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] might be utilized to record TUS-induced LFP changes and acoustic pressure induced artefact in the LFP recordings can be regarded as an evidence of engagement of acoustic waves with the target. Moreover, combining non-invasive brain stimulation with DBS has therapeutic implications, such as measuring alterations in pathological deep brain oscillations as an objective clinical outcome of TUS stimulation [
]. Nevertheless, the safety of this utilization needs to be tested ex vivo before human application. Herein, we report our safety and feasibility experiments with the eventual objective of stimulating DBS-implanted subjects with TUS.
1.1 Experimental setup
Please see Supplemental Methods for full protocol. We designed two phantom models; one consisting of a polycarbonate box filled with a semisolid gel with acoustic properties similar to brain tissue containing a partial human cadaver skull: skull phantom (Fig. 1A) or an empty no-skull phantom (Supp.Figure1A). A four-channel TUS transducer was used with same sonication parameters for all experiment (Power/ch: 22 W, ISPPA: 30 W/cm2, ISPTA: 15 W/cm2, fundamental frequency: 500 kHz, focal depth: 60 mm, burst length: 0.5 ms, duty cycle 50%).
1.2 Sonication effect on continuous LFP recordings
A DBS lead was attached to a 3-axis robotic arm. The robot-driven lead was placed in different spatial locations in x- and y-axes as in a grid while the z-axis kept constant at a 55 mm distance from the transducer in the robotic-arm skull phantom model (Fig. 1A).
1.3 Temperature change of DBS leads
A thermal sensor was attached to a DBS lead that was placed 60 mm away from the transducer with two different attachment methods (Supp.Figure1B). Various conditions with different combinations [skull/no-skull phantom, two different probe attachment methods, continuous or pulsed sonication, sonication time (1, 3 or 30 minutes), no-, 1- or 2-lead] were tested. Recordings were performed and analyzed with Spike 2 software (Cambridge Electronic Design).
1.4 Motion of DBS leads
We captured a video during 10 sonications of 1.0s duration in the no-skull phantom model (Fig. 1C, Supp.Figure1A). Lead tip, electrode shaft and two air bubbles in the gel were marked as areas of interest. The movement of the marked points across the consecutive frames were analyzed using CvMob software (UFBA, Salvador, Brazil).
2.1 Estimation of the spatial profile of TUS sonications by local field potential recordings
During continuous LFP recordings, voltage artefacts were observed synchronizing to pulsed sonications. The mean baseline-to-peak intensity of these artefacts were 5.4 and 914.2 μV for skull and no-skull phantoms, respectively. Corresponding artefact voltages detected in control lead were 0.3 and 1.8 μV (Supp.Figure2).
In a second experiment, the intensity of these artefacts with regards to the spatial position of the lead to the transducer was mapped in the robotic-arm skull phantom model via moving the lead by 1 mm in x(horizontal)-axis and 0.5mm in y(vertical)-axis in a 5 × 8 grid. The highest mean intensity (29.1 μV) was measured zero lateral distance (x = 0) and 40 mm deep to the gel surface (y = −40). For an artefact intensity level over 10 μV, the lateral resolution was confined to 20–30 mm and vertical resolution was 10 mm. 10–15 mm above the main focus in vertical direction, a satellite stimulation focus was present (Fig. 1B).
2.2 Safety profile
The velocity in x- and y-axes of the lead tip and electrode contact were within the ±0.03 pixel/frame limit (1 pixel corresponds to 0.06mm) (Fig. 1C).
Maximum heating recorded on the lead was +1.67 °C that was reached at 83 seconds during 30-min continuous sonication. At the beginning of continuous sonication, +1 °C increment was reached in 5.4 sec, whereas the peak temperature rise was +1.53 °C at 60 seconds. The temperature returned back to baseline in 7.5 seconds after the sonication turned off (Fig. 1D). Results from different combinations of various conditions were given in Supp.Table 1.
Safe utilization of TUS in humans has already been demonstrated by various studies [
]; however, safety of this modality in DBS-implanted patients needs to be examined. The maximal temperature rise observed in these experiments (+1.67 °C) was below the maximal allowable safe limit for brain tissue [
]. Our experiments also demonstrated micro-motion of the electrode tip <0.06mm, which does not present a clear safety concern. These foundational results are encouraging to step up translation to human studies. TUS sonication of DBS-implanted patients may represent an objective measure to optimize TUS parameters by within-subject comparisons of DBS and TUS clinical, neuroimaging and neurophysiological outcomes.
We have a large experience with neurophysiological evaluations of newly implanted DBS patients through externalized leads immediately after their surgeries. However, such a procedure may be risky for TUS experiments because of the potential of trapped intracranial air after surgery. Thus, we opted to use an LFP-sensing implantable pulse generator (Percept PC) in our experiments [
], but used much longer sonication duration (i.e. 30 mins) to investigate the effects under extreme conditions. We faced some limitations during these experiments. A full volumetric mapping of the thermal and artefactual outcomes was not performed. Furthermore, as the phantom gel was homogenous and at room temperature, it could not fully model the cytoarchitecture and vascular nature of human brain tissue. In addition, the Percept PC recordings lacked a physiologic LFP baseline. However, since these are typically on the order of 40 μV, the observed sonication artefact might still be evident.
Our ex vivo experiments showed that TUS sonication did not produce hazardous temperature rise or motion on DBS lead. In addition, acoustic waves exerted artefacts during LFP recording, which may be regarded as feedback for wave-target engagement.
CS, AF, JN, GD, AV designed the study. CS, AF, JN, GD, AV, KY collected the data. AF, CS, JN processed and analyzed the data. AML and RC provided funding and supervision. CS wrote the original draft, which was critically reviewed and edited by all authors. All authors had access to the full data and agreed to be accountable for all aspects of the work.
The study was funded by the Natural Science and Engineering Research Council of Canada (RGPIN-2020-04176, RTI-2020-00249) and the Canadian Institutes of Health Research (FDN-154292).
C.S. has been receiving fellowship grants from Michael and Amira Dan Foundation and Turkish Neurosurgical Society.
A.F. is funded by CIHR Banting and Best Doctoral Award and the University of Manitoba Clinician Investigator Program.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Appendix A. Supplementary data
The following are the Supplementary data to this article: