Development of Cortical Surface Area and Gyrification
in Attention-Deficit/Hyperactivity Disorder
Philip Shaw, Meaghan Malek, Bethany Watson, Wendy Sharp, Alan Evans, and Deanna Greenstein
Background: Delineation of the cortical anomalies underpinning attention-deficit/hyperactivity disorder (ADHD) can powerfully inform
pathophysiological models. We previously found that ADHD is characterized by a delayed maturation of prefrontal cortical thickness. We
now ask if this extends to the maturation of cortical surface area and gyrification.
Methods: Two hundred thirty-four children with ADHD and 231 typically developing children participated in the study, with 837 neuro-
anatomic magnetic resonance images acquired longitudinally. We defined the developmental trajectories of cortical surfaces and gyrifica-
tion and the sequence of cortical maturation, as indexed by the age at which each cortical vertex attained its peak surface area.
Results: In both groups, the maturation of cortical surface area progressed in centripetal waves, both lateral (starting at the central sulcus
and frontopolar regions, sweeping toward the mid and superior frontal gyrus) and medial (descending down the medial prefrontal cortex,
toward the cingulate gyrus). However, the surface area developmental trajectory was delayed in ADHD. For the right prefrontal cortex, the
median age by which 50% of cortical vertices attained peak area was 14.6 years (SE ? .03) in ADHD, significantly later than in typically
developing group at 12.7 years (SE? .03) [log-rank test ?(1)2? 1300, p ? .00001]. Similar, but less pronounced, delay was found in the left
hemispheric lobes. There were no such diagnostic differences in the developmental trajectories of cortical gyrification.
Conclusions: The congruent delay in cortical thickness and surface area direct attention away from processes that selectively affect one
cortical component toward mechanisms controlling the maturation of multiple cortical dimensions.
Key Words: Attention-deficit/hyperactivity disorder, cerebral cor-
tex, cortical gyrification, magnetic resonance imaging, structural
neuroimaging, typical development
We previously reported that attention-deficit/hyperactivity disor-
phase of childhood increase in cortical thickness gives way to an
adolescent phase of cortical thinning (1). The mean age at which
this peak cortical thickness was attained in the cerebrum was
with ADHD, peak cortical thickness was reached around 10 years,
ask whether a similar developmental delay is found in the other
area and cortical curvature, or gyrification.
It is by no means certain that a delay in the maturation of one
component of cortical morphology entails a delay in all others.
Dissociations between morphometric cortical properties have
have simultaneously considered the composite dimensions of the
cortex. Thus, reduced cortical surface area but intact cortical thick-
ness have been reported in dyslexia, ADHD, and autism (2–4) and
lating evidence that these morphometric properties may be partly
biologically distinct, as they can be manipulated independently in
ecent advances in neuroimaging acquisition and analytic
techniques allow an increasingly detailed delineation of the
and in vivo neuroimaging studies of healthy young adults suggest
that while both cortical thickness and area are organized as net-
It is also equally true that cortical thickness, surface area, and
gyrification are unlikely to be completely independent. The dem-
onstration of some unique underlying cellular processes does not
preclude many common ones. Likewise, twin studies report some
common genetic factors controlling surface area and thickness,
frontal gyri (7). Finally, it should be noted that if a pathological
ness (a one-dimensional entity) may reflect lack of power to detect
disorder-related change occurring in the unidimensional cortical
thickness, rather than truly intact thickness.
To date, studies of the development of cortical surface area in
and conducted largely at the level of entire lobes or regions of
interest (5,11). Here, we define trajectories of cortical surface area
development at the level of over 80,000 vertices throughout the
ADHD. This level of spatiotemporal resolution allows us to deter-
mine if the regional delay in cortical thickness development in
ADHD extends to the development of surface area. Answering this
question may guide future searches for etiological processes.
Methods and Materials
Two hundred thirty-four children with ADHD participated. De-
tails of this cohort are elsewhere (1,12,13), but in brief, diagnosis
was based on the Parent Diagnostic Interview for Children and
Adolescents (14), Conner’s Teacher Rating Scales (15), and the
Mental Health, Bethesda, Maryland; and ACE NeuroImaging Laboratory
(AE), Montreal Neurological Institute, Montreal, Quebec, Canada.
