Non-invasive modulation of the human dorsal anterior cingulate attenuates acute pain perception and homeostatic cardiovascular responses

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

2023 · 10.1101/2023.06.30.547251

human healthyhealthyeeg megautonomic physiologybehaviour

Abstract

Homeostasis is the process of maintaining physiologic balance in the body that is critical for maintaining health and is dysfunctional in several disorders like chronic pain. The dorsal anterior cingulate cortex (dACC) is a critical brain area for homeostatic cardiovascular responses and pain processing, making it a promising non-invasive therapeutic target. We leverage the high spatial resolution and deep focal lengths of low-intensity focused ultrasound (LIFU) to non-invasively modulate the dACC for an effect on behavioral and cardiac autonomic responses using a transient heat pain stimulus. N = 16 healthy human volunteers (6M/10F) 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 perceived pain ratings, homeostatic measures including heart-rate variability, blood pressure, EDR response as well as the amplitude of the contact heat-evoked potential (CHEP). LIFU reduced pain ratings by 1.08 ± 0.21 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 blood pressure or EDR. LIFU resulted in a 25.1% reduction in the N1-P1 CHEP amplitude driven primarily by effects on the P1 amplitude. Our results demonstrate LIFU to the dACC reduces perceived pain and alters homeostatic cardiovascular responses to a transient heat pain stimulus. These results have implications for the causal understanding of human pain and autonomic processing in the dACC and the potential for future therapeutics for pain relief and homeostatic modulation. SIGNIFICANCE STATEMENT New lines of inquiry now demonstrate cardiac homeostatic signals like heart rate variability (HRV) are aberrant in mental health disorders, addiction, and chronic pain and may contribute to their underlying etiology. The dorsal anterior cingulate cortex (dACC) is a key homeostatic center with direct influences on cardiovascular autonomic function, but its depth precludes direct access without invasive surgery. For the first time in humans, we demonstrate low-intensity focused ultrasound (LIFU) can non-invasively and selectively modulate the dACC to reduce acute pain perception and homeostatic cardiovascular responses as well as pain processing signals. This work helps establish a causal role of the dACC in pain perception and homeostatic signaling with potential future clinical applications in chronic pain and neuropsychological populations.

Abstract via europepmc.

Specieshuman

Subjects16 participants

Sessions per subject1

Randomisedyes

Blindingnot reported

Sham / controlundescribed

Auditory controlmasking sound

Readout timingonline

Anaesthesianot applicable

Readoutseeg meg, autonomic physiology, behaviour — contact heat-evoked potential (CHEP, N1-P1 amplitude); heart rate variability (SDNN, RMSSD, pNN50, CV, LF/HF power); blood pressure; electrodermal response (EDR); pain ratings (0-9 numerical rating scale)

Direction of effectinhibitoryLIFU to the dACC reduced pain ratings and the CHEP N1-P1 peak-to-peak amplitude (driven by P1) relative to Sham, and increased heart-rate-variability measures (SDNN, CV, LF power, LF/HF ratio) towards pre-task baseline, consistent with the authors' hypothesised inhibitory effect on the dACC.

Adverse eventsobservedFor the LIFU condition, one participant reported a mild headache, one reported mild unusual scalp sensations, two reported mild neck pain, one reported mild tooth pain, and one reported mild nausea. For the Sham condition, mild unusual feelings, tingling, itching, sleepiness, inattentiveness, twitching, anxious feeling, and balance issues were each reported by one to three participants. No moderate or serious adverse events were reported for either condition.

Exposures

Exposure 1: LIFU to the dorsal anterior cingulate cortex (dACC), time-locked to contact heat pain

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)	370	✓✓✓⚑
Free-field Isppa (W/cm²)	4.5	✓✓✓
Free-field Ispta (W/cm²)	1.62	✓✓✓
In-situ estimate	simulationmean or range across subjects
In-situ pressure (kPa)	60.13	✓✓✓
In-situ Isppa (W/cm²)	not reported
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

Channel 1 was a 5Vp-p square wave burst of 1kHz (N = 1000) with a 36% duty cycle used to gate channel 2 that was a 500 kHz sine wave. This resulted in a 1 second waveform of 1000 pulses of 360 microseconds. LIFU delivery was time-locked to the CHEP stimulus, beginning at -200 ms (prior to stimulus) and ending at +800 ms after heat stimulus delivery. A total of 40 such LIFU/CHEP trials were delivered per session, with a random inter-stimulus interval of 10-20 seconds between trials.

Flags from extraction

sham_type — The paper never describes the physical mechanism of the Sham condition (e.g. transducer off, angled away, etc.); classified as 'other' pending that detail.
blinding — Participants were counterbalanced across Sham/LIFU sessions and auditory-masked, but the paper does not explicitly state whether participants or experimenters were blinded to condition.
n_sessions_per_subject — Design used one crossover session with real LIFU and one separate session with Sham (2 formal testing sessions total); n_sessions_per_subject here counts only the session in which active LIFU was delivered.
exposures[0].free_field.pressure_kpa — The 370 kPa 'extracranial' pressure is a simulation/model output (matched to empirical free-water field mapping), not a direct free-water hydrophone measurement of this exact value; placed in free_field since it represents pressure prior to transcranial transmission.
exposures[0].timing.pulse_duration_ms — Burst-rule check: duty cycle (36%) / PRF (1000 Hz) = 0.36 ms, matching the stated '360 microsecond' pulse length, so no conflict; recorded directly from the stated 360 microsecond value.