In this first fMRI study of 2–3 year-old children with ASD, we identified a pattern of neural response to speech that differed in children with ASD from both their chronological age- and mental age-matched typically developing controls. In comparison to MA-matched controls, the ASD group showed reduced activity in an extended number of brain regions in response to speech. In comparison to their CA-matched controls, the ASD group showed both a delayed and deviant pattern of brain response to speech, characterized by a greater recruitment of right hemisphere frontal regions.
A deviant pattern of laterality in ASD in response to speech vs. rest was identified in three separate analyses. First, in comparison to their CA-matched controls, the ASD group recruited greater right frontal regions (). Second, in a paired hemispheric comparison, the ASD group showed a trend toward greater recruitment of right hemisphere frontal and temporal regions during the forward speech condition, while the CA group showed a trend towards greater left hemisphere recruitment in a number of brain regions (). Third, correlations with receptive language age revealed a greater reliance on primarily right hemisphere frontal and temporal regions with increasing language abilities and decreasing autism severity (). Autism severity, however, was also correlated with a similar pattern in the left hemisphere. These findings suggest that not only is the right hemisphere recruited to a greater extent in autism than in controls at 2–3 years of age, but also that early right hemisphere recruitment may be predictive of a better language outcome in autism.
In comparison to their MA-matched controls, the ASD group showed reduced activity in an extended network of brain regions. In a previous paper (31
), we hypothesized that an extended network of brain regions including frontal, occipital, and cerebellar regions may be recruited at the cusp of the rapid burst in language skills seen in the second year of life. This hypothesis is additionally supported by ERP studies in which the response to known words progresses from widespread to more focal patterns with increasing language skill in typically developing 20 month-old children (37
). In addition to reduced activity in a number of frontal, occipital, and cerebellar regions, the ASD group also showed deviant patterns of right and medial frontal activation in comparison to their CA-matched controls. Taken together, these findings reveal that the pattern of activity in ASD is both reduced and deviant as compared to the pattern recruited in the MA-matched controls. The reduced and deviant activation in the ASD group could reflect a failure to engage the full network of brain regions which may facilitate language learning. Studies of 1–2 year old children with provisional ASD will be needed to determine whether a typical extended network is ever recruited or whether evidence of a deviant developmental trajectory is already present at even younger ages.
This pattern of deviant lateralization and immature, frontal recruitment in autism as compared to controls suggests a possible lack of specialization for language systems in autism by 2–3 years of age. Previous studies of the older child and adult have identified patterns of reduced or reversed laterality in frontal and/or temporal cortex in structural studies (40
) and functional studies using ERP (44
), PET (8
), fMRI (8
), and MEG (46
). However, this is the first study to suggest abnormal laterality in children with ASD as young as 2–3 years of age. Furthermore, the significant correlation of right hemisphere frontal and temporal activation to speech with receptive language skill in autism suggests that by 2–3 years of age, children with autism may already be on a deviant developmental trajectory characterized by right hemisphere recruitment for language.
The cause of this deviant developmental trajectory can only be speculated. Some evidence suggests recruitment of right hemisphere regions may be a compensatory mechanism to account for the more effortful processing required to process language in autism (9
). However, the current study was conducted during natural sleep, suggesting cognitive strategies alone cannot account for the reversed asymmetries seen in the autism group. Structural MRI studies have revealed that a number of structures which showed evidence of deviance in functional laterality at 2–3 years of age in the current study (e.g. inferior frontal and posterior middle and inferior temporal regions) also show greater rightward asymmetry at 5–11 years of age in ASD (42
), suggesting a possible structural bias underlying the deviant functional patterns. However, it is not possible to disentangle whether this structural asymmetry is a cause or consequence of aberrant functional patterns early in life. Some evidence suggests brain volume in right temporal and frontal regions is strongly dependent on genetic factors, whereas left hemisphere regions are more influenced by experience (48
) and develop more slowly than the right (49
). It is possible that a combination of both genetic and experiential factors very early in life results in a greater reliance on right hemisphere regions, and possible reduced development of left hemisphere regions for language processing. Given the differing rates of development within each hemisphere, the timing of brain insults could be particularly important in altering hemispheric asymmetries.
Three limitations of the current study warrant discussion as they have may have potential implications for the interpretation of the findings. First, while the ASD group contained only males, both control groups contained a small number of females (4 out of 12 in the CA group and 2 out of 11 in the MA group). This limitation is addressed in Supplementary Information
through a post-hoc analysis with a male-only control sample and supplementary text (Figure S1, Table S4)
Second, while this study contained two typical control groups for the ASD sample (one chronological age- and one language-age matched group), it did not contain a contrast group of children with developmental language disorder (DLD), or specific language impairment (SLI). Evidence suggests some overlap in language profiles (6
) and anatomical asymmetries (43
) between children with autism and those with language-impairments but not autism. Thus, the inclusion of this third contrast group could elucidate functional activation patterns that may be specific to autism and not due to language impairments alone.
A third limitation of the current study is that data were recorded during natural sleep without monitoring sleep stage. As discussed in our previous paper (31
), REM onset latency differs between 1 and 3 year-old typical children; however, for both ages mean REM onset latency is reported to be approximately 60 minutes or greater (50
). These data were recorded approximately 45 minutes into sleep, and thus, a systematic difference in sleep stage is not expected between groups. In studies of older children and adolescents with autism, REM onset latency was not significantly different between autism and control groups (52
). Thus, while sleep stage could affect patterns of brain activation, between group differences are not expected to be due to sleep stage differences alone. However, further studies would benefit from polysomnographic recording as much variability is often seen in latency to REM onset (50
The use of fMRI during natural sleep poses a number of advantages. First, fMRI data can be acquired from infants, toddlers and young children with minimal motion artifact. Second, children across a broad range of cognitive and behavioral function can be studied. FMRI studies of awake and performing older children and adults inherently require high-functioning participants with ASD: a narrow subset of the autism population. Third, effects of arousal, anxiety, or attentional state that typically can confound fMRI studies of patient populations are not present. Thus, sleep fMRI may be a valuable tool in understanding the biological bases of autism. Identification of specific structures and networks showing functional abnormalities at the time of emergence of autism could give clues for where to look for microstructural differences or gene candidates (e.g. those involved in hemispheric patterning) in autism.