TMS in cognitive neuroscience: Virtual lesion and beyond

Transcranial magnetic stimulation (TMS) excites axons of cortical neurons, leading in turn to synaptic activation of excitatory and inhibitory target neurons. However, the exact neurophysiological mechanisms of how TMS activates the brain are still relatively unclear (Di Lazzaro et al., 2008; Rotem and Moses, 2008; Wagner et al., 2009). Despite this lack of detailed knowledge, TMS is increasingly more often used in cognitive neuroscience to test brain-behavior relation, through its capacity to disrupt task-related neuronal activity (‘virtual lesion’) (Pascual-Leone et al., 1999; Silvanto and Muggleton, 2008; Walsh and Pascual-Leone, 2003). ‘Virtual lesion’ is used in this article in its broadest term, i.e., transient alteration of the function of the cortical target induced by single-pulse TMS or short trains of TMS during a cognitive task (online mode), or by TMS plasticity protocols prior to the task (offline mode). The important question is: How valid is TMS as a tool to test brainbehavior relation, if its modes of action are not fully known? This account will be written from the perspective of TMS applications in the motor system, but the conclusions pertain to any field of cognitive neuroscience. It is currently thought that single-pulse TMS alters ongoing (task-relevant) neuronal activity by exciting many neurons by virtue of artificially synchronizing their action potentials, followed by long lasting inhibition (Siebner et al., 2009). If TMS alters cognitive task performance, then most people would agree with the statement that the stimulated brain region is causally involved in that task. While this, in its broad sense, is correct, many qualifications exist which may preclude more specific conclusions. The first problem is that it is still not exactly known which neuronal elements are excited by TMS and whether the main effect is excitatory or inhibitory. Extracellular single cell recordings in cat visual cortex showed that low-intensity TMS typically results in early excitation (increase in spontaneous