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Abstract

Background:

Gait disturbances and balance remain challenging issues in Parkinsonian patients (PD) with deep brain stimulation (DBS). Short pulse deep brain stimulation (spDBS) increases the therapeutic window in PD patients, yet the effect on gait and postural symptoms remains unknown.

Objective:

We assessed the efficacy of spDBS compared to conventional DBS (cDBS) within the subthalamic nucleus (STN) on Parkinsonian gait.

Methods:

The study was a single-centre, randomized, double-blind, clinical short-term trial. 20 PD patients were studied postoperatively in three different conditions (DBS stimulation switched off (off DBS), spDBS with 40μs pulse width, cDBS with 60μs pulse width) on regular medication. The primary endpoint was the relative difference of gait velocity at self-paced speed during quantitative gait analysis between stimulation conditions. Secondary endpoints were changes of further measures of quantitative gait analysis, Ziegler course, Berg balance scale, FOG questionnaire, MDS-UPDRS, PDQ-39, and HADS. Mixed-model analysis and post-hoc t-tests were performed.

Results:

Both spDBS and cDBS improved gait velocity at self-paced speed compared to off DBS, however, there was no significant difference between both stimulation modes. Still, 40% of the patients preferred spDBS over cDBS subjectively. Both stimulation modes were equally effective in improving secondary endpoints of gait, balance, motor and non-motor performances.

Conclusion:

The use of spDBS and cDBS is equally effective in improving gait and balance in PD and might be beneficial in specified cohorts of PD patients.

Keywords

Deep brain stimulation freezing of gait gait disorder Parkinson’s disease short pulse width subthalamic nucleus

INTRODUCTION

Gait and balance disorders remain a tremendous challenge in the therapy of Parkinson’s disease (PD) with considerable reduction in quality of life [1]. Freezing of gait (FOG) represents one particularly disturbing “episodic” aspect of the gait disorder [2, 3], that seems to be interrelated to “continuous” PD gait characteristics as gait variability and gait asymmetry [4, 5].

Subthalamic nucleus deep brain stimulation (STN-DBS) has been proven to be highly effective in the improvement of cardinal motor symptoms in PD [6 –8]. Conventional settings of STN-DBS are continuous delivery of pulses at 130 Hz and 60μs pulse width (PW). However, with usage of this conventional DBS (cDBS) mode, there remain postoperative issues particularly in the long-term follow up of increasing numbers of operated PD patients [9], which require DBS reprogramming and trouble-shooting. Particularly gait disturbances represent postoperative remaining or newly occurring symptoms [10 –12]. For specific and targeted trouble-shooting of gait disturbances in PD, a focus of interest has become the development of new stimulation modes of STN-DBS. Current DBS strategies to treat gait disorders and FOG comprise low-frequency stimulation around 60 Hz [13, 14], adjustment of DBS amplitudes to compensate gait asymmetry as a “better-side-down” strategy [15] or combined subthalamic and nigral DBS to release the brainstem of inhibitory control [16].

Currently, new DBS devices were designed to enable the release of stimulation pulses with shorter PW than 60 μs. Short pulse DBS (spDBS) revealed in PD patients an increased therapeutic window and a reduction of unintentional side effects such as dysarthria [17 –20]. This new stimulation option was proven to be more energy-saving than DBS with longer PW and therefore minimized the frequency of recharging the DBS battery [17–19 , 21]. To date, the effect of spDBS on the Parkinsonian gait disorder remains unknown. The pathophysiological hypothesis of potential beneficial mechanisms of spDBS on gait would be that unintended current diffusion to structures around the STN, particularly bypassing small-diameter fibres of the pedunculopontine nucleus in the brainstem, could be avoided [13]. The aim of the present study is to assess effects of spDBS on gait, balance and FOG in PD and compare those effects with cDBS.

We conducted a randomized, double-blind, single-centre study comparing DBS with short PW (40μs) versus conventional PW (60μs) and DBS stimulation switched off (off DBS) using established clinical scores for gait and postural symptom assessments and quantitative gait analysis in PD patients.

METHODS

This single-centre, prospective study was conducted at the Department of Neurology of the University Medical Center Hamburg-Eppendorf between May 2018 and December 2019. The study was performed in accordance with the Declaration of Helsinki and approved by the local Ethics Committee of the Medical Council in Hamburg (Referenznr. PV5281). Written informed consent was given by all participants.

Participants

Twenty patients (6 females, mean age 63.1±1.5 years, mean disease duration 12.1±0.9 years, mean Hoehn & Yahr stage 2.4±0.1) diagnosed with PD with implanted STN-electrodes (mean time period between DBS surgery and study assessment 16.9±3.0 months) participated in the study. None of the PD patients suffered from clinically relevant cognitive decline with Montreal Cognitive Assessment (MoCA) scores > 22/30 points (see Table 1).

