Research

JAMA Psychiatry | Original Investigation

Association of White Matter Structure With Autism Spectrum

Disorder and Attention-Deficit/Hyperactivity Disorder
Yuta Aoki, MD, PhD; Yuliya N. Yoncheva, PhD; Bosi Chen, BA; Tanmay Nath, PhD; Dillon Sharp, BA;
Mariana Lazar, PhD; Pablo Velasco, PhD; Michael P. Milham, MD, PhD; Adriana Di Martino, MD

Editorial
IMPORTANCE Clinical overlap between autism spectrum disorder (ASD) and Supplemental content
attention-deficit/hyperactivity disorder (ADHD) is increasingly appreciated, but the
underlying brain mechanisms remain unknown to date.

OBJECTIVE To examine associations between white matter organization and 2 commonly

co-occurring neurodevelopmental conditions, ASD and ADHD, through both categorical and
dimensional approaches.

DESIGN, SETTING, AND PARTICIPANTS This investigation was a cross-sectional diffusion tensor
imaging (DTI) study at an outpatient academic clinical and research center, the Department of
Child and Adolescent Psychiatry at New York University Langone Medical Center. Participants
were children with ASD, children with ADHD, or typically developing children. Data collection
was ongoing from December 2008 to October 2015.

MAIN OUTCOMES AND MEASURES The primary measure was voxelwise fractional anisotropy
(FA) analyzed via tract-based spatial statistics. Additional voxelwise DTI metrics included
radial diffusivity (RD), mean diffusivity (MD), axial diffusivity (AD), and mode of anisotropy
(MA).

RESULTS This cross-sectional DTI study analyzed data from 174 children (age range, 6.0-12.9
years), selected from a larger sample after quality assurance to be group matched on age and
sex. After quality control, the study analyzed data from 69 children with ASD (mean [SD] age,
8.9 [1.7] years; 62 male), 55 children with ADHD (mean [SD] age, 9.5 [1.5] years; 41 male), and
50 typically developing children (mean [SD] age, 9.4 [1.5] years; 38 male). Categorical
analyses revealed a significant influence of ASD diagnosis on several DTI metrics (FA, MD, RD,
and AD), primarily in the corpus callosum. For example, FA analyses identified a cluster of
4179 voxels (TFCE FEW corrected P < .05) in posterior portions of the corpus callosum.
Dimensional analyses revealed associations between ASD severity and FA, RD, and MD in
more extended portions of the corpus callosum and beyond (eg, corona radiata and inferior
longitudinal fasciculus) across all individuals, regardless of diagnosis. For example, FA
analyses revealed clusters overall encompassing 12121 voxels (TFCE FWE corrected P < .05)
Author Affiliations: Department of
with a significant association with parent ratings in the social responsiveness scale. Similar Child and Adolescent Psychiatry at
results were evident using an independent measure of ASD traits (ie, children communication NYU Langone Medical Center, New
checklist, second edition). Total severity of ADHD-traits was not significantly related to DTI York (Aoki, Yoncheva, Chen, Nath,
Sharp, Di Martino); Center for
metrics but inattention scores were related to AD in corpus callosum in a cluster sized 716
Biomedical Imaging, Department of
voxels. All these findings were robust to algorithmic correction of motion artifacts with the Radiology, New York University
DTIPrep software. School of Medicine, New York
(Lazar); Center for Brain Imaging,
New York University, New York
CONCLUSIONS AND RELEVANCE Dimensional analyses provided a more complete picture of
(Velasco); The Nathan S. Kline
associations between ASD traits and inattention and indexes of white matter organization, Institute for Psychiatric Research,
particularly in the corpus callosum. This transdiagnostic approach can reveal dimensional Orangeburg, New York (Milham);
relationships linking white matter structure to neurodevelopmental symptoms. Child Mind Institute, New York, New
York (Milham).
Corresponding Author: Adriana
Di Martino, MD, Department of
Child and Adolescent Psychiatry
at NYU Langone Medical Center,
One Park Avenue, Seventh Floor,
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.2573 New York, NY 10016
Published online September 6, 2017. (adriana.dimartino@nyumc.org).

