What explains variability in brain regions associate with Theory of Mind in a large sample of neurotypical adults and adults with ASD?

What explains variability in brain regions associated with Theory of Mind in a large sample of neurotypical adults and adults with ASD? Nicholas Dufour 1 , Elizabeth Redcay 2 , Liane Young 3 , Penelope L Mavros 1 , M Joseph Moran 4 , Christina Triantafyllou 1,5 , John Gabrieli 1,5 , and Rebecca Saxe 1,5 1. Department of Brain and Cognitive Sciences, MIT 2. Department of Psychology, University of Maryland 3. Department of Psychology, Boston College 4. Psychology Department, Harvard University 5. McGovern Institute for Brain Research, MIT opposite pattern, hyperactivation, in ASD (Dichter, Felder, & Bodfish, 2009). One explanation of these conflicting results may be that sample sizes are small, and individual variability is large. Small samples of individuals with ASD are problematic because individuals with ASD may be highly heterogeneous in their neural responses (e.g., Hasson et al., 2009). Small samples of NT participants are equally problematic, because they allow for calculation of only the mean response, not the distribution. Understanding the distribution is critical if neural measures are to be useful in a clinical setting. For most clinical applications, it is more important to be able to describe the neural activity pattern of each specific individual, relative to typical and atypical distributions. For example, using fMRI to help diagnose ASD would require comparing each individual to the typical distribution. In order to measure the distribution of responses in ToM brain regions of NT participants, we aggregated data collected over 5 years from 477 NT participants. This large sample allowed us to investigate variability in ToM region responses, and measure any difference between NT participants and adults with ASD, with unusually high sensitivity. The main goal of the current paper is therefore to compare the response in these regions in a large sample of NT participants and a moderate sample of high-functioning adults with ASD. In order to do so, we also (i) identify and remove variance in the measured response, associated with basic experimental parameters such as the stimulus modality, number of stimuli, or experimental task, and (ii) test whether the response of ToM regions is related to basic demographic factors that may be relevant for ASD, including gender, age, and IQ. Abstract Theory of mind (‘ToM’) tasks elicit highly reliable neural activity across individuals and experimental paradigms. We compared activity in a very large sample of neurotypical (‘NT’, N=477) individuals, and a group of high functioning individuals with autism spectrum disorders (‘ASD’, n=27), using both region of interest (‘ROI’) and whole-brain analyses. Although ToM activity showed significant and reliable individual differences, these differences were not explained by participant gender or age, or most experimental parameters. Furthermore, there were no differences between ASD and NT individuals. These results imply that the social cognitive impairments typical of ASD can occur without gross changes in the size or response magnitude of ToM brain regions. Keywords: Theory of mind; ASD; fMRI; TPJ; PC; precuneus; MPFC; DMPFC; MMPFC Introduction Theory of Mind (‘ToM’) is the capacity to represent the mental states of others (Premack & Woodruff, 1978). Individuals with autism spectrum disorders (ASD) appear to have particular difficulty with aspects of ToM. In particular, children with ASD are disproportionately delayed on tasks that tap inferences about other people’s beliefs (Baron- Cohen, 1989). The neural mechanism of this deficit remains unknown. However, in neurotypical (NT) adults and children, fMRI studies reveal a remarkable reliable group of brain regions recruited during ToM tasks. These regions include the left and right temporo-parietal junction (RTPJ and LTPJ), right anterior superior temporal sulcus (rSTS), the medial precuneus (PC), and the medial prefrontal cortex (MPFC) (U. Frith & Frith, 2003). Thus, a tempting hypothesis is that dysfunction of the brain regions typically implicated in ToM is responsible for the social cognitive impairments observed in ASD. Previous attempts to characterize the function of ToM brain regions in adults with ASD have yielded conflicting results. Some studies suggest that ToM regions are hypoactive (i.e., produce a smaller or less selective response, (Kennedy & Courchesne, 2008; Lombardo, Chakrabarti, Bullmore), while other studies find no difference between ASD and NT individuals (Gilbert, Bird, Brindley, Frith, & Burgess, 2008), and still others find the Methods Typical Participants: Data were analyzed from 477 NT participants (M=25.2 years, range: 18-69 years; 179 male). IQ was measured in 60 of these participants (IQ 84-141, M=117.5, SD=12.4). Participants provided informed consent, in accordance with the guidelines of the MIT Committee on the Use of Human Experimental Subjects (COUHES), and were compensated approximately $30 per hour for their time. ASD Participants: 27 individuals with a clinical diagnosis of ASD (M=33.9yrs, range 18-66yrs; 20 male) were