A modeling framework to understand and optimize ultrasound neuromodulation

Over the last decade, Low Intensity Focused Ultrasound Stimulation (LIFUS) has emerged as an attractive technology to modulate the activity of deep neural targets without invasive procedures. However, the underlying mechanisms by which ultrasonic waves can excite neurons are still unclear, which prevents a reliable and targeted application of the LIFUS technology and hinders its translation into clinical settings. The Neuronal Intramembrane Cavitation Excitation (NICE) model hypothesizes that ultrasound excites neurons through the nucleation and resonance of nanoscale membrane structures (bilayer sonophores) that can alter membrane capacitance and induce depolarizing currents. The model predictions of LIFUS neuromodulatory effects match a wide range of empirical observations in the brain. However, because it neglects cellular morphology, the NICE model cannot address important questions on the interaction of ultrasonic waves with neural structures. In this thesis, I propose several strategies to address these limitations, and to bridge the gap towards an experimental validation of this mechanism. I begin with an introduction establishing the background, describing the state-of-the-art and issues plaguing the field of ultrasound neuromodulation, and motivating the global objectives that will be pursued throughout the thesis. In a second part, I provide a mathematical description of the two pillars of the NICE model, namely a cavitation model describing mechanical membrane oscillations, and a point-neuron model describing the membrane electrical response. In doing so, I also discuss the inherent model assumptions, the potential implications for its validity range, and its sensitivity to key parameters. In a third part, I present a novel multi-Scale Optimized Neuronal Intramembrane Cavitation (SONIC) model that alleviates the stiffness of the NICE model by numerically separating its two constituent time scales. I demonstrate how this approach drastically reduces computational costs and confers interpretability to LIFUS neuromodulatory effects in terms of effective membrane dynamics. In a fourth part, I present a morphological expansion of the SONIC model (termed morphoSONIC) allowing to simulate intramembrane cavitation in a wide variety of realistic neuron models.With this framework, I investigate LIFUS neuromodulatory effects in peripheral nerve fibers. I predict that myelinated and unmyelinated axons can be distinctively and selectively recruited by LIFUS, thereby opening exciting avenues for peripheral neuromodulation. In a fifth part, I present the results of a parallel collective effort to track down the mechanisms of ultrasound neuromodulation in sensory neurons extracted from the medicinal leech.We found that LIFUS can reliably induce spiking activity within an optimal intensity range, and identified common and differing response features between acoustically and electrically evoked spikes.This chapter ends with a discussion of the implications of our findings for the validity of the intramembrane cavitation hypothesis. The achievements presented in this thesis provide an increased understanding of the mechanisms by which ultrasound modulates neural activity, as well as computational tools for their investigation. Moreover, they pave the way towards the development of reliable modeling frameworks to simulate ultrasound neuromodulatory effects across spatial, temporal and functional scales, helping to propel LIFUS into the clinics.