Modulating Brain Perfusion, Functional Connectivity, and Metabolite Patterns through Theta Burst Transcranial Ultrasonic Stimulation
Daniel Keeser, Lukas Roell, Veronica Meedt, Maximilian Haßlberger, Maxim Korman, Enrico Schulz, Maximilian Lueckel, Berkhan Karsli, Genc Hasanaj, Theresa Faeßler, Gizem Vural, Kai-Yen Chang, Lucia Bulubas, Frank Padberg, Florian Raabe, Peter Falkai, Til Ole Bergmann, Boris-Stephan Rauchmann
2025 · 10.1101/2025.06.25.661571
Abstract
Background Transcranial ultrasonic stimulation (TUS) is an emerging non-invasive neuromodulation technique with the potential to target both cortical and subcortical brain regions. This study investigates the effects of theta-burst TUS (tb-TUS), a neuromodulatory pattern characterized by bursts of pulses repeated at a theta frequency, on cerebral blood flow, functional connectivity, and metabolite concentrations in the primary motor cortex (M1). The aim of this study is to take a first step towards the mechanistic and methodological feasibility of tb-TUS at the M1 using multimodal neuroimaging. Methods Seventeen healthy participants underwent a double-blind, sham-controlled crossover design, receiving both active and sham tb-TUS to the left M1 over three days. Multimodal MRI, including pseudo-continuous arterial spin labeling (PCASL), resting-state functional MRI (rs-fMRI), and magnetic resonance spectroscopy (MRS), was conducted at baseline, pre-, and post-stimulation. Acoustic simulations and finger-tapping BOLD-peak signal guided individualized TUS targeting. Results Active tb-TUS significantly reduced cerebral blood flow (p Conclusion This pilot study demonstrates that tb-TUS of the M1 induces reductions in cerebral blood flow and functional connectivity in healthy participants. Our findings indicate that tb-TUS may be mitigating neural hyperactivity patterns, but preliminary studies so far arrive at differing results, highlighting the need for further research to replicate our findings, elucidate the underlying mechanisms, and optimize stimulation protocols.
Abstract via europepmc.
Exposures
Exposure 1: Theta-burst TUS to left M1 (active) vs left ventricle (sham)
Target: primary motor cortex — “left primary motor cortex”
Device: NeuroFUS · Sonic Concepts (sold by Brainbox) · NeuroFUS PRO - CTX-500 ✓
| Waveform | theta burst | |
|---|---|---|
| Fundamental frequency (kHz) | 500 | ✓✓✓ |
| Pulse duration (ms) | not reportedimplied by duty cycle ÷ PRF: 20 ms (not stated by the paper) | ⚑ |
| Pulse repetition frequency (Hz) | 5 | ✓✓✓ |
| Duty cycle (%) | 10 | ✓✓✓ |
| Sonication duration (s) | 80 | ✓✓✓ |
| Free-field pressure (kPa) | not reported | |
|---|---|---|
| Free-field Isppa (W/cm²) | not reported | |
| Free-field Ispta (W/cm²) | not reported | |
| In-situ estimate | simulationsingle value | |
| In-situ pressure (kPa) | not reported | |
| In-situ Isppa (W/cm²) | not reported | |
| In-situ Ispta (W/cm²) | 0.62, 0.72swept | ✓✓✓⚑ |
| Isppa, domain unspecified (W/cm²) | 6.2, 7.2swept | ✓✓✓ |
Theta-burst TUS (bursts of pulses repeated at a theta frequency, typically around 5 Hz) to the left M1, individually targeted with neuronavigation and acoustic simulation; sham aimed at the left ventricle. Sonication parameters are in supplemental Table S1, not in the main text.
Flags from extraction
exposures[0].in_situ.ispta_w_cm2— Stated as 620-720 mW/cm2; recorded as [0.62, 0.72] W/cm2 (unit conversion only). It is the simulated intracranial ISPTA target window for the active condition.exposures[0].timing.pulse_duration_ms— Pulse, PRF, duty cycle and duration are in supplemental Table S1 only.sham_type— Sham is real ultrasound focused in the left ventricle with a deeper focus and lower ISPTA, hence active_control_site.n_sessions_per_subject— Active and sham sessions over three days; number of stimulation sessions not stated explicitly.auditory_control— Transducer position and orientation kept identical to avoid differential auditory confounds; no masking sound reported.