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Toward focused ultrasound neuromodulation in deep brain stimulator implanted patients: Ex-vivo thermal, kinetic and targeting feasibility assessment

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    Can Sarica
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    Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
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    Anton Fomenko
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    Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
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    Jean-François Nankoo
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    Krembil Research Institute, University Health Network, Toronto, ON, Canada
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  • Ghazaleh Darmani
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    Krembil Research Institute, University Health Network, Toronto, ON, Canada
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  • Artur Vetkas
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    Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
    Department of Neurosurgery, School of Medicine, University of Tartu, Tartu, Estonia
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  • Kazuaki Yamamoto
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    Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
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    Andres M. Lozano
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    2 equal senior author contribution.
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    Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada
    Krembil Research Institute, University Health Network, Toronto, ON, Canada
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    Robert Chen
    Correspondence
    Corresponding author. Movement Disorders Centre, Toronto Western Hospital, 399 Bathurst St., 7 Mc412, Toronto, ON, M5T 2S8, Canada.
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    Affiliations
    Krembil Research Institute, University Health Network, Toronto, ON, Canada
    Edmond J. Safra Program in Parkinson's Disease, University Health Network, Toronto, ON, Canada
    Division of Neurology, Department of Medicine, University of Toronto, Toronto, ON, Canada
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Open AccessPublished:February 01, 2022DOI:https://doi.org/10.1016/j.brs.2021.12.012
      Dear Editor,
      Non-invasive transcranial ultrasound (TUS) neuromodulation is an emerging technique that has been demonstrated as safe in humans for cortical [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ,
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in Alzheimer's disease-A new navigated focal brain therapy.
      ,
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ] and subcortical [
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ,
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ] targets. Deep brain stimulation (DBS) systems with local field potential (LFP) recording ability [
      • Sarica C.
      • Iorio-Morin C.
      • Aguirre-Padilla D.H.
      • Najjar A.
      • Paff M.
      • Fomenko A.
      • et al.
      Implantable pulse generators for deep brain stimulation: challenges, complications, and strategies for practicality and longevity.
      ] 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 [
      • Ni Z.
      • Udupa K.
      • Hallett M.
      • Chen R.
      Effects of deep brain stimulation on the primary motor cortex: insights from transcranial magnetic stimulation studies.
      ]. 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. Methods

      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%).
      Fig. 1
      Fig. 1Experimental setup and results. (A) Skull phantom model consisted of a polycarbonate box that was filled with polyacrylic acid sodium salt gel. A four-channel TUS transducer (NeuroFus CTX-500, BrainBox Ltd, UK) was attached to the holder arm of the acoustic measurement tank (Acertara Acoustic Laboratories, CO, USA), while the lead was connected to the robotic arm at a point 10 cm proximal to lead tip. The skull specimen was placed flush to the transducer and the top of the transducer was leveled to the gel surface.An additional lead was placed 2–6 cm away from the test lead as a control. (B) The robotic arm placed the lead to various spatial positions in x- and y-axes, while the z-axis was kept constant at 55 mm distance from the transducer. Local field potentials were continuously recorded (left) during sonications of 1 second duration. Voltage artefacts were observed synchronizing to these pulsed sonications. The baseline-to-peak intensity of voltage artefacts was spatially mapped (right). The highest mean intensity (29.1 μV) was measured at 40 mm from the gel surface (X = 0, Y = −40). (C) The motion experiments were conducted in no-skull phantom model. The captured video was imported to CvMob software and points of interests were marked (electrode tip (orange), contact (pink) and two air bubbles (blue and green) (left). Frame-based velocity analysis revealed that the velocity of electrode tip and contact was stable over time (within ±0.03 pixel/frame limit), while the velocity of air bubbles were synchronized to 1-s sonications in both X and Y axes (right). (D) Temperature experiments were performed in both skull and no-skull phantom. Six 1-s sonications increased the temperature over the lead contacts up to 0.65 °C in skull phantom model (left). The temperature rise reached to a peak of 1.53 °C during 60-s sonication. The temperature returned to baseline in 7.5 seconds following the cessation of sonication (right). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

      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. Results

      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

      2.2.1 Motion

      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).

      2.2.2 Temperature

      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.

      3. Discussion

      Safe utilization of TUS in humans has already been demonstrated by various studies [
      • Legon W.
      • Sato T.F.
      • Opitz A.
      • Mueller J.
      • Barbour A.
      • Williams A.
      • et al.
      Transcranial focused ultrasound modulates the activity of primary somatosensory cortex in humans.
      ,
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ,
      • Lee W.
      • Kim H.C.
      • Jung Y.
      • Chung Y.A.
      • Song I.U.
      • Lee J.H.
      • et al.
      Transcranial focused ultrasound stimulation of human primary visual cortex.
      ,
      • Beisteiner R.
      • Matt E.
      • Fan C.
      • Baldysiak H.
      • Schonfeld M.
      • Philippi Novak T.
      • et al.
      Transcranial pulse stimulation with ultrasound in Alzheimer's disease-A new navigated focal brain therapy.
      ,
      • Zeng K.
      • Darmani G.
      • Fomenko A.
      • Xia X.
      • Tran S.
      • Nankoo J.F.
      • et al.
      Induction of human motor cortex plasticity by theta burst transcranial ultrasound stimulation.
      ,
      • Cain J.A.
      • Visagan S.
      • Johnson M.A.
      • Crone J.
      • Blades R.
      • Spivak N.M.
      • et al.
      Real time and delayed effects of subcortical low intensity focused ultrasound.
      ,
      • Nicodemus N.E.
      • Becerra S.
      • Kuhn T.P.
      • Packham H.R.
      • Duncan J.
      • Mahdavi K.
      • et al.
      Focused transcranial ultrasound for treatment of neurodegenerative dementia.
      ]; 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 [
      • Matsumi N.
      • Matsumoto K.
      • Mishima N.
      • Moriyama E.
      • Furuta T.
      • Nishimoto A.
      • et al.
      Thermal damage threshold of brain tissue--histological study of heated normal monkey brains.
      ]. 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 [
      • Sarica C.
      • Iorio-Morin C.
      • Aguirre-Padilla D.H.
      • Najjar A.
      • Paff M.
      • Fomenko A.
      • et al.
      Implantable pulse generators for deep brain stimulation: challenges, complications, and strategies for practicality and longevity.
      ]. We used sonication parameters similar to our previous paper [
      • Fomenko A.
      • Chen K.S.
      • Nankoo J.F.
      • Saravanamuttu J.
      • Wang Y.
      • El-Baba M.
      • et al.
      Systematic examination of low-intensity ultrasound parameters on human motor cortex excitability and behavior.
      ], 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.

      4. Conclusion

      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.

      Contributors

      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.

      Funding

      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.

      Acknowledgements

      None.

      Appendix A. Supplementary data

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