Focused Ultrasound Modulates Dopamine in a Mesolimbic Reward Circuit

Greatness Olaitan, Mallikarjunarao Ganesana, Andrew Strohman, Wendy J. Lynch, Wynn Legon, B. Jill Venton

Journal of Neurochemistry 2025, 169 · 10.1111/jnc.70001

rodenthealthyotherhistology molecular

Abstract

Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low-intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm 2 I SPPA ) of 2-min LIFU to the prelimbic cortex (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast-scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm 2 to the PLC significantly reduced dopamine release by ~50% for up to 2 h. However, double the intensity (26 W/cm 2 ) resulted in less inhibition (~30%), and half the intensity (6.5 W/cm 2 ) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm 2 , suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases.

Abstract via europepmc.

Speciesrat (Sprague-Dawley)

Subjects38 animals

Sessions per subject1

Randomisedno

Blindingnot reported

Sham / controlinactive transducer, active control site

Auditory controlnot reported

Readout timingboth

Anaesthesiaanaesthetised

Readoutsother, histology molecular — Fast-scan cyclic voltammetry (FSCV) via carbon-fiber microelectrode measuring electrically-evoked dopamine release in the NAc core (and control regions: caudate-putamen, NAc shell); H&E histology for cell damage/death assessment

Direction of effectinhibitory2-min LIFU sonication of the PLC at 13 W/cm2 ISPPA inhibited electrically-evoked dopamine release in the NAc core by ~50% for up to 2 h; 26 W/cm2 produced less inhibition (~30%) and 6.5 W/cm2 produced no significant inhibition, i.e. a non-monotonic (U-shaped) intensity-response. Effects were anatomically/circuit specific (no change with LIFU to S1J-NAc core, or PLC-CP/PLC-NAc shell).

Adverse eventsnone observedH&E histology showed no significant cell damage or death in sonicated PLC tissue at any tested intensity (6.5, 13, 26 W/cm2) versus no-LIFU controls; Pennes bioheat modelling predicted maximum brain temperature rises of only 0.2-0.9 degC across intensities, below thermal-mechanism thresholds and within natural brain temperature fluctuation.

Exposures

Exposure 1: LIFU to prelimbic cortex (PLC), dopamine recorded in NAc core

Target: prefrontal cortex — “prelimbic cortex (PLC) of the medial prefrontal cortex (dmPFC)”
Device: Olympus / Panametrics · Olympus-ims · XMS-310-B miniature-case immersion transducer ✓

Pulse timing
Waveform	pulsed
Fundamental frequency (kHz)	10,000	✓✓✓
Pulse duration (ms)	0.36	✓✓✓⚑
Pulse repetition frequency (Hz)	1,000	✓✓✓
Duty cycle (%)	36pulse duration × PRF gives 36%	✓✓✓
Sonication duration (s)	120	✓✓✓

Pressure and intensity, by domain
Free-field pressure (kPa)	not reported
Free-field Isppa (W/cm²)	not reported
Free-field Ispta (W/cm²)	not reported
In-situ estimate	measurementsingle value
In-situ pressure (kPa)	470, 710, 1,060swept	✓?⚑
In-situ Isppa (W/cm²)	6.5, 13, 26swept	✓?
In-situ Ispta (W/cm²)	not reported

Protocol, in the paper’s words

500 ms pulse trains of 500 pulses each (1 kHz PRF, 360 microsecond/36% duty-cycle pulses), with pulse trains separated by a 4.5-s interval for a total of 24 pulse trains (pulse train repetition frequency 0.1 Hz, pulse train duty cycle 3.6%), giving a 120-s total sonication duration delivered once through a burr hole over the PLC. Baseline ISPPA was 13 W/cm2 (0.71 MPa, MI 0.44); separate conditions halved (6.5 W/cm2, 0.47 MPa, MI 0.29) or doubled (26 W/cm2, 1.06 MPa, MI 0.65) this intensity.

Flags from extraction

exposures[0].in_situ.pressure_kpa — Intensity/pressure were calibrated in a water tank (hydrophone + voltage sweep) and then described as 'delivered to the target'; transducer was applied through a burr hole with no intervening skull, so free-field vs in-situ is not explicitly distinguished by the authors. Recorded as in_situ (method=measurement) because the paper frames the values as delivered to the target; could equally be read as free-field.
exposures[0].timing.pulse_duration_ms — Two-level burst structure (360 microsecond pulses at 1 kHz PRF forming 500 ms pulse trains, pulse trains repeated at ~0.1-0.2 Hz for 120 s total); pulse_duration/PRF/duty_cycle here describe the inner pulse level, consistent with the stated 36% PDC = 0.36 ms x 1000 Hz.
exposures[0].target.terms — Paper interchangeably calls the target the prelimbic cortex (PLC) and dmPFC; mapped to prefrontal_cortex as the most specific available vocabulary term.