Search Results (205)

Among the leading etiologies of limb amputations are diabetes mellitus, alongside trauma and peripheral vascular disease conditions, whose complications are major indications for surgery, which can subsequently elicit chronic refractory postamputation pain. ‘Phantom limb pain’ (PLP) denotes pain that is perceived as occurring in an absent part of the limb following amputation. Even though it is a relatively common complication among amputees—with an estimated prevalence as high as ~80 percent—the underlying mechanisms of this puzzling condition remain poorly understood. Current theories predominantly emphasize the role of the nervous system and neuropsychopathology in the development of PLP. However, these neurocentric explanations are disputed and have not yet been translated into effective treatments or a definitive cure for the condition, nor have several notable anomalies been settled, which has prompted researchers to call for the exploration of alternative theories. The aim of this paper is to offer an alternative mechanical mechanism for explaining PLP and spontaneous phantom sensations. This work introduces a theoretical model for the mechanism of PLP, drawing on a recent study that proposed this model to explain fibromyalgia-type psychosomatic syndromes as disorders driven by overactive soft tissue myofibroblasts. The manuscript proposes a shift from purely neurocentric models of PLP to a framework where the extracellular matrix and connective tissue, specifically myofascial tissue and inflammatory myofibroblasts—which are often overlooked in research—take part in its pathogenesis. In this suggested model, surgical interventions disrupt the biomechanical stability of the fascio-musculoskeletal biotensegrity-like system, thus acting as a contributing factor in the chronic pain manifestation. The term ‘biotensegrity’ refers to the dynamic biomechanical behavior of a living system that is stabilized by compressive and tensile force elements, a characteristic quality of myofascial tissue. In this framework, abnormal extracellular matrix remodeling, driven by overactive peripheral myofibroblasts, and the concomitant mechanical effects exerted on sensory nerves embedded within the fascia and reaching the neuroma microenvironment contribute to the generation and perception of spontaneous PLP and phantom sensations. The interplay between abnormal extracellular matrix, the neuroma’s intrinsic excitability, as well as peripheral and central neurophysiological mechanisms, collectively provide a biophysical neuropathophysiological basis to help explain PLP. This offers a different unexplored perspective on a condition with poorly understood mechanisms. Full article

The gut microbiota influences both energy metabolism and central nervous system (CNS) functions. This influence is mediated by humoral factors, including various metabolites, neurotransmitters, cytokines, and hormones, in addition to neural pathways such as the vagus nerve. Notably, short-chain fatty acids (SCFAs)—comprising acetic, propionic, and butyric acids—merit specific attention. These compounds originate from the anaerobic fermentation of dietary fibers by the gut microbiota. Growing evidence indicates that SCFAs confer beneficial effects on diverse pain conditions. Although previous review articles have summarized animal studies suggesting the possibility that SCFAs can alleviate pathological pain, there are few reviews on the neurophysiological mechanisms by which SCFAs modulate the excitability of nociceptive neurons in the pain pathway under nociceptive and pathological conditions. Extending previous in vitro findings, our laboratory recently conducted in vivo neurophysiological studies using animal models to explore the pain-relieving properties of SCFAs. Our published results demonstrate two significant effects: (i) an intravenous anesthetic action against nociceptive pain and (ii) an anti-inflammatory contribution to chronic pain alleviation. This review synthesizes the current understanding of the mechanisms by which SCFAs modulate pain and explores their contribution to the attenuation of nociceptive and/or pathological pain. Furthermore, we discuss their prospective clinical application Full article

Lactate is not only the end product of glycolysis but also plays a key role in epigenetic regulation. Recently, lactate-derived histone lactylation has been identified as a novel epigenetic modification that can directly influence gene transcription. Histone lactylation has been associated with various pathological conditions and shows significant therapeutic potential. However, studies on histone lactylation in central nervous system diseases are still quite limited. In this review, we summarize the latest research progress on histone lactylation, detailing the specific mechanisms and sites of histone lactylation, including lactylation and delactylation. We also discuss the role of histone lactylation in Alzheimer’s disease (glycolysis/H4K12la/PKM2 feedback loop), depression (neuronal excitation), neuroinflammation (anti-inflammatory/pro-inflammatory balance of microglia), aging, stroke (infarct volume), and glioblastoma (activation of oncogenes), pointing out the research directions for the future. This may provide new ideas for the diagnosis and treatment of neurological diseases. Full article

This work investigates the macroscopic behavior of skeletal muscles from a system-theoretic perspective. Based on data available in the literature, we propose an initial evaluation model for isometric force generation, i.e., force produced at a constant muscle length or in quasi-static conditions, as a function of muscle length and neuronal excitation frequency. This model enables a more physics-inspired representation of isometric force by employing a nonlinear spring framework with controllable properties such as stiffness and rest length. Finally, we introduce a hybrid dynamical filter model to describe components of the sensory system responsible for relaying information about muscle length and its rate of change back to the Central Nervous System. As an application case, we present the modeling of the oculomotor system, highlighting the relevance of the proposed modeling approach in a physiologically meaningful control task. Full article

Precision neurosurgery is rapidly evolving as a medical specialty by merging genomic medicine, multi-omics technologies, and artificial intelligence (AI) technology, while at the same time, society is shifting away from the traditional, anatomic model of care to consider a more precise, molecular model of care. The general purpose of this review is to contemporaneously reflect on how these advances will impact neurosurgical care by providing us with more precise diagnostic and treatment pathways. We hope to provide a relevant review of the recent advances in genomics and multi-omics in the context of clinical practice and highlight their transformational opportunities in the existing models of care, where improved molecular insights can support improvements in clinical care. More specifically, we will highlight how genomic profiling, CRISPR-Cas9, and multi-omics platforms (genomics, transcriptomics, proteomics, and metabolomics) are increasing our understanding of central nervous system (CNS) disorders. Achievements obtained with transformational technologies such as single-cell RNA sequencing and intraoperative mass spectrometry are exemplary of the molecular diagnostic possibilities in real-time molecular diagnostics to enable a more directed approach in surgical options. We will also explore how identifying specific biomarkers (e.g., IDH mutations and MGMT promoter methylation) became a tipping point in the care of glioblastoma and allowed for the establishment of a new taxonomy of tumors that became applicable for surgeons, where a change in practice enjoined a different surgical resection approach and subsequently stratified the adjuvant therapies undertaken after surgery. Furthermore, we reflect on how the novel genomic characterization of mutations like DEPDC5 and SCN1A transformed the pre-surgery selection of surgical candidates for refractory epilepsy when conventional imaging did not define an epileptogenic zone, thus reducing resective surgery occurring in clinical practice. While we are atop the crest of an exciting wave of advances, we recognize that we also must be diligent about the challenges we must navigate to implement genomic medicine in neurosurgery—including ethical and technical challenges that could arise when genomic mutation-based therapies require the concurrent application of multi-omics data collection to be realized in practice for the benefit of patients, as well as the constraints from the blood–brain barrier. The primary challenges also relate to the possible gene privacy implications around genomic medicine and equitable access to technology-based alternative practice disrupting interventions. We hope the contribution from this review will not just be situational consolidation and integration of knowledge but also a stimulus for new lines of research and clinical practice. We also hope to stimulate mindful discussions about future possibilities for conscientious and sustainable progress in our evolution toward a genomic model of precision neurosurgery. In the spirit of providing a critical perspective, we hope that we are also adding to the larger opportunity to embed molecular precision into neuroscience care, striving to promote better practice and better outcomes for patients in a global sense. Full article

Microneedle arrays (MNAs) are becoming increasingly popular due to their ease of use and effectiveness in drug delivery and diagnostic applications. Improvements in three-dimensional (3D) printing techniques have made it possible to fabricate MNAs with high precision, intricate designs, and customizable properties, expanding their potential in medical applications. While most studies have focused on transdermal applications, non-transdermal uses remain relatively underexplored. This review summarizes recent developments in 3D-printed MNAs intended for non-transdermal drug delivery and diagnostic purposes. It includes a literature review of studies published in the past ten years, organized by the target delivery site—such as the brain and central nervous system (CNS), oral cavity, eyes, gastrointestinal (GI) tract, and cardiovascular and reproductive systems, among other emerging areas. The findings show that 3D-printed MNAs are more adaptable than skin-based delivery, opening up exciting new possibilities for use in a variety of organs and systems. To guarantee the effective incorporation of polymeric non-transdermal MNAs into clinical practice, additional research is necessary to address current issues with materials, manufacturing processes, and regulatory approval. Full article

