https://orcid.org/0000-0002-5914-0804
Figures
Abstract
Background
Deep brain stimulation (DBS) has been increasingly introduced for patients with Parkinson’s disease (PD). However, there has been extensive controversy regarding its surgical timing. This study aimed to evaluate surgical outcomes of DBS across different PD durations and identify key prognostic factors.
Methods and findings
In this multicenter cohort study, patients with PD who underwent subthalamic DBS between 1/1/2011 and 12/31/2020 from seven representative Chinese national centers were included. Two-year follow-up data were analyzed, accordingly. These patients were classified into short (<5 years), mid (5−10 years), and long (≥10 years) PD duration groups. Primary assessments included part III of the Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS-III) at the off-medicine state, Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), and Parkinson Disease Questionnaire-39 (PDQ-39) scales. Relative changes in scores were analyzed for within- and between-group comparisons, and prognostic factors were identified via multivariable linear regression. A total of 1,859 patients were screened, and 1,717 patients (749 females) were included for analysis. Respectively, 141, 978, and 598 patients underwent surgeries after short-, mid-, and long-duration. The scores of the MDS-UPDRS-III (off-medicine), HAM-A, HAM-D, and PDQ-39 significantly improved by 46.7% ± 14.1% (mean difference [MD] 25.1, 95% confidence interval [CI] [24.5, 25.7], P < 0.001), 54.4% ± 22.4% (MD 8.0, 95%CI [7.5, 8.5], P < 0.001), 43.4% ± 22.6% (MD 6.3, 95%CI [5.8, 6.8], P < 0.001), and 47.9% ± 17.8% (MD 28.0, 95%CI [27.0, 29.0], P < 0.001), respectively, and all the study groups achieved significant improvements (all P < 0.001). Notably, patients with mid-PD duration achieved greatest improvements in motor outcomes (versus short: MD 8.0%, 95%CI [4.7%, 11.3%], P = 0.008; versus long: MD 5.6%, 95%CI [2.8%, 9.4%], P = 0.01), neuropsychological evaluations (anxiety, versus long: MD 15.2%, 95%CI [12.3%, 18.1%], P = 0.002; depression, versus long: MD 19.1%, 95%CI [15.6%, 22.6%], P < 0.001), and quality of life (versus long: MD 7.6%, 95%CI [5.2%, 10.0%], P = 0.007). Levodopa response (short: adjusted β 0.42, 95% CI [0.30, 0.54], P < 0.001; mid: adjusted β 0.17, 95% CI [0.12, 0.22], P < 0.001; long: adjusted β 0.20, 95% CI [0.12, 0.28], P < 0.001) was a unified positive factor of motor response for all three groups. Higher MDS-UPDRS-III (off-medicine) scores (mid: adjusted β 0.10, 95% CI [0.05, 0.15], P < 0.001; long: adjusted β 0.30, 95% CI [0.23, 0.38], P < 0.001) were positively correlated with motor outcomes for the mid- and long-duration groups. Nevertheless, it was a negative factor for the short duration group (adjusted β −0.25, 95% CI [−0.36, −0.14], P < 0.001). The main limitation of this study is the nonrandomized observational nature introduced potential selection bias and imbalanced comparisons.
Conclusions
DBS significantly improved motor, neuropsychological, and quality-of-life outcomes across all PD durations, with the most substantial benefits observed in mid-duration (5–10 years) patients. While levodopa response was a consistent positive prognostic factor for motor response, caution is warranted for short-duration patients with rapidly progressive motor symptoms, as they exhibited less favorable outcomes.
Author summary
Why was this study done?
- Deep brain stimulation (DBS) has been increasingly introduced for patients with Parkinson’s disease (PD).
- Increasing enthusiasm has been raised in advocating DBS for patients with shorter duration of PD, but there has been extensive controversy regarding its surgical timing.
- Limited studies have compared patients underwent DBS at different PD durations, leaving the potential optimal surgical timing unclear.
What did the researchers do and find?
- A total of 1,717 patients with PD who underwent subthalamic DBS between 1/1/2011 and 12/31/2020 from seven representative national centers were included and classified into short (< 5 years, n=141), mid (5–10 years, n=978), and long (≥10 years, n=598) PD duration groups; and their two-year follow-up data were collected and analyzed.
- DBS significantly improved motor, mood, and quality-of-life outcomes across all PD durations, with the most substantial benefits observed in mid-duration (5–10 years) patients.
- Greater levodopa response suggested better motor improvement, regardless of disease duration, whereas higher baseline motor severity predicted better outcomes in mid-/long-duration PD but poorer outcomes in short-duration PD.
What do these findings mean?
- DBS significantly improved motor function, mood, and quality of life across all PD durations and mid-duration (5–10) might be the optimal surgical timing window.
- While levodopa response predicted motor improvement in all groups, short-duration patients with rapid symptom progression showed reduced benefits.
- The main limitation is that as an observational study, inherent differences between patient groups may affect outcomes, necessitating prospective studies with random patient assignment.
Citation: Wang S, Hu W, Gao Y, Wang A, Chen L, Liang Z, et al. (2025) Deep brain stimulation surgical timing, outcomes, and prognostic factors in patients with Parkinson’s disease: A Chinese retrospective multicenter cohort study. PLoS Med 22(8): e1004670. https://doi.org/10.1371/journal.pmed.1004670
Academic Editor: Joshua Z. Willey, Columbia University, UNITED STATES OF AMERICA
Received: November 5, 2024; Accepted: July 8, 2025; Published: August 1, 2025
Copyright: © 2025 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: The data set cannot be shared directly under current legislation for data protection and ethical restriction on patients’ privacy, which must be requested directly from the Beijing Neurosurgical Institute, Beijing Tiantan Hospital, Capital Medical University (neurosurgeon@126.com), after approval by the ethics committee of Beijing Tiantan Hospital, Capital Medical University (ttyyirb@163.com).
Funding: This study was supported by the National Key Research and Development Program of China (2022YFC2405100 to FM, 2016YFC0105900 to JZ), the National Natural Science Foundation of China (81830033 to JZ, 81971070 to FM), the Key R&D Program of Jiangsu Science and Technology Project (BE2022049 to WZ), and the Key Research and Development Program of Henan Province (241111310100 to FM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Abbreviations: AE, adverse event;; HAM-A, Hamilton Anxiety Scale; HAM-D, Hamilton Depression Scale; LEDD, levodopa equivalent daily dose; MDS-UPDRS, Unified Parkinson’s Disease Rating Scale; MMSE, Mini-Mental Status Exam; MoCA, Montreal Cognitive Assessment; PD, Parkinson’s disease; PDQ-39, Parkinson Disease Questionnaire-39; RCT, randomized clinical trials; STN-DBS, subthalamic deep brain stimulation
Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disease with increased prevalence [1,2], causing enormous burdens worldwide [3]. Although dopaminergic medication provides initial relief, fluctuations in medication responses and levodopa-induced complications can occur after disease progression within a few years [4,5], which causes functional decline and contributes to a significant loss of quality of life [6]. For these patients, deep brain stimulation (DBS) has shown great potential in achieving better control of symptoms [7–10]. In early clinical practice and studies, DBS was typically deferred for an extended duration of PD [11]. Several randomized clinical trials (RCTs) [12–16] have provided strong evidence that subthalamic deep brain stimulation (STN-DBS) is superior in terms of outcomes than best medical therapy alone for long-term advanced PD [8]. Recently, several studies have suggested that early DBS can also be efficacious and feasible [17–19]. The EARLYSTIM trial enrolled patients with PD with early fluctuations (mean PD duration as 7.5 years) and revealed its benefits in terms of motor symptoms and quality of life over standard medical therapy [20]. With these encouraging results, stepwise approvals for DBS in patients with advanced (since 2002) to earlier (since 2016, at least 4 years of PD and inadequate medication control) PD have been granted by the U.S. Food and Drug Administration (FDA) [8,21].
