Clarifying Order and Carry‐Over Considerations in Dual‐Target MRgFUS for Parkinson's Disease

We appreciate the thoughtful comments regarding our recent article, “Immediate Motor Control Enhancement via Pallidothalamic Tract (PTT) Circuit Ablation: A Dual-Target MR-Guided Focused Ultrasound Approach for Tremor-Dominant Parkinson's Disease” 1. We welcome this opportunity to address concerns regarding the possible influence of order effects and carry-over phenomena in our intraoperative design. All participants underwent ventral intermediate nucleus (VIM) ablation first, followed by PTT ablation within the same MRgFUS session. This sequence was deliberately selected based on safety and anatomical hierarchy. The VIM is a well-validated and relatively superficial target for tremor control, whereas the PTT lies deeper, adjacent to eloquent structures such as the Mammillothalamic tract (MTT) and subthalamic nucleus (STN). Performing VIM first ensured procedural safety, patient tolerance, and adequate acoustic transmission before proceeding to the deeper lesion. To mitigate potential sequence bias, clinical evaluations were performed immediately before and after each step (VIM evaluation → PTT evaluation), allowing within-subject comparison. Distinct temporal and domain-specific effects were observed: all tremor subtypes improved primarily after VIM, while rigidity improved most prominently after PTT. These differential response patterns argue against a non-specific additive or order-driven gain. We concur that transient edema or temperature-dependent conduction block may transiently influence immediate post-lesion testing. To minimize such effects, the VIM score used for analysis was obtained immediately before the first effective PTT sonication, with a latency of less than 10 min. Lesion overlap was also evaluated by post-op MRI, confirming confinement to the intended PTT zone. While our study design cannot fully exclude microlesional carry-over, the parameter-specific dissociation (rigidity versus tremor) and the consistency across subjects support target-specific physiological effects rather than generalized intraoperative augmentation. We fully agree that randomized or counterbalanced target order, standardized lesion metrics, and objective blinded kinematic assessments are essential to confirm causality. These refinements have already been incorporated into our upcoming multi-center trial, which will include a VIM-only intraoperative control arm to rigorously evaluate the incremental contribution of PTT lesioning. Our present study was intended as a physiological feasibility investigation, not as a definitive randomized comparison. In clinical practice, patients with Parkinson's disease frequently present with a mixed motor phenotype in which disabling tremor coexists with varying degrees of rigidity and bradykinesia. For such individuals, our standard treatment algorithm prioritizes VIM ablation as the initial intervention, given its well-established efficacy in tremor suppression. However, it is not uncommon for rigidity and bradykinesia to remain insufficiently improved following VIM targeting alone, particularly in patients whose symptom burden is not purely tremor-dominant. For these patients, our experience—and the data derived from the present cohort—indicate that additional lesioning of the PTT is a reasonable and evidence-supported next step. When applied in appropriately selected cases, stepwise PTT ablation in the same session appears to offer meaningful incremental benefit for rigidity as well as bradykinesia, without compromising safety. These observations suggest that a stepwise VIM-plus-PTT strategy may represent a practical and effective approach for managing mixed-phenotype PD patients who exhibit only partial motor response to VIM alone. We appreciate the reader's constructive critique, which will help further refine dual-target MRgFUS paradigms toward more mechanistically precise and clinically optimized therapies for Parkinson's disease. Sincerely, Jui-Cheng Chen: conceptualization, writing – original draft. The authors declare no conflicts of interest. Data sharing not applicable to this article as no datasets were generated or analyzed during the current study.