Simulation study on high spatio-temporal resolution acousto-electrophysiological neuroimaging.

Objective.Acousto-electrophysiological neuroimaging (AENI) is a technique hypothesized to record electrophysiological activity of the brain with millimeter spatial and sub-millisecond temporal resolution. This improvement is obtained by tagging areas with focused ultrasound (fUS). Due to mechanical vibration with respect to the measuring electrodes, the electrical activity of the marked region will be modulated onto the ultrasonic frequency. The region's electrical activity can subsequently be retrieved via demodulation of the measured signal. In this study, the feasibility of this hypothesized technique is tested.Approach.This is done by calculating the forward electroencephalography response under quasi-static assumptions. The head is simplified as a set of concentric spheres. Two sizes are evaluated representing human and mouse brains. Moreover, feasibility is assessed for wet and dry transcranial, and for cortically placed electrodes. The activity sources are modeled by dipoles, with their current intensity profile drawn from a power-law power spectral density.Results.It is shown that mechanical vibration modulates the endogenous activity onto the ultrasonic frequency. The signal strength depends non-linearly on the alignment between dipole orientation, vibration direction and recording point. The strongest signal is measured when these three dependencies are perfectly aligned. The signal strengths are in the pV-range for a dipole moment of 5 nAm and ultrasonic pressures within Food and Drug Administration (FDA)-limits. The endogenous activity can then be accurately reconstructed via demodulation. Two interference types are investigated: vibrational and static. Depending on the vibrational interference, it is shown that millimeter resolution signal detection is possible also for deep brain regions. Subsequently, successful demodulation depends on the static interference, that at MHz-range has to be sub-picovolt.Significance.Our results show that mechanical vibration is a possible underlying mechanism of acousto-electrophyisological neuroimaging. This paper is a first step towards improved understanding of the conditions under which AENI is feasible.

Quantitative analysis of the optogenetic excitability of CA1 neurons.

Introduction: Optogenetics has emerged as a promising technique for modulating neuronal activity and holds potential for the treatment of neurological disorders such as temporal lobe epilepsy (TLE). However, clinical translation still faces many challenges. This in-silico study aims to enhance the understanding of optogenetic excitability in CA1 cells and to identify strategies for improving stimulation protocols. Methods: Employing state-of-the-art computational models coupled with Monte Carlo simulated light propagation, the optogenetic excitability of four CA1 cells, two pyramidal and two interneurons, expressing ChR2(H134R) is investigated. Results and discussion: The results demonstrate that confining the opsin to specific neuronal membrane compartments significantly improves excitability. An improvement is also achieved by focusing the light beam on the most excitable cell region. Moreover, the perpendicular orientation of the optical fiber relative to the somato-dendritic axis yields superior results. Inter-cell variability is observed, highlighting the importance of considering neuron degeneracy when designing optogenetic tools. Opsin confinement to the basal dendrites of the pyramidal cells renders the neuron the most excitable. A global sensitivity analysis identified opsin location and expression level as having the greatest impact on simulation outcomes. The error reduction of simulation outcome due to coupling of neuron modeling with light propagation is shown. The results promote spatial confinement and increased opsin expression levels as important improvement strategies. On the other hand, uncertainties in these parameters limit precise determination of the irradiance thresholds. This study provides valuable insights on optogenetic excitability of CA1 cells useful for the development of improved optogenetic stimulation protocols for, for instance, TLE treatment.

Influence of Temporal Interference Stimulation Parameters on Point Neuron Excitability.

Temporal interference (TI) stimulation is a technique in which two high frequency sinusoidal electric fields, oscillating at a slightly different frequency are sent into the brain. The goal is to achieve stimulation at the place where both fields interfere. This study uses a simplified version of the Hodgkin - Huxley model to analyse the different parameters of the TI-waveform and how the neuron reacts to this waveform. In this manner, the underlying mechanism of the reaction of the neuron to a TI -signal is investigated. Clinical relevance- This study shows the importance of the parameter choice of the temporal interference waveform and provides insights into the underlying mechanism of the neuronal response to a beating sine for the application of temporal interference stimulation.

Improved alpha-beta power reduction via combined electrical and ultrasonic stimulation in a parkinsonian cortex-basal ganglia-thalamus computational model.

