Search Results (23)

Exposure to blast waves without kinetic, penetrating, thermal, or toxic components causes a distinct form of traumatic brain injury, termed primary blast-induced TBI (pbTBI). Clinical manifestations of pbTBI span a wide spectrum, ranging from life-threatening intracranial hemorrhage, hyperemia, and delayed cerebral edema to mild and transient neurological symptoms without detectable structural abnormalities on routine imaging. At the mild end of the spectrum, symptoms after a single exposure may resolve quickly, yet repeated exposures—even at very low levels, termed “subconcussive”—can develop into post-concussive syndrome (PCS) or persistent post-concussive symptoms (PPCS) in a subset of individuals. Despite extensive studies, the molecular pathobiology linking primary blast exposure to delayed and sometimes chronic neurobehavioral deficits remains incompletely understood. A mechanistic framework connecting blast-wave physics to biomechanics to biological vulnerability may therefore help define exposure hazards, interpret clinical symptomatology, and guide diagnostic and therapeutic development. This review summarizes the physics of primary blast waves, the resulting biomechanical responses, and candidate biological substrates, emphasizing structures and interfaces with distinct acoustic impedances across anatomical, tissue, cellular, and molecular scales. We synthesize evidence supporting the hypothesis that the cerebral vasculature and endothelial cells represent critically vulnerable substrates of primary blast-wave injury, in part because the vascular tree constitutes the brain’s largest and most widely distributed interface between compartments with different acoustic impedances. Across experimental and human studies, endothelial stress, vascular injury, and downstream neuroinflammation emerge as convergent molecular responses to primary blast exposure. Temporal dynamics are central to understanding pbTBI because many blast-induced processes unfold in sequential phases. These observations support conceptualizing pbTBI as a condition characterized by prominent cerebrovascular injury of varying severity with secondary consequences for neuronal signaling, network function, and behavior. Within this framework, cerebrovascular and neurovascular unit (NVU) dysfunction provides a parsimonious bridge between primary blast-wave exposure and chronic symptom trajectories, where vascular pathology may offer more accessible therapeutic targets than neuronal injury. Key knowledge gaps include identifying which physical component(s) of the blast are most injurious, establishing biologically meaningful dose–response relationships at molecular and physiological levels, and defining windows of vulnerability during recovery that are relevant to repeated exposures. Addressing these gaps is essential for refining safety protocols, improving diagnostic specificity through mechanism-informed biomarkers, and developing evidence-based molecular and vascular therapeutic targets for pbTBI-associated conditions. Progress will require integrating waveform-aware dosimetry with longitudinal physiological and molecular monitoring across both preclinical and human cohorts. Such integration offers a practical path toward translating blast physics into actionable medical guidance for prevention, triage, and recovery management. Full article

Background: Sex-based variations in brain structure, hormonal balance, and neurochemistry may influence symptom presentation and recovery after mild traumatic brain injury (mTBI). This systematic review investigated sex-related differences in mTBI severity, symptoms, and recovery outcomes across different injury mechanisms. Methods: This review followed PRISMA 2020 guidelines and was registered with PROSPERO (CRD420251011379). Searches were conducted in PubMed, SPORTDiscus, Web of Science, and Scopus for articles published between 2000 and 2024. Eligible studies included adults (≥18 years) diagnosed with mTBI or concussion (Glasgow Coma Scale 13–15) with quantifiable outcome data for both sexes. Data extraction and quality assessment followed the JBI critical appraisal tools. Results: Forty-one studies involving 15,656 participants (8671 males; 6985 females) met the inclusion criteria. Female participants reported a greater symptom burden, higher pain intensity, and longer recovery times for gait abnormalities and return to activity compared with males. Neuroimaging studies showed more extensive white matter alterations in females, whereas males displayed greater reductions in cerebral blood flow. Cognitive and neurosensory outcomes revealed poorer cognitive performance, slower reaction times, and higher rates of vestibular–ocular and visual abnormalities in females. A limited number of studies explored electrophysiological measures, indicating sex-based differences in early brain responses to emotional stimuli. Conclusions: Sex plays an important role in symptom presentation and recovery after mTBI. Female patients demonstrate heightened vulnerability across several clinical domains, likely due to biological and neurochemical differences. Recognising these sex-specific patterns can support more targeted diagnostic and rehabilitation strategies. Future research should further explore the structural and biochemical mechanisms underlying these differences to improve precision in mTBI management. Full article

