Understanding ultrasound neuromodulation using a computationally efficient and interpretable model of intramembrane cavitation

Abstract

Objective. Low-intensity focused ultrasound stimulation (LIFUS) emerges as an attracting technology for noninvasive modulation of neural circuits, yet the underlying action mechanisms remain unclear. The neuronal intramembrane cavitation excitation (NICE) model suggests that LIFUS excites neurons through a complex interplay between microsecond-scale mechanical oscillations of so-called sonophores in the plasma membrane and the development of a millisecond-scale electrical response. This model predicts cell-type-specific responses that correlate indirectly with experimental data, but it is computationally expensive and difficult to interpret, which hinders its potential validation. Here, we introduce a multi-Scale Optimized Neuronal Intramembrane Cavitation (SONIC) model to achieve fast, accurate simulations and confer interpretability in terms of effective electrical response. Approach. The NICE system is recast in terms of smoothly evolving differential variables affected by cycle averaged internal variables that are a function of sonophore size and charge density, stimulus frequency and pressure amplitude. Problem separation allows to precompute lookup tables for these functions, which are interpolated at runtime to compute coarse-grained, electrophysiologically interpretable and spatially distributed predictions of neural responses. Main Results. The SONIC model accelerates computation by more than three orders of magnitude, accurately captures millisecond-scale electrical responses of various cortical and thalamic neurons and offers an increased interpretability to the effects of ultrasonic stimuli in terms of effective membrane dynamics. Using this model, we explain how different spiking behaviors can be achieved in cortical neurons by varying LIFUS parameters, and interpret predictions of spike amplitude and firing rate in light of the effective electrical system. We demonstrate the substantial influence of sonophore size on excitation thresholds, and use a nanoscale spatially extended SONIC model to suggest that partial sonophore membrane coverage has a limited impact on neuronal excitability. Significance. By providing an electrophysiologically interpretable description, the SONIC model clarifies cell-type-specific LIFUS neuromodulation according to the intramembrane cavitation hypothesis.

Mechanistic modeling suggests that low-intensity focused ultrasound can selectively recruit myelinated or unmyelinated nerve fibers

“…Sundt unmyelinated membrane and SENN Ranvier nodes). We chose a typical sonophore radius (a = 32 nm) used in previous studies (Lemaire et al, 2019;Plaksin et al, 2016Plaksin et al, , 2014) and a physiologically plausible sonophore coverage fraction (fs = 80%) falling within a range of conserved excitability in cortical point-neuron models (see (Lemaire et al, 2019), Fig. 10).…”

“…The SONIC paradigm relies on the assumption that membrane charge density and ion channel kinetics evolve at a much slower speed than microsecond-scale capacitance oscillations, thereby allowing for the accurate integration of neural responses using pre-computed cycle-averaged quantities of fast-oscillating variables. While that assumption is valid for point-neuron models (Lemaire et al, 2019), a recent study using a nanoscale two-compartment model have shown that under tight axial coupling conditions, strong intracellular currents mediate a significant intra-cycle charge redistribution that influences local membrane dynamics in a way that is not captured by the SONIC paradigm, resulting in overestimated sub-threshold charge build-ups and underestimated excitation thresholds (Tarnaud et al, 2020). It was also demonstrated that this numerical inaccuracy could be resolved by taking into account a limited number of Fourier components from precomputed oscillatory variables (as opposed to the SONIC approach that only considers their first component).…”

“…In its most basic form, the multi-compartmental expansion of point-neuron NICE / SONIC models requires the addition of axial current terms contributing to the evolution of charge density in each compartment (see (Lemaire et al, 2019), equation 5). However, that formulation only considers intracellular axial coupling, and is therefore not adapted to "double-cable" models that account for both intra and extracellular longitudinal coupling.…”

Cetuximab-Conjugated Perfluorohexane/Gold Nanoparticles for Low Intensity Focused Ultrasound Diagnosis Ablation of Thyroid Cancer Treatment

“…Recently, triggerable drug-charged nanocarriers coupled withmultiple internal or external stimuli, such as pH, temperature,ultrasound, laser, and microwave radiation, have been extensivelyexplored for personalized treatment to enable controlled release.They have shown an excellent possibility to deliver enhancedanticancer treatment impact, with decreased systemic toxicity [12][13][14]. Low-intensity concentrated ultrasound (LIFUS) has beenexhaustively researched for tumor treatment along with the use ofultrasound imaging analysis as a potential exterior activate, whichis noninvasive and displays signi cant tissue-penetratingcapacity.…”

Cetuximab-conjugated perfluorohexane/gold nanoparticles for low intensity focused ultrasound diagnosis ablation of thyroid cancer treatment

“…These systems have excellent potential for delivering enhanced anticancer treatment, while also decreasing systemic toxicity [12][13][14]. Low-intensity concentrated ultrasound (LIFUS) has been exhaustively researched for tumor treatment with ultrasound imaging analysis as one of the probable exterior activators, as it is non-invasive and displays significant tissuepenetrating capacity.…”