Cardiovascular autonomic responses in patients with Parkinson disease to pedunculopontine deep brain stimulation

  • Jonathan A. Hyam
  • Holly A. Roy
  • Yongzhi Huang
  • Sean Martin
  • Shouyan Wang
  • Jodi Rippey
  • Terry J. Coyne
  • Ian Stewart
  • Graham Kerr
  • Peter Silburn
  • David J. Paterson
  • Tipu Z. Aziz
  • Alexander L. GreenEmail author
Research Article



Dysautonomia can be a debilitating feature of Parkinson disease (PD). Pedunculopontine nucleus (PPN) stimulation may improve gait disorders in PD, and may also result in changes in autonomic performance.


To determine whether pedunculopontine nucleus stimulation improves cardiovascular responses to autonomic challenges of postural tilt and Valsalva manoeuver, eight patients with pedunculopontine nucleus deep brain stimulation were recruited to the study; two were excluded for technical reasons during testing. Participants underwent head up tilt and Valsalva manoeuver with stimulation turned ON and OFF. Continuous blood pressure and ECG waveforms were recorded during these tests. In a single patient, local field potential activity was recorded from the implanted electrode during tilt.


The fall in systolic blood pressure after tilt was significantly smaller with stimulation ON (mean − 8.3% versus − 17.2%, p = 0.044). Valsalva ratio increased with stimulation from median 1.15 OFF to 1.20 ON (p = 0.028). Baroreflex sensitivity increased during Valsalva compared to rest with stimulation ON versus OFF (p = 0.028). The increase in baroreflex sensitivity correlated significantly with the mean depth of PPN stimulating electrode contacts. This accounted for 89% of its variance (r = 0.943, p = 0.005).


PPN stimulation can modulate the cardiovascular system in patients with PD. In this study, it reduced the postural fall in systolic blood pressure during head-up tilt and improved the cardiovascular response during Valsalva, presumably by altering the neural control of baroreflex activation.


Pedunculopontine nucleus Deep brain stimulation Parkinson disease Postural hypotension Autonomic nervous system 



We would like to thank Amanda Rojek, Nor Faizal Ahmad Bahuri and John-Stuart Brittain for their support in data collection. This study was supported by a research grant from Medtronic Europe S.A. and grants from the Oxford Biomedical Research Centre of the UK NIHR, the Norman Collisson Foundation, the Wolfson Charitable Trust and the National Health and Medical Research Council (Australia).

Author contributions

Conception of project: JAH, ALG, DJP, TZA. Study design: JAH, ALG, DJP, GK, PS. Data collection: JAH, JSB, SW, NFAB, JR, IS. Insertion of DBS electrodes: ALG, TZA, TC. Analysis and manuscript composition: JAH, HAR, YH, ALG, GK. Manuscript feedback: all authors

Compliance with ethical standards

Conflict of interest

JA Hyam, TJ Coyne, TZ Aziz and AL Green have received honoraria from Medtronic Inc. and St. Jude Medical. No author is employed or has investment in either company. Prof Green is on an Executive Advisory Board (Movement Disorders) for Abbott and holds a consultancy agreement with Abbott. He also has a Consultancy agreement with Renishaw plc. He has given Expert testimony (unrelated) and receives Royalties from Oxford University Press (unrelated). He holds an MRC grant (unrelated to this project).


  1. 1.
    Goldstein DS (2003) Dysautonomia in Parkinson’s disease: neurocardiological abnormalities. Lancet Neurol 2:669–676CrossRefGoogle Scholar
  2. 2.
    Palma JA, Kaufmann H (2017) Epidemiology, diagnosis and management of neurogenic orthostatic hypotension. Mov Disord Clin Pract 4(3):298–308CrossRefGoogle Scholar
  3. 3.
    Martin-Galleo A, Andrade-Andrade I, Dawid-Milner MS, Dominguez-Paez M, Romero-Moreno L, Gonzalez-Garcia L, Carrasco-Brenes A, Segura-Fernandez-Nogueras M, Ros-Lopez B, Arraez-Sanchez MA (2016) Autonomic dysfunction elicited by a medulla oblongata injury after fourth ventricle tumor surgery in a pediatric patient. Auton Neurosci 194:52–57CrossRefGoogle Scholar
  4. 4.
    Udow SJ, Robertson AD, MacIntosh BJ, Espay AJ, Rowe JB, Lang AE, Masellis M (2016) Under pressure: is there a link between orthostatic hypotension and cognitive impairment in α-synucleinopathies? J Neurol Neurosurg Psychiatr 1:5–9. Google Scholar
  5. 5.
    Green AL, Wang S, Owen SLF, Xie K, Liu X, Paterson DJ, Stein JF, Bain PG, Aziz TZ (2005) Deep brain stimulation can regulate arterial blood pressure in awake humans. Neuroreport 16(16):1741–1745CrossRefGoogle Scholar
  6. 6.
    Carter HH, Dawson EA, Cable NT, Basnayake S, Aziz TZ, Green AL, Paterson DJ, Lind CR, Thijssen DH, Green DJ (2011) Deep brain stimulation of the periaqueductal grey induces vasodilation in humans. Hypertension 57(5):e24–e25CrossRefGoogle Scholar
  7. 7.
    Sverrisdottir YB, Green AL, Aziz TZ, Bahuri NFA, Hyam J, Basnayake SD, Paterson DJ (2014) Differentiated baroreflex modulation of sympathetic nerve activity during deep brain stimulation in humans. Hypertension 63(5):1000–1010CrossRefGoogle Scholar
  8. 8.
    Ludwig J, Remien P, Guballa C, Binder A, Binder S, Schattschneider J, Herzog J, Volkmann J, Deuschl G, Wasner G, Baron R (2007) Effects of subthalamic nucleus stimulation and levodopa on the autonomic nervous system in Parkinson’s disease. J Neurol Neurosurg Psychiatr 78(7):742–745CrossRefGoogle Scholar
  9. 9.
    O’Callaghan E, Hart EC, Sims-Williams H, Javed S, Burchell AE, Papouchado M, Tank J, Heusser K, Jordan J, Menne J, Haller H, Nightingale AK, Paton JFR, Patel NK (2017) Chronic deep brain stimulation decreases blood pressure and sympathetic nerve activity in a drug- and device- resistant hypertensive patient. Hypertension 69:522–528CrossRefGoogle Scholar
  10. 10.
    Green AL, Wang S, Owen SLF, Paterson DJ, Stein JF, Aziz TZ (2006) Controlling the heart via the brain: a potential new therapy for orthostatic hypotension. Neurosurgery 58:1176–1183CrossRefGoogle Scholar
  11. 11.
    Patel N, Javed S, Khan S, Papouchado M, Malizia AL, Pickering AE, Paton JFR (2011) Deep brain stimulation relieves refractory hypertension. Neurology 76:405–407CrossRefGoogle Scholar
  12. 12.
    Pereira EA, Wang S, Paterson DJ, Stein JF, Aziz TZ, Green AL (2010) Sustained reduction of hypertension by deep brain stimulation. J Clin Neurosci 17:124–127CrossRefGoogle Scholar
  13. 13.
    Wang JW, Zhang YQ, Zhang XH, Wang YP, Li JP, Li YJ (2017) Deep brain stimulation of pedunculopontine nucleus for postural instability and gait disorder after Parkinson’s disease: a meta-analysis of individual patient data. World Neurosurg 102:72–78CrossRefGoogle Scholar
  14. 14.
    Chong RKY, Bedford TG (1997) Heart rate, blood pressure, and running speed responses to mesencephalic locomotor region stimulation in anesthetized rats. Eur J Physiol 434:280–284CrossRefGoogle Scholar
  15. 15.
    Eldridge FL, Millhorn DE, Waldrop TG (1981) Exercise hyperpnea and locomotion: parallel activation from the hypothalamus. Science 211(4484):844–846CrossRefGoogle Scholar
  16. 16.
    Yasui Y, Cechetto DF, Saper CB (1990) Evidence for a cholinergic projection from the pedunculopontine tegmental nucleus to the rostral ventrolateral medulla in the rat. Brain Res 517:19–24CrossRefGoogle Scholar
  17. 17.
    Dampney RAL, Coleman MJ, Fontes MAP, Hirooka Y, Horiuchi J, Li Y-W, Polson JW, Potts PD, Tagawa T (2002) Central mechanisms underlying short- and long-term regulation of the cardiovascular system. Clin Exp Pharmacol Physiol 29:261–268CrossRefGoogle Scholar
  18. 18.
    Ross CA, Ruggiero DA, Park DH, Joh TH, Sved AF, Fernandez-Pardal J, Saavedra JM, Reis DJ (1984) Tonic vasomotor control by the rostral ventrolateral medulla: effect of electrical or chemical stimulation of the area containing C1 adrenaline neurons on arterial pressure, heart rate, and plasma catecholamines and vasopressin. J Neurosci 4:474–494CrossRefGoogle Scholar
