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 perf