Search Results (255)

Chronic pain (CP) represents a multidimensional condition in which cognitive and emotional factors shape the individual experience from perception to action. The purpose of this study was to characterize the functional significance of alterations in neural oscillatory dynamics underlying the transition from resting-state to cognitive load across distinct CP phenotypes. Continuous electroencephalographic data were acquired from patients with headache, migraine, and spine-related pain, as well as healthy controls, during rest and three visual–cognitive–motor (VCM) tasks: reaction time, working memory, and associative learning. First, within CP subgroups, we examined cognitive-load-related changes in oscillatory activity. In migraine patients, alpha/beta power attenuation induced during cognitive processing correlated with higher reported pain intensity. Relative to the spine-related pain group, migraine patients exhibited increased occipital alpha and gamma band activity during working memory and associative learning conditions, as a possible neurophysiological signature of cortical hyperexcitability. By comparing a subset of headache patients to healthy controls, we found elevated resting-state delta and gamma activity in the patient group. Under cognitive load conditions, headache patients showed higher power across delta, theta, beta, and gamma frequency bands. Delta and theta activity elicited during the working memory task correlated negatively with pain intensity. Our results demonstrate that the experience of chronic pain is accompanied by frequency-specific alterations in both resting and cognitive-associated oscillatory dynamics, reflecting impaired visual working-memory processing and top–down modulation of behaviorally relevant stimuli. Full article

Background. MiR-218 is a micro-RNA expressed in two isoforms (miR-218-1 and miR-218-2) in the brain and, within the mesencephalic area, it represents a specific regulator of differentiation and functional maturation of the dopamine-releasing neurons (DAn). Deletion of miR-218 isoforms within the midbrain alters the expression of synaptic mRNAs, the neuronal excitability of DAn of the substantia nigra pars compacta (SNpc), and their ability to release dopamine (DA) within the dorsal striatum. Objectives. Here we have investigated if miR-218 impacts the function of the DAn population adjacent to SNpc, the mesencephalic ventral tegmental area (VTA) innervating the nucleus accumbens (NAcc), and the medial prefrontal cortex. Methods. With the use of miR-218-1, miR-218-2, and double conditional knock-out mice (KO1, c-KO2, c-dKO), we performed electrophysiological recordings in VTA DAn to investigate firing activity, measurements of DA release in NAcc slices by constant potential amperometry (CPA), and in vivo behavioral analysis. Results. We find that KO1 VTA neurons display hyperexcitability in comparison with c-KO2, c-dKO, and wild type (WT) neurons. DA efflux in the NAcc core and shell is reduced in all single- and double-conditional KO striatal slices in comparison with controls. The KO1 mice display a tendency toward an anxiety-like trait, as revealed by the elevated plus maze test. Conclusions. Our data indicate that miR-218-1 is the isoform that mainly regulates VTA DA neuron excitability whereas both miR-218-1 and miR-218-2 impair DA release in the mesoaccumbens pathway. Full article

Calcium-dependent cysteine proteases, known as calpains, emerge as important regulators of spinal cord physiology, plasticity, and pathology. First characterized in the brain, they influence a wide range of processes in the spinal cord, maintaining neuronal homeostasis, shaping both synaptic and intrinsic plasticity, and modulating glial responses. When dysregulated, calpains contribute to the pathophysiology of traumatic and neurodegenerative spinal cord disorders, as well as to their associated motor and sensory complications, including spasticity and neuropathic pain. A recurring feature of these conditions is calpain-mediated proteolysis of ion channels, transporters, and cytoskeletal proteins, which promotes disinhibition and neuronal hyperexcitability. The resultant protein fragments are examined as prospective biomarkers for damage and disease progression. Meanwhile, promising strategies for neuroprotection and functional recovery in the clinic emerge as a result of innovative pharmacological and genetic approaches to modulate calpain activity. In this review, we present the current state of knowledge regarding the functions and regulation of calpains in the spinal cord and assess their translational potential as both therapeutic targets and effectors in spinal cord disorders. Full article

