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Altered Cortical Thickness and Tract Integrity of the Mirror
Neuron System and Associated Social Communication
Performance in Autism Spectrum Disorder


Journal: Autism Research
Manuscript ID: Draft
Wiley - Manuscript type: Research Article
Date Submitted by the Author: n/a
Complete List of Authors: Chien, Hsiang-Yun; National Taiwan University College of Medicine, Center
for Optoelectronic Biomedicine
Gau, Susan Shur-Fen; National Taiwan University Hospital and College of
Medicine, Department of Psychiatry; National Taiwan University, Graduate
Institute of Brain and Mind Sciences
Hsu, Yung-Chin; National Taiwan University College of Medicine, Center for
Optoelectronic Biomedicine
Chen, Yu-Jen; National Taiwan University College of Medicine, Center for
Optoelectronic Biomedicine
Lo, Yu-Chun; National Taiwan University College of Medicine, Center for
Optoelectronic Biomedicine
Shih, Yao-Chia; National Taiwan University College of Medicine, Center for
Optoelectronic Biomedicine
Tseng, Wen-Yih; National Taiwan University, Molecular Imaging Center;
National Taiwan University, Graduate Institute of Brain and Mind Sciences;
National Taiwan University College of Medicine, Center for Optoelectronic
Biomedicine; National Taiwan University Hospital, Department of Medical
Imaging
Keywords:
tractography, mirror neuron system, autism spectrum disorder, diffusion
spectrum imaging, cortical thickness



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Altered Cortical Thickness and Tract Integrity of the Mirror Neuron
System and Associated Social Communication in Autism Spectrum
Disorder

Hsiang-Yun Chien
1
, Susan Shur-Fen Gau
2,3
*, Yung-Chin Hsu
1
, Yu-Jen Chen
1
, Yu-
Chun Lo
1
, Yao-Chia Shih
1
, and Wen-Yih Isaac Tseng
1,3,5
**

1
Center for Optoelectronic Medicine, National Taiwan University College of
Medicine, Taipei, Taiwan
2
Department of Psychiatry, National Taiwan University Hospital and College of
Medicine, Taipei, Taiwan
3
Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei,
Taiwan
4
Molecular Imaging Center, National Taiwan University, Taipei, Taiwan
5
Department of Medical Imaging, National Taiwan University Hospital, Taipei,
Taiwan



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Correspondence to:
** Wen-Yih Isaac Tseng, M.D., Ph.D., Center for Optoelectronic Medicine, National
Taiwan University College of Medicine, No. 1, Sec. 1, Jen-Ai Road, Taipei 10051,
Taiwan
Fax: +886 2 23926922
E-mail: wytseng@ntu.edu.tw

* Susan Shur-Fen Gau, M.D, Ph.D., Department of Psychiatry, National Taiwan
University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei
10002, Taiwan
Fax: +886 2 23812408
Email: gaushufe@ntu.edu.tw


Keywords: autism spectrum disorder, mirror neuron system, diffusion spectrum
imaging, cortical thickness, white matter integrity, tractography, social
communication
Word Count: lay abstract, 189; scientific abstract, 234; full text, 4666; 5 figures; 1
table; 3 supplementary figures; 1 supplementary table.
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Lay Abstract
The mirror neuron system (MNS) is related to action understanding and imitation, and
is considered to play an important role in the social mechanism of the human brain.
Individuals with autism spectrum disorder (ASD) have been reported to show
abnormal MNS activation in previous neuroimaging studies. However, a few studies
focusing on the gray and white matter structures of the MNS have revealed
inconsistent results. The present study recruited adolescents and young adults with
ASD and age-matched typically developing controls. The cortical thickness (CT) of
the core regions within the MNS and the integrity of the tracts connecting these
regions were analyzed. The results showed no significant differences in the CT and
tract integrity of the ASD and TD groups, although the ASD group generally had
greater CTs and decreased tract integrity. The structural co-variance of the CT within
the MNS presented a weak coordination in ASD. The right fronto-parietal tracts were
significantly associated with social communication performance in the ASD
individuals, suggesting a neural correlate for communication processingin ASD. Our
results imply that aberrant coordination of the MNS structures may be one of
underlying factors causing ASD.
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Scientific Abstract
Previous studies using neural activity recording and neuroimaging techniques have
reported functional deficits in the mirror neuron system (MNS) for individuals with
autism spectrum disorder (ASD). However, a few studies focusing on gray and
white matter structures of the MNS have yielded inconsistent results. The current
study recruited adolescents and young adults with ASD (aged 15-26 years) and age-
matched controls (aged 14-25 years). The cortical thickness (CT) and
microstructural integrity of the tracts connecting the core regions of the MNS were
investigated. High-resolution T1-weighted imaging and diffusion spectrum imaging
were performed to quantify the CT and tract integrity, respectively. The results
showed that there were no significant between-group differences in the CTs and
tract integrity. However, the ASD group generally had larger CTs and decreased
tract integrity. The structural co-variance of the CT of the MNS regions revealed a
weaker coordination of the MNS network in ASD. A strong correlation was found
between the integrity of the right fronto-parietal tracts and the social
communication sub-scores measured by the Chinese version of the Social
Communication Questionnaire. In conclusion, aberrant structural coordination may
be an underlying factor affecting the function of the MNS in ASD patients. The
association between the right fronto-parietal tracts and social communication
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performance implies a neural correlate of communication processing in the autistic
brain. This study provides evidence of abnormal MNS structures and their
influence on social communication in individuals with ASD.
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1. Introduction
The mirror neuron system (MNS) has long been reported to be an important
mechanism in action understanding and imitation [Brass & Heyes, 2005; Buccino et
al., 2004; Heyes, 2001; Iacoboni et al., 1999; Rizzolatti, 2005; Rizzolatti et al., 2014;
Rizzolatti & Craighero, 2004]. The human MNS network consists of the rostral part
of the inferior parietal lobule (IPL), lower part of the precentral gyrus, and posterior
part of the inferior frontal gyrus (IFG). It forms connections and interactions between
the frontal and parietal regions of the brain [Cattaneo & Rizzolatti, 2009]. In
particular, it is related to human language evolution [Arbib, 2005; Arbib et al., 2008;
Corballis, 2003; Corballis, 2010; Rizzolatti & Arbib, 1998] and has a critical role in
the motor regions involved in communication [Hickok et al., 2011; Pulvermller &
Fadiga, 2010; Pulvermuller et al., 2014; Watkins & Paus, 2004; Watkins et al., 2003;
Wilson et al., 2004]. Although the MNS is involved in higher complex cognitive
functions [Dinstein et al., 2008; Molenberghs et al., 2009; Spengler et al., 2010], it is
regarded as the neural basis of an internal simulation mechanism that creates a direct
link between the sender of a message and its receiver. The MNS also plays an
important role in the processing of human social behavior [Oberman &
Ramachandran, 2007; Rizzolatti & Craighero, 2004].
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Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized
by appreciative deficits in imitation [Smith & Bryson, 1994; Williams et al., 2004;
Williams et al., 2001], theory of mind [Baron-Cohen et al., 1994; Castelli et al., 2002],
social interaction, and communication [Lee et al., 1994; Mundy et al., 1986; Volden
& Lord, 1991]. Oberman and Ramachandran [2007] proposed that an impaired MNS
is an underlying cause of the social and communicative deficits in ASD. Previous
electroencephalography studies have shown that during observation or execution of
specific actions, the mu rhythm is suppressed in normal controls, but not in
individuals with ASD [Martineau et al., 2008; Oberman et al., 2005]. Cattaneo et al.
[2007] also used magnetoencephalography to show that typically developing (TD)
children understood intentions by activating a specific action chain in their muscle,
whereas this activation was absent in children with ASD. These electrophysiology
studies have suggested that an impaired MNS is implicated in ASD.
As neuroimaging has advanced, more specific patterns of a dysfunctional MNS
have been reported [Martineau et al., 2010; Williams et al., 2006]. Dapretto et al.
[2006] used functional magnetic resonance imaging (fMRI) to demonstrate reduced
activity in the pars opercularis (Pop) when ASD children imitated and observed
emotional expressions. They found a strong association between Pop activity and
measured scores on social subscales. Ramachandran and Oberman [2006] used this
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accumulating evidence to propose the broken mirror theory explaining the
pathophysiology of ASD.
The abnormal structural development of the brain may result in dysfunction of
the MNS network. Previous structural MRI studies evaluating the cortical thickness
(CT) in ASD have reported abnormal cortical thinning of the MNS regions and its
correlation with the severity of social communication symptoms in adults with ASD
[Hadjikhani et al., 2006]. Doyle-Thomas et al. [2013] found widespread cortical
thinning in TD controls as age increased from childhood to adulthood. However,
individuals with ASD had less age effect on their CTs, including in the MNS areas
such as the IFG and IPL. The inconsistency of the above findings may arise from
different segmentation methods or patient populations. Nonetheless, these analyses
imply abnormal CT development in ASD.
Considering their developmental effect, neuroanatomical differences can be
measured by structural co-variance (SC), which calculates the correlation between the
morphometric index of one brain region and that of another brain region to reflect
developmental coordination or synchronized maturation between the two brain
regions [Alexander-Bloch et al., 2013]. Reduced SC of cortical volume [Bassett et al.,
2008; Bullmore et al., 1998; Collin et al., 2013; Mitelman et al., 2005; Mitelman et al.,
2006] and CT [Narr et al., 2005; Zhang et al., 2012] has been reported in individuals
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with mental disorders, such as schizophrenia. However, relatively fewer studies have
investigated SC in ASD than other mental disorders. Sato et al. [2013] reported the
influence of SC on ASD by demonstrating the association between the whole-brain
average of inter-regional CT correlations and symptom severity in ASD individuals.
Given the abnormal developmental trajectory of CT and the potential influence of SC
on ASD, this study investigated the SC of the CT within the MNS network.
White matter integrity is also essential for the MNS network to process
information. The left arcuate fasciculus (AF) connects Brocas area in the IFG,
Geschwinds area in the IPL, and Wernickes area in the posterior superior temporal
gyrus [Catani et al., 2005]. It has been reported to manifest higher radial diffusivity in
patients with ASD [Fletcher et al., 2010]. Reduced left lateralization in ASD patients
has been found in language-related tracts [Fletcher et al., 2010; Lange et al., 2010; Lo
et al., 2011; Nagae et al., 2012]. Considering the interhemispheric connections,
altered white matter integrity of the frontal and parietal parts of the callosal fiber
tracts has been found in ASD [Lo et al., 2011; Shukla et al., 2011]. These findings
imply that disturbed white matter integrity is related to the MNS network. However, it
remains unknown as to how the integrity of the tracts connecting the specific MNS
regions is associated with deficient social performance in ASD.
The purpose of this study was to investigate the CT and tract integrity to clarify
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gray and white matter abnormalities in the MNS of individuals with ASD. The MNS
is closely related to human communication functions and Tager-Flusberg [2000]
reported the reciprocity of influenced communication and social abilities in
individuals with ASD. Furthermore, the newly release of DSM-5 includes deficits in
social communication and social interaction as one of two essential symptom domains
[American Psychiatric Association, 2013]. Thus, we hypothesized that individuals
with ASD will show altered structural indices in the MNS compared to TD
individuals and that the structural alterations will be associated with impaired social
functions, especially social communication. The structural indices of ASD and TD
individuals were directly compared and the SC patterns of the CT were explored to
determine the developmental coordination of the two groups. The correlations
between the structural indices and the patients social-related symptoms were also
investigated.


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2. Materials and Methods
2.1 Participants
This study was approved by the Research Ethics Committee of the National
Taiwan University Hospital (approval number: 200903062R, Clinical Trials
gov.number: NCT00916851). The purpose and procedures were clearly explained to
the participants and their parents. Written informed consent was obtained from the
participants and the parents of the participants under 20 years. All of the participants
underwent a clinical assessment and an MRI study.
We recruited 30 Taiwanese adolescents and young adults with ASD (aged 15-26
years, full scale intelligence quotient (IQ) above 70, and clinically assessed as cases
of high-functioning autism) from the Department of Psychiatry, National Taiwan
University. We also recruited 30 TD age-matched controls (aged 14-25 years). The
participants with ASD were clinically diagnosed according to the Diagnostic and
Statistical Manual of Mental Disorders-IV (DSM-IV) and the International
Classification of Diseases-10 criteria by the corresponding author (SSG), a senior
child psychiatrist. The diagnoses were confirmed by the Chinese version of the
Autism Diagnostic Interview-Revised (ADI-R), which was approved by the Western
Psychological Services in 2007 [Gau et al., 2010; Rutter et al., 2003b].
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The TD participants were recruited if they did not have any current or lifetime
DSM-IV psychiatric disorders, as assessed by the Chinese version of the Kiddie
epidemiologic version of the Schedule for Affective Disorders interview [Gau et al.,
2005]. The TD participants were excluded if they had any past or current medical or
neurological illnesses, or currently took psychotropic medication. If any of their
relatives were suspected of ASD, such as Aspergers, pervasive developmental, or
autistic disorders, they were excluded from the study.
The subjects IQ scores were assessed with the Wechsler Intelligence Scale, 3rd
edition. There were no significant differences in the full-scale IQ (p = 0.061),
performance IQ (p = 0.12), and verbal IQ (p = 0.083) scores of the 27 ASD
individuals and 29 TD individuals (Table 1).
2.2 MRI data acquisition
Images were acquired on a 3T MRI system (Trio, Siemens, Erlangen, Germany)
with a balanced number of 32-channel and 16-channel phased array head coils in two
groups ( !! = 0.148, p = 0.7). Head movement was restricted with expandable foam
cushions and was assessed immediately after image acquisition. To obtain anatomical
references for diffusion MRI coregistration and CT information, high-resolution T1-
weighted MR images were acquired covering the whole head with a 3D
magnetization-prepared rapid gradient echo (MPRAGE) sequence (repetition time
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(TR)/echo time (TE) = 2530 / 3.4 ms, flip angle = 9, field of view = 256 !192 ! 208
mm
3
, acquisition matrix = 256 !192 ! 208), resulting in an isotropic spatial resolution
of 1 mm
3
. Multiple trans-axial T2-weighted MR images were acquired with a fast spin
echo sequence (TR/TE = 5920/102 ms, flip angle = 150, 256 ! 256 acquisition
matrix, field of view = 250 ! 250 mm
2
and slice thickness = 3.9 mm).
2.3 Diffusion MRI acquisition
Diffusion spectrum imaging (DSI) was performed using a pulsed-gradient spin-
echo diffusion echo planar imaging sequence with a twice-refocused balanced echo
[Reese et al., 2003]. DSI was used to resolve crossing fibers and obtain more reliable
tractography results. To reduce the scan time, we acquired half of the datasets with
102 diffusion-encoding directions, which corresponded to grid points in the half
sphere of the q-space within a radius of three units [Kuo et al., 2008]. The parameters
were bmax = 4000 sec mm
-2
, TR/TE = 9600/130 ms, slice thickness = 2.5 mm, in-
plane resolution = 2.5 mm, and scan time = 16 min. As the data in the q-space were
real and symmetrical about the origin, the acquired half-sphere data could be
projected to fill the other half of the sphere [Kuo et al., 2013]. The probability density
function was acquired by performing a 3D Fourier transformation. The orientation
distribution function in 362 radial directions was obtained by computing the second
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moment of the probability density function along each corresponding direction
[Wedeen et al., 2005].
2.4 Assessment of social communication
The Chinese version of the Social Communication Questionnaire (SCQ) was used to
assess the severity of the ASD participants autistic symptoms. The Chinese SCQ is a
40-yes/no-item screening tool based on the ADI-R algorithm, which corresponds to
the DSM-IV diagnostic criteria. It is designed for parents or caregivers to report on
the core ASD symptoms of patients. A higher score indicates more severe symptoms
[Rutter et al., 2003a]. The Chinese SCQ has been approved by the Western
Psychological Services [Gau et al., 2011]. The factor structure is the same as in the
original version: reciprocal social interaction, social communication, and restricted,
repetitive, and stereotyped patterns. Based on our hypothesis and previous studies
showing that the MNS is mainly related to social interactions and communication
with others, we selected these two subscales to investigate the correlations between
the MNS structures and deficits in ASD individuals social interaction and
communication.
2.5 MRI data analysis
2.5.1 Whole brain segmentation and CT calculation
