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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.

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.

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.