Focused ultrasound neuromodulation of cortical and subcortical brain structures using 1.9 MHz.

Hermes A S Kamimura,Qi Wang,Elisa E Konofagou,Christian Aurup,Camilo Acosta,Antonio A O Carneiro,Hong Chen,Shutao Wang

doi:10.1118/1.4963208

Abstract

Ultrasound neuromodulation is a promising noninvasive technique for controlling neural activity. Previous small animal studies suffered from low targeting specificity because of the low ultrasound frequencies (<690 kHz) used. In this study, the authors demonstrated the capability of focused ultrasound (FUS) neuromodulation in the megahertz-range to achieve superior targeting specificity in the murine brain as well as demonstrate modulation of both motor and sensory responses. FUS sonications were carried out at 1.9 MHz with 50% duty cycle, pulse repetition frequency of 1 kHz, and duration of 1 s. The robustness of the FUS neuromodulation was assessed first in sensorimotor cortex, where elicited motor activities were observed and recorded on videos and electromyography. Deeper brain regions were then targeted where pupillary dilation served as an indicative of successful modulation of subcortical brain structures. Contralateral and ipsilateral movements of the hind limbs were repeatedly observed when the FUS was targeted at the sensorimotor cortex. Induced trunk and tail movements were also observed at different coordinates inside the sensorimotor cortex. At deeper targeted-structures, FUS induced eyeball movements (superior colliculus) and pupillary dilation (pretectal nucleus, locus coeruleus, and hippocampus). Histological analysis revealed no tissue damage associated with the FUS sonications. The motor movements and pupillary dilation observed in this study demonstrate the capability of FUS to modulate cortical and subcortical brain structures without inducing any damage. The variety of responses observed here demonstrates the capability of FUS to perform functional brain mapping.

Highlights

Ultrasound neuromodulation has gained attention as a promising technique to overcome limitations of current techniques such as the implantation of electrodes when using deep brain stimulation (DBS); the poor spatial resolution (≈1 cm), inadequate depth of penetration, and short-lasting effects of transcranial magnetic stimulation (TMS); and the gene modification required by optogenetics
Tufail et al 2011 (Ref. 8) presented a general protocol for the stimulation of intact mouse brain and a review with the most recent findings in ultrasonic neuromodulation is presented in Naor et al, 2016.9 The ultrasound frequencies used in most previous small animal neuromodulation studies were lower than 690 kHz
Once the robustness of modulating shallower brain regions by Focused ultrasound (FUS) was confirmed, we evaluated its capability of modulating deeper structures in the brain at DV: −3 mm

Summary

Introduction

Ultrasound neuromodulation has gained attention as a promising technique to overcome limitations of current techniques such as the implantation of electrodes when using deep brain stimulation (DBS); the poor spatial resolution (≈1 cm), inadequate depth of penetration, and short-lasting effects (milliseconds) of transcranial magnetic stimulation (TMS); and the gene modification required by optogenetics. Focused ultrasound (FUS) has been shown to be capable of modulating— suppressing or stimulating—specific parts of the brain such as the motor, sensorimotor, and visual cortices. Tufail et al 2011 (Ref. 8) presented a general protocol for the stimulation of intact mouse brain and a review with the most recent findings in ultrasonic neuromodulation is presented in Naor et al, 2016.9 The ultrasound frequencies used in most previous small animal neuromodulation studies were lower than 690 kHz. Focused ultrasound (FUS) has been shown to be capable of modulating— suppressing or stimulating—specific parts of the brain such as the motor, sensorimotor, and visual cortices.. FUS with lower frequencies generally has large focal spots generating problems of target specificity, especially with small animal models (rodents). A more confined focus can be formed using higher frequencies, which allows spatialselective modulation of the brain. Higher selectivity of ultrasound neuromodulation would allow stimulation of the specific groups of neurons, e.g., different brain regions or brain structures, which in turn would help understanding previous results with inconsistent lateralization of motor responses.. Previous studies have demonstrated the feasibility of utilizing megahertz frequency ultrasound to elicit motor activations of limbs, tail, and whiskers of mice, but Higher selectivity of ultrasound neuromodulation would allow stimulation of the specific groups of neurons, e.g., different brain regions or brain structures, which in turn would help understanding previous results with inconsistent lateralization of motor responses. Previous studies have demonstrated the feasibility of utilizing megahertz frequency ultrasound to elicit motor activations of limbs, tail, and whiskers of mice, but

Methods

Results

Conclusion