doi:10.

1093/brain/awm129 Brain (2007), 130, 2117^2122

Increased motor cortex white matter volume

predicts motor impairment in autism
Stewart H. Mostofsky,1,2,3, Melanie P. Burgess1 and Jennifer C. Gidley Larson1
1
Kennedy Krieger Institute, 707 North Broadway, Baltimore, MD 21205, USA, Johns Hopkins School of Medicine,
Departments of 2Neurology and 3Psychiatry, Baltimore, MD, USA
Correspondence to: Stewart H. Mostofsky, MD, Kennedy Krieger Institute, 707 N. Broadway, Baltimore, MD 21205, USA
E-mail: mostofsky@kennedykrieger.org

Careful consideration of motor impairments, such as those documented in autism, can afford valuable
insights into the neurological basis of developmental disorders. Motor signs are highly quantifiable and reprodu-
cible and can serve as markers for deficits in parallel systems important for socialization and communication.

Downloaded from brain.oxfordjournals.org by guest on October 14, 2010

Correlations of motor signs with anatomic MRI (aMRI) measures therefore offer an important means of inves-
tigating brain abnormalities contributing to autism. Prior aMRI studies have revealed increased cerebral volume
in young children with autism, particularly in ‘outer zone’ radiate white matter; however functional correlates
of these findings have not been reported. In this study, we examined whether radiate white matter within
the primary motor cortex would predict impaired motor performance in children with autism. Subjects
included children ages 8^12 years: 20 with autism, 36 typically developing (TD) controls and 20 clinical
controls with attention-deficit/hyperactivity disorder (ADHD). Regional tissue volumes were measured
using an automated tissue classification algorithm followed by a semi-automated parcellation method. Motor
performance was assessed using the Physical and Neurologic Examination of Subtle Signs (PANESS),
with higher scores indicating poorer performance. Independent linear regression analyses revealed that for TD
controls there was a significant negative correlation between total PANESS score and primary motor cortex
white matter volume in both the right and left hemispheres, such that increased white matter volume predicted
improved motor skill. In contrast, children with autism showed a robust positive correlation between total
PANESS score and left hemisphere primary motor and premotor white matter volumes, such that increased
white matter volume predicted poorer motor skill. No significant correlations were found for ADHD.
Multivariate regression analyses revealed that the correlation between PANESS score and left motor cortex
white matter volume in children with autism significantly differed from those in both ADHD and TD children.
The correlation in ADHD did not significantly differ from that in TD children. The findings for the first
time demonstrate an association between increasing radiate white matter volume and functional impairment
in children with autism, in this case basic motor skill impairment. The observed association, which appears
specific to autism, may be representative of global patterns of brain abnormality that not only contribute
to motor dysfunction in autism, but also deficits in socialization and communication that define the disorder.

Keywords: autism; white matter; imaging; motor; central coherence

Abbreviations: ADHD ¼ attention deficit hyperactivity disorder; PANESS ¼ Physical and Neurologic Examination
of Subtle Signs; TD ¼ typically developing
Received October 30, 2006. Revised May 9, 2007. Accepted May 10, 2007. Advance Access publication June 15, 2007

Introduction Larson and Mostofsky, 2006) and include difficulties with

Abnormalities on motor examination have often afforded both basic motor control (Jansiewicz et al., 2006) and
valuable insights into developmental disorders of the brain performance of complex motor skills and gestures (Rogers
(Denckla and Roeltgen, 1992). Such abnormalities have et al., 1996; Mostofsky et al., 2006). Increased insight into
been well documented in individuals with autism (Gidley the brain mechanisms underlying autism can be gained

