The most important finding of the current study is that the participants with autism showed functional underconnectivity among several brain areas involved in Theory of Mind processing. As predicted, the frontal Theory of Mind regions (medial frontal gyrus, anterior paracingulate, orbital frontal gyrus) were found to be functionally underconnected with the posterior Theory of Mind regions (right middle and superior temporal gyrus) in autism during mentalizing. In addition, underconnectivity was found in the connections between the frontal lobe and other more posterior regions, and within the occipital and parietal lobes. Castelli et al. (2002)
reported a correlation across autistic and control participants between the amount of activation (averaged over the entire course of the task) in occipital and temporal regions in a PET study. The current study, using the same stimuli, provides new evidence of a lower degree of synchronization (with observations obtained once per second) between frontal and posterior areas in autism during the viewing of these animations. The fMRI measures provide critical detail that speaks to the underlying mechanisms that distinguish the two groups, namely the lower degree of synchronization and hence coordination among brain areas in autism.
Interestingly, functional connectivity in the frontal-posterior Theory of Mind network was modulated by condition in both groups, but in different ways. Normal control participants showed an increase in functional connectivity in this network only when viewing the ToM animations, suggesting an adaptive engagement of processes involving communication among the areas only in the condition in which such processes are necessary. In contrast, the group with autism showed an increase in functional connectivity relative to the RD condition for both the GD and ToM conditions. This differential pattern of modulation resulted in the group with autism showing reliable underconnectivity relative to controls in both the RD condition and the ToM conditions, but not in the GD condition. These results suggest that individuals with autism attempt to carry out processes dependent on communication between frontal and posterior Theory of Mind areas for both types of animation involving interactions between the triangles, but that such communication is less efficient overall and less adaptive to the demands of the task.
Although the functional underconnectivity in autism is widespread in this study, affecting not only frontal-posterior connectivity but also occipital-temporal connectivity, the most intriguing facet of this is that the frontal lobe seems to be the epicenter of underconnectivity. This observation emphasizes the significant participation of the frontal lobe and its integration with other areas in a complex task, such as mental state attribution. Lower activation in frontal areas in autism has been found in several different functions, such as language comprehension (Just et al., 2004
; Harris et al., 2006
), verbal working memory (Koshino et al., 2005
), face working memory (Koshino et al., 2008), visuospatial processing (Ring et al., 1999
), and understanding emotions of others (Dapretto et al., 2006
). In addition, our previous studies of executive functioning (Just et al., 2007
), visual imagery (Kana et al., 2006
), response inhibition (Kana et al., 2007
) and discourse processing (Mason et al., 2008) have found frontal-posterior underconnectivity in autism. These findings from brain activation and functional connectivity, in conjunction with findings of structural abnormalities, such as delayed maturation of frontal lobe (Zilbovicius et al., 1995
), increased frontal cortical folding (Hardan et al., 2004
), anatomical shifting of major sulci in the frontal lobe (Levitt et al., 2003
), and maldevelopment in minicolumns in the frontal cortex (Casanova et al., 2002
; Buxhoeveden et al., 2004
) suggest impairment in information transfer from and to the frontal lobe in autism.
Although the differences in frontal lobe activation between groups found for the contrast between the ToM condition and the RD condition could conceivably lead to reduced functional connectivity in the group with autism if there was simply no frontal activation in this group, note that the ROIs for which the signal intensity was extracted were not based on areas showing a group difference for this contrast, but rather were defined by the within-group contrasts between the ToM condition and the fixation baseline, a contrast for which both groups showed activation in medial frontal and bilateral inferior orbitofrontal areas. In addition, the procedure for calculating functional connectivity ignored regions within participants that did not show a sufficient volume of activation in this contrast to provide a stable estimate of the time-course of signal intensity. Given a measurable and stable signal from the involved regions of interest, our measure of functional connectivity depends on the correlation of signal change among regions during viewing of the animation, rather than on the amplitude of the signal intensity within individual regions. We also note that in previous work we have found lower functional connectivity in autism despite similar levels of activation between the groups for the regions considered (e.g., Just et al., 2007
) and that such differences are found even during a resting baseline condition (Cherkassky et al., 2006
). Note also that in the present study we found group differences in functional connectivity in posterior regions that did not show differences in activation between the groups. Although the present study can not distinguish whether reduced frontal activation in autism is a cause or a consequence of reduced communication between frontal and posterior Theory of Mind areas, reduced activation is not a necessary precondition for reduced functional connectivity.
