Search Results (2,112)

Background: Mild traumatic brain injury (mTBI) is frequently followed by persistent cognitive, affective, and sensory complaints despite unremarkable conventional structural imaging. Resting-state functional MRI (rs-fMRI) has been increasingly employed to detect subtle alterations in large-scale brain networks. However, variability in analytical approaches and the potential influence of neurovascular factors complicate interpretation of BOLD-derived connectivity findings. Objective: This study provides a focused, evidence-informed synthesis integrating umbrella review principles with a targeted narrative analysis of recent high-quality rs-fMRI studies in mild traumatic brain injury (mTBI). Rather than a comprehensive systematic review, the aim was to identify convergent patterns of network dysfunction while critically examining methodological constraints, including neurovascular confounds and variability in analytical approaches. Conclusions: This synthesis supports a network-level model of mTBI characterized by distributed connectivity disturbances. However, given the limited number of eligible studies and substantial methodological heterogeneity, findings should be interpreted as qualitative convergence rather than quantitative generalization. Future longitudinal, multimodal, and standardized imaging approaches are required to clarify the translational relevance of rs-fMRI findings. Full article

Background: Chronic critical illness (CCI) following acute brain injury involves persistent immune dysfunction, yet its genetic determinants remain unclear. We investigated whether the rate of T-cell receptor excision circle (TREC) depletion—a proposed marker of adaptive homeostatic resilience—is associated with the burden of rare damaging genetic variants. Methods: Whole-exome sequencing (WES) was performed on a cohort of 84 patients (64 with traumatic brain injury, 20 with stroke). In a longitudinal sub-cohort (n = 27), patients were stratified into quartiles (Q1–Q4) based on the slope of their TREC trajectories. ‘Qualifying variants’ (QVs) were defined using strict rarity (gnomAD allele frequency ≤ 0.001) and pathogenicity criteria. Gene-level burden (collapsing) analysis and permutation-based statistical testing (10,000 iterations) were employed to evaluate genetic enrichment in the extreme quartiles. Results: While baseline TREC levels were strictly age dependent (p < 0.0001), the rate of change (TREC slope) was age independent. Rapid TREC decline (Q1) correlated with significantly higher final SOFA scores (p = 0.001) and neutrophil-to-lymphocyte ratios (p = 0.020). Rare variant burden analysis revealed that Q1 patients were significantly more likely to harbor QVs in immune-related genes compared to the Q4 recovery group (odds ratio = 8.25; permutation p = 0.016). Patients with rapid decline were enriched for QVs in putative core “housekeeping” pathways essential for T-cell maintenance and DNA repair (e.g., ERCC3, FANCM), whereas variants in recovering patients were restricted to peripheral effector or structural pathways. Conclusions: Our findings suggest, as a conceptual framework, that an individual’s ability to maintain T-cell homeostasis during critical illness is influenced by their underlying genetic buffering capacity. We propose a hypothetical “two-hit” framework where physiological stress unmasks pre-existing fragilities in core homeostatic pathways—potentially reflecting a state of functional haploinsufficiency under extreme proliferative demand—leading to accelerated immune exhaustion. These results position the TREC slope as a dynamic, age-independent biomarker of genomic resilience in the ICU. All findings are exploratory and hypothesis generating. Full article

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

Recent paradigms in traumatic brain injury have transitioned from focal-lesion models to an emphasis on diffuse axonal injury and white matter disruption as the primary drivers of cognitive morbidity. This selective review frames information processing speed as the functional signature of this connectivity loss. While processing speed is often theorized as a “cognitive bottleneck” that constrains higher-order functions, we identify critical methodological and conceptual pitfalls in the existing literature. Specifically, we argue that current research is frequently confounded by: (1) measurement impurity, where tasks like the SDMT and TMT-B recruit executive and mnemonic variance; (2) circularity, where speed measures are used to predict time-dependent outcomes; and (3) the neglect of speed–accuracy trade-offs, which may mask volitional cautiousness as neurobiological incapacity. To resolve these challenges, we offer evidence-based recommendations for the clinical setting, including the integration of construct-pure chronometric measures and dual-scoring protocols. We conclude that because white matter integrity functions as a rate-limiting substrate, processing speed must be prioritized as a primary target in early neurorehabilitation. By isolating processing speed from focal-driven deficits, clinicians can more accurately map the path from microstructural disruption to functional recovery. Recognizing this infrastructure is essential to understanding the full scope of cognitive consequences. Full article

Traumatic brain injury (TBI) is one of the leading causes of acquired epilepsy, with a significant proportion of patients developing post-traumatic epilepsy (PTE) even months or years after the initial injury. The identification of reliable imaging biomarkers able to predict epileptogenesis remains a major clinical challenge. In recent years, diffusion-weighted imaging (DWI) and structural connectome analysis have emerged as promising tools to investigate brain network alterations associated with late seizure development. Machine learning approaches may further support the detection of predictive patterns in complex neuroimaging data. The goal of this study is to perform a binary classification between seizure-free and late seizure-affected patients following TBI, with a specific focus on the identification of the anatomical regions potentially connected with late seizure development. A dataset of 59 diffusion weighted images (DWI) scans from the EpiBioS4Rx project, including 42 seizure-free and 17 late seizure-affected TBI patients, was analyzed. A Random Forest classification algorithm was applied, incorporating network feature importance based on the Gini index to investigate model’s decisions and allow a clinical interpretation. The model reported a 69% ± 0.03 accuracy for discrimination and a 73% AUC ± 0.05. Despite the limited and imbalanced nature of the dataset, and the fact that the performance does not significantly exceed chance once all data-dependent steps are taken into account, our approach allows us to achieve accurate classification results compared to the literature and to identify brain regions potentially associated with epileptogenesis. Full article

Background: Traumatic brain injury (TBI) remains a major cause of neurological morbidity and mortality. Mitochondria, being embedded as one of the key organelles disrupted after injury, play a central role in regulating neuronal metabolism, oxidative balance, and cell survival, hence the growing interest in their role after TBI. Methods: We present a narrative review of the literature on mitochondrial dysfunction after TBI to highlight the potential role in diagnosis, monitoring, prognostication and treatment strategies. Following SANRA guidelines we conducted a synthesis of 159 selected references published between 1997 and 2026, including 70 references published from 2020 onward. Results: Mitochondrial dysfunction underpins bioenergetic failure through the impairment of critical regulatory pathways, including oxidative phosphorylation, dysregulated reactive oxygen species production, and dysregulated calcium handling. These changes trigger downstream processes of oxidative damage, epigenetic and proteomic remodeling, and activation of regulated cell death pathways such as apoptosis, necroptosis, and ferroptosis in the context of an inflammatory milieu. As such, mitochondrial-derived molecules (such as mitochondrial DNA and microRNA) are emerging candidate biomarkers of TBI severity and prognosis. Additionally, therapeutic approaches under investigation include inhibition of the mitochondrial permeability transition pore, mitigation of mitochondrial oxidative stress using targeted antioxidants, restoration of NAD⁺-dependent metabolic pathways, and metabolic support through ketogenic interventions. Conclusions: Mitochondrial biology is advancing our understanding of TBI and offers a promising framework for improving its management. Full article

Background: Mild traumatic brain injuries (mTBIs) are a significant public health concern in the US. Understanding incidence and demographic patterns is essential for developing targeted prevention and intervention strategies. The most recent study using national healthcare records to examine incidence utilized data from 2016, highlighting the need for updated estimates that reflect current trends. Methods: The MarketScan^® Database was used for this study which includes person-specific clinical utilization, expenditures, and enrollment across different services. A query for mTBIs (S06.0x.xx) or post-concussion syndrome (F07.89) from January–December 2023 was performed for patients aged 0–64. Patients with the same diagnosis codes for the prior 12 months (i.e., chronic diagnosis), moderate to severe TBIs (S06.2–9), skull fractures (S02.xx), and/or brain hemorrhages (S06.3x) were excluded. Results: Out of 11,737,855 insured members with data in 2023, 43,213 new mTBIs were recorded (incidence rate = 0.37%), with the highest rate in adolescents (incidence rate = 1.27%). From the ages of 0–14 years, males had a higher incidence of concussion, but from 15 to 65 years, females had a higher incidence. Minimal differences were seen between urban and rural zip codes. Conclusions: Concussion incidence in adolescents is higher than other age groups, which may reflect increased participation in sports or heightened vulnerability during development. Males had a higher incidence than females during childhood, but females did later in life. These differences may reflect true disparities in injury risk, variations in reporting patterns, or a combination of both. Further research is warranted to understand the underlying mechanisms and to inform age- and sex-specific prevention efforts. Full article