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 Research Original Investigation White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder
S
hared clinical and biological traits across psychiatric di-
agnoses have challenged the usefulness of a categori-
cal nosology of psychiatric disorders for biological
research.1-3 The challenges associated with categorical per-
spectives of illness are exemplified by the frequent clinical over-
lap between autism spectrum disorder (ASD) and attention-
deficit/hyperactivity disorder (ADHD).4-6 Whether such shared
clinical presentations reflect common underlying neural
mechanisms remains unknown to date.
In both ASD and ADHD, abnormal large-scale networks
have been consistently reported using a range of neuroimag-
ing methods.3,7-13 Among these modalities, diffusion tensor
imaging (DTI) can provide insight into the pathology of white
matter organization.14 Diffusion tensor imaging studies have
found atypical structural connectivity in individuals with
ASD15-17 or ADHD18,19 compared with typical controls, but the
findings were based on independent comparisons. These stud-
ies varied in regard to DTI metrics examined, specific spatial
locations, and the nature of the DTI abnormalities found in ASD
or ADHD. Nevertheless, in most cases, lower fractional anisot-
ropy (FA) in different areas of the corpus callosum (CC) has been
reported in ADHD19,20 or ASD15 relative to typical controls.
The only 2 studies21,22 that have directly contrasted white
matter structure in individuals with ADHD, those having ASD,
and typically developing children (TDC) yielded mixed re-
sults. One tractography study21 of 8 children with ASD, 20 chil-
dren with ADHD, and 20 TDC revealed disorder-specific pat-
terns of densely interconnected hubs (ie, rich clubs). Beyond
concerns about sample size, that preliminary study did not as-
sess the influence on white matter organization of co-
occurring ASD or ADHD symptoms across diagnoses, thus miss-
ing a potential source of commonalities in DTI associations. A
second DTI study22 applied tract-based spatial statistics (TBSS)
to a larger sample (n = 200) of school-aged children with ASD,
ADHD, or obsessive-compulsive disorder compared with TDC.
Decreased FA within the splenium of the CC was common
among the 3 groups.22 Brain-behavior relationships with symp-
tom domains characteristic of each disorder, examined sepa-
rately, did not yield significant findings.22 Therefore, the im-
plications of shared CC abnormalities remain unclear. While
functional MRI studies23,24 have shown the utility of stratify-
ing ASD subgroups based on ADHD comorbidity, no imaging
study to date has simultaneously examined both ASD and
ADHD dimensionally in the same sample.
Accordingly, to identify specific or shared patterns of white
matter organization, we analyzed DTI data from 174 school-
aged children with ASD, those having ADHD, or TDC. We ad-
opted both a categorical diagnostic approach (ie, compari-
sons of diagnostic groups) and dimensional analyses of ASD-
related and ADHD-related traits across diagnostic groups. The
Social Responsiveness Scale by Parents (SRS-P)25 and Con-
ners’ Parent Rating Scales–Revised: Long Version (CPRS-R:LV)26
were used for dimensional analyses. To examine their unique
contributions, these measures were included in the same
model, hence removing shared variance. Fractional anisot-
ropy was our primary measure of interest. Because other DTI
metrics may provide distinct complementary information
about white matter structure,27 although rarely investigated
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Key Points
Question Do the neural correlates of autistic traits extend across
diagnostic boundaries among children with autism spectrum
disorder and children with attention-deficit/hyperactivity
disorder?
Findings This cross-sectional diffusion tensor imaging study
analyzed data from 174 children, including 50 typically developing
children and children with a primary diagnosis of autism spectrum
disorder (n = 69) or attention-deficit/hyperactivity disorder
(n = 55). While categorical comparisons detected a significant
influence of autism spectrum disorder on multiple white matter
metrics in the corpus callosum, dimensional analyses yielded an
association with autism spectrum disorder symptoms and white
matter metrics in a set of both callosal and other tracts, regardless
of diagnosis.
Meaning The frequent co-occurrence of autism spectrum
disorder and attention-deficit/hyperactivity disorder symptoms
may reflect underlying neural mechanisms that transcend
diagnostic boundaries.
together in ASD or ADHD, 20 secondary analyses also ex-
plored voxelwise mean diffusivity (MD), radial diffusivity (RD),
axial diffusivity (AD), and mode of anisotropy (MA). Data col-
lection was ongoing from December 2008 to October 2015.
Methods
Participants
We analyzed data from 174 children (age range, 6.0-12.9 years),
including 50 TDC and children with a primary diagnosis of
either ASD (n = 69) or ADHD (n = 55), selected from a larger
sample after quality assurance (see “Preprocessing” and the
eAppendix in the Supplement) to be group matched on age and
sex (Table and eTable 1 in the Supplement). Clinicians’ diag-
noses of ASD and ADHD were based on DSM-IV-TR codes sup-
ported by parent interview, direct observation, available
teacher forms, and prior records (eAppendix in the Supple-
ment). Autism spectrum disorder diagnosis was supported by
the Autism Diagnostic Observation Schedule (research reli-
able n = 68) 28,29 and the Autism Diagnostic Interview–
Revised (research reliable n = 65).30,31 Absence of Axis I diag-
nosis per the S chedule for Affec tive Disorders and
Schizophrenia for School-Age Children–Present and Lifetime
Version32 and absence of a history of psychotropic medica-
tion use were required for inclusion as TDC. Exclusion crite-
ria for all participants were current use of antipsychotics,
known genetic diseases, or below 80 on the estimated full-
scale IQ.33,34
To discern brain-behavior relationships, we used parent
ratings of ASD traits and ADHD traits indexed by SRS-P total T
scores25 and CPRS-R:LV DSM-IV total T scores,26 respectively
(eFigure 1 in the Supplement). Parent ratings of the Children’s
Communication Checklist 2 (CCC-2)35 and the Child Behavior
Checklist36 further characterized the sample. Parents also re-
ported on race and socioeconomic status indexed by the Four-
Factor Index of Socioeconomic Status by Hollingshead.37 Data
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 White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder Original Investigation Research

Table. Participant Characteristics

ASD ADHD TDC
Variable (n = 69) (n = 55) (n = 50) df F χ2 Scorea P Value Post hoc
Age, mean (SD), y 8.9 (1.7) 9.5 (1.5) 9.4 (1.5) 2,171 2.7 .07 NA
IQ, mean (SD)
Full 109 (17) 110 (14) 114 (13) 2,171 1.4 .26 NA
Verbal 108 (16) 110 (13) 114 (15) 2,171 2.4 .10 NA
Performance 110 (19) 108 (16) 111 (14) 2,171 0.5 .63 NA
Handedness score, mean (SD)b 0.6 (0.4) 0.6 (0.3) 0.6 (0.3) 2,168 0.4 .65 NA
CPRS-R:LV T scores, mean (SD)c
DSM-IV inattention 63.7 (10.7) 71.3 (9.6) 46.1 (6.3) 2,170 100.3 <.001 ADHD>ASD>TDC
DSM-IV hyperactivity/impulsivity 63.3 (11.5) 68.4 (12.0) 47.1 (6.2) 2,170 58.7 <.001 ADHD>ASD>TDC
DSM-IV total 64.4 (10.1) 71.5 (9.5) 46.2 (6.1) 2,170 108.1 <.001 ADHD>ASD>TDC
CTRS-R:LV T scores, mean (SD)d
DSM-IV inattention 59.0 (8.2) 64.1 (11.5) 45.2 (4.6) 2,114 33.9 <.001 ADHD>ASD>TDC
DSM-IV hyperactivity/impulsivity 57.5 (10.3) 62.1 (13.8) 45.9 (4.1) 2,114 17.2 <.001 ADHD = ASD>TDC
DSM-IV total 58.4 (9.7) 64.5 (11.3) 45.3 (4.5) 2,114 32.5 <.001 ADHD>ASD>TDC
SRS-P total T scores, mean (SD)e 74.9 (14.0) 62.8 (16.4) 45.4 (7.3) 2,168 70.2 <.001 ASD>ADHD>TDC
SRS-T total T scores, mean (SD)f 63.0 (8.8) 54.4 (8.6) 42.8 (3.5) 2,114 49.2 <.001 ASD>ADHD>TDC
Child Behavior Checklist T scores,
mean (SD)g
Attention problems 66.6 (9.8) 70.2 (10.7) 52.4 (4.1) 2,69 57.3 <.001 ADHD = ASD>TDC
Internalizing problems 62.7 (8.9) 60.3 (9.8) 47.3 (9.6) 2,169 41.7 <.001 ASD = ADHD>TDC
Externalizing problems 56.7 (9.3) 60.2 (9.7) 43.7 (9.9) 2,169 42.5 <.001 ADHD = ASD>TDC
Total problems 63.5 (8.6) 64.4 (7.6) 43.5 (11.2) 2,169 88.0 <.001 ADHD = ASD>TDC
Children’s Communication Checklist
2 scaled score, mean (SD)h
Inappropriate initiation 5.9 (1.9) 6.9 (2.7) 11.0 (2.9) 2,160 64.8 <.001 TDC>ADHD = ASD
Stereotyped language 5.6 (3.1) 7.8 (3.7) 10.2 (2.8) 2,160 28.9 <.001 TDC>ADHD>ASD
Use of context 4.2 (2.4) 7.0 (4.0) 10.6 (3.2) 2,160 58.0 <.001 TDC>ADHD>ASD
Nonverbal communication 3.6 (2.5) 7.0 (3.4) 10.3 (3.0) 2,160 75.6 <.001 TDC>ADHD>ASD
Social relations 3.4 (2.9) 5.5 (3.1) 9.3 (3.1) 2,160 54.8 <.001 TDC>ADHD>ASD
Interests 5.0 (1.8) 6.6 (2.3) 10.6 (3.4) 2,160 70.6 <.001 TDC>ADHD>ASD
Global communication 44.5 (16.6) 59.8 (21.8) 83.3 (19.6) 2,160 58.1 <.001 TDC>ADHD>ASD
composite
Social interaction deviance −7.0 (12.6) −5.1 (9.2) 0.2 (7.2) 2,160 7.3 .001 TDC>ADHD = ASD
composite
Motion, mean (SD), mm
Mean 3.6 (0.7) 3.6 (0.6) 3.4 (0.7) 2,171 0.8 .45 NA
Maximum 6.0 (1.5) 6.4 (2.5) 6.1 (1.8) 2,171 0.6 .57 NA
Male, No./total No. (%) 62/69 (89.9) 41/55 (74.5) 38/50 (76.0) 2 5.8 .05 NA
Socioeconomic status class 4 or 5, 50/62 (80.6) 33/49 (67.3) 30/44 (68.1) 2 3.1 .21 NA
No./total No. (%)i
Race, No.j
White 45 27 24
African American 6 12 8 4 5.7 .22 NA
Other 17 13 14
ADOS, mean (SD)k
Social affect 8.8 (3.4) NA NA NA NA NA NA
RRBs 3.0 (1.6) NA NA NA NA NA NA
ADOS 11.8 (3.9) NA NA NA NA NA NA
Calibrated severity score 6.8 (2.0) NA NA NA NA NA NA

(continued)

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 Research Original Investigation White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

Table. Participant Characteristics (continued)

ASD ADHD TDC
Variable (n = 69) (n = 55) (n = 50) df F χ2 Scorea P Value Post hoc
Autism Diagnostic
Interview–Revised, mean (SD)l
Social 17.2 (6.0) NA NA NA NA NA NA
Nonverbal communication 8.4 (3.2) NA NA NA NA NA NA
Verbal communication 14.3 (4.4) NA NA NA NA NA NA
RRBs 5.4 (2.4) NA NA NA NA NA NA
g
Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ADOS, Autism Parent scores on the Child Behavior Checklist were missing in 1 child with ASD
Diagnostic Observation Schedule; ASD, autism spectrum disorder; CPRS-R:LV, and 1 typically developing child.
Conners’ Parent Rating Scales–Revised: Long Version; CTRS-R:LV, Conners’ h
Parent scores on the Children’s Communication Checklist 2 were missing in 3
Teacher Rating Scales–Revised: Long Version; NA, not applicable; RRBs, children with ADHD, 1 child with ASD, and 1 TDC.
restricted and repetitive behaviors; SRS-P, Social Responsiveness Scale by i
Data on socioeconomic status were missing in 6 children with ADHD, 7
Parents; SRS-T, Social Responsiveness Scale by Teachers; TDC, typically
children with ASD, and 6 TDC.
developing children.
j
a Information was missing in 1 child with ASD and 5 children with ADHD. “Other”
F scores are reported for continuous variables χ2 for categorical variables.
includes Asian and mixed races.
b
Handedness was missing in 1 child with ADHD and 2 children with ASD. k
Forty-eight children with ASD were evaluated with the ADOS generic, and 21
c
Parent scores on the CPRS-R:LV were missing in 1 typically developing child. children with ASD were evaluated with module 3 of the ADOS second edition
d
Teacher scores on the CTRS-R:LV were missing in 3 children with ADHD, 28 algorithm by Gotham et al.28 All schedules but one were administered and
children with ASD, and 26 TDC. coded by research-reliable evaluators.
e l
Parent scores on the CPRS-R:LV were missing in 1 typically developing child. Sixty-five children with ASD were evaluated with the research-reliable Autism
f
Teacher scores on the SRS-T were missing in 3 children with ADHD, 28 children Diagnostic Interview–Revised.
with ASD, and 26 TDC.

from 29 TDC and 29 children with ADHD in our sample were
included in a previous DTI study.38 The institutional review
boards of the New York University and the New York Univer-
sity School of Medicine granted ethical approval of the study.
Written parental consent and verbal assent were obtained for
all participants; children older than 7 years also provided writ-
ten informed assent.
children with ASD, 66 of 82 children with ADHD, and 68 of 79
TDC passed quality assurance; they did not differ from those
excluded in demographic or primary clinical measures (eTable
2 and eTable 3 in the Supplement). As detailed in the eAppendix
in the Supplement, to match diagnostic groups by age and sex,
11 children with ADHD and 18 TDC were further excluded,
yielding a final sample of 174 children.

Data Acquisition TBSS Proprocessing

Two DTI scans were acquired using a twice-refocused diffusion-
weighted echoplanar imaging sequence (repetition time, 5200
milliseconds; echo time, 78 milliseconds; 50 sections; 64 × 64–
pixel acquisition matrix; field of view, 192 mm; voxel size,
3 × 3 × 3 mm; 64 noncollinear diffusion directions, uniformly dis-
tributed around a unit sphere with B value of 1000 s/mm2; 1 im-
age with no diffusion weighting) at the New York University Cen-
ter for Brain Imaging using a 3.0-T imaging system (Allegra;
Siemens). We obtained T1-weighted images using 3-dimen-
sional magnetization-prepared rapid acquisition gradient echo
for anatomical registration (eAppendix in the Supplement).
Preprocessing
To enhance signal to noise, analyses were conducted only in chil-
dren who completed 2 DTI scans. Analyses were conducted with
Functional Magnetic Resonance Imaging of the Brain (FMRIB)
Software Library version 5 (http://www.fmrib.ox.ac.uk). Quality
assurance involved eddy current and motion corrections, as well
as removal of nonbrain tissue. Our head motion index was the
mean absolute intervolume displacement with respect to the first
image of each run; root-mean-square (RMS) deviation was
calculated using FSL (the FMRIB Software Library) rmsdiff.39
Given that motion introduces artifacts in DTI metrics,40 we only
included data with a mean absolute RMS less than 5 mm and
image quality passing visual inspection. As a result, 69 of 83
First, nonlinear registration to a common space was con-
ducted by aligning each participant’s FA image to the Mon-
treal Neurologic Institute 152 space template. Then, a mean FA
image and a mean FA skeleton of the aligned images were cre-
ated. Voxelwise analyses were subsequently conducted for
skeleton areas with an FA of at least 0.2. Analyses with more
stringent FA thresholds (ie, ≥0.25 and ≥0.3) yielded similar re-
sults (eFigure 2 in the Supplement). Voxelwise analyses for sec-
ondary DTI metrics were conducted using values projected
onto the mean FA skeleton.
Group Analyses
Categorical Approach
To examine the main influence of diagnosis on DTI metrics,
we performed an F test using FSL Randomize.41 Age, sex, and
motion were included as nuisance covariates. Statistical sig-
nificance was set at threshold-free cluster enhancement (TFCE)
P < .05 to control for familywise error (FWE) rate (α = .05), thus
accounting for multiple comparisons.42 Post hoc pairwise group
comparisons were conducted for clusters showing signifi-
cant main group associations for each metric separately.
Dimensional Approach
We assessed the association between DTI metrics and ASD traits
or ADHD traits (indexed by SRS-P or CPRS-R:LV DSM-IV total

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 White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder
Figure 1. Results of Categorical Analyses
R
x=7 y = −29
R MD AD
FA 12
11
0 6 0 Dimensional Approach
2229 0 210
295
0 243
1 514
1140
z = 25 TFCE FWE corrected P <.05
The x, y, and z are Montreal Neurologic Institute coordinates. Fractional
anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial
diffusivity (RD) showed significant influences of diagnosis. Statistically
significant clusters converged in the corpus callosum, especially the anterior
portions. FWE indicates familywise error; R, right; and TFCE, threshold-free
cluster enhancement. The numbers in the Venn diagram denote the number of
voxels in the clusters that were significant for each diffusion tensor imaging
metric alone or combined with any of the others. Secondary post hoc group
comparisons showed that these differences were driven by autism spectrum
diagnosis (eFigure 6 in the Supplement).
T scores, respectively) using FSL Randomize across all partici-
pants, regardless of diagnosis (ie, ASD, ADHD, and TDC). Nui-
sance covariates were age, sex, and motion. In addition, to iden-
tify their unique contributions to brain-behavior relationships
and given their significant relationship (r = 0.59, df = 169,
P < .001), we included both SRS-P and CPRS-R:LV DSM-IV total
T scores in the same model. There was no multicollinearity across
covariates (variation inflation factor <4).43 Analogous to the cat-
egorical approach, statistical significance was set at TFCE FWE
corrected 1-sided P < .05. For interpretation, only TBSS results
within the International Consortium for Brain Mapping DTI-81
atlas44 are reported and labeled accordingly (raw images are
shown in eFigures 3, 4, and 5 in the Supplement).
Results
Categorical Approach
Fractional Anisotropy
Values in clusters located in the genu, body, and splenium of
the CC differed across diagnostic groups (overall 4179 voxels;
Figure 1 and eTable 4 in the Supplement). Post hoc analyses
revealed significantly lower FA among children with ASD com-
pared with both children with ADHD and TDC in these clus-
ters. Children with ADHD and TDC did not differ significantly
in regard to the mean FA for these clusters (eFigure 6 in the
Supplement).
Other DTI Metrics
A significant influence of ASD diagnosis was also evident in
several portions of the CC for all DTI metrics examined ex-
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Original Investigation Research
cept MA (Figure 1 and eTable 4 in the Supplement). Similar to
the FA results, children with ADHD did not differ signifi-
cantly from TDC in any of the diffusivity metrics or MA. In these
clusters, children with ASD had significantly higher mean MD,
RD, and AD compared with those having ADHD and TDC (eFig-
ure 6 in the Supplement). The number of voxels identified by
these categorical TBSS analyses of MD, RD, and AD was 1280,
2721, 523, respectively. Across these DTI metrics, ASD-
related abnormalities converged on the midbody and ante-
rior portions of the CC (Figure 1).
RD
318
Fractional Anisotropy
Dimensional analyses revealed a significant relationship be-
tween FA and SRS-P total T scores but not for CPRS-R:LV
DSM-IV total T scores. Specifically, across participants, FA was
significantly and negatively related to SRS-P scores in clus-
ters overall encompassing 12121 voxels extending from ante-
rior to posterior regions of the CC and other tracts not identi-
fied by the categorical approach (Figure 2 and eTable 5 in the
Supplement). These tracts extending within and outside the
CC encompassed the anterior limb of the internal capsule, the
inferior longitudinal fasciculus, and the corona radiata.
Other DTI Metrics
Among our 4 complementary DTI metrics, MD and RD were
significantly positively related to SRS-P total T scores in clus-
ters of 18058 and 15441 voxels, respectively. These relation-
ships converged in the CC, corona radiata, and inferior longi-
tudinal fasciculus areas that were also identified in FA analyses
(Figure 2 and eTable 5 in the Supplement).
Follow-up Analyses
Validating DTI-ASD Dimensional Relationship
To ensure that the above associations in the Dimensional Ap-
proach subsection did not simply depend on ASD diagnosis,
we assessed the relationship between SRS-P total T scores and
FA measures at the clusters identified in TBSS analyses across
all children after regressing out the nuisance covariates and ASD
diagnostic status (ie, ASD is 1, and non-ASD is 0). The pattern
of results was similar to that observed in primary analyses
(β6,164 = −0.27, P = .01). Similar findings were obtained for MD
(β6,164 = 0.32) and RD (β6,164 = 0.31) (P = .005 for both). To verify
this pattern’s robustness to TFCE FWE correction, we re-
peated a TBSS dimensional DTI-SRS analysis adding ASD mem-
bership as a nuisance covariate. The pattern of DTI-SRS rela-
tionships was similar to the patterns identified in primary
analyses, particularly at corrected P < .10 (eFigure 7 in the
Supplement).
Furthermore, given concerns that SRS-P total T scores may
be confounded by non-ASD behavioral symptoms,45 second-
ary analyses examined the reproducibility of these relation-
ships using an alternative, independent measure of ASD traits.
We focused on the 5 subscales of the CCC-2 capturing prag-
matic aspects of language and behaviors commonly impaired
in ASD. After regressing the influences of age, sex, motion, and
CPRS-R:LV DSM-IV total T scores, we tested the relationships
between these CCC-2 scaled scores and the mean FA, MD, and
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 Research Original Investigation White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder

Figure 2. Results of Dimensional Analyses for the Social Responsiveness Scale by Parents (SRS-P)

7 × 10−2 FA
ASD
R TDC
ADHD
SRS-P
−50 50

−7 × 10−2

−8 × 10−5 RD
x=7
y = −29
6
2229 0 0 SRS-P
FA RD
R −50 50

2736
1400 2124
−8 × 10−5
7974
8 × 10−5 MD
11 5224

SRS-P
2232
−50 50
MD
z = 25
TFCE FWE Corrected P <.05 −8 × 10−5

The x, y, and z are Montreal Neurologic Institute coordinates. The dimensional
approach identified clusters in which fractional anisotropy (FA), radial diffusivity
(RD), and mean diffusivity (MD) were associated with SRS-P total T scores.
Clusters identified by these 3 diffusion tensor imaging metrics converged in the
corpus callosum from its anterior to posterior regions. The numbers in the Venn
diagram denote the number of voxels in the clusters that were significant for
each diffusion tensor imaging metric alone or combined with any of the others.
In the right column, scatterplots show the relationship across all participants
between each diffusion tensor imaging metric and SRS-P total T scores
(residuals accounting for the nuisance covariates included in the model are
plotted). ADHD indicates attention-deficit/hyperactivity disorder; ASD, autism
spectrum disorder; FWE, familywise error; R, right; TDC, typically developing
children; and TFCE, threshold-free cluster enhancement.

RD values in the clusters identified in primary voxelwise di-
mensional analyses. Results were in line with the pattern ob-
served with SRS-P total T scores. Use of context, stereotyped
language, and nonverbal communication subscale scores were
significantly and positively related to FA in these clusters
(β 5162 = 0.22, 0.22, 0.18, and P = .01, 0.01, 0.05, respec-
tively); use of context and stereotyped language were nega-
tively associated with RD (β5162 = ⫺0.25 and ⫺0.20, P = .004 and
0.02, respectively) and MD (β5162 = ⫺0.27 and ⫺0.18, P = .002
and 0.04, respectively) (eFigure 8 in the Supplement).
Exploring the ADHD Subdomains
Because no significant DTI relationships were identified in re-
gard to CPRS-R:LV DSM-IV total T scores for any DTI metrics ex-
amined, we secondarily explored whether subscores of the
ADHD subdomains (ie, inattention and hyperactivity/
impulsivity) may provide additional information. We first per-
formed dimensional TBSS analyses of CPRS-R:LV DSM-IV inat-
tention and hyperactivity/impulsivity T scores separately
(controlling for each other in the same model while also includ-
ing age, sex, and motion). Results indicated a significant rela-
tionship of CPRS-R:LV DSM-IV inattention T scores with AD in
a cluster of 716 voxels localized the anterior and middle CC
(eTable 6 and eFigure 9A in the Supplement). Given that SRS-P
total scores were positively associated with both CPRS-R:LV
DSM-IV subdomains, to determine the specificity of the AD-
inattention relationship, we repeated analyses, including SRS-P
in the model. Results indicated significant effects of CPRS-
R:LV DSM-IV inattention T scores for AD in clusters of overall
6142 voxels centered in CC, as well as for MD in a small cluster
with 37 voxels in the posterior CC (eTable 7 and eFigure 9B in
the Supplement). No significant relationships were detected
with CPRS-R:LV DSM-IV hyperactive/impulsivity T scores.
DTIPrep-Based Analyses
To further address concerns about head motion, we repeated
group TBSS analyses after automatic artifact correction using
DTIPrep (eAppendix in the Supplement).46 The pattern of re-
sults was similar to the patterns reported above in the Cat-
egorical Approach and Dimensional Approach subsections and
in Exploring the ADHD Subdomains in the Follow-up Analy-
ses subsection (eFigures 5, 10, and 11 in the Supplement).
Discussion
We assessed white matter organization within and beyond the
diagnostic boundaries of ASD and ADHD using TBSS analyses
in a moderately large, well-characterized, and low-motion
sample of 174 school-aged children with ASD, those having
ADHD, or TDC. Taken together, our results indicate that white
matter organization was affected by both ASD diagnosis and ASD

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 White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder
traits across diagnoses. While categorical analyses revealed
white matter abnormalities only in children with ASD, dimen-
sional analyses provided a more complete picture of the influ-
ence of ASD or ADHD symptoms on white matter. By indexing
individuals as a function of ASD severity, our approach re-
vealed brain-behavior relationships, regardless of diagnostic sta-
tus. Notably, these relationships were observed across distinct
measures of ASD traits (SRS-P and CCC-2) while controlling for
ADHD severity, thereby underscoring the specific role of autis-
tic traits. Although ADHD total T scores were not significantly
related to any DTI metrics, ADHD subdomain analysis re-
vealed a significant dimensional association, primarily be-
tween AD and inattention, mostly localized in the CC.
Consistent with models emphasizing the role of abnor-
mal interhemispheric interactions in neurodevelopmental
disorders,47-51 results from both our categorical and dimen-
sional approaches converged on the CC. Lower FA, along with
greater MD and RD, in multiple CC regions both characterized
ASD diagnosis, as well as ASD traits across children. While atypi-
cal DTI findings in CC regions have been consistently re-
ported in prior studies15,19,20 comparing ASD or ADHD vs TDC
separately, our assessment of both ASD and ADHD dimen-
sions across groups provided a novel perspective on the in-
fluence of ASD traits on white matter organization in both dis-
orders. Indeed, emerging clinical evidence highlights the
significance of autistic traits in a substantial group of chil-
dren with ADHD and vice versa.5,6 Still, their underlying neu-
ral mechanisms have been virtually ignored to date. Findings
of brain-behavior relationships that are specific to the ASD do-
main and yet shared across disorders suggest that these are po-
tentially shared biomarkers. Future longitudinal studies may
elucidate whether common developmental pathways exist.
The wide spatial extent of significant findings emerging
from dimensional analyses of ASD symptoms likely reflects the
multifaceted nature of ASD-related impairments. The poste-
rior CC has been shown to be involved in sensory and visuo-
spatial processing.52,53 In contrast, consistent with its role of
connecting the bilateral frontal cortex,54 the anterior CC has
been associated with social functioning impairment in ASD.17
The midbody of the CC connects the bilateral premotor, pri-
mary motor, and primary sensory cortex,55 suggesting that
atypicalities in this CC region are related to sensory and mo-
tor processing abnormalities. Social, sensorimotor, and lan-
guage impairments have also been previously reported in chil-
dren with ADHD, but their nature remains unclear. 56-58
Different dimensional impairments common to children with
ASD or ADHD may account for our findings. Future studies that
include fine-grained measures of ASD subdomains and are ob-
tained from multiple sources and in large samples are needed
to differentiate the specific functional roles of these tracts in
children with ASD and ADHD.
Although dimensional analyses with combined ADHD (ie,
inattention and hyperactivity/impulsivity combined) re-
vealed no significant relationships, those exploring inatten-
tion did. These findings converged on the CC and affected AD,
which did not relate to ASD symptoms. A tantalizing hypoth-
esis is that abnormalities in different aspects of white matter
structure might correspond to distinct psychopathological pro-
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Original Investigation Research
files. This hypothesis can only be tested with larger samples
and more advanced diffusion methods able to capture finer
aspects of white matter organization.59,60 Overall, the results
herein suggest that brain-behavior relationships vary depend-
ing on the ADHD subdomains; therefore, inclusion of ADHD
heterogeneous samples without accounting for their core sub-
domains may have contributed to prior conflicting findings.
Lack of regional differences associated with ADHD diag-
nosis is not consistent with results of some prior TBSS stud-
ies, including meta-analyses.20,61 Several scenarios can ex-
plain this inconsistency. First, the effect size of white matter
abnormalities in ADHD may be small and thus missed in mul-
tiple-group comparisons. Second, as discussed in the previ-
ous paragraph, more homogeneous ADHD presentations may
be necessary to detect group differences. Third, negative find-
ings for ADHD diagnosis may reflect our emphasis on groups
not differing in head motion. Indeed, our negative findings are
consistent with recent reports38,62,63 verifying lack of group dif-
ferences in head motion.20 Fourth, other additional factors may
contribute to discrepancies related to ADHD diagnosis. Simi-
lar to the present work, a recent study22 compared multiple
disorders using a broader range of diagnoses (ie, ASD, ADHD,
and obsessive-compulsive disorder). While the authors re-
ported low FA in the posterior CC for each of the 3 clinical
groups relative to controls, our analyses only revealed low FA
with respect to ASD diagnosis and traits. In comparing that
study and the present study, we note that our ADHD sample
had a lower rate of medication use and lower prevalence of psy-
chiatric comorbidities, both of which have been reported to
affect diffusion findings in ADHD.62,64 Our results under-
score the need for future comprehensive investigations of fac-
tors contributing to clinical heterogeneity in substantially large
samples, by using multimodal objective phenotypic assess-
ments and approaches that facilitate replication, such as those
providing for open data sharing.65,66
Limitations
Our findings should be interpreted in light of some limita-
tions. First, although we assessed both categorical and dimen-
sional models, we did not test their interactions (hybrid analy-
ses) as done in prior studies67,68 that only examined either ASD
or ADHD. Measuring interactions between diagnostic status and
2 psychopathological dimensions requires larger samples than
have been seen to date to capture optimal distributions of both
traits within each group. Ideally, these studies should use gold
standard diagnostic measures of ASD (ie, the Autism Diagnos-
tic Observation Schedule 28,29 or the Autism Diagnostic
Interview–Revised30,31) across all groups to confirm exclu-
sion of ASD in ADHD and TDC, as well as providing indepen-
dent metrics of ASD severity. Unfortunately, the extensive train-
ing requirements and lengthy administrations limit their use
in non-ASD populations. Abbreviated assessments, such as the
recently validated Autism Symptom Interview, School-Age,69
may bypass this concern. Second, although the diagnostic
groups did not differ significantly in sex distribution, most par-
ticipants were male, reflecting the higher prevalence of boys
in ASD and ADHD.70 Therefore, results herein may not gener-
alize to girls.
(Reprinted) JAMA Psychiatry Published online September 6, 2017 E7
 Research Original Investigation
Conclusions
In summary, our dimensional approach was more sensitive in
detecting brain-behavior relationships with ASD traits and
ADHD traits than the categorical approach. The clinical obser-
ARTICLE INFORMATION
Accepted for Publication: June 29, 2017.
Published Online: September 6, 2017.
doi:10.1001/jamapsychiatry.2017.2573
Author Contributions: Drs Aoki and Di Martino had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Aoki, Yoncheva, Milham,
Di Martino.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Aoki, Di Martino.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: Aoki, Yoncheva, Nath, Milham,
Di Martino.
Obtained funding: Aoki, Di Martino.
Administrative, technical, or material support: Aoki,
Chen, Nath, Sharp, Velasco, Di Martino.
Study supervision: Milham, Di Martino.
Conflict of Interest Disclosures: Dr Di Martino
reported receiving royalties from the publication of
the Italian version of the Social Responsiveness
Scale–Child Version. No other disclosures were
reported.
Funding/Support: This work was supported in part
by the Japan Society for the Promotion of Science,
the Kanae Foundation for the Promotion of Medical
Science, and the Uehara Memorial Foundation (Dr
Aoki). Funding was also provided by grants
K23MH087770 and R01MH105506 (Dr Di Martino)
and grants R01MH081218 and R01HD065282 from
the Leon Levy Foundation (Dr Di Martino).
Role of Funder/Sponsor: The funding
organizations had no role in the design and conduct
of the study; collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Additional Contributions: F. Xavier Castellanos,
MD (Child Study Center at NYU Langone Medical
Center and The Nathan S. Kline Institute for
Psychiatric Research) contributed helpful
discussions and editorial suggestions (no
compensation was received). We are grateful to the
children and parents who generously contributed
their time to this research. We thank the supporting
staff at the New York University Center for Brain
Imaging for their technical support. We also thank
the research staff at the Autism Research and
Clinical Program and the Phyllis Green and
Randolph Cowen Institute for Pediatric
Neuroscience of the Child Study Center at New York
University Langone Medical Center for their help in
aspects of participant recruitment, assessment,
data collection, and data entry.
Additional Information: Some data included in this
article were deposited as fully anonymized data in
the Autism Brain Imaging Data Exchange (http:
E8 JAMA Psychiatry Published online September 6, 2017 (Reprinted)
© 2017 American Medical Association. All rights reserved.
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White Matter Structure in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder
vation that these traits extend across diagnostic categories4,6
likely reflects shared underlying neural mechanisms. There-
fore, this study emphasizes investigations of constructs and
domains transcending traditional categorical boundaries, with
the ultimate goal of identifying biomarkers on the path to-
ward precision medicine.71,72
//fcon_1000.projects.nitrc.org/indi/abide/) or the
National Database for Autism Research (http://ndar
.nih.gov/).
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