Search Results (93)

Although intracranial hypertension (ICH) has traditionally been framed as simply a numerical escalation of intracranial pressure (ICP) and usually dealt with in its clinical form and not in terms of its complex underlying pathophysiology, an emerging body of evidence indicates that ICH is not simply an elevated ICP process but a complex process of molecular dysregulation, glymphatic dysfunction, and neurovascular insufficiency. Our aim in this paper is to provide a complete synthesis of all the new thinking that is occurring in this space, primarily on the intersection of glymphatic dysfunction and cerebral vein physiology. The aspiration is to review how glymphatic dysfunction, largely secondary to aquaporin-4 (AQP4) dysfunction, can lead to delayed cerebrospinal fluid (CSF) clearance and thus the accumulation of extravascular fluid resulting in elevated ICP. A range of other factors such as oxidative stress, endothelin-1, and neuroinflammation seem to significantly impair cerebral autoregulation, making ICH challenging to manage. Combining recent studies, we intend to provide a revised conceptualization of ICH that recognizes the nuance and complexity of ICH that is understated by previous models. We wish to also address novel diagnostics aimed at better capturing the dynamic nature of ICH. Recent advances in non-invasive imaging (i.e., 4D flow MRI and dynamic contrast-enhanced MRI; DCE-MRI) allow for better visualization of dynamic changes to the glymphatic and cerebral blood flow (CBF) system. Finally, wearable ICP monitors and AI-assisted diagnostics will create opportunities for these continuous and real-time assessments, especially in limited resource settings. Our goal is to provide examples of opportunities that exist that might augment early recognition and improve personalized care while ensuring we realize practical challenges and limitations. We also consider what may be therapeutically possible now and in the future. Therapeutic opportunities discussed include CRISPR-based gene editing aimed at restoring AQP4 function, nano-robotics aimed at drug targeting, and bioelectronic devices purposed for ICP modulation. Certainly, these proposals are innovative in nature but will require ethically responsible confirmation of long-term safety and availability, particularly to low- and middle-income countries (LMICs), where the burdens of secondary ICH remain preeminent. Throughout the review, we will be restrained to a balanced pursuit of innovative ideas and ethical considerations to attain global health equity. It is not our intent to provide unequivocal answers, but instead to encourage informed discussions at the intersections of research, clinical practice, and the public health field. We hope this review may stimulate further discussion about ICH and highlight research opportunities to conduct translational research in modern neuroscience with real, approachable, and patient-centered care. Full article

Introduction: Huntington’s disease (HD) disrupts cortico-striato-thalamocortical circuits decades before clinical onset. Electroencephalography (EEG) offers millisecond temporal resolution, low cost, and broad accessibility, yet its mechanistic and biomarker potential in HD remains underexplored. We conducted a mechanistic review to synthesize half a century of EEG findings, identify reproducible electrophysiological signatures, and outline translational next steps. Methods: Two independent reviewers searched PubMed, Scopus, Google Scholar, ResearchGate, and the Cochrane Library (January 1970–April 2025) using the terms “EEG” OR “electroencephalography” AND “Huntington’s disease”. Clinical trials published in English that reported raw EEG (not ERP-only) in human HD gene carriers were eligible. Abstract/title screening, full-text appraisal, and cross-reference mining yielded 22 studies (~700 HD recordings, ~600 controls). We extracted sample characteristics, acquisition protocols, spectral/connectivity metrics, and neuroclinical correlations. Results: Across diverse platforms, a consistent spectral trajectory emerged: (i) presymptomatic carriers show a focal 7–9 Hz (low-alpha) power loss that scales with CAG repeat length; (ii) early-manifest patients exhibit widespread alpha attenuation, delta–theta excess, and a flattened anterior-posterior gradient; (iii) advanced disease is characterized by global slow-wave dominance and low-voltage tracings. Source-resolved studies reveal early alpha hypocoherence and progressive delta/high-beta hypersynchrony, microstate shifts (A/B ↑, C/D ↓), and rising omega complexity. These electrophysiological changes correlate with motor burden, cognitive slowing, sleep fragmentation, and neurovascular uncoupling, and achieve 80–90% diagnostic accuracy in shallow machine-learning pipelines. Conclusions: EEG offers a coherent, stage-sensitive window on HD pathophysiology—from early thalamocortical disinhibition to late network fragmentation—and fulfills key biomarker criteria. Translation now depends on large, longitudinal, multi-center cohorts with harmonized high-density protocols, rigorous artifact control, and linkage to clinical milestones. Such infrastructure will enable the qualification of alpha-band restoration, delta-band hypersynchrony, and neurovascular coupling as pharmacodynamic readouts, fostering precision monitoring and network-targeted therapy in Huntington’s disease. Full article

