Transcranial ultrasound stimulation in humans is associated with an auditory confound that can be effectively masked

Abstract

14Background 15 Transcranial ultrasound stimulation (TUS) is emerging as a potentially powerful, non-invasive 16 technique for focal brain stimulation. Recent animal work suggests, however, that TUS effects 17 may be confounded by indirect stimulation of early auditory pathways. 18 Objective 19 We aimed to investigate in human participants whether TUS elicits audible sounds and if these 20 can be masked by an audio signal. 21 Methods 22 through earphones while TUS was applied reduced detection rates to chance level and 35 abolished the TUS-induced auditory EEG signal. Ex vivo skull experiments demonstrated that 36 sound is conducted through the skull at the pulse repetition frequency of the ultrasound. 37 Conclusion 38 Future studies using TUS in humans need to take this auditory confound into account and 39 mask stimulation appropriately. 40 41 42 43 44 Neuromodulation; Non-Invasive 46 47 Abbreviations: BDC = burst duty cycle; EEG = electroencephalography; ERP = event related 48 potential; IQR = interquartile range; PRF = pulse repetition frequency; TUS = transcranial 49 ultrasound stimulation 50 51 109 computer screen. In stimulation trials, TUS was applied 2.7-3 s after fixation onset for 300 ms 110 before a question mark appeared prompting participants to indicate whether they thought 111 they were stimulated or not, using their right hand. This block was followed by the masked 112 block in which a masking tone was played through earphones in every trial, approximately 113 112 ms prior to the onset of the ultrasound stimulation for 700 ms, before the question mark 114 appeared prompting participants to indicate whether they thought they were stimulated or 115 Contralateral Ipsilateral CW Coupled Uncoupled

Effect of Low Intensity Transcranial Ultrasound Stimulation on Neuromodulation in Animals and Humans: An Updated Systematic Review

“…The indirect effect of auditory confound might be influenced by the precise investigation of the effect of LI-TUS. This finding is in line with the recent study where Braun et al (2020) found that LI-TUS in humans has auditory confounds (Braun et al, 2020).…”

“…Four recent studies reported that indirect stimulation of auditory pathways may interfere with the neuromodulatory effects of LI-TUS (Guo et al, 2018;Sato et al, 2018;Mohammadjavadi et al, 2019;Braun et al, 2020). Although the impact of auditory confounding can be minimized via delivery of an external auditory waveform, it is important to recognize its existence as it may influence neuromodulatory outcomes.…”

Transcranial Focused Ultrasound Generates Skull-Conducted Shear Waves: Computational Model and Implications for Neuromodulation

“…By 30 µs after the start of FUS application, the shear waves reach the cochlea, applying stress on the order of 100 Pa to this auditory organ. The rapid transmission of shear waves to the cochlea may help explain the off-target auditory responses recorded during neuromodulation experiments [23,24,25].…”

“…Recently, low-intensity transcranial FUS has elicited growing interest as a tool for neuromodulation, owing to its concurrent benefits of relative safety, non-invasiveness and millimeter-scale precision [11][12][13][14][15][16][17][18][19][20][21][22]. However, the biophysical mechanisms underlying neuromodulation are not well understood, and recent studies have documented off-target auditory responses to FUS neuromodulation in rodents [23,24] and humans [25]. To better understand these phenomena at both the tissue and cellular levels, computational models can play a useful role [26,27].…”