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Functional abnormalities of the default network during self- and other-reflection in autism

Functional abnormalities of the default network during self- and other-reflection in autism doi:10.1093/scan/nsn011 SCAN (2008) 3,177–190 Functional abnormalities of the default network during self- and other-reflection in autism 1 1,2 Daniel P. Kennedy, and Eric Courchesne 1 2 Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0662, and Center for Autism Research, Rady Children’s Hospital Research Center, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA 92037, USA Recent studies of autism have identified functional abnormalities of the default network during a passive resting state. Since the default network is also typically engaged during social, emotional and introspective processing, dysfunction of this network may underlie some of the difficulties individuals with autism exhibit in these broad domains. In the present experiment, we attempted to further delineate the nature of default network abnormality in autism using experimentally constrained social and introspective tasks. Thirteen autism and 12 control participants were scanned while making true/false judgments for various statements about themselves (SELF condition) or a close other person (OTHER), and pertaining to either psychological personality traits (INTERNAL) or observable characteristics and behaviors (EXTERNAL). In the ventral medial prefrontal cortex/ventral anterior cingulate cortex, activity was reduced in the autism group across all judgment conditions and also during a resting condition, suggestive of task- independent dysfunction of this region. In other default network regions, overall levels of activity were not different between groups. Furthermore, in several of these regions, we found group by condition interactions only for INTERNAL/EXTERNAL judgments, and not SELF/OTHER judgments, suggestive of task-specific dysfunction. Overall, these results provide a more detailed view of default network functionality and abnormality in autism. Keywords: autism spectrum disorders; retrosplenial cortex; posterior cingulate cortex; default mode; rest INTRODUCTION Along with the few studies that have explicitly examined resting functionality or resting functional connectivity of the Several recent studies of autism have identified functional default network in autism (Kennedy et al., 2006; Cherkassky abnormalities of the default network (Kennedy et al., 2006; et al., 2006; Kennedy and Courchesne, 2008), other studies Cherkassky et al., 2006; Kennedy and Courchesne, 2008). have also found abnormalities in regions of the default This network, comprised of the medial prefrontal cortex network (and, in particular, the MPFC) during a variety of (MPFC)/ventral anterior cingulate cortex (vACC), retro- splenial cortex/posterior cingulate cortex (RSC/PCC) and socioemotional tasks. For instance, such abnormalities have angular gyrus (ANG), among other regions, is so named been noted during viewing of personally familiar faces because it exhibits high levels of metabolic activity at rest, in (Pierce et al., 2004), reading of negatively valenced the absence of an externally imposed cognitively demanding emotional words (Kennedy et al., 2006) and in a mentalizing task (Raichle et al., 2001). In other words, the brain defaults task, where subjects observed geometric objects moving in to this pattern of activity when allowed to rest. Interestingly, particular ways to imply intentionality (Castelli et al., 2002). similarly high activity of this network is also seen when Importantly, there are at least two different explanations typical subjects engage in tasks of a social, emotional or for the pervasiveness of functional abnormality in default introspective nature (Fletcher et al., 1995; Maddock, 1999; network regions across both socioemotional tasks and no-task Gusnard et al., 2001; Maddock et al., 2001; Iacoboni et al., resting conditions. First, perhaps regions of this network are 2004; Ochsner et al., 2004, 2005; D’Argembeau et al., 2005; simply unable to function properly in individuals with Cavanna and Trimble, 2006; Northoff et al., 2006)the very autism, regardless of the task being performedin other tasks which are most difficult for individuals with autism words, a task-independent dysfunction. Alternatively, how- (Kanner, 1943; Hurlburt et al., 1994). ever, such abnormalities may simply reflect the known impairments of individuals with autism to automatically Received 25 July 2007; Accepted 20 March 2008 engage in socioemotional and introspective processes, in the Advance Access publication 28 April 2008 We thank Dr Cindy Carter for clinical assessment, Graham Wideman and Stephanie Carapetian for technical absence of explicit instructions (Klin et al., 2003). In fact, for assistance with stimulus presentation, Doreen Nguyen for assistance with data collection, Elizabeth Redcay and the above described studies, attending to and processing the Graham Wideman for helpful discussions and the researchers and staff at the UCSD Center for Functional MRI. social, emotional or mentalizing aspects of the stimuli were We also thank the participants and their families for graciously giving their time to take part in this study. This research was supported by National Institutes of Health (RO1 MH36840 to E.C.). not explicit requirements of the task. For instance, in Pierce Correspondence should be addressed to Daniel P. Kennedy, Division of Humanities and Social Sciences, et al. (2004), subjects were required simply to identify female California Institute of Technology, HSS 228-77, Pasadena, CA 91125, USA. Email: [email protected]. faces, regardless of whether they were familiar or not. Present address: Daniel P. Kennedy, Division of Humanities and Social Sciences, California Institute of Technology, HSS 228-77, Pasadena, CA 91125, USA. In Kennedy et al. (2006), subjects were asked only to count The Author (2008). Published by Oxford University Press. For Permissions, please email: [email protected] 178 SCAN (2008) D. P. Kennedy and E.Courchesne the number of emotional or neutral words displayed on the (Kennedy and Courchesne, 2008). Informed written consent screen, rather than explicitly process the meaning of the was obtained from all participants or, when appropriate, their words. Lastly, in Castelli et al. (2002), subjects were asked to legal guardians, and all participants received monetary com- describe what they observed, and were free to interpret the pensation for their time. The protocol was approved by the meaning of the movements as either reflecting intentionality Institutional Review Board of UCSD and Children’s Hospital or not (and, in fact, the autism group provided significantly at San Diego. ASD participants were diagnosed by a clinical lower intentionality ratings than the control group). Thus, it psychologist using the Autism Diagnostic InterviewRevised is possible that given explicit instructions and explicit per- (ADI-R) (Lord et al., 1994) and the Autism Diagnostic formance requirements regarding the social, emotional or Observation Schedule (ADOS) (Lord et al., 2000). Individuals mentalizing aspects of such tasks, regions of the default meeting the criteria for an ASD diagnosis but without early network may exhibit more typical patterns of activity in spoken language delay and with average to above-average autism. IQ scores received the diagnosis of Asperger’s Syndrome. In the current experiment, we used explicitly defined social The PDD-NOS subject did not meet the combined social and and introspective tasks to determine whether abnormality communication cutoff score of 10 to warrant a diagnosis of of default network regions reflects task-specific or task- autism on the ADOS, nor did he meet the above criteria for independent dysfunction. To do so, we used a self- and other- Asperger’s Syndrome. With the exception of one control reflection task, which has been shown previously to robustly subject, IQ scores were obtained from all participants using activate regions of the default network, including the MPFC, the Wechsler Adult Intelligence Scale (WAIS) or WAIS-R RSC/PCC and ANG (Fletcher et al., 1995; Gusnard et al., (Revised). The mean age of the autism participants (26.9 2001; Johnson et al., 2002; Kelley et al., 2002; Gallagher and years) and the control participants (27.5 years) was not Frith, 2003; Ochsner et al., 2005). While being scanned, 13 significantly different [t(23)¼ 0.129, P > 0.85]. Subject autism and 12 control subjects read particular statements groups did not differ significantly in verbal, performance or about themselves or about a close other person (i.e. their full-scale IQ [verbal: t(22)¼ 1.641, P¼ 0.115; performance: mother), and made judgments as to whether the statements t(22)¼ 1.512, P¼ 0.145; full-scale: t(22)¼ 1.959, P¼ 0.063]. were true or false. Thus, the subjects’ task (i.e. making true/ See Table 1 for detailed clinical information. false judgments about themselves or others) was directly relevant to the experimental conditions of interest (i.e. Stimuli reflection on oneself and others), reducing the likelihood of While in the scanner, subjects made true/false judgments non-engagement in the mental processes of interest. We also for various statements about themselves (SELF condition) or included two different types of self- and other-reflection a close other person (OTHER condition). These SELF conditions(i) those regarding psychological personality and OTHER statements either referred to psychological traits (which we term INTERNAL) and (ii) those regarding personality traits (INTERNAL condition) or to observable observable external characteristics and behaviors (which we external characteristics and behaviors (EXTERNAL condi- term EXTERNAL)which allowed us to examine whether tion). In all cases, the close other was their mother, with the there may be a selective impairment in one or the other type of exception of one control subject who read statements about a judgment. All person judgment conditions were compared to close friend rather than his mother, as his parents were a cognitively demanding MATH condition, which served as deceased. Thus, there were four person judgment an experimental baseline task. Finally, we included a resting (i.e. MENTAL) conditions in total: INTERNAL-SELF fixation condition (REST) to compare resting default network (e.g. ‘I am polite’), INTERNAL-OTHER (e.g. ‘My mother is activity between groups, to examine the overlap between generous’), EXTERNAL-SELF (e.g. ‘I drink coffee’) and regions of the default network and brain regions involved in EXTERNAL-OTHER (e.g. ‘My mother drives a car’) (see self- and other-reflection, and to functionally define the Appendix A for a complete list of statements). A MATH default network for use in region-of-interest analyses. condition served as an experimental baseline condition, wherein subjects were shown math equations [in the form of a METHODS two-digit number plus a one-digit number equaling either a Participants correct or incorrect answer (e.g. ‘45þ 8¼ 53’)], and again Fourteen male autism spectrum disorder (ASD) and 13 male instructed to respond via button presses as to whether the control subjects were scanned. Due to excessive movement equation was true or false. Finally, there was a REST condition during scanning, one ASD subject and one control subject where subjects passively viewed a fixation cross that appeared were removed from the analysis, resulting in a final sample on the screen. The functional scans also included an episodic size of 13 ASD (six autism, six Asperger’s, one PDD-NOS) memory judgment condition, but this condition was not and 12 control subjects. With the exception of the one subject examined in the current analysis. (A10, Table 1), this sample of control and ASD subjects Each trial consisted of a statement, equation or fixation completely overlapped with those from a separate imaging cross shown for 2500 ms, followed by a blank screen for study that examined resting functional connectivity in autism 500 m. Conditions were presented in a counterbalanced block Default network activity in autism SCAN (2008) 179 Table 1 Clinical information for autism and control participants IQ ADI-R ADOS Subject Diagnosis Age Sex handedness Verbal Performance Full-scale Social Communication Stereotypy Social Communication Stereotypy (cutoff¼ 10) (cutoff¼ 8) (cutoff¼ 3) (cutoff¼ 4) (cutoff¼ 2) A1 Autism 15.7 M Right 73 66 67 10 21 11 10 3 3 A2 Asperger’s 16.2 M Right 120 124 125 13 17 3 11 6 1 A3 Asperger’s 17.4 M Right 99 93 96 23 18 9 9 5 1 A4 Autism 17.7 M Right 101 118 109 26 19 6 7 5 1 A5 Asperger’s 18.3 M Right 108 107 109 14 8 6 5 3 1 A6 Autism 18.8 M Right 55 109 80 28 20 4 9 5 0 A7 Asperger’s 22.9 M Right 97 105 101 13 12 3 6 3 0 A8 Asperger’s 24.0 M Right 116 109 114 7 11 10 8 2 2 A9 Asperger’s 27.7 M Right 111 99 106 21 20 7 11 6 0 A10 PDD-NOS 31.4 M Right 90 126 107 14 14 3 6 3 2 A11 Autism 41.3 M Left 98 114 104 21 22 10 11 5 2 A12 Autism 46.4 M Right 86 115 100 22 19 6 7 5 1 A13 Autism 52.0 M Right 102 105 104 26 17 6 9 4 1 Mean (s.d.) 26.9 (12.3) 96.6 (17.7) 106.9 (15.4) 101.7 (14.6) C1 Control 15.9 M Left 95 99 97 C2 Control 16.2 M Right N/A N/A N/A C3 Control 17.8 M Right 107 119 114 C4 Control 19.0 M Right 106 118 113 C5 Control 20.6 M Left 99 106 103 C6 Control 22.9 M Right 107 93 100 C7 Control 25.3 M Right 109 116 114 C8 Control 29.4 M Right 109 125 118 C9 Control 32.3 M Right 108 128 119 C10 Control 40.7 M Right 108 132 121 C11 Control 44.6 M Right 106 109 108 C12 Control 45.4 M Right 108 128 119 Mean (s.d.) 27.5 (10.9) 105.6 (4.5) 115.7 (12.7) 111.5 (8.3) Cutoff scores for an ASD diagnosis are shown. design manner, with six trials per block, eight blocks per All behavioral analyses were conducted with SPSS condition, and each block lasting 18 s. The specific statements 12.0 statistical software package (SPSS, Chicago, IL, USA). or equations that appeared within each block were random- To compare performance (RT and percent concordance) ized for each subject. The total time of the experiment was between groups across the four MENTAL judgments, we ran 17 min, 28 s, which was divided into two shorter functional two separate three-way repeated measures ANOVAs (SELF/ runs lasting 8 min, 44 s each. OTHER INTERNAL/EXTERNAL group). Follow-up t-tests were run for all significant main effects of group and group by condition interactions. For the MATH condition, Behavioral data acquisition and analysis group differences in RT and accuracy were examined with Stimuli were presented using the Presentation software independent sample t-tests. package (Neurobehavioral Systems, Albany, CA, USA). Subject response (true/false) and reaction time (from Functional imaging data acquisition and analysis stimulus onset until subject response) were recorded during scanning. Responses that occurred any time within Functional and anatomical images were acquired using a 3 the 3000 ms trial were recorded. Tesla GE Signa EXCITE scanner. Whole brain axial slices were After scanning was complete (1 h later), subjects were collected with a gradient-recalled echo-planar imaging pulse asked to again provide true/false judgments for each state- sequence with the following parameters: TR (repetition ment. This procedure allowed us to calculate the reliability of time)¼ 2000 ms; TE (echo time)¼ 30 ms; flip angle¼ 908; each participant’s responses, ensuring they made deliberate field of view (FOV)¼ 220 mm; matrix¼ 64 64 (3.44 mm choices, rather than simply guessing while in the scanner. Due in-plane resolution); slice thickness¼ 4 mm; no. of axial to a computer problem, this second set of true/false responses slices¼ 32; no. of volumes¼ 262 (for each of the two runs). was not recorded from one ASD subject and one control T1-weighted anatomical images were collected for subject. co-registration with the functional images [FOV¼ 256 mm; 180 SCAN (2008) D. P. Kennedy and E.Courchesne matrix¼ 256 256 (1 mm in-plane resolution); slice thick- at a voxel threshold of P < 0.001, and a corresponding mini- ness¼ 1 mm; no. of axial slices¼ 124]. mum cluster volume of 384 mm . Minimum cluster volumes Functional analyses were carried out using the Analyses of were calculated using an iterative Monte Carlo simulation using AFNI’s AlphaSim program with a voxel-wise threshold Functional NeuroImages (AFNI) statistical software package (version 2.56; http://afni.nimh.nih.gov/afni) (Cox, 1996). of P < 0.05. Throughout the text, we use the term ‘volume- First, field maps, which were acquired during the scan corrected’ to refer to analyses that were corrected for sessions, were used to correct for field inhomogeneities. minimum cluster volume. Next, the first 10 TRs (which consisted of 20 s of fixation) were Finally, between-group comparisons were carried out using removed from the beginning of each functional run. Motion a functional region-of-interest (ROI) approach. The first three ROIs were defined as regions in the control group that correction and 3D registration of each participant’s functional were active in the MENTAL (all four conditions) vs MATH images were performed with AFNI’s automated alignment contrast (P < 0.001) and that also overlapped with regions program (3dVolReg), which co-registers each individual with greater activity in the REST vs MATH contrast functional volume with a manually specified middle reference (P < 0.01). These regions of overlap were then volume- volume. Brief periods of subject movement, which were corrected at the more stringent volume threshold (minimum objectively defined from the output of this volume registra- cluster volume¼ 1152 mm ) corresponding to the P < 0.01 tion procedure, were removed from the analysis (for details, threshold used in the REST vs MATH contrast. This created see Kennedy and Courchesne, 2008). Subjects with >20% of ROIs that were both part of a functionally defined default the entire run removed were excluded entirely from the study network and also involved in self- and other-reflection. (one ASD, one control subject). There was no difference in the A fourth region, the dorsal MPFC (dMPFC), was included percent of the scans removed from the remaining participants as an ROI post hoc (see Results section). [control¼ 2.46%; autism¼ 1.93%; t(23)¼ 0.492, P¼ 0.628]. For each ROI, percent signal change values were extracted Images were corrected for timing of slice acquisition, spatially from each subject, averaged across all voxels in the ROI, and smoothed with a Gaussian filter (full-width half-maxi- analyzed using SPSS. Three-way repeated measures ANOVAs mum¼ 6 mm), and linear trend was removed from the time (SELF/OTHER INTERNAL/EXTERNAL group) were series. Next, the data were converted to percent signal change run for each ROI. Additionally, independent sample t-tests values and the two separate functional runs were concate- were run for the REST vs MATH contrast for each ROI. nated, producing a single time series. Follow-up t-tests were run for all significant main effects of Functional data were analyzed using AFNI’s 3dDeconvolve. group and group by condition interactions. First, an impulse response function (IRF) was estimated based on the measured fMRI signal for each voxel and the input stimulus functions. These input functions included six RESULTS experimental conditions (only five of which were examined in the present articleINTERNAL-SELF, INTERNAL- Behavioral results OTHER, EXTERNAL-SELF, EXTERNAL-OTHER and In terms of reliability (percent concordance of a subject’s REST) and six motion parameters [i.e. rotational movement responses) across all four MENTAL judgment conditions, (roll, pitch, yaw) and translational movement (x, y, z)]. The there was no main effect of group [F(1,21)¼ 0.289, P¼ MATH condition served as the baseline state. The estimated 0.596]. Though the three-way interaction was not significant IRF was then convolved with the input stimulus time series, [F(1,23)¼ 0.807, P > 0.80], there were significant group by and multiple regressions were run to determine a goodness- condition interactions in reliability for both INTERNAL vs of-fit coefficient (i.e. linear contrast weight) for 0, 2, 4 and 6 s EXTERNAL judgments [F(1,21)¼ 9.821, P¼ 0.005] and after stimulus presentation. These four linear contrast weights SELF vs OTHER judgments [F(1,21)¼ 8.584, P¼ 0.005]. were summed for each condition separately, yielding a single Follow-up t-tests revealed that the control group had greater linear contrast weight for each of the five conditions at each reliability of responses for SELF compared to OTHER voxel. Next, several a priori contrasts were carried out [SELF judgments [89.4% vs 84.1%, t(10)¼ 2.384, P¼ 0.0384] and vs MATH, OTHER vs MATH, INTERNAL vs MATH, EXTERNAL compared to INTERNAL judgments [88.8% vs EXTERNAL vs MATH, SELF vs OTHER, INTERNAL vs 84.6%, t(10)¼ 2.701, P¼ 0.0223], while reliability between EXTERNAL, MENTAL (all four person judgment conditions) these conditions was not significantly different in the autism vs MATH, and REST vs MATH] at every voxel. group (84.4% vs 86.1% and 83.4% vs 87.1%, respectively; For whole-brain analyses, images were spatially normalized both P-values >0.05). to Talairach space (Talairach and Tournoux, 1988) using In terms of reaction time across all four MENTAL AFNI’s 12 sub-volume piecewise linear transformation based judgment conditions, there was no main effect of group on manually-defined landmarks. The t-tests were run for each [F(1,23) ¼ 3.211, P¼ 0.086]. There were also no significant group separately to determine, for each of the above contrasts, group by condition interactions for either SELF vs OTHER or which voxels were significantly different from zero. Unless INTERNAL vs EXTERNAL judgments [F(1,23)¼ 0.275, indicated otherwise, whole-brain functional maps are shown P¼ 0.605; F(1,23)¼ 1.902, P¼ 0.181], nor a significant Default network activity in autism SCAN (2008) 181 three-way interaction [F(1,21)¼ 0.908, P > 0.90]. Both effect of group nor a group by condition interaction, the groups responded faster to SELF compared to OTHER control group did respond significantly faster than the autism judgments [control: 1341.9 ms vs 1513.4 ms, t(11)¼ 8.519, group for EXTERNAL judgments [t(23)¼ 2.140, P¼ 0.043, P < 0.00001; autism: 1547.3 ms vs 1703.6 ms, t(12)¼ 11.223, all other conditions, P > 0.05]. P < 0.00001], and were faster to INTERNAL compared to Finally, for the MATH baseline condition, there was no EXTERNAL judgments [control: 1401.3 ms vs 1487.8 ms, group difference in accuracy [control: 93.1%, autism: 91.8%, t(23)¼ 0.536, P¼ 0.60] or reaction time [control: 1573.7 ms, t(11)¼ 4.588, P¼ 0.0008; autism: 1543.3 ms vs 1673.8 ms, autism: 1703.5 ms, t(23)¼ 1.639, P¼ 0.12]. t(12)¼ 5.183, P¼ 0.0002]. Although there was neither a main Table 2 Regions significantly active in the MENTAL vs MATH contrast (P <0.001, volume-corrected) Functional imaging results – whole-brain analyses In the MENTAL vs MATH contrast, the control group had Control Autism significantly greater activity in the MENTAL conditions in the Region (X, Y, Z) t-value (X, Y, Z) t-value dMPFC, vMPFC/vACC, RSC/PCC and ANG bilaterally, among other regions (for a complete list of regions, see L superior frontal gyrus (6, 39, 48) 12.24 (6, 7, 60) 6.85 Table 2). In the autism group, among these regions, activation Dorsal medial prefrontal (2, 51, 28) 11.94 (6, 51, 24) 5.82 cortex was limited to the dMPFC, RSC/PCC and left ANG Posterior cingulate/ (2, 49, 28) 8.80 (6, 61, 32) 7.51 (Figure 1A, Table 2). In a voxelwise direct group comparison retrosplenial cortex at a relatively conservative threshold (P < 0.001, volume- L inferior frontal gyrus (42, 19, 16) 8.53 (38, 19, 8) 5.99 corrected), there