Bidirectional and state-dependent modulation of brain activity by transcranial focused ultrasound in non-human primates

Abstract

Transcranial focused ultrasound (FUS) stimulation under MRI guidance, coupled with functional MRI (fMRI) monitoring of effects, offers a precise, noninvasive technology to dissect functional brain circuits and to modulate altered brain functional networks in neurological and psychiatric disorders. Here we show that ultrasound at moderate intensities modulated neural activity bi-directionally. Concurrent sonication of somatosensory areas 3a/3b with 250 kHz FUS suppressed the fMRI signals produced there by peripheral tactile stimulation, while at the same time eliciting fMRI activation at inter-connected, off-target brain regions. Direct FUS stimulation of the cortex resulted in different degrees of BOLD signal changes across all five off-target regions, indicating that its modulatory effects on active and resting neurons differed. This is the first demonstration of the dual suppressive and excitative modulations of FUS on a specific functional circuit and of ability of concurrent FUS and MRI to evaluate causal interactions between functional circuits with neuron-class selectivity.

Region-specific effects of ultrasound on individual neurons in the awake mammalian brain

“…Thus, the difference in ultrasoundevoked responses detected in the hippocampus and the motor cortex is due to brain-region-specific tissue properties. Recently fMRI studies in nonhuman primates showed that focused ultrasound stimulation of somatosensory cortex produces either excitatory or inhibitory effects in the brain depending on the activity states of the somatosensory pathway (Yang et al, 2021). Our observation of brain-region-specific ultrasound neuromodulation effect further highlights that neural circuit properties are critical consideration in ultrasound neuromodulation.…”

“…In rodents, several studies demonstrated that ultrasound directed to the motor cortex can successfully elicit muscle responses (Li et al, 2016;Lee et al, 2018;King et al, 2013). In humans and nonhuman primates, ultrasound can effectively stimulate somatosensory receptors in the hand and modulate responses in the somatosensory cortex and other brain regions (Gavrilov et al, 1976;Legon et al, 2012Legon et al, , 2014Lee et al, 2015Lee et al, , 2016Yang et al, 2018Yang et al, , 2021Kim et al, 2017;Yuan et al, 2020). These studies, though providing convincing evidence that ultrasound can modulate neural activity in intact brain circuits, rely largely on recording downstream motor activations via electromyography (EMG) or aggregated neural signals, such as electroencephalogram (EEG), functional magnetic resonance imaging (fMRI), and functional near-infrared spectroscopy (fNIR), which are either indirect measures of neural activity or have poor spatiotemporal resolution.…”

“…Altered membrane conductance, however, can excite or inhibit neurons, depending on the specific biophysical properties of the stimulated neurons, and the spatiotemporal profiles of the evoked conductance vary depending on the specific ultrasound stimulation parameters (Fry et al, 1958;Tyler et al, 2008;Lin et al, 2019). Indeed, recent observation that the same set of ultrasound stimulation protocol can evoke both excitatory and inhibitory effects in the somatosensory circuits depending on sensory stimulation states underscores the need of high resolution, single neuron level analysis of ultrasound effects in the brain with intact neural circuits (Yang et al, 2021).…”

Transcranial Focused Ultrasound Neuromodulation: A Review of the Excitatory and Inhibitory Effects on Brain Activity in Human and Animals

“…In particular, the study suggests that different neurons respond differently to tFUS stimuli and indicates further parametric studies should pay attention to the regulation of neural activity at the cell level ( Wattiez et al, 2017 ). Yang et al (2021) reported that medium amplitude tFUS (425 kPa free-field at 250 kHz) in the macaque brain modulated the activity of neurons at the target in dual directions (excitation and suppression). This simultaneous excitatory and suppressive neuromodulation may be mediated by activation of large excitatory pyramidal and small inhibitory interneurons, respectively.…”

Long Term Study of Motivational and Cognitive Effects of Low-intensity Focused Ultrasound Neuromodulation in the Dorsal Striatum of Nonhuman Primates

“…Neurophysiological studies implicate the striatum in reward-modulated sensory-motor decision making (Ding & Gold, 2013;Fan et al, 2020. ) Previous studies in macaques have shown that FUS can temporarily enhance neural activity and connectivity to closely related areas in both cortical and subcortical structures (Verhagen et al, 2018;Yang et al, 2021). FUS can also directly affect behavior in rhesus macaques.…”