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Pedunculopontine Nucleus Deep Brain Stimulation Improves Gait Disorder in Parkinson’s Disease: A Systematic Review and Meta-analysis

  • Fabin Lin
  • Dihang Wu
  • Chenxin Lin
  • Huihui Cai
  • Lina Chen
  • Guofa Cai
  • Qinyong Ye
  • Guoen CaiEmail author
Review

Abstract

Deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) has been proposed as a treatment strategy for gait disorder in patients with Parkinson’s disease (PD). We thus performed a systematic review and meta-analysis of randomized and nonrandomized controlled trials to assess the effect of this treatment on gait disorder in patients with PD. We systematically searched PubMed, Cochrane, Web of Knowledge, Wan Fang and WIP for randomized and nonrandomized controlled trials (published before July 29, 2014; no language restrictions) comparing PPN–DBS with other treatments. We assessed pooled data using a random effects model and a fixed effects model. Of 130 identified studies, 14 were eligible and were included in our analysis (N = 82 participants). Compared to those presurgery, the Unified Parkinson Disease Rating Scale (UPDRS) 27–30 scores for patients were lowered by PPN–DBS [3.94 (95% confidence interval, CI = 1.23 to 6.65)]. The UPDRS 13 and 14 scores did not improve with levodopa treatment [0.43 (− 0.35 to 1.20); 0.35 (− 0.50 to 1.19)], whereas the UPDRS 27–30 scores could be improved by the therapy [1.42 (95% CI 0.34 to 2.51)]. The Gait and Falls Questionnaire and UPDRS 13 and 14 scores showed significant improvements after PPN–DBS under the medication-off (MED-OFF) status [15.44 (95% CI = 8.44 to 22.45); 1.57 (95% CI = 0.84 to 2.30); 1.34 (95% CI = 0.84 to 1.84)]. PPN–DBS is a potential therapeutic target that could improve gait and fall disorders in patients with PD. Our findings will help improve the clinical application of DBS in PD patients with gait disorder.

Keywords

Pedunculopontine nucleus Deep brain stimulation Parkinson’s disease Systematic review Meta-analysis 

Notes

Acknowledgements

We thank all the researchers who participated in this study.

Author Contributions

LF, WD and LC searched the scientific literature, collect the data and drafted the manuscript. CH, CL, YQ, CG3 and CG1 helped to collect the data and performed statistical analyses. CG1 contributed to conception, design, data interpretation, manuscript revision. All authors read and approved the manuscript.

Funding

This work is supported by grants from the Fujian Provincial Science and Technology Guiding Project (Nos. 2017Y0041, 2018Y0033), Joint Funds for the Innovation of Science and Technology, Fujian Province (No. 2017Y9010) and the National Key Research and Development Program of China (No. 2017YFC1310200).

Compliance with Ethical Standards

Conflicts of interest

The authors declare no conflicts of interests regarding the publication of this paper.

