Effects of sonication parameters on transcranial focused ultrasound brain stimulation in an ovine model

Abstract

Low-intensity focused ultrasound (FUS) has significant potential as a non-invasive brain stimulation modality and novel technique for functional brain mapping, particularly with its advantage of greater spatial selectivity and depth penetration compared to existing non-invasive brain stimulation techniques. As previous studies, primarily carried out in small animals, have demonstrated that sonication parameters affect the stimulation efficiency, further investigation in large animals is necessary to translate this technique into clinical practice. In the present study, we examined the effects of sonication parameters on the transient modification of excitability of cortical and thalamic areas in an ovine model. Guided by anatomical and functional neuroimaging data specific to each animal, 250 kHz FUS was transcranially applied to the primary sensorimotor area associated with the right hind limb and its thalamic projection in sheep (n = 10) across multiple sessions using various combinations of sonication parameters. The degree of effect from FUS was assessed through electrophysiological responses, through analysis of electromyogram and electroencephalographic somatosensory evoked potentials for evaluation of excitatory and suppressive effects, respectively. We found that the modulatory effects were transient and reversible, with specific sonication parameters outperforming others in modulating regional brain activity. Magnetic resonance imaging and histological analysis conducted at different time points after the final sonication session, as well as behavioral observations, showed that repeated exposure to FUS did not damage the underlying brain tissue. Our results suggest that FUS-mediated, non-invasive, region-specific bimodal neuromodulation can be safely achieved in an ovine model, indicating its potential for translation into human studies.

A retrospective qualitative report of symptoms and safety from transcranial focused ultrasound for neuromodulation in humans

“…In addition to adjusting focal lengths, there are a number of parameters that can be manipulated when using ultrasound including the acoustic frequency, amplitude, duration, duty cycle, pulse repetition frequency etc. and the efficacy of some of these for successful neuromodulation has been addressed in small 3,4 and large animal studies 10 though the mechanism of acoustic energy for neuronal modulation is largely theoretical [28][29][30][31] and the impact of parameter space in humans is not yet well-described. The bioeffects of ultrasound for neuromodulation in humans as described here are likely largely mechanical as opposed to thermal or cavitational as the parameters used are of low intensity and short duration and generate temperatures insufficient for thermal modulation 32 .…”

Sonogenetics for noninvasive and cellular-level neuromodulation in rodent brain

“…2). While we cannot rule out the contribution by the ultrasound mechanical effect, these findings 7 suggest that the activation of the TRPV1 ion channel is dominated by the ultrasound thermal effect.…”

“…However, the broad application of FUS neuromodulation is challenged by the wide variation in neural cell types in the sonicated brain tissue, resulting in neuromodulation with relatively low reliability and replicability 7,8 . Advances in genetics-based tools enable manipulation of a specific type of neurons embedded within densely-wired brain circuits for assessing the causal role that different groups of neurons have in controlling circuit activity and behavior outcomes.…”

Transcranial Focused Ultrasound Neuromodulation of Voluntary Movement-related Cortical Activity in Humans

“…Very recently, 60 the ultrasound-induced illusory visual percepts were further investigated by 61 applying repeated transcranial diagnostic ultrasound at visual cortical region 62 identified by transcranial magnetic stimulation (TMS) eliciting phosphene 63 (Schimek et al, 2020). 64 The motor cortex has been one of the popular sonication targets on animal 65 models for eliciting direct brain activation by tFUS, demonstrated by more 66 direct motor response readout (Kim et al, 2014;King et al, 2013;Mehic et 67 al., 2014;Tufail et al, 2010;Ye et al, 2016;Yuan et al, 2020) and/or 68 measurements from the corresponding muscle activities using 69 electromyogram (EMG) (King et al, 2013;King et al, 2014;Qiu et al, 2017; 70 Yoon et al, 2019). In spite of this, the demonstrations of tFUS modulation on 71 human motor cortex are somehow limited.…”

“…Given the importance of the MRCP in the scientific investigations on healthy 421 human subjects (Dremstrup et al, 2013) and clinical evaluations on patients 422 diagnosed with functional motor disorders, such as Parkinson's disease and 423 Amyotrophic Lateral Sclerosis (ALS) (Gu et al, 2009), it would be valuable 424 to have a non-invasive neuroimaging tool, such as ESI, to map and quantify 425 the MRCP source at specific brain circuits with high spatiotemporal 426 resolution, thus informing the non-invasive neuromodulation for guidance 427 and feedback (Yu et al, 2020). Electrophysiological source imaging (ESI) 428 has been pursued to localize and image brain electrical sources from 429 noninvasive scalp recorded EEG/MEG, and demonstrated to provide greatly 430 enhanced spatial resolution than the raw EEG/MEG in many applications 431 (He & Ding, 2013;He et al, 2018;Sohrabour et al, 2020).…”