Cerebral Cortex, March 2017;27: 1721–1731

doi: 10.1093/cercor/bhx038
Advance Access Publication Date: 18 February 2017
Original Article

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ORIGINAL ARTICLE

Cortical Thickness Abnormalities in Autism Spectrum

Disorders Through Late Childhood, Adolescence, and
Adulthood: A Large-Scale MRI Study
Budhachandra S. Khundrakpam, John D. Lewis, Penelope Kostopoulos,
Felix Carbonell and Alan C. Evans
Montreal Neurological Institute, McGill University, Montreal, QC, Canada H3H2P1
Budhachandra S. Khundrakpam and John D. Lewis equally contributed
Address correspondence to Budhachandra S. Khundrakpam, John D. Lewis. Email: budha@bic.mni.mcgill.ca (B.S.K.), john.d.lewis@mcgill.ca (J.D.L.)

Abstract
Neuroimaging studies in autism spectrum disorders (ASDs) have provided inconsistent evidence of cortical abnormality.
This is probably due to the small sample sizes used in most studies, and important differences in sample characteristics,
particularly age, as well as to the heterogeneity of the disorder. To address these issues, we assessed abnormalities in ASD
within the Autism Brain Imaging Data Exchange data set, which comprises data from approximately 1100 individuals
(~6–55 years). A subset of these data that met stringent quality control and inclusion criteria (560 male subjects; 266 ASD;
age = 6–35 years) were used to compute age-specific differences in cortical thickness in ASD and the relationship of any
such differences to symptom severity of ASD. Our results show widespread increased cortical thickness in ASD, primarily
left lateralized, from 6 years onwards, with differences diminishing during adulthood. The severity of symptoms related to
social affect and communication correlated with these cortical abnormalities. These results are consistent with the
conjecture that developmental patterns of cortical thickness abnormalities reflect delayed cortical maturation and highlight
the dynamic nature of morphological abnormalities in ASD.

Key words: autism spectrum disorders, cortical development, cortical thickness, delayed maturation, symptom severity

Introduction But a portion of these inconsistencies is likely due to small sample

Autism spectrum disorders (ASDs) consist of a collection of neuro-
developmental conditions characterized by difficulties with social
interactions and verbal and nonverbal communication, and by
repetitive behaviors. The neural basis for these behavioral abnor-
malities is as yet unclear; reporting both increases and decreases
in a variety of measures including cortical thickness (Hadjikhani
et al. 2006; Hyde et al. 2010; Jou et al. 2010; Wallace et al. 2010).
These inconsistencies are, to some extent, due to the fact that
ASD is a very heterogeneous disorder characterized by a wide
range of symptoms with varying severity and is often accompan-
ied by one of a number of comorbid conditions (Johnston et al.
2013; Kim et al. 2015; Grzadzinski et al. 2016; Kantzer et al. 2016).
sizes with important differences in sample characteristics, particu-
larly age. For example, Jou et al. (2010) examined children and ado-
lescents ranging from 10 to 16 years and observed greater cortical
thickness in ASD; while cortical thickness reductions were
observed in studies with adolescent and adult samples (Hadjikhani
et al. (2006): age = 21–45 years, Wallace et al. (2010): age = 12–24
years, Hyde et al. (2010): age = 14–34 years). ASD is a developmen-
tal disorder, and age-specific abnormalities might be expected, as
has been indicated in case of functional connectivity studies
(Uddin et al. 2013; Nomi and Uddin 2015).
Accumulating evidence from neuroimaging, as well as from
post-mortem studies, suggests accelerated growth in the first

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 1722 | Cerebral Cortex, 2017, Vol. 27, No. 3
years of development in ASD, with children achieving a near-
adult brain size considerably earlier than is the case for typically
developing children (Bauman and Kemper 1985; Piven et al. 1995;
Kemper and Bauman 1998; Courchesne et al. 2001; Courchesne
et al. 2003). Age-specific differences in brain size between indivi-
duals with ASD and controls have been shown using cross-
sectional and longitudinal magnetic resonance imaging (MRI)
(Courchesne et al. 2003, 2004; Hazlett et al. 2005; Schumann et al.
2010). This enlargement in brain size during childhood in ASD
suggests that there may also be more fine-grained age-specific
structural abnormalities in ASD (Courchesne et al. 2004;
Raznahan et al. 2010; Schumann et al. 2010; Zielinski et al. 2014).
Interestingly, there are reports of age-specific brain gene
expression in ASD that shed light on the possible mechanisms
involved in the age-related brain changes (Chow et al. 2012).
The authors used whole genome analysis in postmortem brain
samples, and showed dysregulated pathways governing cell
number, cortical patterning, and differentiation in young autis-
tic as opposed to dysregulated signaling and repair pathways in
adult autistic brains. Their results suggested age-specific gene
expression changes reflecting different processes in young ver-
sus adult autistic brains. A meta-analysis of several imaging
studies showed that although significant differences are appar-
ent in total gray matter (GM) volume for ASD compared with
typical controls, this difference is much larger in early child-
hood (~12% at 2 years) compared with early adulthood (~2% at
19 years) (Amaral et al. 2008). Imaging studies have explored
the trajectories of cortical anatomy (initial studies using GM
volume, with recent studies focusing on cortical thickness)
across childhood and adolescence in typical development and
autism (Courchesne et al. 2001; Raznahan et al. 2010; Doyle-
Thomas et al. 2013; Ecker et al. 2014; Zielinski et al. 2014; Lange
et al. 2015; Wallace et al. 2015). Although some studies have
examined linear models (Raznahan et al. 2010; Wallace et al.
2010; Doyle-Thomas et al. 2013), many studies have demon-
strated nonlinear models (cubic and quadratic) of cortical tra-
jectories in normal brain development (Shaw et al. 2006, 2008).
Shaw et al. (2008) indicated that cubic models of age were the
best fit for cortical trajectories in the neocortex as opposed to
linear trajectories in the allocortex. Moreover, developmental
trajectories based on cubic models were sensitive to levels of
intelligence: children with higher intelligence quotient (IQ) dis-
played initial accelerated and protracted phase of cortical thick-
ness increase followed by equally dynamic cortical thinning
(Shaw et al. 2006). Earlier studies have examined nonlinear age
models of cortical thickness in ASD (Ecker et al. 2014; Zielinski
et al. 2014). In 154 male individuals (77 ASD) ranging from 7 to
25 years of age, Ecker et al. (2014) observed that models with
quadratic age effects were the best to investigate age-related
group difference in cortical thickness. They also observed thinner
cortices during childhood followed by increased cortical thickness
during adulthood in subjects with ASD. Using longitudinal MRI
scans of 97 males with ASD (age = 3–36 years) and 60 typically
developing males (age = 4–39 years), Zielinski et al. (2014) showed
quadratic age trajectories and suggested that the etiology of ASD
followed 3 phases: accelerated expansion in early childhood,
accelerated thinning in late childhood and adolescence, and
lastly, decelerated thinning in early adulthood. Taken together,
the few prior studies investigating cortical trajectories in autism
were important initial steps toward better understanding the
etiology of autism, and they further emphasize the need for
studying complex developmental trajectories in autism.
Although a large sample size comprised longitudinal data
acquired with a single acquisition protocol would be ideal for the
study of developmental trajectories in ASD (Zielinski et al. 2014),
such data are not publicly available, and there are practical dif-
ficulties in conducting such a study in a single laboratory.
Realizing the need for multi-center acquisition and open sharing
of data, the Autism Brain Imaging Data Exchange (ABIDE) is a
grass-roots initiative that provides data collected from 16 sites (Di
Martino et al. 2014). It comprises MRI scans from over 500 indivi-
duals with ASD and 500 age-matched controls (age ranging from
6 to 55 years). In the present study, these data were subjected to
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a stringent quality control (QC) and strict inclusion criteria that
assured appropriate distribution of subjects across sites. Cortical
thickness was measured in the surviving data (N = 560; 266 ASD)
at 81 924 vertices covering the entire cortex, enabling us to inves-
tigate age-specific differences at the vertex level. We then
explored group differences in cortical thickness of individuals
with ASD and of typical controls within this data set. Based on
literature discussed in preceding paragraphs (e.g. Courchesne
et al. 2004; Redcay and Courchesne 2005; Amaral et al. 2008;
Raznahan et al. 2010; Ecker et al. 2014; Zielinski et al. 2014;
Lange et al. 2015; Wallace et al. 2015), we predicted age-
specific cortical abnormalities in ASD, predominantly in
frontal and temporal regions; and we predicted that cortical
regions with abnormalities would show behavioral associa-
tions, for example with autism symptom severity. Contrary
to null findings (no group difference) of a previous study
using the ABIDE database (Haar et al. 2014), we observed age-
specific cortical abnormalities. Consistent with the principle
of open data-sharing (Belmonte et al. 2008), all processed
data used in this study have been made publicly available
(http://preprocessed-connectomes-project.github.io/abide/).
Materials and Methods
Subjects
Data (1099 structural MRI scans) were downloaded from the
ABIDE database (http://fcon_1000.projects.nitrc.org/indi/abide/).
QC of these data was performed by 2 independent reviewers
(Fig. 1, described in the next section). Of the total 1099 subjects,
721 subjects (males/females = 610/111) passed the QC proced-
ure. Next, we excluded sites for which there were not enough
individuals in each category (ASD and controls) to determine
Raw T1-MRI Scans
N = 1099
ASD/CTL = 517/582
QC Steps
QC Not-Passed Subjects
* Motion
n = 378 (ASD/CTL = 190/188)
* Surface-Surface Intersection
* Failed (n = 211)
* GM and WM Surfaces
* Questionable (n = 167)
* Blood Vessels
QC-Passed Subjects
Total: N = 721
Males/Females = 610/111
ASD/CTL = 327/394
Remove scans from
underrepresented sites
Males (upto 35 years): N = 560
ASD/CTL = 266/294
Figure 1: Details of QC during preprocessing of MRI scans. CTL refers to typical
controls, GM and WM refer to gray and white matter, respectively.
 Cortical Thickness Abnormalities in Autism Spectrum Disorders Khundrakpam et al. | 1723