Mild traumatic brain injury (mTBI) frequently causes subtle brain changes that are difficult to detect with conventional diagnostic approaches. In this exploratory pilot study, we combined tri-exponential intravoxel incoherent motion (IVIM) and pseudocontinuous arterial spin labeling (pCASL) MRI with Multimodal Canonical Correlation Analysis and joint independent component analysis (mCCA+jICA) to identify imaging signatures distinguishing mTBI patients from healthy controls (HCs) and their associations with clinical function. Cerebral blood flow (CBF) and IVIM-derived metrics were extracted from 90 brain regions in 19 mTBI patients and 24 HCs, and multivariate components were identified using mCCA+jICA. Two independent components (IC2, IC15) showed group differences at the uncorrected level (p < 0.05) but did not survive false discovery rate (FDR) correction. IC2 correlated positively with CBF and perfusion fraction (F_p) and negatively with tissue diffusion fraction (F_s), consistent with reduced vascular integrity in mTBI, while IC15 showed similar trends. One component correlated with Glasgow Outcome Scale–Extended (GOS-E) scores (uncorrected p = 0.046). Although this study is preliminary and limited by a small sample size, our findings suggest that mTBI is associated with perfusion and microstructural alterations, particularly in subcortical regions, and demonstrate the potential value of combining IVIM and ASL within multivariate fusion frameworks to reveal patterns not captured by single-modality approaches. Full article

Background: Sport-related concussion is common in rugby union, yet female players remain underrepresented in research. This study examined seasonal changes in cerebral oxygenation, cardiac function, and concussion symptomology in adult female rugby players, and explored acute physiological responses following a single documented concussion. Methods: A total of 29 adult females (19 amateur rugby, 10 control) completed pre-, mid-, and end-season assessments. Measures included functional near-infrared spectroscopy (fNIRS) of the pre-frontal cortex, seismocardiography (SCG)-derived cardiac timing indices, and Sport Concussion Assessment Tool 6 (SCAT6). Group and time effects were analysed using general linear models and statistical parametric mapping. Typical error (TE) and its 90% confidence intervals (90% CI) were used to determine meaningful changes post-concussion. Results: Rugby players reported more SCAT6 symptoms (number: p = 0.006, η²_p = 0.23; severity: p = 0.020, η²_p = 0.17). They also had shorter systolic time (p = 0.002, η²_p = 0.19) and higher twist force values (p = 0.014, η²_p= 0.21) than controls. fNIRS revealed higher right-hemisphere oxyhaemoglobin (ΔO₂Hb) responses for both tasks (ps < 0.001, η²_p = 0.77 and η²_p = 0.80) and lower activation in specific prefrontal channels. No seasonal changes occurred in global oxygenation or frequency band activity. In the exploratory single-concussion case, symptomology, SCG twist force, ΔO₂Hb, and cardiac band power exceeded TE and its 90% CI at 5 days post-injury. Conclusions: The multimodal approach detected stable group-level physiology alongside localised cortical and cardiac differences, and acute changes following concussion. While these results highlight the potential of combined fNIRS and SCG measures to capture physiological disturbances, the small sample size and single-concussion case necessitate cautious interpretation. Further validation in larger, longitudinal cohorts is required before any biomarker utility can be inferred. Full article

