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 this study further revealed the existence of a minimal activation threshold with regard to I sapa .

Abstract via europepmc.

Flags from extraction

• n_subjects — Different sub-experiments used separate cohorts of earthworms (n=4 for PD/intensity, n=6 for PRF, n=1 for pulse-count, n=2 for cavitation); the 3.3 MHz frequency study does not state an n. Recorded as a list of the stated group sizes; total unique animals unclear due to possible overlap between sub-studies.
• randomised — Randomisation refers to the random ordering of FUS burst types within each stimulation sequence (to avoid order/fatigue bias), not allocation to independent treatment arms; there is no sham/control group.
• exposures[0].free_field.isppa_w_cm2 — Paper reports Isapa (spatial-average pulse-average intensity), not Isppa (spatial-peak pulse-average); recorded here as the closest available pulse-average intensity metric.
• exposures[1].free_field.isppa_w_cm2 — Paper reports Isapa (spatial-average pulse-average intensity), not Isppa (spatial-peak pulse-average); recorded here as the closest available pulse-average intensity metric.
• exposures[0].free_field.pressure_kpa — The 1.8-5.2 MPa RMS pressure range is stated once for the overall FUS exposures used in the study; it is not explicitly broken down by the 1.1 MHz vs 3.3 MHz conditions, so the same range is assigned to both exposures.
• exposures[1].timing.duty_cycle_pct — Paper states duty cycles 'ranging from 0.6 to 0.12' for the 3.3 MHz PD sweep (480-960 microseconds at PRF=125 Hz); this ordering (max before min) and the value 0.6 (60%) appear inconsistent with PD*PRF arithmetic (which gives ~6-12%), suggesting a possible typo (0.06 instead of 0.6) in the source text. Recorded as stated (60, 12).
• exposures[0].timing.sonication_duration_s — The paper gives the number of pulses per burst (Npulses) and PRF but does not explicitly state a total burst/train duration in seconds; not computed here per protocol.
• exposures[1].timing.sonication_duration_s — As for exposure 0, total burst duration is not explicitly stated (only Npulses=20 and PRF=125 Hz); not computed here.