Noninvasive neuromodulation of subregions of the human insula differentially affect pain processing and heart-rate variability: a within-subjects pseudo-randomized trial
Wynn Legon, Andrew Strohman, Alexander In, Brighton Payne
Pain 2024 · 10.1097/j.pain.0000000000003171
Abstract
The insula is an intriguing target for pain modulation. Unfortunately, it lies deep to the cortex making spatially specific noninvasive access difficult. Here, we leverage the high spatial resolution and deep penetration depth of low-intensity focused ultrasound (LIFU) to nonsurgically modulate the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact heat-evoked potentials, as well as autonomic measures including heart-rate variability (HRV). In a within-subjects, repeated-measures, pseudo-randomized trial design, 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, electrodermal, electrocardiography and EEG recording. Low-intensity focused ultrasound was delivered to the AI (anterior short gyrus), PI (posterior longus gyrus), or under an inert Sham condition. The primary outcome measure was pain rating. Low-intensity focused ultrasound to both AI and PI similarly reduced pain ratings but had differential effects on EEG activity. Low-intensity focused ultrasound to PI affected earlier EEG amplitudes, whereas LIFU to AI affected later EEG amplitudes. Only LIFU to the AI affected HRV as indexed by an increase in SD of N-N intervals and mean HRV low-frequency power. Taken together, LIFU is an effective noninvasive method to individually target subregions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus.
Abstract via europepmc.
Exposures
Exposure 1: Left anterior insula
Target: anterior insula — “left AI (anterior short gyrus)”
Device: Sonic Concepts · Sonic Concepts · H-281 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 360 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1,000 | ✓✓✓ |
| Duty cycle (%) | 36pulse duration × PRF gives 36000%, which disagrees with the stated value | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | 400 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | 3.5 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 179.3 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
1 kHz gated burst (N=1000) giving a 1.0 s waveform, time-locked to start 200 ms before each of 40 contact heat stimuli delivered at random 12-20 s intervals.
Consistency checks: pd exceeds period.
Exposure 2: Left posterior insula
Target: posterior insula — “left PI (posterior longus gyrus)”
Device: Sonic Concepts · Sonic Concepts · H-281 ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | 360 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 1,000 | ✓✓✓ |
| Duty cycle (%) | 36pulse duration × PRF gives 36000%, which disagrees with the stated value | ✓✓✓ |
| Sonication duration (s) | 1 | ✓✓✓ |
| Free-field pressure (kPa) | 400 | ✓✓✓ |
|---|---|---|
| Free-field Isppa (W/cm²) | 3.5 | ✓✓✓ |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationmean or range across subjects | |
| In-situ pressure (kPa) | 263.5 | ✓✓✓⚑ |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported |
1 kHz gated burst (N=1000) giving a 1.0 s waveform, time-locked to start 200 ms before each of 40 contact heat stimuli delivered at random 12-20 s intervals.
Consistency checks: pd exceeds period.
Flags from extraction
exposures[0].timing.pulse_duration_ms— Text reads 'pulse width of 360 milliseconds' with a 1 kHz burst and 36% duty cycle, which is incompatible; probably 360 microseconds. Recorded as written.exposures[0].unspecified_domain.pressure_kpa— Pressure 'outside the head' (400 kPa peak negative, 3.5 W/cm2 Isppa); medium not stated, left unspecified.exposures[0].in_situ.pressure_kpa— Simulated (k-Wave, individual CT/MR) mean +/- SD across participants.exposures[1].timing.pulse_duration_ms— Text reads 'pulse width of 360 milliseconds' with a 1 kHz burst and 36% duty cycle, which is incompatible; probably 360 microseconds. Recorded as written.exposures[1].unspecified_domain.pressure_kpa— Pressure 'outside the head' (400 kPa peak negative, 3.5 W/cm2 Isppa); medium not stated, left unspecified.exposures[1].in_situ.pressure_kpa— Simulated (k-Wave, individual CT/MR) mean +/- SD across participants.adverse_events— 'No severe AE or symptoms were reported'; mild symptoms such as sleepiness were reported.