However, there is extensive controversy regarding surgical timing [8,22–25]. While some studies have suggested the potential to better enhance quality of life and activities of daily living when DBS is applied early, others are concerned with its uncertain benefits and potential risks [11,22,23,25,26]. To date, only limited evidence is available for the effects of early DBS for PD, especially for patients with very short durations (1–4 years) [11]. In addition, the potential optimal surgical timing could not be determined until patients underwent DBS at different disease durations, including in the same study for comparison [18,23]. To bridge this critical research gap, we collected comprehensive motor outcomes, neuropsychological evaluations, and quality of life data from a large-scale multicenter cohort of patients with PD (1,717 individuals), thus far available for analysis so that DBS performed at different disease durations can be compared to determine the potentially optimal timing for surgery [22]. In addition, we identified several key prognostic factors and their crucial variations, which could help further improve individual outcomes [27,28].
Methods
Study design
We performed a nationwide multicenter retrospective cohort study (DBS-PD Chinese Collaboration-2) on STN-DBS for patients with PD with different disease durations from 7 representative university centers between 1/1/2011 and 12/31/2020. This study was approved by the ethics committee of Beijing Tiantan Hospital, Capital Medical University, and all participating centers (KY2021-159-01). An authoritative third party, the China National Clinical Research Center for Neurological Diseases (NCRCND), supervised this study. All included participants provided written informed consent for the surgery and the use of deidentified data for scientific research. This study was performed under the Declaration of Helsinki and was reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline (S1 Checklist) [29].
On the basis of our previous study regarding the utilization of DBS for PD (DBS-PDCC) [30], we collected data from well-known experienced national DBS centers (S1 Table) for representatives with the assistance from the Chinese Neuromodulation Society [31,32]. Each participating center submitted case report forms. The study committee, which consists of senior neurologists and neurosurgeons, further reviewed these forms, and each center for all data collection. All deidentified data were included in our DBS-PDCC databases [33,34]. Experts in statistics performed data control, analysis, and validation in a blinded manner. The data collection was finished by December 2023, and the data analyses were conducted from January 2024 to May 2024.
Participants
At the time of surgery, all patients have received multidisciplinary assessments and fulfilled the surgical indications of DBS for PD [8,16,35] as follows: (1) idiopathic PD diagnosis on the basis of the Movement Disorders Society Clinical Diagnostic Criteria [36] and the UK Brain criteria [37]; (2) the presence of disabling motor complications or levodopa-induced dyskinesia despite receiving optimal medications; (3) the absence of dementia and other clinically relevant cognitive impairment, ongoing severe psychiatric diseases, and severe brain atrophy; and (4) confirmation for surgical need after carefully considering patients’ willing, expected benefits and risks, and their fitness for surgery without systemic contraindications [8,10], especially for older patients aged ≥75 years [8,38,39]. Patients were eligible for the study if they met the following inclusion criteria: (1) were aged 18 years or older; (2) received bilateral STN-DBS at the seven centers from 2011 to 2020; and (3) finished no less than 2 years of follow-up. Patients without written informed consent or with freezing of gait) were excluded. For patients with inadequate follow-up periods or missing data, the research committee first tried to contact the patients and their relatives for further interviews, and those who could not be contacted were excluded.
A total of 1,859 patients were screened for eligibility; 142 patients (7.6%) were excluded because they did not provide informed consent (n = 12), DBS at targets other than the bilateral STN (n = 38), or had missing data (n = 92). The details of the noneligible samples are summarized in S2 Table. Finally, this study analyzed 1,717 patients (Beijing 1 center included 725 patients, Liaoning 1 center included 113 patients, Shandong 1 center included 313 patients, Jiangsu 1 center included 370 patients, and Guangdong 3 centers included 196 patients), which were then grouped into short (<5 years), mid (5–10 years), and long (≥10 years) PD duration groups based on FDA stepwise approvals [19,21] and clinical practice in early DBS surgeries [11,23]. The study flow is shown in Fig 1.
DBS-PDCC, Deep Brain Stimulation for Parkinson’s Disease Chinese Collaboration; CNMS, Chinese Neuromodulation Society; PD, Parkinson’s disease; STN-DBS, subthalamic nucleus deep brain stimulation; NCRCND, China National Clinical Research Center for Neurological Disease.
Surgical procedures
Each center performed bilateral STN-DBS surgeries independently for patients with PD. Our interviews suggested that their operative routine and principles were similar to those of our previous studies [40,41]. Generally, preoperative MR images are merged with CT scans after stereotactic frame fixation to visually target the STN and determine the trajectory for electrode placement. After that, the stimulation electrodes (Medtronic-3389, Medtronic Plc; or PINS-L301, PINS Medical; with the same design as the quadripolar contact length of 1.5 mm and spaced 0.5 mm apart) were implemented with further refinement via microelectrode recordings and intraoperative testing for clinical response under local anesthesia.
After the surgery, the lead position and potential complications were evaluated with postoperative neuroimaging, and further test stimulation was evaluated. A few days later, the pulse generator (Activa RC, Medtronic Plc; or Model G102R, PINS Medical) was connected to the intracranial leads and positioned in the subcutaneous region under general anesthesia. The stimulator was initiated 1 month later [34], and a specialized programming team adjusted the stimulation parameters in the follow-ups as needed according to individual symptoms.
Outcome measurements
Preoperative characteristics were recorded. Young-onset PD was defined as the onset of symptoms before 40 years of age [42,43]. At (preoperative) baseline, at 6 months and every year postoperatively, patients were evaluated by experienced neuropsychologists at their local centers. All the assessment scales used were validated Chinese versions. For preoperative motor assessments, the clinically defined “off-medicine” and “on-medicine” states [10,27,44] were assessed by movement disorder specialists under conditions of no medication effects (at least medication withdrawal for 12 h) and maximal benefits (approximately 1 h after medication intake), respectively. Postoperative outcomes were evaluated at the “on-stimulation” status (at least a 1-week observation period after continuous stimulation without changes in parameters) and the abovementioned “off-medicine” and “on-medicine” conditions [10,27]. To ensure accuracy and quality control, all original measurements were further reviewed by the study committee.
Primary outcomes
On the basis of assessment tools used at each center, we prospectively selected unified measurements for primary and secondary motor outcomes, neuropsychological evaluations, and quality of life. The outcomes were analyzed at the 2-year follow-up. The Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS; four parts, I, II, III, and IV) [45] was used to assess the severity of PD symptoms [46]. Part III of the MDS-UPDRS (MDS-UPDRS-III) [47] in the “off-medicine” state was assessed as the primary motor outcome. The Hamilton Anxiety Scale (HAM-A) [48] and the Hamilton Depression Scale (HAM-D) [49] were used to evaluate anxiety and depression symptoms, respectively. In addition, the Parkinson Disease Questionnaire-39 (PDQ-39) [50] was used to assess quality of life.
Secondary outcomes
The secondary outcomes for motor measures included part II (MDS-UPDRS-II), part III at the “on-medicine” state, and part IV (MDS-UPDRS-IV) [45] of the MDS-UPDRS; the levodopa equivalent daily dose (LEDD) [51,52]; and the patient motor diary, which includes daily “off-medicine” time (off-time) and “on-medicine” time with troublesome dyskinesia (dyskinesia-time) [53]. Patients were also evaluated with the Hoehn and Yahr scale in the “off-medicine” state [54] and with the levodopa responsiveness score (calculated as a percentage of the MDS-UPDRS-III “off-medicine” score minus the “on-medicine” score divided by the MDS-UPDRS-III “off-medicine” score) [55] at baseline. All motor tests were videotaped with available informed consent. Part I of the MDS-UPDRS (MDS-UPDRS-I) was assessed for nonmotor symptoms. The Mini-Mental Status Exam (MMSE) and the Montreal Cognitive Assessment (MoCA) were also evaluated, whereas lower scores indicate greater cognitive impairment. Any adverse events (AEs) related to the surgery, stimulation, or device were recorded and analyzed as the number of patients and events.
Statistical analysis
The statistical analysis was planned prospectively (S1 File) in designing the study without deviations. Because of the potential inclusion of important variables in the regression analysis and the low percentage of missing data (4.9%), complete data analysis (listwise deletion) was applied without imputation [56]. We also compared samples with missing data to the samples included and found comparable characteristics and outcomes, suggesting its limited influence (S2 Table).
