Noninvasive targeted modulation of pain circuits with focused ultrasonic waves

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.

Trial registration: ClinicalTrials.gov NCT05674903.

Figure 1.

Experimental setup for noninvasive deep brain modulation of chronic pain. (A) The trial design showing randomization to MRI T1 and 10-minute fMRI measure of either active or sham stimulation followed by the first 40-minute ultrasound treatment session outside the MRI scanner, 7-day monitoring, washout, second treatment session outside the MRI scanner, and 7-day monitoring. There were 20 (20) data points available for the active (sham) conditions. See the CONSORT diagram in Supplemental Figure 1 (available at http://links.lww.com/PAIN/C85) for details. (B) Transcranial low-intensity focused ultrasound was delivered into the ACC target using a device described previously.^– (C) The ACC targeting was validated using MRI.^,, Since the ACC is a large structure with respect to the ultrasound focus (2.4 mm × 3.6 mm × 20.4 mm), we targeted 8 ACC subregions, indicated by the white crosses. The green crosshair exemplifies the targeting of one of the subregions. The pink regions outline the corresponding >50% peak intensity focal volume of the ultrasound. ACC, anterior cingulate cortex; fMRI, functional MRI.

Figure 2.

Rapid changes in pain intensity following ultrasonic modulation of the ACC. Mean ± SEM change in NRS scores in response to sham (orange) and active (blue) stimulation of the ACC, relative to the NRS scores before intervention. The individual data points are provided as colored circles. ***P = 0.00013, Wilcoxon signed-rank test. ACC, anterior cingulate cortex; NRS, numerical rating scale.

Figure 3.

Durable changes in pain intensity following ultrasonic modulation of the ACC. Mean ± SEM change in NRS scores relative to baseline NRS scores taken before each intervention. The effects were measured for up to 7 days (abscissa). Data are provided separately for the active (blue) and sham (orange) stimulation. The dashed line represents a pain reduction level that is considered clinically meaningful. The stars denote significant differences between the active and sham effects (*P < 0.05, **P < 0.01; Bonferroni–Holm-corrected for multiple comparisons). ACC, anterior cingulate cortex; NRS, numerical rating scale.

Figure 4.

Response rates. Same format as in Figure 3, now showing the proportion of subjects who attained greater than 33% (A) and greater than 50% (B) reduction in pain intensity.

Figure 5.

Change in PROMIS pain intensity scores at day 7 following ultrasonic modulation of the ACC. Mean ± SEM changes in the PROMIS scores at day 7 following the stimulation, relative to PROMIS scores before the stimulation. The dashed line provides the level of clinically meaningful reduction in pain. **P = 0.0014, Wilcoxon signed-rank test. ACC, anterior cingulate cortex; PROMIS, Patient-Reported Outcomes Measurement Information System.

Figure 6.

Target engagement. Data for all subjects that received active stimulation subgenual ACC (left panel): subject 17 (cluster-level P < 0.0001; false discovery rate corrected, k_E = 369 voxels), subject 2 (cluster-level P < 0001; false discover rate corrected, k_E = 414), subject 21 (cluster-level P < 0.0001; false discovery rate corrected, k_E = 5791 voxels), subject 5 (signal inclusion P < 0.005; cluster-level P = 0.016; false discovery rate corrected, k_E = 183 voxels). aMCC (right panel): subject 19 (cluster-level P < 0.0001; false discovery rate corrected, k_E = 1344 voxels), subject 4 (cluster-level P < 0.0001; false discovery rate corrected, k_E = 1992 voxels), subject 8 (cluster-level P = 0.034; uncorrected, k_E = 47 voxels). Subjects 7 and 9 did not show significant activation at the target region. Group analysis was nonsignificant for both targets. ACC, anterior cingulate cortex; aMCC, anterior midcingulate cortex.