Background/Objectives: Epilepsy is identified by irregular neuronal hyperexcitability, generating recurrent seizures. Despite many available pharmacological treatments, certain patients with drug-resistant epilepsy may require novel therapeutic approaches. In the present study, we aimed to evaluate the effects of lacosamide, low-frequency repetitive transcranial magnetic stimulation, and their combination on intracellular calcium dynamics in an in vitro model of neuronal excitability, hypothesizing that these interventions could mitigate potassium chloride-induced neuronal excitation. Methods: We utilized differentiated SH-SY5Y human neuroblastoma cells as an in vitro model of neuronal excitability. Neuronal excitability was induced with 50 mM KCl, and cells were treated with lacosamide (300 µM), rTMS (1 Hz), or their combination. Intracellular calcium levels were quantified using fluo-4 AM fluorescence calcium imaging, with changes expressed as percentage change in fluorescence intensity (%ΔF/F) relative to baseline. Results: The combination of lacosamide and rTMS was the most effective, significantly reducing KCl-induced calcium elevation (ΔF/F = 9.15) compared to lacosamide alone (ΔF/F = 17.11), rTMS alone (ΔF/F = 23.70), and the untreated cells serving as controls (ΔF/F = 66.70). The combination showed a statistically significant effect, with enhanced suppression of neuronal excitability compared to individual treatments. Conclusions: Lacosamide and low-frequency rTMS (1 Hz) effectively attenuated KCl-induced changes in intracellular calcium levels in vitro, with their combination demonstrating the highest efficacy. These findings suggest a promising foundation in the management of drug-resistant epilepsy. Future studies are necessitated to validate these results and benefit clinical translation. Full article

Myricetin (MYR), a naturally occurring flavonoid widely distributed in fruits and vegetables, was investigated for its potential to reduce inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc), which is associated with hyperalgesia. The study also compared MYR’s impact with that of celecoxib (CEL), a non-steroidal anti-inflammatory drug (NSAID). To induce inflammation, Complete Freund’s adjuvant was injected into the whisker pads of rats. Subsequently, we measured the mechanical escape threshold by applying mechanical stimuli to the orofacial region. We found that inflamed rats exhibited a significantly lower threshold compared to naive rats (each group, n = 4). This reduced threshold returned to the naive level two days after the administration of MYR (16 mg/kg, i.p.), CEL (10 mg/kg, i.p.), and a combination of MYR (8 mg/kg, i.p.) + CEL (5 mg/kg, i.p.). To investigate the nociceptive neural response to orofacial mechanical stimulation, we performed extracellular single-unit recordings to measure the activity of SpVc wide-dynamic range (WDR) neurons in anesthetized subjects. In inflamed rats, administration of MYR, CEL, or 1/2MYR + 1/2CEL (each group, n = 4) significantly reduced both the average spontaneous activity and the evoked firing rate of SpVc neurons in response to non-painful and painful mechanical stimuli. The increased average receptive field size in inflamed rats was normalized to the naive level following treatment with MYR, CEL, or 1/2MYR + 1/2CEL. These findings suggest that MYR administration can mitigate inflammatory hyperalgesia by reducing the heightened excitability of SpVc WDR neurons. This supports the notion that MYR could be a viable therapeutic option in complementary and alternative medicine for preventing trigeminal inflammatory mechanical hyperalgesia, potentially serving as an alternative to selective cyclooxygenase-2 blockers. Full article

Background and Objectives: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease affecting the upper and lower motor neurons, with a bleak prognosis and few treatment options. Non-invasive brain stimulation (NIBS) techniques, such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), represent emerging approaches aimed at modulating cortical hyperexcitability, a relevant pathogenetic mechanism in ALS. Materials and Methods: A systematic review of the literature was conducted following the PRISMA guidelines, exploring the Scopus and PubMed databases from April to June 2025 with terms related to ALS and NIBS. A total of 18 relevant studies were selected from the initial 708 articles, analysing stimulation protocols, clinical and neurophysiological outcomes, and associated biomarkers; their validity was assessed using the revised Cochrane risk-of-bias (RoB2) tool. Results: The selected studies were extremely heterogeneous, with NIBS techniques, including magnetic (rTMS, cTBS, tSMS) and electrical (tDCS) stimulation, showing variable effects. Low-frequency protocols (1 Hz rTMS) and cTBS showed a slight slowing of clinical progression, while prolonged home stimulation with tDCS and tSMS showed more significant improvements in terms of efficacy, tolerability, and adherence. The main limitations concern the heterogeneity of patients and protocols and the lack of standardised biomarkers, which is why the analysis remained at a descriptive level. The use of telemonitoring and caregiver training are essential to ensure safety and accessibility. Conclusions: NIBS represents a promising therapeutic approach for ALS, but further multicentre, standardised studies with prolonged follow-up are needed. Future strategies should include customisation of stimulation, combination with other therapies, and extension of application to pre-symptomatic phases. Full article

