Clinical Benefits of Reprogramming Chronic Subthalamic Stimulation in Parkinson's Disease

Abstract

Background

Reprogramming of chronic deep brain stimulation (DBS) in Parkinson's disease is often underutilized despite potential clinical benefit.

Objective

The aim was to assess the impact of systematic reprogramming in patients with long‐term subthalamic nucleus (STN) DBS.

Methods

Ten patients with long‐term STN‐DBS underwent systematic reprogramming due to recurrence of motor symptoms or increased medication needs. Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) Part III scores (medication off/DBS ON) and levodopa equivalent daily dose (LEDD) were compared across initial programming, pre‐reprogramming, and post‐reprogramming using repeated‐measures analysis of variance (ANOVA).

Results

Reprogramming yielded a significant 24% improvement in MDS‐UPDRS Part III scores (P = 0.02) without significant LEDD change. Imaging revealed that reprogramming commonly engaged dorsolateral or supra‐STN regions by increasing amplitude or changing from bipolar to monopolar settings while maintaining contact pairs.

Conclusions

Systematic reprogramming can improve long‐term motor outcomes in STN‐DBS. Imaging may assist in understanding and guiding effective reprogramming strategies.

Deep brain stimulation (DBS) is a well‐established treatment for alleviating motor symptoms and treatment‐related complications in patients with advanced Parkinson's disease. ¹ Although subthalamic nucleus (STN) DBS can sustain motor improvements for at least 5 years ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ —with reported gains of 24% to 73% ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ and levodopa equivalent daily dose (LEDD) reductions of 23% to 63% ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ , ¹⁴ , ¹⁵ , ¹⁶ —disease progression can attenuate these benefits, ¹⁷ , ¹⁸ , ¹⁹ necessitating stimulation adjustments to maintain clinical benefits in the long term.

To address diminishing DBS efficacy, stimulation parameters are often remodified. Systematic reprogramming—defined by a structured, contact‐by‐contact, and parameter‐wise evaluation—aims to identify the most effective stimulation configuration. ²⁰ , ²¹ Unlike empirical approaches guided only by clinical judgment or patient feedback, systematic reprogramming offers a more objective and comprehensive optimization method. However, despite its potential to achieve sustained benefit, it remains underutilized due to its time‐consuming nature and patient burden. Furthermore, its practical application and long‐term benefits are infrequently reported in the literature. ²² , ²³

This case series evaluates the clinical significance of systematic DBS reprogramming in Parkinson's disease patients undergoing long‐term stimulation. By integrating image‐guided mapping, ²⁴ we analyze the spatial relationship between active contacts and clinical outcomes to validate the anatomical basis of stimulation efficacy. This study aims to support its broader application in chronic DBS management.

Patients and Methods

Patient Selection

We retrospectively reviewed 10 patients who underwent systematic reprogramming of STN‐DBS between July 2020 and June 2021 (Table 1). All patients with advanced Parkinson's disease were implanted with either nondirectional (Lead Model 3389, Activa PC, Medtronic, Minneapolis, MN, USA; patients 1–9) or directional (Vercise Cartesia, Gevia, Boston Scientific, Marlborough, MA, USA; patient 10) lead systems, as previously described. ²⁵ They were consecutively selected from a cohort of 99 patients based on predefined inclusion criteria: return to preoperative baseline in either medication off/DBS ON Movement Disorders Society‐Unified Parkinson's Disease Rating Scale Part III (MDS‐UPDRS III) score or LEDD. Although some of the remaining 89 patients exhibited clinical decline, they did not meet the inclusion criteria and were instead managed with conventional DBS or medication adjustments. All patients provided written informed consent. The study protocol was approved by the institutional review board of the Medical Research Institute Kitano Hospital (2108004).

TABLE 1.

