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Cerebral Cortex Advance Access published November 2, 2011

Cerebral Cortex
doi:10.1093/cercor/bhr292

Is There a Common Neuroanatomical Substrate of Language Deficit between Autism


Spectrum Disorder and Specific Language Impairment?
Judith S. Verhoeven1-3, Nathalie Rommel4, Elena Prodi3,5, Alexander Leemans6, Inge Zink4, Ellen Vandewalle4, Ilse Noens2,7,8,
Johan Wagemans2,9, Jean Steyaert2,10,11, Bart Boets2,7,10, Ann Van de Winckel12, Paul De Cock1,2,13, Lieven Lagae1 and
Stefan Sunaert2,3
1

Address correspondence to Dr Stefan Sunaert, Department of Radiology, University Hospitals of the Catholic University of Leuven, Herestraat 49,
3000 Leuven, Belgium. Email: Stefan.sunaert@uzleuven.be.

Discussion of an overlap between specific language impairment


(SLI) and autism spectrum disorder (ASD) is on going. The most
intriguing overlap between both phenotypes is the similarity in the
observed language deficits described in SLI and a subgroup of ASD
with co-occurring linguistic impairment, ASD-LI. Examining
whether a similar neuroanatomical substrate underlies this
phenotypical linguistic overlap, we studied the white matter
microstructural properties of the superior longitudinal fascicle
(SLF) of 19 ASD-LI adolescents (mean age 13.8 6 1.6 years) and 21
age-matched controls and compared them with 13 SLI children
(mean age 10.1 6 0.4 years) and 12 age-matched controls. A
linguistic profile assessment and a diffusion tensor imaging
analysis of the SLF were performed. Linguistic testing revealed
a mixed receptive--expressive disorder profile in both groups,
confirming their overlap at phenotypical level. At neuroanatomical
level, no significant differences in mean SLF fractional anisotropy
(FA) and mean SLF apparent diffusion coefficient values between
ASD-LI participants and controls were seen. By contrast, the mean
SLF FA was significantly reduced in the SLI children as compared
with their controls. The observation of structural SLF disturbances
in SLI but not in ASD-LI suggests the existence of a different
neuroanatomical substrate for the language deficits in both
disorders.
Keywords: autism spectrum disorder, diffusion tensor imaging, specific
language impairment, superior longitudinal fascicle

Introduction
A possible overlap between autism spectrum disorder (ASD)
and specic language impairment (SLI) has been the subject of
debate for more than 3 decades (Bartak et al. 1975; Williams
et al. 2008). In theory, a clear distinction can be made between
both disorders. SLI is dened as a failure in spoken language
development, despite average nonverbal intelligence, adequate
hearing and vision, absence of neurological, physical, emotional, or social problems, and adequate opportunity to acquire
spoken language skills (Goorhuis and Schaerlaekens 2000;
The Author 2011. Published by Oxford University Press. All rights reserved.
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Verhoeven and van Balkom 2004). Although SLI includes


children with varying proles, arising from combinations of
decits in particular areas of communication (phonology,
morphology, syntax, semantics, and pragmatics), the conventional view of SLI maintains that pragmatic skills are often intact
and that the child may communicate reasonably despite having
limited structural language skills. Decits in each area can
include receptive and/or expressive aspects (Conti-Ramsden
and Botting 2004). In children with ASD, failure in spoken
language development represents only one possible aspect of
a more general problem of restricted verbal and nonverbal
communication. In contrast to SLI, failure in spoken language is
by convention situated in the pragmatic domain while
structural language skills can be intact. In addition, children
with ASD have decits in social behavior and also present with
restricted/repetitive and stereotyped patterns of behavior,
interests, and activities (APA 2000).
Despite this clear theoretical distinction, in everyday
practice, the diagnostic boundaries are not always that evident
(Bartak et al. 1975; Conti-Ramsden et al. 2006; Leyfer et al.
2008; Bishop 2010). At the language level, accumulating
evidence shows that the failure in spoken language in ASD
can be a much more extensive than the apparent pragmatic
decits. Detailed linguistic studies show that the language
decits in ASD are not only restricted to the domain of
language usage, prosody, understanding, and production of
gestures but also encompass semantic and syntactic domains
and sometimes even the phonological domain (Rapin and Dunn
2003; Groen et al. 2008). To overcome this problem, Kjelgaard
and Tager-Flusberg (2001) and Bishop (2010) drew a distinction between pure ASD, SLI, and the apparent comorbid cases
who have classic autism with language impairment and are
referred to as ASD-LI.
The fact that children without ASD but with a primary
language disorder can present with nonstructural language
impairments that are very similar to those found in ASD (Bishop
2010; Bishop and Norbury 2002) further complicates the
picture. This subgroup is dened as children with pragmatic
language impairment or with semantic--pragmatic disorder.

