Cell-Type-Selective Effects of Intramembrane Cavitation as a Unifying Theoretical Framework for Ultrasonic Neuromodulation

Abstract

Diverse translational and research applications could benefit from the noninvasive ability to reversibly modulate (excite or suppress) CNS activity using ultrasound pulses, however, without clarifying the underlying mechanism, advanced design-based ultrasonic neuromodulation remains elusive. Recently, intramembrane cavitation within the bilayer membrane was proposed to underlie both the biomechanics and the biophysics of acoustic bio-effects, potentially explaining cortical stimulation results through a neuronal intramembrane cavitation excitation (NICE) model. Here, NICE theory is shown to provide a detailed predictive explanation for the ability of ultrasonic (US) pulses to also suppress neural circuits through cell-type-selective mechanisms: according to the predicted mechanism T-type calcium channels boost charge accumulation between short US pulses selectively in low threshold spiking interneurons, promoting net cortical network inhibition. The theoretical results fit and clarify a wide array of earlier empirical observations in both the cortex and thalamus regarding the dependence of ultrasonic neuromodulation outcomes (excitation-suppression) on stimulation and network parameters. These results further support a unifying hypothesis for ultrasonic neuromodulation, highlighting the potential of advanced waveform design for obtaining cell-type-selective network control.

Thermal Transients Excite Neurons through Universal Intramembrane Mechanoelectrical Effects

“…For example, we note that membrane mechanoelectrical effects involving dimensional changes were suggested in other contexts involving changes in intramembranal forces, including action potential-related intramembrane thickness variations [51][52][53] and ultrasoundinduced formation of intramembrane cavities (or "bilayer sonophores" [54]). The neuronal intramembrane cavitation excitation theoretical framework putatively explains ultrasonic neuromodulation phenomena (suppression and excitation [55]) and predicts the results of a significant number of related experimental studies [56,57].…”

Neuromodulation with transcranial focused ultrasound

“…47 The study suggested that FUS intensity dictates whether a net outcome is an excitation or an inhibition as much as does a specific FUS pulsing protocol. In particular, short, repetitive pulses of the FUS—which correspond to low values of the duty cycle—are more likely to produce an inhibition, whereas longer repetitive pulses—higher duty cycle values—are more likely to lead to an excitation.…”

“…39 FUS can excite or inhibit cellular activity, depending on specific stimulation parameters. 47 FUS can cause a transient increase in firing rates in motor cortex and in the retina with short latency, 39,55 and thus has a direct capability to influence cellular discharge. It has been hypothesized that these effects are mediated by ion channels that can detect changes in membrane stretch following a propagating pressure wave.…”

“…This hypothesis has not, thus far, found robust experimental support. 50,51 A relatively recent model based on this idea, “intramembrane cavitation,” 29,47,48 predicts a profound drop of the membrane potential in response to FUS onset. The proposed drop measures ≥ 100 mV in the hyperpolarizing direction and can be observed for a period of several milliseconds.…”

“…This dependence reflects the proposition that the activity of certain classes of ion channels can be sensitive to the duty cycle. 47 For example, low-threshold spiking interneurons expressing T-type calcium channels may be activated using pulses of short duty cycles, which may lead to a net inhibition. 47 …”