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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.

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.

The occurrence of atrial fibrillation (AF), one of the most socially significant arrhythmias, is associated with the presence of areas of fibrosis. Fibrosis introduces conduction heterogeneity into the cardiac tissue and, thus, may be a substrate for spiral wave reentry, which provokes the onset of AF and is often associated with its persistence. Despite results from computer and animal models of cardiac tissues, data on the conditions under which microreentries occur in human tissues are limited. In this work, we conducted a study of the new approach to modeling the fibrous atrial tissue, which takes into account the cellular structure and conduction in fibrosis areas. Using the Potts model, we created a realistic texture of atrial tissues remodeled by fibroblasts and showed the presence of pathways in such a system with a low proportion of fibroblasts. Our study revealed the relationship between the shape of the cells' action potential, their location in the tissue, and the direction of the wave propagation. The wavefront obtained in the model creates a dynamic heterogeneity of the tissue, which affects the migration and pinning of spiral waves, and explains the formation of microreentries in the cardiac tissue. In the future, such a model can become a potential tool for predictive modeling of AF and the search for ablation target identification. [ABSTRACT FROM AUTHOR]

Memory consolidation involves the synchronous reactivation of hippocampal cells active during recent experience in sleep sharp-wave ripples (SWRs). How this increase in firing rates and synchrony after learning is counterbalanced to preserve network stability is not understood. We discovered a network event generated by an intrahippocampal circuit formed by a subset of CA2 pyramidal cells to cholecystokinin-expressing (CCK+) basket cells, which fire a barrage of action potentials (“BARR”) during non–rapid eye movement sleep. CA1 neurons and assemblies that increased their activity during learning were reactivated during SWRs but inhibited during BARRs. The initial increase in reactivation during SWRs returned to baseline through sleep. This trend was abolished by silencing CCK+ basket cells during BARRs, resulting in higher synchrony of CA1 assemblies and impaired memory consolidation. [ABSTRACT FROM AUTHOR]

Epileptic seizures are debilitating because of the clinical symptoms they produce. These symptoms, in turn, may stem directly from disruptions in neural coding. Recent evidence has suggested that the specific temporal order, or sequence, of spiking across a population of cortical neurons may encode information. Here, we investigate how seizures disrupt neuronal spiking sequences in the human brain by recording multi-unit activity from the cerebral cortex in five male participants undergoing monitoring for seizures. We find that pathological discharges during seizures are associated with bursts of spiking activity across a population of cortical neurons. These bursts are organized into highly consistent and stereotyped temporal sequences. As the seizure evolves, spiking sequences diverge from the sequences observed at baseline and become more spatially organized. The direction of this spatial organization matches the direction of the ictal discharges, which spread over the cortex as traveling waves. Our data therefore suggest that seizures can entrain cortical spiking sequences by changing the spatial organization of neuronal firing, providing a possible mechanism by which seizures create symptoms. The precise mechanism by which seizures disrupt neural coding remains unclear. Here, the authors show that discharges arising from the seizure source travel macroscopic distances, where they go on to influence spiking sequences at the microscopic scale. [ABSTRACT FROM AUTHOR]

The sense of smell is tightly linked to emotions, a link that is thought to rely on the direct synaptic connections between the olfactory bulb (OB) and nuclei of the amygdala. However, there are multiple pathways projecting olfactory information to the amygdala, and their unique functions are unknown. The pathway via the nucleus of the lateral olfactory tract (NLOT) that receives input from olfactory regions and projects to the basolateral amygdala (BLA) is among them. NLOT has been very little studied, and consequentially its function is unknown. Furthermore, formulation of informed hypotheses about NLOT function is at this stage limited by the lack of knowledge about its connectivity and physiological properties. Here, we used virus-based tracing methods to systematically reveal inputs into NLOT, as well as NLOT projection targets in mice of both sexes. We found that the NLOT is interconnected with several olfactory brain regions and with the BLA. Some of these connections were reciprocal, and some showed unique interhemispheric patterns. We tested the excitable properties of NLOT neurons and the properties of each of the major synaptic inputs. We found that the NLOT receives powerful input from the piriform cortex, tenia tecta, and the BLA but only very weak input from the OB. When input crosses threshold, NLOT neurons respond with calcium-dependent bursts of action potentials. We hypothesize that this integration of olfactory and amygdalar inputs serves behaviors that combine smell and emotion. [ABSTRACT FROM AUTHOR]

Depression, a complex disorder with significant treatment challenges, necessitates innovative therapeutic approaches to address its multifaceted nature and enhance treatment outcomes. The modulation of KCNQ potassium (K+) channels, pivotal regulators of neuronal excitability and neurotransmitter release, is a promising innovative therapeutic target in psychiatry. Widely expressed across various tissues, including the nervous and cardiovascular systems, KCNQ channels play a crucial role in modulating membrane potential and regulating neuronal activity. Recent preclinical evidence suggests that KCNQ channels, particularly KCNQ3, contribute to the regulation of neuronal excitability within the reward circuitry, offering a potential target for alleviating depressive symptoms, notably anhedonia. Studies using animal models demonstrate that interventions targeting KCNQ channels can restore dopaminergic firing balance and mitigate depressive symptoms. Human studies investigating the effects of KCNQ channel activators, such as ezogabine, have shown promising results in alleviating depressive symptoms and anhedonia. The aforementioned observations underscore the therapeutic potential of KCNQ channel modulation in depression management and highlight the need and justification for phase 2 and phase 3 dose-finding studies as well as studies prespecifying symptomatic targets in depression including anhedonia. • Potential antidepressant effects via modulation of dopaminergic activity and restoration of neuronal firing balance. • Significant improvements in depressive symptoms and anhedonia with KCNQ channel activators. • KCNQ channel activators present promising avenues for antidepressant treatment but require further research. [ABSTRACT FROM AUTHOR]

This article explores the use of stimulation current induced non-stimulating electrode voltage (SCINSEV) measures in identifying and repositioning extracochlear electrodes (EE) during cochlear implant (CI) surgery. It presents three cases where SCINSEV successfully detected and corrected electrode extrusion, eliminating the need for additional surgery. The article suggests that SCINSEV has the potential to improve decision-making during surgery and enhance CI surgical outcomes. Additionally, it proposes that SCINSEV may reduce the reliance on x-ray resources and improve efficiency in the operating theater. Another study discussed in the article emphasizes the importance of detecting and addressing electrode extrusion during the same surgical session to avoid radiation exposure and potential delays. The authors recommend the routine use of intraoperative electric field imaging (EFI) measurements in all CI surgeries to ensure optimal electrode array placement. The study underscores the clinical significance of EFI as a valuable tool in intraoperative settings. [Extracted from the article]

The cytoarchitecture of the striatum is remarkably homogeneous, in contrast to the regional variation in striatal functions. Whether differences in the intrinsic membrane properties of striatal neurons contribute to regional heterogeneity has not been addressed systematically. We made recordings throughout the young adult mouse striatum under identical conditions, with synaptic input blocked, from four major striatal neuron types, namely, the two subtypes of spiny projection neurons (SPNs), cholinergic interneurons (ChIs), and fastspiking GABAergic interneurons (FSIs), sampling at least 100 cells per cell type. Regional variation manifested across all cell types. All cell types in the nucleus accumbens (NAc) shell had higher input impedance and increased excitability. Cells in the NAc core were differentiated from the caudate-putamen (CPu) for both SPN subtypes by smaller action potentials and increased excitability. Similarity between the two SPN subtypes showed regional variation, differing more in the NAc than in the CPu. So, in the Str, both the intrinsic properties of interneurons and projection neurons are regionally heterogeneous, with the greatest difference between the NAc and CPu; greater excitability of NAc shell neurons may make the region more susceptible to activity-dependent plasticity. [ABSTRACT FROM AUTHOR]

