Search

The hypothalamic suprachiasmatic nucleus (SCN) is the central pacemaker for mammalian circadian rhythms. As such, this ensemble of cell‐autonomous neuronal oscillators with divergent periods must maintain coordinated oscillations. To investigate ultrastructural features enabling such synchronization, 805 coronal ultrathin sections of mouse SCN tissue were imaged with electron microscopy and aligned into a volumetric stack, from which selected neurons within the SCN core were reconstructed in silico. We found that clustered SCN core neurons were physically connected to each other via multiple large soma‐to‐soma plate‐like contacts. In some cases, a sliver of a glial process was interleaved. These contacts were large, covering on average ∼21% of apposing neuronal somata. It is possible that contacts may be the electrophysiological substrate for synchronization between SCN neurons. Such plate‐like contacts may explain why the synchronization of SCN neurons is maintained even when chemical synaptic transmission or electrical synaptic transmission via gap junctions is blocked. Such ephaptic contact‐mediated synchronization among nearby neurons may therefore contribute to the wave‐like oscillations of circadian core clock genes and calcium signals observed in the SCN. [ABSTRACT FROM AUTHOR]

Electric fields are now considered a major mechanism of epileptiform activity. However, it is not clear if another electrophysiological phenomenon, burst suppression, utilizes the same mechanism for its bursting phase. Thus, the purpose of this study was to compare the role of ephaptic coupling—the recruitment of neighboring cells via electric fields—in generating bursts in epilepsy and burst suppression. We used local injections of the GABA-antagonist picrotoxin to elicit epileptic activity and a general anesthetic, sevoflurane, to elicit burst suppression in rabbits. Then, we applied an established computational model of pyramidal cells to simulate neuronal activity in a 3-dimensional grid, with an additional parameter to trigger a suppression phase based on extra-cellular calcium dynamics. We discovered that coupling via electric fields was sufficient to produce bursting in scenarios where inhibitory control of excitatory neurons was sufficiently low. Under anesthesia conditions, bursting occurs with lower neuronal recruitment in comparison to seizures. Our model predicts that due to the effect of electric fields, the magnitude of bursts during seizures should be roughly 2–3 times the magnitude of bursts that occur during burst suppression, which is consistent with our in vivo experimental results. The resulting difference in magnitude between bursts during anesthesia and epileptiform bursts reflects the strength of the electric field effect, which suggests that burst suppression and epilepsy share the same ephaptic coupling mechanism. [ABSTRACT FROM AUTHOR]

Where is consciousness? Neurobiological theories of consciousness look primarily to synaptic firing and “spike codes” as the physical substrate of consciousness, although the specific mechanisms of consciousness remain unknown. Synaptic firing results from electrochemical processes in neuron axons and dendrites. All neurons also produce electromagnetic (EM) fields due to various mechanisms, including the electric potential created by transmembrane ion flows, known as “local field potentials,” but there are also more meso-scale and macro-scale EM fields present in the brain. The functional role of these EM fields has long been a source of debate. We suggest that these fields, in both their local and global forms, may be the primary seat of consciousness, working as a gestalt with synaptic firing and other aspects of neuroanatomy to produce the marvelous complexity of minds. We call this assertion the “electromagnetic field hypothesis.” The neuroanatomy of the brain produces the local and global EM fields but these fields are not identical with the anatomy of the brain. These fields are produced by, but not identical with, the brain, in the same manner that twigs and leaves are produced by a tree’s branches and trunk but are not the same as the branches and trunk. As such, the EM fields represent the more granular, both spatially and temporally, aspects of the brain’s structure and functioning than the neuroanatomy of the brain. The brain’s various EM fields seem to be more sensitive to small changes than the neuroanatomy of the brain. We discuss issues with the spike code approach as well as the various lines of evidence supporting our argument that the brain’s EM fields may be the primary seat of consciousness. This evidence (which occupies most of the paper) suggests that oscillating neural EM fields may make firing in neural circuits oscillate, and these oscillating circuits may help unify and guide conscious cognition. [ABSTRACT FROM AUTHOR]

The brain is the ultimate control unit of the body. It conducts accurate, fast and reproducible calculations to control motor actions affecting mating, foraging and flight or fight decisions. Therefore, during evolution, better and more efficient brains have emerged. However, even simple brains are complex organs. They are formed by glial cells and neurons that establish highly intricate networks to enable information collection, processing and eventually, a precise motor control. Here, we review and connect some well‐established and some hidden pieces of information to set the focus on ion homeostasis as a driving force in glial differentiation promoting signalling speed and accuracy. [ABSTRACT FROM AUTHOR]

Theta oscillations in the primary visual cortex (VC) have been observed during running tasks, but the mechanism behind their generation is not well understood. Some studies have suggested that theta in the VC is locally generated, while others have proposed that it is volume conducted from the hippocampus. The present study aimed to investigate the relationship between hippocampal and VC LFP dynamics. Analysis of power spectral density revealed that LFP in the VC was similar to that in the hippocampus, but with lower overall magnitude. As running velocity increased, both the power and frequency of theta and its harmonics increased in the VC, similarly to what is observed in the hippocampus. Current source density analysis triggered to theta did not identify distinct current sources and sinks in the VC, supporting the idea that theta in the VC is conducted from the adjacent hippocampus. Phase coupling between theta, its harmonics, and gamma is a notable feature in the hippocampus, particularly in the lacunosum moleculare. While some evidence of coupling between theta and its harmonics in the VC was found, bicoherence estimates did not reveal significant phase coupling between theta and gamma. Similar results were seen in the cross-region bicoherence analysis, where theta showed strong coupling with its harmonics with increasing velocity. Thus, theta oscillations observed in the VC during running tasks are likely due to volume conduction from the hippocampus. [ABSTRACT FROM AUTHOR]