Widespread white matter abnormalities have also been found in autism, including lower fractional anisotropy of the white matter adjacent to the Theory of Mind regions (medial frontal gyrus, anterior cingulate cortex, and right temporoparietal junction) (Barnea-Goraly et al., 2004
), significantly larger frontal and parietal white matter volume (Carper et al., 2002
), disturbances (both increases and decreases in volume in different areas) in white matter (Herbert et al., 2004
), white matter volume deficits in right middle frontal and left superior frontal regions (Waiter et al., 2005
), reduced thickness in orbitofrontal white matter (Chung et al., 2005
), increased regional and global white matter (Hendry et al., 2006
), and abnormalities in corpus callosum size (Egaas et al., 1995
; Piven et al., 1997
; Hardan et al., 2000
). Any or all of these abnormalities could conceivably affect the functional and structural connectivity of the frontal lobe with more posterior regions in autism. These findings taken together point to abnormalities in the neural architecture in autism, which may affect several types of psychological functions, including Theory of Mind.
The critical role of the prefrontal cortex in Theory of Mind processing is supported by neuropsychological studies that show frontal lobe damage associated with impairments in Theory of Mind (Channon &Crawford, 2000
; Rowe et al., 2001
; Stone et al., 1998
; Stuss et al., 2001
), including the medial prefrontal cortex as well as the orbitofrontal cortex. Gallagher and Frith (2003)
propose that while the posterior superior temporal sulcus provides the cues for mentalizing, the medial prefrontal cortex does the mental state reasoning. Therefore a communication between these two regions is vital in Theory of Mind tasks. In other words, cortical underconnectivity in autism among the components of the network for mentalizing provides a plausible neural basis of impaired Theory of Mind in autism. The underconnectivity could simply be at the level of a lack of information coordination between two areas. However, in autism, structural and abnormalities in the white matter connections to the frontal lobe have been reported by several studies, so the functional underconnectivity could well be related to anatomical connectivity properties, as we have demonstrated previously (Just et al., 2007
; Kana et al., 2006
; Cherkassky et al., 2006
; Keller et al., 2007
In addition to showing lower functional connectivity in autism in the Theory of Mind task, the present study also demonstrated a reduction in activation during mentalizing in three key frontal regions: the medial frontal gyrus, the orbitofrontal gyrus, and the anterior paracingulate cortex. This finding is consistent with several previous studies of Theory of Mind processing in autism (Castelli et al., 2002
; Happe et al., 1996
; Baron-Cohen et al., 1999
). Mental state attribution presupposes self-awareness and it likely involves processing in evolutionarily recent regions of the neocortex, such as the frontal cortex (Gallup, 1982
). As mentioned in the earlier part of the discussion, frontal lobe underactivation in autism is not uncommon in other higher cognitive tasks. It may be possible to distinguish the roles of frontal regions and parietal regions in the ToM network, although the differentiation is not critical to the current study, nor do the current results help to distinguish the roles. Three frontal regions have been credited with distinct roles in mental state attribution. The medial prefrontal cortex has been credited with involvement in any kind of thought that uses the self as a referent (Gusnard et al., 2001
), the anterior paracingulate cortex is believed to be involved in the decoupling mechanism that distinguishes mental states from reality (Gallagher &Frith, 2003
), and the orbitofrontal cortex is believed to play a crucial role in Theory of Mind (Baron-Cohen &Ring, 1994
; Brothers and Ring, 1992
), and may be associated with recognition of mental state terms (Baron-Cohen et al., 1994
). The reduced activation in participants with autism in these regions indicates an atypical neural basis for Theory of Mind processing.
