Understanding the rules that shape human central sensory representations is of considerable physiological and clinical interest. Lasting changes of synaptic efficacy, long-term potentiation (LTP) and long-term depression (LTD), have been implicated as physiological mechanisms underlying experience- and injury-driven sensory map changes in humans and animals (Merzenich et al. 1983; Pons et al. 1991). Indeed, LTP/LTD have been documented in the somatosensory cortex of experimental animals using a variety of induction protocols both in vitro (Aroniadou-Anderjaska & Keller, 1995; Castro-Alamancos et al. 1995; Castro-Alamancos & Connors, 1996; Kitagawa et al. 1997; Feldman, 2000; Heusler et al. 2000; Urban et al. 2002) and in vivo (Keller et al. 1990; Glazewski et al. 1998; Froc et al. 2000; Allen et al. 2003; Werk & Chapman, 2003). These protocols differ substantially with respect to their efficacy and physiological properties (for review see Buonomano & Merzenich, 1998; Fox, 2002). Among the protocols, spike-timing-dependent plasticity of synaptic efficacy (STDP; Song et al. 2000) is unique in that the direction of synaptic efficacy changes is determined by the sequence of pre- and postsynaptic neuronal activity (for review see Dan & Poo, 2004). In STDP, LTP is induced if the postsynaptic neurone fires an action potential after the excitatory postsynaptic potential is induced by the presynaptic neurone. In contrast, LTD is generated if the sequence of events is reversed. STDP is largely independent of the neuronal firing rate and possesses significant theoretical advantages over models of plasticity that are solely driven by average correlations between the firing of different neurones (Sejnowski, 1999; Song et al. 2000; Song & Abbott, 2001). In humans, the plasticity of sensory representations has been studied in a variety of clinical and behavioural conditions by the analysis of somatosensory-evoked potentials (SSEPs) (Elbert et al. 1995; Flor et al. 1995, 1997; Knecht et al. 1996; Tinazzi et al. 1997b, 1998, 2004; Bara-Jimenez et al. 1998; Elbert et al. 1998). Different components of SSEPs reflect different stages of somatosensory information processing (Tinazzi et al. 1998). Therefore, the analysis of SSEPs enables the site of plastic changes along the neuroaxis to be located (Tinazzi et al. 1998). SSEPs have also been used to probe excitability changes induced experimentally by various external manipulations such as direct current stimulation (Matsunaga et al. 2004), repetitive transcranial magnetic stimulation (Enomoto et al. 2001; Tsuji & Rothwell, 2002; Ragert et al. 2004), or repetitive peripheral tactile stimulation (Pleger et al. 2001). However, it is not possible, using these protocols, to test for the presence of plasticity mechanisms that exhibit properties of STDP in human primary somatosensory cortex (S1). Recently, we have introduced paired associative stimulation (PAS) in humans as a protocol shaped after animal models of associative LTP/LTD. PAS consists of pairing repetitive peripheral electrical afferent stimulation with transcranial magnetic stimulation (TMS) of the primary motor cortex (Stefan et al. 2000, 2002; Wolters et al. 2003). In this arrangement, transcranial magnetic stimulation probably activates intracortical fibres travelling ‘horizontally’ with respect to the cortical surface (Rothwell, 1997), and peripheral electrical stimulation induces activity in cortico-petal (thalamo-cortical or cortico-cortical) ‘vertical’ fibres (Kaas & Pons, 1988). Unlike other plasticity-inducing protocols, PAS allows the control of the relative timing of neuronal events induced by the two stimulation modalities. PAS targeting the primary motor cortex (M1) induces either potentiation or depression of TMS-evoked potentials (Wolters et al. 2003) depending on the interval between the two stimulation modalities, and the physiological properties of this plasticity resemble those of STDP seen in animal studies (Stefan et al. 2000, 2002; Wolters et al. 2003).
Here, we use PAS with TMS over the somatosensory cortex to test the hypothesis that a timing-dependent plasticity rule governs the induction of bidirectional plasticity in human S1. Together, our findings provide further support for the notion that timing-dependent plasticity may represent an important principle subserving neocortical plasticity in humans.