This scoping review explores the expression patterns and molecular features of sarcoglycans (SGs) in non-muscle organs, challenging the long-standing assumption that their function is confined to skeletal and cardiac muscle. By analyzing evidence from both animal models and human studies, the review highlights the widespread presence of SG subunits in organs, including the nervous system, glands, adipose tissue, oral mucosa, retina, and other structures, with distinct regional and cell-type-specific patterns. Studies on the central nervous system demonstrate a widespread “spot-like” distribution of SG subunits in neurons and glial cells, implicating their involvement in synaptic organization and neurotransmission. Similarly, SGs maintain cellular integrity and homeostasis in glands and adipose tissue. At the same time, the altered expression of SGs is associated with pathological conditions in the gingival epithelium of the oral mucosa. These findings underscore the multifaceted roles of SGs beyond muscle, suggesting that they may contribute to cellular signaling, membrane stability, and neurovascular coupling. However, significant gaps remain regarding SG post-translational modifications and functional implications in non-muscle organs. Future research integrating molecular, cellular, and functional approaches in animal models and human tissues is essential to fully elucidate these roles and explore their potential as therapeutic targets in various diseases. Full article

Pericytes, specialized mural cells surrounding microvessels, play a crucial role in maintaining vascular homeostasis and function across various organs, including the eye. These versatile cells regulate blood flow, support the integrity of the blood–retinal barrier, and contribute to angiogenesis. Recent advancements in molecular and cellular biology have revealed the heterogeneity of pericytes and their critical involvement in ocular physiology and pathology. This review provides a comprehensive analysis of pericyte functions in ocular health and their implications in diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinal vein occlusion. Pericyte dysfunction is implicated in vascular instability, neurovascular coupling failure, inflammation, and pathological neovascularization, contributing to vision-threatening disorders. The review further explores recent findings on pericyte-targeted therapies, including pharmacological agents, gene therapy, and cell-based approaches, aiming to restore pericyte function and preserve ocular health. Full article

Background/Objectives: Jaw deformities affect not only facial aesthetics but also various oral functions. While previous studies have demonstrated that mandibular prognathism (MP) alters masticatory-induced brain blood flow (BBF), the temporal characteristics of these hemodynamic changes have remained unclear. In this cross-sectional observational study, we investigated the following two specific objectives: (1) whether food hardness affects not only the magnitude but also the temporal patterns of BBF changes during mastication and (2) how malocclusion is associated with these temporal hemodynamic responses. Methods: Twenty-six participants with normal occlusion (NORM) and twenty patients with MP participated in this study. BBF was measured using functional near-infrared spectroscopy, while participants chewed soft paraffin or hard gummy candy. Maximum oxygenated hemoglobin (oxy-Hb) values and time-to-peak BBF were analyzed. Results: While food hardness did not significantly affect maximum oxy-Hb within groups, the MP group showed significantly lower responses during hard gummy candy mastication compared to the NORM group. The occlusal contact area exhibited significant positive correlation with maximum oxy-Hb values, while the ANB angle, an indicator of intermaxillary skeletal relationship, showed no significant correlation with BBF parameters. The hard gummy candy/paraffin ratio of maximum oxy-Hb was significantly higher in the NORM group compared to the MP group. Time-to-peak BBF was approximately twice as long for hard gummy candy compared to paraffin in both groups, with no significant differences between groups. Conclusions: These findings reveal that while MP attenuates the magnitude of masticatory-induced BBF, particularly during hard food mastication, the temporal adaptation to increased food hardness is preserved. This dissociation between magnitude and timing effects suggests that intact basic neurovascular coupling mechanisms would be maintained even in the condition of altered masticatory function in a MP subject, which is providing new insights for rehabilitation strategies in orthognathic surgery cases. Full article

