Temporal interference stimulation for treating Wilson disease: A prospective clinical and functional MRI study

Wilson disease (WD) is an inherited disorder of copper metabolism caused by ATP7B mutations, and persistent neurological deficits, especially dystonia and motor disability, may remain despite standard anti-copper therapy. The putamen is a deep gray-matter nucleus frequently affected by copper deposition in WD and may therefore represent a plausible target for non-invasive neuromodulation. This prospective, single-arm, open-label study evaluated the clinical efficacy and neural mechanisms of right putamen-targeted temporal interference stimulation (TIS) in patients with WD. Twenty-five patients received right putamen-targeted TIS once daily for 10 sessions. Clinical outcomes were assessed using the Unified Wilson's Disease Rating Scale (UWDRS) total score and its neurological, hepatic, and psychiatric subscale scores. Resting-state functional magnetic resonance imaging (rsfMRI) was used to evaluate regional homogeneity (ReHo) and seed-based functional connectivity (FC) of the right putamen. Paired tests compared pre- and post-treatment changes, and Spearman correlation analysis examined associations between imaging changes and clinical improvement. After treatment, the UWDRS total score decreased significantly from 59.40 ± 30.54 to 44.12 ± 24.96, with concurrent improvements in neurological, hepatic, and psychiatric subscale scores. The rsfMRI analysis showed increased ReHo in the right putamen and enhanced FC between the right putamen and right Rolandic operculum. After correction for multiple comparisons, greater increases in right putamen ReHo correlated significantly with larger reductions in UWDRS total and neurological scores. In this exploratory study, these preliminary findings suggest that right putamen-targeted TIS may improve clinical symptoms in WD, potentially through enhanced local functional synchronization within the putamen.