Mirror neurons: from discovery to autism

Exp Brain Res (2010) 200:223–237 DOI 10.1007/s00221-009-2002-3

R EV IE W

Mirror neurons: from discovery to autism Giacomo Rizzolatti · Maddalena Fabbri-Destro

Received: 12 June 2009 / Accepted: 27 August 2009 / Published online: 18 September 2009 © Springer-Verlag 2009

How the things started In the winter of 1991 I (GR) sent to Nature a report on a surprising set of neurons that we (Giuseppe Di Pellegrino, Luciano Fadiga, Leonardo Fogassi, Vittorio Gallese) had found in the ventral premotor cortex of the monkey. The fundamental characteristic of these neurons was that they discharged both when the monkey performed a certain motor act (e.g., grasping an object) and when it observed another individual (monkey or human) performing that or a similar motor act (Di Pellegrino et al. 1992). These neurons are now known as mirror neurons (Fig. 1). Nature rejected our paper for its “lack of general interest” and suggested publication in a specialized journal. At this point I called Prof. Otto Creutzfeld, the then Coordinating Editor of Experimental Brain Research. I told him that I thought we found something really interesting and asked him to read our manuscript before sending it to the referees. After a few days he called me back saying that indeed our Wndings were, according to him, of extraordinary interest. G. Rizzolatti (&) · M. Fabbri-Destro Dipartimento di Neuroscienze, Sezione Fisiologia, Università di Parma, via Volturno, 39, 43100 Parma, Italy e-mail: [email protected] M. Fabbri-Destro e-mail: [email protected] G. Rizzolatti Istituto Italiano di Tecnologia (IIT) Unità di Parma, Parma, Italy M. Fabbri-Destro Dipartimento SBTA, Sezione di Fisiologia Umana, Università di Ferrara, via Fossato di Mortara, 17-19, 44100 Ferrara, Italy

Our article appeared in Experimental Brain Research a few months later. The idea of sending our report on mirror neurons to Experimental Brain Research, rather than to another neuroscience journal, was motivated by a previous positive experience with that journal. A few years earlier, Experimental Brain Research accepted an article in which we presented (Rizzolatti et al. 1988) a new view (something that typically referees did not like) on the organization of the ventral premotor cortex of the monkey and reported the Wndings that paved the way for the discovery of mirror neurons. In that article we described how, in the ventral premotor cortex (area F5) of the monkey, there are neurons that respond both when the monkey performs a motor act (e.g., grasping or holding) and when it observes an object whose physical features Wt the type of grip coded by that neuron (e.g., precision grip/small objects; whole hand/large objects). These neurons (now known as “canonical neurons”, Murata et al. 1997) and neurons with similar properties, described by Sakata et al. (1995) in the parietal cortex are now universally considered the neural substrate of the mechanism through which object aVordances are translated into motor acts (see Jeannerod et al. 1995). We performed the experiments on the motor properties of F5 in 1988 using an approach that should almost necessarily lead to the discovery of mirror neurons if these neurons existed in area F5. In order to test the F5 neurons with objects that may interest the monkeys, we used pieces of food of diVerent size and shape. To give the monkey some food, we had, of course, to grasp it. To our surprise we found that some F5 neurons discharged not when the monkey looked at the food, but when the experimenter grasped it. The mirror mechanism was discovered. The next important role of Experimental Brain Research in the discovery of mirror neurons was its acceptance in

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The organization of the human parieto-frontal mirror system

Fig. 1 Example of an F5 mirror neuron selectively discharging during monkey grasping movements and during observation of a grasping movement done by the experimenter. a Lateral view of the brain with indicated the location of F5. b Grasping observation. c Grasping execution. a arcuate sulcus, c central sulcus, ip intraparietal sulcus (from di Pellegrino et al. 1992)

1996 of two articles which Wrst reported the existence of the mirror areas in humans (Rizzolatti et al. 1996; Grafton et al. 1996). The rational of the experiment was as follows: If mirror mechanism exists in humans the observation of actions done by another individual should activate, besides visual areas, also areas that have motor properties. We ran two PET experiments and showed that indeed the areas where the mirror neurons are located in the monkey become also active in humans. This Wnding was subsequently replicated by dozens of experiments (see Rizzolatti and Craighero 2004; Rizzolatti et al. 2009; Cattaneo and Rizzolatti 2009). At present there is an enormous literature on mirror neurons. A set of it concerns experiments in monkeys (see Rizzolatti and Craighero 2004; Rizzolatti et al. 2009) and more recently in birds (Prather et al. 2008); another set, much larger, concerns experiments in humans. In the present article we (GR and MF-D) will review mirror data in humans, examining, however, (by necessity) only part of the enormous mirror neuron studies triggered by our initial PET studies published in Experimental Brain Research.

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In humans the observation of goal-directed motor-acts activates, besides visual areas, the inferior parietal lobule (IPL) and the premotor cortex, mostly its ventral part, plus the caudal part of the inferior frontal gyrus (IFG) roughly corresponding to the pars opercularis of Broca’s area. These two regions form the core of the human parieto-frontal mirror system (Rizzolatti and Craighero 2004; Fabbri-Destro and Rizzolatti 2008) (Fig. 2). Both the premotor and parietal nodes of the human mirror system present a somatotopic organization, albeit rather rough (Buccino et al. 2001; Wheaton et al. 2004; Sakreida et al. 2005; Etzel et al. 2008). Observation of motor acts done by others with the leg, hand, and mouth activates the precentral gyrus and the pars opercularis of IFG in a medial to lateral direction, as in the classical homunculus of PenWeld and Rasmussen (1950)and Woolsey et al. (1952). In IPL, mouth motor acts appear to be represented rostrally, hand/arm motor acts caudally and leg motor acts even more caudally, and dorsally extending into the superior parietal lobule. A similar somatotopic organization based on the motor properties of the recorded neurons has been recently reported in monkey IPL by Rozzi et al. (2008) (see also Hyvarinen 1982). It is open question whether the activations found during the observation of reaching to grasp movements around the superior frontal sulcus (e.g., Grèzes et al. 2003; Buccino et al. 2004a; Gazzola and Keysers 2009) are due to representation of proximal movements or to motor preparation. This uncertainty depends of the fact that there is no clear boundary between the ventral (PMv) and dorsal (PMd) premotor cortices in humans. According to the Wrst, somatotopic, interpretation, the dorsal premotor activation is

Fig. 2 Later view of human brain. The colored areas form the parieto-frontal mirror network. Red parietal mirror node, yellow frontal mirror node

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located in a speciWc sector of PMv where proximal movements are represented. According to the motor preparation interpretation, the dorsal premotor activations are located in PMd, an area that according to monkey single neuron data is mostly involved in covert motor preparation (Kalaska and Crammond 1995; Crammond and Kalaska 2000). The parietal region active during the observation of object-directed motor acts is mostly located in the sector of the IPL close to and inside the intraparietal sulcus. This restricted localization raises an interesting question: Are other types of motor act also represented in other parts of IPL and, in that case, what kinds of act? An answer to these questions has been recently obtained by two fMRI studies. The Wrst investigated the localization of intransitive movements (Lui et al. 2008), the other that of actions performed with tools (Peeters et al. 2009). In the Wrst study, volunteers were scanned while they observed mimed, symbolic, and meaningless motor acts. As during the observation of object-directed actions, fMRI signal increase was found in the premotor cortex and in IPL. However, while the premotor cortex activation overlapped that previously found during the observation of objectdirected actions, in the parietal lobe the signal increase was not restricted to the intraparietal sulcus region, but extended into the posterior part of the supramarginal gyrus and the angular gyrus. Most interestingly, while the mimed actions were located dorsally close to the intraparietal sulcus, that is in a location similar to that activated by the observation of actual object-directed movements, symbolic motor acts were located ventrally, mostly in the angular gyrus. (Lui et al. 2008). In the second study, volunteers observed a variety of motor acts performed by another individual either by hand or using tools. The results showed that the observation of motor acts performed with tools activates the parieto-frontal circuit mediating hand grasping and, in addition, a speciWc sector of the anterior part of the left supramarginal gyrus (aSMG). In a parallel experiment carried out in the same study on naïve as well as on monkeys proWcient in using tools (rake and pliers), no evidence was found for a parietal sector activated during tool action observation. It was concluded that aSMG is a new evolutionary acquisition of homo sapiens that mediates the human capacity to understand the causal relationship between tools and the goal of the action achieved by using tools. Typically, an activation of SPL is absent or marginal in those studies where the experimenters use as visual stimuli distal motor acts or acts in which the distal component is prominent. The possibility of a proximal mirror representation in SPL was recently tested in an fMRI study where volunteers were asked to transport their hand to a particular location in space without grasping objects. The reaching movements were executed, observed, or imagined.

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An overlap between executed, observed, and imagined reaching activation was found in SPL extending into IPS, and in PMd. This study provides the Wrst demonstration of a mirror mechanism for reaching movements (Filimon et al. 2007).

Evidence for the activation of human cortical motor system during the observation of actions done by others The brain imaging studies reviewed above show that human cortical areas, active when individuals watch actions done by others, strictly correspond to the cortical areas that are endowed with mirror properties in the monkey (Rizzolatti et al. 2009; for monkey fMRI data see Nelissen et al. 2005). Because mirror neurons are motor neurons, the observation of motor acts done by others should determine, if mirror neurons are present in humans, an increase of motor cortex excitability congruent with the observed motor act. Evidence that this is the case has been obtained using transcranial magnetic stimulation (TMS). Fadiga et al. (1995) recorded the motor-evoked potentials (MEPs) induced by the stimulation of the left motor cortex in various muscles of the right hands and arms of volunteers asked to watch an experimenter while he grasped objects with his hand or performed meaningless arm movements. As a control for attentional factors there was a third condition in which volunteers detected the dimming of a small light. During both the experimental conditions there was a clear increase in the observer’s MEPs, relative to the control condition. This increase was present in those muscles that were recruited when the tested individuals were asked to execute the observed movements. Several TMS experiments conWrmed these Wndings (e.g., Strafella and Paus 2000; Gangitano et al. 2001; Maeda et al. 2002; Borroni et al. 2005). Among them particularly interesting is the study by Gangitano et al. (2001). These authors showed not only that MEPs recorded from the hand muscles increased during grasping observation, but also that the relative cortical facilitation closely reXected the diVerent grasping phases (Fig. 3). EEG and MEG studies provided further evidence of activation of the motor cortex during action observation. Already, in the 1950s, Gastaut and Bert (1954) showed that the
rhythm, a rhythm recorded in the correspondence of the cortical motor areas and known to desynchronize during movement execution, also desynchronizes during the observation of actions carried out by others. Following the discovery of mirror neurons, several studies (e.g., Altschuler et al. 1997; Cochin et al. 1999) repeated these experiments conWrming the desynchronization of
rhythm during action observation. Similar results were also obtained using magnetoencephalography (MEG) (Hari et al. 1998), a technique that

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Fig. 3 Modulation of the motor cortex excitability during grasping observation. a Schematic sequence of events during a grasping trial. b Averaged values of motor-evoked potentials (MEPs) of a hand muscle (Wrst dorsal interosseus) collected at diVerent times during the

observation of grasping movements. 500 ms: hand at the starting position (time value refers to the onset of the video clip showing the action), 3,000 ms: hand maximum aperture (from Gangitano et al. 2001)

analyses the brain electric activity on the basis of the magnetic Welds it generates. MEG data provided evidence of a desynchronization of the cortical rhythms of observer’s motor cortex (including those originating from the cortex located inside the central sulcus) during object manipulation and when the manipulation was observed.

Mirror neuron activation is also related to the observer’s motor experience of a given action. This has been nicely demonstrated in experiments using dance steps as observed stimuli. First it was shown that, in the observer, the amount of mirror activation correlated with the degree of the observer’s motor skill for that action (Calvo-Merino et al. 2005). A further experiment ruled out the possibility that this eVect could be due to mere visual familiarity with the stimuli. The observation of steps that are peculiar to male dancers determined a stronger mirror activation in male professional dancers than those performed by female dancers and vice versa (Calvo-Merino et al. 2006). A further prospective study showed that dancers initially naïve to certain steps showed an increase in mirror activation over time if they underwent a period of motor training in which they became skillful in performing the same steps (Cross et al. 2006). Some clues to the mechanism responsible for these eVects come from experiments that tested whether convergence of observation and execution of motor acts facilitates the building of motor memories. These experiments showed that after a training period in which participants simultaneously performed and observed congruent movements there was a potentiation of the learning eVect, with respect to motor training alone, as shown by the kinematics

Mirror activity is modulated by motor experience There is evidence that only motor acts that are present in the motor repertoire of the observer are eVective in activating the mirror neuron system. In an fMRI experiment normal volunteers observed video-clips showing mouth motor acts made by humans, monkeys, and dogs. In one condition, the observed motor act was biting, a motor act present in the motor repertoire of all three species and in another condition the stimuli were communicative gestures proper to each species: reading silently a text, lip-smacking, and barking. The data demonstrated that the left IPL and IFG responded to actions made by human and nonhuman performers, as long as the action was part of the human motor repertoire (e.g., biting). In contrast, there was no activation (barking) or almost no activation (lip-smacking) when the action belonged to another species (Buccino et al. 2004b).

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of the movement evoked by TMS (Stefan et al. 2005, 2008). Further evidence in favor of plasticity of the mirror mechanism comes form experiments showing that the mirror responses triggered by a corresponding movement could be modiWed by repetitively coupling the performed movement with the observation of diVerent movements (Catmur et al. 2007, 2008).

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mirror network in the monkey. Other cognitive functions like imitation (see below) and, most likely, language (Rizzolatti and Arbib 1998) evolved on the top of it. In the present review we will discuss Wrst the relations between mirror mechanism and imitation. We will deal later with goal and intention understanding, because the discussion of neurophysiological mechanisms underlying these capacities leads directly to the issue of autism, whose discussion will conclude this article.

The functional roles of mirror neurons Mirror neurons, directly recorded or demonstrated by noninvasive techniques, are present in various cortical areas of primates (Rizzolatti and Craighero 2004) and in birds (Prather et al. 2008). All of them are endowed with the same mechanism: a mechanism that translates sensory information describing motor acts done by others into a motor format similar to that the observers themselves generate when they perform those acts. While the mirror mechanism is the same regardless of the location of neurons endowed with it, the result of the sensory-motor transformation depends on the location of mirror neurons. Those located in emotional centers like the insula or the cingulate cortex intervene in phenomena like empathy (see Gallese et al. 2004), while those located in the parieto-frontal circuit provides the observer with motor representations of others’ motor actions devoid of emotional content (Rizzolatti and Craighero 2004). From the discovery of mirror neurons in area F5 of the monkey, two explanations, not mutually exclusive, have been proposed for the functional role of the mirror neurons in this area and in the IPL. The Wrst was that mirror neurons underlie imitation. The second was that the correspondence between the motor format generated by observing others and that generated internally in order to act enables the observer to understand others’ behavior, without the necessity for complex cognitive elaborations. The Wrst view has been thought of as unlikely because of ethological data showing that monkeys, unlike humans and apes, do not imitate (Visalberghi and Fragaszy 1990). As a matter of fact “imitation” phenomena are also present in “lower” primates (see Zentall 2006). For example, tongue protrusion in response to the same motor act done by another individual, described many years ago by MeltzoV and Moore (1979) in newborn babies, has been recently reported in macaque monkeys (Ferrari et al. 2006). Yet, convincing evidence of “true imitation”, that is imitation in which the learned behavior is performed with the same movements (including hand movements) as shown by the teacher is lacking. Thus, the presence of a well-developed mirror mechanism concerning hand movements suggests that understanding motor acts done by others, rather than imitation, is the evolutionary older function of the parieto-frontal

Mirror mechanism and Imitation The term imitation has many deWnitions in human literature. There are, however, two main senses in which it is most commonly used (see Rizzolatti 2005). The Wrst deWnes imitation as the capacity of an individual to replicate an observed motor act; the second deWnes imitation as the capacity to acquire, by observation, a new motor behavior and to repeat it using the same movements employed by the teacher. In both cases imitation requires the capacity to transform sensory information into a motor representation of it. There is convincing evidence that the mirror mechanism is involved in imitation as an immediate replica of the observed motor act. In an fMRI experiment, volunteers were tested in two main conditions: “observation” and “observation–execution”. In the “observation” condition, participants were shown a moving Wnger, a cross on a stationary Wnger, or a cross on empty background. The instruction was to observe the stimuli. In the “observation– execution” condition, the same stimuli were presented, but, this time, the instruction was to lift the right Wnger, as fast as possible, in response to them. The crucial contrast was between the trials in which the volunteers made the movement in response to an observed action (“imitation”) and the trials in which the movement was triggered by the cross (a non-imitative behavior). The results showed that the activation of the mirror system and in particular of the posterior part of IFG was stronger during “imitation” than in other conditions (Iacoboni et al. 1999). Further evidence that the mirror system plays a crucial role in this kind of imitation was provided by repetitive TMS (rTMS), a technique that determines a transient depression of the stimulated region. In a group of volunteers the caudal part of the left frontal gyrus (Broca’s area) was stimulated while they (a) pressed keys on a keyboard, (b) pressed the keys in response to a point of red light indicating which key to press, (c) imitated a key pressing movement done by another individual. The data showed that rTMS lowered the participants’ performance during imitation, but not during the other two tasks (Heiser et al. 2003).

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Evidence that mirror system is involved in imitation learning comes both from EEG and fMRI studies. Marshall et al. (2009) examined diVerences in EEG desynchronization during observation of drawing of various characters selected from the Cham alphabet, an alphabet used in Southeast Asia, and with which none of the participants was familiar. Compared to carrying out unrelated drawing (Latin letters), brief imitative experience was speciWcally associated with a signiWcantly larger desynchronization in the 11–13 Hz band at mid-frontal sites (F3 and F4) when a previously imitated action was presented again. In addition, higher Wdelity of imitation was signiWcantly correlated with greater bilateral desynchronization of the
rhythm at central sites (C3 and C4) during subsequent observation of the previously imitated action. A more elaborate experimental design was used by Buccino et al. (2004a). Using an event-related fMRI paradigm these authors tested musically naive participants during four events: (1) observation of guitar chords played Fig. 4 Cortical activations during imitation learning. Upper part graphic illustration of the events forming the experimental conditions imitation (IMI) and non-imitation (NON IMI). Both conditions consisted of four events preceded by the presentation of a colored cue (a square) informing the participants on the task they have to perform. IMI condition: event 1 observe the teacher’s hand playing the chord (IMI-1), event 2 rehearse the observed chord (IMI-2), event 3 replicate it. Event 4 keep the hand still. NON IMI condition: event 1 observe the teacher’s hand playing the chord (Non IMI-1), event 2 do not rehearse the observed chord (Non IMI-2), event 3 touch the neck of the guitar, without playing a chord (Non IMI-3). Event 4 keep the hand still. Lower part cortical areas activated during events 1 and 2 in IMI and Non IMI conditions (modiWed from Buccino et al. 2004a, b)

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by a guitarist, (2) a pause following model observation, (3) execution of the observed chords, and (4) rest. The results showed that the basic circuit underlying imitation learning consists of the IPL and the posterior part of IFG plus the adjacent premotor cortex. This circuit starts to be active during the Wrst event: observation. During pause, i.e., during the phase in which visual information is elaborated for action production, activations are observed in the middle frontal gyrus (area 46) and in structures involved in motor preparation (dorsal premotor cortex, superior parietal lobule, rostral mesial areas). The activation of these areas plus the somatosensory and motor areas contralateral to the hand used to execute chords dominates the subsequent execution phase (Fig. 4). On the basis of this experiment and a following one also based on learning of playing guitar chords (Vogt et al. 2007), the authors proposed a model of imitation learning (see Byrne 2002 for a similar model-based ethological observations) consisting of two distinct processes: (a)

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segmentation of the action to be imitated into its individual elements and their transformation into the corresponding potential movements of the observer; (b) organization of these potential movements into a temporal and spatial pattern that replicates that shown by the demonstrator. The Wrst process is achieved through the mirror mechanism, while the second one is mostly due to the activity of the prefrontal lobe and in particular of area 46 that memorizes and recombines the motor elements in the new pattern.

Action and intention understanding Coding the goals of the motor acts Social life is based on our capacity to understand the behavior of others. Let us imagine this situation. John and Mary are in a pub and John’s hand comes into contact with a mug of beer; Mary immediately understands whether he is grasping it or not. Moreover, according to how he grasped it, she can also understand why he is doing it (e.g., for drinking or for giving the mug to a friend). How does Mary understand the goal of the John’s motor act and the intention behind it? One possibility is that she is using an inferential reasoning elaborating the acquired visual information through some cognitive mechanism (see Frith and Frith 1999; Csibra and Gergely 2007). Another possibility is that this is not necessary in this simple situation, and the understanding of what John is doing and why he is doing it, is acquired through a mechanism that directly transforms visual information into a motor format. The proprieties of mirror neurons support the existence of such a mechanism. There is clear evidence from monkey experiments that neurons in the parietal lobe, premotor cortex, and even in the primary motor cortex, code the goal of a motor act rather than, as traditionally thought, movements of body parts (Rizzolatti et al. 1988; Kakei et al. 1999, 2001; Fogassi et al. 2005; Umiltà et al. 2008). Mirror neurons located in F5 and in IPL have motor properties identical to those of purely motor neurons. Thus, because the electrical activity recorded in these experiments during voluntary behavior and action observation always consists of action potentials (the neuron output) the messages conveyed during voluntary movement and during mirror activation are identical. In both cases the neurons send information on the goal of the observed motor act. Given these Wndings, it appears logical to assume that a similar organization does exist also in humans. Evidence in this sense came from fMRI studies. Gazzola et al. (2007a) instructed volunteers to observe video-clips where either a human or a robot arm grasped objects. In spite of diVerences in shape and kinematics between the human and

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robot arms, the parieto-frontal mirror system was activated in both conditions. These data was recently conWrmed and extended by Peeters et al. (2009). Further evidence in favor of goal coding in the human mirror network comes from an fMRI study in which individuals were tested both during motor execution and when listening to the sound of an action made by the same eVector (Gazzola et al. 2006). The results showed, in both cases, a similar activation of the left parieto-frontal circuit. An experiment on aplasic individuals conWrmed that the mirror network codes the goal of motor acts (Gazzola et al. 2007b. In this study the authors addressed the following question: Can the goal of a hand movement be recognized in the absence of any experience of hand movements? To answer it two individuals born without arms and hands were studied. While being scanned they were asked to watch video-clips showing hand actions and their brain activations were compared with those of control volunteers. All participants also made actions with diVerent eVectors (feet, mouth and, for normal volunteers, hands). The results showed that the mirror system of aplasic individuals was activated by the observation of hand motor acts. This demonstrates that the brains of aplasics can mirror motor acts that they have never executed. The goal is recognized through the recruitment of areas involved in the execution of motor acts having the same goal but using diVerent eVectors. The issue of goal coding was recently addressed by Hamilton and Grafton (2006) using the adaptation technique, a technique based on the trial-by-trial reduction of a physiological response to repeated stimuli. Participants observed a series of video-clips showing goal-directed motor acts with the sequence controlled so that some goals were novel and others repeated relative to the previous movements. Repeated presentation of the same goal caused the suppression of the response in the left intraparietal sulcus (IPS) while this region was not sensitive to the trajectory of the actor’s hand. While the fMRI data support, in agreement with monkey data, the notion that mirror neurons code motor acts, most TMS data appear to indicate that during the observation of motor acts performed by others, there is an activation of the neural substrate controlling the muscles that are involved in that motor act (see Rizzolatti and Craighero 2004). There is an ingenious study, however, that was able to demonstrate, using TMS, goal coding in human motor cortex (Gangitano et al. 2001). In this study motor-cortex excitability was tested during the observation of hand movements directed to a speciWc goal (predictable movements) and in trials in which the hand moved in a diVerent direction (unpredictable movements). The data showed that the observation of unpredictable movements did not elicit the expected change in the excitability of the motor cortex corresponding to the

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observed movements. During the observation of the unpredictable movements, the excitability pattern was the same as that found during the observation of the predicted ones. This indicates that the observed motor acts were coded, from their very beginning, in terms of the Wnal goal of the action and not in terms of the movements forming them. Coding the intention behind the motor acts of others Studies of the mirror mechanism have provided evidence for its role in motor act understanding. What about intention understanding? Evidence that the mirror mechanism play a role in this capacity has been Wrst provided by an fMRI study. In this study there were three conditions. In the Wrst one (“context”) the volunteers saw some objects (a teapot, a mug, a plate with some food on it) arranged as if a person was ready to drink the tea or as if a person had just Wnished having his/her breakfast; in the second condition (“action”) the volunteers were shown a hand that grasped a mug without any context; in the third condition (“intention”) the volunteers saw the same hand action within the previous two contexts. The context and the diVerent grip shapes suggested the intention of the agent, i.e., grasping the cup for drinking or grasping it for cleaning the table (Iacoboni et al. 2005). The results showed that in both action and intention conditions there was an activation of the mirror mechanism. Crucial was the comparison between intention and action conditions. This comparison showed that the understanding of the intention of the doer determined a marked increase in the activity of the mirror mechanism. The importance of the mirror system in understanding intention has been recently conWrmed by an fMRI experiment based on the adaptation paradigm. Participants were asked to observe repeated movies showing either the same movement or the same outcome independent of the executed movement. The results showed activity suppression in the right inferior parietal and in the right IFG when the outcome was the same. Kinematic parameters do not appear to inXuence the activity of these regions. These Wnding indicate therefore that the right hemisphere mirror system encodes the physical outcomes of human actions, an initial step for inferring intentions underlying these actions (Hamilton and Grafton 2008). Taken together, these data suggest that the intentions behind the actions of others can be recognized by the mirror neuron mechanism. These Wndings do not imply that other more cognitive ways of “reading minds” do not exist. Indeed, recent fMRI studies showed that, in speciWc conditions, the understanding of motor acts performed by others might require, beside the mirror mechanism, the activation of areas outside those forming the mirror system. For example, when tasks require a top–down inference either to

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assess the meaning of a motor act in an implausible context (Brass et al. 2007; Liepelt et al. 2008) or to judge whether the intention of the observed action was ordinary or unusual (de Lange et al. 2008), there is an increase of activity in the posterior superior temporal sulcus (STS) region, posterior cingulate cortex, and the medial prefrontal cortex. Some studies suggested that a region of right temporoparietal junction, often referred to as right TPJ, plays a crucial role in ‘mentalizing’ (e.g., Saxe and Wexler 2005, 2006). This view, however, should be accepted with caution. In fact, as shown by Mitchell (2008) (see, however, Scholz et al. 2009) the same right TPJ activated during “mentalizing” is also active in task requiring attention. The overlap between these two mental functions casts serious doubts on the hypothesis that TPJ plays a crucial role in intention understanding. In accord with the interpretation of Mitchell’s view are some data by Buccino et al. (2007). In an fMRI study these authors investigated the neural basis of human capacity to diVerentiate between actions reXecting the intention of the agent (intended actions) and actions that did not reXect it (non-intended actions). Volunteers were presented with video-clips showing a large number of actions performed with diVerent eVectors, each in a double version: one in which the actor achieved the purpose of his or her action (e.g., pour the wine), the other in which the actor performed a similar action but failed to reach the goal of it because of a motor slip or a clumsy movement (e.g., spill the wine). The data showed the activation of the mirror system areas in both conditions. The contrast, however, non-intended versus intended actions showed an activation of the right TPJ and the mesial prefrontal cortex. Because there is little doubt that a person observing another person falling down or spilling the wine because of a motor slip does not “put himself in the shoes” of that individual, the activation observed in the experiment by Buccino et al. (2007) is hardly due to an attempt to understand the other’s intention, but rather depends on an increase of the observer’s attention due to the surprising course of the event.

An impairment of the mirror mechanism explains some deWcits in children with autism Autistic spectrum disorder (ASD) is a heterogeneous syndrome characterized by impairment in social skills, verbal and nonverbal communication, coupled with restricted, and repetitive behaviors (DSM-IV-TR 2000). DeWcits in the domains of aVective links and emotional behavior are other aspects of ASD (Kanner 1943). Autism aVects a variety of nervous structures, from the cerebral cortex to the cerebellum and brainstem (see Minshew and Williams 2007). However, in the context of a

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broader neurodevelopmental deWcit, a set of ASD symptoms (impairment in communication, language, and the capacity to understand others) appears to match functions mediated by the mirror mechanism. The hypothesis that this speciWc set of deWcits might depend on an impairment of the mirror mechanism (Altschuler et al. 2000; Williams et al. 2001) has therefore been advanced. Evidence coming from EEG, TMS, and brain imaging studies supports this hypothesis (e.g., Nishitani et al. 2004; Oberman et al. 2005; Theoret et al. 2005; Dapretto et al. 2006). Oberman et al. (2005) studied the suppression of
rhythm during the execution and observation of motor acts in typically developing (TD) and children with autism. The results showed that, in contrast with TD children, ASD do not present
rhythm suppression during the observation of motor acts done by others. The
rhythm suppression is present only during active movements (Fig. 5). Similar data were obtained by Martineau et al. (2008). Additional evidence for an impaired mirror mechanism in autism came from behavioral and TMS studies. Avikainen et al. (2003) showed that, unlike TD individuals, who, when viewing persons face-to-face, tend to imitate them in a mirror way, children with autism do not show this preference. This imitation peculiarity is most likely due to a deWcit of mirror mechanism coding other person’s movements on one’s own. Theoret et al. (2005) demonstrated an impaired motor facilitation in children with autism during action observation by using TMS. Finally, strong evidence in favor of a deWcit of the mirror mechanism in ASD came from an fMRI study. High functioning children with autism and matched controls were scanned while imitating and observing emotional

expressions. The results showed a signiWcantly weaker activation in IFG in children with autism than in typically developing (TD) children. Most interestingly, the activation was inversely related to symptom severity (Dapretto et al. 2006). Taken together, these data indicate that children with autism process the actions done by others in a manner diVerent from that of TD children. The simplest way to account for these diVerences is to postulate (see also above) that children with ASD have an impairment of the mirror mechanism. This hypothesis is also known as the “broken mirror” hypothesis (Ramachandran and Oberman 2006). There are some behavioral studies indicating, however, that this hypothesis is not fully satisfactory and needs speciWcations. These studies reported that children with ASD do not present deWcits in understanding the goal of motor acts done by others (Hamilton et al. 2007; Bird et al. 2007; Leighton et al. 2008; Southgate and Hamilton 2008). It was, therefore, claimed that the “broken mirror” hypothesis of autism is wrong (e.g., Southgate and Hamilton 2008). It must be noted, however, that these studies took into account only one aspect of mirror organization, the one related to the role of the mirror neurons in the recognition of motor acts done by others. If only this aspect of the mirror system is considered, the criticism against the broken mirror hypothesis appears to be well taken. Neurophysiological studies showed, however, that there is a second aspect of the mirror neuron organization based not on the activity of single neurons, but on the organization of cortical motor system. The neural basis of this organization consists of chains of motor acts. These chains are formed by populations of neurons, each coding speciWc,

Fig. 5 Absence of EEG desynchronization during the observation of movements done by others. The charts show desynchronization of the
rhythm in controls (a) and patients with autism spectrum disorder (b). Observation of movement of an inanimate object (pale green), movements made with the hand (green), and active hand movements (red). The bars represent the amount of
activity in central scalp

locations; C3, Cz, and C4 refer to scalp coordinates of the 10/20 EEG system. SigniWcant
activity, indicated by asterisks, is present for the hand observation condition only in controls, showing that patients with autism spectrum disorder fail to react to the observation of other people’s actions in the standard way (modiWed from Oberman et al. 2005)

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serially connected motor acts (e.g., reach-grasp-bring to the mouth; or reach-grasp-move away). During voluntary movements the agent recruits one of these chains according to his/her motor intention. These chains also contain “action constrained” mirror neurons, that is neurons that Wre only if the motor act they code is part of a motor chain (e.g., grasping for placing, but not grasping for eating, or viceversa). During the observation of actions done by others, “action constrained” mirror neurons Wre when the observed behavior matches the speciWc action coded by the chain in which those neurons are embedded. Their Wring activates an entire action chain providing the observer with a motor representation of the action that the agent is ready to do. In virtue of this mechanism the observer understands the agents’ intention (Fogassi et al. 2005). Recently, it has been shown that the chained motor act organization is impaired in autism (Cattaneo et al. 2007). TD children and children with autism were asked to perform the two actions: grasping an object to eat it or grasping to place it into a container (Fig. 6). The EMG activity of Fig. 6 Responses of typically developing children (TD) and children with autism (AU) during the observation and execution of two actions. Upper panel schematic representation of the actions. Top the individual reaches a piece of food located on a touch-sensitive plate, grasps it and brings it to the mouth. Bottom the individual reaches a piece of a paper located on the same plate, grasps it, and puts into a container placed on the shoulder. Middle panel time course of the rectiWed EMG activity of MH muscle for TD children and children with autism (AU) during the observation of the two tasks. Lower panel EMG activity of MH muscle during the execution of the two tasks. Bringing-tothe-mouth action (red), placing action (blue). Vertical bars indicate the SE. All curves are aligned with the moment of object lifting from the touchsensitive plate (t = 0, dashed vertical line) (modiWed from Cattaneo et al. 2007)

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the mylohyoid muscle (MH), a muscle involved in opening of the mouth, was recorded. In TD children the muscle became active as soon they moved the arm to reach the food. In contrast, no MH muscle activation was observed during food reaching and grasping in autistic children. MH muscle activation appeared only when the children brought the food to their mouth. These data indicate that ASD children are unable to organize their motor acts into a unitary action characterized by a speciWc intention. In a further experiment TD children and children with autism were tested while they observed an experimenter either grasping a piece of food for eating or grasping a piece of paper for placing it into a container (Fig. 6). The EMG of MH muscle was recorded. The results showed that in TD children, the observation of food grasping determined the activation of MH, while this activation was lacking in children with autism. In other words, while the observation of an action done by another individual intruded into the motor system of a TD observer, this intrusion was lacking in children with autism. This Wnding

Exp Brain Res (2010) 200:223–237

indicates that, in autism, the mirror system is silent during action observation and the immediate, experiential understanding of others’ intention is absent. Summing up, these data strongly suggest that children with autism have a deWcit in the chained organization of motor acts and, as a consequence, they are unable to activate it during action observation. Without this internal “replica” of the actions of others, they cannot grasp directly, without cognitive inferences, the intention of others. According to this new mirror hypothesis on the neural basis of the autistic deWcit in understanding others, there is a dissociation, in autism, between the capacity to understand the what of an action (carried out by the basic mirror neurons mechanism) and the why of it (depending on the integrity of the chained motor organization). In order to test this point an experiment was recently performed by Boria et al. (2009). In this study TD and autistic children were presented with pictures showing goal-directed motor acts and asked to report what the actor was doing and why he was doing it. These two tasks test two diVerent abilities: the Wrst is that of recognizing the goal of the observed motor act, that is something occurring “now” (e.g., grasping an object); the second consists in understanding the intention of the action that is something that will occur in the future (e.g., grasping to eat). The results showed that while both TD and ASD children recognized what the actor was doing, ASD children were impaired in recognizing the why of that action. The type of why error was systematic: ASD children constantly tended to attribute to the actor the intention related to the common use of the grasped object. Thus, grasping a pair of scissors indicates the intention to cut, while grasping a mug that of drinking, this regardless of how the object was grasped. In other words, ASD children interpreted the behavior of others on the basis of the common use of observed object rather then on the basis of the motor behavior of the actors (Boria et al. 2009).

How the things are now I (GR) suppose that none of the authors of the Wrst short report on mirror neurons (Di Pellegrino et al. 1992) would have predicted the enormous impact that that discovery would have not only on neuroscience but also on a host of disciplines ranging from social sciences to esthetics. What is particularly rewarding for who discovered mirror neurons is that, after so many years, new important Wndings related to the mirror mechanism continue to appear. Three recent particularly interesting contributions on mirror mechanisms in the monkey are worth mentioning. The Wrst shows that, besides mirror neurons describing the motor acts done by others independently of their

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distance from the observer, there are other mirror neurons in area F5 that discharge depending on whether the motor act is performed within or outside the monkey’s peripersonal space. Most interestingly, some of these neurons code space operationally. That is, these neurons describe the action of others in term of their possibility to act on an object. For a set of these neurons, for example, the peripersonal space becomes extrapersonal if a transparent barrier is placed between the observing monkey and the stimulus (Caggiano et al. 2009). A second recent study showed that a subset of neurons, located in area LIP, “mirrors” observed attention by Wring both when monkey looks in the preferred direction of the neuron and when the observed monkey looks in that direction. Another subset of LIP of neurons was, in contrast, suppressed by social gaze cues, possibly subserving behavioral demands by maintaining Wxation on the observed face. As proposed by the authors (Shepherd et al. 2009), these Wndings suggest that the mirror mechanism of area LIP contributes to sharing of observed attention, a fundamental step in social cognition. Finally a third study showed that, in the monkey ventral intraparietal area (VIP) and the adjacent area PFG there are neurons that code the peripersonal space of the observing (recorded) monkey and the peripersonal space of another individual facing it (Ishida et al. 2009). This Wnding suggests that mirror neurons are critical for understanding not only the motor acts of others, but also others’ body parts and body-centered motor acts. As one can imagine, a new view of the neural basis of cognition has also raised doubts and criticisms. Some of them have been very useful for clarifying various points of the “immediate action perception” theory and, more generally, for sharpening and rendering more precise its claims (e.g., Jacob and Jeannerod 2005; Knoblich and Prinz 2005; Csibra and Gergely 2007). Beside these constructive criticisms, recently some articles appeared expressing a curious “anti-mirror” stance (Dinstein 2008; Dinstein et al. 2008; Lingnau et al. 2009). Their main argument is the following: action observation activates in humans, as in the monkeys, parietal and motor areas, but the properties of the activated neurons are diVerent in the two species. While in monkeys the activated neurons are mirror neurons, this is not so in humans. In humans, motor areas are endowed with two distinct populations of neurons: one merely sensory, the other merely motor. The two populations do not communicate one with another. Hence the mirror neurons do not exist in humans. It was also claimed that, in order to prove “really” the existence of mirror neurons in humans, one has to show that they present the “repetition suppression”, that is that they decrease their response not only following repetitive observation of the same motor act done by another, but

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also, crucially, following visual presentation of a motor act after its execution. If mirror neurons do exist, they should habituate in this cross-modal test. As stressed by Logothetis (2008) there are serious diYculties in interpreting the results obtained with the repetition suppression technique. This is especially true for its cross-modal variant. Repetitions suppression, in fact, takes place when information arrives at a neuron using the same or largely common pathways, but not when information reaches a neuron using diVerent pathways. This because repetition suppression is a phenomenon that occurs at the synaptic level and not as a consequence of repetitive discharge of a neuron (Sawamura et al. 2006). It is important to keep in mind that, in the case of the activation of mirror neurons, the communality of input in the cross-modal test is typically lacking because during action observation the input is coming mostly from STS, while during voluntary movement the neurons are triggered by commands arriving form the frontal lobe and other higher order centers. The results of adaptation experiments will depend therefore on the degree of input communality to motor neuron that is introduced in the experimental design. As one may expect from these considerations, the results of the experiments using repetition suppression technique produced contrasting results (e.g., Dinstein 2008; Chong et al. 2008, Lingnau et al. 2009, Kilner et al. 2009). However, the most recent data using this technique show cross-modal adaptation and clearly prove the mirror neuron existence (Kilner et al. 2009). The proposed “two populations” hypothesis is also disproved by experiments in which the authors tested whether the same voxels were active in the mirror areas during action observation and action execution (Gazzola and Keysers 2009). This “shared voxels technique” showed that the same voxels became active during both action observation and execution. While the use of these new techniques may provide interesting information on the organization the mirror network, the neurophysiological reasoning underlying the “two populations” hypothesis is very shaky. To believe that the neurons located in motor areas that respond to action observation are merely sensory or merely motor neurons requires two assumptions. The Wrst is that, unlike monkeys, human motor areas contain a large number of “displaced” sensory neurons. The second is that these “displaced” neurons do not communicate with motor neurons. While the Wrst assumption is unlikely, but possible, the second is hard to reconcile with all we know on the architecture of cerebral cortex. Cerebral cortex is typically organized in columns with rich connections between neurons in diVerent layers. To postulate that information from STS reaching the parietal and then motor areas remains in humans segregated from

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the motor output is absurd. First, even the staunchest cognitivist would admit that sensory information is used for motor purposes and not only for perception. Thus, sensory information must reach cortical motor neurons. Second, TMS studies (see above) showed that there is a clear congruence between the observed motor act and the activated motor representation. In other words higher order sensory information describing motor acts activates neurons that code those motor acts. But, if motor neurons receive sensory information congruent with their motor properties, these neurons are ‘mirror neurons’ by deWnition. The “incommunicado populations” hypothesis seems, therefore, a remote possibility rather than something grounded in physiological reality. However, even wrong assumptions sometimes generate interesting experiments. Acknowledgments The study was supported by Fondazione Monte Parma and by a grant (FIL) of the University of Parma to GR. M.F-D. was supported by Fondazione Cassa di Risparmio di Ferrara. We thank Rachel Wood for her comments on the article.

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