Background/Objectives: Neck pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, affecting the cervical region. It represents one of the leading causes of disability, with a prevalence of 30%. Transcranial direct current stimulation (tDCS) is a non-invasive electrotherapy technique that enables direct modulation of cortical excitability. It involves the application of a low-intensity electrical current to the scalp, targeting the central nervous system. The aim of this study was to analyze the effects of tDCS on functionality, pain, mobility, and pressure pain threshold in patients with chronic nonspecific neck pain. Methods: Thirty participants (18–60 years) were selected to receive ten treatment sessions over a four-week period using tDCS (CG = 15) or transcutaneous electrical nerve stimulation (TENS) (CG = 15), with the following various related variables evaluated: functionality (Neck Disability Index), pain intensity (NPRS), cervical range of motion (ROM), and pressure pain threshold (PPT). Assessments were conducted at baseline, post-treatment, one month, and three months after the intervention. Results: The within-group analysis revealed statistically significant improvements for both groups at post-treatment, one-month follow-up, and three-month follow-up. Conclusions: The comparison between groups shows favorable changes in the tDCS group for PPT measurements. Full article

Being one of the most aggressive primary brain tumors, glioblastoma multiforme (GBM) is known from the median survivals of just 15 months following diagnosis. Conventional treatments, including surgical resection, radiotherapy, and chemotherapy, have limited efficiency due to the invasive nature of glioma cells and the presence of a blood–brain barrier. Therefore, adjuvant therapy in the form of a localized delivery of chemotherapeutic agents is indispensable to increase the chances of patients. Among a variety of advanced drug carriers, collagen has recently emerged as an excellent choice for regional chemotherapy, mainly due to its biocompatibility, biodegradability, weak antigenicity, biomimetics, and well-known safety profile, as well as its native presence in the extracellular matrix of the central nervous system. The aim of this paper is to highlight the most recent studies describing the application of collagen as a drug carrier able to provide an extended delivery of chemotherapeutic agents directly to the GBM site, and to provide exciting opportunities for its future applications. Full article

The intricate brain–heart interaction, essential for physiological balance, is largely governed by the autonomic nervous system (ANS). This bidirectional communication, involving both the sympathetic and parasympathetic branches of the ANS, is critical for maintaining cardiac homeostasis. Dysregulation of the ANS is a significant factor in cardiovascular diseases. Beyond the ANS, higher brain functions, particularly through interoceptive prediction, contribute to this dynamic interplay. The Cav1.3 L-type calcium channel, expressed in both the central nervous system (CNS) and the heart, is crucial for this interaction. Cav1.3, a key regulator of cellular excitability, exhibits genetic variations that are linked to both neurological and cardiac disorders, highlighting its pivotal role in the brain–heart axis. This review aims to delve into the under-explored role of Cav1.3 in brain–heart interaction, specifically examining how it modulates ANS activity and, consequently, the cardiac function. This will illuminate its significant role in the broader context of brain–heart interactions. Full article

Background: Spinal manual therapy (SMT) is widely used in the management of musculoskeletal pain. In addition to mechanical effects, SMT may induce neurophysiological changes at both central and autonomic levels. However, the extent and consistency of these short-term effects remain unclear. Objective: To systematically review the short-term effects of SMT on pain perception, central nervous system (CNS) activity, and autonomic nervous system (ANS) responses in adults with musculoskeletal pain or in healthy controls. Methods: A systematic review was conducted. Three databases (PubMed, ScienceDirect, Embase) were searched up to October 2023, with a final update in March 2025. Randomized controlled trials involving SMT and assessing outcomes related to pain, CNS, or ANS function were included. The methodological quality was assessed using the PEDro scale. The results were synthesized narratively and categorized by outcome domain. Four summary tables were created to present the study characteristics, main findings, methodological quality, and risk of bias. Results: Eleven trials were included. SMT produced variable effects on pain perception, with more consistent results observed when the treatment was applied frequently and followed standardized protocols. The CNS-related outcomes (e.g., fMRI connectivity, motor-evoked potentials) suggested short-term modulation of brain and spinal excitability in some studies. The ANS responses were heterogeneous, ranging from parasympathetic activation to sympathetic stimulation, depending on the intervention and population. The methodological quality was moderate to high in most studies, although the small sample sizes and limited blinding increased the risk of bias. The effect sizes were not consistently reported. Conclusions: SMT may induce short-term neuromodulatory effects on pain, CNS, and ANS activity. These effects appear to be context-dependent and require precise, repeated, and purposeful application. Full article