were no significant differences between Cuneus (bilateral) (3, 97, 24) 8.31 (6, 97, 24) 7.62 L middle frontal gyrus (42, 3, 48) 8.25 (42, 3, 44) 5.06 group in any of these regions. However, at a more liberal L angular gyrus (50, 65, 36) 8.06 (58, 61, 24) 6.67 threshold (P < 0.01, uncorrected), there was significantly vMPFC/vACC (2, 31, 0) 7.07–– reduced activity in the vMPFC/vACC in the autism group. L temporal pole (42, 3, 28) 6.97–– Similarly, in the REST vs MATH contrast, the control R angular gyrus (58, 65, 28) 6.26–– group had significant greater activity in the REST condition in L superior temporal gyrus (50, 33, 4) 4.80 (50, 21, 4) 5.65 the vMPFC/vACC, RSC/PCC and left ANG, among other Brain regions that also had significant activity in the REST vs MATH contrast in regions (for a complete list of regions, see Table 3). In the control subjects. Talairach coordinates and t-values correspond to the most significant autism group, among these regions, significantly greater voxel within each cluster. Only regions with greater activity during MENTAL activity was only seen in the left ANG (Figure 1B, Table 3). judgments relative to MATH are included. At the whole-brain level, there were no significant differences between groups in any of the regions listed above (P <0.001, Again, activity in these regions was not significant between volume-corrected). groups (P < 0.01, corrected), though at a more liberal Fig. 1 Functional activity in control and autism groups for (A) the MENTAL vs MATH contrast (P < 0.001, uncorrected) and (B) the REST vs MATH contrast (P < 0.01, uncorrected); and (C) the regions of overlap between these two contrasts (minimum cluster volume¼ 1152 mm ). These regions of overlap in the control group were used as ROIs for further analysis (red cluster¼ vMPFC/vACC; blue cluster¼ RSC/PCC; green cluster¼ left ANG). The dMPFC ROI (open circle) is also shown. In the autism group, the left ANG just missed the minimum cluster volume threshold (1139 mm ). 182 SCAN (2008) D. P. Kennedy and E.Courchesne threshold (P < 0.05, uncorrected), there was significantly of mental imagery associated with these different types of reduced activity in the vMPFC/vACC in the autism group. judgments (Fletcher et al., 1995; Cavanna and Trimble, 2006). With the exception of the vMPFC/vACC, both the groups recruited largely similar regions during SELF, OTHER, Functional imaging results – ROI analyses INTERNAL and EXTERNAL judgments (relative to the In total, four regions were included in the ROI analysis MATH baseline condition) (Figure 2). Interestingly, both (Figure 1C). Three of these ROIs, the ventral MPFC groups engaged specific regions of RSC/PCC to a greater (vMPFC)/vACC, RSC/PCC and lANG, were defined by extent for EXTERNAL (vs INTERNAL) judgments and functional overlap between MENTAL vs MATH and REST OTHER (vs SELF) judgments (Figure 2, bottom panel; vs MATH contrasts in control subjects. A fourth ROI, the Tables 4 and 5), perhaps reflecting differences in the degree dorsal MPFC (dMPFC), was included as a ROI post hoc. This region demonstrated significant activity in the MENTAL vs MATH contrast in both groups (P < 0.001, volume-cor- Table 3 Regions significantly active in the REST vs MATH contrast (P < 0.01, volume-corrected) rected), but not in the REST vs MATH contrast. However, given that this region is typically found to be part of the Control Autism default network, we refer to all ROIs (including the dMPFC) as default network regions. The dMPFC ROI was created by Region (X, Y, Z) t-value (X, Y, Z) t-value placing a sphere with 8 mm radius at the point of peak R inferior parietal lobule (55, 32, 20) 7.92 (46, 32, 20) 6.31 significance in the MENTAL vs MATH contrast for the vMPFC/vACC (7, 39, 1) 7.26–– control group. This sphere also encompassed the point of R superior parietal lobule (26, 44, 59) 6.84–– peak significance for the autism group. Percent signal change R lateral precentral gyrus (51, 8, 12) 5.82 (54, 9, 15) 5.97 values from these four regions were extracted from each Posterior cingulate/retrosplenial (6, 45, 35) 5.30–– individual and analyzed using SPSS. One ASD subject was a cortex, extending into precuneus large outlier in their vMPFC/vACC activity (>3 SD from the Mid-cingulate (10, 28, 44) 5.05 (10, 25, 40) 5.16 mean of both the autism and control groups) and was L fusiform gyrus –– (17, 37, 9) 4.88 a therefore excluded from all analyses involving this region. L angular gyrus (53, 61, 24) 4.66 (53, 60, 20) 5.00 L insula (37, 12, 0) 4.47 (41, 8, 5) 5.98 Cuneus (bilateral) (2, 89, 20) 4.30 (2, 73, 27) 5.09 Main effects of group. Of the four ROIs, only the vMPFC/vACC demonstrated a main effect of group for the Brain regions that also had significant activity in the MENTAL vs. MATH contrast in MENTAL (all four person judgment conditions) vs MATH control subjects. Talairach coordinates and t-values correspond to the most significant contrast [F(1,22)¼ 12.48, P¼ 0.002; all other regions: voxel within each cluster. Only regions with greater activity during REST relative to MATH are included. At the whole-brain level, there were no significant differences P > 0.30]. In this region, activity was significantly lower in between groups in any of the regions listed above (P < 0.01, volume-corrected). the autism group compared to the control group Fig. 2 Functional activity in control and autism groups for (A) INTERNAL vs MATH, EXTERNAL vs MATH, and INTERNAL vs EXTERNAL contrasts; and (B) SELF vs MATH, OTHER vs MATH, and SELF vs OTHER contrasts (all P < 0.001, volume-corrected). The same mid-sagittal slice location is shown for each image. Regions with greater activity in the MATH condition relative to the other conditions are not shown. In the bottom panel, red/yellow represents regions with greater activity in the INTERNAL (A) or SELF (B) conditions, while blue represents regions with greater activity in the EXTERNAL (A) or OTHER (B) conditions. Default network activity in autism SCAN (2008) 183 Table 4 Regions significantly active in the INTERNAL vs EXTERNAL contrast (P <0.001, volume-corrected) Control Autism Interaction Region (X, Y, Z) t-value (X, Y, Z) t-value (X, Y, Z) t-value Internal > External L inferior frontal gyrus (38, 28, 0) 7.97 –– – – Mid-cingulate (2, 16, 32) 7.54 –– – – Dorsal MPFC (1, 51, 24) 7.00 –– Dorsal anterior cingulate (2, 20, 20) 5.59 –– – – External > Internal Retrosplenial cortex (5, 48, 8) 11.31 (11, 49, 4) 11.66 –– L superior frontal gyrus (21, 20, 48) 8.47 (21, 23, 47) 9.18 –– Posterior cingulate (3, 33, 39) 8.36 (1, 40, 27) 5.43 –– L parahippocampal gyrus (18, 33, 12) 7.96 (25, 25, 9) 9.18 –– L middle temporal gyrus (38, 73, 29) 6.25 (30, 73, 20) 10.12 (38, 77, 23) 4.53 R superior frontal gyrus (38, 20, 52) 5.85 (23, 23, 47) 8.01 (18, 16, 52) 5.28 R middle temporal gyrus (47, 68, 24) 5.40 (42, 76, 35) 5.94 –– Midbrain –– (1, 20, 9) 5.70 (1, 21, 9) 5.43 R thalamus –– (23, 24, 16) 5.39 (22, 13, 8) 4.58 R cuneus –– (14, 77, 11) 9.26 –– R parahippocampal gyrus –– (26, 29, 5) 8.13 –– L cuneus –– (5, 77, 7) 6.28 –– 3 3 A dMPFC cluster [Talairach location¼ (2, 40, 12); t-value¼ 5.12; volume¼ 300 mm ] just missed the cluster volume threshold of 384 mm . Talairach coordinates and t-values correspond to the most significant voxel within each cluster. Group by condition interactions (P <0.001, volume-corrected) are listed for all regions that exhibited significant effects of condition in either the autism or control group. For all regions with significant interactions, the autism group had a greater difference in activity between EXTERNAL and INTERNAL conditions than the control group. Table 5 Regions significantly active in the SELF vs OTHER contrast (P <0.001, volume-corrected) Control Autism Interaction Region (X, Y, Z) t-value (X, Y, Z) t-value (X, Y, Z) t-value Self > Other NONE –– – – – – Other > Self L lingual gyrus (6, 73, 0) 10.27 (25, 76, 4) 6.41 –– R lingual gyrus (22, 68, 4) 9.16 (11, 80, 0) 7.78 –– Posterior cingulate/retrosplenial cortex (7, 57, 27) 8.22 (3, 60, 32) 9.09 –– L posterior parahippocampal gyrus (18, 45, 4) 6.22 –– – – R posterior parahippocampal gyrus (22, 45, 7) 5.81 –– – – R caudate (tail) (18, 25, 17) 5.42 (14, 25, 20) 4.65 –– Talairach coordinates and t-values correspond to the most significant voxel within each cluster. In the regions with significant effects of condition in either the autism or control group, there were no significant group by condition interactions at the whole-brain level (P <0.001, volume-corrected). (percent signal change of 0.17% vs 0.60%, respectively) findings of abnormal resting activity in autism (Kennedy (Figure 3, left panel). Follow-up t-tests revealed that this et al., 2006). reduction of vMPFC/vACC activity was significant in each of Finally, we should emphasize that the above analyses the types of person judgment conditions [INTERNAL: utilized a MATH baseline condition, rather than REST, to t(22)¼ 4.50, P¼ 0.0002; EXTERNAL: t(22)¼ 2.38, avoid the problem of group differences in resting activity P¼ 0.026; SELF: t(22)¼ 3.21, P¼ 0.004; OTHER: affecting the interpretation of the functional results. t(22)¼ 3.47, P¼ 0.002]. However, to facilitate comparison between this and other studies of control subjects that utilize a REST baseline, we ran In the REST vs MATH contrast, a significant group diff- the MENTAL vs REST contrast for the control group alone. erence was also found only in the vMPFC/vACC [t(23)¼ The control group had significantly greater activity during 2.838, P¼ 0.01; all other regions, P > 0.25], with a smaller MENTAL judgments vs REST in the dMPFC [0.59% vs 0.11%; difference in activity between these conditions in the t(11)¼ 5.375, P < 0.001], the RSC/PCC [0.54% vs 0.33%; autism group relative to the control group (0.17% vs 0.67%, t(11)¼ 3.497, P¼ 0.005] and the lANG [0.65% vs 0.42%; respectively) (Figure 3, right panel), replicating previous 184 SCAN (2008) D. P. Kennedy and E.Courchesne Fig. 3 Bar graphs depicting percent signal change in control and autism groups in MENTAL vs MATH and REST vs MATH contrasts, shown separately for each ROI. P 0.01. t(11)¼ 3.217, P¼ 0.008], but no significant difference in EXTERNAL SELF/OTHER) and no significant three-way the vMPFC/vACC [0.60% vs 0.67%; t(11)¼ 0.716, interactions (INTERNAL/EXTERNAL SELF/OTHER P¼ 0.489]. group) in any of the four regions of interest (all P > 0.10), the results from INTERNAL/EXTERNAL analyses and the Group by condition interactions. Because there were no results from the SELF/OTHER analyses are described significant interactions between condition type (INTERNAL/ separately (Figure 3). Default network activity in autism SCAN (2008) 185 INTERNAL/EXTERNAL judgments. In the dMPFC, The group by condition interactions remained non- although there was no main effect of group, there was a significant after including covariates for reliability of SELF and OTHER judgments (all P > 0.05). significant group by condition (INTERNAL/EXTERNAL) interaction [F(1,23)¼ 7.17, P¼ 0.013]. Follow-up t-tests revealed that the control group had greater activity Additional analyses during INTERNAL compared to EXTERNAL judgments To directly examine the relationship between task- [0.72% vs 0.46%, respectively; F(1,11)¼ 51.90, P¼ 0.00002], constrained and task-unconstrained activity of the default while there was no difference between these conditions network, we examined correlations between activity in the in the autism group [0.60% vs 0.55%; F(1,12)¼ 0.568, MENTAL and REST conditions for each ROI and each group P¼ 0.47]. separately. In the control group, there were significant There was also a significant group by condition interaction correlations between MENTAL and REST conditions in all in the RSC/PCC [F(1,23)¼ 12.88, P¼ 0.002]. While there was ROIs [vMPFC/vACC: r(12)¼ 0.650, P¼ 0.022; dMPFC: no difference in the level of activity between INTERNAL and r(12)¼ 0.738, P¼ 0.006; RSC/PCC: r(12)¼ 0.641, EXTERNAL