Table 1

Clinical and demographic characteristics of PD patients

Case, Sex, Age	MoCa	Disease Duration [yrs]	Month since Surgery	LEDD [mg]	DBS System	STN-DBS Parameters –40μs	STN-DBS Parameters –60μs	X/Y/Z - Coordinates
						Left Electrode	Left Electrode	Left Electrode [mm]
						Right Electrode	Right Electrode	Right Electrode [mm]
1 M 65	26	20	24	251.5	BS	2–33%, 3–33%, 4–33%, G+, 2.9 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 2.2 mA, 130 Hz	–11.91, –0.8, –4.44
						2–33%, 3–33%, 4–33%, G+, 3.2 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 2.4 mA, 130 Hz	11.1, –1.48, –3.99
2 F 68	30	12	24	634	BS	5–33%, 6–33%, 7–33%, G+, 3.8 mA, 130 Hz	5–33%, 6–33%, 7–33%, G+, 3.1 mA, 130 Hz	–12.16, 0.35, –2.94
						5–33%, 6–33%, 7–33%, G+, 4.4 mA, 130 Hz	5–33%, 6–33%, 7–33%, G+, 3.6 mA, 130 Hz	11.67, 1.73, –1.68
3 M 59	26	14	12	550	BS	2–33%, 3–33%, 4–33%, G+, 2.3 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.9 mA, 130 Hz	–11.95, 0.2, –1.57
						2–33%, 3–33%, 4–33%, G+, 2.3 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.9 mA, 130 Hz	10.36, –0.87, –1.5
4 M 51	27	3	3	400	BS	5–33%, 6–33%, 7–33%, G+, 4.6 mA, 136 Hz	5–33%, 6–33%, 7–33%, G+, 3.8 mA, 136 Hz	–12.66, 1.08, 1.54
						2–33%, 3–33%, 4–33%, G+, 5.5 mA, 136 Hz	2–33%, 3–33%, 4–33%, G+, 4.5 mA, 136 Hz	11.32, 1.5, –3.2
5 M 63	29	13	4	862.5	BS	2–33%, 3–33%, 4–33%, G+, 3.6 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 3.0 mA, 130 Hz	–13.94, 0.18, –4.4
						2–33%, 3–33%, 4–33%, G+, 2.1 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.7 mA, 130 Hz	12.55, –0.39, –5.73
6 M 52	29	11	19	1373.1	Abbott	2 B-, G+, 2.7 mA, 130 Hz	2 B-, G+, 2.2 mA, 130 Hz	–14.18, 0.91, –0.47
						11 A-, G+, 2.45 mA, 130 Hz	11 A-, G+, 2.0 mA, 130 Hz	12.97, –0.15, –0.6
7 M 63	29	7	4	1230	BS	2–33%, 3–33%, 4–33%, G+, 2.0 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.6 mA, 130 Hz	–13.17, –1.02, –1.63,
						2–33%, 3–33%, 4–33%, G+, 2.0 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.6 mA, 130 Hz	12.44, 0.58, –2.58
8 M 55	30	10	13	99.75	BS	2–100%, G+, 4.3 mA, 159 Hz	2–100%, G+, 3.5 mA, 159 Hz	–12.52, –0.78, –1.9
						5–100%, G+, 3.1 mA 159 Hz	5–100%, G+, 2.5 mA 159 Hz	13.89, 1.2, 1.36
9 M 52	30	13	24	1212.5	BS	1–100%, G+, 2.4 mA, 95 Hz	1–100%, G+, 2.0 mA, 95 Hz	–12.52, –2.08, –3.09
						1–100%, G+, 2.4 mA, 95 Hz	1–100%, G+, 2.0 mA, 95 Hz	11.56, –1.17, –4.07
10 F 68	27	10	35	998.25	BS	5–33%, 6–33%, 7–33%, G+, 2.5 mA, 154 Hz	5–33%, 6–33%, 7–33%, G+, 2.0 mA, 154 Hz	–14.27, 2.29, –1.33
						5–22%, 6–24%, 7–23%, 8–31%, G+, 5.7 mA, 154 Hz	5–22%, 6–24%, 7–23%, 8–31%, 4.7 mA, 154 Hz	14.55, 4.13, –1.37
11 M 68	27	18	24	1237.5	BS	2–33%, 3–33%, 4–33%, G+, 3.0 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 2.5 mA, 130 Hz	–13.64, –1.76, –0.59
						2–33%, 3–33%, 4–33%, G+, 3.6 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 3.0 mA, 130 Hz	11.58, –2.6, –1.95
12 M 60	28	6	4	600	Abbott	3 A-/B-/C-, G+, 3.1 mA, 130 Hz	3 A-/B-/C-, G+, 2.5 mA, 130 Hz	–13.16, –1.26, –1.17
						10 A-/B-/C-, G+, 2.4 mA, 130 Hz	10 A-/B-/C-, G+, 2.0 mA, 130 Hz	12.08, –0.31, –4.56
13 F 71	28	10	4	1312.5	Abbott	2 A-/B-/C-, G+, 1.5 mA, 130 Hz	2 A-/B-/C-, G+, 1.2 mA, 130 Hz	–12.48, –2.91, –3.6
						10 A-/B-/C-, G+, 2.2 mA, 130 Hz	10 A-/B-/C-, G+, 1.8 mA, 130 Hz	11.61, –2.49, –1.7
14 M 73	28	16	21	898.25	Abbott	2 A-/B-/C-, G+, 2.7 mA, 130 Hz	2 A-/B-/C-, G+, 2.2 mA, 130 Hz	–12.16, 0.1, –2.4
						10 A-/B-/C-, G+, 2.4 mA, 130 Hz	10 A-/B-/C-, G+, 2.0 mA, 130 Hz	10.24, –0.29, –3.63
15 M 60	25	15	13	598.5	BS	2–33%, 3–33%, 4–33%, G+, 2.4 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 2.0 mA, 130 Hz	–11.37, –2.48, –1.63
						2–33%, 3–33%, 4–33%, G+, 1.6 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.3 mA, 130 Hz	13.54, –1.84, –2.61
16 M 63	26	14	5	279.5	Abbott	3 A-/B-/C–, G+, 2.6 mA, 130 Hz	3 A-/B-/C-, G+, 2.2 mA, 130 Hz	–12.57, –0.74, –3.23
						11 A-/B-/C-, G+, 2.4 mA, 130 Hz	11 A-/B-/C-, G+, 2.0 mA, 130 Hz	11.83, –2, –1.56
17 F 66	30	13	52	1867.5	BS	4–100%, G+, 3.6 mA, 130 Hz	4–100%, G+, 3.0 mA, 130 Hz	–10.98, –0.59, –2.76
						4–50%, 5–50%, G+, 4.9 mA, 130 Hz	4-50%, 5-50%, G+, 4.0 mA, 130 Hz	8.15, –0.83, –2.85
18 F 71	25	11	38	699.75	BS	5–33%, 6–33%, 7–33%, G+, 3.5 mA, 130 Hz	5–33%, 6–33%, 7–33%, G+, 2.7 mA, 130 Hz	–11.87, –0.09, –2.78
						5–33%, 6–33%, 7–33%, G+, 3.5 mA, 130 Hz	5–33%, 6–33%, 7–33%, G+, 2.7 mA, 130 Hz	11.56, 0.93, –3.61
19 M 70	30	9	8	250	BS	2–33%, 3–33%, 4–33%, G+, 2.0 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.5 mA, 130 Hz	–12.21, –1.75, –2.43
						2–33%, 3–33%, 4–33%, G+, 2.4 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 1.8 mA, 130 Hz	11.58, –1.06, –1.37
20 F 63	27	16	7	140	BS	2–33%, 3–33%, 4–33%, G+, 4.5 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 3.5 mA, 130	–11.01, –0.84, –3.2
						2–33%, 3–33%, 4–33%, G+, 4.3 mA, 130 Hz	2–33%, 3–33%, 4–33%, G+, 3.3 mA, 130 Hz	11.17, –1.47, –1.34

