Low-intensity focused ultrasound to the human dorsal anterior cingulate attenuates acute pain perception and autonomic responses.

Andrew Strohman, Brighton Payne, Alexander In, Katelyn Stebbins, Wynn Legon

The Journal of Neuroscience 2024, e1011232023 · 10.1523/jneurosci.1011-23.2023

human healthyhealthyeeg megautonomic physiologybehaviour

Abstract

The dorsal anterior cingulate cortex (dACC) is a critical brain area for pain and autonomic processing, making it a promising noninvasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to noninvasively modulate the dACC for effects on behavioral and cardiac autonomic responses using transient heat pain stimuli. A N = 16 healthy human volunteers (6 M/10 F) received transient contact heat pain during either LIFU to the dACC or Sham stimulation. Continuous electroencephalogram (EEG), electrocardiogram (ECG), and electrodermal response (EDR) were recorded. Outcome measures included pain ratings, heart rate variability, EDR response, blood pressure, and the amplitude of the contact heat-evoked potential (CHEP).LIFU reduced pain ratings by 1.09 ± 0.20 points relative to Sham. LIFU increased heart rate variability indexed by the standard deviation of normal sinus beats (SDNN), low-frequency (LF) power, and the low-frequency/high-frequency (LF/HF) ratio. There were no effects on the blood pressure or EDR. LIFU resulted in a 38.1% reduction in the P2 CHEP amplitude. Results demonstrate LIFU to the dACC reduces pain and alters autonomic responses to acute heat pain stimuli. This has implications for the causal understanding of human pain and autonomic processing in the dACC and potential future therapeutic options for pain relief and modulation of homeostatic signals.

Abstract via europepmc.

Specieshuman

Subjects16 participants

Sessions per subject1

Randomisednot reported

Blindingsingle

Sham / controlinactive transducer

Auditory controlmasking sound

Readout timingonline

Anaesthesianot applicable

Readoutseeg meg, autonomic physiology, behaviour — Pain ratings (0-9 numerical rating scale); contact heat-evoked potential (CHEP) N2 and P2 amplitudes; heart rate variability (SDNN, CV, MNN, RMSSD, pNN50, LF power, HF power, LF/HF ratio); electrodermal response; blood pressure

Direction of effectinhibitoryLIFU to the dACC reduced pain ratings by 1.09 points (30.3%), increased heart-rate-variability metrics (SDNN, LF power, LF/HF ratio) toward baseline, and reduced the CHEP P2 amplitude by 38.1% relative to Sham, consistent with an inhibitory effect on dACC pain/autonomic processing.

Adverse eventsobservedNo moderate or serious adverse events were reported for either condition; mild symptoms (e.g., headache, scalp sensations, neck pain, tooth pain, nausea for LIFU; unusual feelings, tingling, itching, sleepiness, inattentiveness, twitching, anxious feeling, balance issues for Sham) were reported.

Exposures

Exposure 1: LIFU to dorsal anterior cingulate cortex (dACC)

Target: dorsal anterior cingulate cortex — “dorsal anterior cingulate cortex (dACC, MNI [0,18,30])”
Device: Sonic Concepts · Sonic Concepts · H-104

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	500	✓✓✓
Pulse duration (ms)	0.36	✓✓✓
Pulse repetition frequency (Hz)	1,000	✓✓✓
Duty cycle (%)	36pulse duration × PRF gives 36%	✓✓✓
Sonication duration (s)	1	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	368.5	✓✓✓
Free-field Isppa (W/cm²)	4.34	✓✓✓
Free-field Ispta (W/cm²)	1.56	✓✓✓
In-situ estimate	simulationmean or range across subjects
In-situ pressure (kPa)	115.2	✓✓✓⚑
In-situ Isppa (W/cm²)	not reported
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

LIFU was time-locked to each contact heat pain stimulus, beginning 200 ms before contact heat onset and ending 800 ms after (1 s burst duration); 40 contact heat stimuli (0.3 s duration: 50 ms ramp up, 200 ms plateau, 50 ms ramp down) were delivered to the dorsum of the right hand with a random ISI of 10-20 s over a 10 min testing window.

Flags from extraction

randomised — Paper states participants were 'counterbalanced' for Sham vs LIFU order but never uses the word randomized for this assignment.
exposures[0].in_situ.pressure_kpa — Paper reports mean 115.2 +/- 53.1 kPa with a range of 66.3-287.4 kPa (Table 1); mean recorded per protocol, range in quote.