Increased Anatomical Specificity of Neuromodulation via Modulated Focused Ultrasound

Abstract

Transcranial ultrasound can alter brain function transiently and nondestructively, offering a new tool to study brain function now and inform future therapies. Previous research on neuromodulation implemented pulsed low-frequency (250–700 kHz) ultrasound with spatial peak temporal average intensities (ISPTA) of 0.1–10 W/cm2. That work used transducers that either insonified relatively large volumes of mouse brain (several mL) with relatively low-frequency ultrasound and produced bilateral motor responses, or relatively small volumes of brain (on the order of 0.06 mL) with relatively high-frequency ultrasound that produced unilateral motor responses. This study seeks to increase anatomical specificity to neuromodulation with modulated focused ultrasound (mFU). Here, ‘modulated’ means modifying a focused 2-MHz carrier signal dynamically with a 500-kHz signal as in vibro-acoustography, thereby creating a low-frequency but small volume (approximately 0.015 mL) source of neuromodulation. Application of transcranial mFU to lightly anesthetized mice produced various motor movements with high spatial selectivity (on the order of 1 mm) that scaled with the temporal average ultrasound intensity. Alone, mFU and focused ultrasound (FUS) each induced motor activity, including unilateral motions, though anatomical location and type of motion varied. Future work should include larger animal models to determine the relative efficacy of mFU versus FUS. Other studies should determine the biophysical processes through which they act. Also of interest is exploration of the potential research and clinical applications for targeted, transcranial neuromodulation created by modulated focused ultrasound, especially mFU’s ability to produce compact sources of ultrasound at the very low frequencies (10–100s of Hertz) that are commensurate with the natural frequencies of the brain.

Acoustically targeted chemogenetics for the non-invasive control of neural circuits

“…Compared to emerging ultrasonic neuromodulation techniques in which ultrasound directly activates or inhibits brain regions or releases local neuromodulatory compounds [48][49][50][51][52][53][54][55] , ATAC does not require an ultrasound transducer to be mounted on the subject during modulation. After transduction and expression of chemogenetic receptors in a genetically defined subset of cells at the FUS-targeted site, neuromodulation is conveniently controlled using an orally bioavailable drug.…”

Toward Deep Brain Monitoring with Superficial EEG Sensors Plus Neuromodulatory Focused Ultrasound

“…To implement the pFU protocol we used the ultrasound source and supporting electronics described in Mehić et al (2014) – also see our Figure 1 – a dual element, coaxial, confocal and circular transducer, and associated matching networks (H-148, Sonic Concepts, Woodinville, WA, U.S.) with a central opening filled with a passive cavitation hydrophone from Sonic Concepts. Two Agilent Series 33220A 20 MHz function generators (Agilent Technologies, Santa Clara, CA, U.S.), controlled by a third Agilent function generator drove two ENI brand model A150 55dB amplifiers (Electronic Navigation Industries, Rochester, NY, U.S.) that in turn powered each of the two elements within the focused transducer.…”

“…More recently, we (Mehić et al, 2014) used a high-frequency (2 MHz) system capable of focused delivery of very low-frequency ultrasound (‘modulated focused ultrasound [mFU]), as well as pFU, to demonstrate spatial variability of transcranial activation of brain circuits in mice on length scales of one millimeter, observed through induction of repeatable peripheral motor function. Also Deffieux et al (2013) demonstrated reversible changes in macaque visual function after application of pFU at 0.32 MHz to their prefrontal cortex.…”

Development of a Wearable Robotic Positioning System for Noninvasive Transcranial Focused Ultrasound Stimulation

“…Recently, ultrasonic brain stimulation has emerged as a novel noninvasive brain stimulation modality showing improved penetration and spatial resolution over existing noninvasive brain stimulation methods. Not only animal experiments but also recent experiments on human subjects have shown the promising capabilities of ultrasound as a novel neuro-modulation modality [2][3][4][5][6][7][8][9].…”

“…Mihran et al have shown that ultrasound can modulate neuronal activity through either enhancement or suppression of its excitability in peripheral nerves [11]. Recently, multiple researchers were successful in inducing observable selective motor activities by stimulating the intact brains of mice [5][6][7]; one of these groups recently conducted extended experiments on human subjects, showing that ultrasound can focally modulate human cortical function [2].…”