Patient characteristics of the study population. Age, disease duration, month since surgery and LEDD (L-dopa equivalent daily dose) at study date. DBS parameters include the active contacts, voltage and frequency. BS, Boston Scientific; MoCA, Montreal Cognitive Assessment. X/Y/Z - coordinates relative to the midcommissural point (MCP) between anterior and posterior commissure (AC-PC).

Inclusion criteria were 1) clinical diagnosis of idiopathic PD according to the UK PD Society Brain Bank criteria; 2) bilateral STN-DBS electrode implantation; 3) use of DBS systems enabling the release of short pulses (Abbott, Boston Scientific); 4) time period > 3 months postoperatively to avoid perioperative DBS microlesioning effects; 5) clinically relevant gait disorder. Exclusion criteria were 1) other medical conditions resulting in gait disorders as spinal stenosis, musculoskeletal disorders, or polyneuropathy; 2) physical disability to perform intense motor tests and walks; 3) changes of medication or DBS settings within the last 4 weeks.

At postoperative study enrolment, 14 patients suffered from freezing of gait. One patient showed freezing of gait only during DBS stimulation switched on (on DBS), one patient only during off DBS and 12 patients during both on and off DBS. By comparison, preoperatively, 12 patients showed freezing of gait during medication off state (MED Off), 5 patients in both medication on (MED On) and off state and none only during MED On. Table 1 summarizes the demographic characteristics of the 20 patients included in the final analysis.

Study design

This single-centre, randomized, double-blind short-term trial was conducted to compare the effect of bilateral conventional STN-DBS (cDBS) using 60μs and STN-DBS with short pulses of 40μs (spDBS) vs. off DBS. The chronically active electrode contact was used in the experiment. Amplitudes were adjusted during spDBS along the total electrical energy delivered (TEED) [(amplitude²×frequency×pulse width)/impedance]. The frequencies remained unchanged during cDBS and spDBS (Table 1). The stereotactic coordinates (X/Y/Z-coordinates) of the active contacts were assessed via BrainLab^TM in relation to the midcommissural point (MCP).

Two movement disorder specialists attended the experiment, the unblinded “therapeutic investigator” adjusting the stimulation parameters and the blinded “evaluating investigator” assessing the clinical benefit. Throughout the trial, PD patients were blinded to the counterbalanced order of the three stimulation conditions. Patients were requested 1) to complete questionnaires (Table 2); 2) to perform clinical scores for motor, gait and balance assessment; 3) to conduct objective gait analyses using the GAITRite system (CIR Systems Inc.). After activating one stimulation condition, an intertrial interval of 30 minutes followed before the evaluation of the clinical benefit started. The participants were tested after intake of their regular medication. To assess patient’s subjective overall clinical impression, the patients were asked to assess the three stimulation conditions by their subjective preference from best to worst while they were still blinded. The experiment was performed on one day with a duration of 3.5 to 4 hours.

Table 2

Questionnaires

Questionnaires	Mean±SEM (range)
PDQ 39	28.8±3.6 (7 –72)
HADS A	5.1±0.7 (1 –12)
HADS D	4.8±0.6 (1 –9)
Giladi’s FOG	25.7±3.3 (1 –47)
MDS –UPDRS I	8.9±1.1 (2 –21)
MDS –UPDRS II	15.4±1.7 (5 –29)
MDS –UPDRS IV	5.1±1.1 (0 –13)

Assessment of the status of subjective health-related issues in the PD patient cohort. PDQ 39, Parkinson’s Disease Questionnaire with a maximum score of 100%indicating worse function; HADS A, Hospital Anxiety and Depression Scale –subscale ‘anxiety’; HADS D, Hospital Anxiety and Depression Scale –subscale ‘depression’ with a cut-off≥8 per subscale indicating a possible anxiety or depression disorder; Giladi’s FOG, Giladi’s Freezing of Gait Questionnaire with a maximum score of 64 indicating a high FOG severity; MDS –UPDRS, Unified Parkinson Disease Rating Scale of the Movement Disorder Society with a higher score indicating a severe disability: part I: nonmotor experiences of daily-living (maximum 52), part II: motor experiences of daily-living (maximum 52), part IV: motor complications (maximum 24).

Questionnaires and clinical assessment

Table 2 summarizes the mean values of questionnaires completed by the participants. Questionnaires included 1) German version of the Parkinson’s Disease Questionnaire (PDQ-39) [22], 2) Hospital Anxiety and Depression Scale (HADS) [23], and 3) German version of the FOG questionnaire [24]. Additionally, the Unified Parkinson Disease Rating Scale of the Movement Disorder Society (MDS-UPDRS) part I, II and IV were collected [25]. During the trial, three clinical scores were assessed 1) the revisioned MDS-UPDRS III [25], 2) the FOG Score [26], and 3) the Berg Balance Scale Short Form (BBS-SF) [27].

Quantitative gait analysis

Objective gait parameters were collected through the GAITRite System. The instrumented walkway scales overall 90 cm×7 m×3.2 mm with pressure sensors in a gridline pattern. The patients performed three different gait conditions. First, they walked at their self-paced, preferred walking speed (normal gait, NG). Second, they walked at their own maximum speed without starting to run (fast gait, FG). Third, they performed a dual task walk (DT). During DT walk, the participants were instructed to count backwards and, as an additional gait challenge, make a 180°- turn on the walkway, walking back on the walkway. Each gait condition (NG, FG, DT) was repeated three times. The following spatio-temporal gait parameters were measured: velocity (cm/sec), cadence (steps/min), step length (cm), stride length (cm), step width (cm), stride velocity (cm/sec), single support time (percentage of gait cycle time spent in single support) and double support time (percentage of gait cycle time spent in double support). As an index of gait asymmetry (GA), we calculated the ratio of the longer and shorter step length as well as the longer and shorter step time. Gait variability was computed by the coefficient of variability (CV) of step length, step time, stride length and stride time (CV = standard deviation/mean value^*100).

Data analysis

The primary outcome was the difference of gait velocity at self-paced speed during quantitative gait analysis between stimulation conditions. Sample size calculation for a single sample was performed with respect to the primary endpoint of the relative difference of stimulation induced changes of gait speed. Given an effect size of 0.2 cm/sec as a clinically relevant difference between stimulation conditions, an alpha 0.05/ beta 0.02, 19 PD patients needed to be assessed within the two stimulation conditions. With regard to a potential drop out rate, we assessed 20 PD patients.

Secondary outcomes were changes of further temporal and spatial measures of objective quantitative gait analysis as well as clinical scores. Statistics were performed using the IBM SPSS software version 25.0. Descriptives were given as means and standard error of means (SEM). Distribution was assessed with Shapiro-Wilk tests, histograms and Q-Q plots, respectively. If gait parameter were not normally distributed with a positively skewed distribution, they were natural log transformed to achieve normal distribution prior to analysis - negatively skewed distributions were first reverse-score transformed before the natural log transformation. We conducted mixed-model analysis (SPSS routine MIXED) using restricted maximum likelihood estimation and specified a model with random intercept for patient.

Gait parameters were analysed by using stimulation condition (spDBS, cDBS, off DBS), gait condition (NG, FG, DT) as fixed effects and the interaction terms stimulation condition×gait condition. Additionally, analysing lateralized gait parameters (step length, stride length, stride velocity, single support time, double support time, CV step length, CV stride length, CV step time, CV stride time) the fixed effect body side (best, worst) was added. Within the dual task walk, just the straight footfall patterns before turning on the walkway were analysed, the turning on the mat was excluded from further analysis. For MDS-UPDRS III the fixed effect was stimulation condition. FOG and BBS-SF were analysed by Friedman’s test. If significant, post-hoc pairwise comparisons were performed using Bonferroni correction for multiple comparisons.

To assess a correlation of results on stereotactic coordinates, we pooled bihemispheric active contact locations and used linear regression to compare the stereotactic coordinates of responders vs. non-responders. For all data, level of significance was set at α= 0.05.

RESULTS

Gait assessment by quantitative gait analysis

The primary endpoint was the difference between the extent of the relative stimulation induced improvement of gait velocity during normal gait at self-paced speed with spDBS versus cDBS. Compared to off DBS, gait velocity was slightly more increased during spDBS (16.38±6.44 cm/sec, 76.16±59.38 %) compared to cDBS (13.45±6.82 cm/sec, 73.05±61.05 %), however the difference was not significant (T = –1.258, p = 0.225).

Secondary endpoints of quantitative gait parameters in the three different gait conditions are outlined in Table 3. Four patients tolerated poorly off DBS and stopped this condition prematurely during the different gait tasks. Mixed-model analysis revealed for most gait parameters a significant effect for the factor “gait condition” and “stimulation condition”, however no interaction effect, indicating that the effect of the stimulation was independent of the gait condition.

Table 3

Objective Gait parameters

					p ^*
Gait Parameter	Gait Condition	off DBS	spDBS	cDBS	off DBS vs. spDBS	off DBS vs. cDBS	spDBS vs. cDBS
Velocity (cm/sec)	NG	93.8±7.2 (9.8 – 135.2)	109.5±3.9 (74.9 – 148.1)	107.2±5.1 (58.4 – 151.9)	0.002	0.002	NS
	FG	140.0±8.0 (68.4 – 201.2)	148.9±6.6 (94.4 – 202.3)	150.5±6.6 (98.1 – 197.6)
	DT	94.2±5.2 (57.6 – 126.9)	95.8±4.8 (47.5 – 145.0)	96.5±5.1 (60.5 – 141.6)
Cadence (steps/min)	NG	107.5±4.7 (50.9 – 135.3)	109.5±2.8 (86.2 – 130.8)	107.4±2.7 (88.5 – 128.0)	NS	NS	NS
	FG	129.0±3.0 (100.5 – 144.9)	128.0±2.6 (100.0 – 149.8)	126.9±2.5 (100.9 – 146.0)
	DT	108.6±3.9 (79.1 – 128.7)	106.5±4.2 (57.7 – 130.8)	105.4±4.1 (68.7 – 136.3)
Step Length (cm)	NG	51.6±3.8 (11.5 – 78.9)	60.4±2.2 (44.4 – 78.5)	60.0±2.7 (37.0 – 83.4)	0.000	0.000	NS
	FG	65.5±3.7 (31.1 – 94.1)	69.9±2.9 (43.9 – 93.7)	71.3±3.0 (45.2 – 94.7)
	DT	52.3±2.7 (36.5 – 69.7)	54.5±2.4 (39.3 – 78.1)	55.1±2.3 (35.3 – 77.8)
Stride Length (cm)	NG	103.6±7.6 (23.1 – 158.4)	121.3±4.4 (89.0 – 157.1)	120.5±5.4 (74.2 – 167.5)	0.000	0.000	NS
	FG	131.5±7.4 (62.3 – 188.4)	140.4±5.9 (88.0 – 187.9)	142.9±5.8 (91.0 – 189.9)
	DT	104.9±5.4 (73.2 – 139.9)	109.3±4.9 (79.3 – 156.7)	110.6±4.6 (70.9 – 156.0)
Stride Velocity (cm/sec)	NG	94.5±7.3 (10.0 – 136.2)	110.6±4.0 (75.5 – 149.0)	108.3±5.2 (58.8 – 153.6)	0.000	0.000	NS
	FG	141.2±8.0 (68.2 – 203.2)	150.7±6.8 (95.5 – 203.9)	152.2±6.7 (99.3 – 200.2)
	DT	94.9±5.2 (57.9 – 126.3)	96.8±4.8 (47.0 – 145.9)	97.4±5.1 (61.0 – 143.0)
Single Support (%)	NG	32.3±1.5 (10.3 – 37.6)	35.0±0.5 (31.4 – 37.8)	34.5±0.7 (28.3 – 38.4)	0.000	0.002	NS
	FG	36.6±0.7 (28.9 – 40.9)	37.1±0.5 (32.4 – 41.5)	37.2±0.5 (33.5 – 41.2)
	DT	33.7±0.5 (30.4 – 36.2)	34.1±0.6 (29.9 – 40.5)	33.8±0.6 (28.6 – 37.8)
Double Support (%)	NG	35.7±3.0 (25.2 – 82.6)	30.1±1.0 (23.6 – 38.0)	31.1±1.3 (22.7 – 45.0)	0.001	0.000	NS
	FG	26.8±1.4 (18.2 – 42.2)	25.7±1.1 (16.0 – 33.8)	25.6±1.0 (17.9 – 32.6)
	DT	32.7±0.9 (27.3 – 39.5)	33.9±1.7 (23.5 – 58.4)	32.2±1.2 (23.6 – 43.7)
Step Width (cm)	NG	10.9±0.7 (6.3 – 17.6)	10.1±0.5 (6.0 – 13.4)	9.4±0.5 (6.2 – 13.7)	NS	0.000	0.017
	FG	9.8±0.6 (4.8 – 13.6)	10.2±0.6 (3.9 – 15.4)	9.5±0.5 (6.0 – 15.6)
	DT	10.6±0.6 (6.2 – 14.7)	10.5±0.7 (5.5 – 16.2)	10.2±0.7 (5.4 – 16.3)

Effect of STN-DBS with short pulse width (40μs, spDBS) and conventional pulse width (60μs, cDBS) compared to off DBS on gait characteristics during objective gait analysis. Mean values±SEM (range) calculated of both legs. NG, normal gait; FG, fast gait; DT, dual task; NS, not significant. ^*Overall p values regardless gait condition. spDBS and cDBS (NG, FG and DT): n = 20; off DBS: n = 19 for NG, n = 17 for FG, n = 16 for DT. Both stimulation modes improved equally gait characteristics compared to off DBS.

Effect of gait condition on gait parameters

Gait characteristics in PD patients differed significantly during the three different gait conditions NG, FG and DT. In Mixed-model analysis, the factor “gait condition” showed a significant effect on temporal gait parameters as velocity (F = 162.908, p≤0.001), stride velocity (F = 349.026, p≤0.001), cadence (F = 103.390, p≤0.001), single support percentage time (F = 44.555, p≤0.001) and double support percentage time (F = 65.776, p≤0.001). Besides, there was a significant effect of the factor “gait condition” on variability of step time (F = 6.771, p = 0.001), variability of stride time (F = 10.020, p≤0.001) as well as on asymmetry of step time (F = 5.120, p = 0.007) as indirect markers of gait pattern stability. FG induced significant higher velocity and cadence compared to the other two gait conditions, combined with an increased single support and decreased double support time indicating prolonged swing-phases of the legs. In contrast, during DT, patients demonstrated a decrease of the walking speed combined with increased variability of step time, increased variability of stride velocity and enhanced asymmetry of step time indicating a more unstable gait pattern during DT.

The factor “gait condition” had also significant effect on spatial gait parameters as step length (F = 123.513, p≤0.001), stride length (F = 134.517, p≤0.001), step width (F = 3.955, p = 0.020) and variability of stride length (F = 7.634, p = 0.001). FG was characterised by a significant larger step and stride length. Interestingly, the variability of stride length was significant less in FG compared to both NG and DT indicating possibly a more stable gait pattern during FG. FG had no effect on gait asymmetry. During DT, patients demonstrated a decrease in their step and stride length. A significant difference for step width was found between FG and DT, with a widened step width during DT, again indicating a more unstable gait pattern during DT. In summary, walking with maximum speed during FG seemed to be the best gait condition with a stable gait pattern at high gait velocity, whereas gait with increased cognitive load during DT reduced gait stability and velocity.

Effect of stimulation condition on gait parameters

The factor “stimulation condition” in mixed-model analysis significantly affected temporal gait parameters velocity (F = 8.017, p≤0.001), stride velocity (F = 18.011, p≤0.001), single support time (F = 9.053, p≤0.001) and double support time (F = 9.204, p≤0.001). Regardless of the gait condition, there were significant improvements of temporal gait parameters in both spDBS and cDBS compared to off DBS as faster walking speed (NG: off DBS: 93.8±7.2 cm/sec, spDBS: 109.5±3.9 cm/sec, cDBS: 107.2±5.1 cm/sec) and an increased single support time (NG: off DBS: 32.3±1.5 %, spDBS: 35.0±0.5 %, cDBS: 34.5±0.7 %). Although both stimulation modes were significantly different to off DBS, there were no significant differences of temporal gait parameters between spDBS and cDBS. We found no evidence of stimulation effects on cadence, temporal variability or gait asymmetry.

Similarly, the factor “stimulation condition” significantly affected the spatial gait parameters step length (F = 26.849, p≤0.001), stride length (F =29.248, p≤0.001) and step width (F = 9.302, p≤0.001). Both stimulation modes were characterised by an increased step length (NG: off DBS: 51.6±3.8 cm, spDBS: 60.4±2.2 cm, cDBS: 60.0±2.7 cm) and stride length (NG: off DBS: 103.6±7.6, spDBS: 121.3±4.4 cm, cDBS: 120.5±5.4 cm) compared to off DBS, however without significant differences between spDBS and cDBS. Step width was significantly smaller during cDBS compared to spDBS (p = 0.017) or off DBS (p < 0.001) indicating a more insecure gait pattern during spDBS and off DBS. Furthermore, the factor “stimulation condition” showed a significant effect on step length variability (F = 6.065, p = 0.003) and stride length variability (F = 7.573, p = 0.001) with a decrease of step length and stride length variability in cDBS compared to off DBS, but no significant difference between spDBS and cDBS (Table 4). In summary, comparison of the three stimulation modes revealed recurrent findings with improvement of gait parameters by both stimulation modes compared to off DBS, but no significant difference between cDBS and spDBS, thus indicating no superiority of the new DBS mode spDBS.

Table 4

Gait variability and gait asymmetry

					p ^*
Gait Parameter	Gait Condition	off DBS	spDBS	cDBS	off DBS vs. spDBS	off DBS vs. cDBS	spDBS vs. cDBS
Step Length CV	NG	7.4±1.5 (2.7 – 28.0)	4.7±0.4 (2.9 – 8.2)	5.0±0.5 (2.3 – 10.6)	NS	0.002	NS
	FG	5.6±1.1 (1.8 – 21.9)	4.8±0.6 (2.1 – 12.1)	4.2±0.5 (1.9 – 10.1)
	DT	5.5±0.6 (2.4 – 11.7)	6.2±0.7 (1.6 – 13.0)	5.5±0.6 (1.6 – 12.0)
Step Time CV	NG	5.5±1.1 (2.2 – 20.5)	4.4±0.3 (1.6 – 7.2)	4.3±0.4 (2.7 – 10.0)	NS	NS	NS
	FG	3.9±0.3 (1.8 – 7.8)	4.4±0.3 (2.3 – 8.4)	4.2±0.3 (2.3 – 6.9)
	DT	4.4±0.5 (1.9 – 10.7)	7.6±2.5 (2.7 – 53.9)	6.2±0.9 (1.8 – 19.1)
Stride Length CV	NG	5.5±1.0 (1.9 – 17.1)	3.5±0.3 (1.7 – 6.6)	3.7±0.4 (1.6 – 9.4)	NS	0.000	NS
	FG	3.9±0.7 (0.7 – 12.7)	3.3±0.4 (1.4 – 9.3)	3.0±0.4 (1.4 – 8.8)
	DT	4.1±0.5 (1.4 – 9.7)	4.5±0.6 (1.2 – 10.5)	4.0±0.6 (0.6 – 10.4)
Stride Time CV	NG	4.0±0.8 (1.6 – 15.4)	3.0±0.3 (1.2 – 6.3)	2.9±0.3 (1.7 – 6.6)	NS	NS	NS
	FG	2.3±0.3 (1.1 – 4.9)	2.8±0.3 (1.2 – 7.6)	2.6±0.2 (1.2 – 3.8)
	DT	3.1±0.5 (1.0 – 8.8)	5.1±1.5 (1.1 – 33.0)	4.4±0.8 (0.6 – 14.4)
Step Length GA	NG	1.10±0.02 (1.02 – 1.31)	1.07±0.01 (1.01 – 1.19)	1.07±0.01 (1.01 – 1.24)	NS	NS	NS
	FG	1.11±0.06 (1.01 – 1.97)	1.08±0.01 (1.03 – 1.20)	1.08±0.02 (1.00 – 1.28)
	DT	1.07±0.01 (1.00 – 1.15)	1.10±0.02 (1.01 – 1.34)	1.10±0.02 (1.00 – 1.35)
Step Time GA	NG	1.04±0.01 (1.00 – 1.17)	1.04±0.01 (1.00 – 1.14)	1.04±0.01 (1.01 – 1.22)	NS	NS	NS
	FG	1.03±0.01 (1.00 – 1.13)	1.04±0.01 (1.01 – 1.09)	1.03±0.01 (1.01 – 1.09)
	DT	1.04±0.01 (1.00 – 1.07)	1.08±0.02 (1.00 – 1.35)	1.05±0.01 (1.00 – 1.11)

Effect of STN-DBS with short pulse width (40μs, spDBS) and conventional pulse width (60μs, cDBS) compared to off DBS on gait variability (CV) and gait asymmetry (GA) during objective gait analysis. Mean values±SEM (range) calculated of both legs. NG, normal gait; FG, fast gait; DT, dual task; NS, not significant. ^*Overall p values regardless gait condition. spDBS and cDBS (NG, FG and DT): n = 20; off DBS: n = 19 for NG, n = 17 for FG, n = 16 for DT.

Clinical scores

The factor “stimulation condition” had a significant effect on MDS-UPDRS III (F = 10.047, p≤0.001) (Table 5). Post-hoc pairwise comparisons showed a significant MDS-UPDRS III score difference between off DBS (36.1±4.6) and spDBS (26.2±3.3, p = 0.002) as well as off DBS and cDBS (25.6±3.4, p = 0.001), but no significant difference between spDBS and cDBS. We found no evidence that the factor “stimulation condition” affected FOG and balance impairment measured by Berg Balance scale (see Table 5).

Table 5

Clinical Scores

				p
Clinical Score	off DBS	spDBS	cDBS	off DBS vs. spDBS	off DBS vs. cDBS	spDBS vs. cDBS
MDS-UPDRS III	36.1±4.6 (5 – 57)	26.2±3.3 (5 – 67)	25.6±3.4 (14 – 78)	0.002	0.001	NS
FOG	7.4±2.4 (0 – 34)	4.0±1.2 (0 – 20)	4.4±1.3 (0 – 20)	NS	NS	NS
BBS-SF	25.3±0.7 (17 – 28)	26.2±0.5 (22 – 28)	26.3±0.5 (22 – 28)	NS	NS	NS

Effect of STN-DBS with short pulse width (40μs, spDBS) and conventional pulse width (60μs, cDBS) compared to off DBS on clinical scores. MDS-UPDRS III, motor part of Unified Parkinson Disease Rating Scale of the Movement Disorder Society with maximum score of 132 and higher scores indicating poorer condition; FOG, objective assessment of Freezing of Gait with a maximum score of 36 and higher scores indicating more severe FOG; BBS-SF, Berg Balance Scale –Short Form to evaluate balance impairment with a maximum score of 28 and higher scores indicating less balance impairment. Means±SEM (range) and p values of post-hoc t-tests analysis are given. n = 20 for spDBS and cDBS, n = 19 for off DBS. NS, not significant. Both stimulation modes improved MDS-UPDRS III items compared to off DBS, but not FOG or Berg Balance items.

Subjective overall clinical impression

The subjective overall clinical impressions of the patients were heterogeneous. Within all 20 PD patients, eight participants preferred spDBS and eight patients cDBS. One patient preferred off DBS. Three participants evaluated both “on” conditions as equally effective. We investigated whether stereotactic coordinates could be predictive of a responsiveness and benefit of spDBS versus cDBS. However linear regression of X/Y/Z-coordinates with the dependant factor clinical impression revealed no significant correlations (all p-values > 0.2). We also assessed linear regression of X/Y/Z-coordinates with the dependant factors velocity, step length, FOG and MDS-UPDRS III, but no significant correlation was found.

DISCUSSION

In this prospective, randomised, double-blind, short-term trial, we found no significant difference between stimulation-induced improvement of gait between conventional or short-pulse stimulation, thus the study failed to meet the primary and secondary end points. In terms of subjective impression, 40 %of the patients preferred spDBS, however we could not identify predictive factors for those patients with responsiveness of gait and postural symptoms to spDBS.

