Neurons firing both during self and other's motor behavior (mirror neurons) have been described in the brain of vertebrates including humans. The activation of somatic motor programs driven by perceived behavior has been taken as evidence for mirror neurons' contribution to cognition. The inverse relation, that is the influence of motor behavior on perception, is needed for demonstrating the long-hypothesized causal role of mirror neurons in action understanding. We provide here conclusive behavioral and neurophysiological evidence for that causal role by means of cross-modal adaptation coupled with a novel transcranial magnetic stimulation (TMS)-adaptation paradigm. Blindfolded repeated motor performance of an object-directed action (push or pull) induced in healthy participants a strong visual after-effect when categorizing others' actions, as a result of motor-to-visual adaptation of visuo-motor neurons. TMS over the ventral premotor cortex, but not over the primary motor cortex, suppressed the after-effect, thus localizing the population of adapted visuo-motor neurons in the premotor cortex. These data are exquisitely consistent in humans with the existence of premotor mirror neurons that have access to the action meaning. We also show that controlled manipulation of the firing properties of this neural population produces strong predictable changes in the way we categorize others' actions.

Action observation produces automatic "mirror" responses in the observers' motor system. However, in daily life, nonimitative actions are often required to be produced in response to others' acts, generating a conflict between automatic and voluntary responses. First, we used single-pulse transcranial magnetic stimulation (TMS) to assess the temporal dynamics of motor output in healthy volunteers preparing rule-based counter-imitative motor responses cued by different observed hand movements. Second, we applied the same paradigm after 1-Hz repetitive TMS (rTMS) of the left posterior parietal cortex (PPC) and of the left dorsolateral prefrontal cortex (dlPFC). The results showed an early (150 ms from onset of visual stimuli) stimulus-driven mirror response that was followed by a later (300 ms) rule-based nonmirror response. rTMS applied to the PPC modulated only the early mirror response. Conversely, rTMS to the dlPFC modulated specifically the late rule-based motor response. The data indicate that a fast bottom-up process mediated by the dorsal visual stream produces automatic imitative responses. Arbitrary rule-based visuomotor associations are on the contrary mediated by a slower system, relying on the prefrontal cortex. The 2 systems are mutually independent and compete for motor output in socially relevant situations only at a distal level.

Is a short visuomotor associative training sufficient to reverse the visuomotor tuning of mirror neurons in adult humans? We tested the effects of associative training on corticospinal modulation during action observation in the 100-320 ms interval after action onset. In two separate experiments, the acceleration of transcranial magnetic stimulation (TMS)-induced movements was recorded before and after training participants to respond to observed acts with an opposite or similar behavior. Before training, TMS-induced accelerations mirrored the observed action at 250 and 320 ms. After training, responses at 250 ms were unchanged and still mirrored the stimuli, without any effect of training direction. Only at 320 ms, we observed training-dependent changes in evoked responses. A control experiment with non-biological rotational movements as visual stimuli indicated that spatial stimulus-response compatibility is not sufficient to account for the results of the two main experiments. We show that the effects of a short visuomotor associative training are not pervasive on the automatic mirror responses. 'Early' (250 ms) responses were not influenced by training. Conversely only 'late' (320 ms) responses changed according to the training direction. This biphasic time course indicates that two distinct mechanisms produce the automatic mirror responses and the newly learned visuomotor associations.

Empirical evidence indicates that cognitive consequences of cerebellar lesions tend to be mild and less important than the symptoms due to lesions to cerebral areas. By contrast, imaging studies consistently report strong cerebellar activity during tasks of action observation and action understanding. This has been interpreted as part of the automatic motor simulation process that takes place in the context of action observation. The function of the cerebellum as a sequencer during executed movements makes it a good candidate, within the framework of embodied cognition, for a pivotal role in understanding the timing of action sequences. Here, we investigated a cohort of eight patients with chronic, first-ever, isolated, ischemic lesions of the cerebellum. The experimental task consisted in identifying a plausible sequence of pictures from a randomly ordered group of still frames extracted from (a) a complex action performed by a human actor ("biological action" test) or (b) a complex physical event occurring to an inanimate object ("folk physics" test). A group of 16 healthy participants was used as control. The main result showed that cerebellar patients performed significantly worse than controls in both sequencing tasks, but performed much worse in the "biological action" test than in the "folk physics" test. The dissociation described here suggests that observed sequences of simple motor acts seem to be represented differentially from other sequences in the cerebellum.

PMCd on the ipsilateral M1, likely witnessing direct corticocortical connectivity in humans. We also describe a novel paradigm to test ipsilateral PMCd-M1 in humans.

We investigated how haptic information on object geometry is encoded in the parietal operculum (OP) and is used for guiding object-directed motor acts in humans. We tested the effects of conditioning single-pulse transcranial magnetic stimulation (spTMS) applied to the left OP on corticospinal excitability assessed by a test spTMS applied to the ipsilateral motor cortex (M1) 5 ms after conditioning spTMS. Participants explored the size of a graspable object visually or haptically and waited for a go-signal to grasp it in the dark. They received TMS during the delay phase. In a separate group of participants performing the same task, conditioning spTMS was applied to the ventral premotor cortex (vPM) 7 ms before test spTMS. Results showed that conditioning TMS over OP modulated M1 output according to the information on object size that had been acquired haptically but not visually. Vice versa, conditioning TMS over vPM modulated M1 output according to information on object size acquired by vision but not haptically. Moreover spTMS over OP produced a significant modulation of the upcoming reaching behavior only when the object had been explored haptically. We show that OP contains a haptic memory of objects' macrogeometry and the appropriate motor plan for grasping them.

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Skilled hand function relies heavily on the integrity of the primary motor cortex (M1) and on a web of cortico-cortical connections projecting onto it. We used a novel explorative paradigm to map the origin of cortico-M1 pathways assessed by dual transcranial magnetic stimulation (TMS) in three healthy participants. Subthreshold conditioning TMS (cTMS) was delivered over a grid of ≈100 spots. Covering the left hemisphere, and was followed by suprathreshold test (tTMS) delivered over the ipsilateral M1. Grid points were tested eight times, with inter-stimulus intervals between cTMS and tTMS of 4 and 7 ms. Participants were asked to stay relaxed with no particular task. Motor evoked potentials (MEPs) from cTMS + tTMS were normalized to MEPs from tTMS alone and were compared to the value expected from tTMS alone using t-statistics. The t-values from each grid point were then used to plot statistical maps. Several foci of significant cortico-M1 interactions were found in the dorsal–medial frontal cortex, in the ventral frontal cortex, in the superior and inferior parietal lobules and in the parietal operculum. The majority of active foci had inhibitory effects on corticospinal excitability. The spatial location of the network of different subjects overlapped but with some anatomical variation of single foci. TMS statistical mapping during the resting state revealed a complex inhibitory cortical network. The explorative approach to TMS as a brain mapping tool produced results that are self-standing in single subjects overcoming inter-individual variability of cortical active sites.