References

  1. 1.
    Nonnekes J, Ružicka E, Nieuwboer A, Hallett M, Fasano A, Bloem BR (2019) Compensation strategies for gait impairments in Parkinson disease: a review. JAMA Neurol 76(6):718–725.  https://doi.org/10.1001/jamaneurol.2019.0033 CrossRefPubMedGoogle Scholar
  2. 2.
    Nonnekes J, Snijders AH, Nutt JG, Deuschl G, Giladi N, Bloem BR (2015) Freezing of gait: a practical approach to management. Lancet Neurol 14(7):768–778.  https://doi.org/10.1016/s1474-4422(15)00041-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Gazewood JD, Richards DR, Clebak K (2013) Parkinson disease: an update. Am Fam Physician 87(4):267–273.  https://doi.org/10.1056/NEJMct1208070 CrossRefPubMedGoogle Scholar
  4. 4.
    Ferraye MU, Debu B, Pollak P (2008) Deep brain stimulation effect on freezing of gait. Mov Disord Off J Mov Disord Soc 23(Suppl 2):S489–S494.  https://doi.org/10.1002/mds.21975 CrossRefGoogle Scholar
  5. 5.
    Remple MS, Bradenham CH, Kao CC, Charles PD, Neimat JS, Konrad PE (2011) Subthalamic nucleus neuronal firing rate increases with Parkinson’s disease progression. Mov Disord 26(9):1657–1662CrossRefGoogle Scholar
  6. 6.
    Jahanshahi M, Obeso I, Baunez C, Alegre M, Krack P (2015) Parkinson’s disease, the subthalamic nucleus, inhibition, and impulsivity. Mov Disord Off J Mov Disord Soc 30(2):128–140.  https://doi.org/10.1002/mds.26049 CrossRefGoogle Scholar
  7. 7.
    Okun MS (2012) Deep-brain stimulation for Parkinson’s disease. N Engl J Med 367(16):1529–1538CrossRefGoogle Scholar
  8. 8.
    Klein JC, Barbe MT, Seifried C, Baudrexel S, Runge M, Maarouf M, Gasser T, Hattingen E, Liebig T, Deichmann RJN (2012) The tremor network targeted by successful VIM deep brain stimulation in humans. Neurology 78(11):787–795CrossRefGoogle Scholar
  9. 9.
    Limousin P, Foltynie T (2019) Long-term outcomes of deep brain stimulation in Parkinson disease. Nat Rev Neurol 15(4):234–242.  https://doi.org/10.1038/s41582-019-0145-9 CrossRefPubMedGoogle Scholar
  10. 10.
    Martijn B, Annelien D, Veerle VV, Yasin T, Ania W (2011) Impulse control and related disorders in Parkinson’s disease patients treated with bilateral subthalamic nucleus stimulation: a review. Park Relat Disord 17(6):413–417.  https://doi.org/10.1016/j.parkreldis.2011.02.013 CrossRefGoogle Scholar
  11. 11.
    Ryczko D, Dubuc R (2013) The multifunctional mesencephalic locomotor region. Curr Pharm Des 19(24):4448–4470.  https://doi.org/10.2174/1381612811319240011 CrossRefPubMedGoogle Scholar
  12. 12.
    Josset N, Roussel M, Lemieux M, Lafrance-Zoubga D, Rastqar A, Bretzner F (2018) Distinct contributions of mesencephalic locomotor region nuclei to locomotor control in the freely behaving mouse. Curr Biol.  https://doi.org/10.1016/j.cub.2018.02.007 CrossRefPubMedGoogle Scholar
  13. 13.
    Plaha P, Gill SS (2005) Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson’s disease. NeuroReport 16(17):1883–1887.  https://doi.org/10.1097/01.wnr.0000187637.20771.a0 CrossRefPubMedGoogle Scholar
  14. 14.
    The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations (2003). Mov Disord 18(7):738–750.  https://doi.org/10.1002/mds.10473
  15. 15.
    Higgins JPT, Savović J, Page MJ, Elbers RG, Sterne JAC (2019) Chapter 8: assessing risk of bias in a randomized trial. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (eds) Cochrane Handbook for Systematic Reviews of Interventions version 6.0. Wiley, ChichesterGoogle Scholar
  16. 16.
    Mestre TA, Sidiropoulos C, Hamani C, Poon YY, Lozano AM, Lang AE, Moro E (2016) Long-term double-blinded unilateral pedunculopontine area stimulation in Parkinson’s disease. Mov Disord 31(10):1570–1574.  https://doi.org/10.1002/mds.26710 CrossRefPubMedGoogle Scholar
  17. 17.
    Ferraye MU, Debu B, Fraix V, Goetz L, Ardouin C, Yelnik J, Henry-Lagrange C, Seigneuret E, Piallat B, Krack P, Le Bas JF, Benabid AL, Chabardes S, Pollak P (2010) Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson’s disease. Brain 133(Pt 1):205–214.  https://doi.org/10.1093/brain/awp229 CrossRefPubMedGoogle Scholar
