A new temporal window for inducing depressant associative plasticity in human primary motor cortex q S.M. Schabrun a,⇑ , D. Weise b , M.C. Ridding c , J. Classen b a The University of Queensland, NHMRC Centre of Clinical Research Excellence in Spinal Pain, Injury and Health, School of Health and Rehabilitation Science, St. Lucia, Brisbane, Queensland, Australia b The University of Leipzig, Department of Neurology, Leipzig, Germany c The University of Adelaide, The Robinson Institute, School of Paediatrics and Reproductive Health, Adelaide, South Australia, Australia article info Article history: Accepted 11 January 2013 Available online 8 February 2013 Keywords: Human Paired associative stimulation (PAS), Primary motor cortex Spike-timing dependent plasticity highlights  Evidence of a new temporal window for inducing depressant associative plasticity in humans.  Paired associative stimulation (PAS) at long negative inter-stimulus intervals suppresses M1 corticospi- nal excitability, but is not accompanied by changes in inhibitory circuits.  Understanding the temporal rules for inducing plasticity is crucial if therapeutic manipulation is to occur in future. abstract Objective: Spike-timing dependent plasticity (STDP) usually refers to synaptic plasticity induced by near- synchronous activation of neuronal input and neuronal firing. However, some models of STDP predict effects that deviate from this tight temporal synchrony. We aimed to characterise the induction of STDP using paired associative stimulation (PAS) when the pre-synaptic input arrives in primary motor cortex (M1) at (i) intermediate intervals (50–80 ms; PAS 50 ,..PAS 80 ) before the post-synaptic neuron is activated and (ii) long intervals (100–450 ms; PAS 100 ,..PAS 450 ) after the post-synaptic neuron is activated. PAS at near-synchronicity (PAS 25 ) was applied for comparison. Methods: To characterise the physiological effects of the different PAS protocols, we examined short- and long-interval intra-cortical inhibition; intra-cortical facilitation and short- and long-latency afferent inhi- bition, in addition to recording MEPs in 45 healthy individuals. Results: MEP amplitude was reduced at PAS intervals between 250 and 450 ms, increased with PAS 25 , and unaltered at the remaining intervals. There was no change in intra-cortical inhibitory or facilitatory circuits following any PAS protocol. Conclusions: These findings provide evidence of a previously unreported temporal window in which PAS induces a depression of corticospinal excitability in human M1. Significance: Establishing new temporal rules for STDP broadens its applicability for therapeutic usage in future. Crown Copyright Ó 2013 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. All rights reserved. 1. Introduction Spike-timing-dependant plasticity (STDP) provides a cellular model for changes in synaptic strength important for development, learning and memory in the mammalian brain. Synaptic strength is considered to be critically influenced by the spiking order and timing of pre- and post-synaptic neuron activation. Although dependent upon synapse type, presynaptic spiking before postsynaptic spiking in the order of tens of milliseconds generally induces long-term potentiation (LTP) of synaptic strength, while reversing the tempo- ral order induces long-term depression (LTD) (Levy and Steward, 1983). However, considerable diversity exists across synapses lo- cated on different neuron species and subcellular locations in the temporal rules (spike order and timing) needed to induce a persis- tent change in synaptic strength (Caporale and Dan, 2008). Paired-associative stimulation (PAS) is a technique designed to mimic, in the human brain, the STDP observed in animal models. 1388-2457/$36.00 Crown Copyright Ó 2013 Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. All rights reserved. http://dx.doi.org/10.1016/j.clinph.2013.01.004 q Part of this work was presented at the XIX Congress of the International Society for Electromyography and Kinesiology, Brisbane, Australia 19–21st July 2012. ⇑ Corresponding author. Address: School of Health and Rehabilitation Science, The University of Queensland, St. Lucia, Queensland 4072, Australia. Tel.: +61 7 3365 4590; fax: +61 7 3365 1284. E-mail address: s.schabrun@uq.edu.au (S.M. Schabrun). Clinical Neurophysiology 124 (2013) 1196–1203 Contents lists available at SciVerse ScienceDirect Clinical Neurophysiology journal homepage: www.elsevier.com/locate/clinph