Next Article in Journal
Reply to Kalfert, D. Comment on “Zwierz et al. The Long-Term Effects of 12-Week Intranasal Steroid Therapy on Adenoid Size, Its Mucus Coverage and Otitis Media with Effusion: A Cohort Study in Preschool Children. J. Clin. Med. 2022, 11, 507”
Previous Article in Journal
Vertebral Osteomyelitis and Infective Endocarditis Co-Infection
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
JCM
Volume 11
Issue 8
10.3390/jcm11082269
jcm-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Combined Stimulation of the Substantia Nigra and the Subthalamic Nucleus for the Treatment of Refractory Gait Disturbances in Parkinson’s Disease: A Preliminary Study

by
Marta Villadóniga
1,
Lidia Cabañes-Martínez
1,*,
Laura López-Viñas
1,
Samira Fanjul
2,
Marta del Álamo
3 and
Ignacio Regidor
1
1
Department of Clinical Neurophysiology, Hospital Ramón y Cajal, 28034 Madrid, Spain
2
Department of Neurology, Hospital Ramón y Cajal, 28034 Madrid, Spain
3
Department of Neurosurgery, Hospital Ramón y Cajal, 28034 Madrid, Spain
*
Author to whom correspondence should be addressed.
J. Clin. Med. 2022, 11(8), 2269; https://doi.org/10.3390/jcm11082269
Submission received: 1 March 2022 / Revised: 11 April 2022 / Accepted: 12 April 2022 / Published: 18 April 2022
(This article belongs to the Section Clinical Neurology)
Browse Figures
Review Reports Versions Notes

Abstract

:
Deep brain stimulation of the subthalamic nucleus is efficient for the treatment of motor symptoms (i.e., tremors) in patients with Parkinson’s disease. Gait disorders usually appear during advanced stages of idiopathic Parkinson’s disease in up to 80% of patients and have an important impact on their quality of life. The effects of deep brain stimulation of the subthalamic nucleus on gait and balance are still controversial. For this reason, alternative targets have been considered, such as stimulation of the pedunculopontine nucleus and the pars reticulata of substantia nigra, involved in the integration of the functional connections for gait. Due to the proximity of the subthalamic nucleus to the substantia nigra, their combined stimulation is feasible and may lead to better outcomes, improving axial symptoms. Our objective was to prospectively compare simultaneous stimulation of both structures versus conventional subthalamic stimulation in improving gait disorders. In ten patients with advanced Parkinson’s disease, deep brain stimulation leads (eight linear contacts) were implanted, and gait analysis was performed 6 months after surgery in off-stimulation and after 4 weeks of dual or single subthalamic stimulation. An improvement in gait parameters was confirmed with both stimulation conditions, with better results with combined substantia nigra and subthalamic stimulation compared with conventional subthalamic stimulation. Further studies are needed to determine if this effect remains after long-term dual-target stimulation.

1. Introduction

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is an established surgical treatment for selected patients with Parkinson’s disease (PD) [1,2,3]. However, patients with prominent axial symptoms, i.e., gait disorders and instability, have not been considered good candidates, and the effects of STN-DBS on these symptoms remain controversial [4,5]. Gait disorders usually show up in advanced stages of idiopathic PD, appearing in up to 80% of patients [6,7]. This carries a detrimental impact on their quality of life [8]. Although there is evidence of the short-term beneficial effects of STN-DBS on gait and other axial symptoms [4,9], the long-term effect is a matter of debate [10,11]. For this reason, other lines of treatments have been considered, such as different stimulation parameters [12,13], stimulation of the Pedunculopontine nucleus (PPN) [14] and the pars reticulata of Substantia nigra (SNr) [4,15,16] involved in the integration of the functional connections for gait [17]. Due to the proximity of the STN to the SNr, their simultaneous stimulation is feasible and may lead to better outcomes and improved gait results [16,18].
The objective of our study was to demonstrate the beneficial effects of dual STN + SNr stimulation on gait and to test the hypothesis that STN + SNr-DBS is superior to STN-DBS in improving gait disturbances in advanced PD patients.

2. Materials and Methods

2.1. Design

This is a prospective, randomized, cross-over-2×2, double-blinded study carried out in a tertiary hospital in Madrid. Six months after surgery, we compared the effects on gait (through quantitative analysis of the percentage of complete cycles with a normal gait sequence) of dual stimulation (STN + SNr-DBS) with single stimulation (STN-DBS) after 4 weeks of treatment with each type of stimulation.

2.2. Subjects

Ten patients (6 male, 4 female, age 56.8 ± 5.6 years) suffering from advanced idiopathic PD (disease duration 6–15 years) participated in the study. They were treated with implantation of a linear octopolar electrode for DBS (Boston Scientific, Natick, MA, USA) and a rechargeable implantable pulse generator (Vercise™, Boston Scientific, Natick, MA, USA). We included patients with ages between 18 and 70 years, diagnosed with idiopathic PD (according to the British Brain Bank criteria) at an advanced stage, with a good response to levodopa but with refractory fluctuations and medication-induced dyskinesia, and with a disease duration of more than 5 years. All patients were candidates for DBS of the STN and SNr and had clinical, radiological and electrophysiological testing that verified the proper placement of electrodes in STN and SNr. Dopaminergic medication intake was unchanged for at least 4 weeks before surgical intervention. All patients signed informed consent before intervention. Exclusion criteria: pregnancy or planning to become pregnant during the course of the study, cognitive impairment (Mini-Mental State Exam under 25), participation in another study during the clinical trial or 3 months before, serious psychiatric or other severe pathological condition and acute adverse events arising from STN + SNr-DBS.

2.3. Study Protocol

Upon enrollment, the following evaluations were carried out (Figure 1):
  • Baseline: At least 6 months after surgery, the period during which the patients were receiving STN-DBS, quantitative gait analysis was performed. All patients were in off-stimulation (DBS stopped at least 48h before the analysis) and off-medication state (having stopped taking the medication for a minimum of 12 h before). After baseline evaluation, patients were randomized to be programmed in the corresponding stimulation mode (STN-DBS versus STN + SNr-DBS);
  • Visit 1: At the end of the first period, after four weeks, quantitative gait analysis in the off-medication state was repeated. Subsequently, the stimulation type was changed (STN + SNr-DBS vs. STN-DBS) for each group (cross-over);
  • Visit 2: After the second period, lasting 4 weeks, quantitative gait analysis in the off-medication state was repeated.

2.4. Locating the Electrodes

The spatial location of contacts on STN and SNr was determined by image fusion of the magnetic resonance (MR) image taken prior to surgery with the postoperative CT scan using a software System. Implantation of the octopolar electrode for DBS (Boston Scientific, Natick, MA, USA) was performed under local anesthesia using a Leksell (Elekta, Stockholm, Sweden) stereotactic frame at the 3D visualization (x, y and z coordinate system) for the location of STN and SNr. The intervention was performed in an off-medication state, and intraoperative single-cell recordings were used to confirm STN and SNr locations and determine the optimal electrode placement. The final location of the electrode was confirmed by neuronal activity and by relief of symptoms without adverse effects. The implantable pulse generator (VerciseTM, Boston Scientific, Natick, MA, USA) was placed in the subclavicular area and connected subcutaneously to the intracerebral electrodes. The electrodes and their anatomical positioning were visualized using 3D reconstruction software Guide XT (Boston Scientific Corp., Boston, MA, USA), verifying their position in STN and SNr.