This study explores the influence of chinstrap stiffness in baseball helmets on brain stress distribution during high-velocity impacts through a computational biomechanical model integrating neuroanatomical structures and helmet components. Using a framework that combines finite element analysis and smoothed-particle hydrodynamics, this research evaluates fluid–structure interactions between cerebrospinal fluid, brain tissue, and six chinstrap configurations ranging from highly flexible to non-stretchable. The results reveal a critical trade-off: highly flexible straps reduce intracranial stress by dissipating energy through viscoelastic deformation but compromise helmet stability, while non-stretchable designs transmit undampened forces directly to the skull base, amplifying stress in vulnerable neurovascular regions. Intermediate stiffness configurations introduce a hazardous instability regime, where partial decoupling between the helmet and mandible causes lateral sliding of the chin guard, concentrating stresses at bony interfaces. The study identifies a nonlinear relationship between material rigidity and neuroprotection, emphasizing that optimal chinstrap design must balance elasticity to absorb impact energy with sufficient rigidity to maintain alignment and prevent stress redirection. Intermediate stiffness thresholds, despite partial energy absorption, paradoxically heighten risks due to incomplete coupling and dynamic instabilities. These findings challenge conventional helmet design paradigms, advocating for material engineering strategies that prioritize energy dissipation pathways while avoiding detrimental intermediate stiffness ranges. The insights advance concussion mitigation by refining chinstrap performance criteria to address both direct force transmission and instability-mediated injury mechanisms. Full article

A fundamental limitation of fMRI based on the BOLD effect is its limited spatial specificity. This is because the BOLD signal reflects neurovascular coupling, leading to macrovascular changes that are not strictly limited to areas of increased neural activity. However, neuronal activation also induces microstructural changes within the brain parenchyma by modifying the diffusion of extracellular biological water. Therefore, diffusion-weighted imaging (DWI) has been applied in fMRI to overcome BOLD limits and better explain the mechanisms of functional activation, but the results obtained so far are not clear. This is because a DWI signal depends on many experimental variables: instrumental, physiological, and microstructural. Here, we hypothesize that the γ parameter of the fractional diffusion representation could be of particular interest for DW-fMRI applications, due to its proven dependence on local magnetic susceptibility and diffusion multi-compartmentalization. BOLD fMRI and DW-fMRI experiments were performed at 3T using an exemplar application to task-based activation of the human visual cortex. The results, corroborated by simulation, highlight that γ provides complementary information to conventional diffusion fMRI and γ can quantify cellular morphology changes and neurovascular regulation during neuronal activation with higher sensitivity and specificity than conventional BOLD fMRI and DW-fMRI. Full article

Neurovascular coupling (NVC) refers to the dynamic regulation of cerebral blood flow via neuronal activity, a mechanism crucial for maintaining normal brain function. This review elucidates the intricate physiological mechanisms underlying NVC, emphasizing the coordinated roles of neurons, glial cells, and vascular cells in mediating activity-induced changes in blood flow. We examine how NVC is impaired in neurological disorders such as Alzheimer’s disease and stroke, where the dysfunction of this coupling contributes to neurodegeneration and neurological deficits. A broad range of techniques for assessing NVC is discussed—encompassing the established modalities like transcranial Doppler, near-infrared spectroscopy, and functional magnetic resonance imaging (fMRI), as well as emerging technologies such as functional ultrasound imaging and miniaturized endoscopy that enable high-resolution monitoring in deep brain regions. We also highlight the computational modeling approaches for simulating NVC dynamics and identify the novel biomarkers of NVC dysfunction with potential utility in early diagnosis. Finally, emerging translational applications—including neuromodulation techniques and targeted pharmacological interventions—are explored as means to restore normal neurovascular function. These advancements underscore the clinical significance of NVC research, paving the way for improved diagnostic tools and therapeutic strategies in neurological disorders. Full article

