On the Neuromodulatory Pathways of the In Vivo Brain by Means of Transcranial Focused Ultrasound

Abstract

For last decade, low-intensity transcranial focused ultrasound (tFUS) has been rapidly developed for a myriad of successful applications in neuromodulation. tFUS possesses high spatial resolution, focality and depth penetration as a noninvasive neuromodulation tool. Despite the promise, confounding activation can be observed in rodents when stimulation parameters are not selected carefully. Here we summarize the existing classes of observations for ultrasound neuromodulation: ultrasound directly activates a localized area, or ultrasound indirectly activates auditory pathways, which further propagates to other cortical networks. We also present control in vivo animal studies, which suggest that underlying tFUS brain modulation is characterized by localized activation independent of auditory networks activations.

Keywords: brain stimulation; low-intensity focused ultrasound; neuromodulation; tFUS; transcranial focused ultrasound.

Figure 1.

Possible activation pathways of brain activation by tFUS. A. tFUS directly stimulates the target area. B. tFUS leads to indirect activation of the auditory cortex, which propagates to the target area. C. tFUS directly stimulates the target area, with some auditory indirect stimulation, however the activations are independent of each other.

Figure 2.

A. Psuedo-colored maps c-fos+ cell densities at three coronal brain sections. The brain areas between the two white lines were targeted with tFUS. The black arrows indicate the ancillary activations. (adapted from [15]) B. 24-channel rat EEG electrodes covering a 3-D reconstructed rat brain. The current source density reconstructed in electrophysiological source imaging (ESI) is displayed in a coronal section. The green cross indicates the stimulation target of the tone-burst tFUS shown in E. C. Shown as a principal component, local hemodynamic changes detected by optical imaging on awake mice suggested a dependence of brain activations on ultrasound PRF (adapted from [48]. D. The illustrated single cycle mode employs short pulse duration (fundamental frequency FF: 500 kHz). ESI-based global images localize the brain activation due to tFUS aiming at primary somatosensory cortex (S1) in this single-cycle mode. Measured ultrasound peak-to-peak pressure is 88.7 kPa, and the pulse duration is 70 μs. Maximal current density is shown at the local area targeted by tFUS in all ESI frames, while no significant auditory response can be seen among these images. E. The tone burst mode integrates multiple sinusoidal cycles for each pulse. Directing the tone burst mode tFUS onto S1 triggers brain responses at S1 and bilateral auditory cortices. In this mode, the pulse duration is elongated to 200 μs for 100 cycles per pulse.

Figure 3.

A. ABR tests in anesthetized rats before chemical deafening. B. The experimental protocol to induce deafening, conduct ABR tests, and subsequently the intracranial recording. C. ABR tests in anesthetized rats after chemical deafening. D and E. In two chemically-deafened rats, temporal waveforms of local field potentials (LFPs) recorded at S1 from baseline (averaged across 288 trials), tFUS at S1 and anterior control location (sham, both averaged across 318 trials). The ultrasound conditions are illustrated in the inset with corresponding colors for tFUS (orange circle) and sham (green circle). The LFPs are presented with the mean value (solid line) and standard error of the mean (shaded areas). The gray bars indicate significant differences between tFUS and sham conditions (p < 0.05).