2.5. Stimulation Parameters

New electric implantable pulse generators allowed us to distribute electric pulses using multiple independent current control (MICC) to fractionalize current so that the stimulation pulses were distributed at the same time between different contacts. Thus, each contact could be programmed with a specific amplitude while keeping the same stimulation frequency and pulse width for all contacts within one area, therefore enabling optimization of stimulation parameters, minimizing adverse effects [19]. The use of MICC allowed simultaneous stimulation with specific parameters in both areas, STN and SNr (Figure 2). With the selected stimulation parameters, we were able to stimulate both nuclei to maximize the patient’s clinical benefits. Motor symptoms were optimally controlled with the standard stimulation of the STN. The stimulation for both nuclei was delivered using a pulse duration of 60 µs and a stimulation frequency of 130 Hz.

2.6. Gait Analysis

Quantitative gait analysis was carried out using a multichannel recording device STEP 32 (DemItalia, Volpago del Montello, Italy). STEP 32 is a computerized system of movement analysis, which automatically records podobasographical signals and analyzes step cycle characteristics. In addition, this system allows simultaneous video camera recording. For the acquisition of the podobasographical signals, 6 foot switches were placed on the sole of both feet, distributed in the heel bone and the heads of the first and fifth metatarsi (Figure 3). The following parameters were obtained: the number of total cycles and percentage of cycles with normal sequence (heel strike, foot contact, push off and swing; HFPS). Participants were required to walk a distance of around 40 m. In order to obtain reliable results, we studied gait cycles relative to strides recorded during a walk along a straight walkaway; subjects were asked to walk back and forth the corridor twice. Strides involving deceleration, reversing and acceleration were removed automatically by the system, using a multivariate statistical filter that detected and eliminated outliers [20]. Given that currently, they are no normative values regarding the normal percentage of normal cycles, we considered the published data, and assumed that in a healthy subject, the percentage of atypical cycles is around 10% [21,22]. Accordingly, in subjects with gait impairment, the percentage of atypical cycles would be increased, and this fact may be used as a reliable outcome measure to evaluate even subtle improvements [20,21].

2.7. Statistical Analysis

For the purpose of evaluating the effectiveness of dual-target stimulation, assuming an improvement of 20% in the quantitative analysis of the STEP32 gait, a paired t-test was used. For statistical analysis, quantitative gait data from STEP32 were used to compare the effects of 4 weeks of stimulation of the STN versus dual-target stimulation of STN + SNr. The mean and standard error of the mean (SEM) were used due to their normal distribution. We used a paired t-test to test the null hypothesis of equality of these two conditions. Analysis was performed by means of the intent-to-treat strategy. The level of statistical significance required was set to p < 0.05, with bilateral contrast. All statistical analyses were carried out using Stata software (version 13.1. StataCorp. 2013. Stata Statistical Software: Release 13., StataCorp LP, College Station, TX, USA).

3. Results

A difference in the percentage of effective steps in the neurophysiological analysis of gait was found. There is a statistically significant difference in the mean of the normal cycles between STN-DBS and STN + SNr-DBS (p = 0.038). Data are summarized in Table 1 and Figure 4.

