Subthreshold Excitation Research Articles

Optogenetic Modulation of Arrhythmia Triggers: Proof-of-Concept from Computational Modeling.

Early afterdepolarizations (EADs) are secondary voltage depolarizations associated with reduced repolarization reserve (RRR) that can trigger lethal arrhythmias. Relating EADs to triggered activity is difficult to study, so the ability to suppress or provoke EADs would be experimentally useful. Here, we use computational simulations to assess the feasibility of subthreshold optogenetic stimulation modulating the propensity for EADs (cell-scale) and EAD-associated ectopic beats (organ-scale). We modified a ventricular ionic model by reducing rapid delayed rectifier potassium (0.25-0.1 × baseline) and increasing L-type calcium (1.0-3.5 × baseline) currents to create RRR conditions with varying severity. We ran simulations in models of single cardiomyocytes and left ventricles from post-myocardial infarction patient MRI scans. Optogenetic stimulation was simulated using either ChR2 (depolarizing) or GtACR1 (repolarizing) opsins. In cell-scale simulations without illumination, EADs were seen for 164 of 416 RRR conditions. Subthreshold stimulation of GtACR1 reduced EAD incidence by up to 84.8% (25/416 RRR conditions; 0.1μW/mm2); in contrast, subthreshold ChR2 excitation increased EAD incidence by up to 136.6% (388/416 RRR conditions; 50μW/mm2). At the organ scale, we assumed simultaneous, uniform illumination of the epicardial and endocardial surfaces. GtACR1-mediated suppression (10-50μW/mm2) and ChR2-mediated unmasking (50-100μW/mm2) of EAD-associated ectopic beats were feasible in three distinct ventricular models. Our findings suggest that optogenetics could be used to silence or provoke both EADs and EAD-associated ectopic beats. Validation in animal models could lead to exciting new experimental regimes and potentially to novel anti-arrhythmia treatments. The online version contains supplementary material available at 10.1007/s12195-023-00781-z.

Potentiation of neuronal activity by tonic GluD1 current in brain slices

Ion channel function of native delta glutamate receptors (GluDR) is incompletely understood. Previously, we and others have shown that activation of Gαq protein‐coupled receptors (GqPCR) produces a slow inward current carried by GluD1R. GluD1R also carries a tonic cation current of unknown cause. Here, using voltage‐clamp electrophysiological recordings from adult mouse brain slices containing the dorsal raphe nucleus, we find no role of ongoing G‐protein‐coupled receptor activity in generating or sustaining tonic GluD1R currents. Neither augmentation nor disruption of G protein activity affects tonic GluD1R currents, suggesting that ongoing G‐protein‐coupled receptor activity does not give rise to tonic GluD1R currents. Further, the tonic GluD1R current is unaffected by the addition of external glycine or D‐serine, which influences GluD2R current at millimolar concentrations. Instead, GqPCR‐stimulated and tonic GluD1R currents are regulated by physiological levels of external calcium. In current‐clamp recordings, block of GluD1R channels hyperpolarizes the membrane by ~7 mV at subthreshold potentials, reducing excitability. Thus, GluD1R carries a G‐protein‐independent tonic current that contributes to subthreshold neuronal excitation in the dorsal raphe nucleus.

Enhancement of Amplified Spontaneous Emission by Electric Field in CsPbBr3 Perovskites.

Perovskite gain materials can sustain continuous-wave lasing at room-temperature. A first step toward the unachieved goal of electrically excited lasing would be an improvement in gain when electrical stimulation is added to the optical. However, to date, electrical stimulation supplementing optical has reduced gain performance. We find that amplified spontaneous emission (ASE) in a CsPbBr3 perovskite light-emitting diode (LED) held under invariant subthreshold optical excitation can be turned on/off by the addition/removal of an electric field. A positive bias voltage leads to a factor of 3 reduction in the optical ASE threshold, the cause of which can be attributed to an enhancement of the radiative rate. The slow components (10 s time scale) of the modulation in the photoluminescence and ASE when the voltage is changed suggest that the relocation of mobile ions trigger the increased radiative rate and observed lowering of ASE thresholds.

P238 Homonymous Ib inhibition during remote muscle contraction

Objective Conflicting theoretical models exist regarding the mechanism related to the ability of the Jendrassek maneuvre to reinforce reflex parameters. Our objective was to investigate if eventually inhibition of the spinal Ib motoneurone during remote muscle contraction would contribute to H-reflex enhancement. Method Soleus H-reflex from 26 healthy subjects was evoked on both sides by stimulating the tibial nerve at rest and during bilateral vigorous hadgrip. This procedure was repeated using paired stimulation at interstimulus intervals ranging from 2 ms to 15 ms. Mean conditioned H-wave amplitude expressed as a percentage of its unconditioned value (H-ratio) evoked during handgrip was compared with the H-ratio obtained at the same interstimulus interval at rest. Results The size of H-reflex evoked during handgrip was significantly higher then of that evoked at rest. The H-ratio value plotted against the interstimulus interval showed both at rest and during handgrip a similar decrease that was maximal at 5 ms and lasted less than 10 ms. Discussion The size of the conditioned H-reflex is determined by the balance between test Ia excitation and Ib inhibition elicited by the conditioning stimulus. According to our results the interneurones intercalated in pathways from Ib afferents retain their inhibitory effect on the alpha motoneurone during remote muscle contraction. Conclusion H-reflex enhancement during Jendrassek maneuvre is not due to inhibition of Ib interneurones. Significance Further studies are needed in order to test the role of other spinal circuits or descending drives that produce subthreshold excitation of alpha motoneurones by remote muscle contraction.

Abnormal photothermal effect of laser radiation on highly defect oxide bronze nanoparticles under the sub-threshold excitation of absorption

The mechanism of abnormal photo-thermal effect of laser radiation on nanoparticles of oxide bronzes has been proposed in this paper. The basic features of the observed effect are: a) sub-threshold absorption of laser radiation by the excitation of donor-like levels formed in the energy gap due to superficial defects of the oxide bronze nano-crystals; b) an interband radiationless transition of energy of excitation on deep triplet levels and c) consequent recombination occurring at the plasmon absorption. K or Na atoms thermally intercalated to the octahedral crystal structure of TiO2 in the wave SHS combustion generate acceptor levels in the gap. The prepared oxide bronzes of the non-stoichiometric composition NaxTiO2 and KxTiO2 were examined by high resolution TEM, and then grinded in a planetary mill with powerful dispersion energy density up to 4000 J/g. This made it possible to obtain nanoparticles about 50 nm with high surface defect density (1017–1019 cm-2 at a depth of 10 nm). High photo-thermal effect of laser radiation on the defect nanocrystals observed after its impregnation into cartilaginous tissue exceeds 7 times in comparison with the intact ones.

Associative spike timing-dependent potentiation of the basal dendritic excitatory synapses in the hippocampus in vivo

Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing-generating synaptic excitation before a spike-results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of -10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60-120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of -10 ms to 0 ms but no LTD at ES intervals of -20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus.

Epilepsy spectrum disorders: A concept in need of validation or refutation

Episodic psychiatric symptoms are not uncommon and range from panic attacks to repeated violent acts. Some evidence has accumulated over the years that at least in a subset of patients exhibiting these symptoms there may be evidence for the presence of focal cortical/subcortical hyperexcitability. In these cases the condition could be conceptualized as an epilepsy spectrum disorder (ESD) with significant treatment implications. There is currently no clear demarcation of this category of symptoms, their prevalence, an understanding of how these symptoms occur, what is appropriate work up and possible treatments. In this article, we propose that milder degrees of increased neural excitability (i.e., a subthreshold excitation insufficient to cause seizures) may nonetheless be capable of causing observable phenotypic changes. The observable phenotypic changes depend on the degree of hyperexcitability and the location of the hyperexcitable neural tissue. The location of the abnormal neural tissue may dictate the initial manifestation of an attack resulting from activation of the hyperexcitable tissue, but the anatomical connectivity of the abnormal region will dictate the breadth of manifestations. We provide some evidence, derived mainly from either electroencephalography studies of these populations or clinical reports of response to anti-epilepsy treatment, for the assumption and propose methods to test the advanced hypothesis.

On the angular momentum transfer upon excitation of electronic states of molecules by electrons of various energies

The intensities of lines IQ(1) and IQ(3) of the vibrational transition v′ = 0 → v″ = 0 of the Fulcher band system upon excitation of hydrogen molecules by an electron beam are measured. The beamelectron energy is ɛe = 15…30 eV (Δɛe ∼ 1 eV). The effective cross sections of H2 (d3Πu, v = 0) state excitation by electron impact are estimated both without changing themolecule angular momentum and with an appreciable angular momentum transfer. Processes with an appreciable angular momentum transfer are most efficient in the subthreshold excitation energy range (Ethr = 14 eV < Ee ≤ 18 eV) and are related to the formation of an intermediate composite system, i.e., a negative ion in the quasi-discrete state.

Stochastic resonance in noise-induced transitions between self-oscillations and equilibria in spin-valve nanomagnets

The thermally induced synchronization between magnetization transitions and ``weak'' ac excitations is studied for spin-transfer oscillators. A theoretical approach, based on the separation of time scales, is developed to investigate this physical phenomenon. By applying the appropriate averaging technique to the Fokker-Planck equation associated with the stochastic magnetization dynamics, a stochastic differential equation for the ``slow'' (energy) variable is derived. This equation is used to analyze intrawell thermal transitions between magnetization equilibria and self-oscillations. It is demonstrated that the thermally induced synchronization between magnetization transitions and ac excitation can be viewed as a stochastic resonance effect. It is shown that this effect occurs in spin-transfer nano-oscillators both in the classical case of subthreshold ac excitation as well as in the suprathreshold case. The theoretical predictions are in very good agreement with simulations of the Landau-Lifshitz-Slonczewski dynamics.

Neuronal Responses Below Firing Threshold for Subthreshold Cross-Modal Enhancement

Multisensory integration (such as somatosensation-vision, gustation-olfaction) could occur even between subthreshold stimuli that in isolation do not reach perceptual awareness. For example, when a somatosensory (subthreshold) stimulus is delivered within a close spatiotemporal congruency, a visual (subthreshold) stimulus evokes a visual percept. Cross-modal enhancement of visual perception is maximal when the somatosensory stimulation precedes the visual one by tens of milliseconds. This rapid modulatory response would not be consistent with a top-down mechanism acting through higher-order multimodal cortical areas, but rather a direct interaction between lower-order unimodal areas. To elucidate the neuronal mechanisms of subthreshold cross-modal enhancement, we simulated a neural network model. In the model, lower unimodal (X, Y) and higher multimodal (M) networks are reciprocally connected by bottom-up and top-down axonal projections. The lower networks are laterally connected with each other. A pair of stimuli was presented to the lower networks, whose respective intensities were too weak to induce salient neuronal activity (population response) when presented alone. Neurons of the Y network were slightly depolarized below firing threshold when a cross-modal stimulus was presented alone to the X network. This allowed the Y network to make a rapid (within tens of milliseconds) population response when presented with a subsequent congruent stimulus. The reaction speed of the Y network was accelerated, provided that the top-down projections were strengthened. We suggest that a subthreshold (nonpopulation) response to a cross-modal stimulus, acting through interaction between lower (primary unisensory) areas, may be essential for a rapid suprathreshold (population) response to a congruent stimulus that follows. Top-down influences on cross-modal enhancement may be faster than expected, accelerating reaction speed to input, in which ongoing-spontaneous subthreshold excitation of lower-order unimodal cells by higher-order multimodal cells may play an active role.