Where is consciousness? Neurobiological theories of consciousness look primarily to synaptic firing and “spike codes” as the physical substrate of consciousness, although the specific mechanisms of consciousness remain unknown. Synaptic firing results from electrochemical processes in neuron axons and dendrites. All neurons also produce electromagnetic (EM) fields due to various mechanisms, including the electric potential created by transmembrane ion flows, known as “local field potentials,” but there are also more meso-scale and macro-scale EM fields present in the brain. The functional role of these EM fields has long been a source of debate. We suggest that these fields, in both their local and global forms, may be the primary seat of consciousness, working as a gestalt with synaptic firing and other aspects of neuroanatomy to produce the marvelous complexity of minds. We call this assertion the “electromagnetic field hypothesis.” The neuroanatomy of the brain produces the local and global EM fields but these fields are not identical with the anatomy of the brain. These fields are produced by, but not identical with, the brain, in the same manner that twigs and leaves are produced by a tree’s branches and trunk but are not the same as the branches and trunk. As such, the EM fields represent the more granular, both spatially and temporally, aspects of the brain’s structure and functioning than the neuroanatomy of the brain. The brain’s various EM fields seem to be more sensitive to small changes than the neuroanatomy of the brain. We discuss issues with the spike code approach as well as the various lines of evidence supporting our argument that the brain’s EM fields may be the primary seat of consciousness. This evidence (which occupies most of the paper) suggests that oscillating neural EM fields may make firing in neural circuits oscillate, and these oscillating circuits may help unify and guide conscious cognition.

Theta oscillations in the primary visual cortex (VC) have been observed during running tasks, but the mechanism behind their generation is not well understood. Some studies have suggested that theta in the VC is locally generated, while others have proposed that it is volume conducted from the hippocampus. The present study aimed to investigate the relationship between hippocampal and VC LFP dynamics. Analysis of power spectral density revealed that LFP in the VC was similar to that in the hippocampus, but with lower overall magnitude. As running velocity increased, both the power and frequency of theta and its harmonics increased in the VC, similarly to what is observed in the hippocampus. Current source density analysis triggered to theta did not identify distinct current sources and sinks in the VC, supporting the idea that theta in the VC is conducted from the adjacent hippocampus. Phase coupling between theta, its harmonics, and gamma is a notable feature in the hippocampus, particularly in the lacunosum moleculare. While some evidence of coupling between theta and its harmonics in the VC was found, bicoherence estimates did not reveal significant phase coupling between theta and gamma. Similar results were seen in the cross-region bicoherence analysis, where theta showed strong coupling with its harmonics with increasing velocity. Thus, theta oscillations observed in the VC during running tasks are likely due to volume conduction from the hippocampus.

• Dynamical robustness of multilayer neuronal network with inter-layer ephaptic coupling is investigated at different scales. • Strong inter-layer ephaptic coupling is capable of suppressing the resonance like phenomena at mesoscale and macroscale. • The inter-layer ephaptic coupling could enhance dynamical robustness of each layer and the entire multilayer network. • The dynamics of multilayer neuronal network with inter-layer ephaptic coupling is verified in circuits built on Multisim. In nervous system, a non-synaptic communication between neurons, known as the ephaptic coupling, emerges depending on electromagnetic induction which is induced by extracellular electric fields. In this paper, a multilayer neuronal network is constructed by adopting ephaptic coupling between layers, and dynamical robustness of multilayer neuronal networks with inter-layer ephaptic coupling is analyzed at different scales. The macroscopic oscillation of the whole network occupies the middle ground between mesoscopic oscillation of intermediate layer and that of the top (or bottom) layer. Strong inter-layer ephaptic coupling is capable of suppressing the resonance like phenomena of oscillation at mesoscale and macroscale. At weak electrical coupling, dynamical robustness of intermediate layer is stronger than that of top and bottom layers, and is even stronger than that of the whole network. While at strong electrical coupling, dynamical robustness of each layer is comparable to that of the whole network. The inter-layer ephaptic coupling could enhance dynamical robustness of each layer and the entire multilayer neuronal network, which is in stark contrast to electrical coupling with the tendency to spoil the dynamical robustness. Dynamical robustness of the whole network is always weaker than that of intermediate layer, but is stronger than that of top and bottom layers with increasing inter-layer ephaptic coupling. The firing modes of neurons before the critical ratio is analyzed at microscale. The ratio of inactive neurons switches the firing patterns of the active neuron among different firing patterns in multilayer neuronal network. The dynamics of multilayer neuronal network with inter-layer ephaptic coupling is verified in the analog circuit built on Multisim. This study provides new clues to understand mechanism of collective phenomenon in realistic neuronal systems. [ABSTRACT FROM AUTHOR]

Cardiac ephaptic coupling, a mechanism mediated by negative electric potentials occurring in the narrow intercellular clefts of intercalated discs, can influence action potential propagation by modulating the sodium current. Intercalated discs are highly tortuous due to the mingling of plicate and interplicate regions. To investigate the effect of their convoluted structure on ephaptic coupling, we refined our previous model of an intercalated disc and tested predefined folded geometries, which we parametrized by orientation, amplitude and number of folds. Ephaptic interactions (assessed by the minimal cleft potential and amplitude of the sodium currents) were reinforced by concentric folds. With increasing amplitude and number of concentric folds, the cleft potential became more negative during the sodium current transient. This is explained by the larger resistance between the cleft and the bulk extracellular space. In contrast, radial folds attenuated ephaptic interactions and led to a less negative cleft potential due to a decreased net cleft resistance. In conclusion, despite limitations inherent to the simplified geometries and sodium channel distributions investigated as well as simplifications regarding ion concentration changes, these results indicate that the folding pattern of intercalated discs modulates ephaptic coupling. [ABSTRACT FROM AUTHOR]

Electric fields are now considered a major mechanism of epileptiform activity. However, it is not clear if another electrophysiological phenomenon, burst suppression, utilizes the same mechanism for its bursting phase. Thus, the purpose of this study was to compare the role of ephaptic coupling—the recruitment of neighboring cells via electric fields—in generating bursts in epilepsy and burst suppression. We used local injections of the GABA-antagonist picrotoxin to elicit epileptic activity and a general anesthetic, sevoflurane, to elicit burst suppression in rabbits. Then, we applied an established computational model of pyramidal cells to simulate neuronal activity in a 3-dimensional grid, with an additional parameter to trigger a suppression phase based on extra-cellular calcium dynamics. We discovered that coupling via electric fields was sufficient to produce bursting in scenarios where inhibitory control of excitatory neurons was sufficiently low. Under anesthesia conditions, bursting occurs with lower neuronal recruitment in comparison to seizures. Our model predicts that due to the effect of electric fields, the magnitude of bursts during seizures should be roughly 2–3 times the magnitude of bursts that occur during burst suppression, which is consistent with our in vivo experimental results. The resulting difference in magnitude between bursts during anesthesia and epileptiform bursts reflects the strength of the electric field effect, which suggests that burst suppression and epilepsy share the same ephaptic coupling mechanism.