Background: Cardiac arrhythmias are the main cause of sudden death due to Chronic Chagasic Cardiomyopathy (CCC). Here we investigated alterations in connexin 43 (Cx43) expression and phosphorylation in cardiomyocytes as well as associations with cardiac arrhythmias in CCC. Methods: C57Bl/6 mice infected with Trypanosoma cruzi underwent cardiac evaluations at 6 and 12 months after infection via treadmill testing and EKG. Histopathology, cytokine gene expression, and distribution of total Cx43 and its phosphorylated forms Cx43S368 and Cx43S325/328/330 were investigated. Human heart samples obtained from subjects with CCC were submitted to immunofluorescence analysis. In vitro simulation of a pro-inflammatory microenvironment (IL-1β, TNF, and IFN-γ) was performed in H9c2 cells and iPSC-derived cardiomyocytes to evaluate Cx43 distribution, action potential duration, and Lucifer Yellow dye transfer. Results: Mice chronically infected with T. cruzi exhibited impaired cardiac function associated with increased inflammation, fibrosis and upregulated IL-1β, TNF, and IFN-γ gene expression. Confocal microscopy revealed altered total Cx43, Cx43S368 and Cx43S325/328/330 localization and phosphorylation patterns in CCC, with dispersed staining outside the intercalated disc areas, i.e., in lateral membranes and the cytoplasm. Reduced co-localization of total Cx43 and N-cadherin was observed in the intercalated discs of CCC mouse hearts compared to controls. Similar results were obtained in human CCC heart samples, which showed Cx43 distribution outside the intercalated discs. Stimulation of human iPSC-derived cardiomyocytes or H9c2 cells with IL-1β, TNF, and IFN-γ induced alterations in Cx43 localization, reduced action potential duration and dye transfer between adjacent cells. Conclusion: Heart inflammation in CCC affects the distribution and phosphorylation pattern of Cx43, which may contribute to the generation of conduction disturbances in Chagas disease. [ABSTRACT FROM AUTHOR]

Dynamins are large GTPases whose primary function is not only to catalyze membrane scission during endocytosis but also to modulate other cellular processes, such as actin polymerization and vesicle trafficking. Recently, we reported that centronuclear myopathy associated dynamin‐2 mutations, p.A618T, and p.S619L, impair Ca2+‐induced exocytosis of the glucose transporter GLUT4 containing vesicles in immortalized human myoblasts. As exocytosis and endocytosis occur within rapid timescales, here we applied high‐temporal resolution techniques, such as patch‐clamp capacitance measurements and carbon‐fiber amperometry to assess the effects of these mutations on these two cellular processes, using bovine chromaffin cells as a study model. We found that the expression of any of these dynamin‐2 mutants inhibits a dynamin and F‐actin‐dependent form of fast endocytosis triggered by single action potential stimulus, as well as inhibits a slow compensatory endocytosis induced by 500 ms square depolarization. Both dynamin‐2 mutants further reduced the exocytosis induced by 500 ms depolarizations, and the frequency of release events and the recruitment of neuropeptide Y (NPY)‐labeled vesicles to the cell cortex after stimulation of nicotinic acetylcholine receptors with 1,1‐dimethyl‐4‐phenyl piperazine iodide (DMPP). They also provoked a significant decrease in the Ca2+‐induced formation of new actin filaments in permeabilized chromaffin cells. In summary, our results indicate that the centronuclear myopathy (CNM)‐linked p.A618T and p.S619L mutations in dynamin‐2 affect exocytosis and endocytosis, being the disruption of F‐actin dynamics a possible explanation for these results. These impaired cellular processes might underlie the pathogenic mechanisms associated with these mutations. [ABSTRACT FROM AUTHOR]

Limb neuroprostheses aim to restore motor and sensory functions in amputated or severely nerve‐injured patients. These devices use neural interfaces to record and stimulate nerve action potentials, creating a bidirectional connection with the nervous system. Most neural interfaces are based on standard metal microelectrodes. In this work, a new generation of neural interfaces which replaces metals with engineered graphene, called EGNITE, is tested. In vitro and in vivo experiments are conducted to assess EGNITE biocompatibility. In vitro tests show that EGNITE does not impact cell viability. In vivo, no significant functional decrease or harmful effects are observed. Furthermore, the foreign body reaction to the intraneural implant is similar compared to other materials previously used in neural interfaces. Regarding functionality, EGNITE devices are able to stimulate nerve fascicles, during two months of implant, producing selective muscle activation with about three times less current compared to larger microelectrodes of standard materials. CNAP elicited by electrical stimuli and ENG evoked by mechanical stimuli are recorded with high resolution but are more affected by decreased functionality over time. This work constitutes further proof that graphene‐derived materials, and specifically EGNITE, is a promising conductive material of neural electrodes for advanced neuroprostheses. [ABSTRACT FROM AUTHOR]

Insulin has been shown to modulate neuronal processes through insulin receptors. The ion channels located on neurons may be important targets for insulin/insulin receptor signaling. Both insulin receptors and acid-sensing ion channels (ASICs) are expressed in dorsal root ganglia (DRG) neurons. However, it is still unclear whether there is an interaction between them. Therefore, the purpose of this investigation was to determine the effects of insulin on the functional activity of ASICs. A 5 min application of insulin rapidly enhanced acid-evoked ASIC currents in rat DRG neurons in a concentration-dependent manner. Insulin shifted the concentration–response plot for ASIC currents upward, with an increase of 46.2 ± 7.6% in the maximal current response. The insulin-induced increase in ASIC currents was eliminated by the insulin receptor antagonist GSK1838705, the tyrosine kinase inhibitor lavendustin A, and the phosphatidylinositol-3 kinase antagonist wortmannin. Moreover, insulin increased the number of acid-triggered action potentials by activating insulin receptors. Finally, local administration of insulin exacerbated the spontaneous nociceptive behaviors induced by intraplantar acid injection and the mechanical hyperalgesia induced by intramuscular acid injections through peripheral insulin receptors. These results suggested that insulin/insulin receptor signaling enhanced the functional activity of ASICs via tyrosine kinase and phosphatidylinositol-3 kinase pathways. Our findings revealed that ASICs were targets in primary sensory neurons for insulin receptor signaling, which may underlie insulin modulation of pain. [ABSTRACT FROM AUTHOR]