Alzheimer’s disease (AD) is an increasing global healthcare crisis with few effective treatments. The accumulation of amyloid plaques and hyper-phosphorylated tau are thought to underlie the pathogenesis of AD. However, current studies have recognized a prominent role of cerebrovascular dysfunction in AD. We recently reported that SNPs in soluble epoxide hydrolase (sEH) are linked to AD in human genetic studies and that long-term administration of an sEH inhibitor attenuated cerebral vascular and cognitive dysfunction in a rat model of AD. However, the mechanisms linking changes in cerebral vascular function and neuroprotective actions of sEH inhibitors in AD remain to be determined. This study investigated the effects of administration of an sEH inhibitor, 1-(1-Propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl]urea (TPPU), on neurovascular coupling, blood–brain barrier (BBB) function, neuroinflammation, and cognitive dysfunction in an hAPP/PS1 TgF344-AD rat model of AD. We observed predominant β-amyloid accumulation in the brains of 9–10-month-old AD rats and that TPPU treatment for three months reduced amyloid burden. The functional hyperemic response to whisker stimulation was attenuated in AD rats, and TPPU normalized the response. The sEH inhibitor, TPPU, mitigated capillary rarefaction, BBB leakage, and activation of astrocytes and microglia in AD rats. TPPU increased the expression of pre- and post-synaptic proteins and reduced loss of hippocampal neurons and cognitive impairments in the AD rats, which was confirmed in a transcriptome and GO analysis. These results suggest that sEH inhibitors could be a novel therapeutic strategy for AD. Full article

Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. While traditionally viewed through the lens of neuronal dysfunction, emerging evidence highlights the critical role of endothelial dysfunction in HD pathogenesis. This review provides a comprehensive overview of endothelial dysfunction in HD, drawing on findings from both animal models and human studies. Key features of endothelial dysfunction in HD include impaired angiogenesis, altered cerebral blood flow, compromised neurovascular coupling and cerebrovascular reactivity, and increased blood–brain barrier permeability. Genetic factors such as the mutant huntingtin protein, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), Brain-derived neurotrophic factor (BDNF), and the adenosine A2A receptor (ADORA2A) interact to influence endothelial function in complex ways. Various therapeutic approaches targeting endothelial dysfunction, including antioxidants, nitric oxide enhancers, calcium channel blockers, statins, and metformin, have shown promise in preclinical HD models but face translational challenges, particularly regarding optimal timing of intervention and patient stratification. The implications of these findings suggest that reconceptualizing HD as a neurovascular disorder, rather than purely neuronal, could lead to more effective treatment strategies. Future research priorities should include: (1) developing validated vascular biomarkers for disease progression, (2) advancing neuroimaging techniques to monitor endothelial dysfunction in real-time. These directions will be crucial for bridging the current gap between preclinical promise and clinical success in vascular-targeted HD therapeutics. Full article

