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Background: The benefits of oral caffeine intake to enhance several aspects of physical performance, such as aerobic endurance, strength, power, and muscle endurance performance, are well supported. However, how the physical performance benefits of caffeine supplementation are translated into better specific actions in intermittent sports during real or simulated competition has been the topic of fewer investigations, and their results need to be appropriately reviewed and meta-analyzed. Objective: The aim of the study was to investigate the effects of acute caffeine intake on specific actions in intermittent sports involving decision making and high-intensity efforts (eg, team, racket, and combat sports) during real or simulated competitions. Methods: All studies included had blinded and crossover experimental designs, and we conducted a risk-of-bias analysis. In total, we included 24 studies. A meta-analysis was performed using the random-effects model to calculate the standardized mean difference (SMD) estimated by Hedges g and 95% CIs. Results: Caffeine ingestion increased high-intensity sport-specific actions during competition, such as the number of sprints (SMD: 0.48; 95% CI, 0.23–0.74), body impacts (SMD: 0.28; 95% CI, 0.08–0.49), accelerations (SMD: 0.35; 95% CI, 0.06–0.63), decelerations (SMD: 0.63; 95% CI, 0.12–1.14), and high-intensity offensive efforts (SMD: 0.36; 95% CI, 0.11–0.61). Additionally, caffeine ingestion induced a higher positive or success rate of actions during real or simulated competition (SMD: 0.44; 95% CI, 0.19–0.69). Conclusion: The current meta-analysis provides evidence of caffeine supplementation in increasing high-intensity efforts and the success rate of sport-specific actions during real or simulated competition. [ABSTRACT FROM AUTHOR]

BACKGROUND: The characteristics of electrocardiogram (ECG) abnormalities related to cardiac channelopathies potentially linked to sudden cardiac death (SCD) are not widely recognized in Iran. We examined the prevalence of such ECG patterns and their related factors among adult residents of Tehran, Iran. METHODS: The clinical characteristics and 12-lead ECGs of Tehran Cohort Study participants were examined. Long QT intervals, short QT intervals, Brugada syndrome (BrS) patterns, and early repolarization (ER) were evaluated using computer-based assessment software validated by cardiologists. Logistic regression models were employed to identify the factors associated with the prevalence of different ECG patterns. RESULTS: Out of 7678 available ECGs, 7350 were included in this analysis. Long QT interval, ER pattern, BrS patterns, and short QT interval were found in 3.08%, 1.43%, 0.31%, and 0.03% of participants, respectively. The prevalence of long QT interval increased with age, opium consumption, and presence of hypertension. Younger age, lower body mass index (BMI), alcohol use and male sex were independently linked to an elevated prevalence of ER pattern. Most individuals with BrS patterns were men (95%) and had lower BMI, high- and low-density lipoprotein, and total cholesterol compared to those without the BrS pattern. At a mean follow-up of 30.2 ± 5.5 months, all-cause mortality in the group exhibiting abnormal ECG patterns (6.3%) was approximately twice as high as that in the group without such patterns (2.96%). CONCLUSION: Abnormal ECG patterns corresponding to channelopathies were relatively rare among adult residents of the Tehran population, and their prevalence was influenced by various factors. CLINICAL TRIAL NUMBER: Not applicable.

AIMS: The concept of atrial cardiomyopathy (AtCM) had been percolating through the literature since its first mention in 1972. Since then, publications using the term were sporadic until the decision was made to convene an expert working group with representation from four multinational arrhythmia organizations to prepare a consensus document on atrial cardiomyopathy in 2016 (EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication). Subsequently, publications on AtCM have increased progressively. METHODS AND RESULTS: The present consensus document elaborates the 2016 AtCM document further to implement a simple AtCM staging system (AtCM stages 1-3) by integrating biomarkers, atrial geometry, and electrophysiological changes. However, the proposed AtCM staging needs clinical validation. Importantly, it is clearly stated that the presence of AtCM might serve as a substrate for the development of atrial fibrillation (AF) and AF may accelerates AtCM substantially, but AtCM per se needs to be viewed as a separate entity. CONCLUSION: Thus, the present document serves as a clinical consensus statement of the European Heart Rhythm Association (EHRA) of the ESC, the Heart Rhythm Society (HRS), the Asian Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) to contribute to the evolution of the AtCM concept.

Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individuals distinct endophenotype.

The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was

INTRODUCTION: The evidence for spinal cord stimulation (SCS) has been criticized for the absence of blinded, parallel randomized controlled trials (RCTs) and limited evaluations of the long-term effects of SCS in RCTs. The aim of this study was to determine whether evoked compound action potential (ECAP)-controlled, closed-loop SCS (CL-SCS) is associated with better outcomes when compared with fixed-output, open-loop SCS (OL-SCS) 36 months following implant. METHODS: The EVOKE study was a multicenter, participant-blinded, investigator-blinded, and outcome assessor-blinded, randomized, controlled, parallel-arm clinical trial that compared ECAP-controlled CL-SCS with fixed-output OL-SCS. Participants with chronic, intractable back and leg pain refractory to conservative therapy were enrolled between January 2017 and February 2018, with follow-up through 36 months. The primary outcome was a reduction of at least 50% in overall back and leg pain. Holistic treatment response, a composite outcome including pain intensity, physical and emotional functioning, sleep, and health-related quality of life, and objective neural activation was also assessed. RESULTS: At 36 months, more CL-SCS than OL-SCS participants reported ≥50% reduction (CL-SCS=77.6%, OL-SCS=49.3%; difference: 28.4%, 95% CI 12.8% to 43.9%, p

The Na+-Ca2+ exchanger (NCX1) is the dominant Ca2+ extrusion mechanism in cardiac myocytes. NCX1 activity is inhibited by intracellular Na+ via a process known as Na+-dependent inactivation. A central question is whether this inactivation plays a physiological role in heart function. Using CRISPR/Cas9, we inserted the K229Q mutation in the gene (Slc8a1) encoding for NCX1. This mutation removes the Na+-dependent inactivation while preserving transport properties and other allosteric regulations. NCX1 mRNA levels, protein expression, and protein localization are unchanged in K229Q male mice. However, they exhibit reduced left ventricular ejection fraction and fractional shortening, while displaying a prolonged QT interval. K229Q ventricular myocytes show enhanced NCX1 activity, resulting in action potential prolongation, higher incidence of aberrant action potentials, a faster decline of Ca2+ transients, and depressed cell shortening. The results demonstrate that NCX1 Na+-dependent inactivation plays an essential role in heart function by affecting both cardiac excitability and contractility.

TRAAK, TREK-1, and TREK-2 are mechanosensitive two-pore domain K+ (K2P) channels that contribute to action potential propagation, sensory transduction, and muscle contraction. While structural and functional studies have led to models that explain their mechanosensitivity, we lack a quantitative understanding of channel activation by membrane tension. Here, we define the tension response of mechanosensitive K2Ps using patch-clamp recording and imaging. All are low-threshold mechanosensitive channels (T10%/50% 0.6-2.7 / 4.4-6.4 mN/m) with distinct response profiles. TRAAK is most sensitive, TREK-1 intermediate, and TREK-2 least sensitive. TRAAK and TREK-1 are activated broadly over a range encompassing nearly all physiologically relevant tensions. TREK-2, in contrast, activates over a narrower range like mechanosensitive channels Piezo1, MscS, and MscL. We further show that low-frequency, low-intensity focused ultrasound increases membrane tension to activate TRAAK and MscS. This work provides insight into tension gating of mechanosensitive K2Ps relevant to understanding their physiological roles and potential applications for ultrasonic neuromodulation.

