Recent functional neuroimaging studies focused on identifying the neural correlates of autism spectrum disorders (ASD) have generated several encouraging lines of investigation, albeit with varying degrees of replication. Since impairments in social and communicative skills are the hallmarks of ASD (1
), most neuroimaging studies have used social cognition-based paradigms testing the ability to interpret and predict other’s beliefs, intentions and desires (i.e., theory of mind) as well as the perception of specific social stimuli such as human faces. Both processes have been found to be abnormal in early development of individuals with ASD and have been linked to the associated social and communicative impairments (4
Based on models of the social brain (6
), studies have focused on a priori
regions of interest typically implicated in mentalizing, including medial prefrontal cortex/paracingulate cortex, temporo-parietal junction, temporal pole, amygdala, and periamygdaloid cortices. Depending on the specific task employed, ASD-related abnormalities have been reported for each of these regions, with moderate degrees of agreement (10
). For instance, hypoactivations of rostral anterior medial prefrontal cortex, adjacent anterior paracingulate cortex and perigenual anterior cingulate cortex (ACC) have been found in some studies using theory of mind paradigms (13
) but not in others (16
). Likewise, some studies of emotional processing (e.g., 16
) describe ASD-related amygdala hypoactivation, but not others (18
). An area of particular convergence is facial perception, with ASD-related hypoactivation of fusiform gyrus (FG) observed across both studies of facial form and facial expression perception (e.g., 20
). However, negative reports (18
), have raised questions regarding the nature and specificity of FG dysfunction in ASD. In sum, studies of ASD based on social cognitive models have identified candidate regions of dysfunction, albeit with only moderate convergence across studies.
Although deviant development of the ability to engage in appropriate social interactions is the central dysfunction in ASD, additional cognitive and sensorimotor impairments often co-occur (e.g., 25
). For instance, working memory, planning, cognitive flexibility, inhibitory control, and action monitoring are impaired in both children and adults with autism (e.g., 27
). Some authors hypothesize that such abnormalities underlie the pattern of restricted and stereotyped interests which complete the diagnostic triad of autism, along with social and communicative impairments (1
). These observations have motivated parallel lines of investigation on the ASD- neuronal correlates of executive dysfunction. Brain correlates of other functions also found impaired in ASD, such as language, have been also examined (10
Frontal cortical hypoactivation has emerged as one of the most consistent results across these studies. Specifically, reduced activation of dorsolateral prefrontal cortex (DLPFC) and dorsal ACC have been described in individuals with ASD performing working memory, inhibitory control, visuospatial attention, and embedded figure tasks (e.g., 35
). Hypofunction of other frontal regions has been reported depending on the specific task employed (for reviews see 10
). Accompanying hypoactivation in task-targeted regions, increased function in areas implicated in more basic sensory processing such as primary visual cortex has been consistently described (41
). Of note, such patterns of atypical recruitment have also been reported in studies examining social processes (e.g., 20
Despite broadly convergent findings, the neuronal correlates of ASD remain under-specified. Reasons include the use of generally small samples, with substantial heterogeneity with respect to age ranges, clinical presentation, tasks, and statistical methods. Most studies used fixed rather than random effects models, many lacked direct group comparisons, and most relied on region-of-interest analyses which limit generalizability and increase type I error rates. Overcoming these limitations definitively will require pooling larger samples and standardization of data collection methods across laboratories (42
). Pending such a large-scale effort, a systematic assessment of current functional neuroimaging findings can inform the field and suggest priorities for future investigations.
Quantitative meta-analyses have emerged as useful methodological approaches to provide unbiased, objective measures of brain functioning in various clinical populations (43
), but none have been conducted in ASD. In contrast to qualitative syntheses of the current literature (10
), a quantitative meta-analysis can lead to the identification of regions that might otherwise be over-looked, and is less likely to be driven by prominent theoretical models.
Here, we provide a voxel-wise quantitative meta-analysis using activation likelihood estimation (ALE) (49
). The ALE meta-analysis produces voxel-wise formal estimates of probabilities of activation. Using the exact coordinates reported by each study instead of author-assigned anatomical labels, ALE provides better spatial resolution and reduces errors due to overly broad spatial designations or region mislabeling (52
Given that ASD-related abnormalities extend across multiple cognitive domains, it is important to take into account the impact of domain-specificity. In other words, the ability of meta-analytic techniques to detect consistent ASD-related abnormalities in a given region likely depends on the specific processing domain examined. For example, an extensive literature in neurotypical subjects supports the hypothesis that studies examining social cognition would show ASD-related hypoactivation in the perigenual ACC/rostral medial prefrontal cortex (7
). As most studies of non-social cognition in ASD included components of executive functions, we anticipated ASD-related hypoactivation in dorsal ACC/pre-supplementary motor area (pre-SMA) and lateral prefrontal regions commonly identified in normative studies (e.g., 59
). Fortunately, ALE allows comparing different task domains, even when not directly contrasted in the same studies. Accordingly, we conducted ALE meta-analyses of published functional neuroimaging studies of ASD in both social and non-social domains.