Background/Objectives: The voltage-gated potassium channels of the Kv4 family (Kv4.1, Kv4.2, Kv4.3) regulate neuronal excitability and synaptic integration. The dysregulation of these channels has been linked to neurodegenerative diseases, such as Alzheimer’s disease (AD), spinocerebellar ataxias, amyotrophic lateral sclerosis (ALS), prion diseases, and Parkinson’s disease (PD). Current evidence is scattered across diverse models, and a systematic synthesis is lacking. This review seeks to compile and analyze data on Kv4 channel alterations in neurodegeneration, focusing on genetic variants, functional changes, and phenotypic consequences. Methods: A systematic search was conducted for peer-reviewed studies, including human participants, human-derived cell models, and relevant animal models. Studies were considered eligible if they investigated Kv4.1–Kv4.3 (encoded by gene encoding the Kv4.1-Kv4.3 α-subunit of voltage-gated A-type potassium channels (KCND1-KCND3)) expression, function, or genetic variants, as well as associated auxiliary subunits such as DPP6 (dipeptidyl peptidase–like protein 6) and KChIP2 (Kv channel–interacting protein 2), in neurodegenerative diseases. Both observational and experimental designs were considered. Data extraction included disease type, model, Kv4 subunit, functional or genetic findings, and key outcomes. Risk of bias was assessed in all included studies. Results: Kv4 channels exhibit significant functional and expression changes in various neurodegenerative diseases. In AD and prionopathies, reduced Kv4.1- and Kv4.2-mediated currents contribute to neuronal hyperexcitability. In spinocerebellar ataxias, KCND3 mutations cause loss- or gain-of-function phenotypes in Kv4.3, disrupting cerebellar signaling. In models of ALS and PD, Kv4 dysfunction correlates with altered neuronal excitability and can be modulated pharmacologically. Subunit modulators such as DPP6 and KChIP2 influence channel function and could represent therapeutic targets. Conclusions: Kv4 channels are crucial for neuronal excitability in multiple neurodegenerative contexts. Dysregulation through genetic or pathological mechanisms contributes to functional deficits, highlighting Kv4 channels as promising targets for interventions aimed at restoring electrical homeostasis and mitigating early neuronal dysfunction. Full article

This study investigated the potential of astaxanthin (AST), a natural carotenoid, to mitigate inflammation-induced hyperexcitability in the spinal trigeminal nucleus caudalis (SpVc) and the associated hyperalgesia. The efficacy of systemic AST application was compared to that of celecoxib (CEL). Inflammation was induced by injecting Complete Freund’s adjuvant into the whisker pads of rats. The mechanical escape threshold was then assessed by delivering mechanical stimuli to the orofacial region. Although inflamed rats exhibited a significantly lower mechanical threshold compared to naïve rats, this threshold was restored to normal levels two days after treatment with AST, CEL, and the 1/2 CEL + 1/2 AST combination. The activity of SpVc wide-dynamic range (WDR) neurons was measured using extracellular single-unit recordings in response to mechanical stimulation of the orofacial area under anesthesia. In inflamed rats, AST, CEL, and 1/2 CEL + 1/2 AST administration significantly reduced the average firing rate of these neurons elicited by both non-noxious and noxious mechanical stimuli. In addition, all three treatments significantly decreased the heightened average spontaneous activity of SpVc neurons and normalized the increased average receptive field size in inflamed rats. This study provides evidence that systemic AST administration attenuates inflammatory mechanical hyperalgesia. This action is associated with the suppression of hyperexcitability in nociceptive SpVc WDR neurons, likely through the inhibition of the cyclooxygenase-2 signaling pathway. These findings support the potential of AST as a therapeutic agent for complementary and alternative medicine. It may provide a valuable alternative to non-steroidal anti-inflammatory drugs for the prevention of trigeminal inflammatory mechanical hyperalgesia. Full article