Modulation of input from primary afferent fibres has long been examined at the level of the first relays of these fibres. However, recent studies reveal that input to the spinal cord may also be modulated at the level of the very entry of afferent fibres to the spinal grey matter before action potentials in intraspinal collaterals of afferent fibres reach their target neurons. Such modulation greatly depends on the actions of GABA via extrasynaptic membrane receptors. In the reported study we hypothesized that the increase in excitability of afferent fibres following epidural polarization close to the site where collaterals of afferent fibres leave the dorsal columns is due to the release of GABA from two sources: not only GABAergic interneurons but also glial cells. We present evidence, primo, that GABA released from both these sources contributes to a long‐lasting increase in the excitability and a shortening of the refractory period of epidurally stimulated afferent fibres and, secondo, that effects of epidural polarization on the release of GABA are more critical for these changes than direct effects of DC on the stimulated fibres. The experiments were carried out in deeply anaesthetized rats in which changes in compound action potentials evoked in hindlimb peripheral nerves by dorsal column stimulation were used as a measure of the excitability of afferent fibres. The study throws new light on the modulation of input to spinal networks but also on mechanisms underlying the restoration of spinal functions. [ABSTRACT FROM AUTHOR]

This article explores the role of ryanodine receptors (RyR2) in calcium handling in the heart and questions the current understanding of calcium flux balance. The author suggests that the interpretation of experimental observations on calcium handling may be oversimplified, which could hinder the development of new therapeutic agents for heart failure and arrhythmias. The article also discusses the effects of caffeine on calcium transients and the potential contribution of reverse mode sodium-calcium exchange (NCX). The authors propose a hypothesis that reverse mode NCX during the early stages of the action potential allows for efficient uptake of calcium into the sarcoplasmic reticulum (SR) by sarcoplasmic reticulum calcium ATPase (SERCA). They suggest that the effects of caffeine on SR calcium content may be due to its diastolic effects rather than its effects on calcium release during action potentials. The authors call for further experiments to test their hypothesis and emphasize the importance of understanding the timing and balance of calcium fluxes in the heart for cardiac contraction and arrhythmias. [Extracted from the article]

Direct training of Spiking Neural Networks (SNNs) on neuromorphic hardware has the potential to significantly reduce the energy consumption of artificial neural network training. SNNs trained with Spike Timing-Dependent Plasticity (STDP) benefit from gradient-free and unsupervised local learning, which can be easily implemented on ultra-low-power neuromorphic hardware. However, classification tasks cannot be performed solely with unsupervised STDP. In this paper, we propose Stabilized Supervised STDP (S2-STDP), a supervised STDP learning rule to train the classification layer of an SNN equipped with unsupervised STDP for feature extraction. S2-STDP integrates error-modulated weight updates that align neuron spikes with desired timestamps derived from the average firing time within the layer. Then, we introduce a training architecture called Paired Competing Neurons (PCN) to further enhance the learning capabilities of our classification layer trained with S2-STDP. PCN associates each class with paired neurons and encourages neuron specialization toward target or non-target samples through intra-class competition. We evaluate our methods on image recognition datasets, including MNIST, Fashion-MNIST, and CIFAR10. Results show that our methods outperform state-of-the-art supervised STDP learning rules, for comparable architectures and numbers of neurons. Further analysis demonstrates that the use of PCN enhances the performance of S2-STDP, regardless of the hyperparameter set and without introducing any additional hyperparameters. [ABSTRACT FROM AUTHOR]

Background: Spinal cord stimulation (SCS) has demonstrated multiple benefits in treating chronic pain and other clinical disorders related to sensorimotor dysfunctions. However, the underlying mechanisms are still not fully understood, including how electrode placement in relation to the spinal cord neuroanatomy influences epidural spinal recordings (ESRs). To characterize this relationship, this study utilized stimulation applied at various anatomical sections of the spinal column, including at levels of the intervertebral disc and regions correlating to the dorsal root entry zone. Method: Two electrode arrays were surgically implanted into the dorsal epidural space of the swine. The stimulation leads were positioned such that the caudal-most electrode contact was at the level of a thoracic intervertebral segment. Intraoperative cone beam computed tomography (CBCT) images were utilized to precisely determine the location of the epidural leads relative to the spinal column. High-resolution microCT imaging and 3D-model reconstructions of the explanted spinal cord illustrated precise positioning and dimensions of the epidural leads in relation to the surrounding neuroanatomy, including the spinal rootlets of the dorsal and ventral columns of the spinal cord. In a separate swine cohort, implanted epidural leads were used for SCS and recording evoked ESRs. Results: Reconstructed 3D-models of the swine spinal cord with epidural lead implants demonstrated considerable distinctions in the dimensions of a single electrode contact on a standard industry epidural stimulation lead compared to dorsal rootlets at the dorsal root entry zone (DREZ). At the intervertebral segment, it was observed that a single electrode contact may cover 20-25% of the DREZ if positioned laterally. Electrode contacts were estimated to be ~0.75 mm from the margins of the DREZ when placed at the midline. Furthermore, ventral rootlets were observed to travel in proximity and parallel to dorsal rootlets at this level prior to separation into their respective sides of the spinal cord. Cathodic stimulation at the level of the intervertebral disc, compared to an 'off-disc' stimulation (7 mm rostral), demonstrated considerable variations in the features of recorded ESRs, such as amplitude and shape, and evoked unintended motor activation at lower stimulation thresholds. This substantial change may be due to the influence of nearby ventral roots. To further illustrate the influence of rootlet activation vs. dorsal column activation, the stimulation lead was displaced laterally at ~2.88 mm from the midline, resulting in variances in both evoked compound action potential (ECAP) components and electromyography (EMG) components in ESRs at lower stimulation thresholds. Conclusion: The results of this study suggest that the ECAP and EMG components of recorded ESRs can vary depending on small differences in the location of the stimulating electrodes within the spinal anatomy, such as at the level of the intervertebral segment. Furthermore, the effects of sub-centimeter lateral displacement of the stimulation lead from the midline, leading to significant changes in electrophysiological metrics. The results of this pilot study reveal the importance of the small displacement of the electrodes that can cause significant changes to evoked responses SCS. These results may provide further valuable insights into the underlying mechanisms and assist in optimizing future SCS-related applications. [ABSTRACT FROM AUTHOR]

Precision reaching often requires corrective submovements to obtain the desired goal. Most studies of reaching have focused on single initial movements, and implied the cortical encoding model was the same for all submovements. However, corrective submovements may show different encoding patterns from the initial submovement with distinct patterns of activation across the population. Two rhesus macaques performed a precision center-out-task with small targets. Neural activity from single units in the primary motor cortex and associated behavioral data were recorded to evaluate movement characteristics. Neural population data and individual neuronal firing rates identified with a peak finding algorithm to identify peaks in hand speed were examined for encoding differences between initial and corrective submovements. Individual neurons were fitted with a regression model that included the reach vector, position, and speed to predict firing rate. For both initial and corrective submovements, the largest effect remained movement direction. We observed a large subset changed their preferred direction greater than 45° between initial and corrective submovements. Neuronal depth of modulation also showed considerable variation when adjusted for movement speed. By using principal component analysis, neural trajectories of initial and corrective submovements progressed through different neural subspaces. These findings all suggest that different neural encoding patterns exist for initial and corrective submovements within the cortex. We hypothesize that this variation in how neurons change to encode small, corrective submovements might allow for a larger portion of the neural space being used to encode a greater range of movements with varying amplitudes and levels of precision. NEW & NOTEWORTHY: Neuronal recordings matched with kinematic behavior were collected in a precision center-out task that often required corrective movements. We reveal large differences in preferred direction and depth of modulation between initial and corrective submovements across the neural population. We then present a model of the neural population describing how these shifts in tuning create different subspaces for signaling initial and corrective movements likely to improve motor precision. [ABSTRACT FROM AUTHOR]