DBS reprogramming and therapeutic effects

Patient	Age*, sex	Stimulation parameters** cathode (−) and anode (+); amplitude (mA)			TEED (μW)***		MDS‐UPDRS III score		LEDD
		Reprogramming	R	L	R	L	Score	Score improvement (%)	Dosage (mg)	Reduction (%)
1	43, F	Before	#1–#2+; 1.5	#0–#3+; 2.4	38.2	47.4	17	18	1509	0
		After	#1–#2+; 1.8	#1–#2+ ; 2.7	54.7	93.6	14		1509
2	64, M	Before	#2–#C+; 3.8	#1–#C+; 3.8	111.6	91.5	15	20	2167	6.8
		After	#2–#C+; 3.4	#2– #C+; 3.8	91.2	101.0	12		2020
3	64, M	Before	#2–#C+; 2.8	#3–#C+; 3.2	71.0	109.8	38	34	350	0
		After	#2–#C+; 2.8	#2–#C+; 3.2	71.9	105.4	25		350
4	55, M	Before	#1–#C+; 1.8	#1–#C+; 2.2	20.3	56.7	30	47	1372	0
		After	#2– #C+; 2.8	#1–#C+; 2.2	49.3	54.1	16		1372
5	54, M	Before	#1−/#2–#C+; 3.0/3.0	#1−/#2–#C+; 3.0/3.0	62/61.1	70.1/66.4	22	18	905	9.4
		After	#1−/#2–#C+; 3.5 /3.0	#1−/#2–#C+; 3.0/3.0	81.8/59.6	72.2/64.5	18		820
6	62, F	Before	#1–#3+; 2.4	#1–#C+; 2.0	60.7	32.2	42	2	1510	0
		After	#1–#3+; 2.4	#1–#C+; 2.3	61.7	42.3	41		1510
7	56, M	Before	#2−/#3– #C+; 3.0	#2–#C+; 2.8	n/a	n/a	29	28	1875	0
		After	#2 –#C+; 3.0	#2–#C+; 2.8	n/a	n/a	21		1875
8	66, M	Before	#2–#3+; 4.0	#2–#3+; 3.0	122.3	93.9	54	50	1340	7.5
		After	#2–#C+ ; 3.2	#2–#C+; 3.2	65.3	91.6	27		1240
9	63, M	Before	#1–C+; 2.3	#1–C+; 3.0	33.6	105.4	48	19	1688	0
		After	#1–C+; 2.3	#1–C+; 4.0	34.2	187.0	39		1688
10	65, M	Before	#2–C+; 2.5	#1–C+; 1.9	122.0	26.6	51	24	1020	0
		After	#1−/#7– C+; 2.8/1.0	#1−/#6–C+; 2.5/1.0	81.9/14.9	57.8/20.9	39		1020

Red and bold text indicates changed stimulation contacts or amplitudes after reprogramming.

Abbreviations: DBS, deep brain stimulation; TEED, total electrical energy delivered; MDS‐UPDRS III, Movement Disorder Society‐Unified Parkinson's Disease Rating Scale Part III: Motor Examination; LEDD, levodopa equivalent daily dose; n/a, not available.

^*Age at the time of study inclusion.

^**Stimulation parameters are reported as cathode (−) and anode (+), with amplitude in milliamperes. Pulse width and frequency were consistently set to 60 μs and 130 Hz, respectively, except in patient 5, who received interleaved stimulation at 125 Hz.

^*** $\text{TEED}=I^2\times R\times f\times pw,$ $\text{where}I\text{represents stimulation current},R\text{represents impedance},f\text{represents frequency},\text{and}\mathrm{PW}\text{represents pulse width}.$ For bipolar configuration, the same formula is used with the impedance measured between used bipolar contacts.

Systematic DBS Reprogramming

Reprogramming was performed in the medication off state. To ensure standardization, all antiparkinsonian medications, including long‐acting agents, were withheld overnight prior to evaluation. The interval between initial DBS programming and reprogramming was recorded (Table S1). Each contact was screened by increasing the current amplitude stepwise to determine therapeutic and side‐effect thresholds. Complex configurations (double contact, interleaved, or bipolar) were used when beneficial. Stimulation began at a pulse width of 60 μs and a frequency of 130 Hz; adjustments of these parameters were permitted during reprogramming.