Contactin-associated protein-like 2 (CASPR2) is a transmembrane protein of the neurexin superfamily, essential for clustering voltage-gated potassium channels, particularly Kv1, at the juxtaparanodal regions of myelinated axons. This precise localisation is essential for maintaining normal axonal excitability and preventing aberrant signal propagation. Autoantibodies targeting CASPR2 have been associated with various neurological syndromes, notably peripheral nerve hyperexcitability (PNH), which presents clinically with neuromyotonia and myokymia. PNH is characterised by distinctive electrophysiological findings, including neuromyotonic discharges, myokymic discharges, and afterdischarges, which provide diagnostic value and insight into underlying pathophysiology. This review explores the mechanisms of anti-CASPR2-associated PNH, focusing on how antibody-mediated disruption of Kv1 channel clustering leads to altered axonal excitability. Current evidence suggests that both the distal and proximal segments of the axon are sites of pathological activity, where impairments in action potential termination and re-entry prevention result in spontaneous, repetitive discharges. While afterdischarges likely originate within the axon, the precise location—whether in the alpha-motoneuron soma or axon—is uncertain. The involvement of spinal inhibitory circuits has also been proposed, though it remains speculative. Understanding the neurophysiological features of anti-CASPR2-associated PNH is essential for improving diagnostic accuracy and guiding treatment strategies. Further research is needed to clarify the mechanisms of CASPR2-related hyperexcitability. Full article

The bidirectional relationship between epilepsy and depression illustrates shared neurobiological mechanisms of neuroinflammation, hypothalamic–pituitary–adrenal axis dysregulation, and glutamatergic dysfunction. Depression is present in 20–55% of people with epilepsy, far greater than in the general population, while depression doubles epilepsy risk 2.5-fold, indicating shared pathophysiology. Neuroinflammatory mediators (interleukin-6, tumor necrosis factor alpha, high-mobility group box 1) establish a vicious cycle: seizures exacerbate inflammation and mood disruption, and stress lowers seizure thresholds. Hippocampal damage and cortisol toxicity also link these disorders, with early life stress imprinting lifelong risk via epigenetic alteration. Genetic studies identify pleiotropic genes (brain-derived neurotrophic factor) that regulate synaptic plasticity, serotonin activity, and immune responses. New treatments target shared pathways: ketamine and AMPAkines normalize glutamate tone; mGluR5 antagonists attenuate hyperexcitability and inflammation; DNA methyltransferase inhibitors reverse aberrant DNA methylation; and probiotics manipulate the gut–brain axis by boosting neuroprotective metabolites like butyrate. Despite challenges—transient effects, precision dosing, and blood–brain barrier penetration—these advances constitute a paradigm shift toward mechanistic repair rather than symptom management. The way forward includes clustered regularly interspaced short palindromic repeats (CRISPR)-based epigenome editing, biomarker-led therapies, and combination approaches (e.g., ketamine and probiotics). Such comorbidity needs to be managed holistically through integrated neuropsychiatry care, offering hope to patients with treatment-refractory symptoms. Full article

Sleep is a vital biological function governed by neuronal networks in the brainstem, hypothalamus, and thalamus. Disruptions in these circuits contribute to the sleep disturbances observed in neurodegenerative disorders, including Parkinson’s disease, epilepsy, Huntington’s disease, and Alzheimer’s disease. Oxidative stress, mitochondrial dysfunction, neuroinflammation, and abnormal protein accumulation adversely affect sleep architecture in these conditions. The interaction among these pathological processes is believed to modify sleep-regulating circuits, consequently worsening clinical symptoms. This review examines the cellular and molecular mechanisms that impair sleep regulation in experimental models of these four disorders, emphasizing how oxidative stress, neuroinflammation and synaptic dysfunction contribute to sleep fragmentation and alterations in rapid eye movement (REM) sleep and slow-wave sleep (SWS) phases. In Parkinson’s disease models (6-OHDA and MPTP), dopaminergic degeneration and damage to sleep-regulating nuclei result in daytime somnolence and disrupted sleep patterns. Epilepsy models (kainate, pentylenetetrazole, and kindling) provoke hyperexcitability and oxidative damage, compromising both REM and SWS. Huntington’s disease models (R6/2 and 3-NP) demonstrate reduced sleep duration, circadian irregularities, and oxidative damage in the hypothalamus and suprachiasmatic nucleus. In Alzheimer’s disease (AD) models (APP/PS1, 3xTg-AD, and Tg2576), early sleep problems include diminished SWS and REM sleep, increased awakenings, and circadian rhythm disruption. These changes correlate with β-amyloid and tau deposition, glial activation, chronic inflammation, and mitochondrial damage in the hypothalamus, hippocampus, and prefrontal cortex. Sleep disturbances across these neurodegenerative disease models share common underlying mechanisms like oxidative stress, neuroinflammation, and mitochondrial dysfunction. Understanding these pathways may reveal therapeutic targets to improve both motor symptoms and sleep quality in neurodegenerative disorders. Full article

