Frequency Dependence of Ultrasound Neurostimulation in the Mouse Brain

Abstract

Ultrasound neuromodulation holds promise as a non-invasive technique for neuromodulation of the central nervous system. However, much remains to be determined about how the technique can be transformed into a useful technology, including the effect of ultrasound frequency. Previous studies have demonstrated neuromodulation in vivo using frequencies less than 1 MHz, with a trend towards improved efficacy with lower frequency. However, using higher frequencies could offer improved ultrasound spatial resolution. We investigate the ultrasound neuromodulation effects in mice at various frequencies both below and above 1 MHz and find that frequencies up to 2.9 MHz can still be effective for generating motor responses, but also confirm that as frequency increases, sonications require significantly more intensity to achieve equivalent efficacy. We argue that our results provide evidence that favors either a particle displacement or a cavitation-based mechanism for the phenomenon of ultrasound neuromodulation.

Neuromodulation with transcranial focused ultrasound

“…40 In contrast, the probability of observing behavioral responses to FUS stimulation of motor regions in mice is higher at lower FUS frequencies. 27,62 The frequency-dependence mismatch between these data and those obtained in the retina may be explained by the increase in focal width with decreasing frequencies. 40 In a diffraction-limited system, lower frequencies activate a much larger area (~1/ f 2 ) and volume (up to ~1/ f 3 ).…”

“…13,17, 22,34 The current surge of interest in it as a noninvasive neurostimulation modality has been triggered by the following relatively recent findings: 1) FUS can elicit neuromodulatory effects in the CNS by using relatively short stimuli; 59 2) short stimuli of low intensity can trigger visible movements upon motor cortex stimulation in rodents; 25–27,35,38, 56,62 and 3) the method has been safely used in primates, including humans. 9,21,32–34,60 Given the enormous potential of this neurostimulation modality in causal brain mapping and treatments of deep brain circuits, work is currently under way to provide the information necessary for effective use.…”

Accurate simulation of transcranial ultrasound propagation for ultrasonic neuromodulation and stimulation

“…The physical mechanism underlying UNMS remains unclear, although a non-thermal mechanism is suspected, and lower acoustic frequencies have been shown to evoke a response more reliably. 3,6 Most recently ultrasound has been used to elicit electro-encephalogram (EEG) and sensory responses in human subjects, although this has been restricted to superficial cortical brain areas using unfocused single element transducers. [7][8][9] If UNMS is to develop as an effective non-invasive neurostimulation technique, its application to human subjects must be extended to deep brain targets.…”

On the neuromodulatory pathways of the in vivo brain by means of transcranial focused ultrasound

“…tFUS has demonstrated its robust neuromodulatory effects in numerous in vivo preparations of animals ranging from mice [14–18] and rats [19–23], to rabbits [24], swine [25,26], sheep [27], and even monkeys [28,29]. More recently it has been shown to be a safe and effective method for the transcranial stimulation of humans [30–36] with clinical applicability.…”

“…Here we present three potential interpretations for how the brain responds to ultrasound energy deposition (Figure 1). Given the extensive electrophysiological [20,21,30,32], neurovascular [24,29,34,41], motor [14,16–18,22,23] and cognitive [32,35,36] evidences in support of tFUS-induced direct neural effects, we further examine whether the auditory pathway in the small brain volumes of rodent or mouse models dictates or impacts the observed activation patterns.…”