The appropriate growth of the neurons, accurate organization of their synapses, and successful neurotransmission are indispensable for sensorimotor activities. These processes are highly dynamic and tightly regulated. Extensive genetic, molecular, physiological, and behavioral studies have identified many molecular candidates and investigated their roles in various neuromuscular processes. In this article, we show that Beadex (Bx), the Drosophila LIM only (LMO) protein, is required for motor activities and neuromuscular growth of Drosophila. The larvae bearing Bx7, a null allele of Bx, and the RNAi-mediated neuronal-specific knockdown of Bx show drastically reduced crawling behavior, a diminished synaptic span of the neuromuscular junctions (NMJs) and an increased spontaneous neuronal firing with altered motor patterns in the central pattern generators (CPGs). Microarray studies identified multiple targets of Beadex that are involved in different cellular and molecular pathways, including those associated with the cytoskeleton and mitochondria that could be responsible for the observed neuromuscular defects. With genetic interaction studies, we further show that Highwire (Hiw), a negative regulator of synaptic growth at the NMJs, negatively regulates Bx, as the latter's deficiency was able to rescue the phenotype of the Hiw null mutant, HiwDN. Thus, our data indicate that Beadex functions downstream of Hiw to regulate the larval synaptic growth and physiology. NEW & NOTEWORTHY: A novel role for Beadex (Bx) regulates the larval neuromuscular junction (NMJ) structure and function in a tissue-specific manner. Bx is expressed in a subset of Toll-6-expressing neurons and is involved in regulating synaptic span and physiology, possibly through its negative interaction with Highwire (Hiw). The findings of this study provide insights into the molecular mechanisms underlying NMJ development and function and warrant further investigation to understand the role of Bx in these processes fully. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the effects of sex, muscle thickness, and subcutaneous fat thickness (SFT) on corticospinal excitability outcome measures of the biceps brachii. Eighteen participants (10 males and 8 females) completed this study. Ultrasound was used to assess biceps brachii muscle thickness and the overlying SFT. Transcranial magnetic stimulation (TMS) was used to determine corticospinal excitability by inducing motor‐evoked potentials (MEPs) at eight different TMS intensities from 90% to 160% of active motor threshold (AMT) from the biceps brachii during an isometric contraction of the elbow flexors at 10% of maximum voluntary contraction (MVC). Biceps brachii maximal compound muscle action potential (Mmax) was also recorded prior to and after TMS. Males had higher (p < 0.001) biceps brachii muscle thickness and lower SFT, produced higher levels of MVC force and had, on average, higher (p < 0.001) MEP amplitudes at lower (p < 0.05) percentages of maximal stimulator output than females during the 10% elbow flexion MVC. Multiple linear regression modeling revealed that sex was not associated with any of the neurophysiological parameters examined, while SFT showed a positive association with the stimulation intensity required at AMT (p = 0.035) and a negative association with biceps brachii pre‐stimulus electromyography (EMG) activity (p = 0.021). Additionally, there was a small positive association between muscle thickness and biceps brachii pre‐stimulus EMG activity (p = 0.049). Overall, this study suggests that some measures of corticospinal excitability may be different between the sexes and influenced by SFT and muscle thickness. [ABSTRACT FROM AUTHOR]

Cholinergic signaling in the retina is mediated by acetylcholine (ACh) released from starburst amacrine cells (SACs), which are key neurons for motion detection. SACs comprise ON and OFF subtypes, which morphologically show mirror symmetry to each other. Although many physiological studies on SACs have targeted ON cells only, the synaptic computation of ON and OFF SACs is assumed to be similar. Recent studies demonstrated that gene expression patterns and receptor types differed between ON and OFF SACs, suggesting differences in their functions. Here, we compared cholinergic signaling pathways between ON and OFF SACs in the mouse retina using the patch clamp technique. The application of ACh increased GABAergic feedback, observed as postsynaptic currents to SACs, in both ON and OFF SACs; however, the mode of GABAergic feedback differed. Nicotinic receptors mediated GABAergic feedback in both ON and OFF SACs, while muscarinic receptors mediated GABAergic feedback in ON SACs only in adults. Neither tetrodotoxin, which blocked action potentials, nor LY354740, which blocked neurotransmitter release from SACs, eliminated ACh-induced GABAergic feedback in SACs. These results suggest that ACh-induced GABAergic feedback in ON and OFF SACs is regulated by different feedback mechanisms in adults and mediated by non-spiking amacrine cells other than SACs. [ABSTRACT FROM AUTHOR]

Introduction: The value of a sural nerve biopsy for the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is controversial. Evidence-based recommendations for its implementation are lacking. We investigated factors leading to biopsy and analyzed biopsy outcomes and consequences, assessed the predictability of biopsy outcomes through clinical parameters to avoid unnecessary biopsies, and compared results with electrophysiological and clinical severity to determine their prognostic value. Methods: 190 sural nerve biopsies were analyzed in two cohorts. One consisted of 163 biopsies and the second of 72 biopsies from the prospective Immune-mediated Neuropathies Biomaterial and Data registry (INHIBIT). Both have an intersection of 45 patients. 75 data sets from patients without biopsy were used. Analysis of nerve conduction studies, treatment, overall disability sum score (ODSS), biopsy outcomes, and diagnosis was performed. Results: 51% of biopsied patients received the diagnosis CIDP (77% fulfilled EFNS/PNS criteria), 21% were not CIDP typical, and 27% were unspecific. Biopsied patients responded less frequently to immunotherapies at time of biopsy than non-biopsied patients (p = 0.003). Immunotherapy was initiated more frequently after biopsy (p < 0.001) and more often with intravenous immunoglobulins (p < 0.0001). 76% of all biopsied patients met the electrophysiological criteria for CIDP. Sensory nerve action potential amplitudes of 0 µV still provide 73% of histological diagnostic value. Histologic signs of degeneration predicted ODSS worsening after 1 year (p = 0.028) but disease severity did not correlate with histological damage severity. Discussion: The main indication for nerve biopsy was the treatment of refractory cases of autoimmune neuropathies with the therapeutic consequence of treatment initiation or escalation. Sural biopsy also provided prognostic information. Even with extinguished sural SNAP, the biopsy can still have diagnostic value. [ABSTRACT FROM AUTHOR]

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here, we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels. [ABSTRACT FROM AUTHOR]

Intraneural ganglionic cysts are non-neoplastic cysts that can cause signs and symptoms of peripheral neuropathy. However, the scarcity of such cases can lead to cognitive biases. Early surgical exploration of space occupying lesions plays an important role in identification and improving the outcomes for intraneural ganglionic cysts. This patient presented with loss of sensation on the right sole with tingling numbness for six months. A diagnosis of tarsal tunnel syndrome was made. Nerve conduction study revealed that the mixed nerve action potential (NAP) was absent in the right medial and lateral plantar nerves. The magnetic resonance imaging (MRI) found a cystic lesion measuring 1.4×1.8×3.8 cm as the presumed cause of the neuropathy. Surgical exploration revealed a ganglionic cyst traversing towards the flexor retinaculum with baby cysts. The latter finding came as a surprise to the treating surgeon and was confirmed to be an intraneural ganglionic cyst based on the histopathology report. Through integrated commentary by a case discussant and reflection by an orthopedician, this case highlights the significance of the availability heuristic, confirmation bias, and anchoring bias in a case of rare disease. Despite diagnostic delays, a medically knowledgeable patient's involvement in their own care lead to a more positive outcome. A fish-bone diagram is provided to visually demonstrate the major factors that contributed to the diagnostic delay. Finally, this case provides clinical teaching points in addition to a pitfall, myth, and pearl related to availability heuristic and the sunk cost fallacy. [ABSTRACT FROM AUTHOR]