4. Discussion

In this randomized, double-blind, cross-over preliminary study, the effect of combined STN + SNr DBS compared to conventional STN-DBS on gait was studied by a quantitative analysis of gait using the STEP32 system, with the aim of determining the beneficial effects of combined stimulation (STN + SNr-DBS) on gait, and to test the hypothesis that STN + SNr-DBS is superior to STN-DBS for improving gait disturbances on advanced PD patients.
Previous reports described that the frequency of correct sequence cycles (HFPS) is markedly reduced in PD patients [21,23], even in the on-medication state. This parameter could be sensitive to detecting gait instability [20]. In previous studies by our group, this parameter improved markedly in PD patients after STN-DBS, along with the clinical scales (data not published). Here we investigated the percentage of cycles with normal sequence (HFPS) using quantitative gait analysis performed by STEP 32 after four weeks of constant stimulation in either (STN-DBS or STN + SNr-DBS) conditions. After the first 4 weeks, we changed to the other type of stimulation, and the patient remained with this new stimulation for another period of 4 weeks. The results of our study show that there is a significant difference between the pre-and post-surgical situation with regards to the percentage of complete cycles with a normal gait sequence (regardless of the stimulation type: STN-DBS, documenting previous observations in our clinic, or combined STN + SNr-DBS). Furthermore, there was a statistically significant difference in the improvement between these two types of stimulation, with better results when using the combined STN + SNr-DBS paradigm. In our opinion, this finding is especially relevant since spatial-temporal parameters of gait, as the percentage of complete gait cycles, reflect indirect biomarkers for the clinical phenomenon of freezing of gait [24], and their modulation through DBS plays an important role in the clinical improvement of PD patients.
The beneficial effects of simultaneous STN-SNr-DBS on gait [16,18,24,25,26] and other disabling parkinsonian symptoms [27,28] were already described. Our results are in accordance with previous reports, revealing a favorable effect of combined STN + SNr–DBS on gait in PD patients, and confirm the results of the only previous series of cases describing the effects on gait of combined DBS through quantitative gait analysis [24]. STEP 32 gait system equipment allows us to measure an important spatial gait characteristic, the percentage of steps with normal sequence. This parameter is reduced in patients with other pathologies with prominent gait disturbances [21,29] and with idiopathic PD [23] and could be sensitive for detecting gait instability. In our study, this parameter not only showed a statistically significant improvement after STN-DBS, probably reflecting an improvement in the patients’ stability, but the betterment was even more evident after STN + SNr-DBS.
The effects of low and high stimulation frequencies on gait and other axial symptoms were described [30,31]. Valldeoriola et al. described the beneficial effect of combined simultaneous high-frequency STN-DBS with low-frequency SNr-DBS [18]. Despite their promising results, we decided to perform both stimulations with high frequency, as described in previous reports supporting the use of this type of stimulation [16,31,32], based on the hypothesis that high-frequency inhibitory stimulation of the SNr releases the excessive basal ganglia inhibitory tone on the brainstem regions involved in the control of locomotion and posture [24,33,34]. Our results reveal a beneficial effect of STN + SNr-DBS on spatial gait characteristics compared to STN-DBS alone, supporting this hypothesis.
We are aware of the limitations of our study. The small sample size of our series of patients, together with the heterogeneous presentation of gait disturbances in PD patients, may bias our results, and thus our results should be considered preliminary. Further studies enrolling more patients and even multicenter studies would be necessary to draw stronger conclusions.

5. Conclusions

In summary, our work supports the hypothesis that simultaneous stimulation of the STN and SNr improves the short-term effects on gait disturbances, proving better outcomes than conventional stimulation of the STN-DBS. It is necessary to develop further investigations to study the long–term effects of this combined STN + SNr-DBS.

Author Contributions

Conceptualization, I.R. and M.d.Á.; methodology, I.R.; Data Acquisition, M.V.; formal analysis, L.L.-V. and I.R.; investigation, I.R., L.C.-M., M.V. and L.L.-V.; writing—original draft preparation, M.V., L.L.-V. and L.C.-M.; writing—review and editing, M.V., L.C.-M., S.F., M.d.Á. and I.R.; supervision, I.R.; project administration, I.R., funding acquisition: I.R. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Boston Scientific (Valencia, CA, USA) grant number ISROTH60016, and The APC was funded by Boston Scientific (Valencia, CA, USA).

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Hospital Ramón y Cajal (protocol code 135-14).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