Neuropathic pain is a chronic condition resulting from injury or dysfunction in the somatosensory nervous system, which leads to persistent pain and a significant impairment of quality of life. Research has highlighted the complex molecular mechanisms that underlie neuropathic pain and has begun to delineate the roles of microRNAs (miRNAs) in modulating pain pathways. miRNAs, which are small non-coding RNAs that regulate gene expression post-transcriptionally, have been shown to influence key cellular processes, including neuroinflammation, neuronal excitability, and synaptic plasticity. These processes contribute to the persistence of neuropathic pain, and miRNAs have emerged as critical regulators of pain behaviors by modulating signaling pathways that control pain sensitivity. miRNAs can influence neuropathic pain by targeting genes that encode protein kinases involved in pain signaling. This review focuses on miRNAs that have been demonstrated to modulate neuropathic pain behavior through their effects on protein kinases or their immediate upstream regulators. The relationship between miRNAs and neuropathic pain behaviors is characterized as either an upregulation or a downregulation of miRNA levels that leads to a reduction in neuropathic pain. In the case of miRNA upregulation resulting in an alleviation of neuropathic pain behaviors, protein kinases exhibit a positive correlation with neuropathic pain, whereas decreased protein kinase levels correlate with diminished neuropathic pain behaviors. The only exception is GRK2, which shows an inverse correlation with neuropathic pain. In the case of miRNA downregulation resulting in a reduction in neuropathic pain behaviors, protein kinases display mixed relationships to neuropathic pain, with some kinases exhibiting positive correlation, while others exhibit negative correlation. By exploring how protein kinases mediate miRNA modulation of neuropathic pain, valuable insight may be gained into the pathophysiology of neuropathic pain, offering potential therapeutic targets for developing more effective strategies for pain management. Full article

SPS is characterized by progressive spasmodic muscular rigidity. SPS is thought to be an autoimmune disease with a prominent feature of antibodies against glutamic acid decarboxylase (GAD). GAD is responsible for the enzymatic conversion of glutamic acid (glutamate) into the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Reduced GABA activity leads to increased excitability in the central nervous system, resulting in muscle rigidity and spasms characteristic of SPS. While SPS is rare, anti-GAD antibodies seen in SPS are also seen in the much more common autoimmune disease, type 1 diabetes (T1D). There is evolving research showing that the anti-GAD antibodies of T1D are produced in response to the presence of mycobacterial heat shock protein 65 (mHSP65), and the mHSP65 is produced in response to an occult infection by a bacterium, Mycobacterium avium subspecies Paratuberculosis (MAP). Humans are broadly exposed to MAP in food, water, and air. There are linear and conformational similarities between the epitopes of GAD and mHSP65. This article proposes that MAP is also an infectious trigger for SPS. Dehydroepiandrosterone (DHEA) is a principal component of the steroid metabolome; it plateaus in young adults and then steadily declines. Bromo-epi-androsterone (BEA) is a potent synthetic analog of DHEA; unlike DHEA, it is non-androgenic, non-anabolic, and an effective modulator of immune dysregulation. BEA is also an anti-infective agent and has been shown to benefit mycobacterial infections, including tuberculosis and leprosy. With the immune stabilizing capacity of BEA as well as its anti-mycobacterial properties, there is reason to believe that a randomized clinical trial with BEA may be beneficial for SPS. Full article

Voltage-gated Ca²⁺ (Ca_V) channels are transmembrane proteins comprising the pore-forming subunit Ca_Vα₁ and the ancillary proteins Ca_Vα₂δ and Ca_Vβ. They are expressed in various tissues, including the nervous system, where they regulate Ca²⁺ entry in response to membrane potential changes. The increase in intracellular Ca²⁺ allows for regulating cell excitability and releasing neurotransmitters, among other cellular events. Leucine-rich repeat kinase 2 (LRRK2) is a serine–threonine kinase involved in vesicular mobilization. Previously, it has been shown that LRRK2 regulates neurotransmission by phosphorylating the Ca_Vβ auxiliary subunit of the Ca_V2.1 (P/Q-type) presynaptic channels. However, it is unknown whether the kinase can regulate the activity of other Ca_V channel subtypes, such as Ca_V1.3 (L-type), which play a significant role in the excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) and whose dysregulation contributes to neurodegeneration in Parkinson’s disease (PD). Here, we found potential phosphorylation sites for LRRK2 in Ca_Vβ₃ and examined how these molecules interact. We used immunoprecipitation and electrophysiology in HEK-293 cells expressing recombinant Ca_V1.3 channels, both with and without wild-type LRRK2 or its LRRK2^G2019S mutation, which plays a role in familial PD through a possible gain-of-toxic-function mechanism. Our results show that LRRK2^G2019S significantly increases current density through Ca_V1.3 channels, and this effect depends on the presence of Ca_Vβ₃. Site-directed mutagenesis revealed that phosphorylation at S152 in the sequence of Ca_Vβ₃ is necessary and sufficient to explain the abnormal regulation of the channels mediated by LRRK2^G2019S. These data provide new insights into the molecular regulation that mutant LRRK2 may exert on L-type Ca_V1.3 channels, which determine pacemaker activity in dopaminergic neurons of the SNc and may, therefore, play a relevant role in the molecular pathophysiology of PD. Full article