Alzheimer’s disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression. Full article

Post-traumatic auditory and vestibular complaints are frequent after traumatic brain injury (TBI) and temporal bone trauma. They create particular difficulty in medico-legal practice because the evaluator must distinguish diagnosis, functional impact, plausibility of traumatic causation, and the credibility of reported deficits and/or symptoms. This manuscript is a narrative expert review, not a systematic review or a validated forensic prediction rule. It aims to synthesize clinically relevant evidence and propose a practical cross-check framework for structured audio-vestibular assessment in post-traumatic and medico-legal contexts. Pure-tone audiometry remains the functional entry point, but it should be interpreted in conjunction with speech audiometry, tympanometry, acoustic reflexes, transient-evoked and distortion-product otoacoustic emissions, auditory brainstem responses, and auditory steady-state responses. Vestibular evaluation should combine videonystagmography, video head impulse testing, cervical and ocular vestibular evoked myogenic potentials, and computerized dynamic posturography, recognizing that each method interrogates different physiological domains and frequencies. Particular emphasis is placed on the separation between clinical diagnosis, physiological localization, functional impairment, and medico-legal attribution. The article also discusses safeguards against false-positive attribution of malingering, the time course after TBI, inter-rater variability, and the role of specialist expertise in medico-legal reporting. The proposed framework does not eliminate uncertainty; rather, it is intended to make expert reasoning transparent, cautious, internally consistent, and defensible. Full article

Background/Objectives: Traumatic brain injury (TBI) is increasingly understood as a chronic condition, but the role of early post-injury lifestyle behaviors in later cardiometabolic risk remains unclear. We examined whether lifestyle behaviors reported 1 year after injury were associated with the accumulation of common cardiometabolic risk factors by 5 years in the Traumatic Brain Injury Model Systems (TBIMS) National Database. Methods: This retrospective cohort secondary analysis included adults with followed 1-year and 5-year interviews, complete 1-year data on four behaviors, and the complete ascertainment of hypertension, diabetes or high blood sugar, and high cholesterol at both waves. The exposure was a favorable lifestyle count based on not smoking, non-heavy alcohol use, non-obese body mass index, and sports or exercise at least 10 times per month. The primary endpoint was the incident accumulation of at least two new common cardiometabolic conditions between years 1 and 5. The analytic cohort was an observed-data subset defined by follow-up retention, complete behavior data, paired outcome ascertainment, and baseline at-risk status rather than a random sample of all TBIMS participants. Results: Among 10,057 linked participants with followed interviews at both waves, 9593 were adults, 3182 had complete four-behavior exposure data, 689 had complete cardiometabolic ascertainment, and 581 formed the primary at-risk observed-data cohort. The primary endpoint occurred in 39 participants (6.7%). Each additional favorable behavior was associated with lower odds of the primary endpoint in the adjusted model (odds ratio [OR], 0.63; 95% confidence interval [CI], 0.41–0.98; p = 0.040). The results were similar after adjustment for the 1-year Functional Independence Measure cognitive score and in Firth logistic regression. Because the final cohort was selected and the number of primary events was small, the estimates should be interpreted as exploratory and may not generalize to the broader TBI population. Conclusions: More favorable 1-year lifestyle profiles were associated with lower 5-year cardiometabolic risk factor accumulation after TBI. These findings support prevention-oriented follow-up but do not establish causality or validate a prognostic score. Full article