Stimulus size modulation of neuronal firing activity is a fundamental property of the primary visual cortex. Numerous biological experiments have shown that stimulus size modulation is affected by multiple factors at different spatiotemporal scales, but the exact pathways and mechanisms remain incompletely understood. In this paper, we establish a large‐scale neuronal network model of primary visual cortex with layer 2/3 to study how gamma oscillation properties are modulated by stimulus size and especially how long‐range connections affect the modulation as realistic neuronal properties and spatial distributions of synaptic connections are considered. It is shown that long‐range horizontal synaptic connections are sufficient to produce dimensional modulation of firing rates and gamma oscillations. In particular, with increasing grating stimulus size, the firing rate increases and then decreases, the peak frequency of gamma oscillations decreases and the spectral power increases. These are consistent with biological experimental observations. Furthermore, we explain in detail how the number and spatial distribution of long‐range connections affect the size modulation of gamma oscillations by using the analysis of neuronal firing activity and synaptic current fluctuations. Our results provide a mechanism explanation for size modulation of gamma oscillations in the primary visual cortex and reveal the important and unique role played by long‐range connections, which contributes to a deeper understanding of the cognitive function of gamma oscillations in visual cortex. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether honokiol (HNK) acted as an analgesic in connection with inhibiting the voltage-gated proton channel (Hv1). Methods: The model of gouty arthritis was induced by injecting monosodium urate (MSU) crystals into the hind ankle joint of mice. HNK was given by intragastric administration. Ankle swelling degree and mechanical allodynia were evaluated using ankle joint circumference measurement and von Frey filaments, respectively. Hv1 current, tail current, and action potential in dorsal root ganglion (DRG) neurons were recorded with patch-clamp techniques. Results: HNK (10, 20, 40 mg/kg) alleviated inflammatory response and mechanical allodynia in a dose-dependent manner. In normal DRG neurons, 50 µM Zn2+ or 2-GBI significantly inhibited the Hv1 current and the current density of Hv1 increased with increasing pH gradient. The amplitude of Hv1 current significantly increased on the 3rd after MSU treatment, and HNK dose-dependently reversed the upregulation of Hv1 current. Compared with MSU group, 40 mg/kg HNK shifted the activation curve to the direction of more positive voltage and increased reversal potential to the normal level. In addition, 40 mg/kg HNK reversed the down-regulation of tail current deactivation time constant (τtail) but did not alter the neuronal excitability of DRG neurons in gouty mice. Conclusion: HNK may be a potential analgesic by inhibiting Hv1 current. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is a cardiac electrophysiological disease with unknown etiology, associated with sudden cardiac death. Symptomatic patients are treated with implanted cardiac defibrillator, but no risk stratification strategy is effective in patients that are at low to medium arrhythmic risk. Cardiac computational modeling is an emerging tool that can be used to verify the hypotheses of pathogenesis and inspire new risk stratification strategies. However, to obtain reliable results computational models must be validated with consistent experimental data. We reviewed the main electrophysiological and structural variables from BrS clinical studies to assess which data could be used to validate a computational approach. Activation delay in the epicardial right ventricular outflow tract is a consistent finding, as well as increased fibrosis and subclinical alterations of right ventricular functional and morphological parameters. The comparison between other electrophysiological variables is hindered by methodological differences between studies, which we commented. We conclude by presenting a recent theory unifying electrophysiological and structural substrate in BrS and illustrate how computational modeling could help translation to risk stratification. [ABSTRACT FROM AUTHOR]

Fragile X syndrome (FXS), the most frequent monogenic form of intellectual disability, is caused by transcriptional silencing of the FMR1 gene that could render neuronal hyperexcitability. Here we show that pyramidal cells (PCs) in the dorsal CA1 region of the hippocampus elicited a larger action potential (AP) number in response to suprathreshold stimulation in juvenile Fmr1 knockout (KO) than wild‐type (WT) mice. Because Kv7/M channels modulate CA1 PC excitability in rats, we investigated if their dysfunction produces neuronal hyperexcitability in Fmr1 KO mice. Immunohistochemical and western blot analyses showed no differences in the expression of Kv7.2 and Kv7.3 channel subunits between genotypes; however, the current mediated by Kv7/M channels was reduced in Fmr1 KO mice. In both genotypes, bath application of XE991 (10 μM), a blocker of Kv7/M channels: produced an increased AP number, produced an increased input resistance, produced a decreased AP voltage threshold and shaped AP medium afterhyperpolarization by increasing mean velocities. Retigabine (10 μM), an opener of Kv7/M channels, produced opposite effects to XE991. Both XE991 and retigabine abolished differences in all these parameters found in control conditions between genotypes. Furthermore, a low concentration of retigabine (2.5 μM) normalized CA1 PC excitability of Fmr1 KO mice. Finally, ex vivo seizure‐like events evoked by 4‐aminopyiridine (200 μM) in the dorsal CA1 region were more frequent in Fmr1 KO mice, and were abolished by retigabine (5–10 μM). We conclude that CA1 PCs of Fmr1 KO mice exhibit hyperexcitability, caused by Kv7/M channel dysfunction, and increased epileptiform activity, which were abolished by retigabine. Key points: Dorsal pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice exhibit hyperexcitability.Kv7/M channel activity, but not expression, is reduced in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice.Kv7/M channel dysfunction causes hyperexcitability in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice by increasing input resistance, decreasing AP voltage threshold and shaping medium afterhyperpolarization.A Kv7/M channel opener normalizes neuronal excitability in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice.Ex vivo seizure‐like events evoked in the dorsal CA1 region were more frequent in Fmr1 KO mice, and such an epileptiform activity was abolished by a Kv7/M channel opener depending on drug concentration.Kv7/M channels may represent a therapeutic target for treating symptoms associated with hippocampal alterations in fragile X syndrome. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Although several studies have shown the association between continuous glucose monitoring (CGM)‐derived glycemic variability (GV) and diabetic peripheral neuropathy, no studies have focused on outpatients or used NC‐stat®/DPNCheck™, a new point‐of‐care device for nerve conduction study (NCS). We investigated the association between CGM‐derived GV and NCS using DPNCheck™ in outpatients with type 2 diabetes, and further analyzed the difference in results between patients with and without well‐controlled HbA1c levels. Materials and Methods: All outpatients with type 2 diabetes using the CGM device (FreeStyle Libre Pro®) between 2017 and 2022 were investigated. Sural nerve conduction was evaluated by sensory nerve action potential (SNAP) amplitude and sensory conduction velocity (SCV) using DPNCheck™. Associations of CGM‐derived GV metrics with SNAP amplitude and SCV were investigated. Results: In total, 304 outpatients with type 2 diabetes were included. In a linear regression model, most CGM‐derived GV metrics except for the mean amplitude of glucose excursion and low blood glucose index were significantly associated with SCV, but not with SNAP amplitude. The significant associations of most CGM‐derived GV metrics with SCV remained after adjustment for possible confounding factors, but not after adjustment for glycated hemoglobin (HbA1c). Most CGM‐derived GV metrics were significantly associated with SCV after adjustment for HbA1c in patients with a HbA1c ≤ 6.9%, but not in those with a HbA1c ≥ 7.0%. Conclusions: In outpatients with type 2 diabetes, multiple CGM‐derived GV metrics were significantly associated with SCV obtained by DPNCheck™. GV may have independent impacts on peripheral nerve function, particularly in patients with well‐controlled HbA1c levels. [ABSTRACT FROM AUTHOR]

