Low-intensity transcranial ultrasound effects on the ventral intermediate nucleus and zona incerta in Parkinson's disease tremor

BACKGROUND: Tremor in Parkinson's disease (PD) is a disabling symptom that often persists despite pharmacological treatment. High-intensity focused ultrasound (HIFU) targeting the ventral intermediate nucleus (VIM) alleviates Essential Tremor, but recent evidence suggests the zona incerta (ZI) may be a superior target for Parkinsonian tremor. This study compared the effects of transcranial ultrasound stimulation (TUS) to the VIM and ZI on postural and rest tremor, and examined related neural correlates using resting-state fMRI (rs-fMRI). METHODS: In this within-subject, crossover study, 19 participants with PD and right-hand tremor received both left VIM- and ZI-TUS on the same day in randomized order, separated by a 4-h washout period. Tremor severity and rs-fMRI data were collected before and after each session. Normalized changes in tremor intensity, resting-state functional connectivity (Δrs-FC), and fractional amplitude of low-frequency fluctuations (ΔfALFF) within the cerebello-thalamo-cortical network were analysed. RESULTS: TUS effects differed by target and tremor type. VIM-TUS significantly reduced postural tremor (p < 0.001) but not rest tremor, whereas ZI-TUS improved both postural (p = 0.005) and rest (p = 0.005) tremor. Although no overall group-level rs-FC changes were observed, individual Δrs-FC of the ZI following ZI-TUS correlated with tremor improvement (postural: r = 0.762, p < 0.001; rest: r = 0.586, p = 0.008), with similar findings for ΔfALFF. CONCLUSION: ZI-TUS modulates tremor more robustly than VIM-TUS, suggesting that ZI may be a promising target for treatment of Parkinsonian tremor.