Human voltage-gated sodium (hNaV) channels are responsible for initiating and propagating action potentials in excitable cells, and mutations have been associated with numerous cardiac and neurological disorders. hNaV1.7 channels are expressed in peripheral neurons and are promising targets for pain therapy. The tarantula venom peptide protoxin-II (PTx2) has high selectivity for hNaV1.7 and is a valuable scaffold for designing novel therapeutics to treat pain. Here, we used computational modeling to study the molecular mechanisms of the state-dependent binding of PTx2 to hNaV1.7 voltage-sensing domains (VSDs). Using Rosetta structural modeling methods, we constructed atomistic models of the hNaV1.7 VSD II and IV in the activated and deactivated states with docked PTx2. We then performed microsecond-long all-atom molecular dynamics (MD) simulations of the systems in hydrated lipid bilayers. Our simulations revealed that PTx2 binds most favorably to the deactivated VSD II and activated VSD IV. These state-specific interactions are mediated primarily by PTx2's residues R22, K26, K27, K28, and W30 with VSD and the surrounding membrane lipids. Our work revealed important protein-protein and protein-lipid contacts that contribute to high-affinity state-dependent toxin interaction with the channel. The workflow presented will prove useful for designing novel peptides with improved selectivity and potency for more effective and safe treatment of pain.

Primary visual cortex (V1) has been the focus of extensive neurophysiological investigations, with its laminar organization serving as a crucial model for understanding the functional logic of neocortical microcircuits. Utilizing newly developed high-density, Neuropixels probes, we measured visual responses from large populations of simultaneously recorded neurons distributed across layers of macaque V1. Within single recordings, myriad differences in the functional properties of neuronal subpopulations could be observed. Notably, while standard measurements of orientation selectivity showed only minor differences between laminar compartments, decoding stimulus orientation from layer 4C responses outperformed both superficial and deep layers within the same cortical column. The superior orientation discrimination within layer 4C was associated with greater response reliability of individual neurons rather than lower correlated activity within neuronal populations. Our results underscore the efficacy of high-density electrophysiology in revealing the functional organization and network properties of neocortical microcircuits within single experiments.

Over the past decade, stereotactically placed electrodes have become the gold standard for deep brain recording and stimulation for a wide variety of neurological and psychiatric diseases. Current electrodes, however, are limited in their spatial resolution and ability to record from small populations of neurons, let alone individual neurons. Here, we report on an innovative, customizable, monolithically integrated human-grade flexible depth electrode capable of recording from up to 128 channels and able to record at a depth of 10 cm in brain tissue. This thin, stylet-guided depth electrode is capable of recording local field potentials and single unit neuronal activity (action potentials), validated across species. This device represents an advance in manufacturing and design approaches which extends the capabilities of a mainstay technology in clinical neurology.

A remaining challenge for genetically encoded voltage indicators (GEVIs) is the reliable detection of excitatory postsynaptic potentials (EPSPs). Here, we developed ASAP5 as a GEVI with enhanced activation kinetics and responsivity near resting membrane potentials for improved detection of both spiking and subthreshold activity. ASAP5 reported action potentials (APs) in vivo with higher signal-to-noise ratios than previous GEVIs and successfully detected graded and subthreshold responses to sensory stimuli in single two-photon trials. In cultured rat or human neurons, somatic ASAP5 reported synaptic events propagating centripetally and could detect ∼1-mV EPSPs. By imaging spontaneous EPSPs throughout dendrites, we found that EPSP amplitudes decay exponentially during propagation and that amplitude at the initiation site generally increases with distance from the soma. These results extend the applications of voltage imaging to the quantal response domain, including in human neurons, opening up the possibility of high-throughput, high-content characterization of neuronal dysfunction in disease. [Display omitted] • Multiparametric screening generated a GEVI with higher gain and faster onset, ASAP5 • ASAP5 exhibits higher responsivity to action potentials and mEPSPs than other GEVIs • ASAP5 reveals mEPSP dendritic propagation and network activity in rat and human neurons • ASAP5 demonstrated high-SNR voltage recordings in flies, fish, and mice Hao, Lee, et al. report ASAP5, a GEVI that enhances responsivity and accelerates kinetics. It enables single-trial recordings of sub- and suprathreshold activities in flies, mice, and human stem-cell-derived neurons, offering new possibilities to study the dynamics of membrane potentials from 1 to 100 mV. [ABSTRACT FROM AUTHOR]

Patients with myotonia congenita suffer from slowed muscle relaxation caused by hyperexcitability. The diaphragm is only mildly affected in myotonia congenita; discovery of the mechanism underlying its resistance to myotonia could identify novel therapeutic targets. Intracellular recordings from two mouse models of myotonia congenita revealed the diaphragm had less myotonia than either the extensor digitorum longus (EDL) or the soleus muscles. A mechanism contributing to resistance of the diaphragm to myotonia was reduced depolarization of the interspike membrane potential during repetitive firing of action potentials, a process driven by build‐up of K+ in small invaginations of muscle membrane known as t‐tubules. We explored differences between diaphragm and EDL that might underlie reduction of K+ build‐up in diaphragm t‐tubules. Smaller size of diaphragm fibres, which promotes diffusion of K+ out of t‐tubules, was identified as a contributor. Intracellular recording revealed slower repolarization of action potentials in diaphragm suggesting reduced Kv conductance. Higher resting membrane conductance was identified suggesting increased Kir conductance. Computer simulation found that a reduction of Kv conductance had little effect on K+ build‐up whereas increased Kir conductance lessened build‐up, although the effect was modest. Our data and computer simulation suggest opening of K+ channels during action potentials has little effect on K+ build‐up whereas opening of K+ channels during the interspike interval slightly lessens K+ build‐up. We conclude that activation of K+ channels may lessen myotonia by opposing depolarization to action potential threshold without worsening K+ build‐up in t‐tubules. Key points: In mouse models of the muscle disease myotonia congenita, the diaphragm has much less myotonia (muscle stiffness) than the extensor digitorum longus or soleus muscles.Identifying why the diaphragm is resistant to myotonia may help in developing novel therapy.We found the reason the diaphragm has less myotonia is that it is less prone to depolarization caused by K+ build‐up in t‐tubules during repetitive firing of action potentials.Smaller fibre size contributes to resistance to K+ build‐up with differences in K+ currents playing little role.Our data suggest drugs that open K+ channels may be effective in treating myotonia as they may lessen excitability without worsening K+ build‐up in t‐tubules. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss, leading to motor and non‐motor symptoms. Early detection before symptom onset is crucial but challenging. This study presents a framework integrating circuit modeling, non‐equilibrium dynamics, and optimization to understand PD pathogenesis and enable precision interventions. Neuronal firing patterns, particularly oscillatory activity, play a critical role in PD pathology. The basal ganglia network, specifically the subthalamic nucleus‐external globus pallidus (STN‐GPe) circuitry, exhibits abnormal activity associated with motor dysfunction. The framework leverages the non‐equilibrium landscape and flux theory to identify key connections generating pathological activity, providing insights into disease progression and potential intervention points. The intricate STN‐GPe interplay is highlighted, shedding light on compensatory mechanisms within this circuitry may initially counteract changes but later contribute to pathological alterations as disease progresses. The framework addresses the need for comprehensive evaluation methods to assess intervention outcomes. Cross‐correlations between state variables provide superior early warning signals compared to traditional indicators relying on critical slowing down. By elucidating compensatory mechanisms and circuit dynamics, the framework contributes to improved management, early detection, risk assessment, and potential prevention/delay of PD development. This pioneering research paves the way for precision medicine in neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Potassium ion channels play a fundamental role in regulating cell membrane repolarization, modulating the frequency and shape of action potentials, and maintaining the resting membrane potential. A growing number of studies have indicated that dysfunction in potassium channels associates with the pathogenesis and treatment of depression. However, the involvement of potassium channels in the onset and treatment of depression has not been thoroughly summarized. In this review, we performed a comprehensive analysis of the association between multiple potassium channels and their roles in depression, and compiles the SNP loci of potassium channels associated with depression, as well as antidepressant drugs that target these channels. We discussed the pivotal role of potassium channels in the treatment of depression, provide valuable insights into new therapeutic targets for antidepressant treatment and critical clues to future drug discovery. [ABSTRACT FROM AUTHOR]

