Low-Intensity Focused Ultrasound Neuromodulation for Tic Disorder Therapy: Preclinical Validation With Clinically Relevant Parameters

Tourette syndrome (TS) is typically treated with pharmacological therapies, which often induce tolerance. Recently, neuromodulatory therapies, such as deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), have emerged as alternatives for tic disorders. However, these modalities are constrained by invasiveness and insufficient spatial resolution. To address these limitations, we employed low-intensity focused ultrasound (LIFU), an emerging noninvasive therapeutic modality previously applied in various neurological disorders, and established effective stimulation parameters that alleviated tic-like movements. We developed a bicuculline-induced mouse model of tic disorder and validated tic-like features through analyses of electrophysiological brain signals, neural activities, and behavior. We further applied a LIFU stimulation with clinically relevant parameters using a 250-kHz ultrasound transducer. Ultrasound stimulation targeting the secondary motor cortex (M2) significantly reduced the frequency of tic-like movements and pathological electrophysiological spikes by 51% and 87%, respectively. These findings suggest that LIFU brain stimulation alleviates tic symptoms in a preclinical model of TS. Given the clinical compatibility of our stimulation parameters, this approach provides a robust basis for translational research toward human applications in tic disorder treatment.