Sports-associated traumatic brain injury is emerging as an under-recognized driver of acute and chronic cardiovascular diseases. Larger population-based studies show that individuals with moderate-to-severe traumatic brain injury experience up to a two-fold excess risk of incident hypertension, coronary artery disease, myocardial infarction, and stroke that persists for at least a decade. Among former professional American-style football players, a higher lifetime concussion burden is uniquely related to a more atherogenic cardiometabolic profile and greater long-term stroke risk. Mechanistically, an acute “sympathetic storm” triggered by cerebral injury provokes catecholamine surges, endothelial dysfunction, and myocardial stunning, manifesting as neurogenic stunned myocardium or Takotsubo-like cardiomyopathy and malignant arrhythmias. Sub-acute to chronic phases are characterized by persistent autonomic imbalance, reflected by reduced heart-rate variability and impaired baroreflex sensitivity weeks to months after concussion, coupled with neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and lifestyle changes that accelerate atherosclerosis. The interplay of these pathways accounts for the elevated burden of cardiovascular disease observed long after neurological function has been restored. Despite robust evidence linking TBI to adverse cardiac outcomes, contemporary sports–cardiology risk stratification prioritizes hemodynamic load, genetics, and performance-enhancing substances, largely overlooking brain injury history. This review integrates epidemiological, clinical, and mechanistic data to (i) delineate acute neurocardiac complications secondary of sports-related traumatic brain injury, (ii) synthesize evidence for chronic cardiovascular risk, (iii) highlight emerging autonomic and inflammatory biomarkers, and (iv) propose surveillance and therapeutic strategies, ranging from heart-rate-variability-guided return-to-play decisions to aggressive cardiometabolic risk modification aiming to mitigate long-term morbidity in this athletic population. By framing sports-related traumatic brain injury as a modifiable cardiovascular risk factor, we aim to foster interdisciplinary collaboration among neurologists, cardiologists, and sports medicine practitioners, ultimately improving both neurological and cardiovascular outcomes across the athlete’s lifespan. Full article

A properly functioning capillary microcirculation is essential for sufficient oxygen and nutrient delivery to the central nervous system. The physical mechanisms governing the transport of red blood cells (RBCs) inside the narrow and irregularly shaped capillary lumen are complex, but understanding them is essential for identifying the root causes of neurological disorders like cerebral ischemia, Alzheimer’s disease, and other neurodegenerative conditions such as concussion and cognitive dysfunction in systemic inflammatory conditions. In this work, we conducted numerical simulations of three-dimensional capillary models, which were acquired ex vivo from a mouse retina, to characterize RBC transport. We show how the spatiotemporal velocity of the RBCs deviates in realistic capillaries and equivalent cylindrical tubes, as well as how this profile is affected by hematocrit and red cell distribution width (RDW). Our results show a previously unprecedented level of RBC velocity fluctuations in capillaries that depends on the geometric features of different confinement regions and a capillary circularity index $\left(I_{cc}\right)$ that represents luminal irregularity. This velocity fluctuation is aggravated by high hematocrit conditions, without any further effect on RDW. These results can provide a better understanding of the underlying mechanisms of pathologically high capillary transit time heterogeneity that results in microcirculatory dysfunction. Full article

Traumatic brain injury (TBI), which is a global public health concern, can take various forms, from mild concussions to blast injuries, and each damage type has a particular mechanism of progression. However, TBI is a condition with complex pathophysiology and heterogenous clinical presentation, which makes it difficult to model for in vitro and in vivo studies and obtain relevant results that can easily be translated to the clinical setting. Accordingly, the pharmacological options for TBI management are still scarce. Since a wide spectrum of processes, such as glucose homeostasis, food intake, body temperature regulation, stress response, neuroprotection, and memory, were demonstrated to be modulated after delivering glucagon-like peptide 1 (GLP-1) or GLP-1 receptor agonists into the brain, we aimed to speculate on their potential role in TBI management by comprehensively overviewing the preclinical and clinical body of evidence. Based on promising preclinical data, GLP-1 receptor agonists hold the potential to extend beyond metabolic disorders and address unmet needs in neuroprotection and recovery after TBI, but also other types of central nervous system injuries such as the spinal cord injury or cerebral ischemia. This overview can lay the basis for tailoring new research hypotheses for future in vitro and in vivo models in TBI settings. However, large-scale clinical trials are crucial to confirm their safety and efficacy in these new therapeutic applications. Full article

