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

Authors: Badran BW, Caulfield KA, Stomberg-Firestein S, Summers PM, Dowdle LT, Savoca M, Li X, Austelle CW, Short EB, Borckardt JJ, Spivak N, Bystritsky A, George MS

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. 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.<sub>0</sub> 995 mW/cm2, ISPTA.<sub>3</sub> 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. 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. 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.

Introduction

Purpose Transcranial ultrasound stimulation

Study Objective To determine whether MRI-guided transcranial focused ultrasound sonication of the right anterior thalamus can modulate thermal pain thresholds in healthy adults.

Animal model / Human subject Homo sapiens; strain: N/A; age: mean 24.5 years (SD 4.6, range 18–38); sex: both sexes (11 female, 8 male)

Disease model Healthy

MRI or image guidance method Structural MRI-based neuronavigation using Brainsight (3D reconstruction and scalp marking) with in-scanner MRI scout imaging to visually confirm transducer alignment via projected fiducial line (MRI-guided neuronavigation)

Targeted brain region(s) Thalamus

Outcomes and Safety

Summary of Outcomes MRI-guided active transcranial focused ultrasound (right anterior thalamus; 650 kHz, PRF 10 Hz, 5 ms pulse width, 5% duty cycle, 30 s sonications with 30 s inter-sonication interval, 10 sonications, peak rarefactional pressure ~0.72 MPa) produced a significant antinociceptive effect in healthy adults, blunting sensitization to thermal stimuli (thermal pain thresholds decreased less after active tFUS than after sham). Seventeen of 19 participants were accurately targeted and no serious adverse events were observed.

Duration of biological effect 25–45 min

Safety-related matter The study reports no adverse events related to sonication and states tFUS was delivered within FDA power guidelines and was feasible and safe with no serious adverse events; one participant (excluded from analysis) experienced an in-scanner panic attack during non-tFUS scan sequences that resolved within 15 minutes and led to withdrawal.

Brain Region

Ultrasound Parameters

Ultrasound instrument BrainSonix BXPulsar 1002 tFUS System (BrainSonix Corp., Sherman Oaks, CA, USA); single-element, air-backed, spherical ultrasound transducer, 61 mm diameter (80 mm focal length)

FUS Frequency 650 kHz (fundamental); Pulse repetition frequency: 10 Hz

FUS Intensity 0.995 W/cm2 (ISPTA.0), 0.719 W/cm2 (ISPTA.3)

FUS Pressure 0.72 MPa

FUS Mode pulsed

Pulse duration 5 ms

Duration of a single FUS session 10 minutes

Focal Characteristics Focal depth: None; Focal length: 80 mm; Aperture size: 61 mm

Treatment frequency multiple

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