Subthreshold Parameters of Cardiac Tissue in a Bi-Layer Computer Model of Heart Failure

Current density threshold and liminal area are subthreshold parameters of the cardiac tissue that indicate its susceptibility to external and internal stimulations. Extensive experimental and theoretical research has been conducted to quantify these two parameters in normal conditions for both animal and human models. Here we employed a 2D numerical model of human cardiac tissue to assess these subthreshold parameters under the pathological conditions of heart failure and fibrosis. Stimuli were applied over an area ranging from 0.04 to 1 mm² using various pulse durations. The current density threshold decreased with increasing stimulation area or pulse duration. No significant changes were found in both parameters between control conditions and heart failure in the atrial tissue, while in the ventricular tissue, heart failure resulted in significantly reduced excitability with higher stimulation current magnitudes needed for excitation and larger liminal areas. This results from the specific ionic remodeling in ventricular heart failure that affects both subthreshold active currents such as I(K₁) and connexin 43 conductance. In fibrosis, increased fibroblast to myocyte coupling coefficient had a non-linear influence on current density thresholds, with an initial increase of current magnitude followed by a relaxation phase down to the current magnitude threshold for the control condition with no fibrosis. The results show that subthreshold excitation properties of the myocardium are influenced in a complex, non-linear manner by cardiac pathologies. Such observations may contribute to our understanding of impulse capturing properties, relevant, for example, for the generation of ectopic foci-originated arrhythmias and for the efficient design of cardiac stimulating electrodes.

Dynamics of free intracellular Ca2+ during synaptic and spike activity of cricket tibial motoneurons

For all nervous systems, motoneurons are the main output pathway. They are involved in generating episodic motor activity as well as enduring motor rhythms. To determine whether changes in cytosolic Ca(2+) correlate with motor performance, we studied the spatiotemporal dynamics, mode of entry and role of free intracellular Ca(2+) in cricket (Gryllus bimaculatus) front leg tibial extensor and flexor motoneurons. Synaptic activation or intracellular depolarising current injection uniformly increased Ca(2+) with the same dynamics throughout the primary and secondary branches of the dendritic tree of all motoneurons. Ca(2+) rise times (mean tau(rise), 233-295 ms) were lower than decay times (mean tau(decay), 1927-1965 ms), and resulted in a Ca(2+) plateau during repetitive activation, such as during walking. The neurons therefore operate with a different Ca(2+) level during walking than during episodic leg movements. Ca(2+) enters the dendritic processes of motoneurons via a voltage-activated mechanism. Entry is driven by subthreshold excitation, and is largely independent of the neurons' spiking activity. To what extent ligand-activated mechanisms of Ca(2+) entry operate remains uncertain. We found no evidence for any prominent Ca(2+)-activated secondary currents in these motoneurons. Excitatory postsynaptic potentials evoked by extracellular stimulation of descending neurons were unaffected by the level of free intracellular Ca(2+). The activity of tibial motoneurons therefore appears to be only weakly dependent on the level of free intracellular Ca(2+) in dendrites. This is different to what has been found for many other neurons studied, and may represent an essential prerequisite for insect motoneurons to support a wide range of both episodic and rhythmic motor sequences underlying behaviour.