Mild traumatic brain injuries (mTBIs) are highly prevalent and can lead to chronic behavioral and cognitive deficits often associated with the development of neurodegenerative diseases. Oxidative stress and formation of reactive oxygen species (ROS) have been implicated in mTBI-mediated axonal injury and pathogenesis. However, the underlying mechanisms and contributing factors are not completely understood. In this study, we explore these pathogenic mechanisms utilizing a murine model of repetitive mTBI (r-mTBI) involving five closed-skull concussions in young adult C57BL/6J mice. We observed a significant elevation of Na⁺/H⁺ exchanger protein (NHE1) expression in GFAP⁺ reactive astrocytes, IBA1⁺ microglia, and OLIG2⁺ oligodendrocytes across various brain regions (including the cerebral cortex, corpus callosum, and hippocampus) after r-mTBI. This elevation was accompanied by astrogliosis, microgliosis, and the accumulation of amyloid precursor protein (APP). Mice subjected to r-mTBI displayed impaired motor learning and spatial memory. However, post-r-mTBI administration of a potent NHE1 inhibitor, HOE642, attenuated locomotor and cognitive functional deficits as well as pathological signatures of gliosis, oxidative stress, axonal damage, and white matter damage. These findings indicate NHE1 upregulation plays a role in r-mTBI-induced oxidative stress, axonal damage, and gliosis, suggesting NHE1 may be a promising therapeutic target to alleviate mTBI-induced injuries and restore neurological function. Full article

Introduction: Concussion is known to cause transient autonomic and cerebrovascular dysregulation that generally recovers; however, few studies have focused on individuals with an extensive concussion history. Method: The case was a 26-year-old male with a history of 10 concussions, diagnosed for bipolar type II disorder, mild attention-deficit hyperactivity disorder, and a history of migraines/headaches. The case was medicated with Valproic Acid and Escitalopram. Sensor-based baseline data were collected within six months of his injury and on days 1–5, 10, and 14 post-injury. Symptom reporting, heart rate variability (HRV), neurovascular coupling (NVC), and dynamic cerebral autoregulation (dCA) assessments were completed using numerous biomedical devices (i.e., transcranial Doppler ultrasound, 3-lead electrocardiography, finger photoplethysmography). Results: Total symptom and symptom severity scores were higher for the first-week post-injury, with physical and emotional symptoms being the most impacted. The NVC response showed lowered activation in the first three days post-injury, while autonomic (HRV) and autoregulation (dCA) were impaired across all testing visits occurring in the first 14 days following his concussion. Conclusions: Despite symptom resolution, the case demonstrated ongoing autonomic and autoregulatory dysfunction. Larger samples examining individuals with an extensive history of concussion are warranted to understand the chronic physiological changes that occur following cumulative concussions through biosensing devices. Full article

Concussion, caused by a rotational acceleration/deceleration injury mild enough to avoid structural brain damage, is insufficiently captured in recent preclinical models, hampering the relation of pathophysiological findings on the cellular level to functional and behavioral deficits. We here describe a novel model of unrestrained, single vs. repetitive concussive brain injury (CBI) in male C56Bl/6j mice. Longitudinal behavioral assessments were conducted for up to seven days afterward, alongside the evaluation of structural cerebral integrity by in vivo magnetic resonance imaging (MRI, 9.4 T), and validated ex vivo by histology. Blood–brain barrier (BBB) integrity was analyzed by means of fluorescent dextran- as well as immunoglobulin G (IgG) extravasation, and neuroinflammatory processes were characterized both in vivo by positron emission tomography (PET) using [¹⁸F]DPA-714 and ex vivo using immunohistochemistry. While a single CBI resulted in a defined, subacute neuropsychiatric phenotype, longitudinal cognitive testing revealed a marked decrease in spatial cognition, most pronounced in mice subjected to CBI at high frequency (every 48 h). Functional deficits were correlated to a parallel disruption of the BBB, (R² = 0.29, p < 0.01), even detectable by a significant increase in hippocampal uptake of [¹⁸F]DPA-714, which was not due to activation of microglia, as confirmed immunohistochemically. Featuring a mild but widespread disruption of the BBB without evidence of macroscopic damage, this model induces a characteristic neuro-psychiatric phenotype that correlates to the degree of BBB disruption. Based on these findings, the BBB may function as both a biomarker of CBI severity and as a potential treatment target to improve recovery from concussion. Full article

Introduction: Since verbal memory and visual processing transpire within analogous cerebral regions, this study assessed (i) if a visual function can predict verbal memory performance. It also hypothesized whether neurocognitive (e.g., ImPACT) tests focusing on the Visual Memory and Cognitive Efficacy Index will predict Verbal Memory scores and (ii) if vision metrics and age can identify individuals with a history of concussion. Finally, it also hypothesized that King–Devick and near point of convergence scores alongside age considerations will identify candidates with a prior reported history of concussion. Materials and methods: This observational cohort assessed 25 collegiate ice hockey players prior to the competitive season considering age (19.76 ± 1.42 years) and BMI (25.9 ± 3.0 kg/cm²). Hypothesis 1 was assessed using a hierarchical (sequential) multiple regression analysis, assessing the predictive capacity of Visual Memory and Cognitive Efficacy Index scores in relation to Verbal Memory scores. Hypothesis 2 utilized a binomial logistic regression to determine if King–Devick and near point of convergence scores predict those with a prior history of concussion. Results: Hypothesis 1 developed two models, where Model 1 included Visual Memory as the predictor, while Model 2 added the Cognitive Efficacy Index as a predictor for verbal memory scores. Model 1 significantly explained 41% of the variance. Results from Model 2 suggest that the Cognitive Efficacy Index explained an additional 24.4%. Thus, Model 2 was interpreted where only the Cognitive Efficacy Index was a significant predictor (p = 0.001). For every 1 unit increase in the Cognitive Efficacy Index, Verbal Memory increased by 41.16. Hypothesis 2’s model was significant, accounting for 37.9% of the variance in those with a history of concussion. However, there were no significant unique predictors within the model as age (Wald = 1.26, p = 0.261), King–Devick (Wald = 2.31, p = 0.128), and near point of convergence (Wald = 2.43, p = 0.119) were not significant predictors individually. Conclusions: The conflicting findings of this study indicate that baseline data for those with a history of concussion greater than one year may not be comparable to the same metrics during acute concussion episodes. Young athletes who sustain a concussion may be able to overcompensate via the visual system. Future prospective studies with larger sample sizes are required using the proposed model’s objective metrics. Full article

This review explores the application of the conservative management model for pain to sports-related concussions (SRCs), framing concussions as a distinct form of pain syndrome with a pathophysiological foundation in central sensitization. Drawing parallels with proven pain management models, we underscore the significance of a proactive approach to concussion management. Recognizing concussions as a pain syndrome allows for the tailoring of interventions in alignment with conservative principles. This review first covers the epidemiology and controversies surrounding prolonged concussion recovery and persistent post-concussion symptoms (PPCS). Next, the pathophysiology of concussions is presented within the central sensitization framework, emphasizing the need for early intervention to mitigate the neuroplastic changes that lead to heightened pain sensitivity. Five components of the central sensitization process specific to concussion injuries are highlighted as targets for conservative interventions in the acute period: peripheral sensitization, cerebral metabolic dysfunction, neuroinflammation, glymphatic system dysfunction, and pain catastrophizing. These proactive interventions are emphasized as pivotal in accelerating concussion recovery and reducing the risk of prolonged symptoms and PPCS, in line with the philosophy of conservative management. Full article

