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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 2  |  Page : 457-460

Interleaved Stimulation for Freezing of Gait in Advanced Parkinson's Disease

1 Department of Neurology, Saifee Hospital, Mumbai, Maharashtra, India
2 Department of Neurology, All India Institute of Medical Sciences, New Delhi, India
3 Comprehensive Care Center for Movement Disorders, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India

Date of Submission15-Jul-2019
Date of Decision11-Jul-2020
Date of Acceptance06-Aug-2020
Date of Web Publication24-Apr-2021

Correspondence Address:
Asha Kishore
Senior Consultant and Movement Disorder Specialist Center of Excellence in Neurosciences Aster Medicity, Kochi - 682027, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.314570

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 » Abstract 

Background: Freezing of gait (FOG) is a disabling and refractory symptom of advanced Parkinson's disease (PD). Interleaved stimulation (ILS) is a novel paradigm which may benefit axial symptoms of PD.
Objectives: To assess the effect of ILS on FOG in patients unresponsive to conventional subthalamic nucleus (STN) stimulation.
Methods: 19 PD patients receiving subthalamic stimulation and experiencing FOG at both conventional (130–150Hz) and low frequency (60Hz) stimulation were given ILS.The primary outcome measure was the UPDRS part III gait score (item 29) at 3 months after ILS. A subset of patients was tested with the stand–walk–sit (SWS) test, 30 min after ILS.
Results: The mean UPDRS part III gait score (baseline: 1.8 ± 0.6) improved at 30 min (1.1 ± 0.8, P = 0.017) and remained improved at 3 months (1.2 ± 0.8, P = 0.048). FOG episodes reduced during SWS test (P = 0.041).
Conclusions: ILS of STN through two adjacent contacts provided significant short-term beneficial effects on FOG.

Keywords: Deep brain stimulation, freezing of gait, interleaved stimulation, Parkinson's disease, subthalamic nucleus
Key Message: Freezing of gait is a disabling and difficult to treat problem in advanced Parkinson′s disease. In selected patients with PD receiving subthalamic nucleus stimulation, interleaved stimulation may improve freezing of gait

How to cite this article:
Zafar SM, Rajan R, Krishnan S, Kesavapisharady K, Kishore A. Interleaved Stimulation for Freezing of Gait in Advanced Parkinson's Disease. Neurol India 2021;69:457-60

How to cite this URL:
Zafar SM, Rajan R, Krishnan S, Kesavapisharady K, Kishore A. Interleaved Stimulation for Freezing of Gait in Advanced Parkinson's Disease. Neurol India [serial online] 2021 [cited 2021 Jul 30];69:457-60. Available from:

Syed M Zafar, Roopa Rajan contributed equally to this work

Freezing of gait (FOG) is a common problem in advanced Parkinson's disease (PD) which contributes significantly to functional disability.[1] Therapeutic options that alleviate FOG are limited.[2] FOG may be Levodopa responsive in the initial stages of treatment.[2] Medication-unresponsive FOG is generally refractory to conventional subthalamic (STN) stimulation.[3],[4] Low frequency STN stimulation was shown to improve gait in a small subset of patients with FOG.[5] Pedunculopontine nucleus stimulation, though a promising approach, has not shown consistent beneficial effects.[6]

Axial symptoms including gait are known to respond to the modulation of frequency of STN stimulation.[7] Interleaved stimulation (ILS) is a programming strategy in which two different contact pairs on the same deep brain stimulation (DBS) lead are activated at the same frequency but with different amplitude and pulse width.[8] In ILS, the programmed contacts are activated in an alternating manner. The stimulation parameters can be modified to change the volume of tissue activated at each contact. An area of tissue activated will theoretically receive overlapping stimulation from the activated contacts, at double the set frequency. This strategy is effective in improving speech, controlling tremor and shaping the current flow to reduce stimulation-induced adverse effects.[9],[10] Unilateral ILS of STN improved FOG in a single patient.[11] Combined ILS of the STN and substantia nigra pars reticulata (SNr) is reported to improve FOG.[12] Given the sensitivity of FOG to frequency of stimulation, we conducted a pilot study to test the effect of ILS of STN on FOG in PD patients with FOG that was unresponsive to conventional stimulation.

