Pharmacology of TMS.

Testing the effects of CNS active drugs (neurotransmitters, neuromodulators) on motor cortical excitability by means of TMS has developed into an important field of research. At least two major avenues can be followed up. First, testing a drug with a known singular mode of action may provide information on the physiological properties of a novel TMS measure. For instance, it was shown that the recently discovered short latency afferent inhibition was significantly reduced by the anticholinergic (M1 antagonist) scopolamine (Di Lazzaro et al., 2000b). This opened up the opportunity to use short latency afferent inhibition (SLAI) to detect deficiency of central cholinergic innervation in neurological disease, for instance in Alzheimer's disease (Di Lazzaro et al., 2002). The other avenue is to use an array of well characterised TMS measures to obtain knowledge about the modes of action at the systems level of human cortex of a drug with unknown or multiple modes of action. One example is the novel anticonvulsant topiramate for which multiple modes of action were identified in animal experiments, including blocking effects on voltage-gated sodium channels, positive modulation of the GABAA receptor, inhibition of the kainate and AMPA subtypes of the glutamate receptor, inhibition of L-type voltage-gated calcium channels, and increase of cerebral GABA levels. Topiramate resulted in a selective increase of SICI and decrease of ICF without affecting motor threshold or CSP (Reis et al., 2002). From these results it was concluded that the main modes of action of topiramate at the level of the human motor cortex are its enhancing action on GABAA receptors and/or inhibition of glutamate receptors. TMS offers now a wide array of measures of motor cortical excitability which covers many different forms of excitability, such as axon and inhibitory and excitatory synaptic excitability. Increasing numbers of different forms of cortical inhibition are being discovered, such as SICI (GABAA dependent), CSP (GABAB dependent) and SLAI (cholinergic), and it is very likely that more will follow soon.