References

  1. Limousin, P.; Pollak, P.; Benazzouz, A.; Hoffmann, D.; Le Bas, J.F.; Broussolle, E.; Perret, J.E.; Benabid, A.L. Effect of Parkinsonian Signs and Symptoms of Bilateral Subthalamic Nucleus Stimulation. Lancet 1995, 345, 91–95. [Google Scholar] [CrossRef]
  2. Weaver, F.M.; Follett, K.; Stern, M.; Hur, K.; Harris, C.; Marks, W.J.; Rothlind, J.; Sagher, O.; Reda, D.; Moy, C.S.; et al. Bilateral Deep Brain Stimulation vs. Best Medical Therapy for Patients with Advanced Parkinson Disease: A Randomized Controlled Trial. JAMA 2009, 301, 63–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Rodriguez-Oroz, M.C.; Obeso, J.A.; Lang, A.E.; Houeto, J.-L.; Pollak, P.; Rehncrona, S.; Kulisevsky, J.; Albanese, A.; Volkmann, J.; Hariz, M.I.; et al. Bilateral Deep Brain Stimulation in Parkinson’s Disease: A Multicentre Study with 4 Years Follow-Up. Brain J. Neurol. 2005, 128, 2240–2249. [Google Scholar] [CrossRef]
  4. Collomb-Clerc, A.; Welter, M.-L. Effects of Deep Brain Stimulation on Balance and Gait in Patients with Parkinson’s Disease: A Systematic Neurophysiological Review. Neurophysiol. Clin. Clin. Neurophysiol. 2015, 45, 371–388. [Google Scholar] [CrossRef] [Green Version]
  5. 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. [Google Scholar] [CrossRef] [PubMed]
  6. Giladi, N.; Treves, T.A.; Simon, E.S.; Shabtai, H.; Orlov, Y.; Kandinov, B.; Paleacu, D.; Korczyn, A.D. Freezing of Gait in Patients with Advanced Parkinson’s Disease. J. Neural Transm. 2001, 108, 53–61. [Google Scholar] [CrossRef]
  7. Bloem, B.R.; Hausdorff, J.M.; Visser, J.E.; Giladi, N. Falls and Freezing of Gait in Parkinson’s Disease: A Review of Two Interconnected, Episodic Phenomena. Mov. Disord. Off. J. Mov. Disord. Soc. 2004, 19, 871–884. [Google Scholar] [CrossRef]
  8. Kleiner-Fisman, G.; Herzog, J.; Fisman, D.N.; Tamma, F.; Lyons, K.E.; Pahwa, R.; Lang, A.E.; Deuschl, G. Subthalamic Nucleus Deep Brain Stimulation: Summary and Meta-Analysis of Outcomes. Mov. Disord. Off. J. Mov. Disord. Soc. 2006, 21 (Suppl. S1), S290–S304. [Google Scholar] [CrossRef]
  9. McNeely, M.E.; Earhart, G.M. Medication and Subthalamic Nucleus Deep Brain Stimulation Similarly Improve Balance and Complex Gait in Parkinson Disease. Parkinsonism Relat. Disord. 2013, 19, 86–91. [Google Scholar] [CrossRef] [Green Version]
  10. Rodriguez-Oroz, M.C.; Moro, E.; Krack, P. Long-Term Outcomes of Surgical Therapies for Parkinson’s Disease. Mov. Disord. Off. J. Mov. Disord. Soc. 2012, 27, 1718–1728. [Google Scholar] [CrossRef] [Green Version]
  11. Deuschl, G.; Agid, Y. Subthalamic Neurostimulation for Parkinson’s Disease with Early Fluctuations: Balancing the Risks and Benefits. Lancet Neurol. 2013, 12, 1025–1034. [Google Scholar] [CrossRef]
  12. Vallabhajosula, S.; Haq, I.U.; Hwynn, N.; Oyama, G.; Okun, M.; Tillman, M.D.; Hass, C.J. Low-Frequency versus High-Frequency Subthalamic Nucleus Deep Brain Stimulation on Postural Control and Gait in Parkinson’s Disease: A Quantitative Study. Brain Stimulat. 2015, 8, 64–75. [Google Scholar] [CrossRef] [PubMed]
