while tissue type showed substantial influence. This study demonstrates substantial variability of metabolite estimates within the DLPFC. It suggests that when small anatomical structures are of interest, it may be valuable to spend additional acquisition time to obtain specific, localized data.

Magnetic resonance imaging (MRI) can provide a number of measurements relevant to sport-related concussion (SRC) symptoms; however, most studies to date have used a single MRI modality and whole-brain exploratory analyses in attempts to localize concussion injury. This has resulted in highly variable findings across studies due to wide ranging symptomology, severity and nature of injury within studies. A multimodal MRI, symptom-guided region-of-interest (ROI) approach is likely to yield more consistent results. The functions of the cerebellum and basal ganglia transcend many common concussion symptoms, and thus these regions, plus the white matter tracts that connect or project from them, constitute plausible ROIs for MRI analysis. We performed diffusion tensor imaging (DTI), resting-state functional MRI, quantitative susceptibility mapping (QSM), and cerebral blood flow (CBF) imaging using arterial spin labeling (ASL), in youth aged 12-18 years following SRC, with a focus on the cerebellum, basal ganglia and white matter tracts. Compared to controls similar in age, sex and sport (N=20), recent SRC youth (N=29; MRI at 8 ± 3 days post injury) exhibited increased susceptibility in the cerebellum (p = 0.032), decreased functional connectivity between the caudate and each of the pallidum (p=0.035) and thalamus (p=0.021), and decreased diffusivity in the mid-posterior corpus callosum (p < 0.038); no changes were observed in recovered asymptomatic youth (N=16; 41 ± 16 days post injury). For recent symptomatic-only SRC youth (N=24), symptom severity was associated with increased susceptibility in the superior cerebellar peduncles (p=0.011) and reduced activity in the cerebellum (p=0.013). Fewer days between injury and MRI were associated with reduced cerebellar-parietal functional connectivity (p<0.014), reduced activity of the pallidum (p=0.002), increased CBF in the caudate (p=0.005), and reduced diffusivity in the central corpus callosum (p<0.05). Youth SRC is associated with acute cerebellar inflammation accompanied by reduced cerebellar activity and cerebellar-parietal connectivity, as well as structural changes of the middle regions of the corpus callosum accompanied by functional changes of the caudate, all of which resolve with recovery. Early MRI post-injury is important to establish objective MRI-based indicators for concussion diagnosis, recovery assessment and prediction of outcome.

The assessment, management, and prognostication of spinal cord injury (SCI) mainly rely upon observer-based ordinal scales measures. 1H nuclear magnetic resonance (NMR) spectroscopy provides an effective approach for the discovery of objective biomarkers from biofluids. These biomarkers have the potential to aid in understanding recovery following SCI. This proof-of-principle study determined: (a) If temporal changes in blood metabolites reflect the extent of recovery following SCI; (b) whether changes in blood-derived metabolites serve as prognostic indicators of patient outcomes based on the spinal cord independence measure (SCIM); and (c) whether metabolic pathways involved in recovery processes may provide insights into mechanisms that mediate neural damage and repair. Morning blood samples were collected from male complete and incomplete SCI patients (n = 7) following injury and at 6 months post-injury. Multivariate analyses were used to identify changes in serum metabolic profiles and were correlated to clinical outcomes. Specifically, acetyl phosphate, 1,3,7-trimethyluric acid, 1,9-dimethyluric acid, and acetic acid significantly related to SCIM scores. These preliminary findings suggest that specific metabolites may serve as proxy measures of the SCI phenotype and prognostic markers of recovery. Thus, serum metabolite analysis combined with machine learning holds promise in understanding the physiology of SCI and aiding in prognosticating outcomes following injury.

Pituitary dysfunction, specifically growth hormone (GH) deficiency, can occur following traumatic brain injury. Our objective was to characterize the prevalence of GH deficiency (GHD) testing and response to recombinant human GH (rhGH) treatment in adults with persistent symptoms following mild traumatic brain injury (mTBI) referred for assessment of pituitary dysfunction. A retrospective chart review was conducted of patients seen at an outpatient brain injury clinic with a diagnosis of mTBI and persistent post-concussive symptoms who were referred to endocrinology. Clinical assessments of symptoms were collected. Investigations and results of GHD were collected, including initiation of rhGH treatment and treatment response. Of the 253 patients seen in both brain injury and endocrinology clinics, 97 with mTBI were referred for investigation of pituitary dysfunction and 73 (75%) had dynamic testing for assessment of GHD. Of the 26 individuals diagnosed with GHD, 23 (88%) started rhGH. GH therapy was inconsistently offered based on interpretation of GH dynamic testing results. Of those who started rhGH, 18 (78%) had a useful treatment response. This study suggests that clinical management of these patients is varied, highlighting a need for clear guidelines for the diagnosis and management of GHD following mTBI.

Current assessment tools for sport-related concussion are limited by a reliance on subjective interpretation and patient symptom reporting. Robotic assessments may provide more objective and precise measures of neurological function than traditional clinical tests. To determine the reliability of assessments of sensory, motor and cognitive function conducted with the KINARM end-point robotic device in young adult elite athletes. Sixty-four randomly selected healthy, young adult elite athletes participated. Twenty-five individuals (25 M, mean age±SD, 20.2±2.1 years) participated in a within-season study, where three assessments were conducted within a single season (assessments labeled by session: S1, S2, S3). An additional 39 individuals (28M; 22.8±6.0 years) participated in a year-to-year study, where annual pre-season assessments were conducted for three consecutive seasons (assessments labeled by year: Y1, Y2, Y3). Forty-four parameters from five robotic tasks (Visually Guided Reaching, Position Matching, Object Hit, Object Hit and Avoid, and Trail Making B) and overall Task Scores describing performance on each task were quantified. Test-retest reliability was determined by intra-class correlation coefficients (ICCs) between the first and second, and second and third assessments. In the within-season study, ICCs were ≥0.50 for 68% of parameters between S1 and S2, 80% of parameters between S2 and S3, and for three of the five Task Scores both between S1 and S2, and S2 and S3. In the year-to-year study, ICCs were ≥0.50 for 64% of parameters between Y1 and Y2, 82% of parameters between Y2 and Y3, and for four of the five Task Scores both between Y1 and Y2, and Y2 and Y3. Overall, the results suggest moderate-to-good test-retest reliability for the majority of parameters measured by the KINARM robot in healthy young adult elite athletes. Future work will consider the potential use of this information for clinical assessment of concussion-related neurological deficits.

IntroductionPersistent symptoms after mild traumatic brain injury (mTBI) negatively affect daily functioning and quality of life. Fear avoidance behaviour, a coping style in which people avoid or escape from activities or situations that they expect will exacerbate their symptoms, maybe a particularly potent and modifiable risk factor for chronic disability after mTBI. This study will evaluate the efficacy of graded exposure therapy (GET) for reducing persistent symptoms following mTBI, with two primary aims: (1) To determine whether GET is more effective than usual care; (2) to identify for whom GET is the most effective treatment option, by evaluating whether baseline fear avoidance moderates differences between GET and an active comparator (prescribed aerobic exercise). Our findings will guide evidence-based care after mTBI and enable better matching of mTBI patients to treatments.Methods and analysisWe will conduct a multisite randomised controlled trial with three arms. Participants (n=220) will be recruited from concussion clinics and emergency departments in three Canadian provinces and randomly assigned (1:2:2 ratio) to receive enhanced usual care, GET or prescribed aerobic exercise. The outcome assessment will occur remotely 14–18 weeks following baseline assessment, after completing the 12-week treatment phase. The primary outcome will be symptom severity (Rivermead Post-concussion Symptoms Questionnaire).Ethics and disseminationInformed consent will be obtained from all participants. All study procedures were approved by the local research ethics boards (University of British Columbia Clinical Research Ethics Board, University of Calgary Conjoint Health Research Ethics Board, University Health Network Research Ethics Board—Panel D). Operational approvals were obtained for Vancouver Coastal Health Research Institute and Provincial Health Services Authority. If GET proves effective, we will disseminate the GET treatment manual and present instructional workshops for clinicians.Trial registration numberClinicalTrials.gov #NCT05365776

Background Persistent post-concussive symptoms (PPCS) affect up to 30% of individuals following mild traumatic brain injury. PPCS frequently includes exercise intolerance. Sub-symptom threshold aerobic exercise has been proposed as a treatment option for symptom burden and exercise intolerance in this population. The primary aim of this study is to evaluate whether a progressive, sub-symptom threshold aerobic exercise program can alleviate symptom burden in adults with PPCS. Methods Fifty-six adults (18–65) with PPCS (>3mos-5 yrs) will be randomized into two groups: an immediate start 12-week aerobic exercise protocol (AEP) or delayed start 6-week placebo-like stretching protocol (SP), followed by AEP. Aerobic or stretching activities will be completed 5x/week for 30 mins during the intervention. Online daily activity logs will be submitted. Exercise prescriptions for the AEP will be 70–80% of heart rate at the point of symptom exacerbation achieved on a treadmill test with heart rate monitoring. Exercise prescription will be updated every 3-weeks with a repeat treadmill test. The Rivermead Post-concussion Symptom Questionnaire will be the primary outcome measure at 6 and 12-weeks of intervention. Secondary outcomes include assessments of specific symptoms (headache, quality of life, mood, anxiety, fatigue, dizziness, sleep parameters, daytime sleepiness) in addition to blood biomarkers and magnetic resonance imaging and spectroscopy data for quantification of brain metabolites including γ-aminobutyric acid (GABA), glutathione, glutamate and N-acetyl aspartate (NAA) all measured at 6 and 12-weeks of intervention. Discussion This trial will evaluate the use of aerobic exercise as an intervention for adults with PPCS, thus expanding our knowledge of this treatment option previously studied predominantly for adolescent sport-related concussion. Trial registration ClinicalTrials.gov - NCT03895450 (registered 2019-Feb-11).

Background Growth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population. Methods We conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z-score for determining GHD by GST or ITT. Results Sixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 μg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility. Conclusion Baseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve.

The neuropathological sequelae of stroke and subsequent recovery are incompletely understood. Here, we investigated the metabolic dynamics following stroke to advance the understanding of the pathophysiological mechanisms orchestrating stroke recovery. Using a nuclear magnetic resonance (NMR)-driven metabolomic profiling approach for urine samples obtained from a clinical group, the objective of this research was to (1) identify novel biomarkers indicative of severity and recovery following stroke, and (2) uncover the biochemical pathways underlying repair and functional recovery after stroke. Urine samples and clinical stroke assessments were collected during the acute (2–11 days) and chronic phases (6 months) of stroke. Using a 700 MHz 1H NMR spectrometer, metabolomic profiles were acquired followed by a combination of univariate and multivariate statistical analyses, along with biological pathway analysis and clinical correlations. The results revealed changes in phenylalanine, tyrosine, tryptophan, purine, and glycerophospholipid biosynthesis and metabolism during stroke recovery. Pseudouridine was associated with a change in post-stroke motor recovery. Thus, NMR-based metabolomics is able to provide novel insights into post-stroke cellular functions and establish a foundational framework for future investigations to develop targeted therapeutic interventions, advance stroke diagnosis and management, and enhance overall quality of life for individuals with stroke.