An electronically steerable epidural ultrasound interface for deep brain neuromodulation in freely moving rats

Abstract

Low-intensity focused ultrasound (LI-FUS) clinical trials exploit either the neural activity modulating, or the blood-brain barrier opening, capacity of this stimulation modality. However, LI-FUS currently is applied only transcranially which means that it is conducive only for episodic and intermittent stimulation, although, clinical data shows that in numerous neurological and psychiatric applications, chronic and continuous stimulation is required for long-term, stable therapeutic effect. The paper presents experimental data on a novel and innovative approach describing an implantable, epidural focus ultrasound (eFUS) device, designed for continuous, chronic and multi-site steerable neuromodulation. The miniaturized eFUS device consists of a two-dimensional piezoelectric transducer array directly integrated onto a custom ASIC, specifically engineered for proof-of-principle neuromodulation studies in the rat brain. The system generates electronically steerable focused ultrasound with software-defined focal coordinates, sufficient to stimulate neuronal activity in deep brain structures. In vitro acoustic characterization confirmed accurate beam steering and focusing, while in vivo validation demonstrated reliable stimulation of a deep subcortical target with measurable physiological effects. eFUS-mediated targeting of the ventral tegmental area in awake and freely moving rats produced increase in dopamine release in the nucleus accumbens as confirmed using fiber photometry recordings. Post-mortem histological analysis of the target regions showed the absence of inflammatory markers, although the epidural placement of the eFUS device was associated with mild tissue damage. Overall, the study provides in vitro data demonstrating the energy efficiency, and steerability of the technology, and in vivo physiological evidence of neuromodulatory ability of a deep, subcortical brain structure.