Background: Traumatic brain injury (TBI) affects millions of individuals annually and remains a major global cause of neurological disability and death. Tau protein hyperphosphorylation, particularly in its cis conformation, is a major pathological hallmark contributing to neurodegeneration following TBI. Single-chain variable fragments (scFvs), despite their diagnostic potential, suffer from rapid renal clearance and short circulation half-lives, which limit their in vivo performance. PEGylation is therefore employed to prolong systemic circulation and improve the pharmacokinetic behavior of scFvs, enabling more effective brain retention and target engagement. Methods: In this study, we utilized a previously validated anti-cis p-tau scFv antibody fragment, radiolabeled with technetium-99m tricarbonyl (^99mTc(CO)₃), as a diagnostic tracer to detect tau pathology in TBI rat models. The antibody was conjugated with polyethylene glycol (PEG, 20 kDa); PEGylation efficiency was determined by quantifying the products on SDS-PAGE, and the products were subsequently radiolabeled. Results: Radiochemical purity (RCP) was ~95.4% for the non-PEGylated tracer (^99mTc-AININ20) and ~92.7% for the PEGylated form (^99mTc-AININ20-PEG), with both showing >90% radiochemical purity consistently. Upon systemic administration, PEGylated scFv was able to cross the blood–brain barrier (BBB) and selectively accumulated in injured regions, as confirmed by single-photon emission computed tomography (SPECT) imaging. Both PEGylated and non-PEGylated scFv tracers showed significantly higher brain uptake in TBI rats compared to healthy controls (p < 0.0001). At 24 h, the PEGylated form exhibited a significantly higher brain signal than the non-PEGylated version (p < 0.0001), indicating improved tracer retention. Biodistribution analysis at 2 h post-injection showed significantly reduced renal clearance for the PEGylated tracer and increased hepatic uptake compared to the non-PEGylated form. At 24 h, in vivo imaging confirmed sustained brain retention, highlighting improved pharmacokinetics and imaging potential. Conclusions: These results support PEGylated scFv as a promising SPECT imaging agent for early detection of tauopathy in TBI, offering enhanced brain retention and improved pharmacokinetics. Full article

Traditional surgical decision-making in traumatic brain injury (TBI) has relied on static intracranial pressure (ICP) thresholds and fixed volumetric criteria, an approach that inadequately reflects the dynamic physiological nature of secondary brain injury. These conventional metrics fail to capture the critical determinant of clinical deterioration: the progressive loss of intracranial compliance, the brain’s capacity to buffer additional volume without harmful pressure escalation. This manuscript proposes a practical, compliance-based framework for selecting precise, personalized surgical strategies using real-time physiological, imaging, and neuromonitoring indicators. Based on the Intracranial Compartment Syndrome (ICCS) model, this approach translates the loss of compensatory reserve into actionable operative decisions. Compliance is assessed through multimodal tools, including ICP waveform morphology, cerebral oxygenation, and complementary noninvasive neuromonitoring. ICCS staging delineates three operative contexts: Stage 1, preserved compliance; Stage 2, compliance failure with maintained oxygenation requiring physiology-guided interventions to restore buffering capacity; and Stage 3, global decompensation with lost of compliance plus oxygenation failure requiring immediate, aggressive intervention for partial or total brain tissue survival. By shifting surgical reasoning from fixed anatomical thresholds to a physiology-centered assessment of intracranial compliance, this framework aims to enhance the timing, selection, and overall effectiveness of neurosurgical interventions in TBI. Full article

Background and Clinical Significance: Kinesio tape (KT) has gained popularity as an adjunctive approach for treating edema during the rehabilitation phase, following traumatic events, as well as for managing edema in breast cancer patients. Its goal is to reduce swelling and improve mobility in the affected extremity; however, its use in critically ill patients remains limited. To our knowledge, this is the first report of its application in this population. Case presentation: This case series involved three patients in the Intensive Care Unit (ICU) who presented with lower extremity edema. One patient developed a cerebrovascular event secondary to moderate traumatic brain injury and two patients experienced sepsis. KT was applied, and extremity circumference, Godet sign, and Stemmer sign were assessed. The bandage was reapplied every 24 h over a 5-day period, with daily evaluations performed by the same nursing staff to ensure measurement consistency. All three patients exhibited a reduction in extremity circumference, along with improvement or resolution of the Godet and Stemmer signs. No adverse effects associated with KT were observed. Conclusions: Our results suggest that KT may be a beneficial adjunctive therapy for edema reduction in ICU patients. Larger-scale studies are needed to confirm its clinical value. Full article