The Kolmogorov‒Smirnov test and Levene’s test were performed for normality and homogeneity of variance, respectively. Continuous variables were presented as means (± standard deviations, SDs, for normal distribution) or medians (interquartile ranges, IQRs, for nonnormal distribution), whereas categorical variables were reported as numbers (percentages). For within-group comparisons in exploring treatment effects, postoperative scores at 24 months were compared with the baseline using two paired-sample t tests. For between-group comparisons, considering imbalance in baseline assessments among different PD duration groups, we calculated improvement percentages (relative changes, [preoperative minus postoperative score]/preoperative score × 100%, for higher scores indicating more severe symptoms, such as the MDS-UPDRS; or its inverse for lower scores indicating more severe symptoms, such as the MMSE and MoCA) for each patient and assessed statistical differences using one-way ANOVA, with pairwise multiple comparisons adjusted by Bonferroni method (multiplied corrected P values by three times). All within-group (for scores, postoperative minus preoperative) and between-group (for differences in improvement percentages) comparisons were reported with mean difference (MD) and confidence interval (CI). Correlation analysis was performed using Pearson’s correlation coefficient.
Potential prognostic factors were identified using multivariable linear regression. Independent variables showing P < 0.10 in univariable analysis were included in multivariable backward elimination modeling after confirming no significant multicollinearity (variance inflation factors < 10). Final model presented adjusted β coefficients with 95% CI. To make it more intuitive, cognitive impairment measured by MMSE and MoCA was operationalized by reverse-coding their original scores (e.g., impairments in MoCA = -MoCA), where higher values now indicate greater cognitive impairment. In regression models, a negative β coefficient for “impairment in MoCA” signifies worse outcomes with increasing cognitive impairment.
All the statistical tests were two-sided, and a P value (or Bonferroni corrected P value) < 0.05 was considered statistically significant. All the statistical analyses and figures were generated via SPSS software, version 27 (IBM Corp.), R software, version 4.3 (R Foundation), and GraphPad Prism, version 10 (GraphPad Software LLC).
Results
Baseline characteristics
A total of 1,717 patients (749 females, 43.6%) with PD were included from 7 representative specialized DBS centers, of whom 141, 978, and 598 patients underwent DBS after short, mid, and long disease duration, respectively. The study centers and number of patients included at each center are shown in S1 Fig. As shown in Fig 2, most of the patients (57.0%) underwent the surgery after mid PD duration, and the peak disease duration at surgery was 7 years. During the study period, the proportions of mid- and short-duration groups increased, and the yearly median disease duration gradually decreased, with an overall median of 8 years.
A: study groups and their distributions; B: time trends of median PD duration at the surgery and changes in study group distributions with time. PD, Parkinson’s disease; LOWESS, locally weighted scatterplot smoothing.
Table 1 summarizes the characteristics of the participants. The surgical age was significantly greater in the long duration group than the mid-group, which in turn were higher than in the short duration group (66.0, IQR [60.0–70.0] versus 63.0, IQR [56.0–68.0] versus 58.0, IQR [51.0–63.5]; respectively; all P < 0.001). Compared with the short- and mid-duration groups, the long PD duration group presented more severe symptoms on the MDS-UPDRS-III (off-medicine), MDS-UPDRS-II, LEDD, off-time, HAM-A, and HAM-D, whereas the short- and mid-duration groups were comparable. The PDQ-39 scores were significantly different among the 3 groups (64.5, [±17.2] versus 56.4 [±17.3] versus 49.7 [±16.2] for the short-, mid-, and long-duration groups, respectively; all P < 0.001).
Primary motor, neuropsychological outcomes, and quality of life
All surgical outcomes are reported in Table 2 (detailed within-group and between-group comparisons are shown in S3 and S4 Tables) and the primary outcomes are shown in Fig 3. In general, motor outcomes measured by the MDS-UPDRS-III (off-medicine) significantly improved from baseline by 46.7% ± 14.1% (MD 25.1, 95% CI [24.5, 25.7], P < 0.001). In the neuropsychological evaluations, symptoms of anxiety and depression also significantly improved by 54.4% ± 22.4% (MD 8.0, 95%CI [7.5, 8.5], P < 0.001) and 43.4% ± 22.6% (MD 6.3, 95%CI [5.8, 6.8], P < 0.001), respectively (all P < 0.001), and quality of life, as measured by the PDQ-39, significantly improved by 47.9% ± 17.8% (MD 28.0, 95%CI [27.0, 29.0], P < 0.001). All study groups had significant improvements in the MDS-UPDRS-III (off-medicine), HAM-A, HAM-D, and PDQ-39 scores (all P < 0.001). Between-group analyses revealed that surgeries performed after mid PD duration improved the MDS-UPDRS-III score (off-medicine) more than those performed after short and long PD duration did (vs short duration: MD 8.0%, 95%CI [4.7%, 11.3%], P = 0.008; versus long duration: MD 5.6%, 95%CI [2.8%, 9.4%], P = 0.01), whereas the scores of the short and long duration groups were comparable (P = 0.77). For the HAM-A, HAM-D, and PDQ-39 scores, the mid and short duration groups all presented greater improvements than did the long duration group (HAM-A: mid versus long: MD 15.2%, 95%CI [12.3%, 18.1%], P = 0.002, short versus long: MD 12.7%, 95%CI [7.6%, 17.8%], P = 0.03; HAM-D: mid versus long: MD 19.1%, 95%CI [15.6%, 22.6%], P < 0.001, short versus long: MD 17.7%, 95%CI [12.5%, 22.9%], P < 0.001; PDQ-39: mid versus long: MD 7.6%, 95%CI [5.2%, 10.0%], P = 0.007, short versus long: MD 4.3%, 95%CI [0.5%, 8.1%], P = 0.02), whereas no significant differences were revealed between the mid and short duration groups (all P > 0.05).
A: Motor outcomes by MDS-UPDRS-III (off-medicine); B and C: Neuropsychological evaluations by HAM-A and HAM-D; D: quality of life by the PDQ-39. †P < 0.05 (within-group comparisons, paired t test); ††P < 0.01 (within-group comparisons, paired t test); *P < 0.05 (between-group comparisons, one-way ANOVA with multiple comparisons adjusted by Bonferroni method); **P < 0.01 (between-group comparisons, one-way ANOVA with multiple comparisons adjusted by Bonferroni method). The error bars represent the standard deviation (SD). MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (with parts I, II, III, IV); HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; PDQ-39, Parkinson Disease Questionnaire-39.
Secondary outcomes and adverse events
Secondary motor outcomes (Fig 4) measured by the MDS-UPDRS-II (improved 43.3% ± 15.5%, MD 8.8, 95%CI [8.4, 9.2], P < 0.001), and MDS-UPDRS-III (on-medicine; improved 36.0% ± 11.3%, MD 9.3, 95%CI [8.7, 9.9], P < 0.001), and the MDS-UPDRS-IV (improved 30.1% ± 10.6%, MD 2.2, 95%CI [2.0, 2.4], P < 0.001) significantly improved, whereas the postoperative LEDD (decreased 59.4% ± 18.8%, MD 461.5, 95%CI [439.2, 483.8], P < 0.001), off-time (decreased 31.0% ± 14.8%, MD 1.8, 95%CI [1.7, 1.9], P < 0.001), and dyskinesia-time (decreased 30.0% ± 14.9%, MD 1.2, 95%CI [1.1, 1.3], P < 0.001) also decreased significantly for all patients and for the study groups (all P < 0.001).
A–C: improvements in MDS-UPDRS-III (on-medicine), MDS-UPDRS-II, and MDS-UPDRS-IV; D–F: changes in LEDD, daily Off time, and daily On time with troublesome dyskinesia. †P < 0.05 (within-group comparisons, paired t test); ††P < 0.01 (within-group comparisons, paired t test); *P < 0.05 (between-group comparisons, one-way ANOVA with multiple comparisons adjusted by Bonferroni method); **P < 0.01 (between-group comparisons, one-way ANOVA with multiple comparisons adjusted by Bonferroni method). The error bars represent the standard deviation (SD). MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (with parts I, II, III, IV); LEDD, levodopa-equivalent daily dose; Pre, Preoperative; Post, Postoperative; Off time, the daily duration of clinically defined “off-medicine” states (h/d); Dyskinesia time, the daily duration of clinically defined “on-medicine” time with troublesome dyskinesia status (h/d).
In terms of secondary neuropsychological evaluations (S2 Fig), the MDS-UPDRS-I score significantly improved in all patients (MD 1.4, 95%CI [1.2, 1.6], P < 0.001) and in the short (MD 2.0, 95%CI [1.0, 3.0], P < 0.001) and mid (MD 1.8, 95%CI [1.1, 2.5], P = 0.02) duration groups, whereas changes in the long duration group did not reach significance (MD 1.9, 95%CI [−0.5, 2.8], P = 0.11). Cognitive functions measured by the MMSE and MoCA did not significantly differ across all patients and groups (all P > 0.05). A comparison of the relative changes across the different study groups revealed that the mid duration group had significantly greater improvements in MDS-UPDRS-II scores than did the long duration group (MD 4.6%, 95%CI [2.3%, 6.9%], P = 0.003), greater reductions in LEDD than did the short (MD 4.5%, 95%CI [0.8%, 8.2%], P = 0.009) and long (MD 9.3%, 95%CI [6.5%, 12.1%], P < 0.001) duration groups, and greater reductions in the daily off-time score than did the short duration group (MD 8.6%, 95%CI [4.9%, 12.3%], P < 0.001).
A total of 340 AEs were reported in 302 (17.6%) patients. All these AEs were not life-threatening and resolved without major sequelae, and no surgery-related mortality or morbidity occurred (S5 Table). The most frequently reported AEs were dystonia (46 events reported in 41 [2.4%] patients, all resolved with reprogramming), illusion (37 events reported in 37 [2.2%] patients, all resolved with reprogramming), and infection (36 events reported in 35 [2.0%] patients; all resolved with dressing changes and antibiotics). The prevalence of AEs was comparable across the 3 study groups.
Correlation analyses
For the primary outcomes, Spearman correlation analysis suggested that the relative changes in the MDS-UPDRS-III (off-medicine) and HAM-A (r = 0.159, P < 0.001), MDS-UPDRS-III (off-medicine) and HAM-D (r = 0.247, P < 0.001), MDS-UPDRS-III (off-medicine) and PDQ-39 (r = 0.175, P < 0.001), HAM-A and HAM-D (r = 0.350, P < 0.001), HAM-A and PDQ-39 (r = 0.088, P = 0.017), and HAM-D and PDQ-39 (r = 0.165, P < 0.001) scores were positively correlated. In addition, it also revealed widely positive relationships (especially extensive connections of motor and neuropsychological outcomes and quality of life) and a minority of negative correlations (such as LEDD with the MDS-UPDRS-IV, r = −0.188, P < 0.001) with other outcomes. The correlation analyses are shown in S3 Fig and S6 Table.
Prognostic factors
The univariable linear regression analysis was performed first in identifying potential influential factors of motor outcomes (S7 Table), neuropsychological evaluations (S8 and S9 Tables), and quality of life (S10 Table). Factors with P values < 0.10 that might convey important information were then entered into multivariable linear regressions. After adjusting for multivariable models, short (Fig 5), mid (Fig 6), and long (Fig 7) PD duration groups had both consistent and inconsistent prognostic factors. Greater levodopa responses (short: adjusted β 0.42, 95% CI [0.30, 0.54], P < 0.001; mid: adjusted β 0.17, 95% CI [0.12, 0.22], P < 0.001; long: adjusted β 0.20, 95% CI [0.12, 0.28], P < 0.001) were a common positive factor of motor improvement for all three groups. Later age at PD onset (adjusted β −0.39, 95% CI [−0.60, −0.20], P < 0.001) and higher baseline MDS-UPDRS-III (off-medicine) scores (adjusted β −0.25, 95% CI [−0.36, −0.14], P < 0.001) were associated with a worse motor response to stimulation in the short duration group. For the mid and long duration groups, higher baseline MDS-UPDRS-III (off-medicine) scores (mid: adjusted β 0.10, 95% CI [0.05, 0.15], P < 0.001; long: adjusted β 0.30, 95% CI [0.23, 0.38], P < 0.001) were common positive factors for motor improvement, whereas longer daily dyskinesia time (mid: adjusted β −0.89, 95% CI [−1.21, −0.57], P < 0.001; long: adjusted β −1.88, 95% CI [−2.35, −1.42], P < 0.001) was a common negative factor. In addition, longer daily off-time (adjusted β 0.65, 95% CI [0.24, 1.05], P = 0.002) was positively associated with motor outcomes in the mid duration group, and greater cognitive impairment in MoCA (adjusted β −0.93, 95% CI [−1.16, −0.69], P < 0.001) were negatively associated with worse motor outcomes in the long duration group.
A: Factors influencing improvements in MDS-UPDRS-III (off-medicine); B: Factors influencing improvements in HAM-A; C: Factors influencing improvements in HAM-D; D: Factors influencing improvements in PDQ-39. *P < 0.05 (multivariable linear regression); **P < 0.01 (multivariable linear regression). MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (with parts I, II, III, IV); HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; PDQ-39, Parkinson Disease Questionnaire-39.
A: Factors influencing improvements in MDS-UPDRS-III (off-medicine); B: Factors influencing improvements in HAM-A; C: Factors influencing improvements in HAM-D; D: Factors influencing improvements in PDQ-39. *P < 0.05 (multivariable linear regression); **P < 0.01 (multivariable linear regression). MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (with parts I, II, III, IV); HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; PDQ-39, Parkinson Disease Questionnaire-39.
A: Factors influencing improvements in MDS-UPDRS-III (off-medicine); B: Factors influencing improvements in HAM-A; C: Factors influencing improvements in HAM-D; D: Factors influencing improvements in PDQ-39. *P < 0.05 (multivariable linear regression); **P < 0.01 (multivariable linear regression). † “Impairment in MoCA” is derived by reverse-coding the original MoCA scores (impairments in MoCA = -MoCA), whereas a negative β indicates worse motor outcomes with greater cognitive impairment. MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (with parts I, II, III, IV); HAM-A, Hamilton Anxiety Rating Scale; HAM-D, Hamilton Depression Rating Scale; PDQ-39, Parkinson Disease Questionnaire-39.
For neuropsychological evaluations, higher HAM-A scores at baseline (short: adjusted β 1.99, 95% CI [1.25, 2.72], P < 0.001; mid: adjusted β 0.54, 95% CI [0.38, 0.69], P < 0.001; long: adjusted β 4.21, 95% CI [3.68, 4.74], P < 0.001) were associated with greater improvement in anxiety symptoms for all study groups, whereas greater levodopa responses (mid: adjusted β 0.33, 95% CI [0.19, 0.47], P < 0.001; long: adjusted β 0.27, 95% CI [0.04, 0.50], P = 0.02) were a positive factor, and higher baseline HAM-D scores (mid: adjusted β −1.78, 95% CI [−2.11, −1.44], P < 0.001; long: adjusted β −5.22, 95% CI [−5.73, −4.70], P < 0.001) were a negative factor of anxiety symptoms for the mid and long duration groups. Higher preoperative HAM-D scores (short: adjusted β −2.84, 95% CI [−3.23, −2.45], P < 0.001; mid: adjusted β −1.58, 95% CI [−1.85, −1.31], P < 0.001; long: adjusted β −1.10, 95% CI [−1.75, −0.46], P < 0.001) were a negative factor for depression symptoms in all study groups, and higher LEDD at baseline (mid: adjusted β −0.026, 95% CI [−0.034, −0.02], P < 0.001; long: adjusted β −0.04, 95% CI [−0.06, −0.03], P < 0.001) was also a negative prognostic factor for the mid and long duration groups. Furthermore, greater levodopa responses (short: adjusted β 1.17, 95% CI [0.49, 1.86], P < 0.001; mid: adjusted β 0.55, 95% CI [0.22, 0.88], P < 0.001; long: adjusted β 0.86, 95% CI [0.63, 1.09], P < 0.001) and higher baseline PDQ-39 scores (short: adjusted β 0.90, 95% CI [0.38, 1.41], P < 0.001; mid: adjusted β 2.09, 95% CI [1.84, 2.35], P < 0.001; long: adjusted β 0.46, 95% CI [0.27, 0.65], P < 0.001) were associated with greater improvement in quality of life for all study groups.
Discussion
This large-scale cohort study compared outcomes of DBS for PD at different surgical timings. We revealed that DBS performed after different PD durations (short, mid, or long) could lead to improvements in motor and mood outcomes as well as quality of life while maintaining stable cognition and safety; whereas DBS for patients with mid PD duration (5–10 years) achieved the best outcomes.
Even as a minimally invasive therapy, DBS is usually considered for patients with advanced PD with a long duration in early practice [8,11–16,23]. Previous studies reported significant improvements in STN-DBS for patients with PD, with overall relative changes of 30%−60% in motor symptoms and 20%−50% in quality of life [2,9,10,13–16,55,57,58], and a meta-analysis by Lachenmayer and colleagues estimated a 50.5% reduction in the UPDRS-III score and an improvement in the PDQ-39 score of 22.2% [58], data similar to long duration group findings in our study. With respect to neuropsychological effects, previous findings have varied. A cohort study revealed that mood improved in 50% of patients with PD and the other 50% declined at 12 months after STN-DBS [55], whereas a recent meta-analysis suggested a mild improvement in anxiety and depression at a long follow-up interval (1–3 years) [59]. Our findings suggested that anxiety and depression symptoms improved, whereas stimulation-related neuropsychological AEs were also reported. In addition, positive correlations between improvements in quality of life and motor and mood symptoms were revealed. This suggests the synergistic benefits of alleviating motor symptoms and improving daily activities and psychosocial functions [6,60,61]. With respect to cognitive outcomes, some studies reported cognitive decline in patients with PD after STN-DBS [55,59], whereas other studies in our cohort suggested stable cognitive performance [2,12,14]. The nonmotor symptoms of PD are complex, and the outcomes of DBS can differ significantly across individual patients [2,6]. These variations are influenced by factors such as specific stimulation sites (motor, associative, and limbic regions) and associated circuits [62,63], patient age (especially in cases of cognitive decline) [55,59], adjustments in medication [64], and genetic factors (such as GBA mutations) [65]. This complexity necessitates further personalized analyses and thorough discussions regarding potential risks and benefits for each individual [2,6].
Given the positive effects and low surgical risks, increasing enthusiasm has been raised in advocating DBS for patients with shorter duration of PD [18,22,23,66], a trend that was also observed in this study. The most important rationale for early intervention is that it can enhance quality of life in a timely manner and provide occupational benefits as well as possible cost savings for patients with less medication intake [67,68]. Despite several ongoing and finished trials, experience in early DBS is still insufficient [8,17,19,20]. The trial by Schüpbach and colleagues [17] (mean PD duration as 6.8 years; 20 patients), and their subsequent multicenter EARLYSTIM study (mean duration as 7.5 years; 251 patients) included patients with a short PD duration and early motor complications for STN-DBS [20]. They revealed that DBS was superior to medical therapy with respect to quality of life, activities of daily living, and motor symptoms [17,20]. The present study provides potential evidence that DBS for patients with PD after mid duration (5–10 years) might result in best outcomes, while patients with short (but already meet surgical indications as medicine-resistant motor fluctuations or dyskinesias) and long PD duration could receive less but also significant improvement.
However, it should be noted to a different situation in performing DBS for too early PD stages, even at the situation that patients without medication-resistant motor fluctuations or dyskinesias as surgical indications. The trial by Charles and colleagues [69] (2-year follow-up) and Hacker and colleagues [19] (same cohort, 5 years of follow-up) enrolling 30 patients with PD on medication ≥ 6 months but ≤ 4 years (mean 2.1 years) and without motor fluctuations or dyskinesias. Those authors suggested that although patients receiving STN-DBS required lower levodopa doses, there were no significant differences in motor symptoms or quality of life between STN-DBS and medication alone [19,69]. This approach might introduce several risks, including potential confusion of diagnosis only on the basis of initial symptoms [26], insufficient symptom history for proper surgical stratification [23], and unsatisfactory benefits with possible complications [70], which should be alerted as “too early” for DBS.
On the basis of collective experience, several key prognostic factors and their variations among different study groups have been identified, which can help in patient selection and counseling, contributing to future individual outcome improvement [27,28]. Greater levodopa response was considered a unified positive factor of motor and anxiety outcomes as well as quality of life for nearly all groups, a crucial factor also reported in previous studies [27,55,58,71]. A meta-analysis by Lachenmayer and colleagues suggested that levodopa responsiveness was highly predictive of STN-DBS motor outcome across their included studies [58], and their cohort study revealed that a greater levodopa response also predicted improvement in quality of life [58]. With these findings, the levodopa test has been recommended as one of the most important inclusion criteria for DBS, with a minimum of 30%−35% [6,8,72]. This study suggested that its predictive value could be further expanded to include early interventions. However, it should be noted that levodopa responsiveness might not predict long-term outcomes (>3 years) well, which deserves further study [9,27,71]. In addition, longer daily off-time was a positive factor of motor outcomes, whereas longer daily dyskinesia time was negatively associated with motor outcomes. For important dyskinesia, DBS for the globus pallidus internus (GPi) might provide a probable advantage in direct dyskinesia suppression, which could be considered [58,73,74]. With respect to nonmotor outcomes, higher baseline scores on the HAM-A and PDQ-39 correlated with greater improvement, findings that are consistent with those of previous studies [28,55]. However, higher baseline HAM-D scores with higher LEDDs were associated with worse depression outcomes, especially in late surgeries for older patients. Considering the antidepressant effects of dopamine agonists, patients may worsen their depression symptoms with medication reduction, which can more likely occur in patients with large amounts of preoperative medications [6,49,75]. This should be considered in postoperative medication adjustments.
Apart from consistent factors, some prognostic factors could be different or completely opposite for DBS performed at different disease durations. In the mid and long PD duration groups, higher baseline scores on the MDS-UPDRS-III (off-medicine) were associated with better motor response, which was also reported as a positive predictor in previous studies [27,66]. However, our study revealed that higher baseline MDS-UPDRS-III (off-medicine) scores and later disease onset were negative factors in the short PD duration group. For patients with short PD durations but rapidly progressive motor symptoms, Parkinson‒Plus syndrome (also known as atypical Parkinsonism, such as multiple system atrophy, progressive supranuclear palsy, and others) should be considered, as it cannot be effectively alleviated with DBS [26,76]. Thus, unusually rapidly progressing levodopa-resistant symptoms should be considered red flags in surgical patient selection or at least delay the surgery given the difficulty in making a diagnosis on the basis of only early atypical symptoms [11,76]. This may also partially explain why some patients with short PD duration experienced suboptimal outcomes after DBS, attributable to potential alternative diagnosis, and misclassification [26,76]. In addition, increasing cognitive impairment in MoCA was considered related to worse motor symptoms in the long PD duration group. Previous studies have also suggested that cognitive decline is correlated with worse motor outcomes assessed by the MoCA, MMSE, frontal score, and brain imaging findings (e.g., white matter ischemic lesions) [27,77,78], which might be related to combined pathologies involving subcortical nondopaminergic pathways [27]. These findings suggest that preoperative cognitive assessments are important variables in patient selection, especially for older patients with long disease durations. In summary, the current findings highlight the importance of comprehensive assessments before surgery, and it is necessary to separately interpret the prognostic factors of DBS for patients with different disease durations. This point deserves even greater attention for patients undergoing early (PD duration < 5 years) interventions.
This study has several limitations. First, the nonrandomized observational nature of this study introduced selection bias and imbalanced factors for comparisons. We applied relative changes for comparison to increase compatibility and reduce the influence of the baseline differences. Second, loss of follow-up and missing data were inevitable. We performed additional analyses and revealed no significant influence. Third, limited by the data, precious locations of contacts were not available for analysis, which might also involve clues for prognosis [27], and postoperative assessments under nonstimulation conditions were not assessed in routine practice. Although detailed scores in items of MDS-UPDRS were not available for quantitative classification of phenotypes (e.g., tremor dominant and others), we screened clinical manifestations of the included patients from the medical records and revealed comparable breakdown of the symptoms among the three study groups. Fourth, this study included only 2-year outcomes, and future long-term studies are warranted. Notably, longer follow-up studies (e.g., ≥5 years) in patients with short PD duration are essential as a future research direction to confirm diagnostic accuracy and establish long-term prognostic validity. Fifth, although the multicenter design enriched collaborative experience and sample size, a potential imbalance in surgical experience might exist. Thus, we recruited representative experienced DBS centers and analyzed centers and DBS manufactures as potential factors and found no significant differences in outcomes. In addition, the current surgical timing classification is only a given stratification that typically reflects clinical practice; the optimal surgical timing still requires a large amount of experience, and other prognostic factors should also be considered. Finally, a control group with medication only would better compare surgical effects, which requires future evidence from score-matched RCTs.