Most computational models of neurons assume constant ion concentrations, disregarding the effects of changing ion concentrations on neuronal activity. Among the models that do incorporate ion concentration dynamics, simplifications are often made that sacrifice biophysical consistency, such as neglecting the effects of ionic diffusion on electrical potentials or the effects of electric drift on ion concentrations. A subset of models with ion concentration dynamics, often referred to as electrodiffusive models, account for ion concentration dynamics in a way that ensures a biophysical consistent relationship between ion concentrations, electric charge, and electrical potentials. These models include compartmental single-cell models, geometrically explicit models, and domain-type models, but none that model neuronal network dynamics. To address this gap, we present an electrodiffusive network model with multicompartmental neurons and synaptic connections, which we believe is the first compartmentalized network model to account for intra- and extracellular ion concentration dynamics in a biophysically consistent way. The model comprises an arbitrary number of "units," each divided into three domains representing a neuron, glia, and extracellular space. Each domain is further subdivided into a somatic and dendritic layer. Unlike conventional models which focus primarily on neuronal spiking patterns, our model predicts intra- and extracellular ion concentrations (Na+, K+, Cl−, and Ca2+), electrical potentials, and volume fractions. A unique feature of the model is that it captures ephaptic effects, both electric and ionic. In this paper, we show how this leads to interesting behavior in the network. First, we demonstrate how changing ion concentrations can affect the synaptic strengths. Then, we show how ionic ephaptic coupling can lead to spontaneous firing in neurons that do not receive any synaptic or external input. Lastly, we explore the effects of having glia in the network and demonstrate how a strongly coupled glial syncytium can prevent neuronal depolarization blocks. Author summary: Neurons communicate using electrical signals called action potentials. To create these signals, sodium ions must flow into the cells and potassium ions must flow out. This transmembrane flow requires a concentration difference across the neuronal membrane, which the brain works continuously to maintain. When scientists build mathematical models of neurons, they often apply the simplifying assumption that these ion concentration differences remain constant over time. This assumption works well for many scenarios, but not all. For instance, during events like stroke or epilepsy, the ion concentrations can change dramatically, affecting how neurons behave. Moreover, recent literature suggests that changing ion concentrations also play an important role in normal brain function. To study these scenarios, we need models that can dynamically track changes in ion concentrations. The neuroscience community currently lacks a computational model describing the effects of ion concentration dynamics on neuronal networks, while maintaining a biophysical consistent relationship between ion concentrations and electrical potentials. To address the need for such a model, we have developed a neuronal network model that predicts changes in both intra- and extracellular ion concentrations, electrical potentials, and volumes in a biophysically consistent way. [ABSTRACT FROM AUTHOR]

The article discusses the importance of calcium flux balance in the heart, focusing on the equilibrium between calcium entering and leaving cardiac cells to prevent calcium overload. It highlights the role of various proteins and organelles in maintaining this balance, such as SERCA, NCX, LTCC, and RyR. The text responds to criticisms regarding the effects of caffeine on calcium release and emphasizes the necessity of considering calcium flux balance when studying the impact of drugs on calcium handling in the heart. [Extracted from the article]

Background: Spinocerebellar ataxia type 3 (SCA3), also known as Machado–Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in exon 10 of ATXN3. Extra-cerebellar manifestations, including external ophthalmoplegia, dystonia, Parkinsonism, and peripheral neuropathy, are predominantly present in SCA3 cases. Here, we report a case of SCA3 presenting with a split hand and minipolymyoclonus. Case presentation: A 73-year-old female patient presented with a 5-year history of ataxic gait. Neurological examination revealed cerebellar ataxia and minipolymyoclonus in the digits on both sides and muscle atrophy in the right hand, consistent with the split hand pattern. Electrodiagnostic studies demonstrated decreased amplitude of compound muscle action potentials and neurogenic motor unit potentials, indicating lower motor neuron involvement. Conclusions: Our patient's case indicated a split hand and minipolymyoclonus in SCA3. Clinicians should consider these extra-cerebellar manifestations in patients with SCA3. Although neither split hand nor minipolymyoclonus are likely to directly result in a specific etiological diagnosis, a common pathophysiological mechanism for both may be lower motor neuron involvement. This extracerebellar manifestation contributes to narrowing down the diagnostic possibilities for cases presenting with progressive cerebellar ataxia. [ABSTRACT FROM AUTHOR]

Key points Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exist. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry and ultrastructure of these neurons across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections and had high synaptic efficacy constituting an obligatory synapse. At pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold EPSPs like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant vasoactive intestinal polypeptide observed in human but not pig or mouse ganglia, and little substance P or calcitonin gene‐related peptide in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after‐hyperpolarizations. Intrinsic excitability differed; 95% of human neurons were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs and humans identifies similarities and differences in the evolution of ICNs. Intrinsic cardiac neurons (ICNs) are essential to the regulation of cardiac function. We investigated the neurochemistry, morphology, ultrastructure, membrane physiology and synaptic transmission of ICNs from donated human hearts in parallel with identical studies of ICNs from mice and pigs to create a publicly accessible cellular atlas detailing the structure and function of these neurons across species. In addition to presenting foundational data on human ICNs, this comparative study identifies both conserved and derived attributes of these neurons within mammals. The findings have significant implications for understanding the regulation of cardiac autonomic function in humans and may greatly influence strategies for neuromodulation in conditions such as atrial fibrillation and heart failure. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Discussion Medial femoral cutaneous (MFC) sensory nerve action potentials (SNAPs) can be easily recorded using distal stimulation. This study aimed to identify a new parameter using MFC SNAPs for the early electrophysiological diagnosis of length‐dependent axonal polyneuropathy (LDAP) associated with uremic neuropathy.Patients with chronic renal failure who were referred to the electrodiagnostic laboratory due to symptoms suggesting polyneuropathy were included. Assessments encompassed neurological examination, Michigan Neuropathy Screening Instrument (MNSI), and Semmes–Weinstein monofilament test. Antidromic radial, median, ulnar, MFC, sural, and superficial peroneal sensory; median, ulnar, tibial, and peroneal motor nerve conduction studies were performed. Sural‐to‐radial amplitude ratio (SRAR) and sural‐to‐medial femoral cutaneous amplitude ratio (SMFCAR) were calculated, and their diagnostic sensitivities were compared with the age and sex matched healthy controls.Thirty‐two chronic renal failure patients (mean age 60.0 ± 9.6 years) and 37 controls (60.6 ± 9 years) were included. MNSI indicated clinical polyneuropathy in 59.4% of patients, while sural SNAP amplitude was diagnostic in 78%. Median SRAR and SMFCAR values were significantly lower in patients than controls (p < .001 for both). The cut‐off values for SMFCAR and SRAR were <1.82 and <0.30, respectively, both with a sensitivity of 59% and a specificity of 94%.Sural SNAP is the most sensitive parameter in the diagnosis of LDAP. SMFCAR is not superior to SRAR. If the sural SNAP amplitude is normal, SMFCAR can serve as an alternative to SRAR in dialysis patients with bilateral arteriovenous fistulae or in those unable to undergo radial NCS. [ABSTRACT FROM AUTHOR]

Episodic memory is organized in both spatial and temporal contexts. The hippocampus is crucial for episodic memory and has been demonstrated to encode spatial and temporal information. However, how the representations of space and time interact in the hippocampal memory system is still unclear. Here, we recorded the activity of hippocampal CA1 neurons in mice in a variety of one-dimensional navigation tasks while systematically varying the speed of the animals. For all tasks, we found neurons simultaneously represented space and elapsed time. There was a negative correlation between the preferred space and lap duration, e.g., the preferred spatial position shifted more toward the origin when the lap duration became longer. A similar relationship between the preferred time and traveled distance was also observed. The results strongly suggest a competitive and integrated representation of space-time by single hippocampal neurons, which may provide the neural basis for spatiotemporal contexts. [Display omitted] • Hippocampal CA1 single neurons concurrently represent space and time • The preferred location of some cells shifts with lap duration • The preferred time of some cells shifts with lap distance • There is a competitive interaction between space and time To study how the representation of space and time interact in the episodic memory system, Chen et al. showed that hippocampal CA1 neurons simultaneously represented space and elapsed time, and the neuronal firing reflected a trade-off or competition between space and time by shifting their fields in space or time. [ABSTRACT FROM AUTHOR]

Action potential generation underlies some of the most consequential dynamical systems on Earth, from brains to hearts. It is therefore interesting to develop synthetic cell-free systems, based on the same molecular mechanisms, which may allow for the exploration of parameter regions and phenomena not attainable, or not apparent, in the live cell. We previously constructed such a synthetic system, based on biological components, which fires action potentials. We call it "Artificial Axon". The system is minimal in that it relies on a single ion channel species for its dynamics. Here we characterize the Artificial Axon as a dynamical system in time, using a simplified Hodgkin-Huxley model adapted to our experimental context. We construct a phase diagram in parameter space identifying regions corresponding to different temporal behavior, such as Action Potential (AP) trains, single shot APs, or damped oscillations. The main new result is the finding that our system with a single ion channel species, with inactivation, is dynamically equivalent to the system of two channel species without inactivation (the Morris-Lecar system), which exists in nature. We discuss the transitions and bifurcations occurring crossing phase boundaries in the phase diagram, and obtain criteria for the channels' properties necessary to obtain the desired dynamical behavior. In the second part of the paper we present new experimental results obtained with a system of two AAs connected by excitatory and/or inhibitory electronic "synapses". We discuss the feasibility of constructing an autonomous oscillator with this system. [ABSTRACT FROM AUTHOR]

Cardiac action potential (AP) alternans have been linked to the development of arrhythmia. AP alternans may be driven by AP instabilities, Ca2+ transient (CaT) instabilities, or both. The mechanisms underlying CaT driven AP alternans is well-supported experimentally, but the ionic mechanism underlying alternans driven by AP instabilities remain incompletely understood. Here we used the Ca2+ buffer BAPTA to remove the CaT and generate a model of AP alternans driven primarily by AP instabilities. In isolated rabbit ventricle myocytes, AP alternans induced by rapid pacing were either critically damped and persisted over time, overdamped and ceased over seconds, or underdamped progressing to 2:1 capture. Control cells predominantly exhibited critically damped alternans. In contrast, removing CaT with BAPTA destabilized alternans formation in a concentration dependent manner. Importantly, alternans were easier to induce in CaT free cells as evidenced by a higher alternans threshold relative to control cells. While the L-type Ca2+ channel agonist Bay K 8644 had a minor effect on alternans formation in myocytes with conserved CaT, combining the agonist with BAPTA markedly promoted the formation of underdamped alternans and increased the alternans threshold more than four-fold as compared to controls. Our data support a mechanistic model in which AP alternans are a primary self-sustained event in which the CaT serves as a dampening cue that curbs alternans development, likely via a canonical negative feedback process involving Ca2+ induced inhibition of L-type Ca2+ current. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects memory and cognition, characterized by neuronal loss and currently lacking a cure. Mutations in PSEN1 (Presenilin 1) are among the most common causes of early-onset familial AD (fAD). While changes in neuronal excitability are believed to be early indicators of AD progression, the link between PSEN1 mutations and neuronal excitability remains to be fully elucidated. This study examined iPSC-derived neurons (iNs) from fAD patients with PSEN1 mutations S290C or A246E, alongside CRISPR-corrected isogenic cell lines, to investigate early changes in excitability. Electrophysiological profiling revealed reduced excitability in both PSEN1 mutant iNs compared to their isogenic controls. Neurons bearing S290C and A246E mutations exhibited divergent passive membrane properties compared to isogenic controls, suggesting distinct effects of PSEN1 mutations on neuronal excitability. Additionally, both PSEN1 backgrounds exhibited higher current density of voltage-gated potassium (Kv) channels relative to their isogenic iNs, while displaying comparable voltage-gated sodium (Nav) channel current density. This suggests that the Nav/Kv imbalance contributes to impaired neuronal firing in fAD iNs. Deciphering these early cellular and molecular changes in AD is crucial for understanding disease pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Abnormal sensory perception, particularly pain insensitivity (PAI), is a typical symptom of autism spectrum disorder (ASD). Despite the role of myelin metabolism in the regulation of pain perception, the mechanisms underlying ASD-related PAI remain unclear. Methods: The pain-associated gene sphingosine-1-phosphate receptor 1 (S1PR1) was identified in ASD samples through bioinformatics analysis. Its expression in the dorsal root ganglion (DRG) tissues of BTBR ASD model mice was validated using RNA-seq, western blot, RT-qPCR, and immunofluorescence. Pain thresholds were assessed using the von Frey and Hargreaves tests. Patch-clamp techniques measured KCNQ/M channel activity and neuronal action potentials. The expression of S1PR1, KCNQ/M, mitogen-activated protein kinase (MAPK), and cyclic AMP/protein kinase A (cAMP/PKA) signaling proteins was analyzed before and after inhibiting the S1P-S1PR1-KCNQ/M pathway via western blot and RT-qPCR. Results: Through integrated transcriptomic analysis of ASD samples, we identified the upregulated gene S1PR1, which is associated with sphingolipid metabolism and linked to pain perception, and confirmed its role in the BTBR mouse model of ASD. This mechanism involves the regulation of KCNQ/M channels in DRG neurons. The enhanced activity of KCNQ/M channels and the decreased action potentials in small and medium DRG neurons were correlated with PAI in a BTBR mouse model of ASD. Inhibition of the S1P/S1PR1 pathway rescued baseline insensitivity to pain by suppressing KCNQ/M channels in DRG neurons, mediated through the MAPK and cAMP/PKA pathways. Investigating the modulation and underlying mechanisms of the non-opioid pathway involving S1PR1 will provide new insights into clinical targeted interventions for PAI in ASD. Conclusions: S1PR1 may contribute to PAI in the PNS in ASD. The mechanism involves KCNQ/M channels and the MAPK and cAMP/PKA signaling pathways. Targeting S1PR1 in the PNS could offer novel therapeutic strategies for the intervention of pain dysesthesias in individuals with ASD. [ABSTRACT FROM AUTHOR]

The article discusses possible changes in motor neuron discharge characteristics in presymptomatic amyotrophic lateral sclerosis (ALS). It highlights the challenges in diagnosing ALS early and the potential for biomarkers to aid in early detection. The study examines motor unit potentials in ALS patients and proposes a hypothesis on the evolution of motor neuron properties during the course of the disease. The article emphasizes the importance of biomarkers, such as measures of motor neuron excitability, in improving early diagnosis and treatment of ALS. [Extracted from the article]

Synapses in the brain are highly noisy, which leads to a large trial-by-trial variability. Given how costly synapses are in terms of energy consumption these high levels of noise are surprising. Here we propose that synapses use noise to represent uncertainties about the somatic activity of the postsynaptic neuron. To show this, we developed a mathematical framework, in which the synapse as a whole interacts with the soma of the postsynaptic neuron in a similar way to an agent that is situated and behaves in an uncertain, dynamic environment. This framework suggests that synapses use an implicit internal model of the somatic membrane dynamics that is being updated by a synaptic learning rule, which resembles experimentally well-established LTP/LTD mechanisms. In addition, this approach entails that a synapse utilizes its inherently noisy synaptic release to also encode its uncertainty about the state of the somatic potential. Although each synapse strives for predicting the somatic dynamics of its postsynaptic neuron, we show that the emergent dynamics of many synapses in a neuronal network resolve different learning problems such as pattern classification or closed-loop control in a dynamic environment. Hereby, synapses coordinate themselves to represent and utilize uncertainties on the network level in behaviorally ambiguous situations. Author summary: Synapses in the brain are highly noisy leading to a large trial-by-trial variability in their response to presynaptic action potentials. Adopting the principle of predictive processing, which is based on the idea that agents instantiate an internal model of their environment enabling them to make predictions, take actions, and to minimize surprise, we can show that a synapse utilizes its inherently noisy release to encode its uncertainty about the state of its cellular, postsynaptic environment. The resulting model framework leads to a synaptic learning rule that adapts the synaptic efficacy such that the synapse can predict future postsynaptic spiking. This synaptic learning rule resembles experimentally well-established plasticity mechanisms and makes very precise experimental predictions. In addition, we show that this synaptic learning rule enables neuronal networks to utilize the unreliability of synaptic release to master behaviorally ambiguous situations. [ABSTRACT FROM AUTHOR]

Transcranial direct current stimulation (tDCS) has garnered significant interest for its potential to enhance cognitive functions and as a therapeutic intervention in various cognitive disorders. However, the clinical application of tDCS has been hampered by significant variability in its cognitive outcomes. Furthermore, the widespread use of tDCS has raised concerns regarding its safety and efficacy, particularly in light of our limited understanding of its underlying neural mechanisms at the cellular level. We still do not know 'where', 'when' and 'how' tDCS modulates information encoding by neurons, in order to lead to the observed changes in cognitive functions. Without elucidating these fundamental unknowns, the root causes of its outcome variability and long-term safety remain elusive, challenging the effective application of tDCS in clinical settings. Addressing this gap, our study investigates the effects of tDCS, applied over the dorsolateral prefrontal cortex, on cognitive abilities and individual neuron activity in macaque monkeys performing cognitive tasks. Like humans performing a delayed match-to-sample task, monkeys exhibited practice-related slowing in their responses (within-session behavioural adaptation). Concurrently, there were practice-related changes in simultaneously recorded activity of prefrontal neurons (within-session neuronal adaptation). Anodal tDCS attenuated both these behavioural and neuronal adaptations when compared with sham stimulation. Furthermore, tDCS abolished the correlation between response time of monkeys and neuronal firing rate. At a single-cell level, we also found that following tDCS, neuronal firing rate was more likely to exhibit task-specific modulation than after sham stimulation. These tDCS-induced changes in both behaviour and neuronal activity persisted even after the end of tDCS stimulation. Importantly, multiple applications of tDCS did not alter burst-like firing rates of individual neurons when compared with sham stimulation. This suggests that tDCS modulates neural activity without enhancing susceptibility to epileptiform activity, confirming a potential for safe use in clinical settings. Our research contributes unprecedented insights into the 'where', 'when' and 'how' of tDCS effects on neuronal activity and cognitive functions by showing that modulation of the behaviour of monkeys by the tDCS of the prefrontal cortex is accompanied by alterations in prefrontal cortical cell activity ('where') during distinct trial phases ('when'). Importantly, tDCS led to task-specific and state-dependent alterations in prefrontal cell activities ('how'). Our findings suggest a significant shift from the view that the effects of tDCS are merely attributable to polarity-specific shifts in cortical excitability and instead propose a more complex mechanism of action for tDCS that encompasses various aspects of cortical neuronal activity without increasing burst-like epileptiform susceptibility. [ABSTRACT FROM AUTHOR]

The channels commonly responsible for maintaining cell resting membrane potentials are referred to as K2P (two-P-domain K+ subunit) channels. These K+ ion channels generally remain open but can be modulated by their local environment. These channels are classified based on pharmacology, pH sensitivity, mechanical stretch, and ionic permeability. Little is known about the physiological nature of these K2P channels in invertebrates. Acidic conditions depolarize neurons and muscle fibers, which may be caused by K2P channels given that one subtype can be blocked by acidic conditions. Doxapram is used clinically as a respiratory aid known to block acid-sensitive K2P channels; thus, the effects of doxapram on the muscle fibers and synaptic transmission in larval Drosophila and crawfish were monitored. A dose-dependent response was observed via depolarization of the larval Drosophila muscle and an increase in evoked synaptic transmission, but doxapram blocked the production of action potentials in the crawfish motor neuron and had a minor effect on the resting membrane potential of the crawfish muscle. This indicates that the nerve and muscle tissues in larval Drosophila and crawfish likely express different K2P channel subtypes. Since these organisms serve as physiological models for neurobiology and physiology, it would be of interest to further investigate what types of K2P channel are expressed in these tissues. (212 words) [ABSTRACT FROM AUTHOR]

Several ion currents in the mammalian ventricular myocardium are substantially regulated by the sympathetic nervous system via β-adrenergic receptor activation, including the slow delayed rectifier K+ current and the L-type calcium current. This study investigated the downstream mechanisms of β-adrenergic receptor stimulation by isoproterenol (ISO) on the inward rectifier (IK1) and the rapid delayed rectifier (IKr) K+ currents using action potential voltage clamp (APVC) and conventional voltage clamp techniques in isolated canine left ventricular cardiomyocytes. IK1 and IKr were dissected by 50 µM BaCl2 and 1 µM E-4031, respectively. Acute application of 10 nM ISO significantly increased IK1 under the plateau phase of the action potential (0–+20 mV) using APVC, and similar results were obtained with conventional voltage clamp. However, β-adrenergic receptor stimulation did not affect the peak current density flowing during terminal repolarization or the overall IK1 integral. The ISO-induced enhancement of IK1 was blocked by the calcium/calmodulin kinase II (CaMKII) inhibitor KN-93 (1 µM) but not by the protein kinase A inhibitor H-89 (3 µM). Neither KN-93 nor H-89 affected the IK1 density under baseline conditions (in the absence of ISO). In contrast, parameters of the IKr current were not affected by β-adrenergic receptor stimulation with ISO. These findings suggest that sympathetic activation enhances IK1 in canine left ventricular cells through the CaMKII pathway, while IKr remains unaffected under the experimental conditions used. [ABSTRACT FROM AUTHOR]

Introduction: The effectiveness and safety of 50 W, high‐power, short‐duration (HPSD) ablation in superior vena cava isolation (SVCI) for patients with atrial fibrillation (AF) have been reported. However, the acute outcomes of SVCI combined with 90 W/4 s, very high‐power, short‐duration (vHPSD) ablation remain unknown. In this study, we aimed to investigate a novel approach that combines 50 W‐HPSD and 90 W/4 s‐vHPSD ablation in SVCI and to elucidate the characteristics, outcomes, and safety of this approach by comparing SVCI with conventional ablation index (AI)‐guided middle‐power, middle‐duration (MPMD) ablation. Methods: Overall, 126 patients who underwent AF ablation with SVCI using the QDOT MICROTM catheter were retrospectively reviewed; one group underwent SVCI with a combined approach of HPSD and vHPSD ablation (50 W/90 W group, n = 73) and another group underwent AI‐guided MPMD ablation (30–40 W group, n = 53). This study compared the procedural details, radiofrequency (RF) ablation profiles, and complications. The RF settings used in the 50 W/90 W group were 50 W/7 s for the lateral segment close to the phrenic nerve and 90 W/4 s for the nonlateral segment. Results: The 50 W/90 W group required a significantly shorter procedural time (3.2 vs. 5.9 min, p <.001), shorter RF duration (42.0 vs. 162.0 s, p <.001), and lower RF energy (2834 vs. 5480 J, p <.001) than the 30–40 W group. Procedural success, first‐pass SVCI, number of RF applications, and SVC reconnection after isoproterenol loading were comparable between the groups. The maximum tip‐electrode temperature of the multi‐thermocouple system was significantly higher in the 50 W/90 W group than in the 30–40 W group (50.0°C vs. 47.0°C, p <.001). No complications, such as phrenic nerve injury or bleeding requiring transfusion, were observed in either group. Conclusions: The combined approach of 50 W/7 s‐HPSD and 90 W/4 s‐vHPSD ablation resulted in successful and safe SVCI with shorter procedural time, shorter RF duration, and lower RF energy. [ABSTRACT FROM AUTHOR]

Introduction: The novel cryoballoon with 28 mm or 31 mm adjustable diameters, aims to achieve a wide antral pulmonary vein isolation (PVI). However, the distribution of antral lesions and their variations based on left atrial (LA) remodeling require further clarification. Methods: We evaluated 22 patients (67 [59.5–74.8] years, 19 males) who underwent PVI of atrial fibrillation (AF) (13 paroxysmal AF [PAF] and 9 non‐PAF) using size‐adjustable cryoballoons. LA electro‐anatomical mapping was performed post‐PVI with three‐dimensional mapping systems. We assessed the shapes of the LA and pulmonary veins (PVs) and the distribution of isolated areas (IAs), comparing the results between PAF and non‐PAF patients. Results: In the left PVs (LPVs), the distance between the PV orifice and IA edge (PVos‐IA) was larger on the roof and posterior segments (~15 mm) but relatively smaller on the anterior segment near the PV ridge (<10 mm). For the right PVs (RPVs), it was more extensive in the posterior segment (10–15 mm). Comparing PAF and non‐PAF, there were no significant differences in the PVos‐IA except for the right posterior‐carina segment, antrum IA (LPVs: 5.9 ± 1.6 vs. 5.8 ± 0.8 cm², p =.81; RPVs: 4.8 ± 2.3 vs. 4.8 ± 1.2 cm², p =.81), distances between the right and left IAs on the LA posterior wall (LAPW), and un‐isolated LAPW area (9.0 ± 4.9 vs. 9.9 ± 2.5 cm², p =.62). No individual PVIs were observed in either group. Two patients exhibited overlapping IAs on the roof, and one patient who underwent 31 mm balloon applications for all PVs exhibited an LAPW isolation. Conclusion: The size‐adjustable cryoballoon achieved a wide antral PVI even in non‐PAF patients. [ABSTRACT FROM AUTHOR]