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Department of Pediatrics, University Hospitals of the Catholic University of Leuven, Leuven, Belgium,2Leuven Autism Research
Consortium, Catholic University of Leuven, Leuven Belgium,3Department of Radiology and,4Department of Neurosciences, Exp
ORL, University Hospitals of the Catholic University of Leuven, Leuven, Belgium,5Department of Radiology, Istituto Neurologico
Carlo Besta, University of Milan, Milan, Italy,6Image Sciences Institute, Department of Radiology, University Medical Centre Utrecht,
Utrecht, The Netherlands,7Parenting and Special Education Research Group, Department of Educational Sciences, University of
Leuven,8Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, USA, 9Laboratory of
Experimental Psychology, University of Leuven, Leuven, Belgium, 10Department of Child and Adolescent Psychiatry, University
Hospitals of the Catholic University of Leuven, Leuven, Belgium, 11Department of Clinical Genetics, University of Maastricht,
Maastricht, The Netherlands, 12Centre for developmental disabilities, University Hospitals of the Catholic University of Leuven,
Leuven, Belgium and 13Department of Rehabilitation Sciences, Faculty of Kinesiology and Rehabilitation Sciences, University of
Leuven, Leuven, Belgium

Page 2 of 9 Neurolinguistic Imaging in ASD-LI and SLI

Verhoeven et al.

In this study, we examined the expressive--receptive language


prole of participants and correlated it with the WM microstructural properties of the SLF. We hypothesized that if ASD-LI
and SLI share a common etiology, a similar linguistic prole
and similar underlying structural connectivity decits in the
language-processing areas of the SLF would be found.
Materials and Methods
Subjects
Nineteen participants with ASD-LI (mean age 13.8 1.6 years; 16 males
and 3 females) and 21 age-matched controls (mean age 14.4 1.5 years;
16 males and 5 females) were included. We also included 13 children
with SLI (mean age 10.1 0.4 years; 10 males and 3 females) and 12 agematched controls (mean age 10.2 0.3 years; 8 males and 4 females). All
participants were right-handed, native Dutch speakers with normal
hearing. All the included subjects had a normal intelligence with
a performance or full scale IQ above 80.
Inclusion criteria for the ASD-LI group were 1) a diagnosis of autistic
disorder or pervasive developmental disordernot otherwise specied
according to the Diagnostic and Statistical Manual of Mental Disorders,
fourth edition, Text Revision (DSM-IV-TR) criteria (APA 2000), 2)
scores equal to or greater than 15 on the Social Communication
Questionnaire (SCQ) (Rutter et al. 2003) and 3) scores above 60 on the
Social Responsiveness Scale (SRS) (Constantino et al. 2003). ASD
participants with a signicant history of language delay/impairment,
dened by the absence of 2-word combinations at the age of 3, need for
intensive speech therapy during preschool years, and the presence of
language problems at the time of diagnostic assessment, were
specically selected, aiming for a subgroup ASD-LI. Participants were
selected from a clinical sample of children with previous diagnosis
made by a multidisciplinary team including a pediatric neurologist/
psychiatrist and based on the DSM-IV-TR criteria. SCQ and SRS were
used to ensure the current presence of substantial ASD symptoms. Two
individuals were on methylphenidate and one was on risperidone at the
time of DTI acquisition. Participants were excluded if there was an
important medical history or an abnormal neurological examination, if
ASD-LI was associated with a genetic syndrome or if conventional MRI
was found to be abnormal.
For the SLI group, participants were drawn from a longitudinal study
on SLI performed at our University (Vandewalle et al. 2010). All these
children were born in the year 2000 and had a history of signicant
language delay with otherwise normal development, for which
language therapy was started in kindergarten. At the start of therapy,
children scored below percentile 3 on at least one of the subtests of 3
standardized and validated Dutch language tests: Reynell Taalontwikkelingsschalen (Schaerlaekens et al. 2003), Taaltests voor Kinderen
(van Bon and Hoekstra 1982), or Schlichting Test voor Taalproductie
(Schlichting et al. 2003). To ensure the persistent character of the
language problem, children had to score below percentile 10 on at least
one of the subtests of these language tests at a clinical evaluation after
the age of 4.4 years.
Due to age incongruence between both study groups, a separate agematched control group was composed for each study group. These healthy
volunteers were actively recruited. None of them had a history of
neurological or psychiatric conditions nor a current medical, developmental, or psychiatric diagnosis. They did not report any language
problems. The parents of both the SLI participants and the children of
the 2 control groups completed the SCQ and SRS questionnaires to
exclude the presence of substantial ASD symptoms in both groups.
The study was approved by the local Ethical Board, and informed
consent was obtained from all parents/guardians according to the
Declaration of Helsinki, with additional assent from all participating
children.
Neurobehavioral Evaluation
Participants were assessed with an abbreviated version of the Dutch
Wechsler Intelligence Scale for Children, Third Edition (Kort et al.
2005) to estimate IQ. The abbreviated intelligence test involved the

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Unlike children with typical SLI, these children have adequate


syntax and phonology and are often very uent. However, they
exhibit a range of linguistic and communicative (=pragmatic)
decits such as conversational inadequacies, poor turn taking,
and literal interpretation of gurative language (Bishop 2000;
Bishop and Norbury 2002; Conti-Ramsden and Botting 2004). It
should be noted that in this subgroup, pragmatic language
decits do not occur with symptoms of impaired social
reciprocity or restricted behaviors or interests.
Finally, the boundaries between the disorders are weakened
by a gradual fading of the characteristic distinction between SLI
and ASD over time, as was observed in a longitudinal study,
performed by Bartak and colleagues (Bartak et al. 1975;
Cantwell et al. 1989; Mawhood and Howlin 2000).
As a result of these ndings, that is, the potential presence of
structural (Kjelgaard and Tager-Flusberg 2001; Rapin and Dunn
2003; Groen et al. 2008) as well as pragmatic (Bishop 2000;
Bishop and Norbury 2002) decits in both clinical groups and
the congruence of phenotypes throughout development (Bartak
et al. 1975; Cantwell et al. 1989; Mawhood and Howlin 2000),
several researchers have proposed that SLI and ASD-LI represent 2 expressions of the same pathology along a continuum
encompassing varying degrees of language impairment.
A number of studies indeed conrmed this overlap at
a phenotypical level (Bartak et al. 1975; Bishop and Norbury
2002; Bishop 2003; Loucas et al. 2008; Bishop 2010).
However, it becomes quite difcult to draw any rm
conclusions when looking beyond this phenotypical presentation. Family studies exploring patterns of familial transmission of
language impairments show a strong heritability of structural
language impairment in SLI (Bishop et al. 1996, 1999; Barry et al.
2007), whereas aggregation in the families of ASD probands is
more prominent for communication difculties than for structural language impairments (Whitehouse et al. 2007). Genetic
linkage studies show different linkage signals in SLI and ASD
(IMGSAC 1998, 2001; Ashley-Koch et al. 1999; APA 2000;
Bradford et al. 2001; Buxbaum et al. 2001; SLIC 2002, 2004).
Although these ndings do not exclude a relation between both
disorders, it does prevent us from drawing rm conclusions.
The present study aims at exploring the boundaries and
overlaps between SLI and ASD-LI at a phenotypical and
a neurobiological level. At a phenotypical level, the language
prole of the participants was determined by standardized
linguistic testing. For the neurobiological characterization,
diffusion tensor imaging (DTI) was used. DTI, a radiological
technique sensitive to the Brownian motion of water, enables
the measurement of restricted and/or hindered movement of
water molecules as they diffuse in the brain (Basser et al.
1994)for a detailed review article, see Tournier et al. (2011).
Based on DTI, ber tracts can be virtually reconstructed and
compared. More than 26 important WM tracts have already
been described (Wakana et al. 2007; Mori et al. 2008;
Verhoeven et al. 2010). Delineation protocols to reconstruct
these tracts have been published and tested on their reproducibility (Catani et al. 2005; Wakana et al. 2007; Hua et al.
2008; Makris and Pandya 2008). One of these major WM tracts
is the superior longitudinal fascicle (SLF) that can be
considered as one of the key language tracts connecting
Brocas area and Wernickes area, the 2 most critical languagerelevant cortical regions in the human brain (Bornkessel et al.
2005; Friederici et al. 2006; Makris and Pandya 2008; Snijders
et al. 2009).

Neuroanatomical Evaluation
Data Acquisition
All participants underwent MRI examination on a 3T system (Philips,
Best, The Netherlands). The DTI data were acquired using an optimized
single-shot spin-echo, echo planar imaging sequence with the following
parameters (Jones and Leemans 2011): 68 contiguous sagittal slices,
slice thickness = 2.2 mm, repetition time (TR) = 11.043 s, echo time
(TE) = 55 ms, eld-of-view (FOV) = 220 3 220 mm2, matrix size = 112 3
109, in-plane pixel size = 1.96 3 2.00 mm2, acquisition time = 10 min 34
s. Diffusion gradients were applied in 45 noncollinear directions (b =
800 s/mm2) and one nondiffusion-weighted image was acquired. Two
identical DTI data sets were consecutively acquired per subject to
improve the reliability of the estimated diffusion measures, bringing the
total acquisition time to 21 min 8 s.
Additionally, coronal 3D turbo eld echo T1-weighted images were
obtained as a series of 182 contiguous coronal slices covering the
whole brain and brainstem: slice thickness = 1.2 mm, TR = 9.7 ms, TE =
4.6 ms, FOV = 250 3 250 mm2, matrix size = 256 3 256, in-plane pixel
size = 0.98 3 1.20 mm2, and acquisition time = 6 min 38 s.
Data Processing
Raw diffusion MR data were transferred to an ofine workstation. All
the images were rst visually inspected for the presence of apparent
artefacts. Further pre- and postprocessing was done using ExploreDTI
(Leemans et al. 2009). Motion and eddy current correction of the
diffusion-weighted images was performed. During this preprocessing
step, the b-matrix was corrected for the rotational component of
subject motion to ensure that deviations in the diffusion weighting
originating from these rotations could be taken into account (Leemans
and Jones 2009). Due to excessive motion during scanning, the DTI
data sets of 2 controls of the SLI study group had to be discarded.
Subsequently, the diffusion tensors (DT) were estimated using
nonlinear least squares tting (note that this was performed on the
concatenationnot the averageof both DTI data sets to improve the
reliability of the estimated diffusion measures). Whole-brain ber
tractrography was calculated for each DTI data set using a uniform
2-mm seed point resolution, fractional anisotropy (FA) termination
threshold of 0.2, angle threshold of 30, and a minimal ber length
threshold of 50 mm. Region of interest (ROI) delineation for the SLF
was done according to the ROI denition protocols of Wakana (Wakana
et al. 2007), who showed a high reproducibility and reliability of their
tract reconstruction protocols (Fig. 1). A good intrarater and interrater
reliability for this tract reconstruction was conrmed in a previous
study (Verhoeven et al. 2010). Scalar invariants, FA, and apparent
diffusion coefcient [ADC] were determined for left and right SLF for all

subjects. To detect diagnosis-related differences in FA and ADC,


a general linear model analysis was performed with FA and ADC as
dependent variables, respectively. Control groups (controls for ASD-LI
group and controls for SLI group) and clinical groups (ASD-LI and SLI)
were labeled as CO-ASD, CO-SLI, ASD-LI, and SLI, respectively. When
both control groups were combined, they were referred to as CO-all.
Left- and right-sided SLF, as well as subjects groups were dened as
xed factors. The signicance threshold was set at P < 0.05 after
Bonferroni correction for multiple testing.
Correlation of Neuroanatomical and Neurobehavioral Data
For the correlation of FA with behavioral measures, Pearson correlations between FA values for left and right SLF and language measures
were calculated. To limit the number of comparisons, analyses were
limited to the hypothesized language-to-structure correlation. No
comparisons were performed with other behavioral measures such as
SRS and SCQ scores.

Results
Demographics
An overview of the group characteristics is presented in Table 1.
As previously mentioned, the ASD-LI participants (ASD-LI, n = 19)
and their controls (CO-ASD, n = 21) were signicantly older than
the SLI participants (SLI, n = 13) and their controls (CO-SLI, n =
12). Since this age difference may cause different performance
on the language tests, and since a small effect of age on WM
characteristics could not be excluded as well (Hermoye et al.
2006; Lebel et al. 2008; Verhoeven et al. 2010), the SLI study
group and the ASD-LI study group were treated separately.
Within study groups, participants and controls were well
matched for age. The VIQ of each clinical group was signicantly
lower than in the respective control group, reecting the
inherent language problems. In the SLI study group, participants
and controls were not signicantly different for PIQ. In the ASDLI study group, the ASD-LI participants showed a slightly lower
PIQ compared to the age-matched controls (P = 0.041). All
controls scored below the risk value for ASD on the SRS and SCQ
questionnaires, whereas all ASD-LI children presented with SRS
and SCQ values above the set risk value. In the SLI group, 2
children scored above the risk value for SRS only, and one scored
above the cutoff values for both the SRS and SCQ. The latter 3
participants were excluded from further analysis to avoid
inappropriate inclusion of ASD-LI participants in the SLI group,
which brings the number of SLI participants down to 10.
Language Testing
Language skills were evaluated by an experienced speechlanguage pathologist on the day of scanning or in a time interval
of less than 1 month prior to scanning. The duration of testing
was 1.5 h. Standardized language test results could not be
obtained for 3 ASD-LI participants. The results of one
participant were excluded from the linguistic data set of this
study because of the extensive lack of expressive language
skills. The 2 others dropped out of follow-up. All other controls
and SLI participants completed the selected language tests. Due
to a signicant age difference between both clinical groups,
both groups were assessed separately. Raw test scores of the
CELF-4-NL were standardized into age-independent Z scores,
for statistical between-study group comparisons. All language
results are summarized in Table 2.
In the SLI study group, all SLI participants except one, scored
on at least one of the language subtests below percentile 10,
Cerebral Cortex Page 3 of 9

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subtests Block Design and Picture Completion to estimate a performance IQ (PIQ) and the subtests Vocabulary and Similarities to
estimate verbal IQ (VIQ, Sattler 2001). The abbreviated version has
been found to correlate well with a full IQ battery and has been used in
other studies of cognitive ability and language (Hohnen and Stevenson
1999). The IQ scores were used to conrm normal intelligence in all
participants.
The Dutch version of the Clinical Evaluation of Language Fundamentals (CELF-4-NL) (Kort et al. 2008) was used to assess the language
skills of our study population. The following subtests of the CELF-4-NL
were used: Sentence Formulation (SF), Sentence Assembly (SA), Word
Denitions (WD), Word Classes Expressive (WCE) (=expressive
language subtests), Word Classes Receptive (WCR), Text Comprehension (TC), and Semantic Relations (SR) (=receptive language subtests).
Statistical comparison between participants and their respective agematched controls was done using an unpaired t-test of the raw test
scores. The signicance threshold was set at P < 0.05 after Bonferroni
correction for multiple pairwise comparisons. Due to a signicant age
difference between both clinical groups, a direct comparison between
both groups was not possible. Therefore, Z scores standardized relative
to the age-matched control group were calculated and used for
between-patient group comparisons. A composite score for expressive
language ability and a composite score for receptive language ability
was calculated by averaging the Z scores of the constituent subtests.

Figure 1. ROI delineation for the SLF according to the ROI definition protocols of
Wakana et al. (2007). For the seed ROI (blue), a coronal slice is selected at the
middle of the posterior limb of the internal capsule in the axial plane. The core of the
SLF is a triangular shaped tract lateral of the corpus callosum and corona radiata. On
a color-encoded FA image, this tract has an intense green color. The first ROI includes
this core and all branches coming out from the triangular area. For the target ROI
(green), a coronal slice is selected at the splenium of corpus callosum on a midsagittal plane. The second ROI includes all labeled fibers.

Table 1
Participants characteristics
Subject characteristics per group

AGE

VIQ

PIQ

SRS

SCQ

ASD-LI study group

SLI study group

CO-ASD
ASD-LI
P value
CO-ASD
ASD-LI
P value
CO-ASD
ASD-LI
P value
CO-ASD
ASD-LI
P value
CO-ASD
ASD-LI
P value

CO-SLI
SLI

14.4 (1.5)
13.8 (1.6)
0.213
113.7 (12.7)
90.5 (18.7)
#0.001*
105.7 (6.6)
98.11 (13.6)
0.041*
15.4 (12.8)
96.5 (32.6)
#0.001*
3.5 (3.7)
21.8 (6.9)
#0.001*

CO-SLI
SLI
CO-SLI
SLI
CO-SLI
SLI
CO-SLI
SLI

P value between
study groups
10.2 (0.3)
10.1 (0.4)
0.736
109.0 (12.5)
100.6 (6.3)
0.0428*
99.3 (16.0)
105.6 (13.3)
0.295
26.3 (15.3)
25.5 (9.63)
0.883
3.3 (2.8)
5.8 (3.6)
0.106

#0.001*
#0.001*
0.314
0.038*
0.118
0.135
0.035*
#0.001*
0.846
#0.001*

Note: This table shows an overview of the participant characteristics age, VIQ, PIQ, and SCQ for
each patient group (ASD-LI, n 5 19; SLI, n 5 10) and their respective age-matched controls (COASD, n 5 21; CO-SLI, n 5 12). Mean and SD is given for each parameter. P values are given for
within-study group (underneath) and between-study group (right column) comparisons.
Significant differences (P \ 0.05) are indicated by an asterisk.

conrming the persistent character of the language problems.


They scored signicantly poorer than their age-matched controls
on the language subtests SF, WCE, and WCR. Across all language
Page 4 of 9 Neurolinguistic Imaging in ASD-LI and SLI

Verhoeven et al.

Imaging Results
To exclude a possible difference in WM characteristics due to
group differences in age, a Multivariate analysis of variance
(MANOVA) analysis comparing both control groups was
performed rst. FA and ADC SLF values were entered as
dependent variables and participant groups (CO-SLI vs. COASD) and hemisphere (left vs. right) as xed factors. The
controls of both study groups showed no signicant difference
in mean SLF FA (P = 0.369) and mean SLF ADC (P = 0.553). For
further analysis, data of both control groups were collapsed and
treated as one, referred to as CO-all.
Second, a MANOVA analysis was done to compare the
control subjects (CO-all) with the SLI participants and the ASDLI participants. Again, FA and ADC values were used as
dependent variables, and participant groups (CO-all, SLI and
ASD-LI) and hemisphere were entered as xed factors. For FA,
a signicant main effect was seen for group (P = 0.002; mean FA
CO-all = 0.460, mean FA SLI = 0.438, mean FA = 0.459) and
hemisphere (P < 0.001; mean FA right = 0.436, mean FA left =
0.469). There was no interaction effect (group 3 hemisphere,
P = 0.948). For ADC, only a signicant main effect of
hemisphere was present (P < 0.001).
No signicant difference was found in mean SLF FA when
comparing the control subjects and the ASD-LI participants
(P = 1.000). In contrast, mean SLF FA was signicantly reduced
(P = 0.001) in the SLI participants compared with all control
subjects (Fig. 2). This difference persisted when the SLI
participants were compared only with their age-matched controls
(P = 0.007). A signicant difference in mean SLF FA was also
shown between ASD-LI participants and SLI participants
(P = 0.006). No signicant group differences were found for
mean SLF ADC when comparing the CO-all with the ASD-LI
participants nor when comparing them with the SLI participants.
Results of the multivariate linear model analysis are
presented in Table 3. The mean SLF FA and mean SLF ADC
values are given for each participant group (SLI, ASD-LI, and
CO-all) and mean differences as well as 95% condence
intervals of the differences are shown. Figure 2 shows a box
plot representation of the results.
Correlation of FA with Behavioral Measures
Finally, we studied the correlation between the diffusion scalar
measures and the language results. Since signicant diffusion
differences were only found for the FA measure, the correlation

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tests, they scored on average 1.21 standard deviation (SD, range


from 2.15 to 0.26) below the level of their controls.
In the ASD-LI study group, ASD participants scored
signicantly poorer than their age-matched controls on every
language subtest. Therefore, we could identify our ASD
participants as ASD-LI participants (Bishop 2010). Across all
language tests, they scored on average 2.82 SD (range from
5.04 to 2.18) below the mean of their controls. A comparison
of the age-independent Z scores of the ASD-LI and SLI
participants reveals signicantly poorer performance of the
ASD-LI participants on WD and SR.
The composite expressive language Z score and the
composite receptive language Z score indicate that both the
ASD-LI participants and the SLI participants show a signicant
failure in both expressive and receptive language. The receptive language decit is signicantly more severe in the ASDLI group than in the SLI group.

Table 2
Language characteristics for expressive and receptive language subtests
ASD-LI study group

Expressive score

Z score
P value
(B) Language characteristics per group: receptive subtests
TC
CO-ASD
ASD-LI
P value
Z score
WCR
CO-ASD
ASD-LI
P value
Z score
SR
CO-ASD
ASD-LI
P value
Z score
Receptive score

Z score
P value

SLI study group


36.94 (2.31)
31.05 (5.21)
\0.001*
2.50 (2.25)
12.55 (0.75)
10.50 (2.16)
0.001*
2.66 (2.88)
38.98 (5.80)
25.65 (7.32)
\0.001*
2.37 (1.26)
16.10 (2.91)
9.75 (4.16)
\0.001*
2.18 (1.43)

CO-SLI
SLI

CO-SLI
SLI

CO-SLI
SLI

CO-SLI
SLI

2.16 (1.68)
\0.001*
15.28 (0.92)
12.15 (4.00)
0.040*
2.66 (4.35)
17.42 (1.93)
12.54 (3.13)
#0.001*
2.65 (1.62)
19.94 (0.91)
14.80 (4.42)
\0.001*
5.04 (4.86)

Between-group comparison
29.55 (4.57)
19.68 (7.17)
0.004*
2.15 (1.57)
8.10 (2.45)
5.23 (2.95)
0.090
1.16 (1.20)
21.12 (7.74)
13.85 (6.70)
0.135
0.96 (0.87)
8.67 (2.74)
5.20 (2.62)
0.027*
1.27 (0.95)
1.36 (0.62)
\0.001*

CO-SLI
SLI
SLI
CO-SLI
SLI
SLI
CO-SLI
SLI

5.75 (4.80)
\0.001*

9.79 (3.18)
8.73 (3.06)
1.000
0.26 (0.96)
11.70 (2.55)
7.52 (2.42)
0.003*
1.67 (0.95)
12.87 (4.03)
10.20 (2.76)
0.459
0.62 (0.68)
1.06 (0.57)
0.029*

1.000

0.538

0.027*

0.346
0.649

0.400

0.398

0.036*
0.022*

Note: (A) shows the mean and SD of the raw test scores for each of the expressive subtests of the CELF-4-NL (SF, SA, WD, and WCE) for each patient group (ASD-LI, SLI) and their respective agematched controls (CO-ASD, CO-SLI). The indicated P values reflect statistical significance after Bonferroni correction for pairwise comparisons of the raw test scores, using an unpaired t-test. As an
estimate of age-independent effect sizes, raw test scores were also converted into Z scores relative to the mean and SD of the respective control group. These age-independent Z scores were used for
between-study group comparisons for which the P values are shown in the column at the right. A total expressive composite Z score for each patient group (ASD-LI, SLI) is calculated, and associated P
values for the within-study group and between-study group comparisons are given. Significant differences are indicated by an asterisk. (B)Shows the same raw test scores, Z values, and within-study
group and between study-group comparisons for each of the receptive subtests of the CELF-4-NL (TC, WCR, and SR), as well as a total Receptive composite score for each patient group (ASD-LI, SLI)
and their respective age-matched controls (CO-ASD, CO-SLI).

study was restricted to this scalar value. Scatter plots were


generated and Pearson correlation coefcients were calculated
between each language subtest and the mean SLF FA value. No
signicant correlation between the language subtest results and
the mean SLF FA values were found in the control group and the
ASD-LI group, either for the individual language subtests or for
the composite scores. In the SLI group, however, a good model
t was found for the WCR language subtest result that correlates
positively with the mean SLF FA of the SLI participants on the
left (Pearson correlation = 0.682, R 2 = 0.465, P = 0.030) as well as
on the right side (Pearson correlation = 0.672, R 2 = 0.452, P =
0.033) (Fig. 3a,b). A marginally signicant model t was found
for the WCE language subtest result that correlates positively
with the mean SLF FA of the SLI participants on the left side
(Pearson correlation = 0.638, R 2 = 0.407, P = 0.047) (Fig. 3c). The
right-sided SLF FA was not signicantly correlated to the WCE
language subtest results (Pearson correlation = 0.535, R 2 = 0.287,
P = 0.111) (Fig. 3d). The correlation of the mean SLF FA of the
ASD-LI participants with the WCR language subtest and the WCE
language subtest results, respectively, was not signicant.
Discussion
For several decades, an overlap between ASD-LI and SLI
has been debated because of the similarities in the

language prole, clinically observed in children with typical


and atypical development (Bartak et al. 1975; Bishop
and Norbury 2002; Bishop 2003; Loucas et al. 2008; Bishop
2010).
In this study, we explored the neurobiology of ASD-LI and
SLI at the level of language impairment. Because the SLF can be
considered to be a major tract for language processing
connecting the receptive and expressive language areas
(Bornkessel et al. 2005; Makris and Pandya 2008), the target
of this study was to examine the link between the linguistic
prole in ASD-LI and SLI and microstructural decits in
language-processing areas of the SLF.
ASD participants with a clear history of language impairment
were included in this study. Since no recent linguistic
assessment was available at the time of intake, and inclusion
criteria were based on anamnestic measures, we rst assessed
the type and severity of the language disorder through
extensive language testing of all participants. These tests
conrmed the presence of a structural language decit in the
ASD participants with a signicant lower performance compared with their age-matched controls. All assessed language
skills were affected. This resulted in a mixed receptive-expressive language disorder prole, and we therefore could
identify our ASD participants as ASD-LI participants (Bishop
2010).
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(A) Language characteristics per group: expressive subtests


SF
CO-ASD
ASD-LI
P value
Z score
SA
CO-ASD
ASD-LI
P value
Z score
WD
CO-ASD
ASD-LI
P value
Z score
WCE
CO-AS
ASD-LI
P value
Z score

Figure 2. A box plot representation of the mean SLF FA values in controls (CO-all),
participants with SLI and participants with autism spectrum disorder (ASD-LI). The
dark line in the middle of the boxes is the median of the mean FA values for each
subject group. The bottom of the box indicates the 25th percentile. The top of the box
represents the 75th percentile. The T-bars that extend from the boxes extend to the
minimum and maximum values. The indicated P values above the box plots reflect
statistical significance between the indicated study groups using a MANOVA test.

language phenotype was present for the SLI and the ASD-LI
participants.
Looking for a similar common structural basis for the
language impairment, we compared the WM characteristics
of the SLF in SLI and ASD-LI participants. The mean SLF FA was
signicantly reduced in SLI participants, indicating an abnormal
microstructural organization between Broca and Wernicke in
this patient group. These changes in architectural properties
was not present in the ASD-LI participants, with mean SLF FA
and mean SLF ADC values comparable to the controls. Despite
the marked phenotypical overlap in the language decits of
both study groups, our results indicate that, at the level of the
SLF, there is a clear structural distinction between SLI and ASDLI participants.
Current evidence on the shared neurobiology of SLI and ASD
is limited and controversial. De Fosse showed a signicant
reversal of asymmetry in the frontal language-related cortex in
both ASD and SLI (De Fosse et al. 2004) indicating a neurobiological overlap of both conditions. However, in the follow-up
study done by Hodge et al. (2009), the same participants were
found to be signicantly distinct at level of the cerebellum, in
the lobule VIIA Crus I (Hodge et al. 2009). This nding is
important since Crus I area is a cerebellar region consistently
associated with language processing.
Herbert et al. assessed brain asymmetry at several levels of
parcellation. At the cortical parcellation level, a right:left ratio
reversal in both the SLI group as the ASD group was found.
However, the decrease in left asymmetrical cortex present in
the SLI could not be conrmed in the autism group (Herbert
et al. 2005).
Finally, a recent study by Whitehouse and Bishop (2008)
measured cerebral dominance using functional transcranial
doppler ultrasonography, assessing blood ow through the
middle cerebral arteries. Here, the SLI group with persistent
language problems presented a greater right than left hemisphere activation during a word generation task while the
reverse was true for the ASD patients and the controls
(Whitehouse and Bishop 2008). Collating these ndings with
our DTI ndings, we conclude that, in addition to imaging and
language similarities in ASD-LI and SLI, some important
neuroanatomical differences in language-processing areas are
present as well.
Interestingly, recent studies on the phenotypical overlap in the
language decits report qualitative language differences between

Table 3
Mean FA and mean apparent ADC values extracted after deterministic fiber tractography of the SLF in CO-all, SLI, and ASD-LI.
Mean

Mean

Mean difference

P value

95% Confidence interval


Lower bound

FA

ADC

CO-ALL

0.460

SLI

0.438

ASD-LI

0.459

CO-ALL

7.258 3 10

SLI
ASD-LI

7.407 3 10
7.259 3 10

SLI
ASD-LI
CO-ALL
ASD-LI
CO-ALL
SLI
SLI
ASD-LI
CO-ALL
ASD-LI
CO-ALL
SLI

0.438
0.459
0.460
0.459
0.460
0.438
7.407 3
7.259 3
7.258 3
7.259 3
7.258 3
7.407 3

10
10
10
10
10
10

4
4
4
4
4
4

0.022
0.001
0.022
0.021
0.001
0.021
1.493 3
8.544 3
1.493 3
1.484 3
8.544 3
1.484 3

10
10
10
10
10
10

5
8
5
5
8
5

0.001
1.000
0.001*
0.006*
1.000
0.006*
0.131
1.000
0.131
0.220
1.000
0.220

0.007
0.010
0.037
0.037
0.012
0.005
3.266 3
1.350 3
2.800 3
4.493 3
1.332 3
3.418 3

10
10
10
10
10
10

Upper bound

5
5
6
6
5
5

0.037
0.012
0.007
0.005
0.010
0.037
2.800 3
1.332 3
3.266 3
3.418 3
1.350 3
4.493 3

10
10
10
10
10
10

6
5
5
5
5
6

Note: Mean differences between subject groups are calculated. The indicated P values reflect statistical significance using a MANOVA test. Significant differences are indicated by an asterisk. The 95%
confidence intervals are shown in the column on the right-hand side.

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Verhoeven et al.

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In a next step, SLI participants were assessed with a similar


methodology. Taking into account that the age difference
between ASD-LI and SLI participants could bias our results, we
selected a second control group, matched in age with the SLI
group, and assessed their language skills. As with the ASD-LI
participants, we observed a mixed receptive--expressive
disorder prole in the SLI participants, compared to their
age-matched control group. To rule out that possible neuroanatomical differences between the ASD-LI and the SLI group
may result from a different degree of language failure present in
both patient groups, we compared the age-independent
Z scores of each subtest between ASD-LI and SLI participants.
Although the ASD-LI participants generally showed a more
severe language failure, the difference was only signicant for
the SR subtest and the WD subtest. Therefore, at this level, we
can conclude that in our study too, a substantial overlap in

SLI and ASD-LI in addition to the well-known quantitative overlap


(Whitehouse et al. 2007; Lindgren et al. 2009; Riches et al. 2010).
In this respect, Whitehouse et al. (2007) proposed a different
origin of the disturbed language prole in SLI and ASD-LI. The
detailed language data from the current study seem to further
support this hypothesis. Indeed, despite the fact that both SLI and
ASD-LI participants could be classied as having a mixed
receptive--expressive language disorder prole, detailed analysis
of the language subtest results revealed a global pattern of failure
in the ASD-LI participants (failure on all subtests), while the
language failure in the SLI participants was more restricted to
some specic language subtests (only 3).
Finally, also some noteworthy differences were found in the
correlation analysis, linking the anatomical and phenotypical
data. A signicant positive correlation was noted between the
mean SLF FA values and 2 of the signicantly impaired language
subtests (WCR and WCE) only in the SLI group, linking
integrity of the SLF to a better performance on this subtests in
the SLI group. Despite the fact that the performance of the
ASD-LI participants for the same subtest was equally weak (no
signicant difference in Z scores ASD-LI vs. SLI), the ASD-LI
participants did not show a structural decit at the level of the
SLF and no correlations with language performance could be
found. These ndings again support a different origin of the
WCR and WCE subtest failure in both patient groups.

The linkage of microstructural decits in the SLF to


a particular aspect of language processing is complicated
because each language test necessarily embeds several aspects
of language. Whitehouse suggested short-term working memory problems as a possible cause of the disturbed language
prole in SLI (Whitehouse et al. 2008). Short-term working
memory is also an important component in the completion of
the WCR task. Failure in short-term working memory is
believed to be associated with structural and functional
abnormalities in frontal--parietal circuitry (Karlsgodt et al.
2008). The SLF is the main frontoparietal WM connection. At
the moment, it is premature to relate our ndings in the SLF to
these working memory problems, but this might be an
interesting topic for further research. Our ndings of a more
global and a more severe pattern of failure in the ASD-LI
participants without any repercussion on the main language
tract, the SLF, might support the hypothesis that structural
language decits might arise as a part of the broader ASD
phenotype. Further research on the links between language
proles and underlying structural impairments might clarify
their etiological relationship.
This study has a number of limitations of which the rst one
relates to the rather small sample size of the SLI group. SLI at
mid-childhood, however, is quite rare. Furthermore, many
children contacted did no longer present with language
Cerebral Cortex Page 7 of 9

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Figure 3. ( A, B) Scatter plot of Word Classes Receptive Z scores (WCR_Zscore) (x-axis) and mean SLF FA values (y-axis) in control groups (CO-SLI and CO-ASD) and patient
groups (SLI and ASD-LI) at the hemisphere left ( A) versus right (B). A significant positive correlation between WCR test score and mean SLF FA value was observed for the SLI
patient group (R2 5 0.465 for the left SLF and a R2 5 0.452 for the right SLF). (C, D) Scatter plot of Word Classes Expressive Z scores (WCE_Zscore) (x-axis) and mean SLF FA
values (y-axis) in control groups (CO-SLI and CO-ASD) and patient groups (SLI and ASD-LI) at the hemisphere left (C) and right (D). A significant positive correlation between WCE
test score and mean SLF FA value was observed only in the left hemisphere (R2 5 0.407).

Conclusion
For several decades, SLI and ASD research has been characterized by an ongoing debate as to whether SLI and ASD-LI
constitute 2 expressions of the same spectrum of disorder. The
phenotypical overlap in their language decits appears to be
the most remarkable feature linking both conditions. In this
article, we showed that despite this phenotypical overlap, the
neuroanatomical decit underlying the impaired language
processing is not the same.
Funding
Fund for Scientic Research-Flanders, FWO, Belgium
(G.0354.06); IUAP-KUL (FWO fellowship asp/07 to J.S.V.); the
Research Council (IDO/08/013).
Notes
We thank our participants and healthy volunteers that made this
research possible. The authors are grateful to S. Loomans and M. Verly
for their assistance with language testing. Conict of Interest : None
declared.

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