Experimental and theoretical studies have shown that ephaptic coupling leads to the synchronisation and slowing down of spikes propagating along the axons within peripheral nerve bundles. However, the main focus thus far has been on a small number of identical axons, whereas realistic peripheral nerve bundles contain numerous axons with different diameters. Here, we present a computationally efficient spike propagation model, which captures the essential features of propagating spikes and their ephaptic interaction, and facilitates the theoretical investigation of spike volleys in large, heterogeneous fibre bundles. We first lay out the theoretical basis to describe how the spike in an active axon changes the membrane potential of a passive axon. These insights are then incorporated into the spike propagation model, which is calibrated with a biophysically realistic model based on Hodgkin–Huxley dynamics. The fully calibrated model is then applied to fibre bundles with a large number of axons and different types of axon diameter distributions. One key insight of this study is that the heterogeneity of the axonal diameters has a dispersive effect, and that a higher level of heterogeneity requires stronger ephaptic coupling to achieve full synchronisation between spikes. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a challenging complaint for patients and clinicians since there are no effective agents available to get satisfactory outcomes even though the pharmacological agents target reasonable pathophysiological mechanisms. This may indicate that other aspects in these mechanisms should be unveiled to comprehend the pathogenesis of neuropathic pain and thus find more effective treatments. Therefore, in the present study, several mechanisms are chosen to be reconsidered in the pathophysiology of neuropathic pain from a quantum mechanical perspective. The mathematical model of the ions quantum tunneling model is used to provide quantum aspects in the pathophysiology of neuropathic pain. Three major pathophysiological mechanisms are revisited in the context of the quantum tunneling model. These include: (1) the depolarized membrane potential of neurons; (2) the cross-talk or the ephaptic coupling between the neurons; and (3) the spontaneous neuronal activity and the emergence of ectopic action potentials. We will show mathematically that the quantum tunneling model can predict the occurrence of neuronal membrane depolarization attributed to the quantum tunneling current of sodium ions. Moreover, the probability of inducing an ectopic action potential in the axons of neurons will be calculated and will be shown to be significant and influential. These ectopic action potentials are generated due to the formation of quantum synapses which are assumed to be the mechanism behind the ephaptic transmission. Furthermore, the spontaneous neuronal activity and the emergence of ectopic action potentials independently from any adjacent stimulated neurons are predicted to occur according to the quantum tunneling model. All these quantum mechanical aspects contribute to the overall hyperexcitability of the neurons and to the pathogenesis of neuropathic pain. Additionally, providing a new perspective in the pathophysiology of neuropathic pain may improve our understanding of how the neuropathic pain is generated and maintained and may offer new effective agents that can improve the overall clinical outcomes of the patients. [ABSTRACT FROM AUTHOR]

Acute engraftment arrhythmias (EAs) remain a serious complication of remuscularization therapy. Preliminary evidence suggests that a focal source underlies these EAs stemming from the automaticity of immature pluripotent stem cell-derived cardiomyocytes (PSC-CMs) in nascent myocardial grafts. How these EAs arise though during early engraftment remains unclear. In a series of in silico experiments, we probed the origin of EAs—exploring aspects of altered impulse formation and altered impulse propagation within nascent PSC-CM grafts and at the host-graft interface. To account for poor gap junctional coupling during early PSC-CM engraftment, the voltage dependence of gap junctions and the possibility of ephaptic coupling were incorporated. Inspired by cardiac development, we also studied the contributions of another feature of immature PSC-CMs, circumferential sodium channel (NaCh) distribution in PSC-CMs. Ectopic propagations emerged from nascent grafts of immature PSC-CMs at a rate of <96 bpm. Source-sink effects dictated this rate and contributed to intermittent capture between host and graft. Moreover, ectopic beats emerged from dynamically changing sites along the host-graft interface. The latter arose in part because circumferential NaCh distribution in PSC-CMs contributed to preferential conduction slowing and block of electrical impulses from host to graft myocardium. We conclude that additional mechanisms, in addition to focal ones, contribute to EAs and recognize that their relative contributions are dynamic across the engraftment process. [Display omitted] • Acute engraftment arrhythmias remain a serious complication of remuscularization. • Spontaneous beats in graft myocardium intermittently propagated into the host. • Immaturity of graft myocytes contributed to propensity for entrance block. • Site of graft-induced ectopic propagations could change from beat-to-beat. • A reentrant mechanism is likely to contribute to engraftment arrhythmias. [ABSTRACT FROM AUTHOR]

