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Developmental Trajectories of the Corpus Callosum inAttention-Deficit/Hyperactivity DisorderMary Gilliam, Michael Stockman, Meaghan Malek, Wendy Sharp, Deanna Greenstein, Francois Lalonde,Liv Clasen, Jay Giedd, Judith Rapoport, and Philip Shaw

Background: It was recently found that the development of typical patterns of prefrontal, but not posterior, cortical asymmetry is disruptedin right-handed youth with attention-deficit/hyperactivity disorder (ADHD). Using longitudinal data, we tested the hypothesis that therewould be a congruent disruption in the growth of the anterior corpus callosum, which contains white matter tracts connecting prefrontalcortical regions.

Methods: Areas of five subregions of the corpus callosum were quantified using a semiautomated method from 828 neuroanatomicmagnetic resonance scans acquired from 236 children and adolescents with ADHD (429 scans) and 230 typically developing youth (399scans), most of whom had repeated neuroimaging. Growth rates of each diagnostic group were defined using mixed-model linearregression.

Results: Right-handed participants with ADHD showed a significantly higher rate of growth in the anterior-most region of the corpuscallosum (estimated annual increase in area of .97%, SEM .12%) than their typically developing peers (annual increase in area of .32% SEM.13%; t � 3.64, p � .0003). No significant diagnostic differences in growth rates were found in any other regions in right-handed participants,and no significant diagnostic differences were found in non-right-handed participants.

Conclusions: As hypothesized, we found anomalous growth trajectories in the anterior corpus callosum in ADHD. This disrupted anteriorcallosal growth may reflect, or even drive, the previously reported disruption in the development of prefrontal cortex asymmetry. The

finding documents the dynamic, age-dependent nature of callosal and congruent prefrontal cortical abnormalities characterizing ADHD.

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Key Words: Attention-deficit/ hyperactivity disorder, corpus callo-sum, cortical asymmetry, magnetic resonance imaging, structuralneuroimaging, typical development

T here is increasing evidence that neuroanatomic anomalies inchildhood neuropsychiatric disorders may be age-depen-dent, changing over the course of development (1– 4). For

xample, we recently reported anomalous development of pre-rontal cortical asymmetry in attention-deficit/hyperactivity disor-er (ADHD) (5). In right-handed, typically developing individuals,

he left orbitofrontal/prefrontal cortex and right parieto-occipitalortex were relatively thicker than their homologues during earlyhildhood, but with age this asymmetry reversed, so that by earlydulthood the well-known pattern of greater right prefrontal and

eft occipital cortical dimensions emerged. In right-handed childrenith ADHD, the posterior component of this changing cortical

symmetry remained largely intact, but the prefrontal corticalsymmetry was lost. This finding is complemented by earlier re-orts of a loss of typical frontal asymmetry owing to reduced right

rontal volume in ADHD (6 – 8), as well as evidence for abnormalevelopment of prefrontal lateralized processing (9 –12). The find-

ng of anomalous development of prefrontal cortical asymmetry inhildren and adolescents with ADHD would lead one to expectongruent developmental anomalies of other structures, such ashe corpus callosum (CC).

The human CC is a bundle of about 2 million mostly myelinatedbers connecting homologous regions of the left and right cerebralemispheres (13,14). Its development involves the embryonic for-

From the Child Psychiatry Branch, National Institute of Mental Health,Bethesda, Maryland.

Address correspondence to Philip Shaw, M.D., Ph.D., Child PsychiatryBranch, Room 3N202, Building 10, National Institute of Mental Health,Bethesda, MD 20892; E-mail: shawp@mail.nih.gov.

dReceived Aug 10, 2010; revised Nov 19, 2010; accepted Nov 20, 2010.

0006-3223/$36.00doi:10.1016/j.biopsych.2010.11.024

ation of midline glial populations fusing the two hemispheresnd the expression of specific molecules that guide callosal fibers ashey cross the midline (15). Callosal fibers mostly take the shortestoute to transverse the interhemispheric commissure, maintainingtopographic pattern (16). As shown in Figure 1, the anterior-most

egions of the CC connect homologous prefrontal cortical regions.oving rostral to caudal, the successive CC areas connect the pre-otor and supplementary motor cortex, then the motor and sen-

ory cortex, followed finally by parietal, temporal, and occipitalortex. The anterior-most callosal subregion is composed ofmaller-diameter fibers and has the highest proportion of unmyeli-ated axons (17); fibers increase in diameter moving caudally.hese histological differences may be functionally significant; themaller diameter fibers of the anterior CC integrate higher-orderrefrontal cortical functions, whereas larger diameter fiber of theidcallosum are capable of higher conduction velocities (18) and

onnect motor and sensory cortical functions for which rapid inter-emispheric integration may be particularly important (17).

The hypothesis that there is an inverse relationship betweenerebral asymmetry and CC size and connectivity (19) has muchmpirical support, although there are some inconsistencies and theelationship may be complicated by sex effects (20). Several neuro-natomic studies find an inverse correlation between global cere-ral and more local measures of asymmetry in the perisylvian andostcentral sulcal regions with CC size and fiber number, although

here are also findings of a positive correlation (17,21,22). Cross-pecies studies in nonhuman primates link increasing cerebralsymmetry with a smaller CC (expressed as a proportion of totaleocortical volume) (23). Some find CC size to be larger in individ-als with less lateralization of cognitive functions, as assessed byehavioral laterality measures such as dichotic listening tasks, al-

hough the effects are small and somewhat inconsistent (20,24,25).dditionally, most but not all studies find that non-right-handed

ndividuals, who have less lateralized processing in many cognitive

omains, also have larger CC area (25–29). Given the importance of

BIOL PSYCHIATRY 2011;69:839–846© 2011 Society of Biological Psychiatry

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handedness in CC morphology, we thus report data for right andnon-right-handed groups separately. The right-handed group isconsiderably larger and the focus of this study. Data on the non-right-handed group are also reported, but given the relatively smallsample size, these data should be interpreted with caution andconsidered preliminary.

Studies of CC anomalies in ADHD have produced mixed results,with some reporting selective reduction of the anterior CC (30 –32)and some the posterior CC (33–35). Still others find no differencefrom typically developing youth (6,36). These inconsistent resultsmay reflect the relatively small sample sizes of each study, as well asdifferences in scan acquisition parameters and methodologiesused to subdivide and quantify the CC limitations that can be over-come by a single large study using consistent methodology. Nostudy to date has examined the possibility that callosal anomalies inADHD may be dynamic, changing with age. Such an examination ofrates of growth of the corpus callosum would inform our under-standing not only of callosal development in the disorder but alsoof the development of homologous cortical regions in the left andright hemispheres connected by the CC. As stated earlier, the pri-mary focus of this study is right-handed individuals, partly becausethis is by far the larger group and because our previous work hasfound diagnostic differences in the development of prefrontal cor-

Figure 1. Topography of the corpus callosum, as devised by Witelson (B)Witelson SF [1989]: Hand and sex differences in the isthmus and genu of theuman corpus callosum. A postmortem morphological study. Brain 112:

799 – 835, by permission of Oxford University Press); and modified by Hoferand Frahm (A) (reprinted from [41], with permission from Elsevier, copyright2006).

tical asymmetry only in right-handed individuals (5). a

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We thus hypothesized that we would find a selective disruptionn right-handed individuals with ADHD in the growth of the anteriorortion of the corpus callosum, which connects prefrontal cortical

egions that show atypical development of asymmetry in the disor-er. We predicted no difference in CC growth for posterior regions,iven the evidence for relatively intact development of posteriorortical asymmetry in ADHD.

ethods and Materials

Two hundred thirty-six children and adolescents with DSM-IV-efined ADHD participated in this study at the Bethesda campus of

he National Institutes of Health. The DSM-IV diagnosis of ADHDas based on the Parent Diagnostic Interview for Children anddolescents, Conners Teacher Rating Scales, and the Teacher Re-ort Form (threshold was ratings � 2 SD above age- and sex-pecific means). Exclusion criteria were a full-scale IQ of less than 80,vidence of medical or neurological disorders on examination or bylinical history, Tourette’s disorder, psychosis, drug or alcohol mis-se, or any other Axis I psychiatric disorder requiring treatment withedication at study entry. Comorbidities were thus relatively mild

nd predominately oppositional-defiant disorder (ODD). Handed-ess was determined from the Physical and Neurological Examina-

ion for Soft Signs (PANESS) (37), in which right-handed participantstated that they used the right hand for at least 10 of 12 everydayctivities, left-handed participants used the left hand for the sameroportion of activities, and ambidextrous participants occupied

he intermediate ground. One hundred ninety-one (81%) of theDHD participants were right-handed, 11 were left-handed (5%),nd 34 (14%) were ambidextrous. Left-handed and ambidextrousubjects were combined into a “non-right-handed” group, becauseeparate analyses were not feasible because of the small group size;or demographic details see Table S1 in Supplement 1. Most sub-ects were male: the right-handed group included 123 males64.4%); the non-right-handed group included 29 (64.4%). Num-ers of participants at each wave of scanning and their ages areiven in Table 1. IQ was assessed using age-appropriate versions of

he Wechsler Intelligence Scales. Treatment data are given in Sup-lement 1.

Two hundred thirty typically developing children and adoles-ents with no personal history of psychiatric or neurological disor-ers participated in the study, a subset of a cohort reported onreviously (38,39). Each participant underwent a structured diag-ostic interview by a child psychiatrist to rule out any psychiatric oreurological diagnoses (40). Two hundred one (87%) were rightanded, 12 (5%) were left-handed, and 17 (7%) were ambidextrous.emographic and scanning details are given in Table 1 for right-anded and Table S1 in Supplement 1 for non-right-handed partic-

pants. After study description, assent and written informed con-ent were obtained from children and parents respectively.

euroimagingT1-weighted sagittal magnetic resonance images were acquired

sing a 1.5-T scanner (GE Signa; GE Medical Systems, Milwaukee,isconsin) with contiguous 1.5-mm axial slices (echo time � 5sec, repetition time � 24 msec, acquisition matrix � 256 � 192,

ip angle � 45°, number of excitations � 1, and field of view � 24m). Images were manually realigned in the axial plane such thathe interhemispheric fissure was aligned with the y axis and in theoronal plane such that the interhemispheric fissure was alignedith the z axis. In the sagittal plane, the line connecting the anterior-ost and posterior-most points of the callosum was aligned with

he y axis. To quantify the CC, the midsagittal slice was designated

s the slice that contains the maximum upward extent curvature of

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the rostrum and the septum pellucidum (29). The corpus callosumwas then segmented automatically using the Medical Image Pro-cessing, Analysis and Visualization tool (http://mipav.cit.nih.gov),manually outlined by a rater (MG) blind to diagnosis, and split intofive subdivisions according to a protocol devised by Witelson (29)

nd modified by Hofer and Frahm (41). This recent modificationncorporates data from diffusion tensor imaging which better re-ect the origins of the fibers (Figure 1). All measurements wereonducted by a single rater (MG). In the training phase for the study,his rater showed high interrater reliabilities with two other ratersintraclass correlation coefficients � .9). Intrarater reliabilities forhe study rater were determined from repeated measurement ineparate sessions of 48 randomly selected scans, blind to prior

easurement. Intraclass correlation coefficients were high: Region, ICC � .98; Region II, ICC � .98; Region III, ICC � .93; Region IV,

ICC � .94; Region V, ICC � .99.

Statistical AnalysesLinear mixed-model regression was used for longitudinal analy-

ses, because our data contain both multiple observations per par-ticipant measured at different and irregular time periods and singleobservations per participant. Such unbalanced longitudinal datacan be explored statistically by applying mixed effect models (23). Amodel including linear effects of age best fit the data. We tested foreffects of higher order age terms (quadratic and cubic age), andthese did not contribute significantly. A random effect for eachindividual was also included in the model to account for within-person dependence. Thus, the jth area measure of the ith individualwas modeled as

Areaij ) intercept+ di + �1(diagnosis) + �2(age) +

�3(diagnosis * age) + eij, (1)

where di is a random effect modeling within-person dependence;the intercept and � terms are fixed effects, and eij represents theesidual error. Group differences in growth rates were determined

Table 1. Demographic and Clinical Details for the Right-Handed Subjects

ADH

ex: Male n (%) 123 (64o. Subjects at Each Scan, Mean Age (SD) YearsScan 1 191Scan 2 94Scan 3 50Scan 4 11

ge Range 5–25Q Mean (SD)Q Range

109 (1580 –1

Type of ADHDCombinedHyperactive/impulsiveInattentive

175 (914 (2.1

12 (6.3ODD 70 (36CD 13 (6.8Tics 8 (4.2GAD 4 (2.1Panic Disorder 3 (1.6Separation Anxiety Disorder 7 (3.6Mood Disorder 8 (4.2Learning Disabilities 20 (10