Background: The cerebral microvasculature forms a dense network of interconnected blood vessels where flow is modulated partly by astrocytes. Increased neuronal activity stimulates astrocytes to release vasoactive substances at the endfeet, altering the diameters of connected vessels. Methods: Our study simulated the coupling between blood flow variations and vessel diameter changes driven by astrocytic activity in the rat somatosensory cortex. We developed a framework with three key components: coupling between the vasculature and synthesized astrocytic morphologies, a fluid dynamics model to compute flow in each vascular segment, and a stochastic process replicating the effect of astrocytic endfeet on vessel radii. Results: The model was validated against experimental flow values from the literature across cortical depths. We found that local vasodilation from astrocyte activity increased blood flow, especially in capillaries, exhibiting a layer-specific response in deeper cortical layers. Additionally, the highest blood flow variability occurred in capillaries, emphasizing their role in cerebral perfusion regulation. We discovered that astrocytic activity impacted blood flow dynamics in a localized, clustered manner, with most vascular segments influenced by two to three neighboring endfeet. Conclusions: These insights enhance our understanding of neurovascular coupling and guide future research on blood flow-related diseases. Full article

Neurovascular coupling (NVC) refers to the process of local changes in cerebral blood flow (CBF) after neuronal activity, which ensures the timely and adequate supply of oxygen, glucose, and substrates to the active regions of the brain. Recent clinical imaging and experimental technology advancements have deepened our understanding of the cellular mechanisms underlying NVC. Pathological conditions such as stroke, subarachnoid hemorrhage, cerebral small vascular disease, and vascular cognitive impairment can disrupt NVC even before clinical symptoms appear. However, the complexity of the underlying mechanism remains unclear. This review discusses basic and clinical experimental evidence on how neural activity sensitively communicates with the vasculature to cause spatial changes in blood flow in cerebrovascular diseases. A deeper understanding of how neurovascular unit-related cells participate in NVC regulation is necessary to better understand blood flow and nerve activity recovery in cerebrovascular diseases. Full article

Mild cognitive impairment (MCI) affects nearly 20% of older adults worldwide, with no targetable interventions for prevention. COVID-19 adversely affects cognition, with >70% of older adults with Long COVID presenting with cognitive complaints. Neurovascular coupling (NVC), an essential mechanism of cognitive function, declines with aging and is further attenuated in neurocognitive disorders. The effect of COVID-19 on NVC responses has yet to be addressed in older adults who are vulnerable to dementia progression. Participants with MCI and a history of COVID-19 (COV+, N = 31) and MCI participants with no history of infection (COV− N = 11) participated in this cross-sectional study to determine if COVID-19 affects cerebrocortical NVC responses and vascular function. Functional near-infrared spectroscopy was used to measure cerebrocortical NVC responses, and endothelial function was assessed via insonation of the brachial artery during a flow-mediated dilation protocol. NVC responses were elicited by the working memory n-back paradigm. NVC in the left dorsolateral prefrontal cortex and endothelial function was decreased in the COV+ group compared to the COV− group. These data provide mechanistic insight into how COVID-19 may exacerbate long-term cognitive sequela seen in older adults, highlighting the urgent need for further research and clinical trials to explore novel therapeutic interventions aimed at preserving/restoring NVC. Full article

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique that applies a stable, low-intensity (1–2 mA) direct current to modulate neuronal activity in the cerebral cortex. This technique is effective, simple to operate, affordable, and widely employed across various fields. tDCS has been extensively used in clinical and translational research, with growing applications in military and competitive sports domains. In recent years, the use of tDCS in sports science has garnered significant attention from researchers. Numerous studies have demonstrated that tDCS can enhance muscle strength, explosive power, and aerobic metabolism, reduce fatigue, and improve cognition, thereby serving as a valuable tool for enhancing athletic performance. Additionally, recent research has shed light on the physiological mechanisms underlying tDCS, including its modulation of neuronal resting membrane potential to alter cortical excitability, enhancement of synaptic plasticity to regulate long-term potentiation, modulation of neurovascular coupling to improve regional cerebral blood flow, and improvement of cerebral network functional connectivity, which activates and reinforces specific brain regions. tDCS also enhances the release of excitatory neurotransmitters, further regulating brain function. This article, after outlining the role of tDCS in improving physical performance, delves into its mechanisms of action to provide a deeper understanding of how tDCS enhances athletic performance and offers novel approaches and perspectives for physical performance enhancement. Full article