doi:10.

1093/brain/awr364 Brain 2012: 135; 949–960 | 949

BRAIN
A JOURNAL OF NEUROLOGY

A failure of left temporal cortex to specialize for
language is an early emerging and fundamental
property of autism
Lisa T. Eyler,1,2,* Karen Pierce1,3,* and Eric Courchesne1,3,*

1 UCSD Autism Center of Excellence, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA 92037, USA
2 Department of Psychiatry, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA 92037, USA
3 Department of Neurosciences, University of California, San Diego, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA 92037, USA

*These authors contributed equally to this work.

Correspondence to: L. T. Eyler,
UCSD Autism Center of Excellence,
8110 La Jolla Shores Drive,
Suite 201, La Jolla, CA 92037, USA
E-mail: lteyler@ucsd.edu

Failure to develop normal language comprehension is an early warning sign of autism, but the neural mechanisms underlying
this signature deficit are unknown. This is because of an almost complete absence of functional studies of the autistic brain
during early development. Using functional magnetic resonance imaging, we previously observed a trend for abnormally
lateralized temporal responses to language (i.e. greater activation on the right, rather than the expected left) in a small
sample (n = 12) of sleeping 2–3 year olds with autism in contrast to typically developing children, a finding also reported in
autistic adults and adolescents. It was unclear, however, if findings of atypical laterality would be observed in a larger sample,
and at even earlier ages in autism, such as around the first birthday. Answers to these questions would provide the foundation
for understanding how neurofunctional defects of autism unfold, and provide a foundation for studies using patterns of brain
activation as a functional early biomarker of autism. To begin to examine these issues, a prospective, cross-sectional design was
used in which brain activity was measured in a large sample of toddlers (n = 80) during the presentation of a bedtime story
during natural sleep. Forty toddlers with autism spectrum disorder and 40 typically developing toddlers ranging in age between
12–48 months participated. Any toddler with autism who participated in the imaging experiment prior to final diagnosis was
tracked and diagnoses confirmed at a later age. Results indicated that at-risk toddlers later diagnosed as autistic display
deficient left hemisphere response to speech sounds and have abnormally right-lateralized temporal cortex response to lan-
guage; this defect worsens with age, becoming most severe in autistic 3- and 4-year-olds. Typically developing children show
opposite developmental trends with a tendency towards greater temporal cortex response with increasing age and maintenance
of left-lateralized activation with age. We have now demonstrated lateralized abnormalities of temporal cortex processing of
language in autism across two separate samples, including a large sample of young infants who later are diagnosed with
autism, suggesting that this pattern may reflect a fundamental early neural developmental pathology in autism.

Keywords: autism; language; functional magnetic resonance imaging; sleep; temporal cortex
Abbreviation: ADOS = autism diagnostic observation schedule; ASD = austism spectrum disorder