  18. 18.
    Nosko D, Ferraye MU, Fraix V, Goetz L, Chabardes S, Pollak P, Debu B (2015) Low-frequency versus high-frequency stimulation of the pedunculopontine nucleus area in Parkinson’s disease: a randomised controlled trial. J Neurol Neurosurg Psychiatry 86(6):674–679.  https://doi.org/10.1136/jnnp-2013-307511 CrossRefPubMedGoogle Scholar
  19. 19.
    Thevathasan W, Cole MH, Graepel CL, Hyam JA, Jenkinson N, Brittain JS, Coyne TJ, Silburn PA, Aziz TZ, Kerr G, Brown P (2012) A spatiotemporal analysis of gait freezing and the impact of pedunculopontine nucleus stimulation. Brain J Neurol 135(Pt 5):1446–1454.  https://doi.org/10.1093/brain/aws039 CrossRefGoogle Scholar
  20. 20.
    Khan S, Gill SS, Mooney L, White P, Whone A, Brooks DJ, Pavese N (2012) Combined pedunculopontine-subthalamic stimulation in Parkinson disease. Neurology 78(14):1090–1095.  https://doi.org/10.1212/WNL.0b013e31824e8e96 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Khan S, Mooney L, Plaha P, Javed S, White P, Whone AL, Gill SS (2011) Outcomes from stimulation of the caudal zona incerta and pedunculopontine nucleus in patients with Parkinson’s disease. Br J Neurosurg 25(2):273–280.  https://doi.org/10.3109/02688697.2010.544790 CrossRefPubMedGoogle Scholar
  22. 22.
    Perera T, Tan JL, Cole MH, Yohanandan SAC, Silberstein P, Cook R, Peppard R, Aziz T, Coyne T, Brown P, Silburn PA, Thevathasan W (2018) Balance control systems in Parkinson’s disease and the impact of pedunculopontine area stimulation. Brain J Neurol 141(10):3009–3022.  https://doi.org/10.1093/brain/awy216 CrossRefGoogle Scholar
  23. 23.
    Thevathasan W, Coyne TJ, Hyam JA, Kerr G, Jenkinson N, Aziz TZ, Silburn PA (2011) Pedunculopontine nucleus stimulation improves gait freezing in Parkinson disease. Neurosurgery 69(6):1248–1253; discussion 1254.  https://doi.org/10.1227/NEU.0b013e31822b6f71 CrossRefGoogle Scholar
  24. 24.
    Thevathasan W, Pogosyan A, Hyam JA, Jenkinson N, Bogdanovic M, Coyne TJ, Silburn PA, Aziz TZ, Brown P (2011) A block to pre-prepared movement in gait freezing, relieved by pedunculopontine nucleus stimulation. Brain 134(Pt 7):2085–2095.  https://doi.org/10.1093/brain/awr131 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Thevathasan W, Silburn PA, Brooker H, Coyne TJ, Khan S, Gill SS, Aziz TZ, Brown P (2010) The impact of low-frequency stimulation of the pedunculopontine nucleus region on reaction time in Parkinsonism. J Neurol Neurosurg Psychiatry 81(10):1099–1104.  https://doi.org/10.1136/jnnp.2009.189324 CrossRefPubMedGoogle Scholar
  26. 26.
    Stefani A, Lozano AM, Peppe A, Stanzione P, Galati S, Tropepi D, Pierantozzi M, Brusa L, Scarnati E, Mazzone P (2007) Bilateral deep brain stimulation of the pedunculopontine and subthalamic nuclei in severe Parkinson’s disease. Brain 130(Pt 6):1596–1607.  https://doi.org/10.1093/brain/awl346 CrossRefPubMedGoogle Scholar
  27. 27.
    Moro E, Hamani C, Poon YY, Al-Khairallah T, Dostrovsky JO, Hutchison WD, Lozano AM (2010) Unilateral pedunculopontine stimulation improves falls in Parkinson’s disease. Brain J Neurol 133(Pt 1):215–224.  https://doi.org/10.1093/brain/awp261 CrossRefGoogle Scholar
  28. 28.
    Antonini A, Moro E, Godeiro C, Reichmann H (2018) Medical and surgical management of advanced Parkinson’s disease. Mov Disord Off J Mov Disord Soc 33(6):900–908.  https://doi.org/10.1002/mds.27340 CrossRefGoogle Scholar
  29. 29.
    Caliandro P, Insola A, Scarnati E, Padua L, Russo G, Granieri E, Mazzone P (2011) Effects of unilateral pedunculopontine stimulation on electromyographic activation patterns during gait in individual patients with Parkinson’s disease. J Neural Transm (Vienna, Austria: 1996) 118(10):1477–1486.  https://doi.org/10.1007/s00702-011-0705-7 CrossRefGoogle Scholar
  30. 30.
