NEUROSYSTEMS Transcranial direct current stimulation preconditioning modulates the effect of high-frequency repetitive transcranial magnetic stimulation in the human motor cortex Giuseppe Cosentino, Brigida Fierro, Piera Paladino, Simona Talamanca, Simone Vigneri, Antonio Palermo, Giuseppe Giglia and Filippo Brighina Department of Experimental Biomedicine and Clinical Neurosciences (BioNeC), University of Palermo, Via Gaetano La Loggia n. 1, 90129 Palermo, Italy Keywords: homeostatic plasticity, metaplasticity, rTMS, tDCS Abstract Experimental studies emphasize the importance of homeostatic plasticity as a mean of stabilizing the properties of neural circuits. In the present work we combined two techniques able to produce short-term (5-Hz repetitive transcranial magnetic stimulation, rTMS) and long-term (transcranial direct current stimulation, tDCS) effects on corticospinal excitability to evaluate whether and how the effects of 5-Hz rTMS can be tuned by tDCS preconditioning. Twelve healthy subjects participated in the study. Brief trains of 5-Hz rTMS were applied to the primary motor cortex at an intensity of 120% of the resting motor threshold, with recording of the electromyograph traces evoked by each stimulus of the train from the contralateral abductor pollicis brevis muscle. This interventional protocol was preconditioned by 15 min of anodal or cathodal tDCS delivered at 1.5 mA intensity. Our results showed that motor- evoked potentials (MEPs) increased significantly in size during trains of 5-Hz rTMS in the absence of tDCS preconditioning. After facilitatory preconditioning with anodal tDCS, 5-Hz rTMS failed to produce progressive MEP facilitation. Conversely, when 5-Hz rTMS was preceded by inhibitory cathodal tDCS, MEP facilitation was not abolished. These findings may give insight into the mechanisms of homeostatic plasticity in the human cerebral cortex, suggesting also more suitable applications of tDCS in a clinical setting. Introduction Transcranial direct current stimulation (tDCS) and repetitive transcra- nial magnetic stimulation (rTMS) are non-invasive techniques to induce changes in the activity of cortical neurons that outlast the end of stimulation (Hallett et al., 1999; Nitsche & Paulus, 2000; Siebner & Rothwell, 2003). Although the exact mechanisms mediating the after- effects are not fully clarified, there is evidence that changes in synaptic strength play a role (Liebetanz et al., 2002; Iyer et al., 2003). Several data suggest that rTMS-induced cortical plastic changes depend on the functional state of the motor cortex and may be shifted by tDCS preconditioning (Lang et al., 2004; Siebner et al., 2004; Ziemann & Siebner, 2008). Recent studies exploring the preconditioning effects of tDCS on the after-effect of rTMS on corticospinal excitability showed that the facilitatory effects of high-frequency rTMS can be reversed by ‘facilitatory preconditioning’ with anodal tDCS (Lang et al., 2004), as well as ‘inhibitory preconditioning’ with cathodal tDCS can reverse the inhibitory effects of low-frequency rTMS (Siebner et al., 2004). These findings have been interpreted in the context of homeostatic plasticity in the human motor cortex, and demonstrate that precon- ditioning sessions of tDCS can be used to shape the effects of subsequent rTMS on the primary motor cortex (Malenka, 2003; Turrigiano & Nelson, 2004; Cooke & Bliss, 2006; Hoogendam et al., 2010). It is known that long periods of tDCS (e.g. 10 min or more) can alter cortical excitability for up to 1 h, depending on the intensity of the current and the duration of the stimulation. Anodal tDCS applied to the motor cortex increases cortical excitability and activity, whilst cathodal tDCS results in the reverse effect (Nitsche & Paulus, 2001; Nitsche et al., 2003b). Pharmacological studies suggest that the cortical excitability shifts induced by tDCS depend on membrane polarization, thus, modulating the conductance of sodium and calcium channels. Moreover, they suggest that the after-effects involve modulation of N-methyl-d-aspartate (NMDA) receptors efficacy resembling those of long-term potentiation (LTP) and long-term depression (LTD; Nitsche et al., 2003a,b, 2004; Antal et al., 2006). In the present study we evaluated in normal subjects how changes in the state of human motor cortical excitability induced by tDCS may affect motor cortical response to brief trains of 5-Hz rTMS. There is evidence that short trains of suprathreshold 5-Hz rTMS produce a progressive facilitation of the motor-evoked potentials (MEPs; Berardelli et al., 1998; Inghilleri et al., 2005; Pascual-Leone et al., 1994), which is likely due to a calcium-dependent increase in presynaptic glutamate release (Fisher et al., 1997; Zucker & Regehr, 2002; Ziemann et al., 2008). MEP potentiation shortly outlasts the end of brief trains of high-frequency rTMS decaying along a time scale of Correspondence: Dr B. Fierro, as above. E-mail: fierro@unipa.it Received 29 July 2011, revised 13 October 2011, accepted 18 October 2011 European Journal of Neuroscience, Vol. 35, pp. 119–124, 2012 doi:10.1111/j.1460-9568.2011.07939.x ª 2011 The Authors. European Journal of Neuroscience ª 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd European Journal of Neuroscience