IQ data were available on 371 of the right-handed subjects.ADHD, attention-deficit/hyperactivity disorder; CD, conduct disorder; G

y the value and significance of the interaction term (�3), whichpi

ives an estimate of how the relationship between callosal area andge varies as a function of diagnostic group. Growth rates werexpressed as the percentage change in the area of each region perear (taking the mean values for each area at the baseline scan ashe denominator). In the primary analyses, trajectories were deter-

ined for five subregions, and we thus set a level of significance of� .01 (p of .05 divided by five). In other exploratory analyses of theffects of sex and handedness, we used an unadjusted p � .05. Totudy medication effects, we compared areas and rates of growth inDHD participants who were treated with psychostimulantsgainst their unmedicated counterparts.

esults

ypically Developing ParticipantsEstimated rates of callosal growth increased for right-handed

ypically developing subjects moving rostral to caudal, with growthates slowest in Region I (estimated annual increase in area .32%, SE12%) and increasing in Region II (estimated annual increase 1.29%E .17%) and Region III (annual increase 2.11%, SE .22%), peaking in

igure 2. Estimated growth rates in right-handed, typically developing

Typically Developing Significance

130 (64.7%) �2 � .003, p � .95

3 (3.1) 201 10.7 (3.6) t � 1.1, p � .279 (3.6) 102 13.3 (3.9) t � .5, p � .636 (3.8) 46 14.1 (3.4) t � 2.0, p � .052 (3.6) 9 16.1 (2.2) t � .8, p � .40

3.5–23.0111 (13)

80 –142t � 1.8, p � .06

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eneralized anxiety disorder; ODD, oppositional defiant disorder.

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articipants. Bar indicates mean percent change per year in area and linesndicate � SE.

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Region IV (annual increase of 2.50%, SEM .30%), and decliningslightly in region V (annual increase 1.50%, SEM .10%; Figure 2). Forthe entire corpus callosum, the estimated annual growth rate was1.1%, SE .1%. A similar pattern of results was found for the non-right-handed group (Figure S1, Table S2 in Supplement 1).

No significant sex differences in growth rates emerged in the

Figure 3. (A) Estimated growth rates in right-handed participants by diag-nosis. Bars indicate estimated percent change per year in area. Linesindicate � SE. (B) Difference in annual percentage growth rates betweenright-handed participants with attention-deficit/hyperactivity disorder

Table 2. Mean Baseline Area (in mm2) in Right-Handed

MalesMean (SD)

UnadjustedRegion I 160.7 (28.2)Region II 147.4 (26.8)Region III 56.4 (12.8)Region IV 25.9 (7.4)Region V 174.0 (33.2)Total CC 564.3 (93.3)

Mean (SEM)

Adjusted for intracranial volumeRegion I 156.8 (2.07)Region II 145.6 (2.03)Region III 55.4 (1.01)Region IV 25.8 (.59)Region V 170.5 (2.30)Total CC 549.3 (6.30)

CC, corpus callosum.

(ADHD) and typically developing controls. Bars indicate estimated percentchange per year in area. Lines indicate � SE.

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ight-handed typically developing group (Table 2). At baseline,ales had larger callosal area in Regions I, II, and III. However, when

djustment was made for ICV, these differences were abolished oreversed.

ontrast with ADHDOur main hypothesis predicted different growth rates in the

nterior corpus callosum in right-handed ADHD compared withypically developing participants. The hypothesis was confirmed:he model term indicating the interaction of age and diagnosis inhe determination of callosal area (i.e., �3) was significant for Regiononly. The right-handed ADHD group had a higher estimated an-ual increase in Region I of .97% (SE .12%) compared with the

ypically developing group (.32%, SE .13%; t � 3.64, p � .0003;igure 3, Table 3). No other callosal subdivisions showed significantiagnostic differences in growth rates (for Region II: t � .32, p � .75;

