Autism, motor dysfunctions and mirror mechanism - Clinical ...

Clinical Neuropsychiatry (2013) 10, 5, 177-187

AUTISM, MOTOR DYSFUNCTIONS AND MIRROR MECHANISM Maddalena Fabbri-Destro, Valentina Gizzonio, Pietro Avanzini

Abstract Objective: Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental syndrome characterized by a marked impairment in social interaction and communication, restricted, repetitive and stereotyped patterns of behavior, interests, and activities. Although not listed among the core diagnostic domains of impairment in ASDs, motor abnormalities have been consistently reported across the spectrum. Converging evidence from a variety of studies suggests that a dysfunction of motor cognition might be at the basis of some of the social cognitive impairments seen in ASD individuals. Moreover, recent accounts proposed that dysfunctions in mirror mechanism might underlie aspects of ASD contributing to social deficits, particularly with respect to social interaction. Method: We conducted a systematic review of studies examining movement disorders in ASD and discussing the relation between the mirror mechanism and this syndrome. Results: The assessment and characterization of motor disturbances offer a new perspective on ASD, where they are not anymore considered as symptoms simply associated with the diagnosis, but rather as part of the underlying etiology of ASD. Conclusions: Motor impairments interfere with the developmental milestones of individuals with autism and the impairment in the organization of their own motor behavior could be at the basis of many social–cognitive impairments. We believe that, as these motor abnormalities precede the social-communication deficits, they may not only serve as an early disease indicator, but they could be also useful in exposing the neurobiological mechanisms at the basis of this syndrome and in identifying more specific treatments. Key words: autism spectrum disorders, motor deficits, cognitive deficits, action cognition, mirror mechanism Declaration of interest: the authors declare that they have no conflict of interest to be disclosed Maddalena Fabbri-Destro1, Valentina Gizzonio2, Pietro Avanzini2-3 1. Brain Center for Social and Motor Cognition, Italian Institute of Technology, Via Volturno, 39/ E, I-43100 Parma, Italy. 2. Dipartimento di Neuroscienze, Sezione di Fisiologia, Università di Parma, Via Volturno, 39/ E, I-43100 Parma, Italy. 3. Department of Biomedical science, Metabolism, and Neuroscience, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy. Corresponding author Maddalena Fabbri-Destro Phone: +39 0521 903847 Fax: +39 0521 903900 E-mail: [email protected]

1. Introduction Autism is a neurodevelopmental disorder characterized by severe disturbances in social relations and varying degrees of language and communication difficulties (APA 2000). Even if autism epidemiology varies with diagnostic criteria, it is generally accepted that it occurs in about 1% of the general population (Nygren et al. 2012, Simonoff et al. 2012). However, it is very difficult to know the “real” prevalence of autism because no agreement as to what exactly constitutes autism has been reached up to now. Instead, there is overall consensus that autism is a spectrum disorder with severe and mild variants of a continuum. In line with this view, the DSM-V (APA 2013) does not consider anymore the distinction between these variants, pooling them together within the definition of Autism Spectrum Disorders (ASD). This diagnosis comprehends nosographic entities previously labeled as

Submitted August 2013, accepted October 2013© 2013 Giovanni Fioriti Editore s.r.l.

Autistic Disorder, Asperger’s Disorder, and Pervasive Developmental Disorders - Not Otherwise Specified (PDD-NOS). Even if the bases of autism remain uncertain and debated, genetic studies revealed that the liability to ASD is mainly influenced by genetic factors (heritability estimates of 60–90%) and the etiology of autistic traits in the general population is very similar to the etiology of ASD in clinical samples (Ronald and Hoekstra 2011). The deficits typically associated to ASD are mainly relative to social relations and include an impaired use of non-verbal social behaviors such as failure to use eye contact in guiding social interactions, abnormal facial expressions of emotions, lack of social or emotional reciprocity, lack of sharing emotions and interests with other people, as well as failure to develop peer relationships. Aside the extensive description of these deficits, a vast amount of literature revealed that the profile of ASD is characterized also by movement 177

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impairments (Teitelbaum et al. 1998, for more recent studies see Fournier et al. 2010, Staples and Reid 2010, MacNeil and Mostofsky 2012, Whyatt and Craig 2012). However, still in the DSM-V, the proposed diagnostic criteria for ASD maintain the focus on social/communicative symptoms and restricted/ repetitive behaviors (Wing et al. 2011, Nishawala 2012) without considering the motor disturbances as part of the diagnostic criteria of ASD. One of the earliest developing motor-related behaviors is the vocal- and facial-motor coordination that emerges during face-to-face interactions in the first half of the first year of life (Iverson and Fagan 2004). During this time, infants begin to engage in coordinated vocal and facial motor activity routines (such as reciprocal vocalizations, imitation of mouth opening, positive/negative facial expressions, and gaze) on a second-by-second timing scale. Existing evidence suggests that the nature and degree of this early infant coordination and tuning of motor activity with others may predict later infant social-emotional and cognitive development in typically developing infants (Feldman et al. 1996). Yirmiya et al. (2006), investigating a highrisk (siblings of children diagnosed with autism) and a low-risk group of infants, uncovered evidence for weaker communicative synchrony for infant-mother interactions in the high-risk group (see also Brisson et al. 2011). Furthermore, the authors reported that these infants at risk for autism displayed fewer non-verbal requesting behaviors (such as pointing). The absence of pointing gestures (known as deictics) is considered an early warning sign of ASD; both the comprehension and production of deictics were found to be reduced and delayed in ASD (Mundy et al. 1986, Camaioni et al. 1997). Leary and Hill (1996) considered the relation between movement disturbances and symptoms of autism, highlighting how movement abnormalities in ASD can affect a person’s experience of life and how they might precede the appearance of socialcommunication deficits in ASD children. It is possible that social/communicative and motor deficits are independent one from another. However, considering the strong evidence that the motor system plays an important role in action and intention understanding and communication via mirror neurons (Gallese et al. 1996, Rizzolatti et al. 1996, Fogassi et al. 2005), it is plausible that a malfunctioning in a common mechanism is the underlying reason of both these deficits in autism. Moreover, one important line of evidence suggests that children with autism are poor at predicting future events, at planning future actions and chaining actions together. Prediction deficiencies are especially harmful when it comes to planning one’s own actions and monitor other people’s actions (von Hofsten and Rosander 2012). In summary, although the most salient feature of autism is a deficiency in communication and social ability, it is of great importance not to ignore the motor problems associated with ASD, as they might provide crucial information for the understanding of the dysfunction. In this review we will consider a) the studies taking into account the motor impairments typically reported for ASD individuals and b) the evidence supporting the existence of a mirror mechanism dysfunction of ASD. Finally we will try to unify both social/communicative and motor aspects in a single framework, considering the motor problems not only as parallel to the autistic cognitive-communicative deficits, but as a possible original core of the syndrome later reflecting in their incapacity to interact with others in a common way.

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2. Motor dysfunction in autism Since the first description of autism (Kanner 1943), a variety of motor alterations in individuals with autism was reported. In particular, Kanner noticed that while all children demonstrated skilled fine muscle coordination, several of them exhibited clumsiness in gait, gross motor performances and failed to assume an anticipatory posture as well as passive positioning like “a sack of flour” (Kanner 1943, p. 243). Recently, a renewed interest was dedicated to motor disturbances in ASD, allowing to highlight how motor abnormalities can be observed not only in infancy (Teitelbaum et al. 1998, Provost et al. 2007, Brian et al. 2008, although see Ozonoff et al. 2008), but also throughout childhood and adulthood (Ming et al. 2007, Fournier et al. 2010, Van Waelvelde et al. 2010). Teitelbaum et al. (1998), studying videos obtained from parents of children later diagnosed as autistic by conventional methods, found disturbances in some or all of the milestones of development, including lying, righting, sitting, crawling, and walking. These findings support the view that movement disturbances play an intrinsic part in the phenomenon of autism, that they are present at birth, and that they could help to achieve an early diagnosis of autism since the first months of life. Even more, as these alterations were observed since the very early days of life, they can be at the basis of the cognitivecommunicative core deficits of autism, typically reported in literature as arising since 2 years of life. Although data are still controversial (Ozonoff et al. 2008), motor development disorders have often been hypothesized as early bio-marker of autism and are considered one of the first signs which could precede social or linguistic abnormalities in at least a subgroup of children with autism (Esposito et al. 2009). Reviewing the literature on motor disorders in ASD, we will include studies investigating the basic motor inabilities (i.e. clumsiness, postural control impairments and instability, abnormalities of gait, and developmental dyspraxia) and studies focusing on the motor organization, paying particular attention to those investigating action planning. The assessment of motor disturbances in autism and their characterization may offer a new perspective on this syndrome, where they are not anymore considered as simply “associated” with the diagnosis, but rather as part of the underlying etiology of ASD.

2.1. Clumsiness While social impairment, difficulties with communication, and restricted repetitive behaviors are central features of ASD, clumsiness is commonly considered as a co-occurring feature. This symptom was defined as an impairment of skills on standardized tests of motor functioning, below the expected level of intelligence, in the absence of a known neurological disease (Ghaziuddin et al. 1992). Originally, it was labeled as a diagnostic feature of Asperger syndrome, as Asperger himself (1944) in his earliest descriptions reported that children with repetitive activities and resistance to change, problems in speech, non-verbal communication, and social interaction, also display poor motor coordination. Afterward, Wing (1981) reported that not only clumsiness but also poor-coordination are relevant dimensions for Asperger syndrome. Although traditionally associated with this syndrome, in the past two decades many empirical studies

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Autism, motor dysfunctions and mirror mechanism

demonstrated that these symptoms are present also in ASD individuals (Szatmari et al. 1989, Ghaziuddin et al. 1994, Manjiviona and Prior 1995, Ghaziuddin and Butler 1998, Jansiewicz et al. 2006, Dewey et al. 2007, Green et al. 2009). In order to evaluate this hypothesis, many standardized motor batteries were employed, such as Griffith’s gross motor sub-scale, Bruininks–Osertsky test of fine and gross motor skills, Test of Motor Impairment-Henderson Revision, the Movement Assessment Battery for Children and the Pegboard test of motor coordination. In a review of the literature, Ghaziuddin and collaborators (1992) found that, using the Bruininks-Osertsky Test (Bruininks 1978), both high-functioning and Asperger groups have problems with running speed and agility, balance, bilateral coordination, limb strength, upper-limb coordination, visual motor control, and upper-limb speed and dexterity. Interestingly, Ghaziuddin and Butler (1998) not only confirmed these findings, but also found that the intelligent quotient (IQ) was highly correlated with motor abilities and all significant differences disappeared after controlling for IQ. The same issue was investigated by Manjiviona and Prior (1995), reporting no group differences in terms of motor impairment between Asperger and high-functioning children, but lower IQ scores associated with greater deficits in motor function. Thus, lower IQ appears to be related to poor motor functioning and the differences between the two groups are likely due to differences in IQ. In summary, motor clumsiness is spread over the entire autism spectrum and it appears to be a relevant feature of the ASD phenotype.

2.2. Postural stability Postural stability is one of the fundamental aspects of motor ability that allows individuals to sustain and maintain the desired physical position of one’s body. Postural stability was first investigated in children with autism by Kohen-Raz et al. (1992), who measured changes in weight distribution on four footplates. A battery of postural positions was administered, including postures involving some degree of perceptual perturbation (e.g., occluded vision) or postural stress (e.g. standing on pads). Authors reported that children with autism (n=91) had more difficulty in maintaining postural control than children with mental retardation (n=18) and typically developing children (TD) (n=166). Both control groups exhibited better balance when provided with visual and proprioceptive cues. In comparison to normal children, the autistics were less likely to exhibit age-related changes in postural performance, and postures were more variable and less stable with more lateral sway. Autistic subjects also exhibited a “paradoxical” response of greater stability during more “stressful” postures, putting excessive weight on one foot, one toe, or one heel. In the same framework, Molloy et al. (2003) compared the postural stability of ASD and TD children evaluating the postural oscillations on a force platform while sensorial afferences (visual, somatosensory, and vestibular) were varied across conditions. The results confirmed that children with ASD have significantly larger sway areas under all tested conditions, suggesting impairment in the integration of sensorial inputs to maintain postural orientation. Minshew et al. (2004) not only confirmed aforementioned findings, but also showed their relation with the age. Dynamic posturography was performed in 79 autistic individuals without mental retardation and 61 healthy volunteers between 5 and 52 years of ages. Results showed that autistic subjects have reduced Clinical Neuropsychiatry (2013) 10, 5

postural stability, that its development onset is delayed and that it fails to achieve an overall adult level. Similar conclusions were supported also by a recent study by Radonovich et al. (2013), who demonstrated that the postural system in ASD individuals is immature and may never reach adult levels. This impairment can be a limiting factor for the emergence of other motor skills, such as the initiation of gait, and for typical motor development.

2.3. Gait The first studies comparing ASD and TD children in terms of gait analysis (Damasio and Maurer 1978, Vilensky et al. 1981) showed that autistic children between the ages of 3 and 10 walk somewhat like Parkinsonian adults, exhibiting a walking slower than normal, with shorter steps. This issue was investigated also by Rinehart and colleagues (Rinehart et al. 2006) using a movement analysis system in a group of in 11 ASD children (4-7 years old). They reported greater difficulties in walking along a straight line and the coexistence of variable stride length/duration in children with autism relative to a control group matched for age, height, weight and IQ. Furthermore, ASD children were also less coordinated and rated as more variable and inconsistent (i.e. reduced smoothness) relative to controls. These abnormalities were reported to be stable across key developmental periods. More recently, Esposito et al. (2011) investigated the first unsupported gait in toddlers with autism using retrospective video analysis similarly to Teitelbaum et al. (1998). They identified differences in gait patterns among toddlers with autism as opposed to controls. Considering the level of symmetry during walking, these results confirmed the study about walking by Teitelbaum (1998), showing higher level of asymmetry in toddlers with autism compared to typical ones. In line with aforementioned studies, Weiss et al. (2013) evaluated the gait patterns within a group of older teenagers and young adults diagnosed with ASD, using narrowly defined a priori inclusion criteria of ASD in general, and severe impairments in Verbal Communication specifically. Results confirmed a wide difference in many spatiotemporal aspects of gait, including: step and stride length, foot positioning, cadence, velocity, step time, gait cycle time, swing time, stance time, and single and double support time. Moreover, the differences in spatiotemporal parameters of gait were greater and more widespread among individuals presenting more severe forms of ASD and verbal communication disorders. These results were confirmed by the qualitative rating of “Body Use” on the Childhood Autism Rating Scale (CARS), indicating severe levels of unusual body movements for all of the ASD participants.

2.4. Anticipation and action planning Several studies on autism have shown a lack of motor anticipation in children with autism. Sauvage (1988) observed that these infants do not protect themselves by putting their arms in front of them when falling, failing to anticipate the consequences and to adapt their behavior. In line with this observation, a study by Schmitz et al. (2003) suggested that children with ASD are impaired in their ability to generate feed-forward predictions about the consequences of their actions. Eight right-handed 179


children with autism (ranging from 6 to 11 years old) and 16 healthy right-handed children (ranging from 4 to 8 years old) were tested during a bimanual loadlifting task that required maintaining the stabilization of the forearm despite imposed or voluntary unloading. Kinematic data and EMG activity were recorded on the child forearm supporting the load. Despite forearm stabilization was found as good in children with autism as in the control group, in patients the latencies for both kinematics and muscular events indicated an increase of the duration of unloading. These data suggest that ASD children have impairments in both the building of internal representations and the mastering of timing parameters, reflecting in the use of a feedback rather than a feed-forward mode of control. A similar deficit in feed-forward modeling was suggested to underlie deficient spoon anticipation in feeding behavior by Brisson et al. (2011). Based on retrospective analysis of family home movies, authors evaluated how often 3-to-6-months-old children opened their mouth before the spoon touched it. Two populations were investigated, the first comprising children later diagnosed with autism or ASD, the second comprising undiagnosed individuals. ASD children exhibited a clear deficit in mouth opening anticipation, suggesting a prevalence of feedback mode of control (the trigger is provided by the contact between spoon and mouth) relative to a feed-forward one. In addition to an impairment in predicting action consequences, one important line of evidence suggests that children with autism are poor at chaining actions together. Actions are usually made up of several subunits, i.e. motor acts, which are chained together (Fogassi et al. 2005) so as to permit a continuous, global and fluent execution. Cattaneo et al. (2007) recorded electromyography (EMG) of myloioideus (MH), a muscle involved in mouth opening, in a group of eight autistic children and in a group of TD controls, during the execution of two actions. Participants were asked to grasp a piece of food and eat it (grasp to eat) or to grasp a piece of paper and put it into a container positioned on their shoulder (grasp to place). Results showed that in TD children the activity of MH muscle started several milliseconds before the hand grasped the object during the eating task. In contrast, ASD children exhibited a delayed MH activity, starting only once the hand was bringing the food to the mouth. Kinematics studies (Marteniuk et al. 1987, JohnsonFrey et al. 2004) showed that when individuals program an action formed by several motor acts, their kinematics is influenced by both the action final goal and the context in which the action is embedded. In agreement with these studies, Fabbri-Destro et al. (2009) carried out an experiment in order to test if these influences were present also in ASD population. Twelve ASD and 14 TD children were asked to perform two actions made up of three motor acts: reaching, grasping and releasing an object in two differently sized containers. While the first two motor acts were the same in terms of type of object to be grasped and object distance from the agent, the last one differed for its execution difficulty (small and large container). The results showed that, in TD children, the difficulty of the final motor act influenced the movement duration of the first motor act: the initial reaching to the object was slower when the final container was small and faster when it was large. In contrast, the autistic children showed no difference in movement duration according to the container size. Taken together, these data highlight that TD and ASD children have a different action organization: while in TD the final goal of the action is capable to 180

influence the performance of each single chained motor act (since the first one), in ASD each motor act is planned step-by-step, lacking a fluent motor organization and, in many cases, an appropriate motor anticipation. This impairment is reflected in their difficulties to translate their own intention into an appropriate motor sequence. Moreover, this deficiency is especially harmful not only when they plan their own actions, but also when, in everyday life, they observe other people’s actions.

2.6. Developmental dyspraxia and imitation The term apraxia, as used in the (adult) neurologic literature, refers to an acquired disorder of higherorder motor function, resulting in impaired ability to carry out learned skilled movements in the absence of any fundamental sensorimotor impairment sufficient to preclude skilled movement (see Heilman and Rothi 1993, Wheaton and Hallett 2007). When related to neuropsychological terms, the prefix dys- replaces the a- if applied in the developmental context so as to distinguish an acquired from a developmental disorder, even though the etimologies of these prefixes – “lack of” vs. “abnormal” – more strictly refer to severity of the symptoms. Starting from these premises, the term developmental dyspraxia was introduced to describe children with abnormal movements with a presumed congenital rather than acquired origin,. In line with this view, Steinman et al. (2010) pointed out that the term developmental dyspraxia should be used to describe a neurologic sign and not as a disorder unto itself. Furthermore, it should be restricted to situations where the impairment in the execution of skilled movements or gestures is not completely explained by basic motor deficits or perceptuomotor (e.g. visuomotor or somatosensorimotor) impairment. In summary, developmental dyspraxia is not intended like a diagnostic label, but rather it refers to a specific neurologic sign of impaired execution of skilled learned movements. Skilled movements can be subdivided into transitive (involving demonstration of tool use - e.g., using a hammer or a toothbrush) or intransitive (symbolic, communicative gestures - e.g., waving goodbye) movements. Developmental dyspraxia has been investigated in children with autism by several studies (Mostofsky et al. 2006, Dewey et al. 2007, Dziuk et al. 2007, Dowell et al. 2009, MacNeil and Mostofsky 2012, for reviews see Gibbs et al. 2007), mainly using the Florida Apraxia Battery (Rothi et al. 2003; modified for children by Mostofsky et al. 2006). This test evaluates skilled gestures in three different sections: gestures to command, gestures to imitate, and gestures with tool use. Both gestures to command and to imitate include transitive and intransitive gestures, while the tool use section contains only transitive ones. Mostofsky et al. (2006) highlighted how ASD children make a number of different errors in all three sections, including delayed performance, altered amplitude, force or timing of the movement, incorrect limb orientation, the use of a body part as an object (e.g., combing hair with the hand rather than demonstrating the use of a comb) and an incorrect action performance (Mostofsky et al. 2006). Furthermore, the impairment in the performance on praxis examination resulted to correlate with measures of the core social and communicative features of autism (as assessed by the ADOS test), suggesting that a common mechanism might underlie to the impaired development of both motor and social/communicative skills (Dziuk et al. 2007, Dowell et al. 2009). Importantly, Dewey et al. Clinical Neuropsychiatry (2013) 10, 5


(2007) found that children with autism were impaired in both gestural performance and imitation compared not only with TD peers, but also with children with development coordination disorder, attention-deficit/ hyperactivity disorder, and with a combination of the two. Impairments in imitation of skilled gestures have been particularly emphasized, with some investigators suggesting these as a core deficit contributing to abnormal development of empathy, shared (“joint”) attention, and a sense of “other minds” (Rogers and Pennington 1991, Williams et al. 2001). Questions have been raised as to whether deficits in imitation reflect a more basic problem with motor execution/planning, visual processing, or sensory integration (Smith and Bryson 1994, Green et al. 2002, Rogers et al. 2003), or whether they are the result of abnormalities in self–other mapping specific to imitation (Williams et al. 2004). Rogers and Pennington (1991) suggested that a biological impairment in autism restricted the capacity of the infant to self-other correspondence. This hypothesis was taken by Williams et al. (2001) alongside the discovery of mirror neurons, proposing that a deficit in the human mirror neuron system may cause the self-other correspondence problem in ASD. An early developmental failure of the mirror neuron system is likely to result in a cascade of developmental impairments typical of ASD. To unravel this hypothesis, in the next session we will review the literature on autism and mirror neuron system.

3. The mirror mechanism and autism A fundamental issue of cognitive neuroscience is to understand how we are able to comprehend actions and intentions of others. Neurobiological evidence for a direct understanding of behavior of others has been provided by the discovery of a specific class of neurons in the monkey premotor cortex. These neurons - called mirror neurons - discharge both when monkey performs a given motor act and when it observes someone else performing a similar motor act (di Pellegrino et al. 1992, Gallese et al. 1996, Rizzolatti et al. 1996). Subsequently, mirror neurons have been also found in the parietal cortex of the monkey (Fogassi et al. 2005), in motor and viscero-motor human brain centers (see Fabbri-Destro and Rizzolatti 2008) and in songproducing motor areas of birds (Prather et al. 2008, Keller and Hahnloser 2009). Mirror neurons have been demonstrated by single neuron studies (monkeys, birds, and some human data), as well as by studies dealing with non-invasive techniques - EEG, MEG, PET, fMRI, TMS (mostly human data). All these studies reported a basic mechanism - the mirror mechanism - that transforms sensory representations of actions into a motor format. According to its anatomical location, this mechanism subserves different functions, ranging from the recognition of song of conspecifics in birds to action understanding and empathy in humans. Originally, the proposal that a malfunctioning of the mirror mechanism is one of the factors underlying the cognitive aspects of ASD was advanced by Williams et al. (2001) on the basis of theoretical considerations. Subsequently, this hypothesis found empirical support in many studies addressing the mirror activity with different approaches. In this section, we will review studies dealing with mirror mechanism and autism according to the different employed techniques.


3.1 EEG/MEG The oscillations recorded over sensorimotor regions that desynchronize during active movements are known as mu rhythm. Since its first description, it was reported that mu rhythm is blocked not only by movement execution (Gastaut et al. 1952, Gastaut and Bert 1954, Chatrian et al. 1959), but also by the observation of others’ actions. The discovery of mirror neurons (di Pellegrino et al. 1992, Gallese et al. 1996, Rizzolatti et al. 1996) determined a renewed interest in the cortical motor rhythms and indicated mu rhythm as the most reliable electrophysiological marker of the mirror activity for studies in humans. A conceptual link between mu rhythm and the mirror neuron activity was first suggested by Altschuler and co-workers (Altschuler et al. 1997) and it was later confirmed by other researchers (Cochin et al. 1998, Cochin et al. 1999, Nishitani and Hari 2000, Babiloni et al. 2002, Muthukumaraswamy and Johnson 2004, Caetano et al. 2007, Perry and Bentin 2009, Perry and Bentin 2010, Press et al. 2011). This proposal was based on the reactivity of both mu rhythm and mirror neurons in response to action observation and execution. More recently, this link was further strengthened by a study by Braadbart et al. (2013), where EEG and fMRI were simultaneously recorded during a movement observation and imitation task. Mu power modulation resulted to negatively correlate with BOLD response in right inferior parietal lobe, premotor cortex and inferior frontal gyrus, all areas embedded in the mirror network. The first EEG study investigating mu rhythm in ASD was performed by Oberman et al. (2005). The rhythm reactivity was assessed in ten high-functioning individuals with ASD and ten age- and gender-matched control subjects while watching videos of a) a moving hand, b) a bouncing ball, and c) visual noise, or while d) moving their own hand. The results supported the hypothesis of a dysfunctional mirror neuron system in ASD individuals, as they exhibited a significant mu suppression to self-performed hand movements, but not to observed hand movements. Conversely, the control group significantly desynchronized the mu rhythm in both conditions. In line with these data, Bernier et al. (2007) investigated evidence of differential mu rhythm attenuation during movement observation, execution, and imitation in adults with ASD and agematched typical adults. In the EEG task, both groups showed significant attenuation of the mu rhythm when executing an action, but a smaller attenuation of the mu wave was present for ASD group during observation. Furthermore, authors reported a significant and positive correlation between imitation skills and the degree of mu wave attenuation during observation of actions. This correlation was recently confirmed in another study by the same group (Bernier et al. 2013). Further support came from Martineau et al. (2008), who reported no frontal areas desynchronization in autistic children (n=14) during the observation of videos showing human actions. Starting from previous studies (e.g. CalvoMerino et al. 2005) demonstrating that activity from areas endowed with mirror is modulated according to the familiarity/expertise of both the kinematics of movement as well as the actor, Oberman et al. (2008) investigated the sensitivity of mu rhythm desynchronization in ASD children in relation to the familiarity of the agent performing the observed action. Four conditions were administered: “stranger”, i.e. an

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unfamiliar hand grasping an object; “familiar”, i.e. the hand of the child’s relatives performing the same action; “own”, i.e. the participant’s own hand; and, finally, “control condition”, consisting in the display of bouncing balls. Both TD and ASD children showed a larger reactivity when observing grasping made by familiar relative to stranger hand. The desynchronization appeared to be absent in ASD children, but only with unfamiliar stimuli. Recently, Raymaekers et al. (2009), using the same paradigm by Oberman et al. (2005), reported no significant difference in mu suppression between 20 ASD children (8–13 years old) and 20 matched control participants. Specifically, they highlighted a ‘nearly significant’ correlation with age in the ASD sample that was not present in the control group. Authors interpreted these findings as the evidence that age has an influence on MNS functioning in ASD, where a greater suppression may be linked to increasing age. To deeply investigate the relation between mu suppression and the age of ASD children, Oberman et al. pooled together data from four EEG studies (Oberman et al. 2005, 2008; Pineda et al. 2008; Raymaekers et al. 2009) and reported a significant correlation between age and mu suppression in response to the observation of actions, but not execution, for both ASD and TD individuals. According to them, this result provides evidence against the argument that mirror neuron dysfunction improves with age in individuals with ASD, instead demonstrating that the age-dependent mu suppression is due to a diagnosis-independent developmental change. An original approach to the study of autism was used by Puzzo et al. (2010) and Cooper et al. (2013). Instead of testing individuals with ASD, they investigated the cortical rhythms reactivity during action observation in healthy individuals with high- and low- traits of autism assessed by means of the autistic quotient (AQ) test. Both studies revealed that low beta rhythm (12-20 Hz) recorded over motor areas was differently modulated according to the degree of autistic traits. The same frequency band was pointed out in a MEG study by Honaga et al. (2010), who focused on its power increase following movement execution or stimulus presentation (i.e. beta “rebound”) rather than on its desynchronization. ASD and control children were asked to observe and later execute object-related hand actions. They found significantly reduced rebound in ASD relative to controls only during the observation condition. The absence of motor cortex activation during the observation of movements done by others was interpreted by authors as the demonstration of a deficit of mirror system. Using the same technique, Nishitani et al. (2004) had already indicated an abnormal premotor and motor processing in Asperger patients during a facial imitation task. Results showed that the same network is recruited in both patients and controls, but with a different timing and intensity. In particular, activation of the inferior frontal lobe was delayed by 45 to 60 milliseconds for Asperger patients and activations in the inferior frontal lobe and in the primary motor cortex were weaker than in control subjects. Authors suggested that these findings could account for a part of imitation and social impairments typically reported for subjects with Asperger Syndrome.

3.2 fMRI The existence of a mirror mechanism malfunctioning in ASD children was also investigated by means of fMRI. In a highly-cited study, Dapretto et al. (2006) 182

investigated neural activity during imitation and observation of facial emotional expressions in highfunctioning children with ASD and in TD children matched by age and IQ. Even if both groups performed the tasks equally well, children with autism showed no mirror activity in the inferior frontal gyrus (pars opercularis). Most interestingly, activity in this region was inversely related to symptom severity in the social domain, suggesting not only that a dysfunctional mirror system may underlie the social deficits, but also that the extent of the dysfunction might affect the severity of the autistic symptoms. More recently, Bastiaansen et al. (2011) tested twenty-one adult males with ASD and the same number of TD matched for age, sex, and IQ in three conditions: observing short movies showing facial expressions, performing a facial movement, and experiencing a disgusting taste. Results showed an agedependency of the inferior frontal gyrus activity during the observation of facial expressions in subjects with autism, but not in controls. Authors interpreted this finding as the evidence of an increase of mirror neuron system activity with age in autism, accompanied by a parallel improvement of the social functioning. An abnormal involvement of the same area was reported also by Martineau et al. (2010), who investigated seven right-handed high-functioning autistic and eight TD subjects during observation and execution of hand movements relative to a control condition. The comparison of the contrast between observation of human motion and rest condition provided evidence of a bilateral greater activation of inferior frontal gyrus for ASD relative to controls. This hyperactivation may reflect once more a dysfunction of areas typically associated to mirror neurons network. Further support to this view was provided by a functional connectivity study by Villalobos et al. (2005), who evidenced a significantly reduced connectivity between primary visual areas and the bilateral inferior frontal gyrus. Williams et al. (2006) explored the hypothesis that the imitative impairment in ASD might result from dysfunction in mirror neurons network, administering a protocol previously employed by Iacoboni et al. (1999), to compare 16 ASD adolescent of normal intelligence with age, sex and IQ matched controls. They reported a different activity attributable to mirror neurons in areas of the right parietal lobe, with ASD group showing a less extensive activation. In addition, a functional MRI study by Schulte-Rüther et al. (2011) tested both ASD patients and TD controls during an emotion recognition task, where participants had to evaluate either the emotional state observed in a facial stimulus (other-task) or their own emotional response (self-task). Frontal areas associated with the human mirror system were activated in both tasks in control subjects, while ASD patients recruited these areas during the self-task only. Authors interpreted this atypical patterns of activation as the evidence of a disturbed empathy in individuals with ASD, who may use an atypical cognitive strategy to gain access to other people’s emotions.

3.3 TMS The mirror mechanism in autism was investigated also by TMS studies. Theoret et al. (2005) investigated the neural mechanism matching action observation and execution in adults with ASD and normal controls. They applied TMS over the primary motor cortex during observation of 10 seconds video clips depicting intransitive, meaningless movements of index or thumb finger either from an egocentric or from an allocentric Clinical Neuropsychiatry (2013) 10, 5


perspective. They showed that the overall modulation of primary motor cortex (M1) excitability during action observation was significantly lower in individuals with ASD relative to controls during the observation of allocentric finger movements. Interestingly, this results was not replicated with the set of video clips captured from an egocentric viewpoint. Authors ascribed this effect to a higher difficulty for ASD individuals to process other-directed movements, impairment possibly constituting a neurophysiological substrate of social impairments typically associated to autism. In a more recent TMS study (Enticott et al. 2013), 34 patients with ASD and 36 matched control were enrolled. Cortico-spinal excitability was assessed during the observation of hand gestures relative to the observation of a static hand. By means of a regression analysis, authors found a significantly reduced cortical excitability in ASD relative to controls. Interestingly, within ASD group a negative association between the activity of the mirror mechanism and social impairments was reported. In line with the original aforementioned approach, Puzzo et al. (2009) investigated the corticospinal excitability in individuals with high and low traits of autism, as assessed by means of the autistic quotient (AQ) test. Participants were stimulated with single pulse TMS while observing videos of hand and mouth actions and static images representing hand or mouth. While participants with low autistic traits showed significantly greater motor evoked potential (MEPs) during the observation of the hand/mouth actions relative to static stimuli, participants with high traits of autism exhibited MEPs with similar amplitude during the observation of both types of stimuli, suggesting that also the presence of autistic traits affects the overall amount of activity of the motor system in response to action stimuli. Employing a repetitive transcranial magnetic stimulation (rTMS) and EEG, Keuken et al. (2011) temporarily disrupted activity in the left inferior frontal gyrus (LIFG), subsequently investigating the role of this cortical region in social perception. In eighteen participants the LIFG was stimulated (experimental condition), while nineteen underwent to a vertex stimulation (control condition). Results showed that, disrupting LIFG, increased reaction times were found during an emotion recognition task, and no 8–12 Hz EEG mu rhythm suppression was visible. These effect were not replicated in the control group, with the rTMS applied over the vertex. These data were considered by the authors as the evidence for the role of the mirror neuron system in social perception, further demonstrating that this mechanism can be indexed with EEG and mu rhythm quantification.

3.4 EMG and behavioral Recently, the deficit of the mirror mechanism in autism has been addressed from another perspective (Cattaneo et al. 2007). TD children and children with autism were tested while they observed either an experimenter grasping a piece of food in order to eat it or grasping a piece of paper in order to place it into a container (see section 2.4). The EMG activity of the mylohyoideus muscle (MH) was recorded. The results showed that in TD children the observation of food grasping determined the activation of MH, while this activation was totally lacking in children with autism. Authors discussed this finding suggesting that 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. In other Clinical Neuropsychiatry (2013) 10, 5

words, in autism, the lack of a mirror activation during action observation would not lead to an immediate and experiential understanding of others’ intention. When we see a person acting upon an object, we are able, typically, to extract two main information: what this person is doing, but also why the person is doing it, i.e. his/her intention. Additional evidence in favor of a deficit of the intention understanding in ASD, based on the mirror mechanism, has been provided by Boria et al (2009). They tested the capacity to report the goal of an observed motor act (i.e. what, grasping an object) as well as to report the intention underlying it (i.e. why, grasping to eat or to place) in both TD and ASD children. Results showed that both groups were able to recognize what the actor was doing, but ASD children performed worst in recognizing why the actor was doing it. Indeed, ASD children systematically attributed to the actor the intention that could be derived by the semantics of the object, e.g. intention to cut when scissors were shown, regardless of how the object was grasped. This finding indicates that ASD children appear to have deficiencies in reading the intention of others from their motor behavior, deriving it on the basis of the standard use of objects. It may sound surprising that children with autism have no problem in recognizing the motor act of others (e.g. grasping) when this appears to be one of the major functions of the mirror mechanism. However, this can be easily explained if one take into consideration that this capacity could be solved on the basis of a mere visual information. As Jeannerod (2004) wrote: “Mere visual perception, without involvement of the motor system, would only provide a description of the visible aspects of the movements of the agent, but it would not give precise information about the intrinsic components of the observed action which are critical for understanding what the action is about, what is its goal, and how to reproduce it”. This sentence describes how superficial and devoid of real understanding is the visual/inferential way of understanding others relative to the one offered by mirror mechanism, allowing an understanding “from the inside”. All aforementioned studies demonstrate how in autistic children the perception of others relies on the first strategy rather than on the latter.

4. Conclusion In this review we retraced the main stages of the motor development such as postural stability, gait, anticipation and action planning. Compared with typical development peers, children with autism present a series of motor organization deficits, whose appearance precedes the onset of the socio-communicative deficits considered as the core symptoms of autism. Since the first descriptions of this syndrome (Kanner 1943, Ornitz et al. 1977), it was reported that specific motor behaviors characterize the very early life of children later diagnosed as autistic. One of the most striking reports is that when adults attempt to hold a child with autism in their arms, the child does not anticipate by greeting them with open arms as typical children do (Kanner 1943). Following this preliminary observation, a huge amount of literature indicated that motor abnormalities are present across all the diagnoses in the spectrum and how this may be a cardinal feature for autistic conditions. Despite this, motor deficits in autism have traditionally been conceptualized as phenomena peripheral to the core autistic features, possibly even unrelated and certainly secondary to the diagnostic triad of impaired language, social behavior 183


and imagination (Golden 1987). This may be partly due to the highly visible and distressing nature of other symptoms. Only Leary and Hill (1996) attempted to view the central symptoms through the light of a disturbance of the neural motor symptoms. Whilst it is not possible to consider all impairments of autism as directly correlated with a dysfunction in the motor domain, such a dysfunction does correlate with some of the cognitive disturbances (Lohr and Wisniewski 1987). Aspects of action cognition, such as imitation and action understanding, known to be deficient in ASD (Stone et al. 1997, Rogers et al. 2003, Williams et al. 2004, Dewey et al. 2007), correlate with motor impairments along with problems in the social, communicative and behavioral domains (Dziuk et al. 2007). These aspects of action cognition have been linked to a deficit in “selfother mapping” (Williams et al. 2001, Williams 2006), process typically attributed to the mirror mechanism. Thus, it is reasonable to conclude that both social/ communicative and motor aspects peculiar of autism lie within a single framework, offered by an impairment of mirror mechanism, where motor problems are not only parallel to the autistic cognitive-communicative deficits, but they are a possible original core of the syndrome later reflecting in their incapacity to interact with others in a common way.

Acknowledgements VG and PA were supported by ERC Grant Cogsystem contract n. 250013. We thank Prof. Giacomo Rizzolatti for his critical reading and suggestions on the manuscript.

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