conditions in the control group [F(1,11)¼ 1.72, P¼ 0.025; lANG: r(12)¼ 0.617, P¼ 0.033]. However, such P¼ 0.22], there was a significant difference in the autism correlations were absent in the autism group [vMPFC/vACC: group [F(1,12)¼ 32.27, P¼ 0.0001], with greater activity for r(12)¼0.016, P¼ 0.961; dMPFC: r(13)¼ 0.480, P¼ 0.097; EXTERNAL compared to INTERNAL judgments. This RSC/PCC: r(13)¼ 0.260, P¼ 0.391; lANG: r(13)¼ 0.407, difference between the groups was driven largely by reduced P¼ 0.168]. activity in the autism group during INTERNAL judgments In an exploratory analysis, we examined whether there were (autism¼ 0.29%, control¼ 0.52%) rather than differences in differences between the autism subjects (n¼ 6) and Aspe- activity during EXTERNAL judgments (autism¼ 0.51%, rger’s subjects (n¼ 6) within the ASD group. There was a weak trend toward greater activation of the dMPFC in the control¼ 0.56%). MENTAL vs MATH contrast in the Asperger’s sample There were no group by condition interactions for [Asperger’s¼ 0.85%; Autism¼ 0.33%; F(1,10)¼ 3.614, the vMPFC/vACC or lANG (both P > 0.25). Both groups P¼ 0.086]. All other main effects of subgroup and all sub- showed the same pattern of activity for INTERNAL and group by condition type (i.e. INTERNAL/EXTERNAL or EXTERNAL judgmentsnamely, no difference in activity SELF/OTHER) interactions were non-significant (all between these conditions in either the vMPFC/vACC [autism: P > 0.20). Similarly, there were no differences between sub- F(1,11)¼ 3.628, P¼ 0.083; control: F(1,11)¼ 0.169, groups in the REST vs MATH contrast for any of the ROIs P¼ 0.689] or lANG [autism: F(1,12)¼ 1.484, P¼ 0.247; (all P > 0.15). control: F(1,11)¼ 0.044, P¼ 0.837] (Figure 4, left panel). Lastly, there was a marginally significant negative correla- Finally, because there was a significant interaction of group tion in the autism group between vMPFC/vACC activity in and reliability of INTERNAL/EXTERNAL judgments, the the REST vs MATH contrast and ADI-R social subscore above group by condition interaction analyses were repeated [r(12)¼ 0.578, P¼ 0.049]. In other words, those subjects with using reliability of INTERNAL and EXTERNAL judgments as higher scores on a clinical measure of social abnormality had covariates. The results remained unchanged [dMPFC: greater abnormality in vMPFC/vACC activity during REST F(1,19)¼ 10.40, P¼ 0.004; RSC/PCC: F(1,19)¼ 15.766, vs MATH, consistent with an earlier report demonstrating P¼ 0.001; vMPFC/vACC and lANG, both P > 0.10]. this same effect but using a different baseline task (i.e. the Counting Stroop Task) (Kennedy et al., 2006). However, as SELF/OTHER judgments. There were no significant five of the subjects were common across these two studies, this group by condition (SELF/OTHER) interactions for any of analysis should only be viewed as exploratory. the four ROIs (all P > 0.05). Both groups showed largely similar patterns of activity for SELF and OTHER judg- mentsgreater activity during OTHER compared to SELF DISCUSSION judgments in the lANG [autism: F(1,12)¼ 7.20, P¼ 0.02; The present study examined the functioning of the default control: F(1,11)¼ 6.285, P¼ 0.029] and RSC/PCC [autism: network during self and other-person reflection and at rest F(1,12)¼ 23.816, P < 0.0004; control: F(1,11)¼ 31.66, in autism. There were four primary findings. First, the P¼ 0.0002]. Furthermore, with the exception of autism group had reduced functional activity in the marginally significantly greater activity in the vMPFC/ vMPFC/vACC at rest. Second, when collapsed across all vACC during OTHER judgments compared to SELF person judgment conditions, reduced activity was again judgments in the autism group [F(1,11)¼ 5.129, found in the vMPFC/vACC in autism, but there were no P¼ 0.045], there were no other differences in activity group differences in the dMPFC, RSC/PCC or lANG. Third, between these conditions in the vMPFC/vACC [control: although overall levels of activity were similar between F(1,11)¼ 0.465, P¼ 0.509] or dMPFC [autism: groups in the dMPFC and RSC/PCC, there were group by F(1,12)¼ 1.931, P¼ 0.190; control: F(1,11)¼ 0.661, condition interactions across INTERNAL/EXTERNAL judg- P¼ 0.433] (Figure 4, right panel). ments in these regions. Finally, there were no group by 186 SCAN (2008) D. P. Kennedy and E.Courchesne Fig. 4 Bar graphs depicting percent signal change in control and autism groups during INTERNAL and EXTERNAL judgments and SELF and OTHER judgments (each relative to the MATH baseline condition), shown separately for each ROI. For main effects of group collapsed across all person judgment conditions, see Figure 3. P 0.05; P 0.01. condition interactions across SELF/OTHER judgments for Findings of abnormal vMPFC/vACC activity at rest are any ROI. Together, these findings give a more detailed view consistent with a growing body of literature demonstrating of default network functionality and abnormality in autism. resting functional abnormalities of the default network in Below, we discuss the implications of these findings. autism (Kennedy et al., 2006; Cherkassky et al., 2006; Default network activity in autism SCAN (2008) 187 Kennedy and Courchesne, 2008). As activity in default measure as a covariate did not change the results. However, a network regions correlates to ones’ propensity to daydream number of other plausible cognitive and behavioral explana- (Mason et al., 2007) and to the amount of task-unrelated tions may account for these abnormalities. One possibility is thoughts (McKiernan et al., 2006) and self-referential that individuals with autism may have a specific deficit in thoughts (D’Argembeau et al., 2005), one interpretation is making judgments that rely on inference (e.g. INTERNAL that these group differences in functional activity reflect judgments), but an intact ability in making judgments that group differences in resting cognitive processes (Kennedy rely on observation (e.g. EXTERNAL judgments). This et al., 2006). Preliminary support for this possibility comes suggestion is consistent with previous behavioral findings from an interesting behavioral study that attempted to assess of autism. When asked to describe a scene composed of the self-reported inner experience of adults with Asperger’s geometric shapes moving in such a way to imply syndrome (Hurlburt et al., 1994). Remarkably, two of the intentionality, subjects with autism can accurately describe three individuals tested had difficulty simply understanding the physical, observable features of the stimuli, but are what it meant to describe their inner experience and impaired in describing the non-observable, but readily thoughts (though, importantly, their verbal IQ was in the inferable, intentions of the stimuli (Klin, 2000; Castelli normal range and both could describe observable features of et al., 2002). Second, and potentially relating to a bias toward their immediate environment). Thus, the reduced propensity the observable over the inferable, individuals with autism or reduced ability to introspect may underlie the reduced may have less experience and expertise in making inferential vMPFC/vACC activity at rest. personality judgments, but more experience and expertise in However, an alternative explanation of reduced levels of making judgments of externally observable characteristics of resting activity in autism is that there might be a pervasive people. Lastly, there may be group differences in the depth dysfunction of these regionsin other words, the abnor- of processing (e.g. the richness, detail and completeness of mality might be task- or cognition-independent. Previous person representations) across INTERNAL and EXTERNAL task-based studies have provided preliminary support for judgments. For instance, the autism group may have had less this possibility, but the implicit nature of the socioemotional elaborate representations of themselves and others during tasks used previously (Castelli et al., 2002; Pierce et al., 2004; INTERNAL judgments but more elaborate representations Kennedy et al., 2006) leaves open the possibility that the during EXTERNAL judgments. Regardless of the explana- autism subjects simply did not engage the socioemotional tion, however, since overall levels of activity were similar processes of interest. In the present study, we ensured that between groups, these findings point toward task-specific subjects engaged in introspective and socially oriented dysfunction of the dMPFC and the RSC/PCC, rather than a processing, by requiring true/false responses to self- and more pervasive task-independent dysfunction. other-relevant statements. Even with these explicit tasks, we Although the above described abnormalities of default observed abnormality in the vMPFC/vACC region of the regions were found, perhaps equally interesting are the default network, supporting the idea that such functional functional similarities between groups. With the exception of abnormality of this region might be task-independent and the vMPFC/vACC, the responses of the dMPFC, RSC/PCC pervasive. Importantly, such pervasive dysfunction of the and lANG were indistinguishable between groups during vMPFC/vACC could also explain the introspective difficul- SELF and OTHER judgments. In the dMPFC, both groups ties described earlier. had similar levels of activity in the SELF and OTHER Group differences were also observed in the dMPFC conditions, a finding consistent with several previous studies and RSC/PCC, although the nature of these abnormalities of self and close other person reflection in control subjects was quite different from the vMPFC/vACC abnormality (Schmitz et al., 2004; Ochsner et al., 2005; however, also see described earlier. In these regions, group differences were Heatherton et al., 2006). Furthermore, in the RSC/PCC and found in the relative pattern of activity between INTERNAL lANG, both groups had greater activity in OTHER relative to and EXTERNAL conditions, rather than group differences in the SELF condition. This typical pattern of RSC/PCC activity overall levels of activity when collapsed across these tasks in autism, given the abnormal pattern of RSC/PCC activity (as found in the vMPFC/vACC). In other words, group across INTERNAL/EXTERNAL judgments, further under- differences in the dMPFC and RSC/PCC were task-specific scores the task-specific, as opposed to task-independent, (i.e. group by condition interactions), rather than reflecting dysfunction of this region. These findings suggest that, at a a more general, non-specific and pervasive dysfunction (i.e. neural level, high functioning individuals with autism and main effects of group). For both regions, this interaction Asperger’s syndrome are able to differentiate between seems to have been driven primarily by reduced activity judgments of themselves and others, and, with the exception during the INTERNAL condition in the autism group, while of the vMPFC/vACC, recruit the same default network exhibiting similar or slightly increased activity during the regions to do so. EXTERNAL condition. Such functional differences between While the importance of using explicitly defined and well- groups cannot be accounted for simply by differences in controlled experimental conditions is clear, we should reliability of judgments, because using this performance emphasize the importance of also measuring brain activity 188 SCAN (2008) D. P. Kennedy and E.Courchesne during unconstrained or underspecified tasks, since each group differences reported here. Additional studies will be necessary to further explore this possibility. approach provides a unique perspective on brain function- In sum, the present experiment gives further insight into ing. On the one hand, using a non-task resting state or an underspecified experimental task can reveal what the autistic the nature of default network functionality and abnormality brain does naturally (i.e. what it defaults to) when in autism. We provide evidence for task-specific deficits unconstrained by often artificial, rigidly defined and exter- within particular default network regions (dMPFC and RSC/PCC) as well as evidence for more pervasive nally imposed task demands. On the other hand, studies using task-independent abnormalities (vMPFC/vACC). Such experimentally constrained tasks with explicit instructions distinctions between the type of functional abnormality in and explicit requirements can reveal what the autistic brain is these and other brain regions involved in social, capable of doing when challenged with a particular task or emotional and introspective processes will likely be impor- situation. Although it is possible that brain activity (and tant for understanding the nature of such difficulties underlying mental processes) can be similar during both in autism. unconstrained and constrained contexts, this relationship cannot be assumed, especially in patient populations. 