DBS significantly improved motor, neuropsychological, and quality-of-life outcomes across all PD durations, with the most substantial benefits observed in mid-duration (5–10 years) patients. While levodopa response was a consistent positive prognostic factor for motor response, caution is warranted for short-duration patients with rapidly progressive motor symptoms, as they exhibited less favorable outcomes. Prognostic factors showed variations by surgical timing, emphasizing the importance of individualized patient selection.
Supporting information
S1 Fig. Study centers, locations, and number of patients included at each center.
Made with Natural Earth. Free vector and raster map data @ naturalearthdata.com.
https://doi.org/10.1371/journal.pmed.1004670.s001
(TIF)
S2 Fig. Secondary neuropsychological evaluations at 24-month follow-up after the surgery.
A: changes in MDS-UPDRS-I; B: changes in MMSE; C: changes in MoCA. †P < 0.05 (within-group comparisons, paired t test); ††P < 0.01 (within-group comparisons, paired t test). The error bars represent the standard deviation (SD). MDS-UPDRS, Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (with parts I, II, III, IV); MMSE, Mini-Mental Status Examination; MoCA, Montreal Cognitive Assessment.
https://doi.org/10.1371/journal.pmed.1004670.s002
(TIF)
S3 Fig. Correlations regarding relative changes in the outcomes.
*P < 0.05 (Pearson’s correlation coefficient); **P < 0.01 (Pearson’s correlation coefficient). Refer to S6 Table for the detailed P and r values.
https://doi.org/10.1371/journal.pmed.1004670.s003
(TIF)
S1 Table. Study centers, locations, region, and number of collected and included patients with Parkinson’s disease (PD) who underwent bilaterial subthalamic nucleus deep brain stimulation (STN-DBS) during 2011−2020 for the Deep Brain Stimulation for Parkinson’s Disease Chinese Collaboration-2 (DBS-PDCC2) study.
https://doi.org/10.1371/journal.pmed.1004670.s004
(DOCX)
S2 Table. Non-eligible reasons of excluded samples (n = 142) and available information of samples with missing data (n = 92).
https://doi.org/10.1371/journal.pmed.1004670.s005
(DOCX)
S3 Table. Within-group comparisons of changes in scores for primary and secondary motor, neuropsychological outcomes, and quality of life.
https://doi.org/10.1371/journal.pmed.1004670.s006
(DOCX)
S4 Table. Between-group comparisons of improvement (relative change) from baseline (%) for primary and secondary motor, neuropsychological outcomes, and quality of life.
https://doi.org/10.1371/journal.pmed.1004670.s007
(DOCX)
S5 Table. Adverse events (AEs) of the included patients with Parkinson’s disease (PD) during the 24 months after bilaterial subthalamic nucleus deep brain stimulation (STN-DBS).
https://doi.org/10.1371/journal.pmed.1004670.s008
(DOCX)
S6 Table. Correlation of relative changes in motor, neuropsychological outcomes, and quality of life for the included patients with Parkinson’s disease (PD) at 24 months after bilaterial subthalamic nucleus deep brain stimulation (STN-DBS).
https://doi.org/10.1371/journal.pmed.1004670.s009
(DOCX)
S7 Table. Univariable linear regression for potential prognostic factors of motor outcome measured by MDS-UPDRS-III off-medicine relative changes for the included patients with Parkinson’s disease (PD) of different study group at 24 months after subthalamic nucleus deep brain stimulation (STN-DBS).
https://doi.org/10.1371/journal.pmed.1004670.s010
(DOCX)
S8 Table. Univariable linear regression for potential prognostic factors of neuropsychological outcomes evaluated by HAM-A relative changes for the included patients with Parkinson’s disease (PD) of different study group at 24 months after subthalamic nucleus deep brain stimulation (STN-DBS).
https://doi.org/10.1371/journal.pmed.1004670.s011
(DOCX)
S9 Table. Univariable linear regression for potential prognostic factors of neuropsychological outcomes evaluated by HAM-D relative changes for the included patients with Parkinson’s disease (PD) of different study group at 24 months after subthalamic nucleus deep brain stimulation (STN-DBS).
https://doi.org/10.1371/journal.pmed.1004670.s012
(DOCX)
S10 Table. Univariable linear regression for potential prognostic factors of quality of life evaluated by PDQ-39 relative changes for the included patients with Parkinson’s disease (PD) of different study group at 24 months after subthalamic nucleus deep brain stimulation (STN-DBS).
https://doi.org/10.1371/journal.pmed.1004670.s013
(DOCX)
S1 Checklist. STROBE Statement—checklist of items that should be included in reports of observational studies.
https://doi.org/10.1371/journal.pmed.1004670.s015
(DOCX)
Acknowledgments
We are grateful for all the principal investigators, their team members, and included patients for their participation. The Chinese Neuromodulation Society supported in center recruitment and data source. Dr. Shu Wang is a senior collaborator of the Global Burden of Disease (GBD) Collaborator Network, which is supported by the Institute for Health Metrics and Evaluation (IHME), the University of Washington; and he contributes to the latest GBD 2021 studies. Prof. Anxin Wang and Dr. Qin Xu are expert statisticians and epidemiologists from the NCRCND to participate in the study design, data quality control, and statistical analyses to facilitate the rigor of this study, and Prof. Yali Liu and her team members from the Center for Clinical Epidemiology and Evidence-based Medicine, Capital Medical University, served as independent statisticians and epidemiologists for supervision, consultation, and validation.