It has been proposed that when gap junctional coupling is reduced in cardiac tissue, action potential propagation can be supported via ephaptic coupling, a mechanism mediated by negative electric potentials occurring in narrow intercellular clefts of intercalated discs (IDs). Recent studies showed that sodium (Na+) channels form clusters near gap junction plaques in nanodomains called perinexi, where the ID cleft is even narrower. To examine the electrophysiological relevance of Na+ channel clusters being located in perinexi, we developed a 3D finite element model of two longitudinally abutting cardiomyocytes, with a central Na+ channel cluster on the ID membranes. When this cluster was located in the perinexus of a closely positioned gap junction plaque, varying perinexal width greatly modulated impulse transmission from one cell to the other, with narrow perinexi potentiating ephaptic coupling. This modulation occurred via the interplay of Na+ currents, extracellular potentials in the cleft and patterns of current flow within the cleft. In contrast, when the Na+ channel cluster was located remotely from the gap junction plaque, this modulation by perinexus width largely disappeared. Interestingly, the Na+ current in the ID membrane of the pre‐junctional cell switched from inward to outward during excitation, thus contributing ions to the activating channels on the post‐junctional ID membrane. In conclusion, these results indicate that the localization of Na+ channel clusters in the perinexi of gap junction plaques is crucial for ephaptic coupling, which is furthermore greatly modulated by perinexal width. These findings are relevant for a comprehensive understanding of cardiac excitation. Key points: Ephaptic coupling is a cardiac conduction mechanism involving nanoscale‐level interactions between the sodium (Na+) current and the extracellular potential in narrow intercalated disc clefts.When gap junctional coupling is reduced, ephaptic coupling acts in conjunction with the classical cardiac conduction mechanism based on gap junctional current flow.In intercalated discs, Na+ channels form clusters that are preferentially located in the periphery of gap junction plaques, in nanodomains known as perinexi, but the electrophysiological role of these perinexi has never been examined.In our new 3D finite element model of two cardiac cells abutting each other with their intercalated discs, a Na+ channel cluster located inside a narrowed perinexus facilitated impulse transmission via ephaptic coupling.Our simulations demonstrate the role of narrowed perinexi as privileged sites for ephaptic coupling in pathological situations when gap junctional coupling is decreased. [ABSTRACT FROM AUTHOR]

Voltage-gated sodium channels (VGSCs) are transmembrane protein complexes that are vital to the generation and propagation of action potentials in nerve and muscle fibers. The canonical VGSC is generally conceived as a heterotrimeric complex formed by 2 classes of membrane-spanning subunit: an α-subunit (pore forming) and 2 β-subunits (non-pore forming). Na V 1.5 is the main sodium channel α-subunit of mammalian ventricle, with lower amounts of other α-subunits, including Na V 1.6, being present. There are 4 β-subunits (β1-β4) encoded by 4 genes (SCN1B-SCN4B), each of which is expressed in cardiac tissues. Recent studies suggest that in addition to assignments in channel gating and trafficking, products of Scn1b may have novel roles in conduction of action potential in the heart and intracellular signaling. This includes evidence that the β-subunit extracellular amino-terminal domain facilitates adhesive interactions in intercalated discs and that its carboxyl-terminal region is a substrate for a regulated intramembrane proteolysis (RIP) signaling pathway, with a carboxyl-terminal peptide generated by β1 RIP trafficked to the nucleus and altering transcription of various genes, including Na V 1.5. In addition to β1, the Scn1b gene encodes for an alternative splice variant, β1B, which contains an identical extracellular adhesion domain to β1 but has a unique carboxyl-terminus. Although β1B is generally understood to be a secreted variant, evidence indicates that when co-expressed with Na V 1.5, it is maintained at the cell membrane, suggesting potential unique roles for this understudied protein. In this review, we focus on what is known of the 2 β-subunit variants encoded by Scn1b in heart, with particular focus on recent findings and the questions raised by this new information. We also explore data that indicate β1 and β1B may be attractive targets for novel antiarrhythmic therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Cardiac ephaptic coupling, a mechanism mediated by negative electric potentials occurring in the narrow intercellular clefts of intercalated discs, can influence action potential propagation by modulating the sodium current. Intercalated discs are highly tortuous due to the mingling of plicate and interplicate regions. To investigate the effect of their convoluted structure on ephaptic coupling, we refined our previous model of an intercalated disc and tested predefined folded geometries, which we parametrized by orientation, amplitude and number of folds. Ephaptic interactions (assessed by the minimal cleft potential and amplitude of the sodium currents) were reinforced by concentric folds. With increasing amplitude and number of concentric folds, the cleft potential became more negative during the sodium current transient. This is explained by the larger resistance between the cleft and the bulk extracellular space. In contrast, radial folds attenuated ephaptic interactions and led to a less negative cleft potential due to a decreased net cleft resistance. In conclusion, despite limitations inherent to the simplified geometries and sodium channel distributions investigated as well as simplifications regarding ion concentration changes, these results indicate that the folding pattern of intercalated discs modulates ephaptic coupling.

Objective: One of the challenges in treating patients with drug‐resistant epilepsy is that the mechanisms of seizures are unknown. Most current interventions are based on the assumption that epileptic activity recruits neurons and progresses by synaptic transmission. However, several experimental studies have shown that neural activity in rodent hippocampi can propagate independently of synaptic transmission. Recent studies suggest these waves are self‐propagating by electric field (ephaptic) coupling. In this study, we tested the hypothesis that neural recruitment during seizures can occur by electric field coupling. Methods: 4‐Aminopyridine was used in both in vivo and in vitro preparation to trigger seizures or epileptiform activity. A transection was made in the in vivo hippocampus and in vitro hippocampal and cortical slices to study whether the induced seizure activity can recruit neurons across the gap. A computational model was built to test whether ephaptic coupling alone can account for neural recruitment across the transection. The model prediction was further validated by in vitro experiments. Results: Experimental results show that electric fields generated by seizure‐like activity in the hippocampus both in vitro and in vivo can recruit neurons locally and through a transection of the tissue. The computational model suggests that the neural recruitment across the transection is mediated by electric field coupling. With in vitro experiments, we show that a dielectric material can block the recruitment of epileptiform activity across a transection, and that the electric fields measured within the gap are similar to those predicted by model simulations. Furthermore, this nonsynaptic neural recruitment is also observed in cortical slices, suggesting that this effect is robust in brain tissue. Significance: These results indicate that ephaptic coupling, a nonsynaptic mechanism, can underlie neural recruitment by a small electric field generated by seizure activity and could explain the low success rate of surgical transections in epilepsy patients. [ABSTRACT FROM AUTHOR]