  13. Seger, A.; Gulberti, A.; Vettorazzi, E.; Braa, H.; Buhmann, C.; Gerloff, C.; Hamel, W.; Moll, C.K.E.; Pötter-Nerger, M. Short Pulse and Conventional Deep Brain Stimulation Equally Improve the Parkinsonian Gait Disorder. J. Park. Dis. 2021, 11, 1455–1464. [Google Scholar] [CrossRef] [PubMed]
  14. Yu, K.; Ren, Z.; Guo, S.; Li, J.; Li, Y. Effects of Pedunculopontine Nucleus Deep Brain Stimulation on Gait Disorders in Parkinson’s Disease: A Meta-Analysis of the Literature. Clin. Neurol. Neurosurg. 2020, 198, 106108. [Google Scholar] [CrossRef] [PubMed]
  15. Pötter-Nerger, M.; Volkmann, J. Deep Brain Stimulation for Gait and Postural Symptoms in Parkinson’s Disease. Mov. Disord. Off. J. Mov. Disord. Soc. 2013, 28, 1609–1615. [Google Scholar] [CrossRef] [PubMed]
  16. Weiss, D.; Walach, M.; Meisner, C.; Fritz, M.; Scholten, M.; Breit, S.; Plewnia, C.; Bender, B.; Gharabaghi, A.; Wächter, T.; et al. Nigral Stimulation for Resistant Axial Motor Impairment in Parkinson’s Disease? A Randomized Controlled Trial. Brain J. Neurol. 2013, 136, 2098–2108. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Aziz, T.Z.; Davies, L.; Stein, J.; France, S. The Role of Descending Basal Ganglia Connections to the Brain Stem in Parkinsonian Akinesia. Br. J. Neurosurg. 1998, 12, 245–249. [Google Scholar] [CrossRef]
  18. Valldeoriola, F.; Muñoz, E.; Rumià, J.; Roldán, P.; Cámara, A.; Compta, Y.; Martí, M.J.; Tolosa, E. Simultaneous Low-Frequency Deep Brain Stimulation of the Substantia Nigra Pars Reticulata and High-Frequency Stimulation of the Subthalamic Nucleus to Treat Levodopa Unresponsive Freezing of Gait in Parkinson’s Disease: A Pilot Study. Parkinsonism Relat. Disord. 2019, 60, 153–157. [Google Scholar] [CrossRef] [Green Version]
  19. Wojtecki, L.; Vesper, J.; Schnitzler, A. Interleaving Programming of Subthalamic Deep Brain Stimulation to Reduce Side Effects with Good Motor Outcome in a Patient with Parkinson’s Disease. Parkinsonism Relat. Disord. 2011, 17, 293–294. [Google Scholar] [CrossRef]
  20. Benedetti, M.G.; Agostini, V.; Knaflitz, M.; Gasparroni, V.; Boschi, M.; Piperno, R. Self-Reported Gait Unsteadiness in Mildly Impaired Neurological Patients: An Objective Assessment through Statistical Gait Analysis. J. Neuroeng. Rehabil. 2012, 9, 64. [Google Scholar] [CrossRef] [Green Version]
  21. Agostini, V.; Balestra, G.; Knaflitz, M. Segmentation and Classification of Gait Cycles. IEEE Trans. Neural Syst. Rehabil. Eng. 2014, 22, 946–952. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Agostini, V.; Nascimbeni, A.; Gaffuri, A.; Imazio, P.; Benedetti, M.G.; Knaflitz, M. Normative EMG Activation Patterns of School-Age Children During Gait. Gait Posture 2010, 32, 285–289. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Villadoniga, M.; San Millan, A.; Cabanes-Martinez, L.; Aviles-Olmos, I.; Del Alamo-De Pedro, M.; Regidor, I. Quantitative gait analysis in patients with advanced Parkinson’s disease. Rev. Neurol. 2016, 63, 97–102. [Google Scholar] [PubMed]
