Rapid cognitive-emotional responses to ultrasonic neuromodulation of anterior cingulate cortex in pain and depression
Brandon Cooper, Vincent Koppelmans, Thomas Riis, Daniel Feldman, Sarah Kwon, Patrick Brashear, Michael Guynn, Akiko Okifuji, Jan Kubanek, Brian Mickey
2026 · 10.21203/rs.3.rs-10503490/v1
Abstract
The anterior cingulate cortex (ACC) is a key brain center involved in cognitive and emotional processing that is implicated in a variety of neuropsychiatric disorders including chronic pain and depression. Circuit-targeted diagnosis and treatment of these disorders will require the capacity to precisely modulate ACC subregions. Toward that end, we recently developed and validated a novel low-intensity transcranial focused ultrasound device that can noninvasively and directly modulate ACC subdivisions in humans with millimeter precision. Here we describe the subjective reports of 36 individuals diagnosed with either chronic pain or major depression who received repeated brief stimulation trials (807 active, 797 sham; duration 30s-3min) spanning the dorsoventral extent of the ACC. Sonication immediately altered cognitive-emotional states (odds ratio 5.6, active versus sham), eliciting a positive-valence experience more often than negative (29% versus 8%) in both diagnostic groups. Sham-adjusted response rate varied across ACC targets, with the largest effects (Cohen’s d ~ 0.8) observed in pregenual and subgenual ACC in subjects with chronic pain and depression, respectively. These rapid trial-by-trial responses to ACC stimulation predicted subsequent improvements in pain and depression severity at 24 hours. Collectively, these findings reveal that transcranial ultrasound can robustly evoke immediate, target-specific, clinically meaningful changes in cognitive-emotional state, demonstrating the potential of ultrasonic neuromodulation as a tool for individualized probing of circuit function and dysfunction.
Abstract via europepmc.
Exposures
Exposure 1: LIFU to ACC subregions (sgACC, pgACC, dACC) in chronic pain and treatment-resistant depression cohorts
Target: subgenual anterior cingulate cortex, pregenual anterior cingulate cortex, dorsal anterior cingulate cortex — “anterior cingulate cortex (ACC) subdivisions: subgenual (sgACC), pregenual (pgACC), and dorsal ACC (dACC)”
Device: custom-built
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 650 | ✓✓✓ |
| Pulse duration (ms) | 5 | ✓✓✓ |
| Pulse repetition frequency (Hz) | 100 | ✓✓✓⚑ |
| Duty cycle (%) | 50pulse duration × PRF gives 50% | ✓? |
| 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 | deratingsingle value | |
| In-situ pressure (kPa) | 1,000 | ✓✓✓ |
| In-situ Isppa (W/cm²) | 31 | ✓✓✓ |
| In-situ Ispta (W/cm²) | not reported | ⚑ |
Individual brief stimulation trials ranged 30 seconds to three minutes, delivered over three sequential blocks per session and separated by short pauses (15-60 seconds) for subjective reporting; each treatment session lasted approximately 60 minutes with 39-44 cumulative trial minutes. Within each trial, 30-ms bursts (5 ms on/5 ms off, 50% pulse duty cycle) recurred at intervals of 0.7-1.4 s (burst duty cycle 2-4%), giving an overall duty cycle of 1-2% across the trial.
Flags from extraction
exposures[0].target— Chronic pain cohort was sampled across eight ACC targets (sgACC, pgACC, dACC) and the TRD cohort mainly across three sgACC subregions; pooled into one exposure with combined target terms since acoustic parameters were identical across targets and outcomes are reported per-parcel rather than per-exposure.exposures[0].timing.pulse_repetition_frequency_hz— PRF (100 Hz) derived directly from the stated on/off sub-pulse durations (5 ms on + 5 ms off = 10 ms period), a period-to-frequency unit conversion rather than independent arithmetic.exposures[0].timing.sonication_duration_s— The 30-ms burst is treated as the uninterrupted train; bursts recurred every 0.7-1.4 s within a longer 30 s-3 min trial (burst duty cycle 2-4%, overall duty cycle 1-2%), a nested structure described in protocol_description rather than the four numeric fields.exposures[0].in_situ.ispta_w_cm2— Paper states ISPTA was '< 720 mW/cm2' (an upper bound); recorded as 0.72 W/cm2.exposures[0].device— Device manufacturer/model not named in this paper; described only as 'a novel low-intensity transcranial focused ultrasound device' referencing prior publications (Riis et al., IEEE Trans Biomed Eng 2024; Commun Eng 2024).direction_of_effect— Study measured subjective cognitive-emotional valence and clinical scores, not a neurophysiological excitatory/inhibitory readout; classified as not_assessed.