Received August 3, 2011. Revised November 18, 2011. Accepted November 21, 2011
ß The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
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but not always. conversational speech) is severely sponses during language comprehension can be measured in impaired in affected children (Loveland et al. Tesink et al. 1995) study has examined differences between very young children and discriminate familiar from unfamiliar words by 7 months with autism and typically developing children using this technol- (Tincoff and Jusczyk.. T.950 | Brain 2012: 135. 2005. Studies examin- gyrus to auditory stimuli in non-autistic infants as young as ing samples of individuals from the 1980s reported that 50% of 1 week to 3 months old (Anderson et al. 2007).. 1971. Fortunately. technical difficulties in measuring brain function in infants and Wetherby et al. Overall. 2005).. Knaus et al. this neural abnormality must begin ogy. were not significantly ually with age after full symptom onset? What is the developmen- enlarged. Gendry Meresse et al. response to language stimuli in the autism group. group’s response included additional frontal.. a mystery..g. 2004. Both age groups showed super- (Luyster et al. Later in development. 2004. Werker and Lalonde. Bruneau et al. poral cortices in a small sample (n = 12) of 2–3 year olds children Integrity of temporal and frontal cortices is essential for normal with autism compared with both chronological and mental language development. Wang et al. toddlers and young age-matched groups and a non-statistically significant. 1988.. (Fenson et al. Moreover. Redcay very early in development in babies that will eventually show and Courchesne (2008) found reduced functional activity in tem- autism. 2009. 2005. opment must be abnormal in autism. a technique that autism often. children with toddlers with disabilities using functional MRI. although more ined brain response to language stimuli during natural sleep in two recent studies suggest better language outcomes with at least age groups of typically developing children (mean ages of 21 and 75% of the individuals acquiring some functional language 39 months. such as occipital cortex. While Minagawa-Kawai et al. with typical infants advantages for examining brain function in very young autistic demonstrating the ability to discriminate phonemes within the first and typically developing subjects including the ability to test sub- weeks of life (Eimas et al. When brain systems directly engaged in language com. and the younger ment. 2001. brain systems that support language devel. but inter- children these structures display pathological overgrowth (Carper esting trend towards abnormal rightward laterality of brain et al. Zwaigenbaum et al.. 2011). Harris et al. 2010) and decreased left hemisphere (Just Pierce et al. In response to a bedtime story during natural sleep. Mason et al. 1999.. 2008.. Redcay et al. Groen et al. 2009) responsiveness. and temporal cortices has consistently been observed. 1989. Moreover. 1988)..e. 2006). the ‘sleep functional MRI’ severely compromised in children with autism than those with method has demonstrated responsiveness of superior temporal global developmental delay (Bartak et al. given the early Sleep functional MRI provides many scientific as well as safety emergence of language capacity in humans. Gaffrey et al. or a ten- most typical toddlers begin to say words around their first birthday dency towards abnormal right hemisphere lateralization (Dawson et al. including Introduction increased right hemisphere (Boddaert et al.. 2003).... Early subclinical behavioural signs of autism appear in the first 2006.. 2009. occipital and cerebel- are reduced in autism (Loveland et al. 1994). tal trajectory of normal left lateralization for language in the first prehension were challenged in studies of older autistic children. years of life (Palomo et al. speech that is highly repetitive.. Hazlett et al... 1999. 2008. 2009. Not surprisingly. several recent studies have demonstrated (Volden and Lord. More recently. see Pierce. In tional lateralization occurs at the beginning stages of autism has fact. delay in language is reported as the strongest and earliest red never been tested. Anderson et al. This is because of a virtual absence of functional ima.. Despite its strengths. Carper and Courchesne.. thus eliminat- rates of pronoun reversals (Rapin and Dunn. only one recognize their own name at 4 months (Mandel et al.. the lar sites of activation. 2010.. our laboratory exam- tional language (Sigman and McGovern. abnormal functional lateralization in frontal abilities normally takes place in typical infants? Given the relatively . 2011). 2006. Dehaene- the children with autism spectrum disorder have little to no func- Lambertz et al. Flagg et al.. Kleinhans et al.. directly. several years of life in autism when the explosion in language adolescents and adults. 2007. 1998. This is largely due to substantial practical and flag by most experts (De Giacomo and Fombonne.. Carper and There are several natural questions that follow: can abnormal Courchesne (2002) showed that frontal and temporal cortices functional activation in response to language be detected even at were 13% greater in volume in children with autism spectrum the first signs of autism? Is abnormally right lateralized brain disorder relative to typically developing children. demonstrating that expected cortical re- pragmatic use of language (e.... Early studies ing the requirement for infants and toddlers to hold still (for on the topic found that comprehension of speech was more review. during natural sleep. jects from all functioning levels.. ritua- that it is possible to obtain functional MRI data in response to lized or echolalic (McEvoy et al.. 2002. display unusual patterns of language traditionally requires subjects to remain still for extended periods that may include the presence of neologisms [i. but in autistic infants. 2005). 1975). Schumann et al. 2011) but the underlying brain dysfunction remains et al. 2004). 1999). including the use of gestures such as pointing and waving. 1988). 2008. Philofsky very young typically developing children using functional MRI et al. whereas other response present at that at-risk time-point or does it emerge grad- brain regions. Kleinhans et al. 2008). Non-verbal social communication engage- ior temporal gyrus response to language stimuli.. 2002.. When ging studies of the autistic brain during this crucial developmental differences in brain response between hemispheres are measured period.. 2008). made up words of time. develop sophisticated expressive and receptive language. 1988) or characterized by high language sounds from infants during natural sleep. 1991)].. individuals with autism generally display less functional One of the earliest appearing signs of autism is a failure to lateralization (Muller et al. Eyler et al. 949–960 L. For example. 2006... some toddlers who will eventually develop Whether or not such abnormal response and rightward func- autism miss or are slow to achieve this important milestone.. 2010).