Background: Safety data of the latest radiofrequency (RF) technologies during atrial fibrillation (AF) ablation in real‐world clinical practice are limited. Objectives: We sought to evaluate the acute procedural safety of the four latest ablation catheters commonly used for AF ablation. Methods: A total of 3957 AF ablation procedures performed between January 2022 and December 2023 at 20 centers with either the THERMOCOOL SMARTTOUCH SF (STSF), TactiCath (TC), QDOT Micro (QDM), or TactiFlex (TF) were retrospectively analyzed. Results: In total, QDM, STSF, TF, and TC were used in 343 (8.7%), 1793 (45.3%), 1121 (28.4%), and 700(17.7%) procedures. Among 2406 index procedures, electrical pulmonary vein isolations were successfully achieved in 99.5%. Despite similar total procedure times in the four groups, the total fluoroscopic time was significantly shorter for QDM/STSF with CARTO than TF/TC with EnSite (18.7 ± 14 vs. 27.6 ± 20.6 min, p <.001) and longest in the TF group. The incidence of cardiac tamponade was 0.7% (0.5% and 0.9% during index and redo procedures, 0.8% and 0.3% for paroxysmal and non‐paroxysmal AF) and was significantly lower for QDM/STSF than TF/TC (0.2% vs. 1.1%, p =.008) and highest in the TF group. The incidence of cardiac tamponade was higher for TF than TC and STSF than QDM. In the multivariate analysis, TF/TC with EnSite was a significant independent predictor of cardiac tamponade during both the index (odds ratio [OR] = 4.8, 95% confidence interval [CI] = 1.3–17.5, p =.02) and all procedures (OR = 3.0, 95% CI = 1.3–7.2, p =.01). Conclusions: The incidence of cardiac tamponade and the fluoroscopic time during AF ablation significantly differed among the latest RF catheters and mapping systems in real‐world clinical practice. [ABSTRACT FROM AUTHOR]

The precise mechanism behind the supply of adenosine triphosphate (ATP) to approximately half of the presynaptic release sites in axons that lack a stationary mitochondrion is not fully understood. This paper presents a mathematical model designed to simulate the transient ATP concentration in presynaptic en passant boutons. The model is utilized to investigate how the ATP concentration responds to increased ATP demand during neuronal firing in boutons with a stationary mitochondrion and those without one. The analysis suggests that neuron firing may cause oscillations in the ATP concentrations, with peak-to-peak amplitudes ranging from 0.06% to 5% of their average values. However, this does not deplete boutons lacking a mitochondrion of ATP; for physiologically relevant values of model parameters, their concentration remains approximately 3.75 times higher than the minimum concentration required for synaptic activity. The variance in average ATP concentrations between boutons containing a stationary mitochondrion and those lacking one ranges from 0.3% to 0.8%, contingent on the distance between the boutons. The model indicates that diffusion-driven ATP transport is rapid enough to adequately supply ATP molecules to boutons lacking a stationary mitochondrion. [ABSTRACT FROM AUTHOR]

To assess reticulospinal tract excitability, high‐intensity transcranial magnetic stimulation (TMS) has been used to elicit ipsilateral motor‐evoked potentials (iMEPs). However, there is no consensus on robust and valid methods for use in human studies. The present study proposes a standardized method for eliciting and analysing iMEPs in the biceps brachii. Twenty‐four healthy young adults participated in this study. Electromyography (EMG) electrodes recorded contralateral MEPs (cMEPs) from the right and iMEPs from the left biceps brachii. A dynamic preacher curl task was used with ~15% of the subject's one‐repetition maximum load. The protocol included maximal compound action potential (M‐max) determination of the right biceps brachii muscle, TMS hotspot determination, and four sets of five repetitions where 100% stimulator output was delivered at an elbow angle of 110° of flexion. We normalized cMEP amplitude by M‐max (% M‐max) and iMEP by cMEP amplitude ratio (ICAR). Clear iMEPs above background EMG were observed in 21 subjects (88%, ICAR =.31 ±.19). Good‐to‐excellent agreement (intraclass correlation coefficient [ICC] =.795–1.000) and low bias (.01–.08 mV and.60–1.11 ms) were demonstrated when comparing two different analysis methods (i.e. fixed time‐window vs. manual onset detection) to determine the cMEP and iMEP amplitude and latency, respectively. Most subjects demonstrated clear iMEPs above background EMG triggered at a pre‐determined joint angle during a light‐load dynamic preacher curl exercise. Similar results were obtained when comparing a single‐trial manual identification of iMEP and a semi‐automated time‐window data analysis approach. [ABSTRACT FROM AUTHOR]

Objective(s): Quercetin is a plant flavonoid known for its pharmacological activities, such as antioxidant, anti-inflammatory, and anti-cancer properties. However, there is limited information available regarding its potential toxicities. A previous study showed that quercetin can inhibit human ether-a-go-related gene (hERG, also named KCNH2) currents, which may lead to long QT syndrome, torsade de pointes (TdP), and even sudden cardiac death. This study aimed to investigate the effects of quercetin on hERG and its potential mechanism. Materials and Methods: hERG currents and action potential duration (APD) were assessed using the patch clamp technique. Molecular docking was employed to elucidate the binding sites between quercetin and hERG. Transfection of wild-type or mutant plasmids was used to verify the results of molecular docking. Western blot was performed to determine the expression levels of hERG, transcription factor SP1, molecular chaperones HSP70 and HSP90, phosphorylated E3 ubiquitin ligase p-Nedd4-2, serum- and glucocorticoid-inducible kinase (SGK1), and phosphatidylinositol 3-kinase (PI3K). Immunoprecipitation was conducted to evaluate hERG ubiquitination. Results: Quercetin acutely blocked hERG current by binding to F656 amino acid residue, subsequently accelerating channel inactivation. Long-term incubation of quercetin accelerates Nedd4-2-mediated ubiquitination degradation of hERG channels by inhibiting the PI3K/SGK1 signaling pathway. Moreover, the APD of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) is significantly prolonged by 30 µM quercetin. Conclusion: Quercetin has a potential risk of proarrhythmia, which provided useful information for the usage and development of quercetin as a medication. [ABSTRACT FROM AUTHOR]

Resolvin D2 (RvD2), an endogenous lipid mediator derived from docosahexaenoic acid, has been demonstrated to have analgesic effects. However, little is known about the mechanism underlying RvD2 in pain relief. Herein, we demonstrate that RvD2 targeted the P2X3 receptor as an analgesic. The electrophysiological activity of P2X3 receptors was suppressed by RvD2 in rat dorsal root ganglia (DRG) neurons. RvD2 pre‐application dose‐dependently decreased α,β‐methylene‐ATP (α,β‐meATP)‐induced inward currents. RvD2 remarkably decreased the maximum response to α,β‐meATP, without influencing the affinity of P2X3 receptors. RvD2 also voltage‐independently suppressed ATP currents. An antagonist of the G protein receptor 18 (GPR18), O‐1918, prevented the RvD2‐induced suppression of ATP currents. Additionally, intracellular dialysis of the Gαi/o‐protein antagonist pertussis toxin (PTX), the PKA antagonist H89, or the cAMP analog 8‐Br‐cAMP also blocked the RvD2‐induced suppression. Furthermore, α,β‐meATP‐triggered depolarization of membrane potential along with the action potential bursts in DRG neurons were inhibited by RvD2. Lastly, RvD2 attenuated spontaneous nociceptive behaviors as well as mechanical allodynia produced by α,β‐meATP in rats via the activation of the peripheral GPR18. These findings indicated that RvD2 inhibited P2X3 receptors in rat primary sensory neurons through GPR18, PTX‐sensitive Gαi/o‐proteins, and intracellular cAMP/PKA signaling, revealing a novel mechanism that underlies its analgesic effects by targeting P2X3 receptors. [ABSTRACT FROM AUTHOR]

