Neurostimulation success rate of repetitive‐pulse focused ultrasound in an in vivo giant axon model: An acoustic parametric study

Abstract

Purpose: Focused ultrasound (FUS) is a promising tool to develop new modalities of therapeutic neurostimulation. The ability of FUS to stimulate the nervous system,in a noninvasive and spatiotemporally precise manner,has been demonstrated in animals and human subjects, but the underlying biomechanisms are not fully understood yet. The objective of the present study was to investigate the bioeffects involved in the generation of trains of action potentials (APs) by repetitive-pulse FUS stimuli in a simple invertebrate neural model. Methods: The respective influences of different acoustic parameters on the neurostimulation success rate (NSR),defined as the rate of FUS stimuli capable of evoking at least one AP, were explored using the system of afferent nerves and giant fibers of Lumbricus terrestris as neural model. Each parameter was studied independently by administering random FUS sequences while keeping all but one FUS parameter constant. The NSR was evaluated as a function of (i) the spatial-average pulse-average intensity (I sapa ); (ii) the pulse duration (PD); (iii) the pulse repetition frequency (PRF); iv) the number of cycles per pulse (N cycles ); (v) two ultrasound frequencies, f 0 = 1.1 MHz and f 3 = 3.3 MHz, corresponding to the fundamental and third-harmonic resonant frequencies of the FUS transducer, respectively (spherical, radius of curvature: 50 mm); and (vi) levels of emerging stable cavitation and inertial cavitation. Results:The NSR associated to 1.1 MHz repetitive-pulse FUS stimuli was found to increase as a function of increasing I sapa , PD, PRF, and N cycles . When evaluating each parameter at f = 1.1 MHz, it was observed that NSRs close to 100% were achieved when sufficiently elevating their respective values. When computing the NSR as a function of the spatial-average, temporal-average intensity (I sata ), defined as the product of PRF, PD, and I sapa , a significant elevation of the NSR from 0% to close to 100% was measured by increasing I sata from values approximate to 4 W/cm 2 to values higher than 12 W/cm 2 . No clear and consistent trend was observed in trials aimed at exploring the effects of different levels of stable and inertial acoustic cavitation on the NSR. Finally, the feasibility of inducing neural responses with 3.3 MHz repetitive-pulse FUS stimuli was also demonstrated with NSRs reaching up to 60%, in the range of FUS parameters studied. Conclusion:The time-averaged value of the radiation force per unit volume of tissue is proportional to the acoustic intensity. As a result, the observations from this study suggest that the neural structure responding to the stimulus is sensitive to the mean radiation force carried by the FUS sequence, regardless of the combination of FUS parameters giving rise to such force. The results from 682

Low-Energy Transcranial Navigation-Guided Focused Ultrasound for Neuropathic Pain: An Exploratory Study

“…Previous research in both animal and human experiments has explored objective measures, including action potentials, evoked electroencephalographic responses, and tactile sensations experienced by subjects during FUS stimulation, to validate the efficacy of FUS. However, specific objective parameters or biomarkers capable of confirming the results after FUS treatment in patients with neuropathic pain remain unidentified [55,56,67]. Consequently, the assessment of FUS effects relied solely on the patient-reported outcomes.…”

A review of the bioeffects of low-intensity focused ultrasound and the benefits of a cellular approach

“…Another more accessible model preparation is the giant axon system of the earthworm. One study found that FUS application to the giant fibers of the nerve cord was effective in eliciting trains of action potentials; however, this effect was mentioned to be indirect and likely via FUS stimulation of afferent input ( Vion-Bailly et al, 2019 , 2022 ). Another group reported an FUS-induced reduction in action potential amplitude and conduction velocity following sonication, and although a second group, who targeted the medial and lateral giant fibers, could replicate this reduction in action potential amplitude, they did not observe a decrease in conduction velocity ( Yoo et al, 2017 ).…”

“…In recognition of the limitations in their respective intact neural systems, FUS neuromodulation researchers investigating mechanisms of action have applied their efforts to pared down systems, typically cultured mammalian neurons ( Rinaldi et al, 1991 ; Mihran et al, 1996 ; Prieto et al, 2018 ; Qiu et al, 2019 ), mammalian slice preparations ( Rinaldi et al, 1991 ; Bachtold et al, 1998 ; Tyler et al, 2008 ; Muratore et al, 2009 ), or tractable invertebrate models ( Wahab et al, 2012 ; Wright et al, 2015 ; Zhou et al, 2017 ; Kubanek et al, 2018 ; Lin et al, 2019 ; Vion-Bailly et al, 2019 , 2022 ; Dedola et al, 2020 ). Isolation in culture is known to alter the intrinsic electrical properties of neurons ( Turrigiano et al, 1994 ); FUS effects on cultured cells may thus differ from outcomes in intact systems.…”