Noninvasive targeted modulation of pain circuits with focused ultrasonic waves
Thomas S. Riis, Daniel A. Feldman, Adam J. Losser, Akiko Okifuji, Jan Kubanek
Pain 2024, 165, 2829-2839 · 10.1097/j.pain.0000000000003322
Abstract
Direct interventions into deep brain circuits constitute promising treatment modalities for chronic pain. Cingulotomy and deep brain stimulation targeting the anterior cingulate cortex have shown notable improvements in the unpleasantness of pain, but these interventions require brain surgeries. In this study, we have developed an approach that can modulate this deep brain affective hub entirely noninvasively, using low-intensity transcranial-focused ultrasound. Twenty patients with chronic pain received two 40-minute active or sham stimulation protocols and were monitored for one week in a randomized crossover trial. Sixty percent of subjects experienced a clinically meaningful reduction of pain on day 1 and on day 7 following the active stimulation, while sham stimulation provided such benefits only to 15% and 20% of subjects, respectively. On average, active stimulation reduced pain by 60.0% immediately following the intervention and by 43.0% and 33.0% on days 1 and 7 following the intervention. The corresponding sham levels were 14.4%, 12.3%, and 6.6%. The stimulation was well tolerated, and no adverse events were detected. Side effects were generally mild and resolved within 24 hours. Together, the direct, ultrasonic stimulation of the anterior cingulate cortex offers rapid, clinically meaningful, and durable improvements in pain severity.
Abstract via europepmc.
Exposures
Exposure 1: ACC stimulation (8 subregions: subgenual ACC and pACC-to-aMCC)
Target: anterior cingulate cortex, subgenual anterior cingulate cortex — “anterior cingulate cortex (ACC): 2 targets within subgenual ACC (Brodmann Area 25) and 6 targets from pACC to aMCC (Brodmann Areas s24, p24, a24, 33)”
Device: not reported
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 5 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1.42 | ✓✓✓ |
| Duty cycle (%) | 50pulse duration × PRF gives 0.71%, which disagrees with the stated value | ✓✓✓ |
| Sonication duration (s) | 30, 180swept | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | measurementsingle value | |
| In-situ pressure (kPa) | 1,000 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 31 | ✓✓✓ |
| In-situ Ispta (W/cm²) | 0.66 | ✓✓✓ |
Treatment consisted of 2 blocks: Block A contained sixteen 30-second stimulations across 8 targets (each stimulated twice) to test for immediate symptom reduction, with verbal pain reports taken 15-60 s between sonications; the 4 targets with strongest reduction were selected for Block B, which delivered twelve 3-minute sonications randomly interleaved, again spaced by 15-60 s. Each sonication used a 30 ms burst duration containing 5 ms on/5 ms off pulses (duty cycle 50%), with bursts separated by a 0.7 s burst interval (labeled PRF = 1.42 Hz); it is unclear whether pulse_duration should be the 30 ms burst or the 5 ms sub-pulse given the stated duty cycle and PRF do not arithmetically reconcile.
Flags from extraction
n_subjects— Abstract states twenty patients; Methods/Results state 23 patients recruited, with 20 active and 20 sham data points available for analysis; 2 subjects who started in sham never crossed over to active.exposures[0].timing.pulse_duration_ms— Paper states a 30 ms burst duration containing 5 ms on/5 ms off sub-pulses (duty cycle 50%) separated by a 0.7 s burst interval labeled PRF = 1.42 Hz; duty_cycle/PRF does not arithmetically match either the 30 ms or 5 ms duration, so which duration is 'the pulse' cannot be resolved from the text.exposures[0].device— This paper does not restate the device manufacturer/model; it references a device described in prior publications.exposures[0].target— 8 discrete targets spanning subgenual ACC and pACC-to-aMCC were stimulated; the most specific single/paired target IDs were chosen to represent this span.