 » Methods Top

We conducted a prospective, single-arm study in advanced PD patients who underwent bilateral STN stimulation in a single center. Subjects meeting all the following inclusion criteria were recruited: (1) PD with motor fluctuations and levodopa-induced dyskinesias who underwent bilateral STN-DBS; (2) Implanted with a pulse generator which allows interleaved stimulation; (3) FOG unresponsive to levodopa and monopolar stimulation at standard (130–150Hz) and low (≤60Hz) frequencies. Subjects meeting any of the following criteria were excluded: (1) symptomatic cognitive impairment; (2) wheelchair bound patients in stimulation ON after DBS; (3) patient and caregivers unable to manage operations of the patient therapy controller satisfactorily, in the judgment of the investigators. All patients had undergone stereotactic guided bilateral STN electrode implantation, with 5-channel micro electrode recording and clinical monitoring for benefits and adverse events. Written informed consent was obtained from all subjects and the study was approved by the institutional ethics committee.

All the programming sessions and assessments were performed in the stimulation-ON, medication-OFF state (12-h overnight withdrawal of all dopaminergic medications). Subjects were selected for ILS according to the algorithm in [Figure 1]. For ILS, the currently active contact (selected based on best response of the cardinal motor signs to conventional stimulation settings) and the contact adjacent to it were activated. For all stimulation parameter changes, it was attempted to maintain the same amount of total energy equivalent delivered using the formula: TEED = [(voltage × pulse width × frequency)/impedance]2.[12] We calculated the TEED in the baseline setting and attempted to maintain the same TEED shared between STN1 and STN2 for ILS. In subjects with suboptimal control of motor symptoms or troublesome dyskinesias with ILS, further adjustment of stimulation parameters and contacts was done. While switching to ILS, in the majority of patients, we used the just adjacent dorsal contact as the additional contact, in an attempt to avoid ventral/SNr stimulation. In some patients, where the dorsal contact revealed side effects or was estimated to be beyond the upper STN border (as per intraoperative electrophysiology/monopolar review) we activated the adjacent ventral contact. Outcome was assessed at baseline, 30 min after switching to ILS and 3 months after switching to ILS. Medication doses were kept unchanged during this period to maintain stable LEDD. The primary outcome measure was the UPDRS part III gait score (item 29). Secondary outcome measures were UPDRS III total scores and patient-reported global change on a 4-point scale. In a subset of patients, we performed the stand-walk-sit test, 30 min after switching to ILS. The Wilcoxon Signed Ranks Test was used to compare the UPDRS III gait scores before and after ILS.
Figure 1: Algorithm showing programming strategies undertaken prior to interleaved stimulation

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 » Results Top

19 subjects were enrolled and all completed the assessment at 3 months. The mean age of the study population was 59.8 ± 8.6 years (7 female).The mean duration of illness was 14.6 ± 4.7 years. Patients were receiving STN stimulation for a median of 24 (range: 12–120) months prior to enrolment. Baseline characteristics are shown in [Table 1]. The stimulation parameters before ILS and individual ILS parameters are shown in [Table 2]. All 19 subjects continued with the ILS settings for 3 months.
Table 1: Baseline characteristics

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Table 2: STN-DBS stimulation parameters before and after interleaved stimulation (ILS) in individual patients

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UPDRS III gait score

The mean UPDRS III gait (item 29) subscore at baseline was 1.8 ± 0.6 (range: 1–3). At 30 min after ILS, the mean gait score reduced to 1.1 ± 0.8 (range: 0–2, P = 0.017). At 3 months, the mean score (1.2 ± 0.8, range: 0–3, P = 0.048) remained significantly reduced compared to baseline.