ObjectiveLow-intensity transcranial ultrasound stimulation (TUS) is a non-invasive neuromodulation technique with high spatial resolution and feasible penetration depth. To date, the mechanisms of TUS modulated neural oscillations are not fully understood. This study designed a very low acoustic intensity (AI) TUS system that produces considerably reduced AI Ultrasound pulses (ISPTA < 0.5 W/cm2) when compared to previous methods used to measure regional neural oscillation patterns under different TUS parameters.MethodsWe recorded the local field potential (LFP) of five brain nuclei under TUS with three groups of simulating parameters. Spectrum estimation, time-frequency analysis (TFA), and relative power analysis methods have been applied to investigate neural oscillation patterns under different stimulation parameters.ResultsUnder PRF, 500 Hz and 1 kHz TUS, high-amplitude LFP activity with the auto-rhythmic pattern appeared in selected nuclei when ISPTA exceeded 12 mW/cm2. With TFA, high-frequency energy (slow gamma and high gamma) was significantly increased during the auto-rhythmic patterns. We observed an initial plateau in nuclei response when ISPTA reached 16.4 mW/cm2 for RPF 500 Hz and 20.8 mW/cm2 for RPF 1 kHz. The number of responding nuclei started decreasing while ISPTA continued increasing. Under 1.5 kHz TUS, no auto-rhythmic patterns have been observed, but slow frequency power was increased during TUS. TUS inhibited most of the frequency band and generated obvious slow waves (theta and delta band) when stimulated at RPF = 1.5 kHz, ISPTA = 8.8 mW/cm2.ConclusionThese results demonstrate that very low intensity Transcranial Ultrasound Stimulation (VLTUS) exerts significant neuromodulator effects under specific parameters in rat models and may be a valid tool to study neuronal physiology.

Objective: Low-intensity transcranial ultrasound stimulation (TUS) is a non-invasive neuromodulation technique with high spatial resolution and feasible penetration depth. To date, the mechanisms of TUS modulated neural oscillations are not fully understood. This study designed a very low acoustic intensity (AI) TUS system that produces considerably reduced AI Ultrasound pulses (I SPTA < 0.5 W/cm2) when compared to previous methods used to measure regional neural oscillation patterns under different TUS parameters. Methods: We recorded the local field potential (LFP) of five brain nuclei under TUS with three groups of simulating parameters. Spectrum estimation, time-frequency analysis (TFA), and relative power analysis methods have been applied to investigate neural oscillation patterns under different stimulation parameters. Results: Under PRF, 500 Hz and 1 kHz TUS, high-amplitude LFP activity with the auto-rhythmic pattern appeared in selected nuclei when I SPTA exceeded 12 mW/cm2. With TFA, high-frequency energy (slow gamma and high gamma) was significantly increased during the auto-rhythmic patterns. We observed an initial plateau in nuclei response when I SPTA reached 16.4 mW/cm2 for RPF 500 Hz and 20.8 mW/cm2 for RPF 1 kHz. The number of responding nuclei started decreasing while I SPTA continued increasing. Under 1.5 kHz TUS, no auto-rhythmic patterns have been observed, but slow frequency power was increased during TUS. TUS inhibited most of the frequency band and generated obvious slow waves (theta and delta band) when stimulated at RPF = 1.5 kHz, I SPTA = 8.8 mW/cm2. Conclusion: These results demonstrate that very low intensity Transcranial Ultrasound Stimulation (VLTUS) exerts significant neuromodulator effects under specific parameters in rat models and may be a valid tool to study neuronal physiology. [ABSTRACT FROM AUTHOR]

Mathematical models for excitable cells are commonly based on cable theory, which considers a homogenized domain and spatially constant ionic concentrations. Although such models provide valuable insight, the effect of altered ion concentrations or detailed cell morphology on the electrical potentials cannot be captured. In this paper, we discuss an alternative approach to detailed modeling of electrodiffusion in neural tissue. The mathematical model describes the distribution and evolution of ion concentrations in a geometrically-explicit representation of the intra- and extracellular domains. As a combination of the electroneutral Kirchhoff-Nernst-Planck (KNP) model and the Extracellular-Membrane-Intracellular (EMI) framework, we refer to this model as the KNP-EMI model. Here, we introduce and numerically evaluate a new, finite element-based numerical scheme for the KNP-EMI model, capable of efficiently and flexibly handling geometries of arbitrary dimension and arbitrary polynomial degree. Moreover, we compare the electrical potentials predicted by the KNP-EMI and EMI models. Finally, we study ephaptic coupling induced in an unmyelinated axon bundle and demonstrate how the KNP-EMI framework can give new insights in this setting.

Mathematical models for excitable cells are commonly based on cable theory, which considers a homogenized domain and spatially constant ionic concentrations. Although such models provide valuable insight, the effect of altered ion concentrations or detailed cell morphology on the electrical potentials cannot be captured. In this paper, we discuss an alternative approach to detailed modeling of electrodiffusion in neural tissue. The mathematical model describes the distribution and evolution of ion concentrations in a geometrically-explicit representation of the intra- and extracellular domains. As a combination of the electroneutral Kirchhoff-Nernst-Planck (KNP) model and the Extracellular-Membrane-Intracellular (EMI) framework, we refer to this model as the KNP-EMI model. Here, we introduce and numerically evaluate a new, finite element-based numerical scheme for the KNP-EMI model, capable of efficiently and flexibly handling geometries of arbitrary dimension and arbitrary polynomial degree. Moreover, we compare the electrical potentials predicted by the KNP-EMI and EMI models. Finally, we study ephaptic coupling induced in an unmyelinated axon bundle and demonstrate how the KNP-EMI framework can give new insights in this setting. [ABSTRACT FROM AUTHOR]

Spikelets are small spike-like depolarizations that are found in somatic recordings of many neuron types. Spikelets have been assigned important functions, ranging from neuronal synchronization to the regulation of synaptic plasticity, which are specific to the particular mechanism of spikelet generation. As spikelets reflect spiking activity in neuronal compartments that are electrotonically distinct from the soma, four modes of spikelet generation can be envisaged: (1) dendritic spikes or (2) axonal action potentials occurring in a single cell as well as action potentials transmitted via (3) gap junctions or (4) ephaptic coupling in pairs of neurons. In one of the best studied neuron type, cortical pyramidal neurons, the origins and functions of spikelets are still unresolved; all four potential mechanisms have been proposed, but the experimental evidence remains ambiguous. Here we attempt to reconcile the scattered experimental findings in a coherent theoretical framework. We review in detail the various mechanisms that can give rise to spikelets. For each mechanism, we present the biophysical underpinnings as well as the resulting properties of spikelets and compare these predictions to experimental data from pyramidal neurons. We also discuss the functional implications of each mechanism. On the example of pyramidal neurons, we illustrate that several independent spikelet-generating mechanisms fulfilling vastly different functions might be operating in a single cell. [ABSTRACT FROM AUTHOR]

In insects, olfactory receptor neurons (ORNs) are localized in sensilla. Within a sensillum, different ORN types are typically co-localized and exhibit nonsynaptic reciprocal inhibition through ephaptic coupling. This inhibition is hypothesized to aid odor source discrimination in environments where odor molecules (odorants) are dispersed by wind, resulting in turbulent plumes. Under these conditions, odorants from a single source arrive at the ORNs synchronously, while those from separate sources arrive asynchronously. Ephaptic inhibition is expected to be weaker for asynchronous arriving odorants from separate sources, thereby enhancing their discrimination. Previous studies have focused on ephaptic inhibition of sustained ORN responses to constant odor stimuli. This begs the question of whether ephaptic inhibition also affects transient ORN responses and if this inhibition is modulated by the temporal arrival patterns of different odorants. To address this, we recorded co-localized ORNs in the fruit fly Drosophila melanogaster and exposed them to dynamic odorant mixtures. We found reciprocal inhibition, strongly suggesting the presence of ephaptic coupling. This reciprocal inhibition does indeed modulate transient ORN responses and is sensitive to the relative timing of odor stimuli. Notably, the strength of inhibition decreases as the synchrony and correlation between arriving odorants decrease. These results support the hypothesis that ephaptic inhibition aids odor source discrimination., (© The Author(s) 2024. Published by Oxford University Press.)

Background and objectives: Non-motor symptoms in the form of increased sensitivity are often associated with the onset of idiopathic Bell’s palsy (IBP). The aims were to determine whether the pain threshold in the retroauricular regions (RAR) in IBP patients and the time of its occurrence is related to IBP severity. Materials and Methods: The study was conducted among 220 respondents (142 IBP patients, 78 healthy subjects (HS)). The degree of IBP was graded using the House–Brackmann and Sunnybrook Grading Scales (II—mild dysfunction, VI—total paralysis), whereas the pain thresholds were measured using the digital pressure algometer. Results: We found no difference in the degree of the pain threshold between the right and left RAR in the HS group. IBP patients belonging to groups II, III, IV, and V had lower pain thresholds in both RARs than HS and IBP patients belonging to group VI. There was no difference in the degree of pain threshold in RAR between the affected and unaffected side in IBP patients. The incidence of retroauricular pain that precedes paralysis and ceases after its occurrence in groups II and III of IBP patients is noticeably lower and the incidence of retroauricular pain that occurred only after the onset of paralysis is more frequent. Also, we found that the incidence of retroauricular pain that precedes paralysis and ceases after its occurrence in groups V and VI of IBP patients was more frequent. Conclusions: The degree of pain threshold lowering in RAR (bilaterally) is inversely related to the severity of IBP. We suggest that the occurrence of retroauricular pain before the onset of facial weakness is associated with higher severity of IBP while the occurrence after the onset is associated with lower severity of IBP.

It is well documented that synapses play a significant role in the transmission of information between neurons. However, in the absence of synaptic transmission, neural activity has been observed to continue to propagate. Previous studies have shown that propagation of epileptiform activity takes place in the absence of synaptic transmission and gap junctions and is outside the range of ionic diffusion and axonal conduction. Computer simulations indicate that electric field coupling could be responsible for the propagation of neural activity under pathological conditions such as epilepsy. Electric fields can modulate neuronal membrane voltage, but there is no experimental evidence suggesting that electric field coupling can mediate self-regenerating propagation of neural activity. Here we examine the role of electric field coupling by eliminating all forms of neural communications except electric field coupling with a cut through the neural tissue. We show that 4-AP induced activity generates an electric field capable of recruiting neurons on the distal side of the cut. Experiments also show that applied electric fields with amplitudes similar to endogenous values can induce propagating waves. Finally, we show that canceling the electrical field at a given point can block spontaneous propagation. The results from these in vitro electrophysiology experiments suggest that electric field coupling is a critical mechanism for non-synaptic neural propagation and therefore could contribute to the propagation of epileptic activity in the brain. • Spontaneous epileptiform activity propagates by electric field coupling. • Epileptiform activity triggers distal neurons across the cut by electric field coupling. • Interfering with extracellular electric fields can block propagation of activity. • Electric field coupling can explain the existence of non-synaptic propagating waves. • Electric field coupling could explain how micro-seizures recruit neurons through large areas. [ABSTRACT FROM AUTHOR]

Abstract Time-varying networks are prominently present in the nervous system, where the connections between neurons vary according to the activity of pre and post synapses. Using this as motivation, we here consider a system of two ephaptically coupled neurons with a periodically time-varying link between the two membrane potentials. We derive the master stability function in dependence on the membrane potential coupling strength and in dependence on the ephaptic coupling strength. We first determine coupling ranges at which the two neurons are synchronizable if the link between them is static. In doing so, we find that the ephaptic coupling has a negligible impact on synchronization, while the coupling through the membrane potential has a strong effect. We then consider switching in the coupling, determining the average synchronization error for a fixed ephaptic coupling strength and different membrane potential coupling strengths, and for various switching frequencies. We find the values of the switching coefficient that can synchronize the two neurons for each of the considered switching frequencies, and finally, we also use the basin stability method to determine the global stability of synchronization. [ABSTRACT FROM AUTHOR]

Key points: Slow periodic activity can propagate with speeds around 0.1 m s−1 and be modulated by weak electric fields.Slow periodic activity in the longitudinal hippocampal slice can propagate without chemical synaptic transmission or gap junctions, but can generate electric fields which in turn activate neighbouring cells.Applying local extracellular electric fields with amplitude in the range of endogenous fields is sufficient to modulate or block the propagation of this activity both in the in silico and in the in vitro models.Results support the hypothesis that endogenous electric fields, previously thought to be too small to trigger neural activity, play a significant role in the self‐propagation of slow periodic activity in the hippocampus.Experiments indicate that a neural network can give rise to sustained self‐propagating waves by ephaptic coupling, suggesting a novel propagation mechanism for neural activity under normal physiological conditions. Slow oscillations are a standard feature observed in the cortex and the hippocampus during slow wave sleep. Slow oscillations are characterized by low‐frequency periodic activity (<1 Hz) and are thought to be related to memory consolidation. These waves are assumed to be a reflection of the underlying neural activity, but it is not known if they can, by themselves, be self‐sustained and propagate. Previous studies have shown that slow periodic activity can be reproduced in the in vitro preparation to mimic in vivo slow oscillations. Slow periodic activity can propagate with speeds around 0.1 m s−1 and be modulated by weak electric fields. In the present study, we show that slow periodic activity in the longitudinal hippocampal slice is a self‐regenerating wave which can propagate with and without chemical or electrical synaptic transmission at the same speeds. We also show that applying local extracellular electric fields can modulate or even block the propagation of this wave in both in silico and in vitro models. Our results support the notion that ephaptic coupling plays a significant role in the propagation of the slow hippocampal periodic activity. Moreover, these results indicate that a neural network can give rise to sustained self‐propagating waves by ephaptic coupling, suggesting a novel propagation mechanism for neural activity under normal physiological conditions. Key points: Slow periodic activity can propagate with speeds around 0.1 m s−1 and be modulated by weak electric fields.Slow periodic activity in the longitudinal hippocampal slice can propagate without chemical synaptic transmission or gap junctions, but can generate electric fields which in turn activate neighbouring cells.Applying local extracellular electric fields with amplitude in the range of endogenous fields is sufficient to modulate or block the propagation of this activity both in the in silico and in the in vitro models.Results support the hypothesis that endogenous electric fields, previously thought to be too small to trigger neural activity, play a significant role in the self‐propagation of slow periodic activity in the hippocampus.Experiments indicate that a neural network can give rise to sustained self‐propagating waves by ephaptic coupling, suggesting a novel propagation mechanism for neural activity under normal physiological conditions. [ABSTRACT FROM AUTHOR]

Computational modeling indicates that cardiac conduction may involve ephaptic coupling – intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that β1(SCN1B) –mediated adhesion scaffolds trans-activating NaV1.5 (SCN5A) channels within narrow (

Computational models enable a safe and convenient way to study the excitation of nerve fibers under external stimulation. Contemporary models calculate the electric field distribution from transcutaneous stimulation and the resulting neuronal response separately. This study uses finite element methods to develop a multi-scale model that couples electric fields within macroscopic tissue layers and microscopic nerve fibers in a single-stage computational framework. The model included a triaxial myelinated nerve fiber bundle embedded within a volume conductor of tissue layers to represent the median nerve innervating the forearm muscles. The model captured the excitability of nerve fibers under transcutaneous stimulation and their nerve-tissue interactions to a transient external stimulus. The determinants of the strength-duration curve, rheobase, and chronaxie for the proposed model had close correlations with in-vivo experimentation on human participants. Additionally, the excitability indices for the triaxial myelinated nerve fiber implemented using the finite element method agreed well with experimental data from the literature. The validity of the proposed model encourages its use for applications involving transcutaneous stimulation. Capable of capturing field distribution across realistic morphologies, the model can serve as a testbed to improve stimulation protocols and electrode designs with subject-level specificity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Key points: It has been proposed that ephaptic conduction, relying on interactions between the sodium (Na+) current and the extracellular potential in intercalated discs, might contribute to cardiac conduction when gap junctional coupling is reduced, but this mechanism is still controversial. In intercalated discs, Na+ channels form clusters near gap junction plaques, but the functional significance of these clusters has never been evaluated. In HEK cells expressing cardiac Na+ channels, we show that restricting the extracellular space modulates the Na+ current, as predicted by corresponding simulations accounting for ephaptic effects. In a high‐resolution model of the intercalated disc, clusters of Na+ channels that face each other across the intercellular cleft facilitate ephaptic impulse transmission when gap junctional coupling is reduced. Thus, our simulations reveal a functional role for the clustering of Na+ channels in intercalated discs, and suggest that rearrangement of these clusters in disease may influence cardiac conduction. Abstract: It has been proposed that ephaptic interactions in intercalated discs, mediated by extracellular potentials, contribute to cardiac impulse propagation when gap junctional coupling is reduced. However, experiments demonstrating ephaptic effects on the cardiac Na+ current (INa) are scarce. Furthermore, Na+ channels form clusters around gap junction plaques, but the electrophysiological significance of these clusters has never been investigated. In patch clamp experiments with HEK cells stably expressing human Nav1.5 channels, we examined how restricting the extracellular space modulates INa elicited by an activation protocol. In parallel, we developed a high‐resolution computer model of the intercalated disc to investigate how the distribution of Na+ channels influences ephaptic interactions. Approaching the HEK cells to a non‐conducting obstacle always increased peak INa at step potentials near the threshold of INa activation and decreased peak INa at step potentials far above threshold (7 cells, P = 0.0156, Wilcoxon signed rank test). These effects were consistent with corresponding control simulations with a uniform Na+ channel distribution. In the intercalated disc computer model, redistributing the Na+ channels into a central cluster of the disc potentiated ephaptic effects. Moreover, ephaptic impulse transmission from one cell to another was facilitated by clusters of Na+ channels facing each other across the intercellular cleft when gap junctional coupling was reduced. In conclusion, our proof‐of‐principle experiments demonstrate that confining the extracellular space modulates cardiac INa, and our simulations reveal the functional role of the aggregation of Na+ channels in the perinexus. These findings highlight novel concepts in the physiology of cardiac excitation. [ABSTRACT FROM AUTHOR]