Table 1 Site-subject distribution of the subjects used in the study

Site Scanner Subjects (N) Age ASD/CTL

LEUVEN (University of Leuven) INTERA 55 12.1–32 25/30

NYU (New York University) ALLEGRA 127 8–31.7 60/67
OHSU (Oregon Health and Science University) TRIOTIM 27 8–15.3 13/14
OLIN (Olin Center, Institute of Living) ALLEGRA 19 10–23 10/9
PITT (University of Pittsburgh) DK 44 9.3–33.4 22/22
TRINITY (Trinity College) DK 47 12–25.9 23/24

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UM (University of Michigan) DK 66 8.5–28.8 29/37
USM (Utah School of Medicine) TRIOTIM 77 8.7–33.9 37/40
UCLA (University of California, Los Angeles) TRIOTIM 34 10.4–17.9 19/15
YALE (Yale School of Medicine) TRIOTIM 15 7.6–17.8 9/6
CALTECH (California Institute of Technology) TRIOTIM 20 17–28.1 12/8
MAX_MUN (Ludwig Maximilians University Munich) VERIO 29 6.4–34.8 10/19

Table 2 Demographics of the subjects used in the study

N Age FSIQ ADOS Soc ADOS Comm ADOS severity

Control 294 17.0 (6.4) 111.9 (12.1)

6.5–35.0 80–148
ASD 266 17.2 (6.4) 106.4 (15.8)
7.1–35.0 70–148
ASD (with ADOS) 218 17.3 (6.6) 106.1 (14.2) 6.9 (3.6) 3.3 (1.8) 5.4 (2.3)
7.3–34.8 73–145 0–14 0–8 1–9

Means, with standard deviation given in parentheses, and second row denotes the range. FSIQ, full-scale IQ; ADOS Soc, Autism Diagnostic Observation Schedule
Social; ADOS Comm, ADOS Communication. Note: ASD refers to total number of subjects categorized as autistic, while ASD (with ADOS) refers to a subset of the ASD
subjects with concurrent measures of ADOS Soc and ADOS Comm.