or Region III: t � .52, p � .60; for Region IV: t � 1.05, p � .29; foregion V: t � .83, p � .41). The pattern of results held when adjust-ent was made for intracranial volume (difference in estimated

rowth rates for Region I of .61% [SE .18%] t � 3.3, p � .001; foregion II, difference in rates of .00009% [SE .002], t � .04, p � .96; foregion III, difference in rates of .003% [SE .003], t � .7, p � .48;

or Region IV, difference in rates of –.003% [SE .004], t � .67, p � .49;or Region V, difference in rates of .002% [SE .001], t � 1.1, p � .29).he estimated midsagittal areas (with 95% confidence intervals forhe estimate) for each callosal subregion over the course of devel-pment are shown in Figure 4. There were also no significant diag-

cally Developing Participants by Sex

Females DifferenceMean (SD) t (p)

151.5 (20.6) 2.40 (.02)139.7 (22.8) 2.04 (.04)

53.0 (11.3) 1.89 (.06)25.3 (6.2) .56 (.58)

170.8 (24.4) .71 (.48)540.3 (68.2) 1.91 (.06)

Mean (SEM) F(1,194), p

158.8 (2.84) F � .31, p � .58146.2 (2.79) F � .35, p � .56

55.7 (1.38) F � .21, p� .6526.8 (.81) F � 2.55, p � .11

180.0 (3.16) F � 8.19, p � .01567.5 (8.70) F � 2.65, p � .11

able 3. Estimated Growth Rates, in Estimated Percent Change per Yearn Area, with Standard Error of the Estimate, in Right-Handed Typically

eveloping and ADHD Participants

Estimated Value (SE) Difference

Typically Developing ADHD t (p)

egion I .32 (.13) .97 (.12) 3.64 (.0003)egion II 1.29 (.18) 1.37 (.17) .32 (.75)egion III 2.11 (.27) 2.30 (.26) .52 (.60)egion IV 2.50 (.32) 2.03 (.31) �1.05 (.29)egion V 1.50 (.12) 1.63 (.11) .83 (.41)otal CC 1.12 (.01) 1.39 (.01) 1.55 (.12)

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ADHD, attention-deficit/hyperactivity disorder; CC, corpus callosum.

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nostic differences in baseline areas in right-handed individuals,either unadjusted or after adjustment for ICV (Table 4).

No diagnostic differences were found for growth rates nor base-line areas for the non-right-handed participants (all p � .1; Tables

2–S4 in Supplement 1). We did not test for higher order interac-ions of diagnosis, handedness, and sex, given the small sampleizes.

orrelates of Comorbidity, Intelligence, Type of ADHD andedication

ODD and conduct disorder (CD) were the major comorbidities;thers were uncommon and not the focus of treatment. The pat-

ern of results held when the 83 right-handed subjects with ADHDnd comorbid ODD/CD were considered separately from thoseith ADHD uncomplicated by ODD/CD. Thus, for Region I, thoseith ADHD and ODD/CD had an estimated growth rate of .99%/

ear (SE .16%) compared with the rate of .96%/year (SE .17%) forhose with ADHD uncomplicated by ODD/CD, a nonsignificant dif-

Figure 4. (A-E) Estimated area (in mm2) by age in right-handed attention-eficit/hyperactivity disorder (ADHD) and typically developing participants

n callosal Regions I-V, respectively. Solid lines represent fitted growthurves, with dashed lines for 95% confidence intervals, estimated from

inear mixed model regression.

erence (t � .14, p � .89). These growth rates for Region I differed a

ignificantly from the typically developing group: for ADHD withDD/CD versus typically developing t � 3.22, p � .001; for ADHDncomplicated by ODD/CD versus typically developing t � 2.93,� .004. For all other regions, the ADHD groups divided into thoseith and without comorbid ODD/CD did not differ significantly

rom each other nor from the typically developing group (all p � .1).Results also held when analyses were confined to those with

ombined type ADHD only. For Region I, difference in growth ratesemained significant at t � 3.6, p � .001; all other regions did notiffer significantly. When IQ was entered as a covariate, the differ-nce in growth rates remained significant for Region I (t � 3.3, p �

001). There were no significant differences in baseline areas or inrowth rates in ADHD participants who were treated with psycho-timulants compared with those who were unmedicated; Tables S5nd S6 in Supplement 1.