all Here. Using this method. 2009). as well as from 3. in 20-s blocks: complex forward speech. disorder at that time. developmental delay/borderline IQ (n = 1) and autistic fea- sible to study autism prospectively from the first year of life in the tures of insufficient severity to warrant a diagnosis (n = 1)].edu) toddlers visual T-scores and significantly lower Autism Diagnostic Observation ranging in ages between 12 and 48 months were brought to a scan. This study was approved by the tion-based screening method called the 1-Year Well-Baby Check-Up University of California San Diego Institutional Review Board. Functional MRI activation patterns at follow-up were 17. All speech conditions were created using the same session and a total of 80 infants were included in final analyses female speaker. with right instead of left hemisphere specialization. measured during natural sleep diagnoses confirmed by a psychologist (one currently has autism diag- from the largest sample collected to date of infants and toddlers nostic features with diagnosis pending a second follow-up). it has historically been challenging to which autism spectrum disorder diagnoses can be reliably made) at the identify and study toddlers with autism spectrum disorder time of scanning and were judged to be at-risk for autism spectrum prospectively before the onset of full-blown clinical symptoms. Finally. Typically developing controls were obtained from commu. Inc. paediatric offices with a broadband screening instrument. website or outside agency) and a popula. and a Early Learning (Mullen. given earplugs to computer’s speakers. such analyses [revised diagnoses were: typical (n = 2). primary language in the home was headphones (Confon. A total of 12 participants dren’s story written at a comprehension level between 12 and 36 with autism spectrum disorder and 10 typically developing participants months. all other participants slept pseudorandom order. a baby’s bedtime story.. presented nity referrals. toddlers at-risk for provided written informed consent according to the Declaration of an autism spectrum disorder as young as 12 months were identified in Helsinki and were paid for their participation. This method thus allowed for the prospective study of autism beginning at The speech task was identical to that used in our previous pilot study 12 months. During the complex forward speech condition. and all of these have had their provisional stimuli. have made it pos- (n = 1). the difference community referral (e. (Redcay et al.g. 1995) and the McArthur-Bates Communicative failure to develop normal left lateralization patterns across the Development Inventories (Fenson et al. the typically Participants developing group had significantly higher receptive language and As part of an ongoing study (www. Stimulus presentation was through pneumatic aid in staying asleep (n = 1). toddlers woke during the functional scan before two-thirds of the time-points were exposed to the simple story segments played backwards.9 (5.005).ucsd. in mean age was only 6 months.6 (5. for all participants. mean (SD)] with autism spectrum disorder. ning facility on one or more nights. the Mullen Scales of disorder. All standardized assessments were administered by three highly experienced doctoral-level psych- Subjects and methods ologists with over 15 years combined experience in the field of autism.0). were compared with those in typically developing infants. Demographic and clinical summary data for the groups at the time of scanning are presented in Table 1. The total task length was 6 min 25 s.. The stimuli through the entire scan. Schedule scores than the autism spectrum disorder group. examinations of play behaviour) and biological tests as part of a larger study. Autism Diagnostic Observation Schedule-Toddler Module (ADOS-T) firmed at older ages. Total at-risk for autism spectrum disorder whose diagnosis was con. language delayed as the 1-Year Well-Baby Check-Up Approach. There had been collected.. Toddlers at-risk for an autism the typically developing group was significantly younger than the spectrum disorder were obtained from one of two sources: general autism spectrum disorder group (P = 0. new advances in the early detection of autism. in additional behavioural (e. stimulus type. 1993). We predicted abnormalities of functional Schedule-Toddler Module newly validated for use with infants response and lateralization at the earliest ages in autism spectrum as young as 12 months (Luyster et al. so their data were not included in analyses. Toddlers participated years from infancy to young childhood.Brain function in autistic infants Brain 2012: 135.. and were Stimuli and task design recruited and tracked every 6 months until their third birthday.to 4-year-old children scores [social and communication plus repetitive scores. 949–960 | 951 late age of diagnosis. Each stimulus type was repeated three times in a ing more than two-thirds of the scan. toddlers All toddlers participated in a series of psychometric tests across mul- tiple 2-h sessions that included the Autism Diagnostic Observation and very young children. remaining 16 children judged at-risk prior to 30 months of age.g.2) months]. Infants dlers were exposed to segments of a children’s story that was written and toddlers were included in the final sample if both a structural at a comprehension level of over 48 months. the Communication and Symbolic Behaviour Scales-Developmental Profile Infant Toddler Checklist (Wetherby et al.) set to a volume attenuation of 40 dB German (n = 1) and found to have a temporal lobe cyst (n = 1)]. toddlers were exposed to excerpts from a chil- were acquired before the child awoke. however. Of the general population (Pierce et al.autism-center. Data from an additional four participants were presented using commercially available music presentation were excluded for other imaging-related reasons [given an software with maximum volume set both for the software and the over-the-counter medication by the family (n = 1). Parents Approach (Pierce et al. As expected. 2011). . During the simple for- MRI scan and a functional MRI scan examining speech processing ward speech condition.. 2009). tod- (40 autism spectrum disorder and 40 typically developing). One were also 20-s rest blocks (no presented stimuli) between each typically developing participant was included who woke after complet. In addition.. Five of these children were later judged to no longer warrant a spectrum diagnosis and were not included in the However. simple forward speech and A total of 111 toddlers attempted participation in the scanning backward speech. 2011). we report results of the first functional MRI study of but one (who moved out of the area) have participated in at least one autism in the earliest years of life that addresses these foundation. which remains around the age of 4 years A total of 21 participants were younger than 30 months (an age at nationally (Network. follow-up clinical evaluation 6 months to 1 year later [at a mean (SD) al questions. We analysed functional MRI activation to language age of 31. during the backward speech condition. 2002). 2008) and consisted of three types of stimuli.