Hydrogen sulfide (H₂S) has emerged as a pivotal gaseous transmitter in the central nervous system, influencing synaptic plasticity, learning, and memory by modulating various molecular pathways. This review examines recent evidence regarding how H₂S regulates NMDA receptor function and neurotransmitter release in neuronal circuits. By synthesizing findings from animal and cellular models, we investigate the impacts of enzymatic H₂S production and exogenous H₂S on excitatory synaptic currents, long-term potentiation, and intracellular calcium signaling. Data suggest that H₂S interacts directly with NMDA receptor subunits, altering receptor function and modulating neuronal excitability. Simultaneously, H₂S promotes the release of neurotransmitters such as glutamate and GABA, shaping synaptic dynamics and plasticity. Furthermore, reports indicate that disruptions in H₂S metabolism contribute to cognitive impairments and neurodegenerative disorders, underscoring the potential therapeutic value of targeting H₂S-mediated pathways. Although the precise mechanisms of H₂S-induced changes in synaptic strength remain elusive, a growing body of evidence positions H₂S as a significant regulator of memory formation processes. This review calls for more rigorous exploration into the molecular underpinnings of H₂S in synaptic plasticity, paving the way for novel pharmacological interventions in cognitive dysfunction. Full article

Frmpd3 (FERM and PDZ Domain Containing 3), a scaffold protein potentially involved in excitatory synaptic function, has not been thoroughly characterized in terms of its expression and functional role in vivo. Here, we investigated the distribution of Frmpd3 in the central nervous system and its potential regulatory role in epilepsy, a neurological disorder characterized by disrupted excitatory–inhibitory balance. The distribution of Frmpd3 throughout the mouse brain was investigated by immunofluorescence. Western blotting was conducted to examine potential alterations in Frmpd3 protein expression in the hippocampus of a pentylenetetrazol (PTZ)-induced chronic epilepsy model. Using stereotaxic techniques, we delivered Frmpd3 siRNA-AAV9 into the hippocampal CA1 region to achieve targeted protein knockdown. Then, the functional consequences of Frmpd3 depletion were assessed through behavioral observations and electrophysiological recordings in PTZ-treated mice. Finally, protein–protein interactions were investigated using immunoprecipitation and Western blot analysis. Immunofluorescence analysis revealed Frmpd3 expression in cortical, hypothalamic, cerebellar, and hippocampal neurons of adult mice. Subcellular localization studies demonstrated predominant distribution of Frmpd3 in the excitatory postsynaptic density (PSD) of hippocampal CA1 neurons, with additional expression in inhibitory neurons. Quantitative analysis showed significantly elevated Frmpd3 protein levels in the hippocampus of PTZ-induced epileptic mice compared to controls. Frmpd3 knockdown in the CA1 region resulted in the following: (1) reduced seizure frequency, (2) prolonged seizure latency, and (3) decreased incidence of PTZ-induced generalized seizures. Local field potential (LFP) recordings demonstrated that seizure amplitude tended to be reduced, and epileptic discharge durations tended to be shorter in Frmpd3-depleted mice compared to controls. Furthermore, we observed decreased membrane expression of the AMPA receptor GluA2 subunit in the hippocampus of Frmpd3 knockdown mice. Molecular interaction studies revealed that Frmpd3 forms complexes with glutamate receptor-interacting protein (GRIP) and GluA2. Our findings identify Frmpd3 as a novel regulatory scaffold protein that modulates epileptic susceptibility through molecular interactions with GRIP and GluA2. The underlying mechanism appears to involve Frmpd3-mediated regulation of GluA2 trafficking from the cytoplasm to the membrane, ultimately enhancing neuronal excitability through increased membrane expression of GluA2-containing AMPA receptors. Full article