Background Transcranial ultrasound stimulation (TUS) with various parameters can modulate cortical excitability, but its neuromodulatory effects on excitability and behavior have not been consistently replicated across independent labs or compared within subjects. Objective To examine the neuromodulatory effects of four TUS protocols against sham on motor cortical excitability and inhibitory control. Methods Twenty-six healthy adults were enrolled to complete up to five sessions (four active TUS protocols and one sham); 24 completed all the five sessions, separated by at least one week. Motor evoked potentials (MEPs) were recorded at 20 min and 0 min before stimulation, and at 0, 20, and 40 min after stimulation. Stop-signal task (SST) performance was assessed before and after stimulation, and simultaneous EEG was recorded during the SST to extract event-related potentials (ERP). Linear mixed-effects models with false-discovery-rate correction were used for statistical analysis. Results The intermittent and continuous theta-burst TUS protocols (iTBUS/cTBUS), adapted from an animal protocol, produced excitatory and inhibitory MEP effects, respectively, that were directionally consistent with the effects commonly associated with iTBS- and cTBS-patterned TMS; however, this physiological similarity did not translate into the expected behavioral outcomes. The excitatory effects of two TUS protocols on motor cortex were replicated, yet MEPs and ERP changes were associated with divergent SST outcomes. ERP analysis showed that cTBUS significantly reduced P3 amplitudes, whereas other protocols produced no significant group-level ERP changes. Conclusion The bidirectional iTBUS/cTBUS effects observed here provide preliminary human evidence partially consistent with observations from animal models, although mechanistic equivalence and full translational validity across species remain to be established. The excitatory effects observed with two previously described TUS protocols were directionally consistent with earlier reports. Nevertheless, TUS-induced MEP facilitation does not necessarily enhance inhibitory control in the SST, underscoring the need for task-specific multimodal frameworks to advance TUS as a precise neuromodulation technique.
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