Contrary to our prediction, there was no reliable group difference in activation in the right superior temporal sulcus (STS) at the temporoparietal junction while processing Theory of Mind. This is in contrast with the findings of reduced activation in autism in this region in a previous study (Castelli et al., 2002
). However, the present finding raises several interesting questions. First, in contrast to the implicit nature of the task (passively viewing the animations) in the Castelli et al. (2002)
study, the present study included instructions that were designed to require participants to explicitly attempt to attribute mental states to the stimuli (watching animations and answering questions related to mental state). Normal or a higher level of activation in autism has been found in explicit tasks of processing mental states (Wang et al., 2006
). It is possible that the participants with autism might make a more controlled effort to infer a mental state when they are explicitly asked to do so. Second, it is possible that the superior temporal sulcus plays a subordinate role in inferring mental states. Gallagher and Frith (2003)
argued that the STS is more generally associated with social cognition but the dominant roles in Theory of Mind are played by the medial prefrontal cortex and the anterior paracingulate cortex. Third, superior temporal activation has been found during the viewing of simple interactions of moving objects (Blakemore et al., 2003
; Pelphrey et al., 2005
) suggesting that STS activation need not necessarily be associated with attribution of mental states. Although all regions that are found to be part of the ToM network play different roles, it may be the coordination and communication between these regions that is crucial in accomplishing Theory of Mind. As an adaptation in autism to the reduced connectivity with frontal areas, the posterior superior temporal sulcus might function with greater autonomy, assuming a higher than normal degree of control of the task performance. Thus, the present results are consistent with the idea that participants with autism may process the ToM cues in the same way as controls, but if the results of such processing are not communicated efficiently to frontal regions, then the frontal regions may not be able to normally carry out the mental state attribution. This interpretation would also predict reduced synchronization between the activation in anterior and posterior regions involved in the ToM processing in autism, which is what occurred in this study.
An interesting aspect of activation during Theory of Mind processing in autism was that the activation in the right posterior superior temporal sulcus in autism was positively correlated with the Theory of Mind score. In other words, people with autism who had higher Theory of Mind ability also had greater activation in posterior STS. A correlation between a psychometrically measured ability and an activation level in a relevant brain area has previously been found in autism with respect to other abilities, such as the correlation between the psychometric measure of face processing ability measured by a standardized test of face perception and activation in the fusiform face area in autism (Koshino et al., in press; Schultz et al., 2005
). Schultz et al. (2005)
also found the intactness of social functioning in autism (measured by ADOS) to be correlated with the amount of activation in fusiform gyrus in a face processing task in people with autism, with the better-socially-functioning autism participants having more fusiform activation.
The absence of a behavioral group difference was unexpected, given previous findings of such differences and given our finding of group differences in brain activation. Note, however, that each participant’s behavioral data were based on only three items in each condition. Although these few items were apparently sufficient to provide precise enough estimates to detect within-subject effects of condition, they may have been inadequate for detecting between-group differences within the ToM condition. Another possible explanation is that the explicit instructions to attend to the thoughts and feelings of the triangles and the forced choice nature of the response prevented the task from being sensitive to the well-established differences in theory of mind processing between the groups.
The present evidence for functional underconnectivity in autism in a Theory of Mind task adds to the converging evidence of functional underconnectivity in a wide range of complex information processing tasks, including language comprehension (Just et al., 2004
), working memory (Koshino et al., 2005
), executive functioning (Just et al., 2007
), complex inhibition (Kana et al., 2007
), and mental imagery (Kana et al., 2006
). What is common across all these studies is a neural pattern in autism characterized by 1) frontal-posterior underconnectivity; 2) less frontal activation; 3) equivalent, or greater activation in posterior brain areas; and 4) decrease in size of a relevant portion of the corpus callosum. Disruptions in connectivity between frontal and posterior areas in autism could cause the system to adapt in such a way that the posterior regions work more independently to compensate for the impaired communication with the frontal regions. The phenomenon of frontal-posterior underconnectivity and a consequent increased posterior autonomy has been demonstrated in a computational model of a complex executive task (Just et al., in preparation). In summary, the functional connectivity and brain activation results of the present study indicate a systems-level neural impairment in people with autism. The focal point of this impairment seems to be the decreased communication and coordination between frontal regions with others, affecting Theory of Mind processing among other forms of thought.