  24. Horn, M.A.; Gulberti, A.; Hidding, U.; Gerloff, C.; Hamel, W.; Moll, C.K.E.; Pötter-Nerger, M. Comparison of Shod and Unshod Gait in Patients with Parkinson’s Disease with Subthalamic and Nigral Stimulation. Front. Hum. Neurosci. 2022, 15, 751242. [Google Scholar] [CrossRef] [PubMed]
  25. Weiss, D.; Breit, S.; Wächter, T.; Plewnia, C.; Gharabaghi, A.; Krüger, R. Combined Stimulation of the Substantia Nigra Pars Reticulata and the Subthalamic Nucleus Is Effective in Hypokinetic Gait Disturbance in Parkinson’s Disease. J. Neurol. 2011, 258, 1183–1185. [Google Scholar] [CrossRef] [PubMed]
  26. Scholten, M.; Klemt, J.; Heilbronn, M.; Plewnia, C.; Bloem, B.R.; Bunjes, F.; Krüger, R.; Gharabaghi, A.; Weiss, D. Effects of Subthalamic and Nigral Stimulation on Gait Kinematics in Parkinson’s Disease. Front. Neurol. 2017, 8, 543. [Google Scholar] [CrossRef]
  27. Hidding, U.; Gulberti, A.; Pflug, C.; Choe, C.; Horn, A.; Prilop, L.; Braaß, H.; Fründt, O.; Buhmann, C.; Weiss, D.; et al. Modulation of Specific Components of Sleep Disturbances by Simultaneous Subthalamic and Nigral Stimulation in Parkinson’s Disease. Parkinsonism Relat. Disord. 2019, 62, 141–147. [Google Scholar] [CrossRef]
  28. Pflug, C.; Nienstedt, J.C.; Gulberti, A.; Müller, F.; Vettorazzi, E.; Koseki, J.-C.; Niessen, A.; Flügel, T.; Hidding, U.; Buhmann, C.; et al. Impact of Simultaneous Subthalamic and Nigral Stimulation on Dysphagia in Parkinson’s Disease. Ann. Clin. Transl. Neurol. 2020, 7, 628–638. [Google Scholar] [CrossRef] [Green Version]
  29. Agostini, V.; Nascimbeni, A.; Gaffuri, A.; Knaflitz, M. Multiple Gait Patterns within the Same Winters Class in Children with Hemiplegic Cerebral Palsy. Clin. Biomech. 2015, 30, 908–914. [Google Scholar] [CrossRef] [Green Version]
  30. Moreau, C.; Defebvre, L.; Destée, A.; Bleuse, S.; Clement, F.; Blatt, J.L.; Krystkowiak, P.; Devos, D. STN-DBS Frequency Effects on Freezing of Gait in Advanced Parkinson Disease. Neurology 2008, 71, 80–84. [Google Scholar] [CrossRef]
  31. Xie, T.; Padmanaban, M.; Bloom, L.; MacCracken, E.; Bertacchi, B.; Dachman, A.; Warnke, P. Effect of Low versus High Frequency Stimulation on Freezing of Gait and Other Axial Symptoms in Parkinson Patients with Bilateral STN DBS: A Mini-Review. Transl. Neurodegener. 2017, 6, 13. [Google Scholar] [CrossRef] [PubMed]
  32. Chastan, N.; Westby, G.W.M.; Yelnik, J.; Bardinet, E.; Do, M.C.; Agid, Y.; Welter, M.L. Effects of Nigral Stimulation on Locomotion and Postural Stability in Patients with Parkinson’s Disease. Brain J. Neurol. 2009, 132, 172–184. [Google Scholar] [CrossRef] [PubMed]
  33. Georgiades, M.J.; Shine, J.M.; Gilat, M.; McMaster, J.; Owler, B.; Mahant, N.; Lewis, S.J.G. Hitting the Brakes: Pathological Subthalamic Nucleus Activity in Parkinson’s Disease Gait Freezing. Brain 2019, 142, 3906–3916. [Google Scholar] [CrossRef] [PubMed]
  34. Nandi, D.; Aziz, T.Z.; Liu, X.; Stein, J.F. Brainstem Motor Loops in the Control of Movement. Mov. Disord. 2002, 17, S22–S27. [Google Scholar] [CrossRef] [PubMed]
Jcm 11 02269 g001 550
