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Subthalamic suppression defines therapeutic threshold of deep brain stimulation in Parkinson’s disease
  1. Luka Milosevic1,
  2. Suneil K Kalia2,3,4,
  3. Mojgan Hodaie2,3,4,
  4. Andres Lozano2,3,4,
  5. Milos R Popovic1,5,
  6. William Hutchison4,6
  1. 1 Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
  2. 2 Division of Neurosurgery, Toronto Western Hospital, Toronto, Ontario, Canada
  3. 3 Department of Surgery, University of Toronto, Toronto, Ontario, Canada
  4. 4 Krembil Research Institute, Toronto, Ontario, Canada
  5. 5 KITE, Toronto Rehabilitation Institute, Toronto, Ontario, Canada
  6. 6 Department of Physiology, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Luka Milosevic, University of Toronto, Toronto, ON M5T 2S8, Canada; luka.milosevic{at}


Introduction Subthalamic deep brain stimulation (DBS) is beneficial when delivered at a high frequency. However, the effects of current amplitude and pulse width on subthalamic neuronal activity during high-frequency stimulation have not been investigated.

Methods In 20 patients with Parkinson’s disease each undergoing subthalamic DBS, we recorded single-unit subthalamic activity using one microelectrode, while a separate microelectrode was used to deliver 5–10 s trains of stimulation at 100 Hz using varying current amplitudes and pulse widths (44 neurons investigated).

Results Analysis of variance tests confirmed significant (p<0.001) main effects of both current amplitude and pulse width on subthalamic neuronal firing during stimulation and on poststimulus inhibitory silent periods. Prolonged silent periods were often followed by postinhibitory rebound burst excitations. Additionally, a significant (p<0.0001) correlation was found between neuronal firing and total electrical energy delivered (TEED). With TEED values≤31.2 µJ/s (associated with DBS parameters of ≤2.0 mA, 130 Hz stimulation frequency and 60 µs pulse width, assuming 1 kΩ impedance), neuronal firing was sustained at a rate of 32.4%±3.3% (mean±SE), while with values>31.2 µJ/s, neurons fired at only 4.3%±1.2%.

Conclusions Neuronal suppression is likely an important mechanism of action of therapeutically beneficial subthalamic DBS, which may underlie clinically relevant behavioural changes.

  • deep brain stimulation
  • Parkinson’s disease
  • subthalamic nucleus

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  • Contributors (1) Research project: A. Conception, B. Organisation and C. Execution. (2) Data and statistical analysis: A. Design, B. Execution and C. Review and Critique. (3) Manuscript: A. Writing of the first draft and B. Review and Critique. LM: 1A, 1B, 1C, 2A, 2B and 3A. SKK, MH and AL: 1B, 1C, 2C and 3B. MRP: 1A, 2C and 3B. WH: 1A, 1B, 1C, 2C and 3B.

  • Funding This work was supported in part by the Natural Sciences and Engineering Research Council: Discovery Grant RGPIN-2016-06358 (MRP), Dean Connor and Maris Uffelmann Donation (MRP) and the Dystonia Medical Research Foundation (WH).

  • Competing interests SKK, MH and WH have received honoraria, travel funds and/or grant support from Medtronic (not related to this work). AL has received honoraria, travel funds and/or grant support from Medtronic, Boston Scientific, St. Jude-Abbott and Insightec (not related to this work). MRP is a shareholder in MyndTec. AL is a co-founder of Functional Neuromodulation. LM has no competing interests.

  • Patient consent for publication Not required.

  • Ethics approval The experiments conformed to the guidelines set by the Tri-Council Policy on Ethical Conduct for Research Involving Humans and were approved by the University Health Network Research Ethics Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.