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P. Kennedy and E.Courchesne Appendix A Complete list of stimuli used in the present experiment. Statements for the OTHER condition were modified by replacing ‘I’ with ‘My mother’ and modifying the verb appropriately (e.g., I am ...’ becomes ‘My mother is ...’). SELF, INTERNAL SELF, EXTERNAL I am a quiet person I usually wear white socks I am an emotional person I eat pizza often I am a loving person I use computers often I am generous I usually eat breakfast I am a relaxed person I often make my bed I am a good listener I drive on highways often I am funny I drive a car I am talkative I eat fruit often I am polite I read books often I am honest I eat at restaurants a lot I am competitive I eat chicken often I am a patient person I watch a lot of TV I am a quick learner I go shopping often I am friendly I drink coffee often I am a moody person I talk on the phone a lot I am a happy person I take showers in the morning I am easily upset I go to the movies often I am easily stressed I read the newspaper I am a focused person I spend a lot of money I am easily distracted I listen to music often I am a demanding person I wash dishes I am very thoughtful I talk to my family often I am very observant I wear jeans often I am a confident person I am a deep sleeper I am a curious person I usually wake up early I am compassionate I listen to the radio I am a nurturing person I usually go to bed early I am creative I take naps often I am easily bored I usually cook dinner I am easily scared I dance often I am shy I go to the beach sometimes I am dependable I read books often I am kind I watch sports games I am outgoing I swim sometimes I am helpful I check my email often I am sensitive I have a dog I am hard-working I buy a lot of CDs I am easily frustrated I eat burritos often I am a silly person I go to the mall a lot I am a caring person I drink juice often I am lazy I go on walks often I am a selfish person I rent a lot of movies I am controlling I read magazines I am a rude person I eat a lot of candy I am respectful I go to the bank often I am smart I play video games often I am a serious person I work out a lot I am easily disappointed I do my laundry often http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Social Cognitive and Affective Neuroscience Oxford University Press

Functional abnormalities of the default network during self- and other-reflection in autism

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10.1093/scan/nsn011
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doi:10.1093/scan/nsn011 SCAN (2008) 3,177–190 Functional abnormalities of the default network during self- and other-reflection in autism 1 1,2 Daniel P. Kennedy, and Eric Courchesne 1 2 Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0662, and Center for Autism Research, Rady Children’s Hospital Research Center, 8110 La Jolla Shores Drive, Suite 201, La Jolla, CA 92037, USA Recent studies of autism have identified functional abnormalities of the default network during a passive resting state. Since the default network is also typically engaged during social, emotional and introspective processing, dysfunction of this network may underlie some of the difficulties individuals with autism exhibit in these broad domains. In the present experiment, we attempted to further delineate the nature of default network abnormality in autism using experimentally constrained social and introspective tasks. Thirteen autism and 12 control participants were scanned while making true/false judgments for various statements about themselves (SELF condition) or a close other person (OTHER), and pertaining to either psychological personality traits (INTERNAL) or observable characteristics and behaviors (EXTERNAL). In the ventral medial prefrontal cortex/ventral anterior cingulate cortex, activity was reduced in the autism group across all judgment conditions and also during a resting condition, suggestive of task- independent dysfunction of this region. In other default network regions, overall levels of activity were not different between groups. Furthermore, in several of these regions, we found group by condition interactions only for INTERNAL/EXTERNAL judgments, and not SELF/OTHER judgments, suggestive of task-specific dysfunction. Overall, these results provide a more detailed view of default network functionality and abnormality in autism. Keywords: autism spectrum disorders; retrosplenial cortex; posterior cingulate cortex; default mode; rest INTRODUCTION Along with the few studies that have explicitly examined resting functionality or resting functional connectivity of the Several recent studies of autism have identified functional default network in autism (Kennedy et al., 2006; Cherkassky abnormalities of the default network (Kennedy et al., 2006; et al., 2006; Kennedy and Courchesne, 2008), other studies Cherkassky et al., 2006; Kennedy and Courchesne, 2008). have also found abnormalities in regions of the default This network, comprised of the medial prefrontal cortex network (and, in particular, the MPFC) during a variety of (MPFC)/ventral anterior cingulate cortex (vACC), retro- splenial cortex/posterior cingulate cortex (RSC/PCC) and socioemotional tasks. For instance, such abnormalities have angular gyrus (ANG), among other regions, is so named been noted during viewing of personally familiar faces because it exhibits high levels of metabolic activity at rest, in (Pierce et al., 2004), reading of negatively valenced the absence of an externally imposed cognitively demanding emotional words (Kennedy et al., 2006) and in a mentalizing task (Raichle et al., 2001). In other words, the brain defaults task, where subjects observed geometric objects moving in to this pattern of activity when allowed to rest. Interestingly, particular ways to imply intentionality (Castelli et al., 2002). similarly high activity of this network is also seen when Importantly, there are at least two different explanations typical subjects engage in tasks of a social, emotional or for the pervasiveness of functional abnormality in default introspective nature (Fletcher et al., 1995; Maddock, 1999; network regions across both socioemotional tasks and no-task Gusnard et al., 2001; Maddock et al., 2001; Iacoboni et al., resting conditions. First, perhaps regions of this network are 2004; Ochsner et al., 2004, 2005; D’Argembeau et al., 2005; simply unable to function properly in individuals with Cavanna and Trimble, 2006; Northoff et al., 2006)the very autism, regardless of the task being performedin other tasks which are most difficult for individuals with autism words, a task-independent dysfunction. Alternatively, how- (Kanner, 1943; Hurlburt et al., 1994). ever, such abnormalities may simply reflect the known impairments of individuals with autism to automatically Received 25 July 2007; Accepted 20 March 2008 engage in socioemotional and introspective processes, in the Advance Access publication 28 April 2008 We thank Dr Cindy Carter for clinical assessment, Graham Wideman and Stephanie Carapetian for technical absence of explicit instructions (Klin et al., 2003). In fact, for assistance with stimulus presentation, Doreen Nguyen for assistance with data collection, Elizabeth Redcay and the above described studies, attending to and processing the Graham Wideman for helpful discussions and the researchers and staff at the UCSD Center for Functional MRI. social, emotional or mentalizing aspects of the stimuli were We also thank the participants and their families for graciously giving their time to take part in this study. This research was supported by National Institutes of Health (RO1 MH36840 to E.C.). not explicit requirements of the task. For instance, in Pierce Correspondence should be addressed to Daniel P. Kennedy, Division of Humanities and Social Sciences, et al. (2004), subjects were required simply to identify female California Institute of Technology, HSS 228-77, Pasadena, CA 91125, USA. Email: [email protected]. faces, regardless of whether they were familiar or not. Present address: Daniel P. Kennedy, Division of Humanities and Social Sciences, California Institute of Technology, HSS 228-77, Pasadena, CA 91125, USA. In Kennedy et al. (2006), subjects were asked only to count The Author (2008). Published by Oxford University Press. For Permissions, please email: [email protected] 178 SCAN (2008) D. P. Kennedy and E.Courchesne the number of emotional or neutral words displayed on the (Kennedy and Courchesne, 2008). Informed written consent screen, rather than explicitly process the meaning of the was obtained from all participants or, when appropriate, their words. Lastly, in Castelli et al. (2002), subjects were asked to legal guardians, and all participants received monetary com- describe what they observed, and were free to interpret the pensation for their time. The protocol was approved by the meaning of the movements as either reflecting intentionality Institutional Review Board of UCSD and Children’s Hospital or not (and, in fact, the autism group provided significantly at San Diego. ASD participants were diagnosed by a clinical lower intentionality ratings than the control group). Thus, it psychologist using the Autism Diagnostic InterviewRevised is possible that given explicit instructions and explicit per- (ADI-R) (Lord et al., 1994) and the Autism Diagnostic formance requirements regarding the social, emotional or Observation Schedule (ADOS) (Lord et al., 2000). Individuals mentalizing aspects of such tasks, regions of the default meeting the criteria for an ASD diagnosis but without early network may exhibit more typical patterns of activity in spoken language delay and with average to above-average autism. IQ scores received the diagnosis of Asperger’s Syndrome. In the current experiment, we used explicitly defined social The PDD-NOS subject did not meet the combined social and and introspective tasks to determine whether abnormality communication cutoff score of 10 to warrant a diagnosis of of default network regions reflects task-specific or task- autism on the ADOS, nor did he meet the above criteria for independent dysfunction. To do so, we used a self- and other- Asperger’s Syndrome. With the exception of one control reflection task, which has been shown previously to robustly subject, IQ scores were obtained from all participants using activate regions of the default network, including the MPFC, the Wechsler Adult Intelligence Scale (WAIS) or WAIS-R RSC/PCC and ANG (Fletcher et al., 1995; Gusnard et al., (Revised). The mean age of the autism participants (26.9 2001; Johnson et al., 2002; Kelley et al., 2002; Gallagher and years) and the control participants (27.5 years) was not Frith, 2003; Ochsner et al., 2005). While being scanned, 13 significantly different [t(23)¼ 0.129, P > 0.85]. Subject autism and 12 control subjects read particular statements groups did not differ significantly in verbal, performance or about themselves or about a close other person (i.e. their full-scale IQ [verbal: t(22)¼ 1.641, P¼ 0.115; performance: mother), and made judgments as to whether the statements t(22)¼ 1.512, P¼ 0.145; full-scale: t(22)¼ 1.959, P¼ 0.063]. were true or false. Thus, the subjects’ task (i.e. making true/ See Table 1 for detailed clinical information. false judgments about themselves or others) was directly relevant to the experimental conditions of interest (i.e. Stimuli reflection on oneself and others), reducing the likelihood of While in the scanner, subjects made true/false judgments non-engagement in the mental processes of interest. We also for various statements about themselves (SELF condition) or included two different types of self- and other-reflection a close other person (OTHER condition). These SELF conditions(i) those regarding psychological personality and OTHER statements either referred to psychological traits (which we term INTERNAL) and (ii) those regarding personality traits (INTERNAL condition) or to observable observable external characteristics and behaviors (which we external characteristics and behaviors (EXTERNAL condi- term EXTERNAL)which allowed us to examine whether tion). In all cases, the close other was their mother, with the there may be a selective impairment in one or the other type of exception of one control subject who read statements about a judgment. All person judgment conditions were compared to close friend rather than his mother, as his parents were a cognitively demanding MATH condition, which served as deceased. Thus, there were four person judgment an experimental baseline task. Finally, we included a resting (i.e. MENTAL) conditions in total: INTERNAL-SELF fixation condition (REST) to compare resting default network (e.g. ‘I am polite’), INTERNAL-OTHER (e.g. ‘My mother is activity between groups, to examine the overlap between generous’), EXTERNAL-SELF (e.g. ‘I drink coffee’) and regions of the default network and brain regions involved in EXTERNAL-OTHER (e.g. ‘My mother drives a car’) (see self- and other-reflection, and to functionally define the Appendix A for a complete list of statements). A MATH default network for use in region-of-interest analyses. condition served as an experimental baseline condition, wherein subjects were shown math equations [in the form of a METHODS two-digit number plus a one-digit number equaling either a Participants correct or incorrect answer (e.g. ‘45þ 8¼ 53’)], and again Fourteen male autism spectrum disorder (ASD) and 13 male instructed to respond via button presses as to whether the control subjects were scanned. Due to excessive movement equation was true or false. Finally, there was a REST condition during scanning, one ASD subject and one control subject where subjects passively viewed a fixation cross that appeared were removed from the analysis, resulting in a final sample on the screen. The functional scans also included an episodic size of 13 ASD (six autism, six Asperger’s, one PDD-NOS) memory judgment condition, but this condition was not and 12 control subjects. With the exception of the one subject examined in the current analysis. (A10, Table 1), this sample of control and ASD subjects Each trial consisted of a statement, equation or fixation completely overlapped with those from a separate imaging cross shown for 2500 ms, followed by a blank screen for study that examined resting functional connectivity in autism 500 m. Conditions were presented in a counterbalanced block Default network activity in autism SCAN (2008) 179 Table 1 Clinical information for autism and control participants IQ ADI-R ADOS Subject Diagnosis Age Sex handedness Verbal Performance Full-scale Social Communication Stereotypy Social Communication Stereotypy (cutoff¼ 10) (cutoff¼ 8) (cutoff¼ 3) (cutoff¼ 4) (cutoff¼ 2) A1 Autism 15.7 M Right 73 66 67 10 21 11 10 3 3 A2 Asperger’s 16.2 M Right 120 124 125 13 17 3 11 6 1 A3 Asperger’s 17.4 M Right 99 93 96 23 18 9 9 5 1 A4 Autism 17.7 M Right 101 118 109 26 19 6 7 5 1 A5 Asperger’s 18.3 M Right 108 107 109 14 8 6 5 3 1 A6 Autism 18.8 M Right 55 109 80 28 20 4 9 5 0 A7 Asperger’s 22.9 M Right 97 105 101 13 12 3 6 3 0 A8 Asperger’s 24.0 M Right 116 109 114 7 11 10 8 2 2 A9 Asperger’s 27.7 M Right 111 99 106 21 20 7 11 6 0 A10 PDD-NOS 31.4 M Right 90 126 107 14 14 3 6 3 2 A11 Autism 41.3 M Left 98 114 104 21 22 10 11 5 2 A12 Autism 46.4 M Right 86 115 100 22 19 6 7 5 1 A13 Autism 52.0 M Right 102 105 104 26 17 6 9 4 1 Mean (s.d.) 26.9 (12.3) 96.6 (17.7) 106.9 (15.4) 101.7 (14.6) C1 Control 15.9 M Left 95 99 97 C2 Control 16.2 M Right N/A N/A N/A C3 Control 17.8 M Right 107 119 114 C4 Control 19.0 M Right 106 118 113 C5 Control 20.6 M Left 99 106 103 C6 Control 22.9 M Right 107 93 100 C7 Control 25.3 M Right 109 116 114 C8 Control 29.4 M Right 109 125 118 C9 Control 32.3 M Right 108 128 119 C10 Control 40.7 M Right 108 132 121 C11 Control 44.6 M Right 106 109 108 C12 Control 45.4 M Right 108 128 119 Mean (s.d.) 27.5 (10.9) 105.6 (4.5) 115.7 (12.7) 111.5 (8.3) Cutoff scores for an ASD diagnosis are shown. design manner, with six trials per block, eight blocks per All behavioral analyses were conducted with SPSS condition, and each block lasting 18 s. The specific statements 12.0 statistical software package (SPSS, Chicago, IL, USA). or equations that appeared within each block were random- To compare performance (RT and percent concordance) ized for each subject. The total time of the experiment was between groups across the four MENTAL judgments, we ran 17 min, 28 s, which was divided into two shorter functional two separate three-way repeated measures ANOVAs (SELF/ runs lasting 8 min, 44 s each. OTHER INTERNAL/EXTERNAL group). Follow-up t-tests were run for all significant main effects of group and group by condition interactions. For the MATH condition, Behavioral data acquisition and analysis group differences in RT and accuracy were examined with Stimuli were presented using the Presentation software independent sample t-tests. package (Neurobehavioral Systems, Albany, CA, USA). Subject response (true/false) and reaction time (from Functional imaging data acquisition and analysis stimulus onset until subject response) were recorded during scanning. Responses that occurred any time within Functional and anatomical images were acquired using a 3 the 3000 ms trial were recorded. Tesla GE Signa EXCITE scanner. Whole brain axial slices were After scanning was complete (1 h later), subjects were collected with a gradient-recalled echo-planar imaging pulse asked to again provide true/false judgments for each state- sequence with the following parameters: TR (repetition ment. This procedure allowed us to calculate the reliability of time)¼ 2000 ms; TE (echo time)¼ 30 ms; flip angle¼ 908; each participant’s responses, ensuring they made deliberate field of view (FOV)¼ 220 mm; matrix¼ 64 64 (3.44 mm choices, rather than simply guessing while in the scanner. Due in-plane resolution); slice thickness¼ 4 mm; no. of axial to a computer problem, this second set of true/false responses slices¼ 32; no. of volumes¼ 262 (for each of the two runs). was not recorded from one ASD subject and one control T1-weighted anatomical images were collected for subject. co-registration with the functional images [FOV¼ 256 mm; 180 SCAN (2008) D. P. Kennedy and E.Courchesne matrix¼ 256 256 (1 mm in-plane resolution); slice thick- at a voxel threshold of P < 0.001, and a corresponding mini- ness¼ 1 mm; no. of axial slices¼ 124]. mum cluster volume of 384 mm . Minimum cluster volumes Functional analyses were carried out using the Analyses of were calculated using an iterative Monte Carlo simulation using AFNI’s AlphaSim program with a voxel-wise threshold Functional NeuroImages (AFNI) statistical software package (version 2.56; http://afni.nimh.nih.gov/afni) (Cox, 1996). of P < 0.05. Throughout the text, we use the term ‘volume- First, field maps, which were acquired during the scan corrected’ to refer to analyses that were corrected for sessions, were used to correct for field inhomogeneities. minimum cluster volume. Next, the first 10 TRs (which consisted of 20 s of fixation) were Finally, between-group comparisons were carried out using removed from the beginning of each functional run. Motion a functional region-of-interest (ROI) approach. The first three ROIs were defined as regions in the control group that correction and 3D registration of each participant’s functional were active in the MENTAL (all four conditions) vs MATH images were performed with AFNI’s automated alignment contrast (P < 0.001) and that also overlapped with regions program (3dVolReg), which co-registers each individual with greater activity in the REST vs MATH contrast functional volume with a manually specified middle reference (P < 0.01). These regions of overlap were then volume- volume. Brief periods of subject movement, which were corrected at the more stringent volume threshold (minimum objectively defined from the output of this volume registra- cluster volume¼ 1152 mm ) corresponding to the P < 0.01 tion procedure, were removed from the analysis (for details, threshold used in the REST vs MATH contrast. This created see Kennedy and Courchesne, 2008). Subjects with >20% of ROIs that were both part of a functionally defined default the entire run removed were excluded entirely from the study network and also involved in self- and other-reflection. (one ASD, one control subject). There was no difference in the A fourth region, the dorsal MPFC (dMPFC), was included percent of the scans removed from the remaining participants as an ROI post hoc (see Results section). [control¼ 2.46%; autism¼ 1.93%; t(23)¼ 0.492, P¼ 0.628]. For each ROI, percent signal change values were extracted Images were corrected for timing of slice acquisition, spatially from each subject, averaged across all voxels in the ROI, and smoothed with a Gaussian filter (full-width half-maxi- analyzed using SPSS. Three-way repeated measures ANOVAs mum¼ 6 mm), and linear trend was removed from the time (SELF/OTHER INTERNAL/EXTERNAL group) were series. Next, the data were converted to percent signal change run for each ROI. Additionally, independent sample t-tests values and the two separate functional runs were concate- were run for the REST vs MATH contrast for each ROI. nated, producing a single time series. Follow-up t-tests were run for all significant main effects of Functional data were analyzed using AFNI’s 3dDeconvolve. group and group by condition interactions. First, an impulse response function (IRF) was estimated based on the measured fMRI signal for each voxel and the input stimulus functions. These input functions included six RESULTS experimental conditions (only five of which were examined in the present articleINTERNAL-SELF, INTERNAL- Behavioral results OTHER, EXTERNAL-SELF, EXTERNAL-OTHER and In terms of reliability (percent concordance of a subject’s REST) and six motion parameters [i.e. rotational movement responses) across all four MENTAL judgment conditions, (roll, pitch, yaw) and translational movement (x, y, z)]. The there was no main effect of group [F(1,21)¼ 0.289, P¼ MATH condition served as the baseline state. The estimated 0.596]. Though the three-way interaction was not significant IRF was then convolved with the input stimulus time series, [F(1,23)¼ 0.807, P > 0.80], there were significant group by and multiple regressions were run to determine a goodness- condition interactions in reliability for both INTERNAL vs of-fit coefficient (i.e. linear contrast weight) for 0, 2, 4 and 6 s EXTERNAL judgments [F(1,21)¼ 9.821, P¼ 0.005] and after stimulus presentation. These four linear contrast weights SELF vs OTHER judgments [F(1,21)¼ 8.584, P¼ 0.005]. were summed for each condition separately, yielding a single Follow-up t-tests revealed that the control group had greater linear contrast weight for each of the five conditions at each reliability of responses for SELF compared to OTHER voxel. Next, several a priori contrasts were carried out [SELF judgments [89.4% vs 84.1%, t(10)¼ 2.384, P¼ 0.0384] and vs MATH, OTHER vs MATH, INTERNAL vs MATH, EXTERNAL compared to INTERNAL judgments [88.8% vs EXTERNAL vs MATH, SELF vs OTHER, INTERNAL vs 84.6%, t(10)¼ 2.701, P¼ 0.0223], while reliability between EXTERNAL, MENTAL (all four person judgment conditions) these conditions was not significantly different in the autism vs MATH, and REST vs MATH] at every voxel. group (84.4% vs 86.1% and 83.4% vs 87.1%, respectively; For whole-brain analyses, images were spatially normalized both P-values >0.05). to Talairach space (Talairach and Tournoux, 1988) using In terms of reaction time across all four MENTAL AFNI’s 12 sub-volume piecewise linear transformation based judgment conditions, there was no main effect of group on manually-defined landmarks. The t-tests were run for each [F(1,23) ¼ 3.211, P¼ 0.086]. There were also no significant group separately to determine, for each of the above contrasts, group by condition interactions for either SELF vs OTHER or which voxels were significantly different from zero. Unless INTERNAL vs EXTERNAL judgments [F(1,23)¼ 0.275, indicated otherwise, whole-brain functional maps are shown P¼ 0.605; F(1,23)¼ 1.902, P¼ 0.181], nor a significant Default network activity in autism SCAN (2008) 181 three-way interaction [F(1,21)¼ 0.908, P > 0.90]. Both effect of group nor a group by condition interaction, the groups responded faster to SELF compared to OTHER control group did respond significantly faster than the autism judgments [control: 1341.9 ms vs 1513.4 ms, t(11)¼ 8.519, group for EXTERNAL judgments [t(23)¼ 2.140, P¼ 0.043, P < 0.00001; autism: 1547.3 ms vs 1703.6 ms, t(12)¼ 11.223, all other conditions, P > 0.05]. P < 0.00001], and were faster to INTERNAL compared to Finally, for the MATH baseline condition, there was no EXTERNAL judgments [control: 1401.3 ms vs 1487.8 ms, group difference in accuracy [control: 93.1%, autism: 91.8%, t(23)¼ 0.536, P¼ 0.60] or reaction time [control: 1573.7 ms, t(11)¼ 4.588, P¼ 0.0008; autism: 1543.3 ms vs 1673.8 ms, autism: 1703.5 ms, t(23)¼ 1.639, P¼ 0.12]. t(12)¼ 5.183, P¼ 0.0002]. Although there was neither a main Table 2 Regions significantly active in the MENTAL vs MATH contrast (P <0.001, volume-corrected) Functional imaging results – whole-brain analyses In the MENTAL vs MATH contrast, the control group had Control Autism significantly greater activity in the MENTAL conditions in the Region (X, Y, Z) t-value (X, Y, Z) t-value dMPFC, vMPFC/vACC, RSC/PCC and ANG bilaterally, among other regions (for a complete list of regions, see L superior frontal gyrus (6, 39, 48) 12.24 (6, 7, 60) 6.85 Table 2). In the autism group, among these regions, activation Dorsal medial prefrontal (2, 51, 28) 11.94 (6, 51, 24) 5.82 cortex was limited to the dMPFC, RSC/PCC and left ANG Posterior cingulate/ (2, 49, 28) 8.80 (6, 61, 32) 7.51 (Figure 1A, Table 2). In a voxelwise direct group comparison retrosplenial cortex at a relatively conservative threshold (P < 0.001, volume- L inferior frontal gyrus (42, 19, 16) 8.53 (38, 19, 8) 5.99 corrected), there were no significant differences between Cuneus (bilateral) (3, 97, 24) 8.31 (6, 97, 24) 7.62 L middle frontal gyrus (42, 3, 48) 8.25 (42, 3, 44) 5.06 group in any of these regions. However, at a more liberal L angular gyrus (50, 65, 36) 8.06 (58, 61, 24) 6.67 threshold (P < 0.01, uncorrected), there was significantly vMPFC/vACC (2, 31, 0) 7.07–– reduced activity in the vMPFC/vACC in the autism group. L temporal pole (42, 3, 28) 6.97–– Similarly, in the REST vs MATH contrast, the control R angular gyrus (58, 65, 28) 6.26–– group had significant greater activity in the REST condition in L superior temporal gyrus (50, 33, 4) 4.80 (50, 21, 4) 5.65 the vMPFC/vACC, RSC/PCC and left ANG, among other Brain regions that also had significant activity in the REST vs MATH contrast in regions (for a complete list of regions, see Table 3). In the control subjects. Talairach coordinates and t-values correspond to the most significant autism group, among these regions, significantly greater voxel within each cluster. Only regions with greater activity during MENTAL activity was only seen in the left ANG (Figure 1B, Table 3). judgments relative to MATH are included. At the whole-brain level, there were no significant differences between groups in any of the regions listed above (P <0.001, Again, activity in these regions was not significant between volume-corrected). groups (P < 0.01, corrected), though at a more liberal Fig. 1 Functional activity in control and autism groups for (A) the MENTAL vs MATH contrast (P < 0.001, uncorrected) and (B) the REST vs MATH contrast (P < 0.01, uncorrected); and (C) the regions of overlap between these two contrasts (minimum cluster volume¼ 1152 mm ). These regions of overlap in the control group were used as ROIs for further analysis (red cluster¼ vMPFC/vACC; blue cluster¼ RSC/PCC; green cluster¼ left ANG). The dMPFC ROI (open circle) is also shown. In the autism group, the left ANG just missed the minimum cluster volume threshold (1139 mm ). 182 SCAN (2008) D. P. Kennedy and E.Courchesne threshold (P < 0.05, uncorrected), there was significantly of mental imagery associated with these different types of reduced activity in the vMPFC/vACC in the autism group. judgments (Fletcher et al., 1995; Cavanna and Trimble, 2006). With the exception of the vMPFC/vACC, both the groups recruited largely similar regions during SELF, OTHER, Functional imaging results – ROI analyses INTERNAL and EXTERNAL judgments (relative to the In total, four regions were included in the ROI analysis MATH baseline condition) (Figure 2). Interestingly, both (Figure 1C). Three of these ROIs, the ventral MPFC groups engaged specific regions of RSC/PCC to a greater (vMPFC)/vACC, RSC/PCC and lANG, were defined by extent for EXTERNAL (vs INTERNAL) judgments and functional overlap between MENTAL vs MATH and REST OTHER (vs SELF) judgments (Figure 2, bottom panel; vs MATH contrasts in control subjects. A fourth ROI, the Tables 4 and 5), perhaps reflecting differences in the degree dorsal MPFC (dMPFC), was included as a ROI post hoc. This region demonstrated significant activity in the MENTAL vs MATH contrast in both groups (P < 0.001, volume-cor- Table 3 Regions significantly active in the REST vs MATH contrast (P < 0.01, volume-corrected) rected), but not in the REST vs MATH contrast. However, given that this region is typically found to be part of the Control Autism default network, we refer to all ROIs (including the dMPFC) as default network regions. The dMPFC ROI was created by Region (X, Y, Z) t-value (X, Y, Z) t-value placing a sphere with 8 mm radius at the point of peak R inferior parietal lobule (55, 32, 20) 7.92 (46, 32, 20) 6.31 significance in the MENTAL vs MATH contrast for the vMPFC/vACC (7, 39, 1) 7.26–– control group. This sphere also encompassed the point of R superior parietal lobule (26, 44, 59) 6.84–– peak significance for the autism group. Percent signal change R lateral precentral gyrus (51, 8, 12) 5.82 (54, 9, 15) 5.97 values from these four regions were extracted from each Posterior cingulate/retrosplenial (6, 45, 35) 5.30–– individual and analyzed using SPSS. One ASD subject was a cortex, extending into precuneus large outlier in their vMPFC/vACC activity (>3 SD from the Mid-cingulate (10, 28, 44) 5.05 (10, 25, 40) 5.16 mean of both the autism and control groups) and was L fusiform gyrus –– (17, 37, 9) 4.88 a therefore excluded from all analyses involving this region. L angular gyrus (53, 61, 24) 4.66 (53, 60, 20) 5.00 L insula (37, 12, 0) 4.47 (41, 8, 5) 5.98 Cuneus (bilateral) (2, 89, 20) 4.30 (2, 73, 27) 5.09 Main effects of group. Of the four ROIs, only the vMPFC/vACC demonstrated a main effect of group for the Brain regions that also had significant activity in the MENTAL vs. MATH contrast in MENTAL (all four person judgment conditions) vs MATH control subjects. Talairach coordinates and t-values correspond to the most significant contrast [F(1,22)¼ 12.48, P¼ 0.002; all other regions: voxel within each cluster. Only regions with greater activity during REST relative to MATH are included. At the whole-brain level, there were no significant differences P > 0.30]. In this region, activity was significantly lower in between groups in any of the regions listed above (P < 0.01, volume-corrected). the autism group compared to the control group Fig. 2 Functional activity in control and autism groups for (A) INTERNAL vs MATH, EXTERNAL vs MATH, and INTERNAL vs EXTERNAL contrasts; and (B) SELF vs MATH, OTHER vs MATH, and SELF vs OTHER contrasts (all P < 0.001, volume-corrected). The same mid-sagittal slice location is shown for each image. Regions with greater activity in the MATH condition relative to the other conditions are not shown. In the bottom panel, red/yellow represents regions with greater activity in the INTERNAL (A) or SELF (B) conditions, while blue represents regions with greater activity in the EXTERNAL (A) or OTHER (B) conditions. Default network activity in autism SCAN (2008) 183 Table 4 Regions significantly active in the INTERNAL vs EXTERNAL contrast (P <0.001, volume-corrected) Control Autism Interaction Region (X, Y, Z) t-value (X, Y, Z) t-value (X, Y, Z) t-value Internal > External L inferior frontal gyrus (38, 28, 0) 7.97 –– – – Mid-cingulate (2, 16, 32) 7.54 –– – – Dorsal MPFC (1, 51, 24) 7.00 –– Dorsal anterior cingulate (2, 20, 20) 5.59 –– – – External > Internal Retrosplenial cortex (5, 48, 8) 11.31 (11, 49, 4) 11.66 –– L superior frontal gyrus (21, 20, 48) 8.47 (21, 23, 47) 9.18 –– Posterior cingulate (3, 33, 39) 8.36 (1, 40, 27) 5.43 –– L parahippocampal gyrus (18, 33, 12) 7.96 (25, 25, 9) 9.18 –– L middle temporal gyrus (38, 73, 29) 6.25 (30, 73, 20) 10.12 (38, 77, 23) 4.53 R superior frontal gyrus (38, 20, 52) 5.85 (23, 23, 47) 8.01 (18, 16, 52) 5.28 R middle temporal gyrus (47, 68, 24) 5.40 (42, 76, 35) 5.94 –– Midbrain –– (1, 20, 9) 5.70 (1, 21, 9) 5.43 R thalamus –– (23, 24, 16) 5.39 (22, 13, 8) 4.58 R cuneus –– (14, 77, 11) 9.26 –– R parahippocampal gyrus –– (26, 29, 5) 8.13 –– L cuneus –– (5, 77, 7) 6.28 –– 3 3 A dMPFC cluster [Talairach location¼ (2, 40, 12); t-value¼ 5.12; volume¼ 300 mm ] just missed the cluster volume threshold of 384 mm . Talairach coordinates and t-values correspond to the most significant voxel within each cluster. Group by condition interactions (P <0.001, volume-corrected) are listed for all regions that exhibited significant effects of condition in either the autism or control group. For all regions with significant interactions, the autism group had a greater difference in activity between EXTERNAL and INTERNAL conditions than the control group. Table 5 Regions significantly active in the SELF vs OTHER contrast (P <0.001, volume-corrected) Control Autism Interaction Region (X, Y, Z) t-value (X, Y, Z) t-value (X, Y, Z) t-value Self > Other NONE –– – – – – Other > Self L lingual gyrus (6, 73, 0) 10.27 (25, 76, 4) 6.41 –– R lingual gyrus (22, 68, 4) 9.16 (11, 80, 0) 7.78 –– Posterior cingulate/retrosplenial cortex (7, 57, 27) 8.22 (3, 60, 32) 9.09 –– L posterior parahippocampal gyrus (18, 45, 4) 6.22 –– – – R posterior parahippocampal gyrus (22, 45, 7) 5.81 –– – – R caudate (tail) (18, 25, 17) 5.42 (14, 25, 20) 4.65 –– Talairach coordinates and t-values correspond to the most significant voxel within each cluster. In the regions with significant effects of condition in either the autism or control group, there were no significant group by condition interactions at the whole-brain level (P <0.001, volume-corrected). (percent signal change of 0.17% vs 0.60%, respectively) findings