To determine if in vivo cryoneurolysis inhibits ex vivo compound action potential (CAP) conduction in the porcine saphenous nerve and if this occurs rapidly enough to justify performing the technique before stifle surgery. Blinded, controlled, randomized, preclinical study. A group of eight healthy, 8 weeks old, intact, female pigs anesthetized for an unrelated terminal study. Both saphenous nerves of each pig were exposed surgically, and 15 mm of a 20 gauge, closed-tip, commercial cryoneurolysis cannula were inserted cranial to each nerve within the neurovascular fascial sheath along its long axis. The cannula was only actuated on one limb, according to random allocation. Nerves were excised within 15 minutes of actuation and underwent testing in a nerve conduction chamber, where stimulus voltage was increased sequentially (from 0.1 to ≤ 1.9 V). An anesthesiologist blinded to treatment viewed recordings of time versus voltage for each nerve and answered 'yes' or 'no' when asked if an evoked CAP was observed. Fisher's exact test evaluated the incidence of CAP conduction between groups (p < 0.05 considered significant). Nerves were submitted for hematoxylin and eosin staining for blinded histopathological examination. A CAP was conducted in 8/8 and 1/8 of the control and treated nerves, respectively (p = 0.001). Maximal responses in control nerves were 1.92 ± 0.19 mV (mean ± standard error). In the single treated nerve that conducted a CAP, the maximal CAP amplitude was 0.4 mV, lower than the lowest maximal CAP (1.19 mV) in the control nerves. All control nerves were histologically normal, and all treated nerves displayed mild perivascular and perineural inflammation (cuffs of lymphocytes, plasma cells and eosinophils, and edema). The rapid inhibition of CAP conduction warrants clinical investigation of saphenous cryoneurolysis for both intraoperative antinociception and postoperative analgesia in pigs undergoing experimental stifle surgery. [ABSTRACT FROM AUTHOR]

Summary: This paper presents an ultrahigh input impedance, low noise, and wide bandwidth four‐channels analog front‐end (AFE) for low‐power neural recording systems. To achieve high input impedance, the buffer channels are placed between the electrodes and the main amplifier stage of the AFE. The buffer is designed with low noise and low power consumption to obtain high input impedance of overall AFE while maintaining low input‐referred noise and low power consumption. A chopper capacitively coupled chopper instrumentation amplifier (CCIA) is placed after the buffer as the main amplifier stage of the AFE to improve the common mode rejection ratio (CMRR) and the input‐referred noise of the overall AFE design. A new chopper stabilization control technique is proposed and used in the CCIA stage to reduce the charge injection and clock feedthrough and consequently the high‐frequency ripple of the AFE output signal. A programmable gain amplifier (PGA) is designed as the third stage to adjust the overall gain of the AFE. Benefiting from PGA, the AFE can adapt its gain with both action potential and local field potential signals. To reduce the number of the electrode to be implanted and reduce the impedance mismatch that causes the degradation on overall CMRR performance, two AFE channels shared a reference electrode followed by a reference buffer. The proposed AFE is designed and simulated using a standard 180 nm CMOS process and operates in a wide frequency band of 2.1 to 2500 Hz with low input‐referred noise of 1.6 μVrms and a CMRR over 80 dB at 2.1 Hz. The total power consumption is lower than 4.3 μW per channel. With the proposed structure of AFE, the input impedance is 35 GΩ @ 21 Hz and the minimum impedance over operational bandwidth is 75 MΩ @ 2.5 kHz. [ABSTRACT FROM AUTHOR]

A key question for understanding the function of the hippocampus in memory is how information is recalled from the hippocampus to the neocortex. This was investigated in a neuronal network model of the hippocampal system in which "What" and "Where" neuronal firing rate vectors were applied to separate neocortical modules, which then activated entorhinal cortex "What" and "Where" modules, then the dentate gyrus, then CA3, then CA1, then the entorhinal cortex, and then the backprojections to the neocortex. A rate model showed that the whole system could be trained to recall "Where" in the neocortex from "What" applied as a retrieval cue to the neocortex, and could in principle be trained up towards the theoretical capacity determined largely by the number of synapses onto any one neuron divided by the sparseness of the representation. The trained synaptic weights were then imported into an integrate‐and‐fire simulation of the same architecture, which showed that the time from presenting a retrieval cue to a neocortex module to recall the whole memory in the neocortex is approximately 100 ms. This is sufficiently fast for the backprojection synapses to be trained onto the still active neocortical neurons during storage of the episodic memory, and this is needed for recall to operate correctly to the neocortex. These simulations also showed that the long loop neocortex–hippocampus–neocortex that operates continuously in time may contribute to complete recall in the neocortex; but that this positive feedback long loop makes the whole dynamical system inherently liable to a pathological increase in neuronal activity. Important factors that contributed to stability included increased inhibition in CA3 and CA1 to keep the firing rates low; and temporal adaptation of the neuronal firing and of active synapses, which are proposed to make an important contribution to stabilizing runaway excitation in cortical circuits in the brain. [ABSTRACT FROM AUTHOR]

The retrosplenial cortex (RSC) is a key component of the brain's memory systems, with anatomical connections to the hippocampus, anterior thalamus, and entorhinal cortex. This circuit has been implicated in episodic memory and many of these structures have been shown to encode temporal information, which is critical for episodic memory. For example, hippocampal time cells reliably fire during specific segments of time during a delay period. Although RSC lesions are known to disrupt temporal memory, time cells have not been observed there. In this study, we reanalyzed archival RSC neuronal firing data during the intertrial delay period from two previous experiments involving different behavioral tasks, a blocked alternation task and a cued T‐maze task. For the blocked alternation task, rats were required to approach the east or west arm of a plus maze for reward during different blocks of trials. Because the reward locations were not cued, the rat had to remember the goal location for each trial. In the cued T‐maze task, the reward location was explicitly cued with a light and the rats simply had to approach the light for reward, so there was no requirement to hold a memory during the intertrial delay. Time cells were prevalent in the blocked alternation task, and most time cells clearly differentiated the east and west trials. We also found that RSC neurons could exhibit off‐response time fields, periods of reliably inhibited firing. Time cells were also observed in the cued T‐maze, but they were less prevalent and they did not differentiate left and right trials as well as in the blocked alternation task, suggesting that RSC time cells are sensitive to the memory demands of the task. These results suggest that temporal coding is a prominent feature of RSC firing patterns, consistent with an RSC role in episodic memory. [ABSTRACT FROM AUTHOR]

Patients with myotonia congenita suffer from slowed relaxation of muscle (myotonia), due to hyperexcitability caused by loss-of-function mutations in the ClC-1 chloride channel. A recent study suggested that block of large-conductance voltage- and Ca2+- activated K+ channels (BK) may be effective as therapy. The mechanism underlying efficacy was suggested to be lessening of the depolarizing effect of build-up of K+ in t-tubules of muscle during repetitive firing. BK channels are widely expressed in the nervous system and have been shown to play a central role in regulation of excitability, but their contribution to muscle excitability has not been determined. We performed intracellular recordings as well as force measurements in both wild type and BK−/− mouse extensor digitorum longus muscles. Action potential width was increased in BK−/− muscle due to slowing of repolarization, consistent with the possibility K+ build-up in t-tubules is lessened by block of BK channels in myotonic muscle. However, there was no difference in the severity of myotonia triggered by block of muscle Cl− channels with 9-anthracenecarboxylic acid (9AC) in wild type and BK−/− muscle fibers. Further study revealed no difference in the interspike membrane potential during repetitive firing suggesting there was no reduction in K+ build-up in t-tubules of BK−/− muscle. Force recordings following block of muscle Cl− channels demonstrated little reduction in myotonia in BK−/− muscle. In contrast, the current standard of care, mexiletine, significantly reduced myotonia. Our data suggest BK channels regulate muscle excitability, but are not an attractive target for therapy of myotonia. [ABSTRACT FROM AUTHOR]

