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.