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Associative stimulation has been shown to enhance excitability in the human motor cortex (Stefan et al. 2000); however, little is known about the underlying mechanisms. An interventional paired associative stimulation (IPAS) was employed consisting of repetitive application of single afferent electric stimuli, delivered to the right median nerve, paired with single pulse transcranial magnetic stimulation (TMS) over the optimal site for activation of the abductor pollicis brevis muscle (APB) to generate approximately synchronous events in the primary motor cortex. Compared to baseline, motor evoked potentials (MEPs) induced by unconditioned, single TMS pulses increased after IPAS. By contrast, intracortical inhibition, assessed using (i) a suprathreshold test TMS pulse conditioned by a subthreshold TMS pulse delivered 3 ms before the test pulse, and (ii) a suprathreshold test TMS pulse conditioned by afferent median nerve stimulation delivered 25 ms before the TMS pulse, remained unchanged when assessed with appropriately matching test stimulus intensities. The increase of single-pulse TMS-evoked MEP amplitudes was blocked when IPAS was performed under the influence of dextromethorphan, an N-methyl-d-aspartate (NMDA) receptor antagonist known to block long-term potentiation (LTP). Further experiments employing the double-shock TMS protocol suggested that the afferent pulse, as one component of the IPAS protocol, induced disinhibition of the primary motor cortex at the time when the TMS pulse, as the other component of IPAS, was delivered. Together, these findings support the view that LTP-like mechanisms may underlie the cortical plasticity induced by IPAS.
Considerable evidence, including combined behavioral and physiological studies (Rioult-Pedotti et al. 2000), suggests that long-term potentiation (LTP) of synaptic efficacy and its counterpart long-term depression (LTD) are cellular mechanisms underlying learning and memory. LTP has been produced in vitro in neocortical slices derived from virtually any cortical region by different stimulation protocols. Between them, associative LTP may explain how inputs from local intracortical fibres, and cortico-cortical or thalamo-cortical afferents converging onto the same postsynaptic targets could interact to reshape local representational cortical patterns (e.g. Donoghue et al. 1996; Asanuma & Pavlides, 1997; Sanes & Donoghue, 2000). Associative LTP has been generated by pairing stimulation of cortical afferents with depolarization (Baranyi & Szente, 1987) or stimulation-induced firing (Baranyi & Feher, 1981) of the postsynaptic neuron, and by pairing stimulation of ‘vertical’ (thalamo-cortical as well as cortico-cortical fibres) with stimulation of ‘horizontal’ intracortical fibres in cortical layers II/III (Hess & Donoghue, 1994; Hess et al. 1996).
We have recently developed a protocol, shaped after models of associative LTP in experimental animals, to induce plasticity in the human motor cortex (Stefan et al. 2000). A rapidly evolving (< 30 min), long-lasting (duration > 60 min), reversible and topographically specific increase of corticomuscular excitability was induced when peripheral electric stimulation was paired with transcranial magnetic stimulation over the contralateral motor strip and timed to generate approximately synchronous events in the motor cortex. Experiments aimed at locating the level on the neuroaxis where this effect took place employed F-wave testing and electrical brainstem stimulation, which are sensitive to spinal excitability changes, but not to cortical excitability changes. These experiments showed that the excitability increase after interventional paired associative stimulation (IPAS) was generated at a supraspinal and therefore probably the cortical level (Stefan et al. 2000). Because, in addition, the increase of excitability was dependent on the synchronicity of activation of motor cortex output elements by each stimulation modality, we have conjectured that it might represent associative LTP or a closely related phenomenon in the human motor cortex (Stefan et al. 2000). This hypothesis leads to the following considerations which were experimentally tested in the present study: (1) The view that IPAS-induced plasticity is caused by increasing synaptic efficacy, would be supported if intracortical GABAA receptor-mediated inhibition, as one of the major alternative candidate mechanisms, were unchanged after IPAS. (2) Because LTP in the motor cortex depends upon activation of NMDA receptors (Aroniadou & Keller, 1995; Castro-Alamancos et al. 1995; Buonomano & Merzenich, 1998), a pharmacological blockade of these receptors should suppress the increase of IPAS-induced enhancement of motor cortical excitability. Some of the results have been published previously in abstract form (Stefan et al. 1999).