ß The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
2118 Brain (2007), 130, 2117^2122
from careful consideration of these motor signs.
Motor signs can serve as markers for deficits in parallel
brain systems important for control of socialization and
communication; in a developmental disorder such as
autism, procedural learning mechanisms important for
acquisition of motor skills may also contribute to impaired
development of social and communicative skills (Mostofsky
et al., 2000; Ullman, 2004; Walenski et al., 2006). Measures
of motor function are more quantifiable and reproducible
than are measures of complex social behaviour.
Examination of correlations between motor function and
anatomic magnetic resonance imaging (aMRI) measures of
brain structure therefore offers an important means of
investigating brain abnormalities that contribute to the
phenotypic features of autism.
Increased brain volume is the most consistent neuroima-
ging finding in children with autism, with prominent
differences during early childhood that are no longer seen
by adolescence (Courchesne et al., 2001; Carper et al., 2002;
Hazlett et al., 2005). The increased volume has been
principally attributed to larger white matter volumes,
particularly in outer ‘radiate’ regions (Herbert et al., 2004).
For the current study, we examined whether aMRI
measures of radiate white matter volume within primary
motor cortices would predict motor skill deficits in children
with autism, hypothesizing that, for children with autism,
increased white matter volume in the primary motor
cortex would predict the degree of basic motor skill
impairment. Furthermore, we hypothesized that this
association would be specific to autism. We examined
this by including: (i) a group of typically developing (TD)
control children and (ii) a clinical control group of children
with attention deficit/hyperactivity disorder (ADHD), a
developmental disorder which, like autism, has been found
to be associated with impairments in motor execution and
control (Mostofsky et al., 2001, 2003; Klimkeit et al., 2005;
Klein et al., 2006).
Participants and methods
Subjects
Subjects, ages 8–12 years, included 20 high-functioning children
with autism (3 girls), 36 TD controls (10 girls) and 20 children (4
girls) with ADHD; children with ADHD were recruited as part of
a separate ongoing study in our laboratory that also included
neuroimaging and motor assessment. All participants had full-
scale IQ (FSIQ) scores greater than 80, except one child with
autism who had a FSIQ of 78 but a verbal IQ of 88, based on
performance on the Wechsler Intellectual Scale for Children
(WISC), 3rd edition (Wechsler, 1991), or the WISC, 4th edition
(Wechsler, 2003). Participants were recruited from outpatient
clinics at the Kennedy Krieger Institute, local area paediatricians,
support groups for families of children with autism and/or ADHD
(e.g. the Autism Society of America, Children and Adults with
Attention-Deficit Hyperactivity Disorder), schools, social/service
organizations (e.g. Boy and Girl Scouts of America) and from
advertisements in the community (e.g. postings at libraries).
S. H. Mostofsky et al.
Children with autism met Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) criteria. The
diagnosis was confirmed using both the Autism Diagnostic
Observation Schedule—Generic (ADOS-G) (Lord et al., 2000)
and the Autism Diagnostic Interview—Revised (ADI-R) (Lord
et al., 1994). Children with identifiable causes of autism (e.g.
Fragile X syndrome) and known neurological disorders, including
epilepsy, were excluded.
Children in the clinical control group met DSM-IV criteria for
ADHD. The structured parent interview, Diagnostic Interview for
Children and Adolescents—Fourth edition (DICA-IV) (Reich
et al., 1997) and ADHD-specific and broad behaviour rating
scales [Conners’ Parent Rating Scale—Revised (CPRS-R: Conners
et al., 1998a) and Teacher Rating Scale—Revised (CTRS-R:
Conners et al., 1998b)] were used to confirm ADHD diagnosis.
The CPRS-R and DSM-IV criteria were also used to evaluate
ADHD subtype, with 8 children (one girl) meeting criteria for the
Downloaded from brain.oxfordjournals.org by guest on October 14, 2010
predominantly inattentive subtype and 12 (three girls) meeting
criteria for the combined subtype. Children meeting criteria for
other psychiatric diagnoses based on the DICA-IV, other than
Oppositional Defiant Disorder (ODD) and simple phobia, were
excluded from this study. ODD was present in eight of the
subjects and simple phobia was present in two, including one
subject with both. Children with identified neurological disorders,
including epilepsy and tic disorders, were also excluded from
participation. In addition, none of the children with ADHD had a
history of speech/language disorder or a Reading Disability, and
all had a basic reading standard score of 85 (16th percentile) or
higher on the Word Reading subtest from the Wechsler Individual
Achievement Test, First Edition (WIAT; Wechsler, 1992) or
Second Edition (WIAT–II; Wechsler, 2002). Children with ADHD
taking longer-acting medications (i.e. other than stimulants) were
excluded from the study. For children taking stimulant medica-
tion, parents were requested to withhold medication on the day of
and the day prior to testing.
Subjects in the typically developing control group were free of
any neurological, developmental or psychiatric disorders based on
responses from the DICA-IV. None of the controls had a history
of academic problems requiring school-based intervention services
or history of defined primary reading or language-based learning
disability and all had a basic reading standard score of 85 (16th
percentile) or higher on the Word Reading subtest from either the
WIAT or WIAT–II.
Written assent was obtained from all participating children and
written consent was obtained from a parent/guardian under
approval from the Johns Hopkins Medical Institutional Review
Board.
Motor skill assessment
Basic motor skills were assessed using a standardized motor
examination for children, the Physical and Neurologic
Examination of Subtle Signs (PANESS) (Denckla, 1985). This
examination has been used to demonstrate basic motor skill
impairments in both children with ADHD (Mostofsky et al., 2003)
and children with autism (Mandelbaum et al., 2006; Jansiewicz
et al., 2006), and a regression model including PANESS variables
was found to offer a high level of discrimination in distinguishing
boys with autism from controls (Jansiewicz et al., 2006).
Motor white matter in autism
Imaging methods
Fast field echo (FFE) MRI sequences were acquired on a
1.5 Tesla Philips Gyroscan NT Intera with the following
parameters: TR ¼ 35 ms, TE ¼ 6 ms, flip angle ¼ 45
, 256  256,
FOV ¼ 240 mm, slice thickness ¼ 1.5 mm. Images were analysed in
BrainImage using a fuzzy tissue segmentation algorithm (Reiss
et al., 1998) and a semi-automated parcellation method for which
a revised Talairach stereotaxic grid specific for measurement
in paediatric groups was used to subdivide the cerebrum into
lobar and subcortical regions; the frontal lobe was then further
subdivided into functionally relevant regions, including the
primary motor cortex defined by the precentral gyrus (see
Mostofsky et al., 2002 for a more detailed description).
Statistical methods
Analysis of Variance (ANOVA) was used to examine for group
differences in sample characteristics, including FSIQ, age, total
PANESS score, total brain volume (TBV) and motor cortex white
matter volume. Chi-square analyses were used to examine for
group differences in handedness and gender.
Independent linear regression analyses were used to examine for
correlations between motor cortex white matter volume and total
PANESS score in each diagnostic group; these analyses were
conducted both with and without controlling for FSIQ and TBV.
Following this, a multivariate regression model was used to
examine for an interaction effect of diagnosis and primary motor
cortex white matter volume on total PANESS score. The approach
allowed us to first test our hypotheses that, for children with
autism, increased white matter volume in the primary motor
cortex would predict the degree of basic motor skill impairment
and subsequent to that, test whether this association would
significantly differ from that observed in either TD controls or
children with ADHD.
Results
Sample characteristics
The groups did not differ significantly in age (P ¼ 0.7).
There was a significant group effect for FSIQ (P ¼ 0.0001).
Post hoc analyses revealed that TD controls showed
significantly higher FSIQ than both children with autism
(P50.0001) and children with ADHD (P ¼ 0.002); there
was no significant difference in FSIQ between children with
Table 1 Results from ANOVA for all groups
Subjects
Autism (n ¼ 20) TD children (n ¼ 36)
Mean (SD) Mean (SD)
Age (years) 10.3 (1.7) 10.5 (1.3)
FSIQ 104.1 (17.8) 120.2 (11.4)
Total PANESS score 33.4 (12.1) 17.6 (8.0)
Total brain volume (cm3) 1341.3 (96.9) 1352.2 (107.0)
Motor white volume (cm3) 21.0 (2.7) 21.6 (3.5)

