Deep cerebellar tFUS engages cortical circuits via convergent local and sensory-driven mechanisms
Transcranial focused ultrasound (tFUS) enables non-invasive access to deep brain structures with high spatial precision, but its mechanisms of action remain elusive and under active investigation. The leading hypothesis posits that tFUS exerts its neuromodulatory effects through direct activation of neurons, while others attribute effects to indirect activation of auditory pathways. Here, we investigated the neuromodulatory effects of tFUS on the dentato- thalamo-cortical (DTC) pathway by targeting either the lateral cerebellar nucleus (LCN) or auditory cortex (AUD) in anesthetized rats. Electroencephalography (EEG) recordings from bilateral motor cortices and the contralateral auditory cortex revealed that tFUS reliably evoked cortical potentials, whereas sham stimulation produced no responses. Both LCN and AUD stimulation activated the auditory cortex, suggesting auditory pathway involvements. However, only LCN stimulation elicited early and significant event-related potentials and gamma-band activity in the contralateral motor cortex, consistent with DTC pathway engagement. We propose that LCN-targeted stimulation engages the DTC pathway through modulation of neuronal excitability, while concurrent auditory inputs account for global cortical activation. These results are consistent with a hybrid mechanism in which tFUS modulates neuronal dynamics, converging both direct and indirect components depending on the stimulation site. Proposed framework reconciles competing views of tFUS as either a direct or indirect modulator and clarifies how ultrasound can differentially influence cortical circuits depending on the stimulation target.