Neurogenic thoracic outlet syndrome (nTOS) is caused by brachial plexus compression in the thoracic outlet. It accounts for 85%–95% of thoracic outlet syndrome (TOS) cases, which may also be caused by compression of the subclavian artery and vein. Compression occurs in the interscalene triangle, costoclavicular space or subpectoralis minor space, with congenital anomalies and repetitive overhead activities as contributing factors. Diagnosis is challenging due to overlapping symptoms with other conditions. Patients commonly report pain, numbness, tingling and weakness in the neck, shoulder and arm, exacerbated by arm elevation. Symptoms related to nTOS may manifest in the distribution of the upper (C5–C6), middle (C7) and lower plexus (C8–T1). Although widely used, provocative tests have varying degrees of sensitivity and specificity and may have high false-positive rates, complicating the diagnosis. Patterns on electrodiagnostic studies provide key diagnostic clues, such as reduced sensory response in the medial antebrachial cutaneous nerve and low compound motor action potential in the median nerve. Imaging techniques like magnetic resonance imaging (MRI), alongside procedures like diagnostic and therapeutic anterior scalene blocks, assist in identifying anatomical abnormalities and predicting surgical outcomes. Management of nTOS involves lifestyle changes, physical therapy, medication and botulinum toxin injections for symptomatic relief. Surgical options may include supraclavicular, transaxillary and infraclavicular approaches, each offering specific benefits based on patient anatomy and surgeon expertise. Minimally invasive techniques, such as video-assisted thoracoscopic surgery (VATS) and robotic surgery, enhance exposure and dexterity, leading to better outcomes. Future research should focus on developing precise diagnostic tools, understanding nTOS pathophysiology, standardising diagnostic criteria and surgical approaches, comparing long-term treatment outcomes and exploring preventive measures to improve patient care and quality of life. Level of Evidence: Level V (Therapeutic) [ABSTRACT FROM AUTHOR]

Purpose: Cochlear implantation is a prevalent remedy for severe-to-profound hearing loss. Optimising outcomes and hearing preservation, and minimising insertion trauma, require precise electrode placement. Objective monitoring during the insertion process can provide valuable insights and enhance surgical precision. This study assesses the feasibility and performance of an impedance-based method for monitoring electrode insertion, compared to the surgeon's feedback. Methods: The study utilised the Insertion Monitoring Tool (IMT) research software, allowing for real-time measurement of impedance and evoked compound action potential (eCAP) during electrode insertion in 20 patient implantations. This enabled an impedance-based method to continuously assess the status of each electrode during the insertion process. The feasibility and performance was evaluated and compared to the surgeon's feedback approach. eCAP measurements focused merely on feasibility without searching specific responses. Results: The IMT demonstrated feasibility in measuring real-time impedances and eCAP during the insertion of the electrode array. The impedance-based method exhibited potential for accurately monitoring the insertion depth with a high success rate. However, further development is needed to improve the number of usable contacts. Conclusions: Objective monitoring with the impedance-based method shows promise as a valuable tool to enhance the precision of cochlear implant electrode insertion respecting insertion distance estimation. The IMT research software proved feasible in recording real-time impedances and eCAP during electrode insertion. While this impedance-based method exhibits high success rates, further improvements are required to optimise the number of usable contacts. This study highlights the potential of objective monitoring techniques to enhance cochlear implantation outcomes. [ABSTRACT FROM AUTHOR]

Objectives: Objective measurements to predict the position of a cochlear electrode during cochlear implantation surgery may serve to improve the surgical technique and postoperative speech outcome. There is evidence that electrically evoked compound action potentials (ECAP) are a suitable approach to provide information about the site of stimulation. This study aims to contribute to the knowledge about the association between the intraoperative intracochlear ECAP characteristics and the site of stimulation. Methods: In a retrospective cohort study, patients undergoing cochlear implant surgery with flexible lateral wall electrode arrays (12 stimulating channels) between 2020 and 2022 were analyzed. The CDL was measured using a CT-based clinical planning software. ECAP were measured for all electrode contacts and associated to the CDL as well as to the site of stimulation in degree. Results: Significant differences among the amplitudes and slopes for the individual stimulated electrode contacts at the stimulation sites of 90°, 180°, 270°, 360°, 450° and 540° were found. The values showed a trend for linearity among the single electrodes. Conclusions: ECAP characteristics correlate with the electrode's position inside the cochlea. In the future, ECAP may be applied to assess the intracochlear position inside the cochlea and support anatomy-based fitting. [ABSTRACT FROM AUTHOR]

Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or "noise" in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment. [ABSTRACT FROM AUTHOR]

The sarcolemmal Ca2+ efflux pathways, Na+-Ca2+-exchanger (NCX) and Ca2+-ATPase (PMCA), play a crucial role in the regulation of intracellular Ca2+ load and Ca2+ transient in cardiomyocytes. The distribution of these pathways between the t-tubular and surface membrane of ventricular cardiomyocytes varies between species and is not clear in human. Moreover, several studies suggest that this distribution changes during the development and heart diseases. However, the consequences of NCX and PMCA redistribution in human ventricular cardiomyocytes have not yet been elucidated. In this study, we aimed to address this point by using a mathematical model of the human ventricular myocyte incorporating t-tubules, dyadic spaces, and subsarcolemmal spaces. Effects of various combinations of t-tubular fractions of NCX and PMCA were explored, using values between 0.2 and 1 as reported in animal experiments under normal and pathological conditions. Small variations in the action potential duration (≤ 2%), but significant changes in the peak value of cytosolic Ca2+ transient (up to 17%) were observed at stimulation frequencies corresponding to the human heart rate at rest and during activity. The analysis of model results revealed that the changes in Ca2+ transient induced by redistribution of NCX and PMCA were mainly caused by alterations in Ca2+ concentrations in the subsarcolemmal spaces and cytosol during the diastolic phase of the stimulation cycle. The results suggest that redistribution of both transporters between the t-tubular and surface membranes contributes to changes in contractility in human ventricular cardiomyocytes during their development and heart disease and may promote arrhythmogenesis. [Display omitted] • Sarcolemma of cardiac ventricular cells creates a complex net of t-tubules. • T-tubular fractions of NCX and PMCA in human ventricular cardiomyocytes are unclear. • Membrane localisation of NCX and PMCA in cardiomyocytes is altered in heart diseases. • A novel model of human ventricular cardiomyocytes with submembrane spaces was used. • Membrane redistribution of NCX and PMCA affects cell inotropy and arrhythmogenesis. [ABSTRACT FROM AUTHOR]

