Transcranial ultrasound stimulation of motor networks in Parkinson's disease informed by local field potential dynamics.
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Transcranial ultrasound stimulation (TUS) is a promising noninvasive technique for modulating deep brain targets and circuits with high spatial precision. For its successful clinical translation, confirmation of target engagement, together with a deeper understanding of the effects of TUS, is essential. To advance these goals, we obtained direct measures of neural activity using electrodes implanted in the subthalamic nucleus (STN) in patients with Parkinson's disease (PD) during TUS of deep and superficial targets, guided by magnetic resonance imaging-based acoustic modeling and real-time neuronavigation. Seventeen patients were studied in the on-medication and off-deep brain stimulation states. Each patient received one active and one sham session in a randomized order, and 13 of 17 patients (76%) completed a third session, which was always active. Each active condition targeted a single site-either the primary motor cortex (M1), the globus pallidus internus (GPi), or the occipital cortex (control site)-with 10 patients per active target. TUS effects on the STN were found to be target specific. Stimulation of the M1 reduced STN beta oscillation activity compared with sham stimulation and was associated with improvements in motor signs. These effects were brain state specific, showing distinct modulation patterns at rest versus during movement. In contrast, TUS targeting the GPi increased beta activity relative to control conditions and did not improve motor signs. Our results provide mechanistic evidence that TUS can safely and selectively modulate pathological brain rhythms in the STN in PD, supporting its potential as a targeted, noninvasive therapeutic modality.