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Freesurfer V5.1.0 (https://surfer.nmr.mgh.harvard.edu/) was used on a 64-bit Linux
operating system to reconstruct the cortical surface from the MPRAGE images [Fischl,
2012]. A fully automatic process was performed, including skull striping, segmenting
each brain into white matter/gray matter/cerebrospinal fluid, automated Talairach
transformation, intensity correction, and delineation of gray/white/pial boundaries.
Whole brain segmentation [Fischl et al., 2002; Fischl et al., 2004] was performed. The
cortical parcellation units of the cortex were automatically identified and labeled
according to the Desikan atlas [Desikan et al., 2006] within the freesurfer automatic
cortical parcellation routine. The CT was automatically calculated by computing the
shortest distance between the white matter boundary and pial surface at each vertex
[Fischl & Dale, 2000]. The reliability of the CT calculated by freesurfer has been
described [Han et al., 2006]. Each subjects results were checked using the freesurfer
Tkmedit viewer after the initial automatic reconstruction to ensure that the
segmentation was accurately performed and that there was no misregistration of gray
or white matter voxels. The automatic reconstruction and calculation were
reprocessed after manually correcting the detected erroneous part, if needed.
From the cortical parcellation file within the freesurfer software package, we
chose the bilateral Pop and supramarginal gyrus (Smg) as the regions of interest
(ROIs). The CTs of the four regions were recorded for further statistical analysis.
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2.5.2 Template-based tract-specific analysis
We used a template-based approach to analyze and compare the generalized
fractional anisotropy (GFA) values of the targeted tracts between the two groups. An
average DSI study-specific template (SST) was constructed and the transforming
matrices of the SST and each individual were calculated using the large deformation
diffeomorphic metric mapping DSI algorithm [Hsu et al., 2012]. White matter fiber
tracking was performed on this template using an in-house software DSI studio
(http://dsi-studio.labsolver.org) with the ROIs (bilateral Pop and Smg) as endpoints.
To increase the accuracy of the tracts of interest, we restricted the lengths of the two
bundles of corpus callosum (CC) fibers connecting the bilateral Pop (CC_Pop) and
bilateral Smg (CC_Smg) to between 70 mm and 130 mm, and the lengths of the tracts
connecting Pop and Smg on the left (lP_S) and right (rP_S) sides to between 50 mm
and 100 mm. The tracking stopped if the angle deviation was larger than 40
o
. The
tracts bundle was set to contain at least 1000 tracts (Figure 1).
Similar to the fractional anisotropy (FA) value in the diffusion tensor imaging
technique, the GFA value was calculated as an index of the integrity of the white
matter tracts. The GFA was quantified at each voxel of each subjects DSI data, based
on the directional variance of the original orientation distribution function [Tuch,
2004]. The coordinates of the tracts reconstructed on the SST were transformed to
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each individual DSI to sample the individual GFA values. The average GFA values
along each reconstructed tract in each individual were calculated for further statistical
analysis.
2.5.3 Combination of gray and white matter structural information
To analyze the CT and tract integrity under a compatible framework, the size,
shape, and position of the ROIs for CT calculation and for DSI fiber tracking must be
consistent between different imaging spaces. To perform tractography on the SST (see
2.2.2), we generated an average T1 image from all 60 subjects T1-weighted images
and performed whole-brain segmentation with freesurfer to extract the bilateral Pop
and Smg as ROIs. The ROIs on the average T1 space were then transformed to the
SST and the four tracts, CC_Pop, CC_Smg, lP_S, and rP_S, were reconstructed based
on the parameters described in 2.2.2. The positions of the ROIs (from freesurfer) and
tracts (from SST) were merged on each individual DSI to ensure the geometrical
consistency of the two structures (Figure 2).
2.5.4 Statistical analysis
Three ASD subjects and one TD subject were considered outliers because either
their CT or tract integrity results did not fall within 2.5 standard deviations of the
population mean. Therefore, 27 ASD and 29 TD subjects were used in the statistical
analysis. Two-sample t-tests were performed to compare eight structural indices (CT
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of the lPop, rPop, lSmg, and rSmg; and GFA values of the CC_Pop, CC_Smg, lP_S,
and rP_S) between the two groups.
To compare the two groups SC of the CT within the MNS, the Spearman rank
correlation was performed between the CT of each two ROIs, due to the small number
of subjects in each group (< 35). The false discovery rate (FDR) was used to modify
the p values into q values and to correct the multiple comparisons.
To investigate the correlation between the MNS structures and social deficiency
in ASD, the Spearman rank correlation was performed on each of the eight structural
indices and the social-related subscales assessed by the Chinese SCQ (see 2.1.4). To
correct the multiple comparisons, the FDR correction was conducted to obtain valid p
values (as q values).
The analysis was conducted with the SPSS software
(www.ibm.com/software/analytics/spss/ ).