Significant differences between Autism and TD Controls (P50.0001), ADHD and TD controls (P ¼ 0.002).

Significant differences between Autism and TD controls (P50.0001), Autism and ADHD (P ¼ 0.001).
Brain (2007), 130, 2117^2122 2119
autism and children with ADHD (P ¼ 0.4). Chi-square
analyses did not reveal any group differences in handedness
or gender. (See Table 1 for summary of sample
characteristics.)
There was a significant effect of diagnosis on total
PANESS score (P50.0001). Post hoc analyses were con-
sistent with published findings (Jansiewicz et al., 2006),
revealing that children with autism show basic motor
skill impairment, with significantly higher total PANESS
scores than TD controls (P50.0001). Children with
autism also showed significantly higher total PANESS
scores than children with ADHD (P ¼ 0.001). Children
with ADHD showed higher total PANESS scores than TD
controls at a level that trended toward significance
(P ¼ 0.08).
There were no significant group differences in TBV
Downloaded from brain.oxfordjournals.org by guest on October 14, 2010
(P ¼ 0.6) or in primary motor cortex (total, left and right)
white or gray matter volumes, which is consistent with
previously reported total brain and precentral gyrus
findings in children with autism in this age range
(Courchesne et al., 2001; Herbert et al., 2004).
Analyses of correlations between motor
cortex white matter volume and PANESS
score
Independent linear regression analyses revealed that for
children with autism there was a positive correlation
between total PANESS score (with higher score indicating
poorer performance) and left primary motor cortex white
matter volume (R2 ¼ 0.60, P50.0001), such that increased
white matter volume predicted poorer motor skill (Fig. 1A).
Based on the regression, it was estimated that for every
cubic centimetre increase in left motor cortex white matter
volume, there was a 5-point increase in total PANESS score.
No significant correlation was seen with right primary
motor cortex white matter volume.
In contrast, for TD controls there was a significant
negative correlation between total PANESS score and
primary motor cortex white matter volume in the right
(R2 ¼ 0.13, P ¼ 0.03) and left hemispheres (R2 ¼ 0.15,
P ¼ 0.02), such that increased white matter volume
ADHD (n ¼ 20) Statistics
Mean (SD) F-test P-value
10.7 (1.3) F(2,75) ¼ 0.34 0.71
108.0 (13.5) F(2,75) ¼ 10.2 0.0001
22.5 (11.5) F(2,75) ¼ 15.5 50.0001
1321.9 (85.6) F(2,75) ¼ 0.60 0.55
20.3 (2.7) F(2,75) ¼ 1.2 0.31
2120 Brain (2007), 130, 2117^2122
predicted better motor skill (Fig. 1B). Based on the
regressions, it was estimated that for every cubic centimetre
increase in either right or left motor cortex white
matter volume, there was a 1.5 point decrease in total
PANESS score.
Similar to TD controls, children with ADHD showed a
negative correlation between total PANESS score and both
left hemisphere (R2 ¼ 0.06, P ¼ 0.3) and right hemisphere
(R2 ¼ 0.07, P ¼ 0.3) primary motor cortex white matter
volumes, although neither of these correlations was
statistically significant. Based on the regressions, it was
estimated that for every cubic centimetre increase in either
right or left motor cortex white matter volume there was a
2 point decrease in total PANESS score.
After covarying for FSIQ and TBV, the findings in both
children with autism and TD controls remained significant,
with correlations that were more robust. For children with
autism there remained a significant positive correlation
between total PANESS score and left hemisphere white
matter volume (R2 ¼ 0.72, P ¼ 0.0001). For TD controls,
there remained a significant negative correlation between
total PANESS score and primary motor cortex white matter
volume in both the right (R2 ¼ 0.30, P ¼ 0.007) and left
(R2 ¼ 0.23, P ¼ 0.04) hemispheres. Correlations in children
with ADHD remained insignificant after controlling for
FSIQ and TBV.
Multivariate regression analyses including all three
groups of subjects (autism, ADHD and TD) revealed a
significant effect of diagnosis on the correlation between
total PANESS score and left motor cortex white matter
volume (P50.0001). Separate two-group contrasts revealed
that the correlation between total PANESS score and left
motor cortex white matter volume in children with autism
significantly differed from that in TD children (P50.0001)
a Autism
60
50
Total PANESS score
40
30
20
10
0 0
4 6 8 10 12 14
Left Motor Cortex White Matter Volume (cm3)
Fig. 1 Independent linear regression analyses, covaried for FSIQ and TBV, demonstrating (A) for children with autism there is a robust
positive correlation between total PANESS score and left motor cortex white matter volume (R2 ¼ 0.72, P ¼ 0.0001), such that increased
white matter volume predicts poorer motor skill. (B) In contrast, for typically developing children there is a significant negative
correlation between total PANESS score and left motor cortex white matter volume (R2 ¼ 0.23, P ¼ 0.04), such that increased white
matter volume predicts better motor skill.
S. H. Mostofsky et al.
and that in children with ADHD (P ¼ 0.001). The
correlation in TD children and that in children with
ADHD did not significantly differ.
Analyses of correlations of other frontal
regional white matter volumes with
PANESS score
To determine whether the findings were specific to the
primary motor cortex, we examined correlations
of PANESS scores with other frontal cortical regions,
including prefrontal, premotor and anterior cingulate.
For children with autism, a significant positive correlation
was also observed between total PANESS score and left
premotor white matter volume (R2 ¼ 0.29, P ¼ 0.02) and
this remained significant after controlling for FSIQ and
Downloaded from brain.oxfordjournals.org by guest on October 14, 2010
TBV (R2 ¼ 0.42, P ¼ 0.05); no correlations were seen for
right premotor, or either hemisphere prefrontal or anterior
cingulate volumes. For TD children and children with
ADHD there were no significant correlations between
PANESS scores and white matter volumes in any of the
premotor, prefrontal or anterior cingulate regions.
Discussion
Consistent with our hypothesis, increased left motor and
premotor white matter volumes were strong predictors of
poor motor function in children with autism. The findings
are in direct contrast to those seen in TD children, in
whom increased white matter volume in both left and right
motor cortex was associated with improved motor skills.
The strength of these observations is evidenced by the fact
that the correlations were significant both with and without
covarying for FSIQ and TBV.
b TD Children
60
50
Total PANESS score
40
30
20
10
16 4 6 8 10 12 14 16
Left Motor Cortex White Matter Volume (cm3)
Motor white matter in autism
There were no differences in precentral white matter
volume between children with autism and TD children; this
is consistent with previously published precentral white
matter findings in this age range (Herbert et al., 2004) and
the more general observation that increased white matter
volume is seen in younger, but not older, children with
autism (Courchesne et al., 2001). Myelination in the
precentral gyrus reaches maturity around 6 years of age
(Kinney et al., 1988). It may be that for children with
autism, abnormal white matter development in the
precentral cortex occurs at a young age, contributing to
motor dysfunction; TD children instead show a more
gradual increase in precentral white matter development
associated with improvement in motor dexterity, so that by
late childhood no differences in volume are observed.
Examination of correlations between motor function and
white matter volume in younger children would help to
address this hypothesis.
The association of increased motor white matter volumes
and poor motor function appears to be specific to autism.
This association was not observed in the clinical control
group of children with ADHD, another developmental
disorder in which impairments in motor execution and
control are a common finding (Mostofsky et al., 2001,
2003; Klimkeit et al., 2005; Klein et al., 2006). Furthermore,
the correlation between motor skill performance and left
motor cortex white matter volume in children with autism
significantly differed both from that in TD children and
that in children with ADHD. In contrast, the correlation in
children with ADHD did not significantly differ from
that in TD children. The population of children with
ADHD in this study showed higher total PANESS scores
than TD controls at a level that only trended toward
significance. Further evidence for the specificity of the
association of increased motor cortex white matter volume
with motor skill impairment in autism could come from
examining other populations of children with motor
difficulties, for instance those with Developmental
Coordination Disorder, as well as children with features
otherwise related to autism, such as those with specific
language impairments.
The findings provide insight into the pathophysiology of
autism. Autism has been found to be associated with
enlarged cerebral white matter volume, particularly in outer
radiate regions (Courchesne et al., 2001; Herbert et al.,
2004). Consistent with these neuroimaging findings, post-
mortem studies of individuals with autism reveal abnor-
malities in cortical minicolumns that reflect a bias towards
shorter connecting fibers, which are localized to radiate
white matter, at the expense of longer fibers connecting
distant cortical and cortical-subcortical regions (Casanova
et al., 2006). The current findings for the first time
demonstrate an association between increasing radiate
white matter volume and functional impairment, in this
case basic motor skill impairment. The strength of the
correlation in autism, beyond that observed with normal
Brain (2007), 130, 2117^2122 2121
biological variation in TD controls, suggests that it may be
a defining biological feature of the disorder.
The observed association between increased white matter
volume and functional impairment may be representative of
global patterns of brain abnormality that not only
contribute to motor dysfunction in autism, but also to
deficits in socialization and communication that define the
disorder. Investigators have proposed that the pattern of
impairments associated with autism, as well as some relative
strengths in perceptual processing, are secondary to
abnormalities in structural and functional connectivity
(Minshew et al., 1997; Herbert et al., 2004; Happé and
Frith, 2006). Overgrowth of localized cortical connections
and undergrowth of more distant connections between
cerebral cortical regions and with subcortical structures
(Herbert et al., 2004; Happé and Frith, 2006) have been
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hypothesized to result in impaired complex information
processing (Minshew et al., 1997) and ‘weak central
coherence’ (Shah and Frith, 1993) and may also contribute
to impaired motor sequence learning necessary for devel-
opment of complex motor skills and social/communicative
gestures (Mostofsky et al., 2000; Ullman, 2004; Gidley
Larson and Mostofsky, 2006; Walenski et al., 2006).
The measure of precentral white matter volume used in
the present study likely principally comprised localized
connections; it corresponded to white matter within
the precentral gyrus, with deep subcortical white matter
explicitly excluded. The findings in the present study
therefore appear to lend support to the notion that
increasing volume of localized cortical connections
contributes to functional impairment in children with
autism.
Acknowledgements
This research was supported by NIH Grants R01 NS048527
(SHM), HD024061 (Mental Retardation and
Developmental Disabilities Research Center), M01
RR00052 (Johns Hopkins General Clinical Research
Center) and grants from the National Alliance for Autism
Research and Autism Speaks (SHM).
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