Aim: Striatin (Strn) is a scaffold protein expressed in cardiomyocytes (CMs) and alteration of its expression are described in various cardiac diseases. However, the alteration underlying its pathogenicity have been poorly investigated. Methods: We studied the role(s) of cardiac Strn gene (STRN) by comparing the functional properties of CMs, generated from Strn‐KO and isogenic WT mouse embryonic stem cell lines. Results: The spontaneous beating rate of Strn‐KO CMs was faster than WT cells, and this correlated with a larger fast INa conductance and no changes in If. Paced (2–8 Hz) Strn‐KO CMs showed prolonged action potential (AP) duration in comparison with WT CMs and this was not associated with changes in ICaL and IKr. Motion video tracking analysis highlighted an altered contraction in Strn‐KO CMs; this was associated with a global increase in intracellular Ca2+, caused by an enhanced late Na+ current density (INaL) and a reduced Na+/Ca2+ exchanger (NCX) activity and expression. Immunofluorescence analysis confirmed the higher Na+ channel expression and a more dynamic microtubule network in Strn‐KO CMs than in WT. Indeed, incubation of Strn‐KO CMs with the microtubule stabilizer taxol, induced a rescue (downregulation) of INa conductance toward WT levels. Conclusion: Loss of STRN alters CMs electrical and contractile profiles and affects cell functionality by a disarrangement of Strn‐related multi‐protein complexes. This leads to impaired microtubules dynamics and Na+ channels trafficking to the plasma membrane, causing a global Na+ and Ca2+ enhancement. [ABSTRACT FROM AUTHOR]

Introduction This study highlights the relation between compound muscle action potential (CMAP) latency variations and the predictive value of facial nerve (FN) proximal-to-distal (P/D) amplitude ratio measured at the end of vestibular schwannoma resection. Methods Forty-eight patients underwent FN stimulation at the brainstem (proximal) and internal acoustic meatus (distal) using a current intensity of 2 mA. The proximal latency and the P/D amplitude ratio were assessed. House–Brackmann grades I & II indicated good FN function, and grades III to VI were considered fair/poor function. A P/D amplitude ratio > 0.6 was used as a cutoff to indicate a good FN function, while a ratio of ≤ 0.6 indicated a fair/poor FN function. Results The P/D amplitude ratio was measured for all patients, and the calculated sensitivity (SE), specificity (SP), positive predictive value (PPV), and negative predictive value (NPV) were 85.2, 85.7, 88.5, and 81.8%, respectively. The CMAPs from the mentalis muscle were then classified based on their proximal latency into group I (< 6 ms), group II (6–8 ms), and group III (> 8 ms). The SE, SP, PPV, and NPV became 90.5, 90.9, 95, and 83.3%, respectively, in group II. In group I, SE and NPV increased, whereas SP and PPV decreased. While in group III, SP and PPV increased, whereas SE and NPV decreased. Conclusion At a latency between 6 and 8 ms, the P/D amplitude ratio was predictive of outcomes with high SE and SP. When latency was < 6 ms or > 8 ms, the same predictive ability was not observed. Knowing the strengths and limitations is important for understanding the predictive value of the P/D amplitude ratio. [ABSTRACT FROM AUTHOR]

Hypercholesterolemia is one of the most important risk factors for cardiovascular diseases. However, it is mostly associated with vascular dysfunction and atherosclerotic lesions, while evidence of direct effects of hypercholesterolemia on cardiomyocytes and heart function is still incomplete and controversial. In this study, we assessed the direct effects of hypercholesterolemia on heart function and the electro-contractile properties of isolated cardiomyocytes. After 5 weeks, male Swiss mice fed with AIN-93 diet added with 1.25% cholesterol (CHO), developed an increase in total serum cholesterol levels and cardiomyocytes cholesterol content. These changes led to altered electrocardiographic records, with a shortening of the QT interval. Isolated cardiomyocytes displayed a shortening of the action potential duration with increased rate of depolarization, which was explained by increased IK, reduced ICa.L and altered INa voltage-dependent inactivation. Also, reduced diastolic [Ca2+]i was found with preserved adrenergic response and cellular contraction function. However, contraction of isolated hearts is impaired in isolated CHO hearts, before and after ischemia/reperfusion, although CHO heart was less susceptible to arrhythmic contractions. Overall, our results demonstrate that early hypercholesterolemia-driven increase in cellular cholesterol content is associated with direct modulation of the heart and cardiomyocytes' excitability, Ca2+ handling, and contraction. [ABSTRACT FROM AUTHOR]

Huntington's disease (HD) is a neurodegenerative disorder characterized by cognitive deficits and motor function. Levothyroxine (L-T4) is a synthetic form of Thyroxine (T4), which can improve cognitive ability. The aim of the present study was to determine the neuroprotective effect of L-T4 administration in rats with 3-nitropropionic acid (3-NP)-induced Huntingtonʼs disease. Forty-eight Wistar male rats were divided into six groups (n = 8): Group 1 control group that received physiological saline, Group 2 and 3: which received L-T4 (30 and 100 μg/kg), Group 4: HD group that received 3-NP and Groups 5 and 6: The treatment of the HD rats with L-T4 (30 and 100 μg/kg). Spatial memory, locomotor activity, and frequency of neuronal firing were assessed. After decapitation, the Brain-Derived Neurotrophic Factor (BDNF) and Total antioxidant capacity (TAC) levels in the striatum was measured. The results showed that the indices of spatial memory (mean path length and latency time) and motor dysfunction (immobility time) significantly increased, while time spent in the goal quadrant, swimming speed, spike rate, and striatum levels of BDNF significantly decreased in the HD group compared to the control group. L-T4 treatment significantly enhanced time spent in the goal quadrant, swimming speed, motor activity (number of line crossing and rearing), spike rate and striatal BDNF level. This research showed that L-T4 prevented the disruption of motor activity and cognitive deficiencies induced by 3-NP. The beneficial effects of L-T4 may be due to an increase in the concentration of BDNF and enhancement of the spike rate in the striatum. [ABSTRACT FROM AUTHOR]