    Welter ML, Demain A, Ewenczyk C, Czernecki V, Lau B, El Helou A, Belaid H, Yelnik J, François C, Bardinet E, Karachi C, Grabli D (2015) PPNa-DBS for gait and balance disorders in Parkinson’s disease: a double-blind, randomised study. J Neurol 262(6):1515–1525.  https://doi.org/10.1007/s00415-015-7744-1 CrossRefPubMedGoogle Scholar
  31. 31.
    Li J, Ren Z (2017) Pedunculopontine nucleus stimulation improves gait freezing in Parkinson disease. J Clin Neurosurg (in China) 14(5):382–384.  https://doi.org/10.3969/j.issn.1672-7770.2017.05.015 CrossRefGoogle Scholar
  32. 32.
    Peppe A, Pierantozzi M, Chiavalon C, Marchetti F, Caltagirone C, Musicco M, Stanzione P, Stefani A (2010) Deep brain stimulation of the pedunculopontine tegmentum and subthalamic nucleus: effects on gait in Parkinson's disease. Gait Posture 32(4):512–518CrossRefGoogle Scholar
  33. 33.
    Mestre TA, Sidiropoulos C, Hamani C, Poon YY, Lozano AM, Lang AE, Moro E (2016) Long-term double-blinded unilateral pedunculopontine area stimulation in Parkinson’s disease. Mov Disord Off J Mov Disord Soc 31(10):1570–1574.  https://doi.org/10.1002/mds.26710 CrossRefGoogle Scholar
  34. 34.
    Grabli D, Karachi C, Folgoas E, Monfort M, Tande D, Clark S, Civelli O, Hirsch EC, François C (2013) Gait disorders in Parkinsonian monkeys with pedunculopontine nucleus lesions: a tale of two systems. J Neurosci 33(29):11986.  https://doi.org/10.1523/JNEUROSCI.1568-13.2013 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fasano A, Aquino CC, Krauss JK, Honey CR, Bloem BR (2015) Axial disability and deep brain stimulation in patients with Parkinson disease. Nat Rev Neurol 11:98.  https://doi.org/10.1038/nrneurol.2014.252 CrossRefPubMedGoogle Scholar
  36. 36.
    Ginis P, Nackaerts E, Nieuwboer A, Heremans E (2018) Cueing for people with Parkinson’s disease with freezing of gait: a narrative review of the state-of-the-art and novel perspectives. Ann Phys Rehabil Med 61(6):407–413.  https://doi.org/10.1016/j.rehab.2017.08.002 CrossRefPubMedGoogle Scholar
  37. 37.
    Bloem BR, Hausdorff JM, Visser JE, Giladi N (2004) Falls and freezing of gait in Parkinson’s disease: a review of two interconnected, episodic phenomena. Mov Disord 19(8):871–884.  https://doi.org/10.1002/mds.20115 CrossRefGoogle Scholar
  38. 38.
    Jenkinson N, Nandi D, Muthusamy K, Ray NJ, Gregory R, Stein JF, Aziz TZ (2009) Anatomy, physiology, and pathophysiology of the pedunculopontine nucleus. Mov Disord 24(3):319–328.  https://doi.org/10.1002/mds.22189 CrossRefPubMedGoogle Scholar
  39. 39.
    Garcia-Rill E, Tackett AJ, Byrum SD, Lan RS, Mackintosh SG, Hyde JR, Bisagno V, Urbano FJ (2019) Local and relayed effects of deep brain stimulation of the pedunculopontine nucleus. Brain Sci 9(3):64.  https://doi.org/10.3390/brainsci9030064 CrossRefPubMedCentralGoogle Scholar
  40. 40.
    Karachi C, Grabli D, Bernard FA, Tandé D, Wattiez N, Belaid H, Bardinet E, Prigent A, Nothacker H-P, Hunot S, Hartmann A, Lehéricy S, Hirsch EC, François C (2010) Cholinergic mesencephalic neurons are involved in gait and postural disorders in Parkinson disease. J Clin Investig 120(8):2745–2754.  https://doi.org/10.1172/JCI42642 CrossRefPubMedGoogle Scholar
  41. 41.
    French IT, Muthusamy KA (2018) A review of the pedunculopontine nucleus in Parkinson’s disease. Front Aging Neurosci 10:99.  https://doi.org/10.3389/fnagi.2018.00099 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Fabin Lin
    • 1
    • 2
  • Dihang Wu
    • 1
    • 2
  • Chenxin Lin
    • 1
    • 2
  • Huihui Cai
    • 2
  • Lina Chen
    • 1
  • Guofa Cai
    • 3
  • Qinyong Ye
    • 1
  • Guoen Cai
    • 1
    Email author
  1. 1.Department of NeurologyFujian Medical University Union HospitalFuzhouChina
  2. 2.Department of Clinical MedicalFujian Medical UniversityFuzhouChina
  3. 3.College of Information EngineeringGuangdong University of TechnologyGuangzhouChina

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