iscussion

We confirm our hypothesis by demonstrating a selective abnor-ality in developmental trajectories of the anterior CC in right-

anded children and adolescents with ADHD relative to their typi-ally developing peers. This was predicted from our previousnding of anomalous development in ADHD of the asymmetry ofhe prefrontal cortical regions that are connected by the anterior CC5). The anomaly of corpus callosal development we now report wasynamic: although no significant diagnostic differences in areaere present at baseline in either right-handed or non-right-anded groups, significant diagnostic differences emerged whenelocities of growth were examined. Our longitudinal analysis cap-ured this “dysregulated” anterior growth trajectory in the right-anded ADHD cohort.

Interesting parallels and differences exist in other neuropsychi-tric disorders. There is some diagnostic specificity to the finding: inutism and early onset schizophrenia, there appears to be a pro-ressive loss of posterior callosal dimensions throughout child-ood (42,43). In obsessive-compulsive disorder, there is a childhood

ncrease, which is not sustained into adolescence (44). Althoughoth these patterns are distinct from those we find in ADHD, a closearallel to our findings has been reported in Tourette’s syndrome

45). In this disorder, the CC was smaller in childhood, but thisattern reversed by adulthood, implying an accelerated rate of CCrowth similar to that we report in ADHD. However, this anomalousrowth pattern was not localized to the anterior portions of the CCs in ADHD and cannot explain our results because Tourette’s syn-rome was an exclusionary criterion. Nonetheless, both findings

mply that a dysregulation of CC growth is an important feature ofeveral neuropsychiatric disorders. Perhaps the partial failure toevelop typical patterns of prefrontal cortical asymmetry in ADHD

eads to an increased reliance on interhemispheric processing withconcomitant increase in the dimensions of the anterior CC.

There is a complex story linking atypical cerebral lateralizationith ADHD. There is epidemiologic evidence that non-right-anded individuals, particularly those who are ambidextrous, haven increased risk of ADHD (46). Neurophysiological evidence fortypical prefrontal cortical lateralization includes abnormal left–ight electroencephalograph coherence (47,48), atypical asymme-ries in cerebral blood flow, and activation during cognitive tasks10,49), in addition to the abnormalities in tasks directly assessingnterhemispheric integration noted earlier. There is also geneticvidence linking atypical cerebral lateralization with ADHD be-ause polymorphisms of genes that are asymmetrically expressed

n the typical human cerebrum have been found to confer risk for

dult ADHD (50). Clinically, non-right-handed children with ADHD

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have more severe symptoms, although most studies are biased bythe use of referred samples (51). Our study adds to this work bysuggesting that atypical development of the anterior CC may re-flect or drive this tendency to atypical lateralization in ADHD.

Our findings also raise the question of whether developmentalanomalies of callosal growth in ADHD reflect or drive the anoma-lous development in prefrontal cortical asymmetry we reportedearlier (5). The primacy of an anomaly in CC structures derivessupport from evidence of anomalies of other midline, noncerebralbrain structures in ADHD. We recently found evidence that struc-tural compromise of the superior portion of the vermis, a cerebellarmidline structure, was a prominent structural anomaly in a cohort ofchildren with ADHD, a finding in line with many previous studies(52–56). Interestingly, the clustering of midline anomalies, such astotal or partial agenesis of the CC, along with vermis anomalies,has been linked to several cytogenetic lesions that may point toregions harboring genes that regulate CC growth (57). It is equallypossible that the CC anomalies are a downstream effect of disrup-tion in the development of prefrontal cortical asymmetry, given theevidence for regional reductions of the CC following injury to thecortex (58).

We previously reported delayed prefrontal cortical maturationin ADHD—a delay within which the development of anomalousasymmetries is nested (59). Could the CC findings be another in-stance of structural delay? Previous studies of typical callosal devel-opment have reported a rostrocaudal wave of peak growth rates(60,61) with peak growth rates of the anterior CC occurring in earlychildhood. Our main finding could thus be driven by a delayed endto this childhood phase of relatively fast anterior CC growth. Onemajor limitation of this explanation is that it does not explain thepersistence of rate differences into adolescence.

Additionally, this study constitutes the largest study to date oftypical development of the corpus callosum. We find increasingrates of growth moving rostral to caudal, with the slowest rate in theanterior-most callosal subdivision. This pattern was similar in bothsexes. At baseline, males had larger CC areas than females, but this

Table 4. Mean Baseline Area (in mm2) in Right-Handed

Typically DevelopingMean (SD) Range

UnadjustedRegion II 144.7 (25.6)

98.4 –232Region III 55.2 (12.3)

19.7–99.8Region IV 25.7 (7.0)

12.6 – 46.4Region V 172.9 (30.3)

99.8 –254.5Total CC 555.8 (85.8)

385.3– 832.5

Mean (SEM)

Adjusted for Intracranial VolumeRegion I 155.7 (1.73)Region II 143.3 (1.63)Region III 54.4 (.81)Region IV 25.3 (.48)Region V 170.3 (2.0)Total CC 555.8 (5.6)

ADHD, attention-deficit/hyperactivity disorder; CC, c

effect disappeared when adjustment was made for intracranial vol- i

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me (ICV)—a frequent finding in the study of morphometric sexifferences (62,63). The variability in growth rates was higher foregion IV and III, perhaps as these are the smallest CC regions withhe lowest reliability estimates, which could inflate variability. Ad-itionally, the fibers found in these midcallosal regions connectingensory areas are relatively large and show more variance in size17).

imitations

Our phenotype included mainly those with combined typeDHD, and we did not have sufficient numbers of inattentive andyperactive/impulsive subtypes to determine whether theyhowed a different pattern of callosal growth. We also did notollect measures of pubertal status on the ADHD group and thusre unable to tease apart the effects of chronological and pubertalge. We found no significant baseline differences with handedness

n the typically developing youth, although this finding should beegarded as preliminary because larger samples of non-right-anded individuals are needed to test more fully for possible effectsf handedness and its interaction with sex and diagnosis. We esti-ated corpus callosal area from one slice and did not attempt to

efine volume; thus we may have missed some anomalies in thick-ess that have been demonstrated in ADHD using this approach

64). Although we included data concerning the correlates of psy-hostimulant medication, these must be interpreted with caution,iven the small sample sizes involved and the observational naturef the data. There was no evidence of any cohort effect in our studyn measured variables, because there was no significant correlationetween age at study entry and IQ, socioeconomic status, or higherroportions of right-handed subjects or males. It remains possible

hat there are cohort differences on unmeasured variables thatight influence CC development, such as some age-related fac-

ors—for example, familial and scholastic environment.We could not determine the cognitive significance of these find-

ngs because we did not collect longitudinal data on tests reflecting

ipants by Diagnostic Group

ADHD DifferenceMean (SD) Range t (p)

141.3 (25.5)94.2–240.5

1.31 (.19)

53.7 (12.9)28.1–99.8

1.14 (.25)

25.4 (7.6)8.4 –52

.41 (.68)

170.2 (33.3)90 –268.6

.82 (.41)

545.5 (92.5)352.9 – 884.5

1.15 (.25)

Mean (SEM) F(1,372), p

157.8 (1.82) F � .70, p � .40144.4 (1.72) F � .23, p � .62

55.0 (.86) F � .27, p � .6126.0 (.51) F � .95, p � .33

173.6 (2.1) F � 1.38, p � .24548.9 (5.3) F � 1.03, p � .31

s callosum.

Partic

nterhemispheric integration mediated by the CC, such as dichotic

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listening tasks (65), lateralized naming tasks (66), and alternatefinger-tapping tasks (67). Recent studies suggest that children withADHD seem to be most impaired when tasks involve lateralizedprocessing in which the right hemisphere is challenged to mediatetasks it does not typically support, such as linguistic processing andcoordinating writing-like movements (68). Such tasks require rapidinterhemispheric integration with a recruitment of the left hemi-sphere, and the anterior CC anomalies may contribute to thesedeficits. Interestingly, the same study also found that measures ofatypical interhemispheric processing correlated with measures ofoppositional and defiant symptoms in these children.

This first large-scale longitudinal study of callosal growth trajec-tories informs our understanding of the dynamic nature of anoma-lous callosal development in ADHD and the disruptions in corticalasymmetry and connectivity that characterize the disorder.

Supported by the Intramural Research Program of the NationalInstitute of Mental Health.

All authors report no biomedical financial interests or potentialconflicts of interest.

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