Safety and Tolerability of Low Intensity Focused Ultrasound to the Anterior Insula in Patients with Fibromyalgia

Abstract

Background Low-intensity focused ultrasound (LIFU) is an emerging noninvasive neuromodulation technique capable of targeting deep cortical and subcortical structures with high spatial precision. In healthy human volunteers, LIFU has demonstrated a favorable safety and tolerability profile across multiple studies. However, its safety and tolerability in clinical populations remains poorly characterized, representing a critical barrier to clinical translation. Here, we prospectively evaluate the safety and tolerability of LIFU targeting the left dorsal anterior insula (dAI) in patients with fibromyalgia (FM). Methods In a single-blind, sham-controlled, within-subjects crossover design, 13 individuals with FM (43.1 ± 13.2 years; 12 female) received 10 minutes of active LIFU (500 kHz, 1 kHz PRF, 36% duty cycle, 4.2 W/cm 2 Isppa; 100 × 1-second pulse trains with a 5-second inter-train interval) targeting the left dorsal anterior insula (dAI) or sham on separate visits. Safety was evaluated through neuroradiological review of post vs. pre LIFU FLAIR MRI, quantitative voxel-wise FLAIR analysis, and patient report of symptoms (ROS). Tolerability was assessed using an experience assessment. Efficacy of the LIFU intervention was assessed using quantitative sensory testing (QST) including temporal summation of pain (TSP) and conditioned pain modulation (CPM). Results Neuroradiological review identified no new evidence of edema, microhemorrhage, acute ischemia, or white matter injury on post-LIFU structural imaging. Quantitative FLAIR analysis using contralateral-mirror-referenced relative FLAIR (rFLAIR) showed no significant within-subject change in the stimulated beam volume (ΔrFLAIR = 0.002 ± 0.025, t(12) = 0.30, P = 0.769, Cohen’s d z = 0.08). No serious adverse events were documented and ROS indicated no change due to LIFU sonication. Participants rated the procedure as comfortable and could not distinguish active from sham LIFU. LIFU did not result in statistically significant changes for TSP (p = 0.797) or CPM (p = 0.465). Conclusions Ten minutes of LIFU targeting the left dAI was safe and well tolerated in individuals with FM, with no neuroradiological or quantitative MRI evidence of tissue effects and no serious adverse events. Blinding was preserved, and participants rated the procedure as comfortable. Although no significant changes were observed in experimental pain measures, these findings support the feasibility of targeting deep salience and pain amplification circuitry with LIFU in patients with FM and provide a foundation for adequately powered efficacy trials.

Abstract via europepmc.

Flags from extraction

• n_subjects — 19 participants enrolled; 13 completed the protocol and are recorded.
• exposures[0].device.family — Three transducers used: H-281 (9 participants) and H-104 (3), both Sonic Concepts, and a CTX-500 in one participant (which would be neurofus by the family rule). Recorded the majority maker.
• exposures[0].in_situ.pressure_kpa — Mean peak intracranial pressure from subject-specific k-Wave simulation (76.1 +/- 25.6 kPa); discussion also quotes 50-125 kPa in-head.
• exposures[0].timing.pulse_duration_ms — Pulse duration not stated for the in vivo waveform (duty cycle 36% at 1 kHz PRF); not computed.
• exposures[0].timing.sonication_duration_s — Sonication duration is the 1 s train; the full session is 100 trains with 5 s intervals.
• randomised — Order counterbalanced and allocation sequence generated before enrolment; the word randomised is not used.
• adverse_events — Symptoms newly rated moderate/severe at follow-up were observed but not attributed to LIFU by the authors.