References
- 1. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, Marras C, San Luciano M, Tanner C. The epidemiology of Parkinson’s disease. Lancet. 2024;403(10423):283–92. pmid:38245248
- 2. Tanner CM, Ostrem JL. Parkinson’s disease. N Engl J Med. 2024;391(5):442–52. pmid:39083773
- 3. GBD 2021 Nervous System Disorders Collaborators. Global, regional, and national burden of disorders affecting the nervous system, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Neurol. 2024;23(4):344–81. pmid:38493795
- 4. Siderowf A, Concha-Marambio L, Lafontant D-E, Farris CM, Ma Y, Urenia PA, et al. Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using α-synuclein seed amplification: a cross-sectional study. Lancet Neurol. 2023;22(5):407–17. pmid:37059509
- 5. Turcano P, Mielke MM, Bower JH, Parisi JE, Cutsforth-Gregory JK, Ahlskog JE, et al. Levodopa-induced dyskinesia in Parkinson disease: a population-based cohort study. Neurology. 2018;91(24):e2238–43. pmid:30404780
- 6. Foltynie T, Bruno V, Fox S, Kühn AA, Lindop F, Lees AJ. Medical, surgical, and physical treatments for Parkinson’s disease. Lancet. 2024;403(10423):305–24. pmid:38245250
- 7. Okun MS. Deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2012;367(16):1529–38. pmid:23075179
- 8. Deuschl G, Antonini A, Costa J, Śmiłowska K, Berg D, Corvol J-C, et al. European Academy of Neurology/Movement Disorder Society - European Section guideline on the treatment of Parkinson’s disease: I. Invasive therapies. Eur J Neurol. 2022;29(9):2580–95. pmid:35791766
- 9. Limousin P, Foltynie T. Long-term outcomes of deep brain stimulation in Parkinson disease. Nat Rev Neurol. 2019;15(4):234–42. pmid:30778210
- 10. Jost ST, Aloui S, Evans J, Ashkan K, Sauerbier A, Rizos A, et al. Neurostimulation for advanced parkinson disease and quality of life at 5 years: a nonrandomized controlled trial. JAMA Netw Open. 2024;7(1):e2352177. pmid:38236600
- 11. Wagle Shukla A, Okun MS. Surgical treatment of Parkinson’s disease: patients, targets, devices, and approaches. Neurotherapeutics. 2014;11(1):47–59. pmid:24198187
- 12. Limousin P, Krack P, Pollak P, Benazzouz A, Ardouin C, Hoffmann D, et al. Electrical stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 1998;339(16):1105–11. pmid:9770557
- 13. Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schäfer H, Bötzel K, et al. A randomized trial of deep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006;355(9):896–908. pmid:16943402
- 14. Weaver FM, Follett K, Stern M, Hur K, Harris C, Marks WJ Jr, et al. Bilateral deep brain stimulation vs best medical therapy for patients with advanced Parkinson disease: a randomized controlled trial. JAMA. 2009;301(1):63–73. pmid:19126811
- 15. Okun MS, Gallo BV, Mandybur G, Jagid J, Foote KD, Revilla FJ, et al. Subthalamic deep brain stimulation with a constant-current device in Parkinson’s disease: an open-label randomised controlled trial. Lancet Neurol. 2012;11(2):140–9. pmid:22239915
- 16. Williams A, Gill S, Varma T, Jenkinson C, Quinn N, Mitchell R, et al. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol. 2010;9(6):581–91. pmid:20434403
- 17. Schüpbach WMM, Maltête D, Houeto JL, du Montcel ST, Mallet L, Welter ML, et al. Neurosurgery at an earlier stage of Parkinson disease: a randomized, controlled trial. Neurology. 2007;68(4):267–71. pmid:17151341
- 18. Karceski S. Does deep brain stimulation help early or mild Parkinson disease?. Neurology. 2018;91(5):e495–7. pmid:30061351
- 19. Hacker ML, Turchan M, Heusinkveld LE, Currie AD, Millan SH, Molinari AL, et al. Deep brain stimulation in early-stage Parkinson disease: five-year outcomes. Neurology. 2020;95(4):e393–401. pmid:32601120
- 20. Schuepbach WMM, Rau J, Knudsen K, Volkmann J, Krack P, Timmermann L, et al. Neurostimulation for Parkinson’s disease with early motor complications. N Engl J Med. 2013;368(7):610–22. pmid:23406026
- 21. Cabrera LY, Goudreau J, Sidiropoulos C. Critical appraisal of the recent US FDA approval for earlier DBS intervention. Neurology. 2018;91(3):133–6. pmid:29898975
- 22. Hartmann CJ, Fliegen S, Groiss SJ, Wojtecki L, Schnitzler A. An update on best practice of deep brain stimulation in Parkinson’s disease. Ther Adv Neurol Disord. 2019;12:1756286419838096. pmid:30944587
- 23. Okun MS, Foote KD. Parkinson’s disease DBS: what, when, who and why? The time has come to tailor DBS targets. Expert Rev Neurother. 2010;10(12):1847–57. pmid:21384698
- 24. deSouza R-M, Moro E, Lang AE, Schapira AHV. Timing of deep brain stimulation in Parkinson disease: a need for reappraisal? Ann Neurol. 2013;73(5):565–75. pmid:23483564
- 25. Deuschl G, Agid Y. Subthalamic neurostimulation for Parkinson’s disease with early fluctuations: balancing the risks and benefits. Lancet Neurol. 2013;12(10):1025–34. pmid:24050735
- 26. Olfati N, Shoeibi A, Litvan I. Progress in the treatment of Parkinson-Plus syndromes. Parkinsonism Relat Disord. 2019;59:101–10. pmid:30314846
- 27. Cavallieri F, Fraix V, Bove F, Mulas D, Tondelli M, Castrioto A, et al. Predictors of long-term outcome of subthalamic stimulation in Parkinson disease. Ann Neurol. 2021;89(3):587–97. pmid:33349939
- 28. Schuepbach WMM, Tonder L, Schnitzler A, Krack P, Rau J, Hartmann A, et al. Quality of life predicts outcome of deep brain stimulation in early Parkinson disease. Neurology. 2019;92(10):e1109–20. pmid:30737338
- 29. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370(9596):1453–7. pmid:18064739
- 30. Meng F, Hu W, Wang S, Tam J, Gao Y, Zhu XL, et al. Utilization, surgical populations, centers, coverages, regional balance, and their influential factors of deep brain stimulation for Parkinson’s disease: a large-scale multicenter cross-sectional study from 1997 to 2021. Int J Surg. 2023;109(11):3322–36. pmid:37463002
- 31. Wang S, Zhang Y, Ding W, Meng Y, Hu H, Liu Z, et al. Psychological distress and sleep problems when people are under interpersonal isolation during an epidemic: a nationwide multicenter cross-sectional study. Eur Psychiatry. 2020;63(1):e77. pmid:32854786
- 32. Wang S, Zhang Y, Guan Y, Ding W, Meng Y, Hu H, et al. A nationwide evaluation of the prevalence of and risk factors associated with anxiety, depression and insomnia symptoms during the return-to-work period of coronavirus disease 2019 in China. Soc Psychiatry Psychiatr Epidemiol. 2021;56(12):2275–86. pmid:33616693
- 33. Wang S, Liu Q-Z, Zhao R, Zhai X, Zhang K, Cai L, et al. Seizure, motor, and cognitive outcomes after epilepsy surgery for patients with sturge-weber syndrome: results from a multicenter study. Neurology. 2024;103(1):e209525. pmid:38875518
- 34. Wang S, Wang X, Zhao M, Li T, Zhang C, Wang M, et al. Long-term efficacy and cognitive effects of voltage-based deep brain stimulation for drug-resistant essential tremor. Clin Neurol Neurosurg. 2020;194:105940. pmid:32480294
- 35. Chen S, Gao G, Feng T, Zhang J, Chinese Medical Association Neurosurgery Branch of Functional Neurosurgery Group, Chinese Medical Association Neurology Branch of Parkinson’s Disease, et al. Chinese expert consensus on programming deep brain stimulation for patients with Parkinson’s disease. Transl Neurodegener. 2018;7:11. pmid:29719720
- 36. Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord. 2015;30(12):1591–601. pmid:26474316
- 37. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55(3):181–4. pmid:1564476
- 38. Wu W, Gong S, Wang S, Lei W, Yuan L, Wu W, et al. Safety and efficiency of deep brain stimulation in the elderly patients with Parkinson’s disease. CNS Neurosci Ther. 2024;30(8):e14899. pmid:39107966
- 39. Wakim AA, Mattar JB, Lambert M, Ponce FA. Perioperative complications of deep brain stimulation among patients with advanced age: a single-institution retrospective analysis. J Neurosurg. 2021;135(5):1421–8. pmid:33578378
- 40. Liu H, Ma Y, Zhang K, Ge M, Meng F, Feng T, et al. Subthalamic deep brain stimulation with a new device in Parkinson’s disease: an open-label trial. Neuromodulation. 2013;16(3):212–8; discussion 218. pmid:23551404
