Transcranial Low-Intensity Focused Ultrasound Stimulation of the Visual Thalamus Produces Long-Term Depression of Thalamocortical Synapses in the Adult Visual Cortex.

Transcranial focused ultrasound stimulation (tFUS) is a noninvasive neuromodulation technique, which can penetrate deeper and modulate neural activity with a greater spatial resolution (on the order of millimeters) than currently available noninvasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). While there are several studies demonstrating the ability of tFUS to modulate neuronal activity, it is unclear whether it can be used for producing long-term plasticity as needed to modify circuit function, especially in adult brain circuits with limited plasticity such as the thalamocortical synapses. Here we demonstrate that transcranial low-intensity focused ultrasound (LIFU) stimulation of the visual thalamus (dorsal lateral geniculate nucleus, dLGN), a deep brain structure, leads to NMDA receptor (NMDAR)-dependent long-term depression of its synaptic transmission onto layer 4 neurons in the primary visual cortex (V1) of adult mice of both sexes. This change is not accompanied by large increases in neuronal activity, as visualized using the cFos Targeted Recombination in Active Populations (cFosTRAP2) mouse line, or activation of microglia, which was assessed with IBA-1 staining. Using a model (SONIC) based on the neuronal intramembrane cavitation excitation (NICE) theory of ultrasound neuromodulation, we find that the predicted activity pattern of dLGN neurons upon sonication is state-dependent with a range of activity that falls within the parameter space conducive for inducing long-term synaptic depression. Our results suggest that noninvasive transcranial LIFU stimulation has a potential for recovering long-term plasticity of thalamocortical synapses in the postcritical period adult brain.

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

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 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.

Ultrasound Stimulations Induce Prolonged Depolarization and Fast Action Potentials in Leech Neurons.

Objective: Ultrasound (US) stimulation carries the promise of a selective, reversible, and non-invasive modulation of neural activity without the need for genetic manipulation of neural structures. However, the mechanisms of US-induced generation of action potentials (APs) are still unclear. Methods: Here we address this issue by analyzing intracellularly recorded responses of leech nociceptive neurons to controlled delivery of US. Results: US induced a depolarization linearly accumulating in time and outlasting the duration of the stimulation. Spiking activity was reliably induced for an optimal US intensity range. Moreover, we found that APs induced by US differ in smaller amplitude and faster repolarization from those induced by electrical stimulation in the same cell but display the same repolarization rate. Conclusions: These results shed light on the mechanism by which spikes are induced by US and pave the way for designing more efficient US stimulation patterns.

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

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.