MorphoSONIC: A morphologically structured intramembrane cavitation model reveals fiber-specific neuromodulation by ultrasound

Théo Lemaire,Elena Vicari,Esra Neufeld,Niels Kuster,Silvestro Micera

doi:10.1016/j.isci.2021.103085

Abstract

SummaryLow-Intensity Focused Ultrasound Stimulation (LIFUS) holds promise for the remote modulation of neural activity, but an incomplete mechanistic characterization hinders its clinical maturation. Here we developed a computational framework to model intramembrane cavitation (a candidate mechanism) in multi-compartment, morphologically structured neuron models, and used it to investigate ultrasound neuromodulation of peripheral nerves. We predict that by engaging membrane mechanoelectrical coupling, LIFUS exploits fiber-specific differences in membrane conductance and capacitance to selectively recruit myelinated and/or unmyelinated axons in distinct parametric subspaces, allowing to modulate their activity concurrently and independently over physiologically relevant spiking frequency ranges. These theoretical results consistently explain recent empirical findings and suggest that LIFUS can simultaneously, yet selectively, engage different neural pathways, opening up opportunities for peripheral neuromodulation currently not addressable by electrical stimulation. More generally, our framework is readily applicable to other neural targets to establish application-specific LIFUS protocols.

Highlights

Ultrasound-based approaches have been increasingly adopted over the past decades for a variety of noninvasive therapeutic interventions (Escoffre and Bouakaz, 2016)
We developed a multi-Scale Optimized Neuronal Intramembrane Cavitation (SONIC) model that alleviates the numerical stiffness of the Neuronal Intramembrane Cavitation Excitation (NICE) model by integrating the coarse-grained evolution of effective electrical variables as a function of a precomputed, cycle-averaged impact of the oscillatory mechanical system (Lemaire et al, 2019), thereby drastically reducing computational costs while maintaining numerical accuracy
We investigated the mechanisms of US neuromodulation by intramembrane cavitation in peripheral nerve fibers, as these structures represent privileged, accessible neuromodulation targets

Summary

Introduction

Ultrasound-based approaches have been increasingly adopted over the past decades for a variety of noninvasive therapeutic interventions (Escoffre and Bouakaz, 2016) These therapies rely on the mechanical nature of acoustic waves that propagate efficiently through biological tissue and can be accurately steered to concentrate mechanical energy within small volumes ($mm3) around deep anatomical targets. Several in vitro and in vivo studies have shown that such acoustic waves can be used to reversibly modulate the activity of various neural targets with remarkable spatial accuracy (Blackmore et al, 2019) These findings have propelled the development of Low-Intensity Focused Ultrasound Stimulation (LIFUS) as a novel technology to achieve noninvasive, selective, and reversible neuromodulation of virtually any neural structure. It is difficult to provide a mechanistic perspective that would clarify and guide the heterogeneous and sometimes conflicting collection of neuromodulatory effects (excitatory and inhibitory, short and long term, localized and large-scale, reversible and permanent) obtained across animal models, neural targets, and experimental designs

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