Sonication of the anterior thalamus with MRI-Guided transcranial focused ultrasound (tFUS) alters pain thresholds in healthy adults: A double-blind, sham-controlled study

Bashar W Badran, Kevin A Caulfield, Sasha Stomberg-Firestein, Philipp M Summers, Logan T Dowdle, Matt Savoca, Xingbao Li, Christopher W Austelle, E Baron Short, Jeffrey J Borckardt, Norman Spivak, Alexander Bystritsky, Mark S George, Bashar W Badran, Kevin A Caulfield, Sasha Stomberg-Firestein, Philipp M Summers, Logan T Dowdle, Matt Savoca, Xingbao Li, Christopher W Austelle, E Baron Short, Jeffrey J Borckardt, Norman Spivak, Alexander Bystritsky, Mark S George

Abstract

Background: Transcranial focused ultrasound (tFUS) is a noninvasive brain stimulation method that may modulate deep brain structures. This study investigates whether sonication of the right anterior thalamus would modulate thermal pain thresholds in healthy individuals.

Methods: We enrolled 19 healthy individuals in this three-visit, double-blind, sham-controlled, crossover trial. Participants first underwent a structural MRI scan used solely for tFUS targeting. They then attended two identical experimental tFUS visits (counterbalanced by condition) at least one week apart. Within the MRI scanner, participants received two, 10-min sessions of either active or sham tFUS spread 10 min apart targeting the right anterior thalamus [fundamental frequency: 650 kHz, Pulse repetition frequency: 10 Hz, Pulse Width: 5 ms, Duty Cycle: 5%, Sonication Duration: 30s, Inter-Sonication Interval: 30 s, Number of Sonications: 10, ISPTA.0 995 mW/cm2, ISPTA.3 719 mW/cm2, Peak rarefactional pressure 0.72 MPa]. The primary outcome measure was quantitative sensory thresholding (QST), measuring sensory, pain, and tolerance thresholds to a thermal stimulus applied to the left forearm before and after right anterior thalamic tFUS.

Results: The right anterior thalamus was accurately sonicated in 17 of the 19 subjects. Thermal pain sensitivity was significantly attenuated after active tFUS. The pre-post x active-sham interaction was significant (F(1,245.95) = 4.03, p = .046). This interaction indicates that in the sham stimulation condition, thermal pain thresholds decreased 1.08 °C (SE = 0.28) pre-post session, but only decreased .51 °C (SE = 0.30) pre-post session in the active stimulation group.

Conclusions: Two 10-min sessions of anterior thalamic tFUS induces antinociceptive effects in healthy individuals. Future studies should optimize the parameter space, dose and duration of this effect which may lead to multi-session tFUS interventions for pain disorders.

Keywords: Focused ultrasound; Low intensity focued ultrasound; MRI; Pain; Sonication; Thalamus; fus; lifup; tfus.

Conflict of interest statement

Declaration of competing interest AB is employed by BrainSonix, which manufactures the ultrasound device. He holds patents in this area. BWB owns minority stake in Bodhi NeuroTech Inc, which manufactures meditation enhancing devices and holds patents in this area. No other authors have any other conflicts.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1.
Fig. 1.
Study Overview. Experimental visits 2 and 3 were identical except for sham or active tFUS, with outside the scanner QST conducted at baseline and after in-scanner tFUS administration.
Fig. 2.
Fig. 2.
Administration of tFUS in the MRI Scanner. a) compound picture of setup in scanner with thermode, hand pad, tFUS device, b) Photograph of how tFUS is attached to participant in the scanner head coil (32ch), c) Overview of tFUS sonication block design paradigm, d) screenshot of the MRI console screen demonstrating how active-time tFUS targeting is conducted.
Fig. 3.
Fig. 3.
Software-based confirmation of deep brain sonication. a) individual MRI images were used to create trajectory models of the sonication beam and b) the center of the sonication beam coordinates were then mapped onto an MNI-152 template brain. c) The MNI coordinates of the sonication beam were then overlaid on a standard MNI template brain to visualize the center of sonication beam. The large yellow sphere represents the actual size of the stimulation in the target (right anterior thalamus) and the small spheres represent the center of each subject’s individual sonication beam (green = on target, N = 17/19; red = off target, N = 2/19).
Fig. 4.
Fig. 4.
Overall change in QST pain threshold by condition. Temperature sensitivity increases were significantly attenuated (timeXcondition p = 0.046) after active tFUS (0.51° change) relative to sham stimulation (1.08°). That is, across the 2 h study, subjects became more sensitized to the painful stimulus (forearm heat). On the day they received active tFUS stimulation, subjects were not as sensitive over time.

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