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) play essential roles in the brain, influencing neuronal and dendritic growth, as well as neurotransmission. These effects persist throughout life. Numerous studies in animals and humans have demonstrated the beneficial effects of GH therapy on memory and cognitive function, as well as on the restoration of neuronal function following injury. All nerve cells, including neurons, glia, endothelial, epithelial, and perivascular cells, are affected by the actions of GH/IGF-1. IGF-1, in particular, has been associated with cognitive function. The GH-IGF-1 axis increases the proliferation of neuronal progenitor cells and the formation of new neurons, oligodendrocytes, and astrocytes. In this study, we searched databases such as PubMed, Google Scholar, and Embase for human clinical trials evaluating the effect of growth hormone (GH) therapy on dementia, Alzheimer’s disease (AD), post-traumatic brain injury (PTI), and stroke. The following search terms were used: “GH and dementia,” “GH and Alzheimer’s disease,” “GH and TBI,” and “GH and stroke.” Inclusion criteria were all randomized controlled trials and observational studies. Exclusion criteria included the lack of cognitive and memory assessments. We found 28 articles. Most studies show the beneficial effects of GH therapy on memory and recovery of brain function after traumatic injury and stroke; however, consistent data are still lacking. The limited number of clinical trials, the small number of patients, and the lack of data on plasma levels of sex hormones that clearly contribute to brain function are limiting factors. This is the case, for example, with androgens. Other critical factors are dosage and treatment duration. Prolonged administration and supraphysiological doses are more effective in inducing positive clinical changes. Growth hormone (GH) therapy is a very promising intervention for preventing and treating dementia and early-stage Alzheimer’s disease, and it contributes significantly to the recovery of brain function in patients after traumatic injury and stroke. Further studies with more robust methodologies are needed to confirm these results. Full article

Background/Objectives: The evaluation of cognition is central to many neurological conditions, including traumatic brain injury, Alzheimer’s disease, Lewy body disease, frontotemporal degeneration, and vascular disorders. In clinical practice, particularly in aging populations, cognitive complaints often arise in the context of mixed neurological processes, requiring careful integration of cognitive and non-cognitive findings. Despite this, there remains limited clarity regarding the respective roles of neurologists and clinical neuropsychologists and the distinction between cognitive and neuropsychological assessments, terms that are often used interchangeably despite important differences in methodology and scope. This lack of a shared framework has practical consequences. Cognitive test results, when interpreted in isolation for diagnosis, may be misconstrued as comprehensive measures of brain function, particularly when non-cognitive neurological features such as motor, cerebellar, or vestibular abnormalities should have been considered (but were not). Methods: In this narrative review, we synthesize clinical guidelines, consensus statements, regulatory sources, and representative empirical literature to articulate a competence-based framework in which cognitive assessment is a medically integrated process incorporating history, functional evaluation, neurological examination, and the targeted use of standardized neuropsychological instruments. Results: Neurologists are trained to establish medical diagnoses and integrate cognitive findings into the context of neurological disease, while neuropsychologists contribute detailed psychometric characterization, culturally and demographically informed interpretation, cognitive phenotyping, functional characterization, and validity assessment in complex clinical and medicolegal contexts. Although neuropsychologists are qualified to diagnose neurocognitive disorders using standardized diagnostic criteria, attribution to specific neurological etiologies requires a comprehensive medical evaluation that extends beyond cognitive testing alone. Conclusions: We outline a tiered approach to evaluation that aligns assessment methods with clinical questions and supports accurate diagnosis, interdisciplinary collaboration, and patient-centered care. Full article