Address correspondence to Philip Shaw, M.D., Ph.D., National Institute of
Mental Health, Child Psychiatry Branch, Room 3N202, Building 10, Cen-
ter Drive, Bethesda, MD 20892; E-mail: email@example.com.
Received Aug 31, 2011; revised and accepted Jan 6, 2012.
BIOL PSYCHIATRY 2012;72:191–197
© 2012 Society of Biological Psychiatry
ADHD at baseline, 12 had inattentive subtype, and 5 had hyperac-
tive/impulsive subtype. Numbers of subjects at each wave of scan-
review board of the National Institutes of Health approved the
research protocol, and written informed consent and assent to
participate in the study were obtained from parents and children,
respectively. At study entry, 68% of the 208 subjects on whom
medication details could be confirmed were taking psychostimu-
lants. This proportion held relatively constant throughout the re-
maining waves of scanning: 67% were medicated at time 2, and
66% were medicated at time 3. At study entry, 85% of the medi-
cated subjects were taking methylphenidate preparations.
The typically developing subjects were part of the National In-
stitutes of Health intramural project of typical brain development,
which has been reported upon previously (16,17). The group was
Each subject completed the Childhood Behavior Checklist as a
screening tool and then underwent a structured diagnostic inter-
view by a child psychiatrist to rule out any psychiatric or neurolog-
ical diagnoses (18). The numbers of subjects at each wave of scan-
ning and their age are given in Table 1.
All children had neuroanatomic magnetic resonance imaging
on the same 1.5-T General Electric (Milwaukee, Wisconsin) Signa
scanner throughout the study. T1-weighted images with contigu-
ous 1.5-mm slices in the axial plane were obtained using three-
dimensional spoiled gradient recalled echo in the steady state.
msec, flip angle of 45°, acquisition matrix of 256 ? 192, number of
using the cortical surface extraction pipeline CIVET developed at
the Montreal Neurological Institute (19). The native magnetic reso-
nance imaging scans were first masked using Brain Extraction Tool
(20) and then registered into standardized stereotaxic space (MNI-
ICBM152 nonlinear sixth generation symmetric target ) using a
nine-parameter linear transformation (22) and corrected for non-
uniformity artifacts (23). The registered and corrected volumes
were segmented into white matter, gray matter, cerebrospinal
fluid, and background using an advanced neural net classifier
(24,25). The cortical surfaces were extracted by hemispheres using
the constrained Laplacian anatomic segmentation using proximi-
gray matter interfaces (26). A 30-mm surface-blurring algorithm
was used to reduce noise in the thickness and area measurements
(27). Cortical surface area was measured at the middle cortical sur-
face, which lies at the geometric center between the inner and
outer cortical surfaces and thus provides a relatively unbiased rep-
resentation of sulcal versus gyral regions (28,29). This gives the
surface area of every vertex in the surface mesh (40,962 in each
surface area and exposed cortical surface or convex hull area (30).
First, we determined developmental trajectories for the metrics
of surface area and the gyrification index using mixed model re-
gression analysis. This technique was used, as our unbalanced lon-
gitudinal data contain both multiple observations per participant
measured at different and irregular time periods and single obser-
vations per participant. The classification of developmental trajec-
tories was based on a step-down model selection procedure: at
each cortical vertex, we modeled cortical thickness using a mixed-
effects polynomial regression model, testing for cubic, quadratic,
and linear age effects. If the cubic age effect was nonsignificant at
p ? .05, it was removed and we stepped down to the quadratic
model and so on. In this way, we were able to classify the develop-
ment of each cortical measure as being best explained by a cubic,
quadratic, or linear function of age. For metrics where a quadratic
model was appropriate, the jth metric of the ith individual was
where djis a random effect modeling within-person dependence,
the intercept and ? terms are fixed effects, and eijrepresents the
residual error. Where a quadratic fit was appropriate, the age at
which each vertex attained its peak surface area was calculated
from the derivatives of the developmental curves and illustrated
through dynamic time-lapse sequences (movies). Kaplan-Meier
that had reached peak surface area throughout the age range cov-
ered. The significance of the group difference in the mean age by
which half of cortical vertices had attained their peak surface area
was calculated by using the log-rank (Mantel-Cox) test.
both total and lobar surface areas were significantly decreased in
the ADHD group (Table 2). Analyses at the level of each vertex
showed that surface reduction was most pronounced bilaterally in
the prefrontal cortex (especially the medial wall and the lateral
ral cortex, and left medial temporal cortex, extending to posterior
left medial wall (fusiform, lingual gyri, and cuneus).
in both groups. At the lobar level in typically developing children,
surface areas showed an initial childhood increase followed by an
adolescent phase of decrease. The shape of the developmental
in Supplement 1 shows results for the left hemisphere.
The trajectories were then mapped at the level of ?80,000 ver-
Table 1. Demographic Details and Number of Participants at Each Wave
DevelopingTest of Significance
234 (151, 65%) 231 (148, 64%)
?2 ? .005, p ? .95
n ? 234
n ? 115
n ? 60
n ? 17
n ? 231
n ? 121
n ? 46
n ? 13
t (463) ? 1.2, p ? .22
Scan 2t (234) ? 1.0, p ? .29
Scan 3t (104) ? 1.7, p ? .09
Scan 4t (28) ? 1.2, p ? .23
IQt (463) ? .02, p ? .98
ADHD, attention-deficit/hyperactivity disorder; IQ, intelligence quo-
192 BIOL PSYCHIATRY 2012;72:191–197
P. Shaw et al.
dynamic time-lapse sequences (Supplement 2 and 3). In both typi-
cal development and ADHD, there was a similar regional progres-
sion of maturation. The parietal and occipital cortex matured early,
as indexed by surface area, with many regions attaining their peak
surface area before the age of 6 and the remainder reaching this
marker by around age 11. Maturation of the prefrontal cortex oc-
curred earliest, with the precentral and postcentral frontal gyri
spread across the middle frontal gyrus with the last areas to attain
peak surface area being the superior frontal gyrus and a smaller
(e.g., the angular gyrus) followed by the middle, polar, and then
rior regions of the cingulate gyrus attaining their peak surface area
While the order or sequences was similar, there were marked
diagnostic differences in the timing. At a lobar level, Kaplan-Meier
analyses showed that the mean age by which 50% of the cortical
for the ADHD group was 14.6 years (SE ? .03), which was signifi-
cantly later than the mean age of 12.7 years (SE ? .03) for the
typically developing control subjects [log-rank test ?(1)2? 1300, p ?
.00001]. For the left prefrontal cortex, the corresponding values
.001]. For the parietal cortex, there was similar delay in both hemi-
spheres—mean age of peak surface attained on right at 12.5 years
(SE ? .03) for ADHD and 11.1 years (SE ? .03) for the typically
mean age of peak surface was attained at 12.2 years (SE ? .06) for
ADHD and 9.9 years (SE ? .05) for typical development [?(1)2?
hemispheres and the mean age of attaining peak surface area on
the right was 13.9 years (SE ? .04) for the ADHD group and 13.2
years (SE ? .04) for the typically developing group [?(1)2? 32, p ?
years (SE ? .04) for ADHD and 10.9 years (SE ? .05) for typical
development [?(1)2? 249, p ? .0001]. There was no delay for the
occipital cortex, with the mean age of peak surface area in ADHD
2, p ? .05].
a sublobar level. Delay was most prominent in the anterolateral
was prominent bilaterally in the medial temporal gyri, in the right
The results for surface area are compared against data for corti-
cal thickness maturation in the same cohort, taken from our earlier
report in Figure 3 (Shaw et al. ). Two features are clear. First,
thickness for both groups. Second, the diagnostic delay is present
for both prefrontal cortical thickness and cortical surface area.
The trajectory of the convex hull in ADHD showed a later peak
and had a lower value than in typical development, similar to the
Figure S2 in Supplement 1 for the left hemisphere). As a result, the
trajectory of the gyrification index in ADHD, which is the ratio of
(right F ? .39, p ? .76; left F ? 2.0, p ? .13). The developmental
trajectories also showed that peak gyrification was attained for
both groups before the start of the age period covered. Finally, at
the time of study entry, the gyrification index did not differ signifi-
cantly between the groups (Table 2).
