In this study, we tested brain lateralization in autism using functional connectivity MRI and found that abnormal lateralization of functional connectivity during rest in autism is most pronounced in specific left-lateralized connections that involve language regions (that is, Broca area and Wernicke area) and regions of the default mode network (that is, temporoparietal junction and posterior cingulate cortex), rather than diffusely affecting either the left- or right-lateralized functional networks. We also replicated previous results in the typically developing group that two interconnected lateralized networks exist in the brain, one in the left hemisphere, and one in the right hemisphere, with the left-lateralized network involving language and default mode regions, and the right-lateralized network involving brain attentional regions .
Cardinale and colleagues found that abnormal lateralization in autism existed across many intrinsic networks, including primary sensory and higher-level association networks . We, too, found either a lack of left lateralization or greater right lateralization in the autism group; however, the regions or networks involved in abnormal lateralization differed. Rather than finding abnormalities throughout a number of networks as Cardinale and colleagues did, we only found significant differences after multiple comparison corrections in a handful of connections involving language regions and regions of the default mode network. Cardinale and colleagues did find lateralization in the default mode network in some of their supplemental analyses; however, they did not directly test lateralization between language regions and default mode regions.
The inconsistent results may reflect differences in the sample age, sample size, number of data acquisition sites, and/or data analysis methods. In Cardinale et al., aggregate network measures were studied that pooled information across many ROI’s, whereas the present study used a more spatially localized approach tailored to study individual ‘connections’ between discrete brain regions. It is possible that subtle or subthreshold differences in lateralization in regions of the brain distinct from core language hubs, when pooled across entire functional networks, yield significant lateralization differences that may not survive rigorous statistical testing when evaluating small discrete ROI’s. In fact, we find this likely given the results of Figure 2, in which many more connections, including some that are not associated with language regions, exhibit decreased lateralization with P <0.05. Virtually all of these show decreased lateralization in autism. Given the consistent direction of the effect, it seems probable that when pooled together, these connections may result in more widespread network differences in lateralization. Nevertheless, our results suggest the effect is much stronger in core language and default mode regions and our approach allows a more spatially localized assessment of effect size.
Neither our study nor the Cardinale et al. study found a relationship between abnormal lateralization of intrinsic networks and social or communication impairments that survived multiple comparisons . This corresponds with variable relationships found between abnormal brain lateralization and functional connectivity in general. In individuals with autism, reduced functional connectivity within the default mode network relates to more social and communication impairments [34, 41, 45–47]; however, other studies found no relationship between activation patterns or abnormal lateralization and autism severity or language ability [9, 19].
The abnormal lateralization of connections involving regions of the default mode network and core language regions may represent an overall lack of specialization in brain regions that process language and social stimuli. Regions of the default mode network are involved in tasks that require language (for example, internal narrative and autobiographical memory) and theory of mind or understanding of another’s mental state [60–62]. The temporoparietal junction and posterior cingulate cortex participate in the same component as core language regions during a language task . The temporoparietal junction participates in both semantic tasks and deactivates during cognitively taxing tasks (that is, has default mode characteristics) . The posterior cingulate cortex is more active in congruent and coherent language compared to incongruent or incoherent language [65, 66]. The right inferior frontal gyrus is more active in autism compared to typical development during a language task, implying abnormal lateralization in a core language region that may have implications in its relationship with other brain regions (for example, as we found with the connection between Broca area and posterior cingulate cortex) . Together these observations suggest the abnormal lateralization between core language regions and default mode regions could account for some of the communication and social deficits experienced by individuals with autism. This possibility is also supported by findings that abnormal lateralization in language regions are correlated with decreased function on standardized testing .
Reports of abnormal functional lateralization in specific language impairment correspond with previous reports in autism and the present study. Individuals with specific language impairment have less left-lateralized activation in Broca and Wernicke areas during speech tasks [16, 68]. Individuals with developmental dyslexia also have less lateralization across the left hemisphere, as assessed by functional transcranial Doppler ultrasound . One study of note, however, found somewhat different results . It compared individuals with a history of specific language impairment but lacked a current diagnosis, individuals with a current diagnosis of specific language impairment, individuals with autism, and typically developing individuals. Over 80% of the individuals with a current diagnosis of specific language impairment showed right lateralization or bilateral activation during a language task, whereas over 90% of the individuals from the other three groups showed left lateralization. From this study, it appears abnormal lateralization is even more specific to individuals with a current diagnosis of specific language impairment.
The observation that abnormal functional lateralization in autism is most pronounced in connections between core language regions constrains hypotheses of developmental pathophysiology in autism. Our analysis suggests that abnormal language lateralization in autism may be due to abnormal language development rather than a deficit in hemispheric specialization of the entire brain, and would be more consistent with a search for mechanisms involving brain substrates for language acquisition rather than earlier potential mechanisms where hemispheric asymmetries emerge. This constraint is also supported by multimodal observations from DTI, functional MRI, structural MRI, and electrophysiologic studies that have all identified specific deficits in language-related lateralization but not differences in lateralization in other cognitive subsystems.
While the large sample size of the ABIDE dataset can be a tremendous advantage for improving statistical power and external generalizability of the results, it can also be a liability. The individual sites differ in many important data acquisition variables including inclusion criteria, demographics, pulse sequence, scanner type, and length of scan. Most of the included scans were very short, less than 10 minutes duration per subject. It is possible that the heterogeneity of the dataset may limit sensitivity for detecting small changes, and that in a more homogenous data sample, additional differences in lateralization would be found.
An additional limitation is that we did not attempt a discovery of all lateralization differences in an attempt to control the multiple comparison problem that would arise, but instead looked for lateralization differences only between a set of 20 regions that were previously identified as being hubs of lateralized networks in a control population (different from the control subjects used here). It is possible that systematic differences in lateralization are present in brain regions that are not necessarily hubs of lateralization networks in the brain, and which we could not detect. It is also possible that control and autism groups differ in precise spatial coordinates of some lateralization hubs, which we would not be able to detect.