This thresh- presented 18.05 as determined by Monte–Carlo data from these will not be presented in this article. the total scan time was 1 h 15 min. padding of the ard atlas space (Talairach and Tournoux.1 (11.34 Receptive language age (months) 37 20. (15 min later).6 (12. Other functional old and cluster size combination protects a whole-brain rate of false- and anatomical scans were acquired before and after the speech task.09 Minutes asleep before task 40 53.39 0. in-plane Complex Forward and Backward speech between groups in the resolution = 4  4 mm. Specifically.3 9. Analysis of Functional NeuroImages software was also Infants and toddlers were imaged in a 1. repetition time = 2500 ms. but all par. brain analyses. the child was allowed to fall asleep in the during periods of non-stimulation (AllSpeech versus Rest).3  13. Families arrived at the scanning facility sidual motion. bandwidth = 31.6  10 7 ADOS social and communication score 40 14.2 (7.0) 39 206.7) 40 2. scan length = 7 min 24 s) for localization of functional signals (t 5 2.9 0. for adults.41 0.42 for a one-tailed between-group and warping into standard atlas space. the scan was started posterior commissures and at the extremes of the brain in each plane. Whole-brain analyses were repeated with age or sleep la- asleep for the entire procedure.4 (23. 949–960 L. For all whole- view = 24 cm.6) 40 25. Furthermore. 2008) that child during the entire scan and stopped the scan if the child woke up or group averaging following Talairach transformation is at least as ac- made a large movement.6 (241.25. t 5 2. slice thickness = 4 mm.3 min after the onset of scanning. voxel-wise findings based on AllSpeech to each different speech con- Scan parameters were: echo time = 30 ms. positive clusters less than P = 0. A research assistant was present in the room next to the We have found in previous investigations (Redcay et al.9) 36 51. bandwidth = 70 kHz.93 6.9 (15.005 Sex (no. field of view = 25. more ducted for the clinical variables within the region of differential re- than two-thirds of the scan). range n Mean (SD). was minimal: no participant was excluded sponse to speech. in-plane resolution = 1  1 mm. oxygenation level-dependent response between speech blocks and aged to forgo any usual naps by the child and engage the child in rigorous periods of no stimulation while controlling for linear trends and re- physical activity during the day. of males) (%) 40 29 (73) 40 25 (63) 0.91 0.8) 36 58. tency as a covariate in the model using the Analysis of Functional Blood oxygenation level-dependent signal was measured across the NeuroImages program 3dttest + + .6) 40 0.17 Receptive language T-score 37 30..0 (1.6 cm. range Student’s t (or 2) P-value or number (%) or number (%) Age (months) 40 32. there were no speech stimuli within the superior temporal gyrus. Table 1 Participant characteristics Measure Autism spectrum disorder Typically developing Group comparison n Mean (SD). On average.5–47. T. slice thickness = 1. Parents were encour.7) 0. the speech task was comparison) and a volume of at least 32 voxels (2048 ml). The time that the child fell asleep was recorded for full-width at half-maximum Gaussian kernel and normalized to stand- every participant.0 (12.5 (11. the within-group age correlations. field of dividually and for the direct comparison between them. Individual waiting or scanning room and was placed on the scanner bed after subject activation maps were then spatially blurred with an 8-mm 15 min of sleep.7) 36 26.39 0. T1-weighted anatomical scan then created for the typical and autism spectrum disorder groups in- (repetition time = 6.70 Receptive visual T-score 37 40.78 1.01 170 slices.3) 2. 31 slices.6 (153.6 (22. we separately compared the mean response to Simple Forward.75 0.5. observed region of group difference.8) 0. we retained clusters with an individual-voxel P 5 0. no sedation was used. SD = standard deviation..3) 5.4 (9. flip angle = 12 . curate for toddlers with and without autism spectrum disorder as it is The order of scans varied somewhat between individuals.8 1. 1988) by rigid-body trans- head for comfort and motion reduction and covering the child with a formation based on manual placement of markers at the anterior and weighted blanket for warmth and motion reduction. follow-up analyses of the relationship of age to the amplitude and extent of activation Data analyses within the identified region of differential speech response were con- Analysis of Functional NeuroImages software was used to detect and ducted.3–45.86 for within group.1  10 30 ADOS repetitive and restrictive 40 3. After placement of the headphones.7)  18. If not already asleep or if awakened by and simple forward speech and backward speech to the response placement on the scanner bed. for having visually apparent residual motion following motion correc.2  10 14 Receptive visual age (months) 37 27.3) 40 51.5 (1. Head motion in the analysed participants. we examined the contrast between blood 1 h after the child’s typical bedtime and most children had been asleep in oxygenation level-dependent response during periods of both complex the car for 15 min prior to arrival.4)  13. dition.2) 8. Correlation analyses were also con- who slept through the entire scan (or.6) 1. Eyler et al.5 Tesla General Electric MRI used to carry out regression analyses in which we compared blood scanner during natural sleep. We confined our group differences in the amount of motion as determined by t-tests analysis to voxels falling within the boundaries of the superior tem- comparing the average across the scan of the squared movement poral gyrus as defined by the Talairach Daemon (Lancaster et al.1 (10. In addition.1 (9. .8) 36 23. for one participant.68 ADOS = Autism Diagnostic Observation Schedule. parameters in each in-plane direction and each axis of rotation (all Scanning procedure P 4 0. flip angle = 90 .2 mm.2 (3.2 (0.19).2 (8.952 | Brain 2012: 135. If the child remained simulation.9) 1. We tested for a group  age interaction and also calculated correct for head motion.4  10 22 Number of words produced 39 126. We were also interested in examining the laterality of response to tion on more than one-third of time-points. To examine the generality of the whole brain with echoplanar imaging during the language paradigm. Group maps of significant language-related response were ticipants first received a high-resolution.

P = 0.78) = 1. although the across the three superior temporal gyrus subregions (given the age-corrected analysis revealed that middle occipital gyrus lack of regional effects) for response to all speech and simple response was greater in the group with autism spectrum disorder and complex forward speech (the contrasts that showed than the typically developing group (Supplementary Fig. complex forward: F(1. P = 0. right: 277 complex: t(78) = 1. simple forward: F(1. P = 0. 1).and three-way interactions between them on the number of voxels that showed a positive response (t 4 2. as indicated by the number of voxels with t 4 2. P = 0.0 in each hemisphere of the entire superior temporal gyrus during (individual voxel P 5 0.05. Table 3 t(78) = 2.39) = 0. right: Pone-tailed = 0. middle (left: 157 voxels. Pone-tailed = 0.Brain function in autistic infants Brain 2012: 135.03. simple forward gyrus activation.76) = 0.78) = 1. 22) was significantly less responsive to speech stimuli in the group P = 0. speech [F(1.35. P = 0. Neither the extent nor amplitude of response in sphere effects. of significant group effects were then examined.83.06] speech. 1 and Table 2). The extent of activation shows the correlations between age and extent of response in this region.08] or extent factor). 1 and Table 2). There were no main effects of group.0). P = 0.47.04] and sphere and region and their interaction. region (a within-subjects [F (1. right: F(1. increasing age.02.8. but still significant.e.05). simple forward speech [left: F(1.09. but not for complex speech [left: when examining response to the backward passages [backward: F(1. hemi- each voxel t-value was 41.65. Table 2).77].15]. P = 0.05). These tween autism spectrum disorder and typical groups within three maps were then compared between the autism spectrum disorder and typically developing groups with a two-sample t-test.05. response in clusters within bilateral hemisphere effect 40. For the region of interest analysis.10] or backward speech activation (i.54. Clusters were anatomically defined portions of the superior temporal gyrus in considered to be significant if they were 432 voxels in volume and each hemisphere. suggesting that the deficient related to laterality of response.78) = 3. 949–960 | 953 2000). It can be seen . Upon direct compari.1. Our initial analysis found no regions in patterns. Thus. we summed across the of 50.08. there was no thalamus and midline cerebellum (Fig.0) for all speech and for each individual condition in the entire superior Results temporal gyrus.76) = 0.03]. Fig.05. order group for both amplitude [r(38) =  0. 1).4). Among typically developing infants and toddlers. age or group  age  hemisphere interactions. we examined the effects of age. For both hemi- there was a significantly larger mean brain response in the typical spheres. Pone-tailed = 0. This combination sphere or region for any of the conditions. we tested the degree to which responses were lateralized superior temporal gyrus was subtracted from the value in the corres- in each group and examined potential laterality differences be- ponding voxel in the left hemisphere to create a laterality map. we added age to the model as a response in autism spectrum disorder does not normalize with between-subject covariate for any condition that had shown hemi.76) = 3. there were group  age interactions for all speech [left: than autism spectrum disorder group when examining simple F(1.39) = 3. complex: t(78) = 3.12. this region of the superior temporal gyrus was significantly related To further examine the localization of possible group laterality dif.78) = 2.78) = 0. In contrast.5]. Within hemispheric effects).66 (Pone-tailed 5 0. brain response was signifi- factor) and two.35.50]. to clinical severity in the autism spectrum disorder group ferences in the superior temporal gyrus and to replicate our previously (P’s 4 0.09].02. we divided bilateral superior forward speech conditions [simple: t(78) = 1. P = 0. However.03] and and complex story passages separately [simple: t(78) = 2.01. and none of the inter- protected a superior temporal gyrus-wide probability of false positives actions with region was significant. In each condition.09). right: 156 voxels) and posterior (left: backward speech condition [t(78) = 1.9.001] and F(1.04. Figure 3 presents the means of the two groups for extent of activation (volume of voxels in microlitres with t 4 2.06. also was significantly different for the all speech and simple and complex forward speech.16. P = 0.82. we found no significant age  group linear model to test for main effects of group (a between-subjects interactions for the amplitude [F (1. P = 0. Infants and evidence of laterality of total superior temporal gyrus response toddlers in the autism spectrum disorder group showed less within the autism spectrum disorder group (all P’s for within-group extensive. we conducted a voxel-wise analysis in which the guage ability in either group (all P’s 4 0. There were no significant main effects of the region of group difference in the superior temporal gyrus. right: 218 voxels)] with equal anterior–posterior extents.5.56. Pone-tailed = 0.3. 2].75.04.39) = 3. To examine how age was extent [r(38) =  0. Age and clinical correlations with mean activity in clusters three superior temporal gyrus regions to examine laterality effects. there was evidence for superior temporal gyrus and activation of a region within the right leftward laterality in the typically developing group in all but the inferior occipital gyrus (Fig. P = 0.39) = 5.3. listening to P = 0. but differential laterality effects were not signifi- storybook passages resulted in strong bilateral superior temporal cant for all speech [F(1. There was a trend towards an interaction between group and hemisphere for response to complex [F(1. a region of left superior temporal gyrus (in Brodmann’s area speech: F(1.32. we used a repeated-measures general of differential activation.30]. P = 0.05. backward condition [within-group hemisphere effects: all son. magnitude of response to forward speech in each voxel of the right Next. temporal gyrus into three sections [anterior (left: 279 voxels. we examined age-related changes in responsiveness of this region For each speech condition. hemisphere (a within-subjects factor). P = 0. less response during speech than rest) in bilateral [F(1. cantly negatively correlated with age in the autism spectrum dis- Follow-up analyses within each group examined the effects of hemi.76) = 3. When 219 voxels. hemisphere and which the autism spectrum disorder group had significantly greater group and their interactions on volume of activation summed responsiveness than the typically developing group. right: F(1.15) or to our measures of expressive and receptive lan- published findings. with autism spectrum disorder than the typical group (Fig.76) = 4. Pone-tailed = 0. P = 0. P = 0. a difference that remained significant after controlling for To examine the relationship of age to lateralized brain response age (Supplementary Fig.1 and backward: F(1.1.78) = 1. P = 0. Pone-tailed = 0.06.03]. positive response in midline precuneus and de.44.76) = 3.03] but only a trend for the voxels).

