title: Cortical Plasticity Induction by Pairing Subthalamic Nucleus Deep-Brain Stimulation and Primary Motor Cortical Transcranial Magnetic Stimulation in Parkinson's Disease.
abstract: Noninvasive brain stimulation studies have shown abnormal motor cortical plasticity in Parkinson's disease (PD). These studies used peripheral nerve stimulation paired with transcranial magnetic stimulation (TMS) to primary motor cortex (M1) at specific intervals to induce plasticity. Induction of cortical plasticity through stimulation of the basal ganglia (BG)-M1 connections has not been studied. In the present study, we used a novel technique of plasticity induction by repeated pairing of deep-brain stimulation (DBS) of the BG with M1 stimulation using TMS. We hypothesize that repeated pairing of subthalamic nucleus (STN)-DBS and M1-TMS at specific time intervals will lead to plasticity in the M1. Ten PD human patients with STN-DBS were studied in the on-medication state with DBS set to 3 Hz. The interstimulus intervals (ISIs) between STN-DBS and TMS that produced cortical facilitation were determined individually for each patient. Three plasticity induction conditions with repeated pairings (180 times) at specific ISIs (∼ 3 and ∼ 23 ms) that produced cortical facilitation and a control ISI of 167 ms were tested in random order. Repeated pairing of STN-DBS and M1-TMS at short (∼ 3 ms) and medium (∼ 23 ms) latencies increased M1 excitability that lasted for at least 45 min, whereas the control condition (fixed ISI of 167 ms) had no effect. There were no specific changes in motor thresholds, intracortical circuits, or recruitment curves. Our results indicate that paired-associative cortical plasticity can be induced by repeated STN and M1 stimulation at specific intervals. These results show that STN-DBS can modulate cortical plasticity.
  
  
  CONCLUSIONS
  We introduced a new experimental paradigm to test the hypothesis that pairing subthalamic nucleus deep-brain stimulation (STN-DBS) with motor cortical transcranial magnetic stimulation (M1-TMS) at specific times can induce cortical plasticity in patients with Parkinson's disease (PD). We found that repeated pairing of STN-DBS with TMS at short (∼ 3 ms) and medium (∼ 23 ms) intervals increased cortical excitability that lasted for up to 45 min, whereas the control condition (fixed latency of 167 ms) had no effects on cortical excitability. This is the first demonstration of associative plasticity in the STN-M1 circuits in PD patients using this novel technique. The potential therapeutic effects of combining DBS and noninvasive cortical stimulation should be investigated further.
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and.
authors.forename: Kaviraja
authors.initials: K
authors.lastname: Udupa
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and.
authors.forename: Nina
authors.initials: N
authors.lastname: Bahl
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Gunraj
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and Brain and Spinal Cord Rehabilitation Program, Toronto Rehabilitation, University Health Network, University of Toronto, Toronto, Ontario M4G 3V9, Canada, and.
authors.forename: Filomena
authors.identifier: http://orcid.org/0000-0002-0655-7040
authors.initials: F
authors.lastname: Mazzella
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and Service de Neurologie, CHU Grenoble, Joseph Fourier University, Grenoble 38041, France.
authors.forename: Elena
authors.initials: E
authors.lastname: Moro
authors.affiliation: Division of Neurosurgery, Krembil Neuroscience Centre, Toronto Western Research Institute, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Hodaie
authors.affiliation: Division of Neurosurgery, Krembil Neuroscience Centre, Toronto Western Research Institute, Toronto, Ontario M5T 2S8, Canada.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Lozano
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and.
authors.forename: Anthony E
authors.identifier: http://orcid.org/0000-0003-1229-3667
authors.initials: AE
authors.lastname: Lang
authors.affiliation: Edmond J. Safra Program in Parkinson's Disease, Division of Neurology and Robert.Chen@uhn.ca.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0002-8371-8629
authors.initials: R
authors.lastname: Chen
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D046690:Deep Brain Stimulation / Q000379:methods*; D004576:Electromyography; D019054:Evoked Potentials, Motor / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D010300:Parkinson Disease / Q000628:therapy*; D020531:Subthalamic Nucleus / Q000502:physiology*; D013997:Time Factors; D050781:Transcranial Magnetic Stimulation
keywords: deep-brain stimulation; hyperdirect pathway; intracortical circuits; motor cortical plasticity; subthalamic nucleus; transcranial magnetic stimulation