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3. Results
3.1 Between-group comparisons
There were no significant differences in the CTs of the four ROIs between the
ASD and control groups. However, the ASD group in general had thicker CTs than
the TD group in all of the ROIs (Figure 3A, Supplementary table 1).
There were no significant differences in the tract integrity of the four tracts
(CC_Pop, CC_Smg, lP_S, and rP_S) between the two groups. However, the ASD
group had lower GFA values than the TD group for all of the tracts (Figure 3B,
Supplementary Table 1).
3.2 Structural co-variance of the CT within the MNS
In the TD individuals, the CT showed significant positive correlations between
most of the pairs of ROIs, except those between the rPop and lSmg. In the ASD group,
low insignificant correlations were found between the lPop and rPop, lPop and rSmg,
rPop and rSmg, and rPop and lSmg, indicating a weaker SC within the MNS in ASD
individuals (Figure 4).
3.3 MNS structure and social communication deficits in ASD patients
In adolescents and young adults with ASD, the social communication sub-scores
measured by the SCQ were significantly correlated with the GFA value of the rP_S (r
= -0.566, q = 0.016) (Figure 5) and marginally correlated with the GFA value of the
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lP_S (r = -0.423, q = 0.077) and the CT of the rPop (r = -0.421, q = 0.077)
(Supplementary Figure 1). We did not find any correlations between the social
interaction sub-scores and the eight structural indices within the MNS.


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4. Discussion
This study investigated the CT and tract integrity within the MNS and the
associated social deficits in adolescents and young adults with ASD. There are several
major findings. A reduced SC within the MNS of individuals with ASD implies that
the CT has an aberrant developmental trajectory in ASD. The social communication
sub-scores assessed by the SCQ were negatively correlated with the GFA values of
the rP_S tracts, suggesting the involvement of the right fronto-parietal tracts in ASDs
social communication deficits. Despite not reaching a significant level, the four core
MNS regions tended to have larger CT values and the GFA values of the four tracts
connecting the core regions tended to be lower in the autistic brains than in the TD
brains. Our results provide evidence to support the alteration of the MNS structures
and the MNSs involvement in impaired social communication in ASD.
4.1 Anatomical mirror neuron network revealed by SC of the CT
Brain areas that are highly correlated in size usually share common behavioral or
cognitive functions and this co-variance changes across the lifespans of TD
individuals [Alexander-Bloch et al., 2013]. Likewise, the SC of the CT between
specific areas can reflect an underlying structural connectivity between those brain
regions [Bassett et al., 2008; Bernhardt et al., 2011; Bernhardt et al., 2008; Chen et al.,
2008; He et al., 2007; Lerch et al., 2006] because the CT can reflect the size, density,
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and arrangement of cells [Narr et al., 2005; Parent & Carpenter, 1995]. The ASD
group had a weaker SC within the MNS than the TD group, indicating a difference in
the two groups cortical development. Distinctive developmental effects in ASD have
been widely discussed recently, both in structure [Schipul et al., 2011] and function
[Uddin et al., 2013]. The weaker SC pattern in the ASD group may have resulted from
the relatively moderate cortical thinning trend. The developing trend in the ASD
group in some core regions of the MNS was the reverse of that in the TD group
(Supplementary Figure 2).
4.2 Correlation between the MNS structure and social communication deficits in ASD
The significant negative correlation between the GFA values of the rP_S and the
social communication sub-scores indicates that as the white matter integrity of the
rP_S decreases, the impaired social communication in ASD becomes more severe.
Our results imply that the right fronto-parietal tracts have a distinctive role in
communication processing in individuals with ASD. The language function of the
right fronto-parietal pathway in ASD has been emphasized by several studies. Verly
et al. [2014] found that the absence of the right AF in adolescents with ASD
corresponded to lower verbal IQ scores and poorer receptive vocabulary and language
skills, as assessed by many language assessments. In contrast, those who had bilateral
AFs were within the normal range of functioning, indicating the importance of the
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right AF in ASD. Interestingly, they found that the communication abilities assessed
by the SCQ were impaired in all of the ASD patients, regardless of the presence or
absence of the right AF. Our results provide further information that although social
communication abilities are generally influenced in ASD patients, the tract integrity
of the rP_S is still associated with performance, pointing to the important role of the
right fronto-parietal tracts in processing social communication in ASD individuals.
The statistical significance of the negative correlation between the GFA values
of the lP_S and the social communication sub-scores was marginal (r = -0.423, q =
0.077) after a multiple comparison correction. Despite the distinctive role of the rP_S,
the left fronto-parietal tracts may thus also be involved in communication functions in
ASD. This is supported by an fMRI study in which ASD adults showed limited but
existing activation in the left Pop when making semantic decisions [Gaffrey et al.,
2007]. The role of the left fronto-parietal tracts in social deficits in ASD warrants
further investigation.
Another marginally significant correlation (r = -0.421, q = 0.077) after multiple
comparison correction was found between the right Pop CT and the social
communication sub-scores. Previous studies have reported that the cortical volume of
the right Brocas area is significantly larger than the left cortical volume in ASD
children with language impairment [De Fosse et al., 2004; Herbert et al., 2002;
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Herbert et al., 2005]. Joseph et al. [2014] also reported that the increased rightward
asymmetry of the Pop volume was associated with more advanced language abilities
in ASD children. The rightward developmental changes of the gray and white matter
structures in ASD may imply a mechanism for compensating in language and social
communication.
Although we found that some of the MNS structural indices were correlated with
social communication deficits in ASD, we did not find any significant correlations
between the MNS structures and social interaction sub-scores. Our results imply that
although aberrant MNS structures may directly influence ASD individuals social
communication abilities, their influence on social interactions may be indirect and
relatively smaller.
4.3 CT and tract integrity of MNS in ASD
There were insignificant differences between the CTs of the ASD and TD groups,
but the ASD group in general had thicker CTs. These results can be explained by the
atypical developmental trajectory of ASD individuals, compared with TD individuals.
In normal adolescents and adults, most brain areas CTs have been found to decrease
with age [Doyle-Thomas et al., 2013; Misaki et al., 2012; Scheel et al., 2011; Tamnes
et al., 2010]. Hogstrom et al. [2013] confirmed this phenomenon using 322 subjects,
ranging 20-85 years old. In contrast, individuals with ASD have thicker CTs across
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brain regions, including Pop and Smg [Ecker et al., 2013; Hyde et al., 2010], mainly
due to relatively moderate cortical thinning with age [Doyle-Thomas et al., 2013;
Misaki et al., 2012; Scheel et al., 2011]. As our subjects had a relatively wide age
range (15-26 years), we also found that the ASD adolescent participants had thinner
CTs than the TD adolescents, whereas the ASD adult participants had thicker CTs
than the TD adults, especially in the bilateral Pop (Supplementary Figure 2). This may
also explain the insignificant differences in the CT comparisons.
In terms of tract integrity, the interhemispheric tracts reconstructed in this study
belonged to the CC connecting the bilateral Pop and bilateral Smg. Although reduced
GFA values of the CC in ASD have been reported by both diffusion tensor imaging
[Alexander et al., 2007; Barnea-Goraly et al., 2004; Keller et al., 2007; Shukla et al.,
2011] and DSI [Lo et al., 2011] studies, many other studies have failed to find any
differences between ASD and TD subjects [Cheng et al., 2010; Hong et al., 2011].
According to a review of ASD diffusion tensor imaging studies, this discrepancy may
be due to sample heterogeneity such as IQ, cognitive ability, language ability, and
head circumference [Travers et al., 2012]. Although we chose high functioning ASD
patients (full-scale IQ above 70), the within-group IQ variance may still have been
large enough to cause the insignificant difference recorded.
The bilateral fronto-parietal tracts reconstructed in this study included a part of
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the AF, which is an indirect pathway connecting Brocas and Geschwinds territories,
lying lateral and parallel to the classical AF. The fronto-parietal tracts have been
reported to be particularly important in semantic processing and language
development in humans [Catani et al., 2005; Geschwind, 1970]. Known for its
involvement in social communication, the AF has been studied in ASD individuals.
However, the results have been inconsistent, showing reduced FA values in the
bilateral AF [Jeong et al., 2011; Shukla et al., 2011], only in the right AF [Poustka et
al., 2012], or only in the left AF [Jou et al., 2011]. This inconsistency may be due to
the complexity of the fiber geometry and within-group heterogeneity of verbal
abilities [Travers et al., 2012]. Unlike previous studies, we focused on the tracts
within the MNS. The insignificant differences in our results imply that this part of the
AF may not be significantly influenced by ASD. However, based on the inconsistent
results from previous studies, the individual heterogeneity in cognitive abilities
related to those tracts should be considered before making a conclusion regarding
abnormal white matter integrity in ASD.
Previous studies have reported different age-related changes in white matter
integrity in ASD and TD individuals. From normal adolescents to young adults, the
FA values of the CC and AF have been reported to increase with age [Barnea-Goraly
et al., 2005; Cheng et al., 2010; Kochunov et al., 2012]. However, individuals with
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ASD show decreasing FA values with age in the CC and SLF [Cheng et al., 2010].
We found obvious differences between the ASD and TD groups due to age effects on
the GFA in the CC_Pop, but not in the CC_Smg, lP_S and rP_S (Supplementary
Figure 3). The atypical developmental trajectory in ASD seems to happen mainly in
the frontal part of the MNS, including the bilateral Pop and the tracts connecting these
interhemispheric regions. Future studies should investigate the etiology of abnormal
gray and white matter development in the frontal regions of the autistic brains.
4.4 Limitations
This study demonstrates an altered structural MNS in ASD individuals and
correlations between some structural indices and impaired social communication.
However, our study has limitations. We were unable to compare the two groups
correlations between the structural indices and social behavior as the social
performance of the TD participants was not assessed. Future studies should compare
the correlations between brain structure and social function in TD and ASD
individuals.
The validity of choosing the MNS ROIs should also be considered. Although the
ROIs selected here have been consistently reported to be core MNS regions, the
accurate locations of the proposed mirror neurons may still differ from individual to
individual. Future studies should try to combine functional activity and structural
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connectivity within the MNS to confirm the locations of the mirror neurons and to
investigate the aberrant function and structure of the MNS in ASD.

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5. Conclusion
This study found aberrant SC of the CT and a significant correlation between the
integrity of the right frontal-parietal tracts and social communication performance in
adolescents and young adults with ASD. The findings imply an atypical
developmental trajectory of the MNS and underlying relationships between MNS
structures and social communication deficits in this population. Our study provides
insights into the structural alterations of the MNS and associated behavioral deficits in
ASD.

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Acknowledgments
This work was supported by the National Science Council of Taiwan (NSC98-3112-
B-002-004, NSC101-2627-B-002-002, NSC100-2321-B-002-015), National Taiwan
University Hospital (NTUH101-S1910), AIM for Top University Excellent Research
Project (10R81918-03, 101R892103, 102R892103), and the Ministry of Economic
Affairs (102-EC-17-A-19-S1-175).

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the motor system involved in speech production. Neuropsychologia, 41, 989-
994.
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Wedeen, V. J., Hagmann, P., Tseng, W. Y., Reese, T. G., & Weisskoff, R. M. (2005).
Mapping complex tissue architecture with diffusion spectrum magnetic
resonance imaging. Magnetic Resonance in Medicine, 54, 1377-1386.
Williams, J. H., Waiter, G. D., Gilchrist, A., Perrett, D. I., Murray, A. D., & Whiten,
A. (2006). Neural mechanisms of imitation and mirror neuron functioning in
autistic spectrum disorder. Neuropsychologia, 44, 610-621.
Williams, J. H., Whiten, A., & Singh, T. (2004). A systematic review of action
imitation in autistic spectrum disorder. Journal of Autism and Developmental
Disorders, 34, 285-299.
Williams, J. H., Whiten, A., Suddendorf, T., & Perrett, D. I. (2001). Imitation, mirror
neurons and autism. Neuroscience & Biobehavioral Reviews, 25, 287-295.
Wilson, S. M., Saygin, A. P., Sereno, M. I., & Iacoboni, M. (2004). Listening to
speech activates motor areas involved in speech production. Nature
Neuroscience, 7, 701-702.
Zhang, Y., Lin, L., Lin, C. P., Zhou, Y., Chou, K. H., Lo, C. Y., et al. (2012).
Abnormal topological organization of structural brain networks in
schizophrenia. Schizophrenia Research, 141, 109-118.


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Table 1. Demographic Features of the Participants

ASD (n = 27) TD (n = 29)
t or !
2
p
Mean SD Mean SD
Age (range, 15-26 years) 18.81 3.243 19.69 4.343 t =-0.82 .392
Handedness Right = 26 Right = 28 !
2
= 0.00 .959
Gender Male = 25 Male = 26 !
2
= 0.01 .940
Full-scale IQ 101.00 14.58 107.28 8.97 t = -1.92 .061
Performance IQ 100.67 16.00 106.38 10.65 t = -1.56 .120
Verbal IQ 101.56 16.03 107.72 8.57 t = -1.78 .083
SCQ
Reciprocal social interaction 11.96 5.72
Social communication 3.81 1.66
Total social-related score 15.78 6.27
ASD = autism spectrum disorder; TD = typically developing control; SD = standard
deviation; SCQ = social communication questionnaire.


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Figure 1. Template-based tractography results with bilateral pars opercularis (lPop,
rPop) and supramarginal gyrus (lSmg, rSmg) as regions of interest shown on the
average T1 template. The corpus callosum connecting the bilateral Pop (CC_Pop) and
bilateral Smg (CC_Smg) are shown in red. The bilateral fronto-parietal tracts
connecting the pars opercularis and supramarginal gyrus (lP_S, rP_S) are shown in
green. l = left; r = right.