the group difference. In some cases, there were too few indivi-
duals with ASD; in some cases, there were too few controls. In
some cases, there were too few females. This resulted to
excluding all of all females. Additionally, since the age distribu-
tion was nonuniform, with few subjects over 35 years of age,
we limited our sample to those under 35 years of age. In the
end, our sample comprised 560 male subjects, of which 294
were controls (17 ± 6.4 years) and 266 were individuals with
ASD (17.2 ± 6.4 years). The details of the QC steps and site dis-
tribution for all the subjects used in the study are presented in
Figure 1 and Table 1. The demographics of the resulting sub-
jects as well as the subject-site distribution used for the study
are given in Table 2 and Figure 2.
Criteria for ASD diagnosis were identical to previous reports
(Di Martino et al. 2014). In brief, ASD diagnoses were reached
by combining clinical judgment and diagnostic instruments—
Autism Diagnostic Observation Schedule (ADOS) and/or
Autism Diagnostic Interview-Revised (ADI-R). Some sites had
Figure 2. Subject-site distribution for the study. ASD cases are shown as red
missing information for the ADOS scores; and therefore, a sub-
crosses, and typical controls as blue circles. See Table 1 for the full site names.
set (n = 218) of the total data (n = 266) used for the group differ-
ence analysis was utilized for behavioral correlates within the
ASD group (see Table 2). ICBM152 data set). The nonuniformity correction was then
repeated using the template mask. The nonlinear registration
from the resultant volume to the MNI152 template was then com-
Cortical Thickness Measurements
puted, and the transform used to provide priors to segment the
The CIVET processing pipeline (http://www.bic.mni.mcgill.ca/ image into GM, WM, and cerebrospinal fluid. Inner and outer GM
ServicesSoftware/CIVET), developed at the Montreal Neurological surfaces were then extracted using the Constrained Laplacian-
Institute, was used to compute the cortical thickness measure- based Automated Segmentation with Proximities (CLASP) algo-
ments. A summary of the steps involved follows; the steps are rithm, and cortical thickness was measured in native space using
detailed elsewhere (Khundrakpam et al. 2015). The T1-weighted the linked distance between the 2 surfaces at 81 924 vertices.
image was first nonuniformity corrected, and then linearly regis- Each subject’s cortical thickness map was blurred using a 30-mm
tered to the Talairach-like MNI152 template (established with the full width at half maximum surface-based diffusion smoothing
 1724 | Cerebral Cortex, 2017, Vol. 27, No. 3
kernel to impose a normal distribution on the corticometric data,
and to increase the signal to noise ratio.
QC process was performed after running the CIVET pipe-
line. The 2 independent reviewers rated the data in scores of
“0 = failed, 1 = questionable, 2 = passed” on the following cri-
teria: the presence of motion artifacts, low signal to noise
ratio, artifacts due to hyper-intensities from blood vessels,
large number of surface–surface intersections, poor placement
of the GM and WM surface (Fig. 1).
Statistical Analyses
In order to determine age-related abnormalities in cortical
thickness, group differences in cortical thickness were assessed
at each vertex, with the data centered at 1-year intervals
between 6 and 35 years (with age as a continuous variable). The
spatial multiple comparisons were dealt with via a false discov-
ery rate correction (Benjamini and Hochberg 1995); the tem-
poral multiple comparisons were dealt with via a Bonferroni
correction (Bonferroni 1935).
As a first step, we explored models with linear, quadratic,
and cubic age effects. For this, the best fit model was selected
using Akaike information criterion (AIC) (Akaike 1974). AIC was
used to penalize the added parameters, and the model with the
lowest AIC value was selected. Models with cubic age terms
which had the lowest AIC values were, therefore, selected.
Next, cortical thickness was modeled as follows:
Ti = Intercept + β1 Site + β2Group + β3 Age + β4 (Age × Group)
+ β5 Age2 + β6 ( Age2× Group) + β7 Age3 + β8 ( Age3× Group) + ε i
where i is a vertex, Age is centered as described above, ε is the
residual error, and the intercept and the β terms are the fixed
effects. All statistical analyses were done with general linear
models, using the SurfStat toolbox (http://www.math.mcgill.ca/
keith/surfstat/).
The main effect of diagnostic group was assessed with the
data centered at each integer age between 6 and 35, and regions
of cortex were identified that showed statistically significant
differences (FDR and Bonferroni corrected for multiple compari-
sons) in cortical thickness between individuals with ASD and
typical controls. This provides a 4D map of the group differ-
ences in cortical thickness.
To further characterize the differences in the trajectories of
cortical thickness in the 2 groups, we identified the vertex with
the maximum t-statistic at any age within each of the areas
showing significant group differences. At each of these vertices,
we fit cubic polynomial curves to the thickness data for both of
the groups separately. In order to mitigate the effects of outliers
within the relatively sparse data at either end of the age range,
the end-points of the fit lines were constrained by the group
means of the 10% of the subjects closest in age to each end of
the range. It may be noted that constraining end-points of the
fit lines was done in the group comparisons.
Cortical Thickness and Symptom Severity
We next did a post hoc analysis to explore whether the clus-
ters with age-related cortical abnormalities show a relation
between cortical thickness and the severity of symptoms
associated with ASD. In order to fully characterize the influ-
ence of the fitted curve, we obtained residual cortical thick-
ness (difference of measured cortical thickness from the
corresponding value in the fitted curve at the vertices with
maximum t-statistics within each cluster). For the behavioral
scores, the social and communication domain of the ADOS
was used (Lord et al. 2000). The raw ADOS scores were con-
verted to calibrated symptom severity scores as a function of
raw score, module, and age, as specified in Hus et al. (2013)
and Hus and Lord (2014). Pearson correlation coefficients were
then used to investigate the correlation between residual cor-
tical thickness and the symptom severity scores.
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Results
Increased Cortical Thickness in ASD During
Development
We first analyzed group difference in mean cortical thickness at
the mean sample age (adjusted for age and site). We observed
increased cortical thickness (F = 6.21, df = 1577, P = 0.01) for the
ASD compared with the control group.
Next, we estimated age-specific group differences in cortical
thickness maps for ASD and controls by centering the data at
1-year intervals between 6 and 35 years. Increased cortical thick-
ness in children with ASD versus typical controls was observed in
several cortical regions from 6 years onwards until about 20 years
(see t-maps in upper panel of Figure 3 and accompanying
Supplementary Video). Significant group differences (P < 0.05, cor-
rected for multiple comparisons across age bins), were present for
ages 6–14 years across broad regions of cortex, predominantly in
the left hemisphere (Fig. 3, lower panel). These group differences
were maximal at around 10 years of age, and faded to nonsignifi-
cance during adolescence. There were no areas showing signifi-
cantly increased cortical thickness in controls at any age. It may
be noted that in our model (which included linear, quadratic, and
cubic age effects and their interactions with group), few cortical
regions showed significant linear interactions.
Age-Specific Abnormalities of Cortical Thickness in ASD
A single t-map for all age bins was obtained (see Methods)
showing clusters of vertices with significant group difference
(center panel of Fig. 4). Table 3 locates these cortical clusters
based on their spatial coordinates, using a more stringent
threshold (P < 0.01) to provide greater precision. These cortical
clusters are located predominantly in the left hemisphere, in
the inferior and precentral gyri of the frontal lobe, postcentral,
and supramarginal gyri of the parietal lobe, middle, and super-
ior temporal and fusiform gyri of the temporal lobe, and the
anterior of the inferior and middle occipital gyri of the occipital
lobe. Note that many of these regions lie adjacent to the left
arcuate fasciculus. Right hemispheric regions included the
superior and inferior frontal gyri, medial prefrontal gyrus, pre-
cuneus, and fusiform gyrus.
Next, growth curves of the cortical thickness data were fitted
at the vertices with maximum t-statistics within each cluster that
showed a significant group difference (Table 3; Fig. 4). Across all
clusters, there was a similar pattern: in typically developing indi-
viduals cortical thickness gradually declines during adolescence;
whereas in individuals with ASD, this decline is more rapid.
Abnormalities in Cortical Thickness Predict Symptom
Severity in ASD
In our post hoc analysis for behavioral correlates, significant
positive correlations (P < 0.05) between residual cortical thickness
and the social affect and communication symptom severity
scores were observed in the left precentral and postcentral gyri,
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Figure 3. Group differences in cortical thickness between the ASD and control groups. The t-statistics (across vertices on the surface) and multiple comparison-
corrected P-statistics (across age bins) for the group differences (ASD–CTL) in cortical thickness across time. The statistics are shown as surface maps, with lateral
views of the left and right hemispheres shown for both statistics. The upper 2 rows of surface maps show the t-statistics for the group differences at ages ranging
from 6 to 35 years of age, with age increasing from left to right, and the left hemisphere shown above the right hemisphere. The lower 2 rows show the significant
P-statistics (P < 0.05, corrected for multiple comparisons across the age bins, see Methods) for the group differences. Note that ASD shows increased cortical thickness
compared with controls until mid-adolescence in regions of the left frontal, temporal, parietal, and occipital cortex, and the right frontal cortex. No significant group
differences are observed thereafter. Note also that all significant group differences were increased cortical thickness in ASD; there were no cortical regions with sig-
nificantly decreased cortical thickness in ASD compared with controls. CTL = controls. LH and RH denote left and right hemispheres, respectively. The numbers above
the top row of surface maps indicate the age (in years) for the statistics depicted in that column.

left supramarginal and fusiform gyri, right inferior frontal and
middle frontal gyri, and bilateral inferior frontal gyri (Fig. 5).
Again, note the overlap with the left arcuate fasciculus.
Discussion
Neuroimaging studies of cortical structure in ASD have shown
both increased and decreased cortical thickness as well as null
results (Hadjikhani et al. 2006; Hardan et al. 2006; Amaral et al.
2008; Haar et al. 2014). Small sample sizes and the large hetero-
geneity of the disorder are likely a portion of the issue, but
given that ASD is a developmental disorder, differences in the
age ranges of the samples need to be carefully examined
(Uddin et al. 2013; Nomi and Uddin 2015). To investigate the
relationship between age and abnormalities in cortical thick-
ness, we analyzed the large ABIDE data set using stringent QC
procedures to remove a significant proportion of MRI scans that
had serious motion artifacts or other issues that would affect
data quality. The final sample consisted of MRI scans from 266
individuals with autism and 294 age-matched controls span-
ning 6–35 years of age. This large age range allowed us to
assess group differences in cortical thickness throughout this
swath of life. We measured cortical thickness at the same
81 924 locations for all subjects, and fitted models with cubic age
terms to the cortical thickness measures. Our analysis revealed a
dynamic pattern of group differences, with significantly increased
cortical thickness in children with ASD over broad regions of
cortex, but with differences fading over adolescence to virtually
identical cortical thickness by 35 years of age. Our analysis of
the fitted growth curves in each of the regions with significant
group differences indicated that the dynamic pattern of group
differences was the result of more rapid cortical thinning in
ASD after an initial delay in the cortical thinning seen in typic-
ally developing children (Hadjikhani et al. 2006; Ducharme
et al. 2016; Mills et al. 2016; Walhovd et al. 2016). Moreover, sev-
eral of the regions showing these abnormal growth curves also
showed a relation between these abnormalities and the sever-
ity of their social affect and communication autism symptoms,
with greater morphometric abnormality associated with greater
symptom severity. Thus, the increased cortical thickness dur-
ing development appears to be a functionally significant aspect
of the disorder.
The biological meaning of the increased cortical thickness
seen in children with ASD using MRI is, however, not strictly a
reflection of cortical differences; rather, given that MRI-based
measures of cortical thickness are based on the placement of
the white and pial surfaces on the MRI image, it is likely a
reflection of differences in both GM and WM. The increased
cortical thickness measures in ASD could arise from various
microstructural GM changes, such as a greater number or larger
neurons or glia, increased dendritic arborization, potentially with
a greater number of synapses, larger or more axons, or greater
capillary support (Huttenlocher 1991; Chklovskii 2004; Muotri and
Gage 2006) or differences in the WM at the inner-edge of cortex
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Figure 4. Fitted growth curves of cortical thickness in autism group and typical controls. The center panel shows a surface map of the cortical regions for which there
were significant group differences in cortical thickness (ASD and CTL). The scatter plots around the periphery show the curves fit to the cortical thickness data for
each group at the vertices with the maximum t-statistics within each region showing a significant group difference (hence, the clusters of cortical regions resulted
from all the analyses across ages, see Methods and Table 3). Note, x-axis = age (years), y-axis = cortical thickness (mm), L = left hemisphere, R = right hemisphere.

that reflect reductions in the degree of myelination or the num-
ber of myelinated axons projecting into or out of cortex; or a rela-
tive increase in myelin adjacent to the cortex, for example in the
U-fibers.
There is evidence of abnormality in autism for several of
these potential contributors to the observed changes in MRI-
based cortical thickness. Children and adolescents with ASD
have been shown to have an abnormally high number of synap-
tic spines and reduced developmental synaptic pruning (Tang
et al. 2014). The synaptic pruning deficits have further been asso-
ciated with impaired macroautophagy: improper elimination of
damaged synapses (Tang et al. 2014). This appears linked to find-
ings of greater microglial cell density and somal volume in ASD
from childhood through adulthood in GM (and WM) (Morgan
et al. 2010; Suzuki et al. 2013; Petrelli et al. 2016). This evidence of
reduction in the rate of developmental synaptic pruning in ASD
is mirrored by evidence of a reduction in neuron size in early
childhood in ASD, and an increase in neuron number, with both
neuron size and number normalizing during adolescence and
adulthood (Courchesne et al. 2011; Azmitia and Impallomeni
2014; Wegiel et al. 2014, 2015). There is also evidence of excess
neuronal cell bodies in the subplate (within the WM beneath the
cortical plate) of ASD subjects possibly due to reduced apoptosis
or migration deficits (Hutsler and Casanova 2016). These abnor-
malities in neuron number are reflected in WM. Measures of
myelination in young children with autism are elevated with
respect to controls (Gozzi et al. 2012), a trend that normalizes
later in development (Deoni et al. 2015).
Knowledge of typical brain development is critical to under-
standing the dynamic nature of the abnormalities. Brain vol-
ume increases 4-fold during postnatal development, and this
increase is seen in both the GM and WM. These increases, how-
ever, belie a host of regressive processes, as well progressive
processes, overlapping in time, some of which extend into ado-
lescence and even adulthood (Petanjek et al. 2011). For example,
synaptic pruning begins around birth and continues into adoles-
cence, myelination begins around birth and continues into the
third decade of life, and increases in axon caliber begin pre-
natally and continue into adolescence. These processes are, to a
degree, independent. Differences in the balance or timing of
these processes might alter various MRI-derived brain measures,
including cortical thickness.
In this light, it is interesting to consider our findings of
increased cortical thickness during childhood and adolescence
 Cortical Thickness Abnormalities in Autism Spectrum Disorders Khundrakpam et al. | 1727

Table 3 Cortical regions with altered trajectories in autism com- the connectivity between these regions, develop more rapidly
pared with typical controls than their right hemisphere counterparts (Dubois et al. 2009).
This asymmetric development is most prominent for language-
Area label BA Stereotaxic T P
related cortex and connections, for example Broca’s area,
coordinates
Wernicke’s area, and the arcuate fasciculus, and has been linked
(MNI space)
to language development and lateralization (Vernooij et al. 2007).
x y z Increased cortical thickness in children with ASD was seen in
Broca’s area, Wernicke’s area, and in all cortical regions adjacent
Left hemisphere
to the arcuate fasciculus: the pars triangularis, pars opercularis,
Postcentral gyrus 2 −59 −28 45 5.7 1.3E-05

