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

Abstract

Non-invasive transcranial ultrasound (TUS) neuromodulation is an emerging technique that has been demonstrated as safe in humans for cortical [1Legon 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.Nat Neurosci. 2014; 17: 322-329Google Scholar, 2Fomenko 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.Elife. 2020; 9Google Scholar, 3Lee 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.Sci Rep. 2016; 6: 34026Google Scholar, 4Beisteiner 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.Adv Sci. 2020; 7: 1902583Google Scholar, 5Zeng 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.Ann Neurol. 2021; ([Online ahead of print])Google Scholar] and subcortical [[6]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.Sci Rep. 2021; 11: 6100Google Scholar,[7]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.Alzheimers Dement (N Y). 2019; 5: 374-381Google Scholar] targets. Deep brain stimulation (DBS) systems with local field potential (LFP) recording ability [[8]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.Front Hum Neurosci. 2021; 15Google Scholar] 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 [[9]Ni Z. Udupa K. Hallett M. Chen R. Effects of deep brain stimulation on the primary motor cortex: insights from transcranial magnetic stimulation studies.Clin Neurophysiol. 2019; 130: 558-567Google Scholar]. 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. 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%). 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). 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). 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). 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). 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 [1Legon 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.Nat Neurosci. 2014; 17: 322-329Google Scholar, 2Fomenko 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.Elife. 2020; 9Google Scholar, 3Lee 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.Sci Rep. 2016; 6: 34026Google Scholar, 4Beisteiner 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.Adv Sci. 2020; 7: 1902583Google Scholar, 5Zeng 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.Ann Neurol. 2021; ([Online ahead of print])Google Scholar, 6Cain 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.Sci Rep. 2021; 11: 6100Google Scholar, 7Nicodemus N.E. Becerra S. Kuhn T.P. Packham H.R. Duncan J. Mahdavi K. et al.Focused transcranial ultrasound for treatment of neurodegenerative dementia.Alzheimers Dement (N Y). 2019; 5: 374-381Google Scholar]; 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 [[10]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.Neurol Med -Chir. 1994; 34: 209-215Google Scholar]. 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 [[8]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.Front Hum Neurosci. 2021; 15Google Scholar]. We used sonication parameters similar to our previous paper [[2]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.Elife. 2020; 9Google Scholar], 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.

Topics & Concepts