COGNITIVE NEUROSCIENCE Short-term and long-term plasticity interaction in human primary motor cortex Ennio Iezzi, 1, * Antonio Suppa, 1,2, * Antonella Conte, 1,2 Pietro Li Voti, 1,2 Matteo Bologna 1,2 and Alfredo Berardelli 1,2 1 Neuromed Institute, Sapienza University of Rome, Viale dell’Universita `, 30 00185 Rome, Italy 2 Department of Neurology and Psychiatry, Sapienza University of Rome, Viale dell’Universita ` , 30 00185 Rome, Italy Keywords: plasticity, primary motor cortex, repetitive transcranial magnetic stimulation, theta-burst stimulation Abstract Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short- and long-term forms of synaptic plasticity, resembling short-term potentiation (STP) and long-term potentiation ⁄ depression (LTP ⁄ LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5-Hz rTMS interferes with LTP ⁄ LTD-like plasticity induced by intermittent and continuous theta-burst stimulation (iTBS and cTBS). The effects induced by 5-Hz rTMS and iTBS ⁄ cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5-Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5-Hz rTMS. Interactions between 5-Hz rTMS and iTBS ⁄ cTBS were investigated under several experimental conditions by delivering 5-Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5-Hz rTMS and TBS, and delivering one and ten 5-Hz rTMS trains. We also investigated whether 5-Hz rTMS induces changes in intracortical excitability tested with paired-pulse transcranial magnetic stimulation. When given alone, 5-Hz rTMS induced short-lasting and iTBS ⁄ cTBS induced long-lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5-Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS ⁄ cTBS-induced after-effects disappeared. The 5-Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5-Hz rTMS abolishes iTBS ⁄ cTBS-induced LTP ⁄ LTD-like plasticity through non-homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short-term and long-term rTMS-induced plasticity in human M1. Introduction Plasticity refers to the nervous system’s ability to undergo activity- dependent changes that can strengthen or weaken synaptic transmission. In experimental studies, one possible approach to exploring synaptic plasticity is to measure changes in post-synaptic responses after repetitive stimulation of pre-synaptic terminals (Cooke & Bliss, 2006). Plasticity-inducing protocols may elicit lasting changes in test responses ranging from milliseconds (short-term plasticity) to minutes or hours (long-term plasticity), mainly through activation of the N-methyl-d- aspartate (NMDA) glutamatergic receptors (Collingridge et al., 1983). In human studies, short-term and long-term plasticity can be tested by delivering repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) and then measuring changes in motor evoked potential (MEP) size during or after rTMS (Siebner & Rothwell, 2003; Ziemann et al., 2008). Short trains of high-frequency suprathreshold rTMS elicit a progressive increase in MEP size during and for a few hundred milliseconds after stimulation ends (short-term plasticity) (Pascual-Leone et al., 1994; Jennum et al., 1995; Berardelli et al., 1998; Lorenzano et al., 2002; Gilio et al., 2007; Ziemann et al., 2008). The mechanism responsible for the MEP size increase resembles the NMDA-dependent short-term potentiation (STP) described in animal experiments (Bliss & Lømo, 1973; Zucker, 1989; Cooke & Bliss, 2006). With a different approach, theta-burst stimulation (TBS), according to the protocol used, induces facilitatory or inhibitory changes in MEP size lasting 30–60 min after stimulation ends (long-term plasticity) (Huang et al., 2005). After intermittent TBS (iTBS) MEPs increase in size; conversely, after continuous TBS (cTBS) they decrease. TBS resembles experimental protocols used in animal studies inducing NMDA-mediated long-term potentiation (LTP) or long-term depression (LTD) plasticity (Andersen & Lømo, 1967; Bliss & Lømo, 1973; Larson et al., 1986; Castro-Alamancos et al., 1995; Hess & Donoghue, 1996; Huang et al., 2005, 2010; Teo et al., 2007; Ziemann et al., 2008). In humans, it is unknown whether STP as elicited by 5-Hz rTMS interacts with LTP ⁄ LTD-like plasticity elicited by TBS. Answering this question would be useful in providing new information on short- and long-term plasticity in human cortical motor areas. Because changes in synaptic activity induced by a conditioning rTMS protocol influence the after-effects of rTMS through a priming effect (Iyer et al., 2003; Siebner et al., 2004; Hamada et al., 2008; Todd et al., 2009; Gamboa et al., 2010; Siebner, 2010), in this study Correspondence: Professor Alfredo Berardelli, 1 Neuromed Institute and 2 Department of Neurology and Psychiatry, as above. E-mail: alfredo.berardelli@uniroma1.it *These authors contributed equally to the study. Received 10 January 2011, revised 23 February 2011, accepted 8 March 2011 European Journal of Neuroscience, Vol. 33, pp. 1908–1915, 2011 doi:10.1111/j.1460-9568.2011.07674.x ª 2011 The Authors. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience