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 non-invasive 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 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 (LTS) 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.​

Significance Statement: Recent studies have demonstrated that ultrasound waves are capable of stimulating or suppressing neural circuits, thereby opening up an important new route towards targeted noninvasive neuromodulation. However, the underlying mechanism for ultrasonically eliciting specific neuromodulatory effects has not been clarified. Our new theoretical analysis reveals that ultrasound can selectively excite different cortical neuron subtypes simply by changing the stimulation pattern, driven by the response properties of T-type calcium channels. Interestingly, the model's predictions at the single-neuron and network levels are shown to closely agree with and explain the emerging field's entire body of experimental results, spanning from rodents to humans, and can thus facilitate the development of new ways of treating or diagnosing brain disorders.