Counting on Inhibition and Rate-Dependent Excitation in the Auditory System

The intervals between acoustic elements are important in audition. Although neurons have been recorded that show interval tuning, the underlying mechanisms are unclear. The anuran auditory system is well suited for addressing this problem. One class of midbrain neurons in anurans responds selectively over a narrow range of pulse-repetition rates (PRRs) and only after several sound pulses have occurred with the "correct" timing. This "interval-counting" process can be reset by a single incorrect interval. Here we show, from whole-cell patch recordings of midbrain neurons in vivo, that these computations result from interplay between inhibition and rate-dependent excitation. An individual pulse or slowly repeated pulses elicited inhibition and subthreshold excitation. Excitation was markedly enhanced, however, when PRR was increased over a neuron-specific range. Spikes were produced when the enhanced excitation overcame the inhibition. Interval-number thresholds were positively correlated with the strength of inhibition and number of intervals required to augment the excitation. Accordingly, interval-number thresholds decreased when inhibition was attenuated by loading cells with cesium fluoride. The selectivity of these neurons for the interpulse interval, and therefore PRR, was related to the time course of excitatory events and the rate dependence of enhancement; for cells that were tuned to longer intervals, EPSPs were broader, and enhancement occurred at slower PRRs. The frequency tuning of the inhibition generally spanned that of the excitation, consistent with its role in temporal computation. These findings provide the first mechanistic understanding of interval selectivity and counting in the nervous system.

Rethinking Tuning:In VivoWhole-Cell Recordings of the Inferior Colliculus in Awake Bats

Tuning curves were recorded with patch electrodes from the inferior colliculus (IC) of awake bats to evaluate the tuning of the inputs to IC neurons, reflected in their synaptic tuning, compared with the tuning of their outputs, expressed in their discharge tuning. A number of unexpected features were revealed with whole-cell recordings. Among these was that most neurons responded to tones with inhibition and/or subthreshold excitation over a surprisingly broad frequency range. The synaptic tuning in many cells was at least 1.5-2.0 octaves wide and, on average, was more than twice as wide as the frequency range that evoked discharges even after inhibition was blocked. In most cells, tones evoked complex synaptic response configurations that varied with frequency, suggesting that these cells were not innervated by congruent excitatory and inhibitory projections. Synaptic tuning was not only wide but was also diverse, in which some cells were dominated by excitation (n = 20), others were dominated by excitation with sideband inhibition (n = 21), but most were dominated by inhibition with little evidence of excitation (n = 31). Another unexpected finding was that some cells responded with inhibition to the onset and offset of tones over a wide frequency range, in which the patterns of synaptic responses changed markedly with frequency. These cells never fired to tones at 50 dB sound pressure level but fired to frequency-modulated sweeps at that intensity and were directionally selective. Thus, the features revealed by whole-cell recordings show that the processing in many IC cells results from inputs spectrally broader and more complex than previously believed.

Well-Timed, Brief Inhibition Can Promote Spiking: Postinhibitory Facilitation

Brief synaptic inhibition can overwhelm a nearly coincident suprathreshold excitatory input to preclude spike generation. Surprisingly, a brief inhibitory event that occurs in a favorable time window preceding an otherwise subthreshold excitation can facilitate spiking. Such postinhibitory facilitation (PIF) requires that the inhibition has a short (decay) time constant tauinh. The timescale ranges of tauinh and of the window (width and timing) for PIF depend on the rates of neuronal subthreshold dynamics. The mechanism for PIF is general, involving reduction by hyperpolarization of some excitability-suppressing factor that is partially recruited at rest. Here we illustrate and analyze PIF, experimentally and theoretically, using brain stem auditory neurons and a conductance-based five-variable model. In this auditory case, PIF timescales are in the sub- to few millisecond range and the primary mechanistic factor is a low-threshold potassium conductance gKLT. Competing dynamic influences create the favorable time window: hyperpolarization that moves V away from threshold and hyperexcitability resulting from reduced gKLT. A two-variable reduced model that retains the dynamics only of V and gKLT displays a similar time window. We analyze this model in the phase plane; its geometry has generic features. Further generalizing, we show that PIF behavior may occur even in a very reduced model with linear subthreshold dynamics, by using an integrate-and-fire model with an accommodating voltage-dependent threshold. Our analyses of PIF provide insights for fast inhibition's facilitatory effects in longer trains. Periodic subthreshold excitatory inputs can lead to firing, even one for one, if brief inhibitory inputs are interleaved within a range of favorable phase lags. The temporal specificity of inhibition's facilitating effect could play a role in temporal processing, in sensitivity to inhibitory and excitatory temporal patterning, in the auditory and other neural systems.