Final MDS‐UPDRS III scores in the medication off/DBS ON state were recorded ~30 min after reprogramming, and the corresponding LEDD was recalculated. Reprogramming was done without reference to imaging data, and the clinician was blinded to electrode localization. Retrospective imaging analysis was independently performed using Lead‐DBS by separate examiners. Pre‐ and post‐reprogramming stimulation settings—including active contact configurations and parameter values—were documented and compared (Table 1). Based on these parameters, total electrical energy delivered (TEED, $\mathrm{\mu W}$) was calculated as

$$\text{TEED}\left[\mu \text{W}\right]=\left(I^2\times R\times \mathrm{pw}\times f\right)$$

where I is the amplitude (mA), R is the impedance (Ω), pw is the pulse width (μs), and f is the frequency (Hz) (Table 1). ²⁶ For bipolar configurations, TEED was calculated for each contact pair using the impedance between the selected contacts. ²⁶

DBS Lead Imaging Analysis

Alongside systematic reprogramming, we used 3D Slicer (https://www.slicer.org/) ²⁷ to assess possible DBS lead migration by comparing postoperative and follow‐up CT (computed tomography) images. Rigid registration identified lead tip coordinates, and Euclidean distance quantified displacement. Full details of the imaging workflow and lead migration analysis are provided in the Supplementary Methods.

Post hoc anatomical analysis was performed using Lead‐DBS (version 3.1, https://www.lead-dbs.org/). Active contacts were reconstructed in MNI ICBM 2009b Nonlinear Asymmetric space ²⁸ from coregistered CT/magnetic resonance imaging, and volumes of tissue activated (VTA) were estimated using the SimBio/FieldTrip model using patient‐specific stimulation parameters. Active contacts and VTAs were visualized using the DBS Intrinsic Template Atlas ²⁹ , and distances to the STN sweetspot ³⁰ were calculated. The control data were collected from 10 STN‐DBS Parkinson's disease patients with chronically stable conditions. Imaging workflows, spatial mapping procedures, and group comparison strategies are detailed in the Supplementary Methods.

Statistical Analysis

Descriptive data were summarized using frequencies, percentages, and means with ranges. The interval between initial and reprogramming sessions was reported as the median (interquartile range [IQR]) due to skewness. Longitudinal changes in MDS‐UPDRS III scores and LEDD across 4 timepoints (before and after initial programming, and before and after reprogramming) were assessed using repeated‐measures analysis of variance (ANOVA) with timepoint as the within‐subject factor and individual patients as repeated measures. Post hoc paired t‐tests with Bonferroni correction were applied. Sphericity was tested, and statistical significance was defined as a 2‐tailed P‐value <0.05 after Bonferroni adjustment. Analyses and visualizations were performed using R version 4.4.2 (https://www.R-project.org).

Results

Ten patients (8 men and 2 women; mean age: 59, range: 43–66; Table 1; Table S1) with STN‐DBS underwent reprogramming. After initial programming, all patients demonstrated significant improvements in medication off MDS‐UPDRS motor scores and reductions in LEDD (Fig. 1A,B). However, over time, they reported a waning of the STN‐DBS effects. The median time from initial DBS programming to reprogramming was 7.6 years (IQR: 3.3–9.4 years; Table 1). The average DBS lead displacement was minimal (right: 0.24 mm, left: 0.15 mm), with no patient exceeding 1 mm migration (Table S1; Fig. S1).

FIG. 1.

(A, B) Longitudinal changes in MDS‐UPDRS (Movement Disorder Society‐Unified Parkinson's Disease Rating Scale) Part III scores during the (A) medication off/DBS ON condition and (B) levodopa equivalent daily dose (LEDD) across 4 timepoints in patients undergoing STN‐DBS (subthalamic nucleus deep brain stimulation) reprogramming (n = 10). Each line represents an individual patient; dashed lines indicate group means. Timepoints include before initial DBS, after initial programming, before reprogramming, and after reprogramming. Statistical comparisons were performed using repeated‐measures ANOVA (analysis of variance) with Bonferroni correction. *P < 0.05, **P < 0.01, and ***P < 0.001. (C–F) Visualization of DBS leads, volumes of tissue activated (red) and STN subregions (sensorimotor [orange], associative [blue], limbic [yellow]) in 2 representative patients. In (C, D) patient 1, reprogramming increased amplitude and modified stimulation from a (C) broader bipolar configuration to (D, arrow) adjacent contacts. In (E, F) patient 10, reprogramming enhanced amplitude and added dorsal contacts bilaterally to target the (F, arrowheads) supra‐STN region.