Sodium and potassium channels, especially Nav1.5 and Kir2.1, play key roles in the formation of action potentials in cardiomyocytes. These channels interact with, and are regulated by, synapse‐associated protein 97 (SAP97). However, the regulatory role of SAP97 in myocyte remains incompletely understood. Here, we investigate the function of SAP97 phosphorylation in the regulation of Nav1.5 and Kir2.1 channel complexes and the upstream regulation of SAP97. We found that SAP97 is phosphorylated by casein kinase II (CK2) in vitro. In addition, transfection of casein kinase 2 interacting protein‐1 (CKIP‐1) into cardiomyocytes to drive CK2 from the nucleus to the cytoplasm, increased SAP97 phosphorylation and Nav1.5 and Kir2.1 current activity. These findings demonstrated that CKIP‐1 modulates the subcellular translocation of CK2, which regulates Nav1.5 and Kir2.1 channel complex formation and activity in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Introduction/Aims Methods Results Discussion F‐wave testing frequently reveals after‐discharges of varied morphologies in patients with primary peripheral nerve hyperexcitability syndrome (PNHS), although reports are scant. This study aimed to explore the morphological characteristics of the after‐discharges during F‐wave tests in PNHS, and to assess the association between after‐discharges and the disease classification.We conducted a retrospective analysis of patients diagnosed with PNHS between 2014 and 2022. The morphological characteristic and duration of after‐discharges during F‐wave tests were analyzed. After‐discharges in the Morvan syndrome group were compared with those in non‐Morvan group, and between groups with positive or negative voltage‐gated potassium channel (VGKC) complex antibodies.Twenty‐nine patients were included in the study, of which 25 exhibited after‐discharges. All after‐discharges in Morvan patients occurred following compound muscle action potential (CMAP). In non‐Morvan patients, after‐discharges occurred following F‐wave (32%) and CMAP (47%). The durations of after‐discharges following CMAP were significantly prolonged in Morvan (54.2 ± 18.8 ms) compared to non‐Morvan patients (34.5 ± 15.0 ms). The majority of antibody‐positive patients (18/20) exhibited after‐discharges following CMAP, whereas 67% of antibody‐negative patients (6/9) showed after‐discharges following F‐wave.The varying presentations of after‐discharges, including their location (after CMAP or F‐wave) and the duration of after‐discharge can assist in clinically classifying PNHS. [ABSTRACT FROM AUTHOR]

Modulation of neuronal firing rates by the spatial locations of physical objects is a widespread phenomenon in the brain. However, little is known about how neuronal responses to the actions of biological entities are spatially tuned and whether such spatially tuned responses are affected by social contexts. These issues are of key importance for understanding the neural basis of embodied social cognition, such as imitation and perspective-taking. Here, we show that spatial representation of actions can be dynamically changed depending on others' social relevance and agents of action. Monkeys performed a turn-taking choice task with a real monkey partner sitting face-to-face or a filmed partner in prerecorded videos. Three rectangular buttons (left, center, and right) were positioned in front of the subject and partner as their choice targets. We recorded from single neurons in two frontal nodes in the social brain, the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC). When the partner was filmed rather than real, spatial preference for partner-actions was markedly diminished in MPFC, but not PMv, neurons. This social context-dependent modulation in the MPFC was also evident for self-actions. Strikingly, a subset of neurons in both areas switched their spatial preference between self-actions and partner-actions in a diametrically opposite manner. This observation suggests that these cortical areas are associated with coordinate transformation in ways consistent with an actor-centered perspective-taking coding scheme. The PMv may subserve such functions in context-independent manners, whereas the MPFC may do so primarily in social contexts. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is a critical compartment in neurons. It converts postsynaptic input into action potentials that subsequently trigger information transfer to target neurons. This process relies on the presence of several voltage-gated sodium (NaV) and potassium (KV) channels that accumulate in high densities at the AIS. TRAAK is a mechanosensitive leak potassium channel that was recently localized to the nodes of Ranvier. Here, we uncover that TRAAK is also present in AISs of hippocampal and cortical neurons in the adult rat brain as well as in AISs of cultured rat hippocampal neurons. We show that the AIS localization is driven by a C-terminal ankyrin G-binding sequence that organizes TRAAK in a 190 nm spaced periodic pattern that codistributes with periodically organized ankyrin G. We furthermore uncover that while the identified ankyrin G-binding motif is analogous to known ankyrin G-binding motifs in NaV1 and KV7.2/KV7.3 channels, it was acquired by convergent evolution. Our findings identify TRAAK as an AIS ion channel that convergently acquired an ankyrin G-binding motif and expand the role of ankyrin G to include the nanoscale organization of ion channels at the AIS. [ABSTRACT FROM AUTHOR]

Which proportion of the long-term potentiation (LTP) expressed in the bulk of excitatory synapses is postsynaptic and which presynaptic remains debatable. To understand better the possible impact of either LTP form, we explored a realistic model of a CA1 pyramidal cell equipped with known membrane mechanisms and multiple, stochastic excitatory axo-spinous synapses. Our simulations were designed to establish an input–output transfer function, the dependence between the frequency of presynaptic action potentials triggering probabilistic synaptic discharges and the average frequency of postsynaptic spiking. We found that, within the typical physiological range, potentiation of the postsynaptic current results in a greater overall output than an equivalent increase in presynaptic release probability. This difference grows stronger at lower input frequencies and lower release probabilities. Simulations with a non-hierarchical circular network of principal neurons indicated that equal increases in either synaptic fidelity or synaptic strength of individual connections also produce distinct changes in network activity, although the network phenomenology is likely to be complex. These observations should help to interpret the machinery of LTP phenomena documented in situ. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'. [ABSTRACT FROM AUTHOR]

Prostaglandin E2 (PGE2) is a major contributor to inflammatory pain hyperalgesia, however, the extent to which it modulates the activity of nociceptive axons is incompletely understood. We developed and characterized a microfluidic cell culture model to investigate sensitisation of the axons of dorsal root ganglia neurons. We show that application of PGE2 to fluidically isolated axons leads to sensitisation of their responses to depolarising stimuli. Interestingly the application of PGE2 to the DRG axons elicited a direct and persistent spiking activity propagated to the soma. Both the persistent activity and the membrane depolarisation in the axons are abolished by the EP4 receptor inhibitor and a blocker of cAMP synthesis. Further investigated into the mechanisms of the spiking activity showed that the PGE2 evoked depolarisation was inhibited by Nav1.8 sodium channel blockers but was refractory to the application of TTX or zatebradine. Interestingly, the depolarisation of axons was blocked by blocking ANO1 channels with T16Ainh-A01. We further show that PGE2-elicited axonal responses are altered by the changes in chloride gradient within the axons following treatment with bumetanide a Na-K-2Cl cotransporter NKCC1 inhibitor, but not by VU01240551 an inhibitor of potassium-chloride transporter KCC2. Our data demonstrate a novel role for PGE2/EP4/cAMP pathway which culminates in a sustained depolarisation of sensory axons mediated by a chloride current through ANO1 channels. Therefore, using a microfluidic culture model, we provide evidence for a potential dual function of PGE2 in inflammatory pain: it sensitises depolarisation-evoked responses in nociceptive axons and directly triggers action potentials by activating ANO1 and Nav1.8 channels. [ABSTRACT FROM AUTHOR]

Chronic heart failure is one of the most common reasons for hospitalization. Current risk stratification is based on ejection fraction, whereas many arrhythmic events occur in patients with relatively preserved ejection fraction. We aim to investigate the mechanistic link between proarrhythmic abnormalities, reduced contractility and diastolic dysfunction in heart failure, using electromechanical modelling and simulations of human failing cardiomyocytes. We constructed, calibrated and validated populations of human electromechanical models of failing cardiomyocytes, that were able to reproduce the prolonged action potential, reduced contractility and diastolic dysfunction as observed in human data, as well as increased propensity to proarrhythmic incidents such as early afterdepolarization and beat-to-beat alternans. Our simulation data reveal that proarrhythmic incidents tend to occur in failing myocytes with lower diastolic tension, rather than with lower contractility, due to the relative preserved SERCA and sodium calcium exchanger current. These results support the inclusion of end-diastolic volume to be potentially beneficial in the risk stratifications of heart failure patients. [ABSTRACT FROM AUTHOR]