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the inferior end of the precentral and postcentral gyrus, the
Inferior frontal gyrus 46 −42 51 9 5.5 4.6E-05
supramarginal and angular gyri, and the superior temporal gyrus.
Supramarginal gyrus 40 −54 −36 30 5.1 0.0002
Both the progressive and regressive processes that comprise cor-
Precentral gyrus 6 −52 −5 29 5.1 0.0002
Middle temporal gyrus 21 −58 −11 −6 4.7 0.0018
tical development are activity-driven, and thus the increased cor-
Inferior occipital gyrus 19 −39 −72 −6 4.6 0.0024 tical thickness in these language-related regions likely reflects
Superior temporal gyrus 21 −62 −16 −1 4.5 0.0045 their language delays/deficits. This conjecture is supported by
Middle occipital gyrus 19 −32 −82 6 4.4 0.0075 the fact that the severity of social and communication symptoms
Fusiform gyrus 37 −16 −67 −1 4.3 0.0089 was related to cortical thickness in many of the regions in which
Right hemisphere cortical thickness was abnormally increased in children with
Middle frontal gyrus 6 38 12 57 5.1 0.0003 ASD, with regions adjacent to the left arcuate fasciculus showing
Inferior frontal gyrus 46 47 45 1 4.7 0.0015 both some of the greatest abnormalities in cortical thickness and
Precuneus 31 19 −68 25 4.7 0.0015 the strongest relationships between these abnormalities and
Fusiform gyrus 37 24 −71 −5 4.4 0.0072 symptom severity.
Medial prefrontal cortex 8 3 35 47 4.4 0.0076 The anterior portion of the right hemisphere homolog of
Broca’s area also showed both greater than normal cortical
Peak vertices of cortical regions of significant group difference (ASD–CTL) (max- thickness, and a relation between cortical thickness and symp-
imum T-statistics with P < 0.01) are shown (for details, see Online Methods).
tom severity, possibly reflecting a delay in the typical lateraliza-
Note BA, Brodmann area; CTL, typical controls.
tion of language.
Individuals with ASD also often show sensori-motor abnor-
malities (Gal et al. 2002; Leekam et al. 2007; Jasmin et al. 2009;
together with the pattern of early brain overgrowth seen in ASD. Lloyd et al. 2013). Greater than normal cortical thickness was
Post-mortem studies (Bauman and Kemper 1985; Kemper and found in both the left primary motor cortex, and in bilateral
Bauman 1998), head circumference measures (Courchesne et al. premotor cortex, and cortical thickness was found to be related
2003; Hazlett et al. 2005) and MRI volumetric analyses (Piven to symptom severity. These regions have previously been
et al. 1995; Courchesne et al. 2001) have shown increased brain related to motor deficits in autism (Mostofsky et al. 2009; Nebel
size in children with ASD, but not adults. These larger-than- et al. 2014). Greater than normal cortical thickness was also
normal brains comprise greater-than-normal GM and WM found in sensory areas related to audition, touch, and vision:
(Courchesne et al. 2007; Amaral et al. 2008; Schumann et al. Heschl’s gyrus, the post-central gyrus, and peristriate area 19.
2010). The abnormal brain growth pattern begins in the first year These regions have previously been related to sensory process-
of life with a period of accelerated growth which continues dur- ing abnormalities in ASD (Brambillaa et al. 2004; Marco et al.
ing early childhood, achieving near-adult brain size earlier than 2011; Kaiser et al. 2016).
in typical development (Courchesne et al. 2003; Dementieva et al. Relatedly, individuals with ASD show difficulties with face
2005; Hazlett et al. 2005). This increased brain size relative to typ- processing (Schultz 2005; Dziobek et al. 2010), particularly with
ically developing children persists into adolescence (Redcay and the dynamic aspects of face processing, for example gaze
Courchesne 2005). The overlap with our findings of increased cor- (Dalton et al. 2005; Bedford et al. 2012). The regions involved
tical thickness during childhood and adolescence suggests that include the fusiform face area, the posterior portion of the
the processes that drive this brain overgrowth are reflected in superior temporal sulcus, and the frontal eye fields, each of
cortical thickness. Additionally, the fitted growth curves of the which has been implicated in ASD (Dalton et al. 2005; Takarae
cortical thickness data in each of the regions with significant et al. 2007). Greater than normal cortical thickness was found
group differences indicated that in ASD there is an initial delay in each of these regions, and cortical thickness was found to be
in the cortical thinning seen in typical development, followed by related to symptom severity.
more rapid than normal cortical thinning during adolescence. Given the inconsistencies in the findings of ASD studies, it is
This largely agrees with earlier trajectory-based studies of cor- important to discuss how our findings align with those of earl-
tical thickness in ASD (Zielinski et al. 2014), and with suggestions ier studies. Contrary to our findings, a recent study using ABIDE
that this brain overgrowth stems from a delay in regressive neu- data showed no group difference in cortical thickness between
rodevelopmental processes, for example synaptic/axonal prun- ASD and controls (Haar et al. 2014). In order to understand the
ing, and that the increased brain size in ASD may subsequently inconsistency of their results with ours, first let us compare the
drive greater than normal neural losses (Lewis and Elman 2008; final data sample used in both studies. Out of the total 1113
Tang et al. 2014). MRI scans, the authors applied exclusion criteria (age <35 years,
It is important to note that more clusters of significantly males only with IQ scores) to remove 120 scans. Of the remain-
increased cortical thickness were observed in the left hemisphere ing 992 scans, 42 were removed during QC: thus, the authors
than the right hemisphere possibly indicating asymmetry of the attributed 4% of the data to poor quality. In contrast to their
observed abnormalities in cortical thickness. Delayed neurodeve- study, our strict QC procedure resulted to removal of 378 scans
lopment may underlie this asymmetry. In typically developing from a total of 1099 (~34%). Thus, it is plausible that their study
children, many cortical regions within the left hemisphere, and might have included scans with poor quality. This becomes an
 1728 | Cerebral Cortex, 2017, Vol. 27, No. 3
Figure 5. Relation between abnormalities in cortical thickness and symptom severity. Correlation of residual cortical thickness at the identified peak vertices (see
Table 3) and ASD Social and Communication severity scores obtained from the ADOS within the ASD group. Note: x-axis = symptom severity, y-axis = residual cor-
tical thickness (mm), L = left hemisphere, R = right hemisphere.
important issue because head motion during MRI acquisition
(which is quite common in subjects with ASD) has been shown
to reduce cortical thickness estimates (Reuter et al. 2015). Our
QC procedure eliminated a large amount of data that had
motion artifacts. The potential inclusion of such data would
have added to the variance in cortical thickness within the ASD
group and possibly yielded a null result; this may be the
explanation for the reported null result. It may also be noted
that Haar et al. (2014) adopted the usual approach of centering
age at the middle of the age range and then computing the
interaction effects, which may be less sensitive to detection of
group difference (as opposed to our shifting-mean-center
approach).
Some earlier age-related (trajectory-based) studies reported
reverse age × group interaction: greater cortical thickness/volume
in typically developing children (compared with ASD) with fas-
ter age-related decline resulting to greater thickness/volume in
ASD by adolescence (Raznahan et al. 2010; Ecker et al. 2014). A
closer look revealed that in the age range 6–14 years (in which
we observed significant group difference), these studies had
very sparse data (compared with a large sample in our study)
which might lead to uncertainty in the fitted growth curves. On
the other hand, consistent with our findings, Zielinski et al.
(2014) using longitudinal data, showed increased cortical thick-
ness in children with ASD declining at a faster rate than normal
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controls in the same age range (6–14 years). Our findings of
a dynamic pattern of group difference, which was the result
of more rapid cortical thinning in ASD after an initial excess
in cortical thickening, also echoed observations from post-
mortem studies that showed faster decrease in thickness
with age in ASD compared with controls (Hutsler et al. 2007),
giving credence to our observations. It may be noted that the
inconsistencies between cortical thickness studies on ASD
may also be attributed to poor differentiation of GM–WM
boundary in ASD. Compared with normal subjects, ASD sub-
jects display an indistinct transition between GM and WM
(Avino and Hutsler 2010), which in turn, may lead to variabil-
ity of cortical thickness measures (Hutsler and Casanova
2016).
A primary limitation of the study is the use of multi-site
cross-sectional data. The uneven subject-site distribution in
terms of age and sex make the pooling in of data complicated.
Regressing site in our analyses partially solve some of the
concerns. Due to the heavy skewness of data toward males,
female subjects were not included in the study. As such, our
findings of cortical abnormalities in ASD should be inter-
preted primarily for males with ASD. The variability in the
residual cortical thickness within either group is also note-
worthy. Both the specificity and sensitivity of MRI-derived
cortical thickness measures are relatively low. This may be in
 Cortical Thickness Abnormalities in Autism Spectrum Disorders Khundrakpam et al. | 1729

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