Modulation of the noradrenergic system using transcranial ultrasonic stimulation targeted to the brainstem locus coeruleus in awake mice
Emma Lescrauwaet, Robrecht Raedt, Tom Plovie, Sielke Caestecker, Bethany Stieve, Sara Neyt, Thomas Tarnaud, Emmeric Tanghe, Keith Murphy, Evelien Carrette, Paul Boon, Kristl Vonck
Neuropsychopharmacology 2026 · 10.1038/s41386-026-02576-y
Abstract
Transcranial ultrasound stimulation (TUS) is a novel neuromodulation technique that can be used to non-invasively target the locus coeruleus (LC). The LC provides the majority of noradrenergic input to the brain and has been implicated in several neurological and psychiatric disorders. Before translation to human studies, establishing a dose-response relationship requires systematic characterization of two distinct effects: (1) the influence of stimulation protocol variations on norepinephrine (NE) release in LC target structures, and (2) the broader brain and bodily effects of LC-targeted TUS. We used fiber photometry to measure TUS-induced activation of LC neurons and release of NE in one of its major projection areas, the hippocampus. To evaluate widespread functional effects, we investigated changes in [ 18 F]FDG uptake in the brain and body in response to LC-targeted TUS using small-animal PET imaging. Five-second trains of TUS resulted in intracellular calcium level increases in the LC, accompanied by a biphasic change in NE levels in the hippocampus and LC, i.e., an initial rise followed by a transient decrease. The same TUS protocol showed a decrease in [ 18 F]FDG uptake across the brain and a strong increase in [ 18 F]FDG uptake in brown adipose tissue. If TUS was prolonged to 30 s the initial biphasic change in hippocampal NE levels was followed by a secondary increase that persisted throughout the remainder of the stimulation period. This study provides the first demonstration that TUS can modulate the LC-NE system in awake mice. Adjusting the stimulation protocol resulted in distinct patterns of hippocampal NE release, highlighting the therapeutic potential of LC-targeted TUS as distinct stimulation protocols may differentially restore disrupted NE levels across disorders. PET imaging further revealed engagement of both central and peripheral systems, emphasizing the broad physiological reach of this approach.
Abstract via europepmc.
Exposures
Exposure 1: LC-targeted TUS (ON target) with OFF-target control 3 mm dorsal; intensity sweep and PRF/duration sweep
Target: locus coeruleus — “locus coeruleus (LC)”
Device: not reported · PhoCUS single-element ring transducer ✓
| Waveform | pulsed | |
|---|---|---|
| Fundamental frequency (kHz) | 515 | ✓✓✓ |
| Pulse duration (ms) | 80 | ✓✓✓⚑ |
| Pulse repetition frequency (Hz) | 0.5, 1, 2, 2.5swept | ✓✓✓⚑ |
| Duty cycle (%) | 20 | ✓✓✓⚑ |
| Sonication duration (s) | 5, 30swept | ✓✓✓⚑ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | not reported | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | not reported | |
| Isppa, domain unspecified (W/cm²) | 0.06, 2.55swept | ✓✓✓⚑ |
Main protocol: 515 kHz, 0.65 W/cm2 Isppa, 20% DC, 2.5 Hz PRF, 5 s pulse train repeated 15 times with a 3 min stimulus onset asynchrony. Sweeps: five intensities from 0.06 to 2.55 W/cm2 at 20% DC, 2.5 Hz, 5 s; and 30 s trains at 0.5, 1 and 2 Hz PRF with the duty cycle adjusted to keep pulses at 80 ms and Isppa 0.65 W/cm2.
Flags from extraction
exposures[0].unspecified_domain.isppa_w_cm2— Sweep recorded as [min, max]; the main protocol 0.65 W/cm2 and a 1.43 W/cm2 level fall between them. Domain not stated (calibrated in water with an implanted skull in the path).exposures[0].timing.duty_cycle_pct— 20% applies to the 2.5 Hz protocol; in the 30 s PRF sweep the duty cycle was adjusted per PRF and the values are not stated.exposures[0].timing.pulse_repetition_frequency_hz— List combines 2.5 Hz (main protocol) with 0.5, 1 and 2 Hz (sweep); quote covers the sweep sentence.exposures[0].timing.pulse_duration_ms— 80 ms stated for the PRF sweep; equals 20% of the 400 ms period of the main protocol (not stated directly).exposures[0].timing.sonication_duration_s— 5 s main protocol, 30 s in the PRF sweep; quote is the main protocol sentence.exposures[0].device.family— Transducer maker not named; custom matching network built by the authors, transducer origin only cited.auditory_control— Authors state an auditory contribution cannot be excluded and no deafening or masking was used.sham_type— OFF-target condition 3 mm dorsal still delivered about 61% of ON-target intensity at the LC.