There are limitations of the study due to the experimental design. One limitation is the confinement to short-term effects of DBS neglecting long-term effects of chronic spDBS on gait. The wash-out period of 30 min might be short for the evaluation of postural and gait symptoms. Another limitation is the potential “ceiling effect” by the assessment of PD patients on their regular medication with the potential failure to detect subtle differences between stimulation algorithms. We aimed to assess the DBS stimulation modes in an “every-day” condition which might be easier to transfer in clinical routine practise. The assessment in the MED On condition risks potential residual fluctuations of dopa-responsive gait symptomatology within the experiment, however we included PD patients with no or less fluctuations postoperatively and randomized stimulation conditions to minimize interdependence of the recorded gait and postural performance on the medication phase. We compared only DBS conditions using pulse widths of 60μs vs. 40μs and not long pulses as 90μs. It remains to be speculated whether further enhancement of the pulse width to 90μs would have emphasised the contrast to short pulse DBS resulting in significant differences. We used stimulation settings for cDBS that we recorded on admission to hospital, that was 60μs, and assessed patients on regular medication. We aimed to implement a double-blind design in the best possible way for clinical DBS studies, yet, as PD patients commonly show worse motor function during off DBS, a possible unblinding by the evaluating investigator during off DBS cannot be fully eliminated.

Therapeutic options to treat gait disorders and FOG in PD remain a main challenge in clinical practise. One of the current therapeutic DBS strategies for optimizing the effect of STN-DBS on the PD gait disorder include frequency modulation such as low-frequency DBS [13], that was shown to be advantageous in about 64 %of PD patients in the long-term [28]. The pathophysiological hypothesis of potential mechanisms of low-frequency DBS was the assumption that current diffusion of conventional DBS to structures around the STN, particularly bypassing small-diameter fibres of the pedunculopontine nucleus in the brainstem, could result in worsening of gait [13].

Recent studies assessed potential mechanisms of action of spDBS. From computational modelling [18] it was proposed that spDBS might be more specific to activate selectively small-diameter, local STN axons along the chronaxie of neuronal elements compared to more distant and thick myelinated axons of the capsula interna [18] resulting in decreased side effects and an increased therapeutic window [17 , 20]. Another recent computational modelling study proposes that spDBS reduces side effects by non-dose equivalent stimulation resulting in reduced spread of neural activation [29]. While there are incongruent computational results in terms of mechanisms of action of short pulses, the clinical effect of reducing side effects due to unintentional co-stimulation of neighbourhood structures has become an important strategy of DBS troubleshooting in the clinical routine. With respect to the parkinsonian gait disorder, we hypothesised that spDBS might enhance the subthalamic fibre selectivity and preserve the accidental co-stimulation of bypassing pedunculopontine fibres. However, we could not confirm this hypothesis in general by the current findings.

This finding is in line with observations of a long-term study investigating the use of spDBS compared to cDBS in terms of dysarthria [30]. In that previous study, they found spDBS to be equivalent to cDBS in terms of dysarthric speech, but not superior [30]. They proposed to look at the individual level identifying responders and non-responders to short PW. In fact, our findings also suggest that some patient benefit of spDBS, as 40 %of patients preferred spDBS after finishing the trial.

In conclusion, this single-centre, randomised, double-blind trial revealed not significant different effects of spDBS compared to cDBS on gait and postural symptoms in PD, but in part of the patients a subjective superior benefit during spDBS. Future studies should focus on revealing factors predicting responsiveness to spDBS and investigate long-term effects of DBS with short pulses.

Footnotes

ACKNOWLEDGMENTS

We appreciate the assistance of Maja Kirsten.

This work was supported by a grant of the German Research Foundation (SFB 936, project C8).

CONFLICT OF INTEREST

A. Seger, E. Vettorazzi and H. Braaß report no disclosures.

A. Gulberti received travel reimbursements from Medtronic Inc.

C. Buhmann served on the scientific advisory boards for Bial and Zambon and received honoraria for lectures from Abbvie, Bial, GE Healthcare, Grünenthal, TAD and UCB.

C. Gerloff reports personal fees and other from Bayer Healthcare and Boehringer Ingelheim, personal fees from Acticor Biotech, Sanofi Aventis Amgene, and Prediction Bioscience.

C.K.E. Moll served as medico-scientific consultant to Abbott.

W. Hamel received lecture fees and honoraria for serving on advisory boards and travel grants from Boston Scientific, Medtronic, and Abbott.

M. Pötter-Nerger received lecture fees from Abbott and Licher, travel grants from Abbvie and served as consultant for Medtronic, Boston scientific, Abbvie and Abbott.

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Short Pulse and Conventional Deep Brain Stimulation Equally Improve the Parkinsonian Gait Disorder

Abstract

Background:

Objective:

Methods:

Results:

Conclusion:

Keywords

INTRODUCTION

METHODS

Participants

Study design

Questionnaires and clinical assessment

Quantitative gait analysis

Data analysis

RESULTS

Gait assessment by quantitative gait analysis

Effect of gait condition on gait parameters

Effect of stimulation condition on gait parameters

Clinical scores

Subjective overall clinical impression

DISCUSSION

Footnotes

ACKNOWLEDGMENTS

CONFLICT OF INTEREST

References