Sport-related concussions (SRC) are characterized by impaired autonomic control. Heart rate variability (HRV) offers easily obtainable diagnostic approaches to SRC-associated dysautonomia, but studies investigating HRV during sleep, a crucial time for post-traumatic cerebral regeneration, are relatively sparse. The aim of this study was to assess nocturnal HRV in athletes during their return to sports (RTS) after SRC in their home environment using wireless wrist sensors (E4, Empatica, Milan, Italy) and to explore possible relations with clinical concussion-associated sleep symptoms. Eighteen SRC athletes wore a wrist sensor obtaining photoplethysmographic data at night during RTS as well as one night after full clinical recovery post RTS (>3 weeks). Nocturnal heart rate and parasympathetic activity of HRV (RMSSD) were calculated and compared using the Mann–Whitney U Test to values of eighteen; matched by sex, age, sport, and expertise, control athletes underwent the identical protocol. During RTS, nocturnal RMSSD of SRC athletes (Mdn = 77.74 ms) showed a trend compared to controls (Mdn = 95.68 ms, p = 0.021, r = −0.382, p adjusted using false discovery rate = 0.126) and positively correlated to “drowsiness” (r = 0.523, p = 0.023, p adjusted = 0.046). Post RTS, no differences in RMSSD between groups were detected. The presented findings in nocturnal cardiac parasympathetic activity during nights of RTS in SRC athletes might be a result of concussion, although its relation to recovery still needs to be elucidated. Utilization of wireless sensors and wearable technologies in home-based settings offer a possibility to obtain helpful objective data in the management of SRC. Full article

(1) Background: Cerebral autoregulation is altered during acute mild traumatic brain injury, or concussion. However, it is unknown how a history of concussion can impact cerebral haemodynamic activity during a task that elicits an autoregulatory response. (2) Methods: We assessed cerebral haemodynamic activity in those with a history of three or more concussions. The study included 44 retired athletes with concussion history and 25 control participants. We recorded participants’ relative changes in right and left pre-frontal cortex oxygenation collected by near-infrared spectroscopy and continuous beat-to-beat blood pressure measured by finger photoplethysmography. Participants completed a 5-min seated rest followed by a 5-min repeated squat (10-s) stand (10-s) maneuver (0.05 Hz) to elicit a cerebral autoregulatory response. Wavelet transformation was applied to the collected signals, allowing separation into cardiac interval I (0.6 to 2 Hz), respiratory interval II (0.145 to 0.6 Hz), and smooth muscle cell interval III (0.052 to 0.145 Hz). (3) Results: Significant increases at cardiac interval I were found for the wavelet amplitude of oxy-haemoglobin and haemoglobin difference at the right pre-frontal cortex. No significant difference was found at the left pre-frontal cortex or the blood pressure wavelet amplitudes. (4) Conclusions: Contributions from cardiac activity to the pre-frontal cortex oxygenation are elevated when eliciting dynamic cerebral autoregulation in those with a history of three or more concussions. Full article

This study reviewed traumatic axonal injury (TAI) in patients with concussion. Concussion refers to transient changes in the neurological function of the brain resulting from head trauma that should not involve any organic brain injury. On the other hand, TAI has been reported in autopsy studies of the human brain and histopathological studies of animal brains following concussion before the development of diffusion tensor imaging (DTI). The diagnosis of TAI in live patients with concussion is limited because of the low resolution of conventional brain magnetic resonance imaging. Since the first study by Arfanakis et al. in 2002, several hundred studies have reported TAI in patients with concussion using DTI. Furthermore, dozens of studies have demonstrated TAI using diffusion tensor tractography for various neural tracts in individual patients with concussion. Hence, DTI provides valuable data for the diagnosis of TAI in patients with concussion. Nevertheless, the confirmation of TAI in live patients with concussion can be limited because a histopathological study via a brain biopsy is required to confirm TAI. Accordingly, further studies for a diagnostic approach to TAI using DTI without a histopathological test in individual patients with concussion will be necessary in the clinical field. Full article