Figure 2. Analysis of the CT and tract integrity. Freesurfer was used to calculate the
individual CT for group analysis. The four ROIs were obtained by segmenting the
average T1 image with freesurfer. These ROIs were transformed to DSI SST to
reconstruct four tracts within the MNS. Individual GFA values of the four tracts were
sampled for further group analysis. CT = cortical thickness; ROI = region of interest;
DSI = diffusion spectrum imaging; SST = study specific template; MNS = mirror
neuron system; GFA = generalized fractional anisotropy.

Figure 3. Between-group comparisons of (A) the CT of the lPop, rPop, lSmg, and
rSmg and (B) the GFA values of the CC_Pop, CC_Smg, lP_S, and rP_S. There are no
significant differences between the ASD and TD groups in the eight structural indices.
CT = cortical thickness; Pop = pars opercularis; Smg = supramarginal gyrus; GFA =
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generalized fractional anisotropy; CC = corpus callosum; P_S = fronto-parietal tracts
connecting Pop and Smg; ASD = autism spectrum disorder; TD = typically
developing control; l = left; r = right.

Figure 4. An SC matrix of the CT within the MNS in the ASD and TD groups. The
right upper part of the matrix represents the SC of the TD group, which shows
significant correlations between most of the paired regions within the MNS after FDR
correction, except between the rPop and lSmg. The left lower part of the matrix
represents the SC of the ASD group, which shows obviously weaker correlations
between the lPop and rPop, lPop and rSmg, rPop and rSmg, and rPop and lSmg. In
each element, the correlation coefficient (r) and significance of the correlation (q) are
listed. SC = structural co-variance; CT = cortical thickness; MNS = mirror neuron
system; ASD = autism spectrum disorder; TD = typically developing control; FDR =
false discovery rate; Pop = pars opercularis; Smg = supramarginal gyrus; l = left; r =
right.

Figure 5. A significant negative correlation between the rP_S GFA values and
communication sub-scores assessed by the SCQ was measured in the ASD group. P_S
= fronto-parietal tracts connecting the pars opercularis and supramarginal gyrus; GFA
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= generalized fractional anisotropy; SCQ = social communication questionnaire; ASD
= autism spectrum disorder; r = right.

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Figure 1. Template-based tractography results with bilateral pars opercularis (lPop, rPop) and supramarginal
gyrus (lSmg, rSmg) as regions of interest shown on the average T1 template. The corpus callosum
connecting the bilateral Pop (CC_Pop) and bilateral Smg (CC_Smg) are shown in red. The bilateral fronto-
parietal tracts connecting the pars opercularis and supramarginal gyrus (lP_S, rP_S) are shown in green. l =
left; r = right.
43x51mm (300 x 300 DPI)


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Figure 2. Analysis of the CT and tract integrity. Freesurfer was used to calculate the individual CT for group
analysis. The four ROIs were obtained by segmenting the average T1 image with freesurfer. These ROIs
were transformed to DSI SST to reconstruct four tracts within the MNS. Individual GFA values of the four
tracts were sampled for further group analysis. CT = cortical thickness; ROI = region of interest; DSI =
diffusion spectrum imaging; SST = study specific template; MNS = mirror neuron system; GFA =
generalized fractional anisotropy.
118x89mm (300 x 300 DPI)


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Figure 3. Between-group comparisons of (A) the CT of the lPop, rPop, lSmg, and rSmg and (B) the GFA
values of the CC_Pop, CC_Smg, lP_S, and rP_S. There are no significant differences between the ASD and
TD groups in the eight structural indices. CT = cortical thickness; Pop = pars opercularis; Smg =
supramarginal gyrus; GFA = generalized fractional anisotropy; CC = corpus callosum; P_S = fronto-parietal
tracts connecting Pop and Smg; ASD = autism spectrum disorder; TD = typically developing control; l =
left; r = right.
127x54mm (300 x 300 DPI)


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Figure 4. An SC matrix of the CT within the MNS in the ASD and TD groups. The right upper part of the
matrix represents the SC of the TD group, which shows significant correlations between most of the paired
regions within the MNS after FDR correction, except between the rPop and lSmg. The left lower part of the
matrix represents the SC of the ASD group, which shows obviously weaker correlations between the lPop
and rPop, lPop and rSmg, rPop and rSmg, and rPop and lSmg. In each element, the correlation coefficient
(r) and significance of the correlation (q) are listed. SC = structural co-variance; CT = cortical thickness;
MNS = mirror neuron system; ASD = autism spectrum disorder; TD = typically developing control; FDR =
false discovery rate; Pop = pars opercularis; Smg = supramarginal gyrus; l = left; r = right.
69x65mm (300 x 300 DPI)


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Figure 5. A significant negative correlation between the rP_S GFA values and communication sub-scores
assessed by the SCQ was measured in the ASD group. P_S = fronto-parietal tracts connecting the pars
opercularis and supramarginal gyrus; GFA = generalized fractional anisotropy; SCQ = social communication
questionnaire; ASD = autism spectrum disorder; r = right.
103x74mm (300 x 300 DPI)


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