title: Interaction between different interneuron networks involved in human associative plasticity.
abstract: BACKGROUND
  Paired associative stimulation (PAS) is a widely used method to study spike timing dependent plasticity in motor cortex. Repeated pairing of an electrical stimulus to the median nerve with transcranial magnetic stimulation (TMS) over the contralateral motor cortex at interstimulus intervals (ISIs) of 21.5-25 ms leads to a long term potentiation (LTP)-like synaptic plasticity in the corticospinal system. Previously we found that concurrent transcranial direct current stimulation (TDCS) over cerebellum blocked the effect of PAS25 but not PAS21.5, implying that two separate mechanisms were involved.
  
  
  OBJECTIVE
  We hypothesized that if PAS21.5 and PAS25 increased corticospinal excitability by two entirely separate mechanisms then their effects might summate if we intermixed them in the same session.
  
  
  METHODS
  Twenty-four healthy volunteers were studied. Eight subjects were selected who showed the expected facilitation after both standard PAS21.5 and PAS25 with 180 pairs. They participated to two sessions in which PAS consisted of 360 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right APB at randomly delivered ISIs of 25 ms and of 21.5 ms (180 pairs for each ISI) (PASvar360p). Either sham or anodal TDCS (2 mA, 30 min) was applied to the cerebellum simultaneously with PASvar360p. Subsequently, we applied a protocol with 90 pairs for each ISI (PASvar180p). We measured motor evoked potentials (MEPs) before and after each intervention.
  
  
  RESULTS
  Although PAS21.5 and PAS25 each produce corticospinal facilitation when applied alone, the after-effects disappeared if we randomly intermixed PAS21.5 and PAS25 using either 180 pairs (PASvar360p) or 90 pairs (PASvar180p) for each ISI. Facilitation is restored if anodal but not sham TDCS is applied concurrently over the cerebellum to block the effect of PAS25.
  
  
  CONCLUSIONS
  PAS21.5 and PAS25 not only engage two separate mechanisms but also they are mutually inhibitory.
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, United Kingdom; Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale ''A. Avogadro'', Novara, Italy.
authors.forename: Gionata
authors.initials: G
authors.lastname: Strigaro
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, United Kingdom; Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address: mhamada-tky@umin.net.
authors.forename: Masashi
authors.initials: M
authors.lastname: Hamada
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, United Kingdom; Department of Neurology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
authors.forename: Nagako
authors.initials: N
authors.lastname: Murase
authors.affiliation: Department of Translational Medicine, Section of Neurology, University of Piemonte Orientale ''A. Avogadro'', Novara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Cantello
authors.affiliation: Sobell Department of Motor Neuroscience and Movement Disorders, University College London Institute of Neurology, London, United Kingdom.
authors.forename: John C
authors.initials: JC
authors.lastname: Rothwell
mesh_terms: D000293:Adolescent; D000328:Adult; D004558:Electric Stimulation / Q000379:methods; D019054:Evoked Potentials, Motor / Q000502:physiology*; D005260:Female; D006801:Humans; D007395:Interneurons / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008297:Male; D008475:Median Nerve / Q000502:physiology; D008875:Middle Aged; D009044:Motor Cortex / Q000502:physiology*; D009415:Nerve Net / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D050781:Transcranial Magnetic Stimulation / Q000379:methods*; D055815:Young Adult
keywords: Associative plasticity; Heterosynaptic interaction; Transcranial magnetic stimulation