Giant somatosensory evoked potentials (gSEPs) are abnormally high-amplitude cortical responses to peripheral nerve stimulation, traditionally regarded as electrophysiological hallmarks of progressive myoclonic epilepsies (PMEs). However, accumulating evidence shows their presence in a broader range of non-epileptic conditions, including focal lesions, metabolic encephalopathies, neurodegenerative diseases, and even functional disorders. This review offers a comprehensive analysis of the physiological mechanisms, diagnostic criteria, and clinical significance of gSEPs, integrating data from both classical and emerging neurophysiological techniques. gSEPs are mainly produced in the primary somatosensory cortex through mechanisms involving cortical disinhibition, impaired GABAergic transmission, and altered thalamocortical connectivity. In epileptic syndromes such as Unverricht–Lundborg disease and other PMEs, gSEPs reflect cortical hyperexcitability and are closely linked to cortical myoclonus. Conversely, in non-epileptic contexts, they may indicate transient or chronic cortical dysfunction. The diagnostic utility of gSEPs ranges from differential diagnosis of myoclonus to monitoring disease. However, heterogeneity in amplitude definitions and recording protocols hinders the standardization of these measurements. This may result in the identification of the right threshold to differentiate conditions associated with simple increased versus giant SEP, the latter of which may help identify truly epileptic conditions from other disorders simply associated with increased SEP amplitude. Full article

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Epilepsy remains a major therapeutic challenge, with approximately one-third of patients experiencing drug-resistant epilepsy (DRE) despite the availability of multiple antiseizure medications (ASMs). This review aims to evaluate emerging ASMs—cenobamate, fenfluramine, ganaxolone, ezogabine (retigabine), and perampanel—with a focus on their mechanisms of action, pharmacological profiles, and potential role in precision medicine. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science to identify preclinical and clinical studies evaluating the pharmacodynamics, pharmacokinetics, efficacy, and safety of the selected ASMs. Relevant trials, reviews, and mechanistic studies were reviewed to synthesize the current understanding of their application in DRE and specific epilepsy syndromes. Each ASM demonstrated unique mechanisms targeting hyperexcitability, including the modulation of γ-aminobutyric acid receptor A (GABA-A) receptors, sodium and potassium channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptors), and serotonin systems. These mechanisms correspond with specific pathophysiological features in syndromes such as Dravet and Lennox–Gastaut. Evidence from clinical trials supports their use as adjunctive therapies with generally favorable tolerability, though adverse events and variable efficacy profiles were noted. The mechanistic diversity of these emerging ASMs supports their value in personalized epilepsy management, particularly in treatment-resistant cases. While the promise of precision medicine is evident, further studies are required to address challenges related to long-term safety, cost, and equitable access. Full article

Astrocytes, a subtype of glial cells, have multiple roles in regulating neuronal development and homeostasis. In addition to the typical mammalian astrocytes, in the primate cortex, interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. Previously, we described a human stem cell based chimeric mouse model where interlaminar astrocytes develop. Here, we utilized this model to study the calcium signaling properties of interlaminar astrocytes. To determine how interlaminar astrocytes could contribute to neurodevelopmental disorders, we generated a chimeric mouse model for Fragile X syndrome (FXS). We report that FXS interlaminar astrocytes exhibit hyperexcitable calcium signaling and are associated with dendritic spines with increased turnover rate. Full article