Figure 1. Representation of the protocol via block diagram. PD: Parkinson’s disease. STN-DBS: Subthalamic deep brain stimulation. STN + SNr-DBS: Dual subthalamic and nigral deep brain stimulation.
Figure 1. Representation of the protocol via block diagram. PD: Parkinson’s disease. STN-DBS: Subthalamic deep brain stimulation. STN + SNr-DBS: Dual subthalamic and nigral deep brain stimulation.
Jcm 11 02269 g001
Jcm 11 02269 g002 550
Figure 2. Stimulation Field Model of the STN (A) and STN+SNr (B). Green = STN; Blue = SNr; Ferrari Red = Red Nucleus; Dusty Red = Volume Tissue Activated.
Figure 2. Stimulation Field Model of the STN (A) and STN+SNr (B). Green = STN; Blue = SNr; Ferrari Red = Red Nucleus; Dusty Red = Volume Tissue Activated.
Jcm 11 02269 g002
Jcm 11 02269 g003 550
Figure 3. Gait cycle. H: heel contact, F: foot contact, P: push off, S: swing.
Figure 3. Gait cycle. H: heel contact, F: foot contact, P: push off, S: swing.
Jcm 11 02269 g003
Jcm 11 02269 g004 550
Figure 4. Differences of mean between baseline and the different STN parameters in percentage of cycles with the right sequence (HFPS). STN: Subthalamic nucleus stimulation; STN + SNR: Dual Subthalamic and nigral stimulation.
Figure 4. Differences of mean between baseline and the different STN parameters in percentage of cycles with the right sequence (HFPS). STN: Subthalamic nucleus stimulation; STN + SNR: Dual Subthalamic and nigral stimulation.
Jcm 11 02269 g004
Table
Table 1. Summary of gait analysis data HFPS: heel strike, foot contact, push off and swing; STN: Subthalamic nucleus stimulation; STN + SNR: Dual Subthalamic and nigral stimulation; SEM: Standard error of the mean.
Table 1. Summary of gait analysis data HFPS: heel strike, foot contact, push off and swing; STN: Subthalamic nucleus stimulation; STN + SNR: Dual Subthalamic and nigral stimulation; SEM: Standard error of the mean.
HFPS CyclesBaselineSTNSTN + SNr
Mean (± SEM)0.57 (0.41; 0.73)0.71 (0.63; 0.79)0.79 (0.74; 0.84)
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Villadóniga, M.; Cabañes-Martínez, L.; López-Viñas, L.; Fanjul, S.; del Álamo, M.; Regidor, I. Combined Stimulation of the Substantia Nigra and the Subthalamic Nucleus for the Treatment of Refractory Gait Disturbances in Parkinson’s Disease: A Preliminary Study. J. Clin. Med. 2022, 11, 2269. https://doi.org/10.3390/jcm11082269

AMA Style

Villadóniga M, Cabañes-Martínez L, López-Viñas L, Fanjul S, del Álamo M, Regidor I. Combined Stimulation of the Substantia Nigra and the Subthalamic Nucleus for the Treatment of Refractory Gait Disturbances in Parkinson’s Disease: A Preliminary Study. Journal of Clinical Medicine. 2022; 11(8):2269. https://doi.org/10.3390/jcm11082269

Chicago/Turabian Style

Villadóniga, Marta, Lidia Cabañes-Martínez, Laura López-Viñas, Samira Fanjul, Marta del Álamo, and Ignacio Regidor. 2022. "Combined Stimulation of the Substantia Nigra and the Subthalamic Nucleus for the Treatment of Refractory Gait Disturbances in Parkinson’s Disease: A Preliminary Study" Journal of Clinical Medicine 11, no. 8: 2269. https://doi.org/10.3390/jcm11082269

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop