Cerebral Cortex Advance Access originally published online on November 23, 2005
Cerebral Cortex 2006 16(9):1276-1282; doi:10.1093/cercor/bhj069
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Anatomical Differences in the Mirror Neuron System and Social Cognition Network in Autism
1 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA, 2 Division of Health Sciences and Technology, Harvard–Massachusetts Institute of Technology, Cambridge, MA 02139, USA and 3 Boston University School of Medicine, Boston, MA 02118, USA
Address correspondence to Nouchine Hadjikhani, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Building 36, First Street, Room 417, Charlestown, MA 02129, USA. Email: nouchine{at}nmr.mgh.harvard.edu.
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Abstract |
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social and emotional skills, the anatomical substrate of which is still unknown. In this study, we compared a group of 14 high-functioning ASD adults with a group of controls matched for sex, age, intelligence quotient, and handedness. We used an automated technique of analysis that accurately measures the thickness of the cerebral cortex and generates cross-subject statistics in a coordinate system based on cortical anatomy. We found local decreases of gray matter in the ASD group in areas belonging to the mirror neuron system (MNS), argued to be the basis of empathic behavior. Cortical thinning of the MNS was correlated with ASD symptom severity. Cortical thinning was also observed in areas involved in emotion recognition and social cognition. These findings suggest that the social and emotional deficits characteristic of autism may reflect abnormal thinning of the MNS and the broader network of cortical areas subserving social cognition.
Key Words: autism • cortical thickness • empathy • mirror neuron system
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Introduction |
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TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by debilitating socioemotional impairments, yet its neural substrates remain unknown. ASD affects as many as 1 in 166 children (Fombonne 2003
) and is four times more prevalent in boys than in girls. ASD is usually diagnosed between the ages of 2 and 3 years, but early signs may be detectable by 12 months of age (Osterling and Dawson 1994). Defining features of autism include qualitative impairments in communication and reciprocal social interaction as well as repetitive and stereotyped behaviors (APA 1994).
One characteristic of ASD is the lack of empathy and emotional engagement with others (Gillberg 1992; APA 2000). Individuals with ASD have difficulty in relating to others and recognizing their emotions and fail to show the usual empathic reaction when other people demonstrate emotions of fear, pleasure, or pain (Hobson 1993). Lack of empathy in ASD has been quantified with objective test measures, such as the Empathy Quotient Questionnaire (Baron-Cohen and Wheelwright 2004).
A possible neural substrate of empathy is the mirror neuron system (MNS). The MNS was first identified as area F5 of the premotor cortex in the monkey by Rizzolatti, Gallese, and their colleagues (Gallese and others 1996; Rizzolatti, Fadiga, Gallese, and others 1996; Rizzolatti and others 1999), who demonstrated that a set of neurons in this area fired not only when a monkey was moving its own hand or mouth but also when it saw another individual (monkey or human) performing the same action. The activation of the same area of cortex in the observation as well as the execution of a given action led to the concept of an MNS.
Functional evidence for the presence of an MNS in humans comes from several studies using transcranial magnetic stimulation (TMS), electroencephalography (EEG), megnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) methodologies (Fadiga and others 1995, 2005; Grafton and others 1996; Rizzolatti, Fadiga, Matelli, and others 1996; Decety and others 1997; Hari and others 1998; Cochin and others 1999; Decety and Grezes 1999; Iacoboni and others 1999; Nishitani and Hari 2000; Strafella and Paus 2000; Buccino and others 2001; Gangitano and others 2001; Grezes and Decety 2001; Maeda and others 2002; Carr and others 2003; Grezes and others 2003; Leslie and others 2004). Since its discovery, the MNS has been found to be composed of a network of areas, including the pars opercularis of the inferior frontal gyrus (IFG) and its adjacent ventral area (inferior frontal cortex [IFC]), the inferior parietal lobule (IPL), and the superior temporal sulcus (STS), which are activated during the observation and imitation of an action. Insofar as the MNS generates internal representations of actions common to one's self and others, it is likely to be involved in our capacity to understand the actions and experiences of other people. Such an understanding is critical to social–communicative functioning, and accordingly, the MNS has been hypothesized by various researchers to be the basis of "mind reading," imitative learning, and empathy (Gallese 2003; Leslie and others 2004). Several recent functional brain-imaging studies have found evidence of mirror neuron dysfunction in autism (Nishitani and others 2004; Oberman and others 2005; Theoret and others 2005), implicating this neural system in autistic social impairment (Williams and others 2001).
Both the imitation and the attribution of mental states involve translating from another person's perspective into one's own. In addition, imitation requires a shared representation of perceived and executed action, and there is evidence suggesting that the MNS together with the superior parietal lobule serve this function (Iacoboni and others 1999; Williams and others 2001; Decety and others 2002; Heiser and others 2003; Koski and others 2003; Leslie and others 2004; Buxbaum and others 2005). Several studies have found imitative deficits in autism (for review, see Williams and others 2004), including deficits in imitating simple body movements and actions with symbolic meaning (Rogers and Pennington 1991) and in imitating facial expressions of emotion (Hertzig and others 1989; Loveland and others 1994). These deficits are present early in development (Rogers and others 2003). Together, these findings suggest that the basis for imitative and empathic deficits in autism could arise from a dysfunction in the MNS.
One consistent finding in the neuropathology of autism is the presence of enlarged head and brain size (Bailey and others 1993; Davidovitch and others 1996; Woodhouse and others 1996; Lainhart and others 1997; Fidler and others 2000; Fombonne 2000; Miles and others 2000; Aylward and others 2002) that is not present at birth but becomes evident during the first year of life (Lainhart and others 1997; Stevenson and others 1997; Courchesne and others 2001) and that appears to be mostly due to white matter increases (Herbert and others 2003). There is also evidence of a range of cortical abnormalities in autism (Gaffney and Tsai 1987; Berthier and others 1990; Piven and others 1990; Berthier 1994; Bailey and others 1998; Kemper and Bauman 1998), but the findings have shown little consistency. This might be for several reasons, including significant heterogeneity within the syndrome as well as the different ages of the cohorts that have been examined (for review, see Brambilla and others 2003; Palmen and Van Engeland 2004). Most magnetic resonance studies (Abell and others 1999; McAlonan and others 2002, 2005; Boddaert and others 2004; Waiter and others 2004) have used voxel-based morphometry (VBM), a technique that does not give a direct measure of the cortical thickness but instead gives probabilistic information about gray matter volume, which risks partial voluming. VBM studies have found gray matter abnormalities in the inferior frontal (Abell and others 1999; McAlonan and others 2002), parietal (McAlonan and others 2002), and temporal regions, including the STS (Boddaert and others 2004), as well as changes in the basal ganglia, the amygdala, and the cerebellum (Abell and others 1999; McAlonan and others 2002). More recently, McAlonan and others (2005) have shown generalized as well as localized gray matter reduction in the fronto-striatal, parietal, and temporal cortex in high-functioning autistic children, pointing to an early structural abnormality of the "social brain."
In contrast to VBM, direct measures of cortical thickness can reveal subtle cortical differences that are likely to reflect the underlying neuropathological abnormalities. For example, in schizophrenia, cortical thickness measures have proven useful in identifying abnormalities in prefrontal and temporal cortices (Kuperberg and others 2003). Direct measurement of the cortical mantle avoids the risk of introducing confounding factors by normalizing brains of different volumes into a common space and examining voxel intensities that might have been affected by this transformation.
In this study, we used a direct measurement of cortical thickness to examine the gray matter integrity and to explore the anatomical substrate of behavioral symptoms in ASD. This automated method, developed by Fischl and Dale (2000), accurately measures the thickness of the cerebral cortex across the entire brain and generates cross-subject statistics in a coordinate system based on cortical anatomy. The intersubject standard deviation of the thickness measure is less than 0.5 mm, allowing the detection of focal atrophy in small populations or even individual subjects. The reliability and accuracy of this new method have been assessed by within-subject test–retest studies as well as by comparison of cross-subject regional thickness measures with published values. This technique has also been validated with histological (Rosas and others 2002) and manual (Kuperberg and others 2003) measurements. It has been powerful in showing cortical thinning in schizophrenia (Kuperberg and others 2003), Huntington disease (Rosas and others 2002), and aging populations (Salat and others 2004).
Brain size is correlated with sex (Caviness and others 1996; Giedd and others 1996), age (Caviness and others 1996; Giedd and others 1996), intelligence quotient (IQ) (Andreasen and others 1993; Thompson and others 2001; Posthuma and others 2002), and handedness (Witelson and Goldsmith 1991). In order to restrict possible confounds due to these variations, we compared a group of 14 high-functioning ASD young male adults with a group of 14 male normal control (NC) subjects closely matched for age, IQ, and handedness.
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Materials and Methods |
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Participants
Informed consent was obtained for each participant, and all procedures were approved by the Massachusetts General Hospital Internal Review Board. Twenty-eight male subjects (14 ASD and 14 matched controls) closely matched for age (ASD: 33 ± 12 years; NC: 31 ± 9 years; P < 0.6, nonsignificant [NS]), IQ (ASD: 113 ± 15; NC: 118 ± 13; P < 0.4, NS), and handedness (all right handed) participated in the study.
All participants were diagnosed with autism (8 subjects), Asperger disorder (4 subjects), or pervasive developmental disorder not otherwise specified (2 subjects) by an experienced clinician on the basis of their current presentation and developmental history. The diagnoses were confirmed using the Autism Diagnostic Interview–Revised (ADI-R) (Lord and others 1994) and the Autism Diagnostic Observation Schedule (Lord and others 2000) (see Table 1).
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Imaging
Two high-resolution (1.0 x 1.0 x 1.25 mm) structural images were obtained with a magnetization-prepared rapid acquisition with gradient echoes sequence (128 slices, 256 x 256 matrix, echo time [TE] = 3.44 ms; repetition time [TR] = 7.25 ms; flip = 7°) on a 1.5-T Sonata MR scanner (Siemens, Munich, Germany).
Surface Reconstruction and Cortical Thickness Estimation
The 2 scans were motion corrected and averaged to create a single-image volume with high contrast-to-noise. Brain surfaces were reconstructed and inflated as described previously (Dale and others 1999; Fischl and others 1999). Cortical thickness measurements were obtained by reconstructing the gray/white matter boundary (Dale and Sereno 1993; Dale and others 1999; Fischl and others 1999) and the cortical surface. The distance between these 2 surfaces was calculated individually at each point across the cortical mantle (representing a total of 
147 000 vertices in each individual). The maps of cortical thickness were created using spatial intensity gradients across tissue classes and were not restricted to individual voxel intensities, allowing subvoxel resolution and submillimetric difference detection between groups (Fischl and Dale 2000).
Statistical Analysis
Data were then aligned according to cortical folding (Dale and others 1999) and smoothed on the surface tessellation, using an iterative nearest neighbor procedure. Smoothing was restricted to the cortical surface, thus avoiding the averaging of data across sulci or outside the gray matter (Dale and others 1999). This method has the advantage of matching morphologically homologous cortical areas based on the main gyri/sulci patterns with minimal metric distortion. Per voxel t-tests were then calculated between groups for the smoothed values on the target surface.
In addition, definition of the regions of interest (ROIs) was performed by the detection of contiguous regions of statistical significance (P < 0.01) in the maps described above. These areas of regional thinning were used to create ROIs on a standard brain that were mapped back to each individual subject using spherical morphing to find homologous regions across subjects. A mean thickness score over each location was calculated for each subject. These scores were used to perform a t-test between the 2 groups for each ROI. Spearman rank-order correlation coefficients were computed to assess the degree of relationship between cortical thickness and behavioral (social and communication) symptoms as measured with ADI-R scores. Cortical locations were defined according to Duvernoy (1999)
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Results |
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Several areas were significantly thinner in the autism group, including the IFG pars opercularis, IPL, and STS (Fig. 1). These areas are part of the network argued to be the basis of imitative and empathic behavior (e.g., Iacoboni and others 1999
; Buccino and others 2001; Rizzolatti and Craighero 2004).
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Thinning was also present in areas involved in facial expression production and recognition (face regions in sensory and motor cortex and in middle temporal gyrus) and in areas involved in social cognition (prefrontal cortex, anterior cingulate, medial parietal cortex, supramarginal gyrus, and middle and inferior temporal cortex).
There was no difference between groups in the remaining areas of the cortex. Cortical thinning was not associated with IQ scores in any of the areas of the MNS.
Significant associations between cortical thinning and autism symptom severity were found in—and nearly restricted to—all the areas constituting the MNS. Specifically, ADI-R combined social and communication diagnostic algorithm scores, which are based on the parental report of an individual's behaviors between the ages of 4 and 5 years, were correlated with cortical thinning bilaterally in the IFG pars opercularis, IPL, and right STS (see Table 2). The other areas that showed correlations with ADI-R symptoms were the right superior parietal lobule, involved in action observation and imitation (e.g., Buccino and others 2001); the inferior occipital gyrus, involved in face perception (e.g., Haxby and others 2000); and the supramarginal gyrus, involved in phonological processing (e.g., Celsis and others 1999).
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Discussion |
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With this direct measurement of cortical mantle thickness, we found significant thinning of areas belonging to the MNS (IFC, IPL, and STS) and of other areas involved in social cognition in individuals with ASD. The MNS couples action perception and action production. This shared-representation model may also apply to the domain of emotion. Empathy can be defined as a phenomenon in which the perception of another's state activates one's own corresponding representation, which in turn activates somatic and autonomic responses. The MNS is arguably the basis of mind reading and empathy (Leslie and others 2004
) and as such may well be implicated in the neuropathology of autism. Lack of empathy and emotional engagement with others is indeed one of the defining characteristics and very early signs of autism (Charman and others 1997; Baron-Cohen and Wheelwright 2004).
Our finding of thinning of the STS in individuals with ASD is consistent with robust evidence of abnormal processing of eye gaze in autism (Mundy and others 1986; Phillips and others 1992; Baron-Cohen and others 1997; Leekam and others 1998; Ristic and others 2002; Pelphrey and others 2005). In healthy individuals, observation of gaze direction is associated with STS activation (Perrett and others 1992; Puce and others 1998; Wicker and others 1998; Hoffman and Haxby 2000; Pelphrey and others 2003, 2004). STS is sensitive to the intention or goal directedness of a gaze shift (Pelphrey and others 2003), and the right STS is preferentially involved in the processing of social information conveyed by shifts in eye gaze (Pelphrey and others 2004). Deficits of activation of STS in ASD have been found in a variety of tasks involving attribution of intentions on the basis of shifts of gaze, body movements, or geometric figure movement (Baron-Cohen and others 1999; Castelli and others 2002; Mosconi and others 2005; Pelphrey and others 2005). Our findings of cortical thinning in the right STS of ASD are also in line with findings of volumetric differences (Boddaert and others 2004) and sulcal displacement (Levitt and others 2003) of STS in children with ASD.
Thinning was also observed bilaterally in the superior parietal lobule, an area involved in imitation (Buxbaum and others 2005; Chaminade and others 2005), a function that has been shown to be impaired as early as 34 months of age in children with autism (Rogers and others 2003). Other areas of cortical thinning included the face regions of the motor and premotor cortex bilaterally, the right face somatosensory cortex, and the middle temporal gyrus. These areas are involved in emotion production and recognition. Damage to these areas results in deficits in facial expression recognition, consistent with the fact that deficits in production and recognition of emotion reliably co-occur (e.g., Adolphs and others 1996). These findings could cast light on the abnormalities shown by individuals with ASD in facial expression recognition.
Additional areas of cortical thinning were found in the lateral, medial, and ventral prefrontal cortex, the anterior cingulate, the medial parietal cortex, and the supramarginal gyrus. These regions have critical functions in social cognition (Brothers 1990), and functional imaging in autism has suggested altered functionality in these regions (Baron-Cohen and others 1999). For example, reduced medial prefrontal dopaminergic activity and reduced glucose metabolism in the anterior cingulate gyrus have been reported (Schultz and Klin 2002), and medial prefrontal cortex activation has been reported for tasks involving the attribution of mental states in NCs (Fletcher and others 1995) but not in ASD subjects (Happe and others 1996).
The cortical thickness differences observed might be due to primary developmental histopathological abnormalities, including defective neuronal proliferation or migration (Rorke 1994), cell density, and microcolumnar changes (Casanova and others 2002). Alternatively, or in combination, the cortical thinning we observed in ASD could be a secondary consequence of a lack of input to specific brain areas resulting either from abnormal subcortical or cortical function or from primary white matter abnormalities. The latter possibility is consistent with recent findings of reduced cortical connectivity in ASD (Belmonte and others 2004; Just and others 2004; Welchew and others 2005).
The correlation of MNS thinning with ADI-R scores, based on symptoms reported for the preschool years, may indicate that MNS abnormalities are already present in early childhood. This possibility is supported by recent data from McAlonan and others (2005), who found changes in gray matter volumes in high-functioning children with autism. Early dysfunction of the MNS could generate abnormal development of other areas of the social brain and result in several of the clinical features that characterize autism, including the failure to develop reciprocal social and emotional abilities. Indeed, if social understanding has its basis in experiential sharing, a function sustained by the MNS, autistic symptoms could be seen as developing as a consequence of a lack of mimicry and empathic activity caused by an underlying failure of the MNS system. Future studies using in vivo magnetic resonance spectroscopy imaging, a method allowing the characterization of a cell population involved in pathological processes (e.g., Cheng and others 2002), might clarify the underlying neuropathological change in autism, and diffusion studies will cast light on the anatomical connectivity in ASD brains.
Our technique is limited to measures of the cortex and does not allow us to examine potentially affected subcortical structures that play a pivotal role in the social brain, such as the amygdala and the basal ganglia (Baron-Cohen and others 2000; Hrdlicka and others 2005; McAlonan and others 2005). In addition, the present findings cannot determine whether the anatomical differences observed are a cause or a consequence of behavioral abnormalities, which will need to be resolved by longitudinal studies. More studies are needed to finely probe the functional integrity of this network in ASD and to investigate the associations among cortical thickness changes, brain-activation patterns, and the severity of the behavioral manifestations of autism. Finally, studies of neurofunctional changes in children receiving skills training in imitation and emotional decoding may help to further specify the cerebral bases of empathic behavior as well as to determine the degree of plasticity in this neural system.
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Funding to pay the Open Access publication charges for this article was provided by a National Institutes of Health grant RO1 NS44824-01 to NH.
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Acknowledgments |
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This research was supported by National Institute of Health (NIH) grant RO1 NS44824-01 to NH and by grant PO1/U19 DC 03610, part of the National Institute of Child Health and Human Development/National Institute on Deafness and Other Communication Disorders NICHD/NIDCD funded Collaborative Programs of Excellence in Autism to HT-F, as well as by the Mental Illness and Neuroscience Discovery (MIND) Institute. We thank Bruce Fischl for allowing us to use the cortical thickness analysis program; Christopher Chabris, Jill Clark, Lauren McGrath and Shelly Steele for their help in collecting the data for this study; Gordon Harris for his comments on the manuscript.
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