Sub-threshold excitation of luminescence of defects in diamond

Optically active defects in diamond can be excited by photons with an energy less thanthat of the zero-phonon transition. We show that this process is thermally activated. Fordiamonds in which one type of defect is dominant, the activation energy is equal to theenergy difference between the zero-phonon line and the photons used for excitation.

How could a chirp be more effective than a louder clock-resonant transfer of energy between subthreshold excitation pulses and excitable tissues

By definition, electrical resonance of excitable biomembranes reflects their remarkable ability to select input signals with preferential frequencies as ones that will pass through the chain of information exchange within a coordinated organism. This feature is known to be caused and regulated by the voltage-dependent kinetics of transmembrane ion channels. Knowledge about the resonant behavior of excitable cells may prove crucial toward better underpinning those essential properties of neurons which make them to function as a highly coordinated network. In this work we present novel experimental evidence which strongly supports the paradigm of selective communication between excitable cells, by no more than efficient transfer of energy which takes place when the frequency of subthreshold presynaptic pulses matches the natural, resonant frequency of a target excitable tissue. As a possible direct application, our novel experimental results prove the functional importance of bursting activity of pre-synaptic neurons as an effective physiological mechanism for discriminatory communication between neurons.

Plasmon excitation and electron promotion in the interaction of slow Na+ ions with Al surfaces

We studied the energy distributions of electrons emitted in the interaction of slow Na+ ions with polycrystalline Al surfaces. To study sub-threshold plasmon excitation we performed measurements as a function of emission angle which showed the excitation of bulk plasmons, confirming the kinetic nature of the excitation process.Electron spectra show narrow transition lines due to Auger decay in vacuum of sodium projectiles excited in the 2p-shell by electron promotion in collisions with Al target atoms. Several previously unidentified transition lines could be attributed to the autoionization of doubly excited projectiles.

Nonclassical light generation in quasi-phase-matched parametric self-frequency conversion

We present a quantum theory of the parametric self-conversion of the laser radiation frequency in active nonlinear crystals with a regular domain structure. Such crystals feature simultaneous lasing and quasi-phase-matched parametric conversion of the laser radiation frequency. These processes are described using the Heisenberg-Langevin equations in two regimes of the subharmonic generation: super-and subthreshold. The spectral properties of the quadrature components of the laser frequency and its subharmonic and the photon statistics have been studied as dependent on the pump power, crystal length, and reflectance of the laser cavity output mirror. Using the obtained analytical expressions, these characteristics are calculated for a active nonlinear Nd:Mg:LiNbO3 crystal with a regular domain structure. In the subthreshold regime, the maximum decrease in the spectral density of fluctuations in the subharmonic quadrature component relative to the standard quantum limit may reach 90%; in the above-threshold regime, these fluctuations are virtually not suppressed. A decrease in the spectral density of fluctuations of the laser frequency quadrature does not exceed 10%. In the subthreshold excitation regime, the subharmonic photons obey a super-Poisson statistics; in the above-threshold regime, the photon statistics is Poisson-like.

Resonant inelastic x-ray scattering at the F1sphotoabsorption edge in LiF: Interplay of excitonic and conduction states, and Stokes’ doubling

The excitation-decay processes at the F $1s$ photoabsorption edge in LiF crystal are studied using resonant inelastic x-ray scattering spectroscopy. The Raman-type linear dispersion and the narrowing of the x-ray fluorescence peak are observed at resonant excitation. A theoretical model based on the Kramers-Heisenberg formula describes well the main features in fluorescence spectra and allows one to separate the contributions of the exciton and the conduction states in the scattering spectra. At the same time, the role of the shape of the spectral distribution within the incident radiation is emphasized as being critically sensitive to the number, kind, and onset of the spectral features which finally appear in the scattering spectra at a particular incident photon energy, particularly in the subthreshold excitation region.