  19. 19.
    Padley JR, Kumar NN, Li Q, Nguyen TBV, Pilowsky PM, Goodchild AK (2007) Central command regulation of circulatory function mediated by descending pontine cholinergic inputs to sympathy excitatory rostral ventrolateral medulla neurons. Circ Res 100:84–291CrossRefGoogle Scholar
  20. 20.
    Plaha P, Gill SS (2005) Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson’s disease. Neuroreport 16(7):1883–1887CrossRefGoogle Scholar
  21. 21.
    Mathias CJ, Low DA, Iodice VA, Bannister R (2013) Investigation of autonomic disorders. In: Mathias CJ, Bannister R (eds) Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 5th edn. Oxford University Press, LondonCrossRefGoogle Scholar
  22. 22.
    Brinton TJ, Cotter B, Kailasam MT, Brown DL, Chio SS, O’Connor DT, DeMaria AN (1997) Development and validation of a noninvasive method to determine arterial pressure and vascular compliance. Am J Cardiol 80:323–330CrossRefGoogle Scholar
  23. 23.
    Barbieri R, Bianchi AM, Triedman JK, Mainardi LT, Cerutti S, Saul JP (1997) Model dependency of multivariate autoregressive spectral analysis. IEEE Eng Med Biol Mag 16:74–85CrossRefGoogle Scholar
  24. 24.
    Blaho A, Sutovsky S, Valkovic P, Siarnik P, Sykora M, Turcani P (2017) Decreased baroreflex sensitivity in Parkinson’s disease is associated with orthostatic hypotension. J Neurol Sci 377:207–211CrossRefGoogle Scholar
  25. 25.
    Stemper B, Beric A, Welsch G, Haendl T, Sterio D, Hilz MJ (2006) Deep brain stimulation improves orthostatic regulation of patients with Parkinson’s disease. Neurology 67(10):1781–1785CrossRefGoogle Scholar
  26. 26.
    Holmberg B, Corneliusson O, Elam M (2005) Bilateral stimulation of nucleus subthalamicus in advanced Parkinson’s disease: no effects on, and of, autonomic dysfunction. Mov Disord 20(8):976–981CrossRefGoogle Scholar
  27. 27.
    Thornton JM, Aziz TZ, Schlugman D, Paterson DJ (2002) Electrical stimulation of the midbrain increases heart rate and arterial blood pressure in awake humans. J Physiol 539(Pt 2):615–621CrossRefGoogle Scholar
  28. 28.
    Rothwell PM, Howard SC, Dolan E, O’Brien E, Dobson JE, Dahlof B, Sever PS, Poulter NR (2010) Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 375:895–905CrossRefGoogle Scholar
  29. 29.
    de Bruyne MC, Kors JA, Hoes AW, Klootwijk P, Dekker JM, Hofman A, van Bemmel JH, Grobbee DE (1999) Both decreased and increased heart rate variability on the standard 10-second electrocardiogram predict cardiac mortality in the elderly: the Rotterdam study. Am J Epidemiol 150(12):1282–1288CrossRefGoogle Scholar
  30. 30.
    Aravamuthan BR, Muthusamy KA, Stein JF, Aziz TZ, Johansen-Berg H (2007) Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei. Neuroimage 37:694–705CrossRefGoogle Scholar
  31. 31.
    Muthusamy KA, Aravamuthan BR, Kringelbach ML, Jenkinson N, Voets NL, Johansen-Berg H, Stein JF, Aziz TZ (2007) J Neurosurg 107:814–820CrossRefGoogle Scholar
  32. 32.
    Benarroch EE (1997) Central autonomic network: functional organization and clinical correlations. Futura, New YorkGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jonathan A. Hyam
    • 1
    • 2
    • 3
  • Holly A. Roy
    • 2
    • 7
  • Yongzhi Huang
    • 3
  • Sean Martin
    • 3
  • Shouyan Wang
    • 1
  • Jodi Rippey
    • 4
  • Terry J. Coyne
    • 5
  • Ian Stewart
    • 4
  • Graham Kerr
    • 4
  • Peter Silburn
    • 8
    • 6
  • David J. Paterson
    • 1
  • Tipu Z. Aziz
    • 1
    • 2
    • 3
  • Alexander L. Green
    • 1
    • 2
    • 3
    • 9
    Email author
  1. 1.Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
  2. 2.Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
  3. 3.Nuffield Department of Surgical SciencesUniversity of OxfordOxfordUK
  4. 4.Institute of Health and Biomedical InnovationQueensland University of TechnologyBrisbaneAustralia
  5. 5.St. Andrews and Wesley HospitalsBrisbaneAustralia
  6. 6.University of Queensland, Centre for Clinical Research, Royal Brisbane and Women’s HospitalBrisbaneAustralia
  7. 7.Neurosurgery DepartmentDerriford HospitalPlymouthUK
  8. 8.Queensland Brain InstituteUniversity of QueenslandBrisbaneAustralia
  9. 9.Department of NeurosurgeryJohn Radcliffe HospitalOxfordUK

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