Secondary outcomes

The total UPDRS III score remained similar at baseline (18.3 ± 10.2) and at three months (15.4 ± 8.0). At 30 min, 89% (17/19) subjects reported at least “some beneficial response” on FOG. This was sustained at three months in only 74% (14/19), with the rest reporting no benefit. No major stimulation-related adverse events were noted with ILS.

Stand-Walk-Sit (SWS) test

The SWS test was done in five subjects at baseline and 30 min after switching to ILS. There was a significant reduction in the number of freezing episodes at 30 min (mean number of episodes, 1.1 ± 2.5) compared to baseline (2.4 ± 1.1, P = 0.041) [Figure 2]. The time taken for completing SWS also improved (baseline: 41.5 ± 41.8, 30 min: 33.2 ± 31.2, P = 0.043). There was no change in the number of steps taken to complete the task (baseline: 31.0 ± 19.6, 30 min: 29.1 ± 19.6, P = 0.273).
Figure 2: Number of freezing of gait (FOG) episodes before (pre-ILS) and 30 min after switching to interleaved stimulation (post-ILS) on the stand-walk-sit test

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 » Discussion Top

In this preliminary study, ILS was found to be beneficial in improving gait in subjects with advanced PD receiving STN stimulation who had FOG unresponsive to levodopa and conventional stimulation settings. Given that postural instability and number of steps taken remained unchanged after ILS, the improvement in gait can be attributed to improvement in FOG. Majority of the patients (89%) reported improvement in FOG immediately after switching to ILS, and this effect was sustained in 74% even at three months. The overall control of motor symptoms remained stable, as evident from the UPDRS part III scores.

The mechanism of action of ILS is not clear. Specifically, FOG is known to be frequency- responsive as it improves with low frequency (60Hz) stimulation and with ILS during which the effective frequency at the overlapping region is doubled.[7] The beneficial effects may not only be due to a frequency change alone but also due to the alternating stimulation of different tissue volumes at the same frequency which may positively influence the cadence of walking.[10] Alternatively, a large volume of stimulation or higher frequency in the overlapping region may override the inhibitory influence on the cadence of gait. It is also possible that the beneficial effects were due to the ability to optimize stimulation in terms of current delivery and tissue volume beyond what was possible with conventional parameters alone.[13]

Our study has certain limitations; we have chosen a highly select group of patients with FOG unresponsive to conventional and low frequency stimulation. Our results may not hold true for a larger population of PD patients with FOG. We used the UPDRS part III item 29 as a measure of gait without objective gait analysis. However, UPDRS part III is routinely used in clinics worldwide to assess motor functions including gait and it correlates well with accelerometric gait variables in PD.[14] This is a single-arm study and further studies including a control group and blinded outcome assessment are required to establish a true effect. In many patients, further adjustments were required for optimal symptom control which may have led to deviations from the calculated TEED. However, this may be reflective of standard practice in clinical STN stimulation, and studies have previously shown that for narrow pulse width ranges below 100Hz, TEED remains relatively constant despite changes in frequency and voltage.[15] Finally, postoperative imaging was not available in this group to confirm the location of electrodes. Hence, a beneficial effect on FOG due to interleaved stimulation of structures other than the STN, such as the substantia nigra cannot be completely excluded.[12] However, we consider this less likely as all patients experienced good benefit on motor symptoms (other than gait) without adverse effects following STN stimulation prior to enrolment indicating placement within motor area of the STN.

In conclusion, this prospective study provides preliminary evidence that ILS of the STN may be beneficial in alleviating FOG in patients with advanced PD receiving conventional STN stimulation or despite low frequency stimulation. Randomized controlled studies of ILS with blinded objective outcome assessment including a larger number of patients are needed to confirm these findings.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Sree Chitra Tirunal Institute for Medical Sciences and Technology, Comprehensive Care Center for Movement Disorders in-house research funds.

Conflicts of interest

There are no conflicts of interest.

