Efficacy and safety of a novel directional deep brain stimulation system from China in the treatment of Parkinson’s disease

To the Editor: Deep brain stimulation (DBS) is an established therapy for managing advanced Parkinson’s disease (PD), commonly targeting the subthalamic nucleus (STN) or globus pallidus internus (GPi). Although traditional omnidirectional electrodes effectively alleviate symptoms, they can inadvertently stimulate adjacent structures, resulting in side effects such as dysarthria and paresthesia, which may hinder optimal clinical outcomes. Directional electrodes, using segmented technology, address this limitation by enabling precise “current steering” for targeted stimulation, thereby reducing side effects.[1] Although global studies have shown promising results with directional DBS, its clinical application in China, particularly in GPi-targeted therapy, remains limited. This study evaluates the safety and efficacy of a novel Chinese directional DBS system, focusing on its performance in both GPi and STN targets. This multicenter, prospective, open-label, nonrandomized trial was registered on ClinicalTrials.gov (NCT05992701) and received approval from the institutional review boards of all participating centers. Informed consent was obtained from each participant. Eligible participants were aged 18–75 years with idiopathic PD, Hoehn and Yahr stage ≥2.5, and symptoms inadequately controlled by medication. Exclusion criteria included prior lesioning surgery, cognitive impairment (mini-mental state examination [MMSE] ≤17 for individuals with primary education or ≤24 for those with higher education), and severe comorbid medical conditions. The sample size calculation was based on achieving a 65% success rate in attaining a wider therapeutic window (TW) with directional stimulation, compared to a 50% success threshold. To account for a 10% attrition rate, the study aimed to enroll a minimum of 26 participants, targeting at least 24 completers. Between July 28, 2021, and November 13, 2023, 32 patients provided informed consent and were assessed for eligibility across nine centers. Six patients were excluded after further evaluation for not meeting inclusion criteria or meeting exclusion criteria, with detailed reasons provided in Supplementary Table 1, https://links.lww.com/CM9/C508. Ultimately, 26 patients met the inclusion criteria, and 25 underwent DBS surgery, including 18 with GPi-DBS and 7 with STN-DBS. Follow-up assessments were completed for all patients at one and three months, with 23 patients completing the 6-month follow-up [Supplementary Figure 1A, https://links.lww.com/CM9/C508]. The cohort had a median age of 60 (54–66) years and a median disease duration of 12 (10–15) years. On average, participants demonstrated a 63.5 ± 16.9% improvement on the levodopa challenge test. Baseline demographic and clinical characteristics are presented in Supplementary Table 2, https://links.lww.com/CM9/C508. The directional DBS system (PINS Medical, Beijing, China), consisting of L305/L306 directional leads and the G107R/G107 implanted pulse generator (IPG), was used in this study. The leads featured a 1-3-3-1 configuration with segmented contacts designed for precise directional stimulation, allowing targeted current delivery. Contacts were labeled from bottom to top: R1–R4 (E1–E8) represented contacts on lead 1 (connected to the front channel of the IPG), and R5–R8 (E9–E16) represented contacts on lead 2 (connected to the back channel of the IPG). Typically, lead 1 was implanted on the right hemisphere and lead 2 on the left. Notably, the R2 and R3 contacts were further subdivided into E2, E3, E4 and E5, E6, E7, respectively, whereas R6 and R7 were subdivided into E10, E11, E12 and E13, E14, E15, enabling more refined directional stimulation [Supplementary Figure 1B, C, https://links.lww.com/CM9/C508]. The G107R model featured a rechargeable IPG, whereas the G107 was nonrechargeable [Supplementary Figure 1D, https://links.lww.com/CM9/C508]. Lead implantation was performed under anesthesia, with optional microelectrode recording, as previously reported.[2] Preoperative magnetic resonance imaging (MRI) and computed tomography (CT) fusion were used for surgical planning, whereas postoperative CT conducted one month after surgery confirmed lead positioning using the MR_NeuroPilot toolbox (National Engineering Research Center of Neuromodulation, Tsinghua University, Beijing, China) [Supplementary Figure 2A, B, https://links.lww.com/CM9/C508]. The primary outcome of this study was the TW, defined as the range of stimulation amplitudes that effectively alleviate symptoms while avoiding adverse side effects. A wider TW is critical in clinical practice as it allows greater flexibility in treatment adjustments, providing a safer and more effective stimulation range. In contrast, a narrower TW necessitates precise calibration to balance therapeutic effects and side effects. At one month postimplantation, TW measurements were conducted on 50 leads (bilaterally implanted in 25 participants). Each lead comprised two layers of segmented contacts (e.g., R2 and R3), enabling both directional and omnidirectional (ring mode) stimulation. For each layer, the segmented contact with the widest TW was identified as the optimal directional setting and compared with the corresponding omnidirectional setting, resulting in 100 comparisons (two per lead). Directional stimulation significantly increased the TW in 61 layers (61% of cases), a proportion that exceeded the 50% threshold (P = 0.035, Binomial test), with a 95% confidence interval of 0.507–0.706 [Supplementary Figure 3A, B, https://links.lww.com/CM9/C508]. The choice between constant-voltage and constant-current stimulation was determined by the treating clinicians, based on the specific symptoms of each patient. In voltage mode, directional stimulation significantly increased the TW in 54 levels (64.29%), outperforming omnidirectional stimulation (P <0.001). The median therapeutic threshold for directional stimulation was lower (1.0 vs. 1.5 V, P = 0.012), whereas the side effect threshold was higher (5.0 vs. 4.6 V, P <0.001) [Supplementary Figure 3C–E, https://links.lww.com/CM9/C508]. In the current mode, evaluated in eight leads targeting the GPi (16 levels), directional stimulation increased the TW in seven levels (43.75%), with a median TW of 3.00 mA for directional stimulation compared to 2.75 mA for omnidirectional stimulation (P = 0.230) [Supplementary Figure 3F, https://links.lww.com/CM9/C508]. Therapeutic and side effect thresholds across all contacts in a representative case are shown in Supplementary Figure 3G, https://links.lww.com/CM9/C508. Significant improvements were observed across multiple secondary outcomes. Motor function, evaluated using the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale, Part III (MDS-UPDRS III), showed substantial enhancements at 1, 3, and 6 months compared to baseline, in both Med-off (P = 0.001) and Med-on conditions (P = 0.007). Quality of life, assessed by Parkinson’s Disease Questionnaire-39 (PDQ-39) scores, improved significantly at 3 months (P = 0.037) and further at 6 months (P = 0.003). Furthermore, the “on time without troublesome dyskinesia” increased from 7 to 13 hours at 6 months (P = 0.048), and the levodopa equivalent daily dose (LEDD) was reduced from 718.8 to 478.1 mg (P = 0.042) [Supplementary Figure 4A–F, https://links.lww.com/CM9/C508]. In the GPi group, directional stimulation resulted in significant improvements in both MDS-UPDRS III scores and quality of life at all postoperative time points [Supplementary Figure 5A–F, https://links.lww.com/CM9/C508]. In contrast, the STN group demonstrated significant improvements at 6 months (P = 0.010), with a trend toward improvement at 3 months (P = 0.066). Total electrical energy delivered (TEED) was calculated using the following formulas: TEED = (voltage2 × frequency × pulse width) / impedance for constant-voltage mode, and TEED = (current2 × frequency × pulse width) × impedance for constant-current mode. In the STN group, TEED at 3 months was significantly lower with directional stimulation (P = 0.011) [Supplementary Figure 5G–L, https://links.lww.com/CM9/C508]. At the 6-month follow-up, eight patients (8/25, 32%) experienced 18 adverse events, including 11 surgery-related events in five patients (5/25, 20%), such as hyperventilation, brain edema, acute cerebral infarction, fever, and vomiting. No device-related adverse events were reported. However, several device-related complications, not classified as adverse events, were observed [Supplementary Table 3, https://links.lww.com/CM9/C508]. Mild discomfort at the incision site was effectively managed with standard care. Three patients with nonrechargeable pulse generators experienced a bulge at the implant site due to the device size, though this did not cause significant discomfort. Transient paresthesias or muscle twitches were noted when stimulation exceeded the TW; these symptoms resolved promptly after adjusting the settings. One patient with STN-DBS developed dyskinesia postactivation, which was successfully managed through adjustments in stimulation parameters and medication. Two patients with GPi-DBS required multiple programming sessions to achieve stable symptom control, possibly reflecting the initial learning curve with directional stimulation. All device-related complications were transient or manageable and did not require discontinuation of therapy. Our findings align with previous studies showing that directional DBS enhances the TW and improves clinical outcomes in PD patients.[3,4] Similar to the studies by Contarino et al[3] and Steigerwald et al[4], we observed significant improvements in motor function and quality of life with directional stimulation. Notably, our study extends these benefits to both STN and GPi targets, whereas prior research primarily focused on the STN.[3–5] Regarding safety, we reported no device-related adverse events, consistent with other trials that have demonstrated the safety and tolerability of directional DBS systems.[4,5] These comparisons suggest that this novel system offers efficacy and safety profiles comparable to existing technologies, with the added advantage of targeting both major DBS sites in PD. An important consideration is the potential cost-effectiveness of the novel directional DBS system. As a domestically manufactured device in China, it may offer cost advantages over imported systems, thereby reducing the financial burden on both patients and healthcare providers. The enhanced TW and improved clinical outcomes associated with directional stimulation could reduce the need for frequent programming adjustments and minimize side effects, potentially lowering long-term healthcare costs. Although a formal economic analysis was beyond the scope of this study, future research should focus on evaluating the cost-effectiveness of this system in comparison to traditional DBS technologies. Although this initial report is promising, the study’s small sample size and the absence of long-term randomized controlled trials limit the ability to definitively compare the efficacy of directional vs. omnidirectional DBS. Further research with larger sample sizes and extended follow-up periods is necessary to validate these findings and evaluate the long-term safety and effectiveness of directional DBS. In conclusion, the novel Chinese directional DBS system demonstrates significant advantages in treating PD, particularly by increasing the TW and reducing side effects. The preliminary results suggest that directional DBS could be a promising treatment option, warranting further investigation through larger, randomized trials to confirm these findings and explore its potential for other clinical applications. Funding This work was supported by the National Key Research and Development Program of China (No. 2022YFC2405105), the National Natural Science Foundation of China (Nos. 82401713, 82301655, 82171442, 82371256), and the Postdoctoral Fellowship Program of CPSF (No. GZC20231742). Conflicts of interest We sincerely thank PINS Medical (Beijing, China) for their invaluable support and extend our deepest appreciation to all the patients who participated in this project for their cooperation.