MorphoSONIC: A Morphologically Structured Intramembrane Cavitation Model Reveals Fiber-Specific Neuromodulation by Ultrasound

Théo Lemaire, Elena Vicari, Esra Neufeld, Niels Kuster, and Silvestro Micera, iScience, September 2021, Volume 24, Issue 9, Article No. 103085, online 6 September 2021; doi: https://doi.org/10.1016/j.isci.2021.103085

Low-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 modulation of 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 that are currently not addressable by electrical stimulation. More generally, our framework is readily applicable to other neural targets to establish application-specific LIFUS protocols.

The scientific and technical impact of the study can be summarized as:

• The novel morphoSONIC framework, which simulates intramembrane cavitation in neuron models as electrical circuits numerically compatible with the SONIC model, is described
• The framework is used to investigate mechanisms of ultrasonic neuromodulation in myelinated and unmyelinated peripheral fibers to analyze predicted LIFUS neuronal responses and recruitment mechanisms in both fiber types
• The LIFUS excitability of both fiber types is characterized across a wide range of model and stimulation parameters, and findings compared to those obtained by means of electrical stimulation
• Key morphological features underlying the distinct LIFUS sensitivities of myelinated and unmyelinated axons are identified
• Cell-type-specific neuronal responses to repeated acoustic exposure are analyzed, and pulsing regimes that yield a robust modulation of fiber spiking activity are identified
• A new type of pulsing protocol is proposed for modulation of myelinated and unmyelinated axons within heterogeneous nerve bundles

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