Background We explore a minimally invasive method (combined ultrasound detection, electrode placement and electrophysiologic nerve examination) to evaluate the early-stage quality of a nerve suture site. Methods Ten patients with median and/or ulnar nerve injuries who had undergone nerve suture were recruited. Postoperative ultrasound examination found that the nerve injury was sutured. Then, a stimulating electrode and recording electrode were located beside the nerve proximal and distal to the suture site guided by ultrasound. Measurement of nerve action potentials (NAP) were performed with these electrodes, followed by surgical exploration. The pre- and intraoperative electrophysiologic findings were compared, together with amplitude, latency, and wave shape of NAP. Results Of the 10 patients, 3 patients were diagnosed with median nerve injury, 2 with ulnar nerve injury, and 5 with the median nerve and ulnar nerve injury. NAP could not be detected pre- and intraoperatively in three median nerves from three patients and in two ulnar nerves from two patients. NAP was detected in 10 nerves from the remaining 5 patients. The pre- and intraoperative NAP results showed consistent results concerning the status of the nerve suture. Wilcoxon's signed-rank test indicated no significant difference in the amplitude and latency detected via sonographically placed electrodes and during surgical exploration. The number of negative-phase waves were equally distributed. Conclusion Ultrasound-guided electrode placement and NAP detection can substitute surgery and serve as a minimally invasive approach to evaluate the regeneration of a sutured nerve. [ABSTRACT FROM AUTHOR]

This article discusses the use of SCINSEV measures in cochlear implant surgery to detect and correct electrode extrusion. The study presents three cases where SCINSEV was used to identify extrusion and make immediate surgical corrections, eliminating the need for revision surgery. The authors suggest that SCINSEV, along with other measures, can improve the efficiency and outcomes of cochlear implant surgery by reducing the reliance on x-rays and the need for revision surgery. The article provides detailed information on the methodology and results of the study, highlighting the potential of SCINSEV as an important tool in intraoperative decision-making and correction. [Extracted from the article]

Over the years, there has been an increase in demand for plant-based foods as alternatives. In line with this, this work explores the production and in vitro digestion of a fermented plant-based beverage (FPBB) produced with pea and rice proteins and 0% (FPBB-C), 5% (FPBB-5), and 10% (FPBB-10) uvaia pulp through lactic fermentation with Lacticaseibacillus rhamnosus GG. The in vitro gastrointestinal digestion process was conducted to assess the bioaccessibility of L. rhamnosus GG, total phenolic content (TPC), and antioxidant activity before and after simulating the gastrointestinal conditions. After 48 h of digestion, highly viable L. rhamnosus GG cells remained throughout the gastrointestinal system. FPBB-C (106.89%) and FPBB-5 (109.38%) exhibited higher survival rates than FPBB-10 (102.20%), indicating that these beverages have a higher prebiotic action potential. Compared with the non-digested samples, after 48 h of digestion, all samples exhibited a significant increase in TPC. The same behavior occurs for the antioxidant activity of FPBB-C, FPBB-5, and FPBB-10 by DPPH (4.06, 3.96, and 8.44 mg TEAC mL-1), ABTS (10.28, 11.06, 11.97 mg TEAC mL-1), and FRAP method (917.02, 863.87, and 1983.23 mg TEAC mL-1). Thirteen compounds were identified and quantified in uvaia pulp by HPLC-DAD-ESI-MS, particularly epigallocatechin gallate, quercetin-3-rhamnose, and quercetin-3-glucoside. Isorhamnetin was the main phenolic compound detected in the colon, assumably due to the conversion of quercetin-3-glucoside by the probiotic cells. In conclusion, as all counts were above 9 log CFU g-1, the FPBB formulations containing pea, rice protein, and uvaia pulp become a promising vehicle for carrying L. rhamnosus GG. [ABSTRACT FROM AUTHOR]

Voltage-gated potassium channels are a widely distributed subgroup of potassium channels responsible for the efflux of potassium in the repolarisation of the cell membrane, and hence contribute to the latency and propagation of action potentials. As they are causal to synaptic transmission, alterations to the structure of these channels can lead to a variety of neurological and psychiatric diseases. The Kv3 subfamily of voltage-gated potassium channels are found on many neurons in the brain, including inhibitory interneurons where they contribute to fast-frequency firing. Changes to the firing ability of these interneurons can lead to an imbalance of inhibitory and excitatory neurotransmission. To date, we have little understanding of the mechanism by which excitatory and inhibitory inputs become imbalanced. This imbalance is associated with cognitive deficits seen across neurological and neuropsychiatric disorders, which are currently difficult to treat. In this review, we collate evidence supporting the hypothesis that voltage-gated potassium channels, specifically the Kv3 subfamily, are central to many neurological and psychiatric disorders, and may thus be considered as an effective drug target. The collective evidence provided by the studies reviewed here demonstrates that Kv3 channels may be amenable to novel treatments that modulate the activity of these channels, with the prospect of improved patient outcome. [ABSTRACT FROM AUTHOR]

AbstractThis study proposes a method for analysing decomposed electromyographic signals to enhance the characterization of motor units (MU). It involves two steps: (i) clustering groups of motor units based on firing rate (FR), recruitment threshold, and MU action potential amplitude, and (ii) segmentation of data at the time of interest. Such method, capable of distinguishing different groups of MU, could help understanding muscle force production. FR of MU in Vastus Lateralis and Rectus Femoris during knee extension was investigated. The findings distinguish MU groups and reveals differences in: FR between both contractions types; clustered groups; and segmented MU data in both contraction types. [ABSTRACT FROM AUTHOR]

Genetic studies have identified the voltage‐gated sodium channel 1.7 (Nav1.7) as pain target. Due to the ineffectiveness of small molecules and monoclonal antibodies as therapeutics for pain, single‐domain antibodies (VHHs) are developed against the human Nav1.7 (hNav1.7) using a novel antigen presentation strategy. A 70 amino‐acid peptide from the hNav1.7 protein is identified as a target antigen. A recombinant version of this peptide is grafted into the complementarity determining region 3 (CDR3) loop of an inert VHH in order to maintain the native 3D conformation of the peptide. This antigen is used to isolate one VHH able to i) bind hNav1.7, ii) slow the deactivation of hNav1.7, iii) reduce the ability of eliciting action potentials in nociceptors, and iv) reverse hyperalgesia in in vivo rat and mouse models. This VHH exhibits the potential to be developed as a therapeutic capable of suppressing pain. This novel antigen presentation strategy can be applied to develop biologics against other difficult targets such as ion channels, transporters and GPCRs. [ABSTRACT FROM AUTHOR]

Developing accurate electrophysiological recording platforms is crucial for investigating cellular electrical activities, understanding the mechanisms underlying cardiovascular disease, and advancing therapeutic strategies. While the successful recording of intracellular electrophysiological status has been achieved by 3D micro/nano devices, their preparation through demanding micro/nanofabrication and poorly controllable solvothermal synthesis is an impediment to widespread utilization. Easier‐to‐access recording electrodes are needed. To address this challenge, a simple and efficient supramolecular self‐assembly strategy that allows access to novel 3D electrodes is introduced. It relies on small organic molecules that can be self‐assembled efficiently into various 3D nanostructures, including lamellated nanosheets, thin nanobelts, and short rod‐like structures. Electrodes prepared through the present self‐assembly process are considerably simpler and more cost‐effective than conventional 3D micro/nanoelectrodes prepared through fabrication or solvothermal synthesis. It is demonstrated that the present electrodes allow for higher quality and prolonged intracellular recordings of action potentials as compared to similarly sized conventional planar electrodes. The noted improvements are attributed to the fact that 3D geometrical electrodes enhance the cell‐electrode interface, ensuring tight coupling and effective electroporation. This work showcases how supramolecular self‐assembly might emerge as a promising and powerful electrode preparation strategy that may facilitate low‐cost electrophysiological studies. [ABSTRACT FROM AUTHOR]