08  0.15 0. Table 2 Significant clusters of brain response to speech in typically developing and autism spectrum disorder infants and toddlers and the difference between them Cluster Location Voxel Centre Peak All speech Simple Complex Backward count of mass coordinates mean effect forward speech forward speech speech coordinates size (2) mean effect mean effect mean size (2) size (2) effect size (2) Typically developing 1 Left superior temporal gyrus 393 56L.20 3 Bilateral thalamus 148 0R.14 0.23a  0.21 0. 82P. P = posterior. 13P. 8S 0. 8S 0. 13P.11 0. and negative values (cool colours) indicate lower brain response to speech compared with non-stimulation in individual group maps. 75P.08 0. 12I 0. 31I 6L.18 2 Right superior temporal gyrus 285 57R. 14P. positive values (warm colours) indicate greater brain response in the typically developing compared with autism spectrum disorder group]. 81P.e. 1A.11 Autism spectrum disorder 1 Right superior temporal gyrus 181 56R. 5S 14R. for group comparison map.954 | Brain 2012: 135. 28I 0.22  0. L = left. 61P. R = right.10 Typically developing 4 autism spectrum disorder 1 Left superior temporal gyrus 40 55L. 9S 66L. 6S 58R. 10S 58R. T. 5P.24 0.09 0.22 0.05  0.17 5 Midline precuneus 58 1L. 18P.19 0. 949–960 L. 8S 0. 2I 46L.04 a 2 values are signed to indicate direction of the effect. 41S 6L. Eyler et al. R = right. Negative values indicate negative response (i. S = superior.24 0. A = anterior. . 4S 0.23 0. I = inferior. 40S 0.17 2 Left superior temporal gyrus 131 54L. 17P. positive values (warm colours) indicate greater brain response to speech compared with non-stimulation. 15P. 17P. and clusters of significant difference in brain response between groups. 61P.20 0. 8S 0.22 0. L = left. 58P. less response during speech than during rest).16 0.03 0. 4I 0.32 0. 6I 54L.18 4 Midline cerebellum 110 3L.12 0. 21P. 21P. 5P. 4S 54L.17 0.29 0.12 0.08 0. Figure 1 Clusters of significant response to all speech stimuli in the typically developing (n = 40) and autism spectrum disorder (n = 40) groups.17 0.30 0. Colours indicate relative strength and direction of the effect size (2) [for individual group maps.18 3 Left inferior occipital gyrus 52 40L.

949–960 | 955 Figure 2 Graphs of amplitude (mean fit coefficient) (A) and extent (volume in ml of active voxels with t 4 2.25) or to our measures of expressive and receptive mental trends in the two groups—small positive relationships with language ability in either group (all P’s 4 0. 2008). Extent of and to replicate previously published trends (Redcay and response to all speech and simple and complex forward speech Courchesne. Values are shown for all speech and separately for the component conditions.0) (B) of brain response within the cluster of significant group difference in brain response to all speech in the left hemisphere superior temporal gyrus. Mean values for the autism spectrum disorder (ASD) group are shown in red for left hemisphere and pink for right hemisphere. Mean values for the autism spectrum disorder (ASD) group are shown in red and those for the typically developing group are shown in blue. and those for the typically developing group are shown in blue for the left hemisphere and light blue for the right hemisphere. Error bars indicate the standard error of the mean. Figure 3 Graph of extent (volume in ml of active voxels with t 4 2. Values are shown for all speech (used to identify the significant cluster) and separately for the component conditions. (all P’s 4 0. Error bars indicate the standard error of the mean. that the group  age interactions are driven by opposite develop.14). age in the typically developing group and negative relationships To explore the precise localization of group laterality differences with age in the autism spectrum disorder group.0) of brain response within each hemisphere of the entire superior temporal gyrus anatomical region of interest. we undertook a voxel-based analysis in in left and right superior temporal gyrus was not significantly which we directly subtracted response levels between homologous related to clinical severity in the autism spectrum disorder group left and right hemisphere voxels during the forward speech .Brain function in autistic infants Brain 2012: 135.

13 0. Flagg et al.13 0. but was negatively related to age in the autism spec. stronger activation on the right relative to the left in the anterior P = 0.66.41 the development of more social language abilities that would nor- Response to complex forward speech mally require activity of that hemisphere.956 | Brain 2012: 135.. One possibility is that Response to simple forward speech the right superior temporal gyrus is compensating for ineffectual Left  0. 2004).22 0.28 0. The typical group showed significantly greater left-lateralized magnitude of response compared with the autism Discussion spectrum disorder group within a region of anterior superior tem.20 left.04 0. one of the earliest appearing signature deficits in autism. failure to develop normal language comprehension. colleagues (2003) that revealed that American babies only learned Figure 4 (A and B) Voxel-based within-group laterality score maps during the forward speech condition (expressed as signed 2 effect size values..01.04 0. Developmental neuro- Left  0. condition (Fig. reduced left temporal cortex activity and that this difference from tomical region of interest-based analyses.12 0. there was a significant normal grows more pronounced with age. of response such as analysis of prosodic information. the direction of the interaction was similar but not toddlers. Similar to the ana... the right hemisphere.96].05). 2008. thus crowding out Right  0.11 0. Minagawa-Kawai et al. 5P. relative to the Left  0. brain response in all speech and simple and complex We hypothesize that a failure of left hemisphere specialization forward speech conditions in the entire superior temporal during language comprehension in early life may not only delay gyrus region of interest basic language acquisition in infants and toddlers with autism. Pone-tailed = 0.44 0. 4S (Brodmann’s area 22)].. left hemisphere responsiveness in this absent laterality patterns. Furthermore. We did not find any relation. warm colours = left greater than right. 5 posterior and 4 superior].31 in toddlers with autism spectrum disorder.08 0.26 0. Bruneau ship of the measured clinical variables with speech response in et al. Specifically. superior temporal gyrus-wide P 5 0. 949–960 L. Eyler et al. but Measure of extent Group may also impair the development of social language behaviours. may be due to very early defects in the superior temporal gyrus and Table 3 Relationship of age and extent of hemispheric these defects may last across the lifetime.01 0. portion of the superior temporal gyrus. Thus. . 2010).. In response to a simple bedtime story. which is typically Autism spectrum Typically disorder (n = 40) developing (n = 40) mediated by right hemisphere neural processes (Friederici and Response to all speech r P r P Alter.05). This abnormal lateralization is consistent with studies of significant [F(1.32 0.003]. whereas age  group interaction for left hemisphere extent of response to typical toddlers show the expected pattern of left side dominance forward speech [F(1. 2005.08).05 0. Muller et al. with more left-lateralized values in the typically developing compared with autism spectrum disorder group [36 voxels (each with t = 1.17 0. Consider the elegant study by Kuhl and The bold values indicate the one significant correlation (and its P-value).47 processing by the left superior temporal gyrus.04] in this region of differ.81 are inextricably linked. with a peak at 50 left. with revealed that infants and toddlers with autism display abnormally a peak at 50L. sleep functional MRI poral gyrus [36 voxels (each with t = 1. Anderson et al.45. 1989. T. the brain region most trum disorder group [r(38) =  0.95 scientists have long known that language and social development Right  0.05.15]. 1999. Specifically. 2009. P = 0. toddlers with autism exhibit reversed or ential laterality. (C) Group difference map showing the cluster of significant difference in laterality between groups. strongly responsive to language sounds in typically developing sphere. toddlers with autism display region was not related to age in the typical group [r(38) =  0. older autistic children and adults (Dawson et al. cool colours = right greater than left) for typically developing and autism spectrum disorder groups in the superior temporal gyrus (shown at 51 left/right).77 0. In our study. P = 0. in response to stories.20 0. Kleinhans these regions (all P’s 4 0. 1999.1. et al.. 4).98.66. Pone-tailed = 0. In the right hemi. P = 0.76) = 1.76) = 2.20 0. was disproportionately involved in processing speech sounds Right  0.

2007) has also lead to further failure of functional specialization during early been shown at 10 months of age. there were no statistically significant relationships be to perform diffusion tensor imaging as well on subjects and found between the volume or strength of activation in the left examine the cross relationship between diffusion tensor imaging superior temporal gyrus and language ability or symptom severity and functional activation results. 2011). 2003. with the single exception and Pallie.. functional connectivity ever. Results from that study showed consistent with near-infrared spectroscopy results showing that reduced correlations between right and left superior temporal activation of temporal cortex is reliably observed in response to gyrus and inferior frontal gyrus in 2-year olds with autism relative hearing language stimuli (Rossi et al. 2009).. These studies. response to auditory signals. 2006. of heavy exposure to the particular acoustic properties of speech ity (Muller et al. adults. 1997. chance levels when exposed to the identical linguistic information 2010). between early functional brain profiles ascertained between 12 tions to posterior superior temporal gyrus via the arcuate fascic.. longer sylvian fissure (Geschwind and Levitsky. 2006. 2004). increased contact by afferent fibres typical 2. although sometimes overconnectiv.g. Imada and colleagues (2006) component (Dehaene-Lambertz et al. Our sleep functional MRI findings are autism (Dinstein et al. 2011). neurons (Hutsler. adolescents and regions of temporal cortex.Brain function in autistic infants Brain 2012: 135. 2011). lateralization in response to language has a very strong genetic between 6 and 12 months. Interestingly. At the young ages we tested. In the current 1981). which were in some cases as young as 12 months in among the autism spectrum disorder group may suggest particular age. In autism. activity across development (in fact. Dinstein et al. The relatively anterior location of the region of abnormal some instability of language test scores for the youngest toddlers brain response and laterality within the superior temporal gyrus in our study.. however. in toddlers with ing infants and toddlers. Kuhl. occipital. the ventral pathway to anterior superior temporal gyrus Language development most certainly involves a complex inter- seems to subserve processing of local syntax whereas the dorsal play between environmentally driven and genetic factors (Quartz pathway to posterior superior temporal gyrus is more involved in and Sejnowski. This pathway has been shown to be involved Courchesne.. adults with the disorder.and 3-year olds recruited multiple brain areas in frontal.. Development of functional of a study examining inter-hemispheric correlation patterns lateralization of speech processing has also been examined using between brain areas key to language development. 1999). The relationship in sentence processing. 1973. Connectivity studies during the toddler appear to be enlarged even in foetuses and infants (Witelson years in autism are almost non-existent. at least for natural The current study demonstrated negative correlations of superior speech (Pena et al. as showed that infants recruit both traditional auditory areas in su. this actions with a Chinese Mandarin speaker. such as the functional near-infrared spectroscopy in awake typically develop- superior temporal gyrus and inferior frontal gyrus. some exclusively been conducted with older children. 2011) and showing evidence to typically developing as well as language delay contrast groups. 2002.. the typically developing group engaged parietal. Most of and cerebellar regions in addition to the strong response within what is known regarding left–right structural asymmetries. One key to answering how frontal and temporal designed to isolate prosody from other types of speech processing.. 2010). has been gleaned from studies using adults or older children studies generally report highly aberrant patterns of functional con.. nections during early development. The early emergence of left systems that support sophisticated language depend on the initial lateralization in response to language has led to the idea that left coordinated activity of widespread networks.. (Seldon. regions in autism spectrum disorder early in life may lead to later Why is the left superior temporal gyrus hypoactive in autism to syntactic problems and aberrant functional organization of the begin with and why does it fail to show a steady increase in superior temporal gyrus. 1996). have almost (Dehaene-Lambertz et al. 2010).. Clearer relationships may emerge based on language and connectivity issues in the ventral pathway from Broca’s area to symptom profiles at slightly older ages (e. 1981). 3 years old) as we superior temporal gyrus via the extreme capsule fibre system have found in other studies from our laboratory (Redcay and (Brauer et al. increased width of cortical columns (Seldon. along with more immature dorsal connec. very early in development (Dehaene-Lambertz et al. 2011). Kotilahti et al. Redcay increased area measures (Lyttelton et al. 949–960 | 957 Mandarin phonemes within the context of natural play inter. and it is unclear whether these anatomic asymmetries are the nectivity usually in the form of underconnectivity (Just et al. Babies performed at functional specialization has not yet developed (Brauer et al.. Price. the left side of the brain has enlarged perior temporal gyrus as well motor areas in the frontal lobes in white matter underlying Heschl’s gyrus (Penhune et al. which may suggest that early connectivity problems prosodic versus flattened stimuli (Homae et al. but the disruption of response and lateralization of anterior delivered via television or audio tape alone. compared with the right. subcortical and thicker myelinated fibres (Anderson et al.. of early emergence of leftward lateralization.. larger pyramidal and colleagues (2008) showed that in response to bedtime stories. which will be a future line of in toddlers with autism spectrum disorder. showing less activity with Our study also adds to a body of literature on typical brain age)? One possibility may relate to a wider problem of a failure function documenting left lateralization in response to language of the superior temporal gyrus to develop effective functional con. 2008. Slightly later in development. For example. cerebellar as well as temporal cortices. 2010). but our stimuli were not development. 2003).. In in follow-up studies. 2010).. in typically developing 7-year-olds (Brauer et al. cause of language abilities in our species or only the consequence 2004. such as the left planum temporale. 1968) study. how- the superior temporal gyrus. 2010) and disentangling contributions . However. Pierce and Eyler. Rightward lat- temporal gyrus activations with age in the autism spectrum dis. This could be due to inquiry. 2006). Chi et al. 1977). hierarchical syntactic processing. eralization of functional near-infrared spectroscopy response to order group. Successful function of brain Dehaene-Lambertz and Gliga... systems connect with each other and mature in autism would Interestingly. and 18 months and outcome at 3–4 years in age will be examined ulus.

stage of the participants in the study. Why is this the case? Funding Although adverse environmental influences that may be occurring National Institutes of Health (R01-MH036840 to E. it is still possible CNTNAP2 as an autism-susceptibility gene. Linkage. Auditory associative cortex dysfunction in children with autism: evidence from late auditory observed in this study appears to be early and invariant and evoked potentials (N1 wave-T complex). specific development receptive language disorder. however. out. and gene-expression analyses identify children with autism spectrum disorder to date. languages (Eimas et al. Friederici AD. are collecting imaging data from relevant comparison groups and Bartak L. 31: 131–9. other developmental delays. In this way. Neuroanatomical prerequisites for ferent between the groups and did not impact the findings of language functions in the maturing brain. Scott-Van Zeeland et al. AJNR Am J Neuroradiol 2010. In addition.P. we Neuropsychiatry Neuropsychol Behav Neurol 1999. that we failed to detect small differences between groups or com. Stone JL. Znamirowski.. Magn Reson Imaging 2001. by the first birthday. which typically is confirmed sometime around administrative team: C. 2010 for review). Barthelemy C. is within a time imaging team: S. et al. Powers RE. Hazin. We would especially like to thank the families of to those destined for a typical trajectory. This crit. Eyler et al. Anderson AW.958 | Brain 2012: 135. Peterson BS. Alarcon M. . 82: 150–9. J. Brauer J. our study demonstrates that the brain region highly engaged in language processing. 459–66. Colson ER. I. these aberrant response patterns may serve Carper RA. Solso. Ongoing studies in our laboratory aim to elucidate the pathways from genes to aberrant functional lateralization in autism spectrum disorder. Belin P. at face value. the cross. Given the very early emergence of these functional deficits. and the clinical and autism diagnosis. We also wish such. et al. develop autism compared with those who go on to experience Anderson B. Lange N. R. Bourgeois M. while babies are born with a tional defects before they become a permanent hindrance to universal ability to detect phoneme contrasts from all the world’s actualizing their full cognitive and emotional potential. the children who participated in the study. Marois R. Sleep latency was not dif. Spendlove. T. association. the superior temporal gyrus. 161: 2117–20. Ahrens-Barbeau. References Some potential limitations to this study should be noted. Clin Neurophysiol 1999. selectively in this group during this time period cannot be ruled P50-MH081755 to E.. 12: 247–54. are likely similar. First. 2006). suggest a strong genetic component. although this is the largest functional MRI study of very young et al. M. Duvall JA. Weinfeld. although our functional MRI results from Br J Psychiatry 1975. In the present analysis. 21: group differences. Froehlich A. may reflect a core.. Gallagher. what they hear most frequently) and lose the ability to dis- Acknowledgements criminate sounds from other cultures (Kuhl et al. Lopez. 57: 126–33.C. although our longitudinal measurement of clinical status is a Ehrenkranz RA. In our ongoing study. the early language environment between birth and the to thank E. of each has puzzled scientists for centuries. While the genetics of language development are far from clear. we were not able functional magnetic resonance imaging. our ence of environment. Duncan CC. 2009). sleeping babies are similar to those seen in awake typical children Boddaert N. studies have shown that exposure to lan. 2008. For example. Cox A.C. are dysregulated in autism (Alarcon et al. Desmond. Barthelemy C. As such. Carter. Bomar JM. Campbell. plicated developmental interactions. in autism. 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