There is a delay in the maturation of cortical surface area in
ADHD that mirrors the delayed maturation of cortical thickness we
neuropsychiatric disorders that have deficits of either just surface
area or cortical thickness, such as dyslexia and autism (2,3). This, in
example, deficits in cortical thickness but not surface area have
been linked with mutations of Pax6, Id4, and other genes that
impact on the abundance of intermediate progenitor cells that are
critical for early neurogenesis (6). Our finding of a congruent delay
in both cortical thickness and surface area in ADHD points instead
Table 2. Baseline Values of Total and Lobar Surface Areas and Gyrification Index
Test of Significance
t(df 463), p Value
Right Hemispheric Surfaces
Total surface area
Left Hemispheric Surfaces
Total surface area
t ? 4.3, p ? .0001
t ? 4.1, p ? .0001
t ? 3.5, p ? .001
t ? 3.1, p ? .002
t ? 2.9, p ? .003
t ? 4.1, p ? .0001
t ? 3.2, p ? .001
t ? 3.4, p ? .001
t ? 3.7, p ? .0002
t ? 2.7, p ? .006
t ? 1.5, p ? .13
t ? 1.5, p ? .13
ADHD, attention-deficit/hyperactivity disorder.
P. Shaw et al.
BIOL PSYCHIATRY 2012;72:191–197 193
might be responsible, although plausible candidates include neu-
rotrophins, essential for the proliferation, differentiation, and sur-
vival of neuronal and nonneuronal cells. Indeed, polymorphisms
within the brain-derived neurotrophic factor and nerve growth
factor 3 genes have already been linked with ADHD (31,32).
area and gyrification but intact cortical thickness in ADHD (4). Sev-
eral factors may explain the discrepancy. The earlier study was
cross-sectional; it had a smaller sample size and thus may have not
cortical thickness. There are also some differences in the studies’
define surface area.
ing children. We find that posterior, parieto-occipital cortex ma-
tures earlier than more anterior regions. Prefrontal cortical surface
mid and superior frontal gyrus) and medial (descending down the
highlighting the similarities in the maturation of cortical thickness
and surface area.
At a lobar level, delay was found in the ADHD group in the
frontal, temporal, and parietal, but not occipital, lobes. However,
anterior frontal gyri, particularly on the right. Structural cortical
anomalies of the prefrontal regions have been frequently reported
by others, particularly studies that have used the metric of cortical
thickness. Four independent groups have reported thinning of the
cortex in children with ADHD in prefrontal regions, particularly the
anterior portions of the superior, middle, and inferior frontal gyri
(12,35–37). This cortical thinning has been further linked with im-
cated core cognitive deficits in ADHD (35). It will be interesting to
see if a similar consensus emerges on reduction in cortical surface
attaining peak surface area in ADHD was prominent bilaterally in
the medial temporal gryi, in the right postcentral and middle tem-
poral gyri, and left supramarginal gyrus. These areas were less ex-
pected, although it is notable that cortical anomalies of the medial
temporal cortex and underlying amygdala and hippocampus are
. 8 10 12 14 16 .
Surface area (mm2)
. 8 10 12 14 16 .
. 8 10 12 14 16 .
Surface area (mm2)
. 8 10 12 14 16 .
lobar surface areas. 95% confidence intervals for the esti-
mate are given in the dotted lines. ADHD, attention-defi-
Figure 2. Regions where age of attaining peak surface
hyperactivity disorder compared with typically develop-
194 BIOL PSYCHIATRY 2012;72:191–197
P. Shaw et al.
the regulation of emotion found in many people who have ADHD
task being performed (41–48). Studies examining cortical activity
of anomalies, encompassing the cingulate and precuneus, as well
as lateral prefrontal cortex (49,50). The distributed nature of task-
related and resting-state functional hypoactivation is congruent
with the distributed nature of the structural delay we report.