After reprogramming, 9 of 20 STN‐DBS leads were adjusted to different contact settings (Table 1). Precisely, 4 leads were adjusted to dorsal contacts, 2 to ventral contacts, 2 switched from bipolar to monopolar settings, and 1 changed the bipolar contact pair. Post hoc Lead‐DBS analysis demonstrated that initial contacts were generally located within or near the STN (Fig. S2), and reprogramming optimized stimulation toward the dorsolateral subregions of the STN (Fig. 1C–F; Fig. S2). The final active contacts (Fig. S3) were located an average of 1.9 mm (left) and 2.1 mm (right) from the STN sweetspot. These distances were slightly greater, but not significantly different, compared to the control group (1.4 mm on the left, P = 0.089; 2.0 mm on the right, P = 0.047; see Supplementary Results). Among the 11 leads retaining the original contacts, 4 had an increased amplitude, and 1 decreased (Table 1). Pulse width and frequency adjustments were trialed in selected patients but yielded no consistent benefit. Final programming was based on amplitude modulation. TEED did not change significantly (paired t‐test, P = 0.32; Table 1).

Reprogramming significantly improved medication off/DBS ON MDS‐UPDRS III, with a mean reduction of 25% (range: 2.4%–50%). Pre‐reprogramming mean scores were 32 (range: 14–54), which improved to a post‐reprogramming mean of 24 (range: 12–41; Fig. 1A). Whereas reprogramming improved motor subscores in 4 to 7 patients, speech, facial expression, postural stability, posture, gait, and global spontaneity of movement worsened in 1 to 3 patients (Table S2). MDS‐UPDRS III scores differed significantly across the 4 timepoints (repeated‐measures ANOVA: F(3, df) = 7.005, P = 0.0008). Post hoc Bonferroni‐corrected pairwise comparisons revealed significant reductions in UPDRS scores after initial DBS programming (P = 0.0004), further improvements after reprogramming (P = 0.02), and significant reduction in UPDRS scores after initial DBS programming compared to baseline (P = 0.008), indicating a sustained improvement in motor symptoms from baseline through reprogramming.

Notably, patient 10, who exhibited moderate dyskinesia, experienced a significant reduction in dyskinesia after the additional supra‐STN stimulation, as assessed using MDS‐UPDRS Part IV; scores on items 4.1 and 4.2 decreased from 3 and 3 to 1 and 1, respectively (Fig. 1E,F).

The mean LEDD remained relatively unchanged after reprogramming, with a pre‐reprogramming dose of 1374 mg (range: 350–2167 mg) compared to a post‐reprogramming dose of 1340 mg (range: 350–2020 mg; Fig. 1B). Repeated‐measures ANOVA revealed no significant main effect of timepoint on LEDD (F(3, df) = 0.894, P = 0.448), indicating no overall group‐level change in medication dosage across the 4 timepoints. Post hoc Bonferroni‐corrected comparisons between individual timepoints identified an initial reduction after introduction of DBS (P = 0.01) but no further statistically significant reduction during reprogramming. Although some patients exhibited reductions in LEDD after initial programming or reprogramming, these changes were not consistent at the group level.

Adverse effects during reprogramming, assessed via MDS‐UPDRS III subscores (Table S2), included speech deterioration in 3 patients and gait disturbance in 2. At a mean follow‐up of 25 months (range: 16–29), mild speech disturbance in 1 patient and mild gait disturbances persisted in 1 patient. No hardware‐related complications were reported.

Discussion

Systematic reprogramming restored clinical benefit in several long‐standing STN‐DBS patients, with motor scores improving despite stable LEDD, suggesting medication was already optimized. Post hoc imaging showed that newly selected contacts often engaged dorsolateral or supra‐STN regions associated with motor improvement, but because imaging was retrospective, these observations remain descriptive.

Lead migration was minimal, yet periodic reassessment is advisable as disease progression or brain atrophy may subtly alter the optimal stimulation site. Although monopolar review averaged 60 to 90 min per session, it frequently uncovered superior configurations and revealed occasional speech or gait disturbances, underscoring the need for individualized programming. ²² , ²³ Combining clinical review with emerging electrophysiology‐ or image‐guided tools could shorten sessions while preserving patient‐specific adjustments.

This study's limitations included its small and single‐arm design without investigator or patient blinding, introducing observer bias and placebo effects; the absence of nonmotor or quality‐of‐life measures and reliance on post hoc electrode imaging rather than prospective guidance; and possible residual effects from long‐acting dopaminergic agonists despite overnight withdrawal. Limited exploration of pulse width and frequency, along with the modest sensitivity of the MDS‐UPDRS III to subtle stimulation‐induced side effects, such as mild dysarthria or gait disturbances, may also have constrained our observation. Symptom recurrence, despite anatomically similar lead locations in controls, may reflect disease progression or network‐level changes rather than suboptimal lead placement alone.

In conclusion, systematic, clinically guided reprogramming remains essential for managing symptom recurrence and side effects in chronic STN‐DBS. Although imaging and other advanced guidance methods can enhance efficiency, structured clinical evaluation is likely to remain central to long‐term DBS optimization.

Author Roles

(1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical analysis: A. Design, B. Execution, C. Review and critique; (3) Manuscript preparation: A. Writing of the first draft, B. Review and critique.

J.S.: 1A, 1C, 2B, 3A, 3B

Y.O.: 1A, 1B, 1C, 2C, 3B

S.I.: 1C, 2C, 3B

K.O.: 1C, 2C, 3B.

A.T.: 1C, 2C, 3B

M.S.: 1A, 1C, 2C, 3A, 3B

Y.T.: 1A, 1B, 1C, 2C, 3B

Y.S.: 1C, 2C, 3B

N.N.: 2C, 3B

T.I.: 1C, 2C, 3B

M.T.: 1B, 2C, 3B

S.K.: 1B, 2C, 3B

H.T.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

Disclosures

Ethical Compliance Statement: The Medical Research Institute Kitano Hospital institutional review board approved the study (ID 2108004). Written informed patient consent was obtained from the participants for this work. We confirm that we have read the journal's position on issues involved in ethical publication and affirm that this work complies with its guidelines.

Funding Sources and Conflicts of Interest: H.T. received a Grant‐in‐Aid for Scientific Research (C) 21K09116 and 24K12298 from the Japan Society for the Promotion of Science. The authors declare no conflicts of interest relevant to this work.

Financial Disclosures for the Previous 12 Months: Y.T. reported personal fees from Boston Scientific, AbbVie, Eisai, Ono Pharmaceutical, Kyowa Kirin, Sumitomo Pharma, Daiichi Sankyo, Takeda Pharmaceutical, Medtronic, Insightec, and Medixpost and grants from AbbVie outside the submitted work. The other authors declare that there are no additional disclosures to report.

Supporting information

Data S1. Supplementary methods and results. This document describes the imaging acquisition protocols, assessment of lead migration, reprogramming procedures, and retrospective imaging analysis using Lead‐DBS. It also includes statistical comparisons between the reprogrammed and control groups, along with electrode localization results and group‐level visualization findings.

Table S1. Patient profile, initial DBS (deep brain stimulation) effects, and lead migration assessment during chronic stimulation.

Table S2. MDS‐UPDRS (Movement Disorder Society‐Unified Parkinson's Disease Rating Scale) Part III subscore before and after reprogramming.

Figure S1. A spaghetti plot illustrating DBS (deep brain stimulation) lead tip migration between initial programming and reprogramming. Three‐dimensional trajectories connecting the DBS lead tip positions at initial programming and at chronic reprogramming for each patient. Red lines represent left‐sided leads, and blue lines represent right‐sided leads. The plot is shown in stereotactic space, where the x‐axis indicates mediolateral position (positive values lateral), the y‐axis indicates anteroposterior position (positive values posterior), and the z‐axis indicates dorsoventral position (positive values inferior). Each line connects the original and revised lead tip positions for individual electrodes, visualizing the degree and direction of positional change. Overall, only minor migrations were observed (<1 mm in all cases), supporting lead stability over time.

Figure S2. (A–J) Anatomical locations of initial and reprogrammed active contacts and their corresponding volumes of tissue activated (VTA) in patients 1 to 10. Reprogrammed VTAs are indicated by red spheres (arrows). Data were visualized using Lead‐DBS mapping in MNI (Montreal Neurological Institute) space on the DISTAL (DBS Intrinsic Template Atlas) to illustrate reprogrammed VTA. The subthalamic nucleus is shown with its functional subdivisions: sensorimotor zone (orange), limbic zone (yellow), and associative zone (blue).

Figure S3. (A, B) Axial and (C, D) coronal projections of subthalamic DBS (deep brain stimulation) lead locations in the reprogramming (A, C) and control (B, D) cohorts. Active contacts are shown in blue (A, C) and gray (B, D). The subthalamic nucleus (dark yellow) and red nucleus (dark red) are overlaid for anatomical reference.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.