- 41. Wang S, Fan S, Gan Y, Zhang Y, Gao Y, Xue T, et al. Efficacy and safety of combined deep brain stimulation with capsulotomy for comorbid motor and psychiatric symptoms in Tourette’s syndrome: Experience and evidence. Asian J Psychiatr. 2024;94:103960. pmid:38368692
- 42. Post B, van den Heuvel L, van Prooije T, van Ruissen X, van de Warrenburg B, Nonnekes J. Young onset Parkinson’s disease: a modern and tailored approach. J Parkinsons Dis. 2020;10(s1):S29–36. pmid:32651336
- 43. Mehanna R, Jankovic J. Young-onset Parkinson’s disease: its unique features and their impact on quality of life. Parkinsonism Relat Disord. 2019;65:39–48. pmid:31176633
- 44. Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al. Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson’s disease. N Engl J Med. 2003;349(20):1925–34. pmid:14614167
- 45. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, et al. Movement Disorder Society-sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129–70. pmid:19025984
- 46. Martinez-Martin P, Rodriguez-Blazquez C, Alvarez-Sanchez M, Arakaki T, Bergareche-Yarza A, Chade A, et al. Expanded and independent validation of the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). J Neurol. 2013;260(1):228–36. pmid:22865238
- 47. Goetz CG, Choi D, Guo Y, Stebbins GT, Mestre TA, Luo S. It is as it was: MDS-UPDRS part III scores cannot be combined with other parts to give a valid sum. Mov Disord. 2023;38(2):342–7. pmid:36480107
- 48. Leentjens AFG, Dujardin K, Marsh L, Richard IH, Starkstein SE, Martinez-Martin P. Anxiety rating scales in Parkinson’s disease: a validation study of the Hamilton anxiety rating scale, the Beck anxiety inventory, and the hospital anxiety and depression scale. Mov Disord. 2011;26(3):407–15. pmid:21384425
- 49. Shabnam G-N, Th C, Kho D, H R, Ce C. Therapies for depression in Parkinson’s disease. Cochrane Database Syst Rev. 2003;(3):CD003465. pmid:12917968
- 50. Hagell P, Nygren C. The 39 item Parkinson’s disease questionnaire (PDQ-39) revisited: implications for evidence based medicine. J Neurol Neurosurg Psychiatry. 2007;78(11):1191–8. pmid:17442762
- 51. Tomlinson CL, Stowe R, Patel S, Rick C, Gray R, Clarke CE. Systematic review of levodopa dose equivalency reporting in Parkinson’s disease. Mov Disord. 2010;25(15):2649–53. pmid:21069833
- 52. Jost ST, Kaldenbach M-A, Antonini A, Martinez-Martin P, Timmermann L, Odin P, et al. Levodopa dose equivalency in Parkinson’s disease: updated systematic review and proposals. Mov Disord. 2023;38(7):1236–52. pmid:37147135
- 53. Hauser RA, Deckers F, Lehert P. Parkinson’s disease home diary: further validation and implications for clinical trials. Mov Disord. 2004;19(12):1409–13. pmid:15390057
- 54. Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, et al. Movement disorder society task force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord. 2004;19(9):1020–8. pmid:15372591
- 55. Smeding HMM, Speelman JD, Huizenga HM, Schuurman PR, Schmand B. Predictors of cognitive and psychosocial outcome after STN DBS in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 2011;82(7):754–60. pmid:19465417
- 56. Graham JW. Missing data analysis: making it work in the real world. Annu Rev Psychol. 2009;60:549–76. pmid:18652544
- 57. Krack P, Volkmann J, Tinkhauser G, Deuschl G. Deep brain stimulation in movement disorders: from experimental surgery to evidence-based therapy. Mov Disord. 2019;34(12):1795–810. pmid:31580535
- 58. Lachenmayer ML, Mürset M, Antih N, Debove I, Muellner J, Bompart M, et al. Subthalamic and pallidal deep brain stimulation for Parkinson’s disease-meta-analysis of outcomes. NPJ Parkinsons Dis. 2021;7(1):77. pmid:34489472
- 59. Bucur M, Papagno C. Deep brain stimulation in parkinson disease: a meta-analysis of the long-term neuropsychological outcomes. Neuropsychol Rev. 2023;33(2):307–46. pmid:35318587
- 60. Dafsari HS, Weiß L, Silverdale M, Rizos A, Reddy P, Ashkan K, et al. Short-term quality of life after subthalamic stimulation depends on non-motor symptoms in Parkinson’s disease. Brain Stimul. 2018;11(4):867–74. pmid:29655587
- 61. Jost ST, Visser-Vandewalle V, Rizos A, Loehrer PA, Silverdale M, Evans J, et al. Non-motor predictors of 36-month quality of life after subthalamic stimulation in Parkinson disease. NPJ Parkinsons Dis. 2021;7(1):48. pmid:34103534
- 62. Prange S, Lin Z, Nourredine M, Danaila T, Laurencin C, Lagha-Boukbiza O, et al. Limbic stimulation drives mania in STN-DBS in Parkinson disease: a prospective study. Ann Neurol. 2022;92(3):411–7. pmid:35703252
- 63. Eraifej J, Cabral J, Fernandes HM, Kahan J, He S, Mancini L, et al. Modulation of limbic resting-state networks by subthalamic nucleus deep brain stimulation. Netw Neurosci. 2023;7(2):478–95. pmid:37397890
- 64. Zoon TJC, van Rooijen G, Balm GMFC, Bergfeld IO, Daams JG, Krack P, et al. Apathy induced by subthalamic nucleus deep brain stimulation in Parkinson’s disease: a meta-analysis. Mov Disord. 2021;36(2):317–26. pmid:33331023
- 65. Pal G, Mangone G, Hill EJ, Ouyang B, Liu Y, Lythe V, et al. Parkinson disease and subthalamic nucleus deep brain stimulation: cognitive effects in GBA mutation carriers. Ann Neurol. 2022;91(3):424–35. pmid:34984729
- 66. Kleiner-Fisman G, Herzog J, Fisman DN, Tamma F, Lyons KE, Pahwa R, et al. Subthalamic nucleus deep brain stimulation: summary and meta-analysis of outcomes. Mov Disord. 2006;21 Suppl 14:S290-304. pmid:16892449
- 67. Stoker V, Krack P, Tonder L, Barnett G, Durand-Zaleski I, Schnitzler A, et al. Deep brain stimulation impact on social and occupational functioning in Parkinson’s disease with early motor complications. Mov Disord Clin Pract. 2020;7(6):672–80. pmid:32775513
- 68. Deuschl G, Schüpbach M, Knudsen K, Pinsker MO, Cornu P, Rau J, et al. Stimulation of the subthalamic nucleus at an earlier disease stage of Parkinson’s disease: concept and standards of the EARLYSTIM-study. Parkinsonism Relat Disord. 2013;19(1):56–61. pmid:22841616
- 69. Charles D, Konrad PE, Neimat JS, Molinari AL, Tramontana MG, Finder SG, et al. Subthalamic nucleus deep brain stimulation in early stage Parkinson’s disease. Parkinsonism Relat Disord. 2014;20(7):731–7. pmid:24768120
- 70. Hariz M. There is no credible rational for deep brain stimulation in very early Parkinson’s disease!. Parkinsonism Relat Disord. 2015;21(3):345–6. pmid:25443552
- 71. Piboolnurak P, Lang AE, Lozano AM, Miyasaki JM, Saint-Cyr JA, Poon Y-YW, et al. Levodopa response in long-term bilateral subthalamic stimulation for Parkinson’s disease. Mov Disord. 2007;22(7):990–7. pmid:17443692
- 72. Deuschl G, Follett KA, Luo P, Rau J, Weaver FM, Paschen S, et al. Comparing two randomized deep brain stimulation trials for Parkinson’s disease. J Neurosurg. 2019;132(5):1376–84. pmid:30952118
- 73. Rughani A, Schwalb JM, Sidiropoulos C, Pilitsis J, Ramirez-Zamora A, Sweet JA, et al. Congress of neurological surgeons systematic review and evidence-based guideline on subthalamic nucleus and globus pallidus internus deep brain stimulation for the treatment of patients with Parkinson’s disease: executive summary. Neurosurgery. 2018;82(6):753–6. pmid:29538685
- 74. Hariz M, Blomstedt P. Deep brain stimulation for Parkinson’s disease. J Intern Med. 2022;292(5):764–78. pmid:35798568
- 75. Huang YH, Chen JH, Loh EW, Chan L, Hong CT. The effect of monoamine oxidase-B inhibitors on the alleviation of depressive symptoms in Parkinson’s disease: meta-analysis of randomized controlled trials. Ther Adv Psychopharmacol. 2021;11:2045125320985993. pmid:33520156
- 76. Badihian N, Jackson LM, Klassen BT, Hassan A, Low PA, Singer W, et al. The effects of deep brain stimulation in patients with multiple system atrophy. J Parkinsons Dis. 2022;12(8):2595–600. pmid:36442207
- 77. Merola A, Zibetti M, Angrisano S, Rizzi L, Ricchi V, Artusi CA, et al. Parkinson’s disease progression at 30 years: a study of subthalamic deep brain-stimulated patients. Brain. 2011;134(Pt 7):2074–84. pmid:21666262
- 78. Tsai S-T, Lin S-H, Chou Y-C, Pan Y-H, Hung H-Y, Li C-W, et al. Prognostic factors of subthalamic stimulation in Parkinson’s disease: a comparative study between short- and long-term effects. Stereotact Funct Neurosurg. 2009;87(4):241–8. pmid:19556833