 » References Top

Macht M, Kaussner Y, Möller JC, Stiasny-Kolster K, Eggert KM, Krüger HP, et al. Predictors of freezing in Parkinson's disease: A survey of 6,620 patients. Mov Disord 2007;22:953-6.  Back to cited text no. 1
Nonnekes J, Snijders AH, Nutt JG, Deuschl G, Giladi N, Bloem BR. Freezing of gait: A practical approach to management. Lancet Neurol 2015;14:768-78.  Back to cited text no. 2
Schlenstedt C, Shalash A, Muthuraman M, Falk D, Witt K, Deuschl G. Effect of high-frequency subthalamic neurostimulation on gait and freezing of gait in Parkinson's disease: A systematic review and meta-analysis. Eur J Neurol 2017;24:18-26.  Back to cited text no. 3
Malek N. Deep brain stimulation in Parkinson's disease. Neurol India 2019;67:968-78.  Back to cited text no. 4
[PUBMED]  [Full text]  
Moreau C, Defebvre L, Destée A, Bleuse S, Clement F, Blatt JL, et al. STN-DBS frequency effects on freezing of gait in advanced Parkinson disease. Neurology 2008;71:80-4.  Back to cited text no. 5
Thevathasan W, Debu B, Aziz T, Bloem BR, Blahak C, Butson C, et al. Pedunculopontine nucleus deep brain stimulation in Parkinson's disease: A clinical review. Mov Disord 2018;33:10-20.  Back to cited text no. 6
Xie T, Vigil J, MacCracken E, Gasparaitis A, Young J, Kang W, et al. Low-frequency stimulation of STN-DBS reduces aspiration and freezing of gait in patients with PD. Neurology 2015;84:415-20.  Back to cited text no. 7
Miocinovic S, Khemani P, Whiddon R, Zeilman P, Martinez-Ramirez D, Okun MS, et al. Outcomes, management, and potential mechanisms of interleaving deep brain stimulation settings. Parkinsonism Relat Disord 2014;20:1434-7.  Back to cited text no. 8
Zhang S, Zhou P, Jiang S, Wang W, Li P. Interleaving subthalamic nucleus deep brain stimulation to avoid side effects while achieving satisfactory motor benefits in Parkinson disease: A report of 12 cases. Medicine (Baltimore) 2016;95:e5575.  Back to cited text no. 9
Ramirez-Zamora A, Kahn M, Campbell J, DeLaCruz P, Pilitsis JG. Interleaved programming of subthalamic deep brain stimulation to avoid adverse effects and preserve motor benefit in Parkinson's disease. J Neurol 2015;262:578-84.  Back to cited text no. 10
Brosius SN, Gonzalez CL, Shuresh J, Walker HC. Reversible improvement in severe freezing of gait from Parkinson's disease with unilateral interleaved subthalamic brain stimulation. Parkinsonism Relat Disord 2015;21:1469-70.  Back to cited text no. 11
Weiss D, Walach M, Meisner C, Fritz M, Scholten M, Breit S, et al. Nigral stimulation for resistant axial motor impairment in Parkinson's disease? A randomized controlled trial. Brain 2013;136:2098-108.  Back to cited text no. 12
Moro E, Esselink RJA, Xie J, Hommel M, Benabid AL, Pollak P. The impact on Parkinson's disease of electrical parameter settings in subthalamic nucleus stimulation. Neurology 2002;59:706-13.  Back to cited text no. 13
Mera TO, Filipkowski DE, Riley DE, Whitney CM, Walter BL, Gunzler SA, et al. Quantitative analysis of gait and balance response to deep brain stimulation in Parkinson's disease. Gait Posture 2013;38:109-14.  Back to cited text no. 14
Moro E, Lang E, Strafella AP, Poon YW, Arango PM, Dagher A, et al. Reply to: Calculating total electrical energy delivered by deep brain stimulation systems. Ann Neurol 2005;58:168-9.  Back to cited text no. 15


  [Figure 1], [Figure 2]

  [Table 1], [Table 2]


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