Objective. To investigate computationally the interaction of combined electrical and ultrasonic modulation of isolated neurons and of the parkinsonian cortex-basal ganglia-thalamus loop.Approach. Continuous-wave or pulsed electrical and ultrasonic neuromodulation is applied to isolated Otsuka plateau-potential generating subthalamic nucleus (STN) and Pospischil regular, fast and low-threshold spiking cortical cells in a temporally alternating or simultaneous manner. Similar combinations of electrical/ultrasonic waveforms are applied to a parkinsonian biophysical cortex-basal ganglia-thalamus neuronal network. Ultrasound-neuron interaction is modelled respectively for isolated neurons and the neuronal network with the NICE and SONIC implementations of the bilayer sonophore underlying mechanism. Reduction inα-ßspectral energy is used as a proxy to express improvement in Parkinson's disease by insonication and electrostimulation.Main results. Simultaneous electro-acoustic stimulation achieves a given level of neuronal activity at lower intensities compared to the separate stimulation modalities. Conversely, temporally alternating stimulation with50 Hzelectrical and ultrasound pulses is capable of eliciting100 HzSTN firing rates. Furthermore, combination of ultrasound with hyperpolarizing currents can alter cortical cell relative spiking regimes. In the parkinsonian neuronal network, continuous-wave and pulsed ultrasound reduce pathological oscillations by different mechanisms. High-frequency pulsed separated electrical and ultrasonic deep brain stimulation (DBS) reduce pathologicalα-ßpower by entraining STN-neurons. In contrast, continuous-wave ultrasound reduces pathological oscillations by silencing the STN. Compared to the separated stimulation modalities, temporally simultaneous or alternating electro-acoustic stimulation can achieve higher reductions inα-ßpower for the same safety contraints on electrical/ultrasonic intensity.Significance. Focused ultrasound has the potential of becoming a non-invasive alternative of conventional DBS for the treatment of Parkinson's disease. Here, we elaborate on proposed benefits of combined electro-acoustic stimulation in terms of improved dynamic range, efficiency, spatial resolution, and neuronal selectivity.

Double Two-State Opsin Model With Autonomous Parameter Inference.

Optogenetics has a lot of potential to become an effective neuromodulative therapy for clinical applications. Selecting the correct opsin is crucial to have an optimal optogenetic tool. With computational modeling, the neuronal response to the current dynamics of an opsin can be extensively and systematically tested. Unlike electrical stimulation where the effect is directly defined by the applied field, the stimulation in optogenetics is indirect, depending on the selected opsin's non-linear kinetics. With the continuous expansion of opsin possibilities, computational studies are difficult due to the need for an accurate model of the selected opsin first. To this end, we propose a double two-state opsin model as alternative to the conventional three and four state Markov models used for opsin modeling. Furthermore, we provide a fitting procedure, which allows for autonomous model fitting starting from a vast parameter space. With this procedure, we successfully fitted two distinctive opsins (ChR2(H134R) and MerMAID). Both models are able to represent the experimental data with great accuracy and were obtained within an acceptable time frame. This is due to the absence of differential equations in the fitting procedure, with an enormous reduction in computational cost as result. The performance of the proposed model with a fit to ChR2(H134R) was tested, by comparing the neural response in a regular spiking neuron to the response obtained with the non-instantaneous, four state Markov model (4SB), derived by Williams et al. (2013). Finally, a computational speed gain was observed with the proposed model in a regular spiking and sparse Pyramidal-Interneuron-Network-Gamma (sPING) network simulation with respect to the 4SB-model, due to the former having two differential equations less. Consequently, the proposed model allows for computationally efficient optogenetic neurostimulation and with the proposed fitting procedure will be valuable for further research in the field of optogenetics.

Membrane Charge Oscillations During Ultrasonic Neuromodulation by Intramembrane Cavitation.

OBJECTIVE: To investigate the importance of membrane charge oscillations and redistribution in multi-compartmental ultrasonic neuromodulation (UNMOD) intramembrane cavitation models. METHODS: The Neuronal Intramembrane Cavitation Excitation (NICE) model and multiScale Optimized model of Neuronal Intramembrane Cavitation (SONIC) of UNMOD are compared for a nanoscale multi-compartmental and point neuron approximation of the bilayer sonophore and surrounding proteins. The temporal dynamics of charge oscillations and their effect on the resulting voltage oscillations are investigated by fourier series analysis. RESULTS: Comparison of excitation thresholds and neuronal response between nanoscale multi-compartmental and point models, implemented in the SONIC and NICE framework, demonstrates that the explicit modeling of fast spatial charge redistribution is critical for an accurate multi-compartmental UNMOD-model. Furthermore, the importance of modeling partial protein coverage is quantified by the excitability thresholds. Subsequently, we establish by fourier analysis that these charge oscillations are slowly changing in time. CONCLUSION: Fast charge redistribution significantly alters neuronal excitability in a multi-compartmental nanoscale UNMOD-model. Also the mutual exclusivity between protein and sonophore coverage should be taken into account, when simulating the dependency of neuronal excitability on coverage fractions. Charge oscillations are periodic and their fourier components change on a slow timescale. Furthermore, the resulting voltage oscillations decrease in energy with overtone number, implying that an extension of the existing multiscale model (SONIC) to multi-compartmental neurons is possible by taking into account a limited number of fourier components. SIGNIFICANCE: First steps are taken towards a morphologically realistic and computationally efficient UNMOD-model, improving our understanding of the underlying ultrasonic neuromodulation mechanisms.

SECONIC: Towards multi-compartmental models for ultrasonic brain stimulation by intramembrane cavitation.

OBJECTIVE: To design a computationally efficient model for ultrasonic neuromodulation (UNMOD) of morphologically realistic multi-compartmental neurons based on intramembrane cavitation. APPROACH: A Spatially Extended Neuronal Intramembrane Cavitation model that accurately predicts observed fast Charge Oscillations (SECONIC) is designed. A regular spiking cortical Hodgkin-Huxley type nanoscale neuron model of the bilayer sonophore and surrounding proteins is used. The accuracy and computational efficiency of SECONIC is compared with the Neuronal Intramembrane Cavitation Excitation (NICE) and multiScale Optimized model of Neuronal Intramembrane Cavitation (SONIC). MAIN RESULTS: Membrane charge redistribution between different compartments should be taken into account via fourier series analysis in an accurate multi-compartmental UNMOD-model. Approximating charge and voltage traces with the harmonic term and first two overtones results in reasonable goodness-of-fit, except for high ultrasonic pressure (adjusted R-squared ≥0.61). Taking into account the first eight overtones results in a very good fourier series fit (adjusted R-squared ≥0.96) up to 600 kPa. Next, the dependency of effective voltage and rate parameters on charge oscillations is investigated. The two-tone SECONIC-model is one to two orders of magnitude faster than the NICE-model and demonstrates accurate results for ultrasonic pressure up to 100 kPa. SIGNIFICANCE: Up to now, the underlying mechanism of UNMOD is not well understood. Here, the extension of the bilayer sonophore model to spatially extended neurons via the design of a multi-compartmental UNMOD-model, will result in more detailed predictions that can be used to validate or falsify this tentative mechanism. Furthermore, a multi-compartmental model for UNMOD is required for neural engineering studies that couple finite difference time domain simulations with neuronal models. Here, we propose the SECONIC-model, extending the SONIC-model by taking into account charge redistribution between compartments.

Sensitivity Study of Neuronal Excitation and Cathodal Blocking Thresholds of Myelinated Axons for Percutaneous Auricular Vagus Nerve Stimulation.

OBJECTIVE: Excitation of myelinated nerve fibers is investigated by means of numerical simulations, for the application of percutaneous auricular vagus nerve stimulation (pVNS). High sensitivity to axon diameter is of interest regarding the goal of targeting thicker fibers. METHODS: Excitation and blocking thresholds for different pulse types, phase durations, axon depths, axon-electrode distances, temperatures and axon diameters are investigated. The used model consists of a 50 mm long axon and a centrally located needle electrode in a layered medium representing the auricle. Neuronal excitation is simulated using the Frankenhaeuser-Huxley equations for all combinations of parameter values. RESULTS AND CONCLUSION: Multiple modes and locations of excitation along the axon were observed, depending on the pulse type and amplitude. When increasing the axon-electrode distance from 1 mm to 2 mm, sensitivity of thresholds to axon depth decreased with ca. 50%, while sensitivity to axon-electrode distance, axon diameter and phase duration each increased with ca. 15% to 20%, except from monophasic anodal pulses, showing a 45% decrease for axon-electrode distance. These trends for axon diameter and axon-electrode distance allow for more selective stimulation of thicker target fibers using monophasic anodal pulses at higher axon-electrode distances. Cathodal monophasic pulses did not perform well due to blocking of the thicker fibers, which was only rarely seen for other pulse types. SIGNIFICANCE: Sensitivities of stimulation thresholds to these parameters by numerical simulation reveal how the stimulation parameters can be changed in order to increase therapeutic effect and comfort during pVNS by enabling more selective stimulation.

Current Directions in the Auricular Vagus Nerve Stimulation I - A Physiological Perspective.

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects - a discussion of engineering aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

Current Directions in the Auricular Vagus Nerve Stimulation II - An Engineering Perspective.

Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve - a powerful entrance to the brain - affects a large number of physiological processes implicating interactions between the brain and body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, in silico modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on engineering aspects - a discussion of physiological aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.

Computational Modeling of Ultrasonic Subthalamic Nucleus Stimulation.

OBJECTIVE: To explore the potential of ultrasonic modulation of plateau-potential generating subthalamic nucleus neurons (STN), by modeling their interaction with continuous and pulsed ultrasonic waves. METHODS: A computational model for ultrasonic stimulation of the STN is created by combining the Otsuka-model with the bilayer sonophore model. The neuronal response to continuous and pulsed ultrasonic waves is computed in parallel for a range of frequencies, duty cycles, pulse repetition frequencies, and intensities. RESULTS: Ultrasonic intensity in continuous-wave stimulation determines the firing pattern of the STN. Three observed spiking modes in order of increasing intensity are low frequency spiking, high frequency spiking with significant spike-frequency and spike-amplitude adaptation, and a silenced mode. Continuous-wave stimulation has little capability to manipulate the saturated spiking rate in the high frequency spiking mode. In contrast, STN firing rates induced by pulsed ultrasound insonication will saturate to the pulse repetition frequency with short latencies, for sufficiently large intensity and repetition frequency. CONCLUSION: Computational results show that the activity of plateau-potential generating STN can be modulated by selection of the stimulus parameters. Low intensities result in repetitive firing, while higher intensities silence the STN. Pulsed ultrasonic stimulation results in a shorter saturation latency and is able to modulate spiking rates. SIGNIFICANCE: Stimulation or suppresion of the STN is important in the treatment of Parkinson's disease, e.g., in deep brain stimulation. This explorative study on ultrasonic modulation of the STN, could be a step in the direction of minimally invasive alternatives to conventional deep brain stimulation.

Investigation of the Stimulation Capabilities of a High-Resolution Neurorecording Probe for the Application of Closed-Loop Deep Brain Stimulation.

Deep brain stimulation is an established surgical treatment for several neurological and movement disorders, such as Parkinson's disease, in which electrostimulation is applied to targeted deep nuclei in the basal ganglia through implanted electrode leads. Recent technological improvements in the field have focused on the theoretical advantage of current steering and adaptive (closed-loop) deep brain stimulation. Current steering between several active electrodes would allow for improved accuracy when targeting the desired brain structures. This has the additional benefit of avoiding undesired stimulation of neural tracts that are related to side effects, e.g., internal capsule fibres of passage in subthalamic nucleus deep brain stimulation. Closed-loop deep brain stimulation is based on the premise of continuous recording of a proxy for pathological neural activity (such as beta-band power of measured local field potentials in patients with Parkinson's disease) and accordingly adapting the used stimulus parameters. In this study, we investigate the suitability of an existing highresolution neurorecording probe for high-precision neurostimulation. If a subset of the probe's recording electrodes can be used for stimulation, then the probe would be a suitable candidate for closed-loop deep brain stimulation. A finiteelement model is used to calculate the electric potential, induced by current injection through the high-resolution probe, for different sets of active electrodes. Volumes of activated tissue are calculated and a comparison is made between the highresolution probe and a conventional stimulation lead. We investigate the capability of the probe to shift the volume of activated tissue by steering currents to different sets of active electrodes. Finally, safety limits for the injected current are used to determine the size of the volume in which neurons can be activated with the relatively small electrodes patches on the highresolution probe.

Dependence of excitability indices on membrane channel dynamics, myelin impedance, electrode location and stimulus waveforms in myelinated and unmyelinated fibre models.

Neuronal excitability is determined in a complex way by several interacting factors, such as membrane dynamics, fibre geometry, electrode configuration, myelin impedance, neuronal terminations[Formula: see text] This study aims to increase understanding in excitability, by investigating the impact of these factors on different models of myelinated and unmyelinated fibres (five well-known membrane models are combined with three electrostimulation models, that take into account the spatial structure of the neuron). Several excitability indices (rheobase, polarity ratio, bi/monophasic ratio, time constants[Formula: see text]) are calculated during extensive parameter sweeps, allowing us to obtain novel findings on how these factors interact, e.g. how the dependency of excitability indices on the fibre diameter and myelin impedance is influenced by the electrode location and membrane dynamics. It was found that excitability is profoundly impacted by the used membrane model and the location of the neuronal terminations. The approximation of infinite myelin impedance was investigated by two implementations of the spatially extended non-linear node model. The impact of this approximation on the time constant of strength-duration plots is significant, most importantly in the Frankenhaeuser-Huxley membrane model for large electrode-neuron separations. Finally, a multi-compartmental model for C-fibres is used to determine the impact of the absence of internodes on excitability. Graphical Abstract Electrostimulation models, obtained by combining five membrane models with three representations of the neuronal cable equation, are fed with electrode and stimulus input parameters. The dependency of neuronal excitability on the interaction of these input parameters is determined by deriving excitability indices from the spatiotemporal model response. The impact of the myelin impedance and the fibre diameter on neural excitability is also considered.