Paradoxical targeting: Overlap between optimal and gait-impairment stimulation sites in essential tremor

Background Deep brain stimulation (DBS) is an effective treatment for medication-refractory essential tremor (ET), typically targeting the ventral intermediate nucleus (VIM), posterior subthalamic area (PSA), or dentato-rubro-thalamic tract (DRTT). However, up to one-third of patients develop gait impairment, possibly due to stimulation of unintended or overlapping pathways. This study investigated stimulation areas specifically linked to tremor improvement and gait impairment. Methods We retrospectively analyzed clinical data from 40 ET patients (80 hemispheres) treated with DBS. Tremor improvement was assessed with the Fahn-Tolosa-Marin (FTM) tremor rating scale and gait impairment was assessed with the first item of the Scale for Assessment and Rating of Ataxia (SARA). Volume of tissue activated (VTA) were modeled using Lead-DBS and voxel-wise associations were examined with Spearman-rank correlations. Mixed effects regression was used to evaluate clinical and stimulation-related covariates. Results Regions linked to both tremor reduction and gait impairment overlapped with the VIM, PSA, and DRTT (p < 0.05, FDR corrected). No distinct region was exclusively associated with gait impairment. Stimulation location was not statistically significant related to postoperative gait outcome. Patients with more severe baseline gait ataxia were more likely to deteriorate, although this association was not statistically significant after bootstrapping. Conclusion Our findings suggest that DBS may simultaneously engage therapeutic and adverse pathways within the DRTT. A potential somatotopic organization of the cortico-thalamo-cerebellar (CTC) network may underlie this overlap, though it could not be disentangled in this study. Future work integrating individual functional connectivity and tractography may help delineate specific pathways, enabling more precise targeting and improved outcomes for ET patients.