Active contact proximity to the hyperdirect pathway is associated with bradykinesia response after STN DBS

The hyperdirect pathway (HDP) is a key cortico-subthalamic circuit implicated in the therapeutic effects of subthalamic nucleus (STN) deep brain stimulation (DBS) for Parkinson's disease (PD). Although HDP-related connectivity has been linked to motor benefit, it remains unclear whether clinically active contact proximity to the HDP is associated with global motor improvement or domain-specific responses. We evaluated whether active contact-to-HDP distance, measured using patient-specific tractography, was associated with lateralized motor outcomes following STN DBS.

We retrospectively analyzed patients with idiopathic PD who underwent STN DBS at a single center and had high-quality diffusion MRI, postoperative CT, documented stimulation parameters, and standardized motor assessments. Patient-specific HDP tractography was reconstructed using probabilistic methods. The shortest distance from the clinically active contact to the HDP was measured and associated with lateralized MDS-UPDRS III composite and domain-specific motor improvements using linear regression with robust standard errors clustered by patient to account for non-independence of bilateral hemispheres. Primary models were adjusted for preoperative levodopa equivalent daily dose (LEDD) and time since surgery. Exploratory sensitivity analyses incorporated total electrical energy delivered (TEED) to partially account for heterogeneity in stimulation parameters.

Eighteen patients contributing 31 hemispheres met inclusion criteria. Active contact-to-HDP distance was not significantly associated with improvement in composite motor scores, tremor, or rigidity. In contrast, shorter contact-to-HDP distance was significantly associated with greater bradykinesia improvement in the primary model (p = 0.006), and this association remained significant after exploratory adjustment for TEED and time since surgery (p = 0.007).

In this exploratory study, closer proximity of clinically active STN DBS contacts to the HDP was associated with greater bradykinesia improvement, but not with composite motor outcomes, tremor, or rigidity. These findings suggest that HDP proximity may capture a bradykinesia-relevant anatomical signal beyond differences in delivered stimulation energy alone. However, distance-based metrics do not directly quantify pathway engagement, and future studies incorporating patient-specific VTA or electric field modeling are needed to validate these findings.