Most data in this study (92% of scans) were from individuals
this data, which reflects a childhood phase of increase followed by
eling is helpful in capturing early milestones of cortical develop-
ment, such as the age of attaining peak dimensions. However, it is
which the cortex settles into relatively stable adult dimensions.
More data from adults over 18 and perhaps a different analytic
approach are needed to determine these adult milestones. Such
adult data would allow us to determine the degree to which nor-
malization occurs by adulthood or whether the delay in attaining
peak dimensions is carried forward into persistent adult structural
cortical deficits. Our developmental trajectories for surface area
(Figure 1) suggest that some degree of normalization may occur,
although extrapolation of the curves beyond the age range cov-
ered is not possible, and more data on adult ADHD are greatly
It is interesting to speculate on the possible clinical significance
of normalization as opposed to persistence of early cortical delay
clinical remission, whereas persistent deficits might drive ADHD
that lasts into adulthood. There is some evidence that this may be
found that persistence of ADHD was associated with a progressive
divergence away from the trajectory of typical development,
resembled those of typical development (51). This study, however,
dealt only with adolescence and there were little data on adult
ADHD. In a recent cross-sectional study, Proal et al. (52) found that
regions, whereas adults who had recovered from their childhood
symptoms had no significant deficits relative to control subjects.
ADHD into adulthood is underpinned by abnormal cortical devel-
opment, which may manifest in childhood as delay in attaining an
early milestone of development.
icantly in the degree of gyrification at study entry or in its develop-
mental trajectory. This reflects the fact that both surface area and
Figure 3. Kaplan-Meier curves showing the proportion of cortical vertices
that attain peak thickness and peak surface area at each age for both the
attention-deficit/hyperactivity disorder (ADHD) and typically developing
the cortical vertices attained peak dimensions was significantly later in
ADHD (at p ? 1.0?4).
. 8 10 12 14 16
Surface area (mm2)
. 8 10
12 14 16 .
. 8 10 12 14 16 .
Figure 4. Developmental trajectories for the right hemispheric convex hull, total surface area, and gyrification index. Both the convex hull and surface area
hull, does not differ diagnostically. Results for the left hemisphere are very similar.
P. Shaw et al.
BIOL PSYCHIATRY 2012;72:191–197 195
the exposed cortical surface or convex hull were similarly reduced
in ADHD and had similarly delayed trajectories. Thus, the gyrifica-
differ from typical dimensions. It is also noteworthy that the gyrifi-
cation index attained its peak value before the onset of the age
period covered, in line with previous reports of early maturation of
this measure (11,53).
There are several limitations to this study. The majority of the
subjects in the ADHD group were medicated at some stage and
there was insufficient power to examine neurodevelopmental tra-
sectional studies and one longitudinal observational study found
tion of cortical structural deficits, making the finding of anomalies
in surface area less likely to be attributable to medication effects
(13,54–56). This has been confirmed by a recent meta-analysis of
chostimulant treatment was associated with more normative di-
was largely recruited from an affluent socioeconomic region, was
free of major comorbidities beyond oppositional defiant disorder,
and had a high IQ, all factors that may limit the generalizability of
the findings. We were unable to test for sex effects, as splitting the
higher order effects of age on the development of most of the
of the sample. There is evidence that sex effects may be important
in ADHD, affecting patterns of neural activity (58,59), and studies
into sexual dimorphism in brain structure in ADHD are a priority
when sufficient sample sizes are attained.
Our finding of congruent delays in the maturation of cortical
thickness and surface directs attention toward mechanisms that
ture as potentially pivotal in the pathogenesis of ADHD.
This work was supported by the Intramural Research Programs of
the National Human Genome Research Institute and the National In-
attend the Nordic Psychiatry Assembly on Attention-Deficit/Hyperac-
tivity Disorder in 2010 and from Jansen-Cilag to attend the Biennial
Neuroscience Multidisciplinary Meeting in Madrid in 2011. He has re-
cently become jointly affiliated with The National Human Genome
Research Institute, Section on Neurobehavioral Clinical Research, So-
cial and Behavioral Research Branch, Bethesda, Maryland. All other
authors reported no biomedical financial interests or potential con-
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