We propose and present converging evidence for the Cytoelectric Coupling Hypothesis: Electric fields generated by neurons are causal down to the level of the cytoskeleton. This could be achieved via electrodiffusion and mechanotransduction and exchanges between electrical, potential and chemical energy. Ephaptic coupling organizes neural activity, forming neural ensembles at the macroscale level. This information propagates to the neuron level, affecting spiking, and down to molecular level to stabilize the cytoskeleton, "tuning" it to process information more efficiently. • Cytoelectric Coupling Hypothesis proposed. • Electric fields are causal down to cytoskeleton. • Ephaptic coupling to LFPs can organize neural activity. • Evidence from developmental biology and neuroscience. • Discussion of electrodiffusion, mechanotransduction and tensegrity. [ABSTRACT FROM AUTHOR]

• Trigeminal autonomic cephalalgias(TACs) could be the initial sole brainstem manifestation of neuromyelitis optica spectrum disorders (NMOSD). • An underlying cause for SUNCT /SUNA should be considered, especially if there is a limited response to anti-epileptic medication. • The activation of trigeminal-autonomic reflex and ephaptic coupling might be the underlying mechanism of symptomatic TACs in NMOSD. The pathophysiology of trigeminal autonomic cephalalgias (TACs) is poorly understood at present. Symptomatic TACs are rarely reported in neuromyelitis optica spectrum disorders (NMOSD). To better clarify this distinct clinical manifestation in NMOSD and to investigate its possible pathophysiology, we reviewed articles describing such cases including our own case. We performed a search of all clinical studies of TACs in NMOSD published up to September 1st, 2022. We put no restrictions on the year of English publication in our search. The following keywords were searched: trigeminal autonomic cephalalgias, cluster headache, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA), hemicrania continua, paroxysmal hemicrania, neuromyelitis optica, neuromyelitis optica spectrum disorder, Devic's disease. We reviewed six cases (five published reports and our own case study) that fulfilled the diagnosis of NMOSD and TACs. Four of them were SUNCT, one was SUNA, and one was paroxysmal hemicrania. In three of these cases, headache was the initial sole manifestation. Only one case had a good response to routine TACs' treatment. All these patients had lesions in the medulla oblongata and cervical cord. Three cases' TACs were side-locked, and two of them had a left dorsolateral medulla oblongata lesion that corresponded with the left side TACs, while three cases' headaches happened on either side of the head. The phenomenon could be explained by the activation of trigeminal-autonomic reflex and ephaptic coupling. TACs could be the initial sole brainstem manifestation of NMOSD. An underlying cause for SUNCT/SUNA should be considered, especially if there is a limited response to anti-epileptic medication. The activation of trigeminal-autonomic reflex and ephaptic coupling might be the underlying mechanism of symptomatic TACs in NMOSD. [ABSTRACT FROM AUTHOR]

Background: Tumor Necrosis Factor α (TNFα) upregulation during acute inflammatory response has been associated with numerous cardiac effects including modulating Connexin43 and vascular permeability. This may in turn alter cardiac gap junctional (GJ) coupling and extracellular volume (ephaptic coupling) respectively. We hypothesized that acute exposure to pathophysiological TNFα levels can modulate conduction velocity (CV) in the heart by altering electrical coupling: GJ and ephaptic.Methods and Results: Hearts were optically mapped to determine CV from control, TNFα and TNFα + high calcium (2.5 vs. 1.25 mM) treated guinea pig hearts over 90 mins. Transmission electron microscopy was performed to measure changes in intercellular separation in the gap junction-adjacent extracellular nanodomain—perinexus (WP). Cx43 expression and phosphorylation were determined by Western blotting and Cx43 distribution by confocal immunofluorescence. At 90 mins, longitudinal and transverse CV (CVL and CVT, respectively) increased with control Tyrode perfusion but TNFα slowed CVT alone relative to control and anisotropy of conduction increased, but not significantly. TNFα increased WP relative to control at 90 mins, without significantly changing GJ coupling. Increasing extracellular calcium after 30 mins of just TNFα exposure increased CVT within 15 mins. TNFα + high calcium also restored CVT at 90 mins and reduced WP to control values. Interestingly, TNFα + high calcium also improved GJ coupling at 90 mins, which along with reduced WP may have contributed to increasing CV.Conclusions: Elevating extracellular calcium during acute TNFα exposure reduces perinexal expansion, increases ephaptic, and GJ coupling, improves CV and may be a novel method for preventing inflammation induced CV slowing.

Two mathematical models are part of the foundation of Computational neurophysiology; (a) the Cable equation is used to compute the membrane potential of neurons, and, (b) volume-conductor theory describes the extracellular potential around neurons. In the standard procedure for computing extracellular potentials, the transmembrane currents are computed by means of (a) and the extracellular potentials are computed using an explicit sum over analytical point-current source solutions as prescribed by volume conductor theory. Both models are extremely useful as they allow huge simplifications of the computational efforts involved in computing extracellular potentials. However, there are more accurate, though computationally very expensive, models available where the potentials inside and outside the neurons are computed simultaneously in a self-consistent scheme. In the present work we explore the accuracy of the classical models (a) and (b) by comparing them to these more accurate schemes. The main assumption of (a) is that the ephaptic current can be ignored in the derivation of the Cable equation. We find, however, for our examples with stylized neurons, that the ephaptic current is comparable in magnitude to other currents involved in the computations, suggesting that it may be significant—at least in parts of the simulation. The magnitude of the error introduced in the membrane potential is several millivolts, and this error also translates into errors in the predicted extracellular potentials. While the error becomes negligible if we assume the extracellular conductivity to be very large, this assumption is, unfortunately, not easy to justify a priori for all situations of interest.