of abnormal resting activity in autism (Kennedy (Figure 3, left panel). Follow-up t-tests revealed that this et al., 2006). reduction of vMPFC/vACC activity was significant in each of Finally, we should emphasize that the above analyses the types of person judgment conditions [INTERNAL: utilized a MATH baseline condition, rather than REST, to t(22)¼ 4.50, P¼ 0.0002; EXTERNAL: t(22)¼ 2.38, avoid the problem of group differences in resting activity P¼ 0.026; SELF: t(22)¼ 3.21, P¼ 0.004; OTHER: affecting the interpretation of the functional results. t(22)¼ 3.47, P¼ 0.002]. However, to facilitate comparison between this and other studies of control subjects that utilize a REST baseline, we ran In the REST vs MATH contrast, a significant group diff- the MENTAL vs REST contrast for the control group alone. erence was also found only in the vMPFC/vACC [t(23)¼ The control group had significantly greater activity during 2.838, P¼ 0.01; all other regions, P > 0.25], with a smaller MENTAL judgments vs REST in the dMPFC [0.59% vs 0.11%; difference in activity between these conditions in the t(11)¼ 5.375, P < 0.001], the RSC/PCC [0.54% vs 0.33%; autism group relative to the control group (0.17% vs 0.67%, t(11)¼ 3.497, P¼ 0.005] and the lANG [0.65% vs 0.42%; respectively) (Figure 3, right panel), replicating previous 184 SCAN (2008) D. P. Kennedy and E.Courchesne Fig. 3 Bar graphs depicting percent signal change in control and autism groups in MENTAL vs MATH and REST vs MATH contrasts, shown separately for each ROI. P 0.01. t(11)¼ 3.217, P¼ 0.008], but no significant difference in EXTERNAL SELF/OTHER) and no significant three-way the vMPFC/vACC [0.60% vs 0.67%; t(11)¼ 0.716, interactions (INTERNAL/EXTERNAL SELF/OTHER P¼ 0.489]. group) in any of the four regions of interest (all P > 0.10), the results from INTERNAL/EXTERNAL analyses and the Group by condition interactions. Because there were no results from the SELF/OTHER analyses are described significant interactions between condition type (INTERNAL/ separately (Figure 3). Default network activity in autism SCAN (2008) 185 INTERNAL/EXTERNAL judgments. In the dMPFC, The group by condition interactions remained non- although there was no main effect of group, there was a significant after including covariates for reliability of SELF and OTHER judgments (all P > 0.05). significant group by condition (INTERNAL/EXTERNAL) interaction [F(1,23)¼ 7.17, P¼ 0.013]. Follow-up t-tests revealed that the control group had greater activity Additional analyses during INTERNAL compared to EXTERNAL judgments To directly examine the relationship between task- [0.72% vs 0.46%, respectively; F(1,11)¼ 51.90, P¼ 0.00002], constrained and task-unconstrained activity of the default while there was no difference between these conditions network, we examined correlations between activity in the in the autism group [0.60% vs 0.55%; F(1,12)¼ 0.568, MENTAL and REST conditions for each ROI and each group P¼ 0.47]. separately. In the control group, there were significant There was also a significant group by condition interaction correlations between MENTAL and REST conditions in all in the RSC/PCC [F(1,23)¼ 12.88, P¼ 0.002]. While there was ROIs [vMPFC/vACC: r(12)¼ 0.650, P¼ 0.022; dMPFC: no difference in the level of activity between INTERNAL and r(12)¼ 0.738, P¼ 0.006; RSC/PCC: r(12)¼ 0.641, EXTERNAL conditions in the control group [F(1,11)¼ 1.72, P¼ 0.025; lANG: r(12)¼ 0.617, P¼ 0.033]. However, such P¼ 0.22], there was a significant difference in the autism correlations were absent in the autism group [vMPFC/vACC: group [F(1,12)¼ 32.27, P¼ 0.0001], with greater activity for r(12)¼0.016, P¼ 0.961; dMPFC: r(13)¼ 0.480, P¼ 0.097; EXTERNAL compared to INTERNAL judgments. This RSC/PCC: r(13)¼ 0.260, P¼ 0.391; lANG: r(13)¼ 0.407, difference between the groups was driven largely by reduced P¼ 0.168]. activity in the autism group during INTERNAL judgments In an exploratory analysis, we examined whether there were (autism¼ 0.29%, control¼ 0.52%) rather than differences in differences between the autism subjects (n¼ 6) and Aspe- activity during EXTERNAL judgments (autism¼ 0.51%, rger’s subjects (n¼ 6) within the ASD group. There was a weak trend toward greater activation of the dMPFC in the control¼ 0.56%). MENTAL vs MATH contrast in the Asperger’s sample There were no group by condition interactions for [Asperger’s¼ 0.85%; Autism¼ 0.33%; F(1,10)¼ 3.614, the vMPFC/vACC or lANG (both P > 0.25). Both groups P¼ 0.086]. All other main effects of subgroup and all sub- showed the same pattern of activity for INTERNAL and group by condition type (i.e. INTERNAL/EXTERNAL or EXTERNAL judgmentsnamely, no difference in activity SELF/OTHER) interactions were non-significant (all between these conditions in either the vMPFC/vACC [autism: P > 0.20). Similarly, there were no differences between sub- F(1,11)¼ 3.628, P¼ 0.083; control: F(1,11)¼ 0.169, groups in the REST vs MATH contrast for any of the ROIs P¼ 0.689] or lANG [autism: F(1,12)¼ 1.484, P¼ 0.247; (all P > 0.15). control: F(1,11)¼ 0.044, P¼ 0.837] (Figure 4, left panel). Lastly, there was a marginally significant negative correla- Finally, because there was a significant interaction of group tion in the autism group between vMPFC/vACC activity in and reliability of INTERNAL/EXTERNAL judgments, the the REST vs MATH contrast and ADI-R social subscore above group by condition interaction analyses were repeated [r(12)¼ 0.578, P¼ 0.049]. In other words, those subjects with using reliability of INTERNAL and EXTERNAL judgments as higher scores on a clinical measure of social abnormality had covariates. The results remained unchanged [dMPFC: greater abnormality in vMPFC/vACC activity during REST F(1,19)¼ 10.40, P¼ 0.004; RSC/PCC: F(1,19)¼ 15.766, vs MATH, consistent with an earlier report demonstrating P¼ 0.001; vMPFC/vACC and lANG, both P > 0.10]. this same effect but using a different baseline task (i.e. the Counting Stroop Task) (Kennedy et al., 2006). However, as SELF/OTHER judgments. There were no significant five of the subjects were common across these two studies, this group by condition (SELF/OTHER) interactions for any of analysis should only be viewed as exploratory. the four ROIs (all P > 0.05). Both groups showed largely similar patterns of activity for SELF and OTHER judg- mentsgreater activity during OTHER compared to SELF DISCUSSION judgments in the lANG [autism: F(1,12)¼ 7.20, P¼ 0.02; The present study examined the functioning of the default control: F(1,11)¼ 6.285, P¼ 0.029] and RSC/PCC [autism: network during self and other-person reflection and at rest F(1,12)¼ 23.816, P < 0.0004; control: F(1,11)¼ 31.66, in autism. There were four primary findings. First, the P¼ 0.0002]. Furthermore, with the exception of autism group had reduced functional activity in the marginally significantly greater activity in the vMPFC/ vMPFC/vACC at rest. Second, when collapsed across all vACC during OTHER judgments compared to SELF person judgment conditions, reduced activity was again judgments in the autism group [F(1,11)¼ 5.129, found in the vMPFC/vACC in autism, but there were no P¼ 0.045], there were no other differences in activity group differences in the dMPFC, RSC/PCC or lANG. Third, between these conditions in the vMPFC/vACC [control: although overall levels of activity were similar between F(1,11)¼ 0.465, P¼ 0.509] or dMPFC [autism: groups in the dMPFC and RSC/PCC, there were group by F(1,12)¼ 1.931, P¼ 0.190; control: F(1,11)¼ 0.661, condition interactions across INTERNAL/EXTERNAL judg- P¼ 0.433] (Figure 4, right panel). ments in these regions. Finally, there were no group by 186 SCAN (2008) D. P. Kennedy and E.Courchesne Fig. 4 Bar graphs depicting percent signal change in control and autism groups during INTERNAL and EXTERNAL judgments and SELF and OTHER judgments (each relative to the MATH baseline condition), shown separately for each ROI. For main effects of group collapsed across all person judgment conditions, see Figure 3. P 0.05; P 0.01. condition interactions across SELF/OTHER judgments for Findings of abnormal vMPFC/vACC activity at rest are any ROI. Together, these findings give a more detailed view consistent with a growing body of literature demonstrating of default network functionality and abnormality in autism. resting functional abnormalities of the default network in Below, we discuss the implications of these findings. autism (Kennedy et al., 2006; Cherkassky et al., 2006; Default network activity in autism SCAN (2008) 187 Kennedy and Courchesne, 2008). As activity in default measure as a covariate did not change the results. However, a network regions correlates to ones’ propensity to daydream number of other plausible cognitive and behavioral explana- (Mason et al., 2007) and to the amount of task-unrelated tions may account for these abnormalities. One possibility is thoughts (McKiernan et al., 2006) and self-referential that individuals with autism may have a specific deficit in thoughts (D’Argembeau et al., 2005), one interpretation is making judgments that rely on inference (e.g. INTERNAL that these group differences in functional activity reflect judgments), but an intact ability in making judgments that group differences in resting cognitive processes (Kennedy rely on observation (e.g. EXTERNAL judgments). This et al., 2006). Preliminary support for this possibility comes suggestion is consistent with previous behavioral findings from an interesting behavioral study that attempted to assess of autism. When asked to describe a scene composed of the self-reported inner experience of adults with Asperger’s geometric shapes moving in such a way to imply syndrome (Hurlburt et al., 1994). Remarkably, two of the intentionality, subjects with autism can accurately describe three individuals tested had difficulty simply understanding the physical, observable features of the stimuli, but are what it meant to describe their inner experience and impaired in describing the non-observable, but readily thoughts (though, importantly, their verbal IQ was in the inferable, intentions of the stimuli (Klin, 2000; Castelli normal range and both could describe observable features of et al., 2002). Second, and potentially relating to a bias toward their immediate environment). Thus, the reduced propensity the observable over the inferable, individuals with autism or reduced ability to introspect may underlie the reduced may have less experience and expertise in making inferential vMPFC/vACC activity at rest. personality judgments, but more experience and expertise in However, an alternative explanation of reduced levels of making judgments of externally observable characteristics of resting activity in autism is that there might be a pervasive people. Lastly, there may be group differences in the depth dysfunction of these regionsin other words, the abnor- of processing (e.g. the richness, detail and completeness of mality might be task- or cognition-independent. Previous person representations) across INTERNAL and EXTERNAL task-based studies have provided preliminary support for judgments. For instance, the autism group may have had less this possibility, but the implicit nature of the socioemotional elaborate representations of themselves and others during tasks used previously (Castelli et al., 2002; Pierce et al., 2004; INTERNAL judgments but more elaborate representations Kennedy et al., 2006) leaves open the possibility that the during EXTERNAL judgments. Regardless of the explana- autism subjects simply did not engage the socioemotional tion, however, since overall levels of activity were similar processes of interest. In the present study, we ensured that between groups, these findings point toward task-specific subjects engaged in introspective and socially oriented dysfunction of the dMPFC and the RSC/PCC, rather than a processing, by requiring true/false responses to self- and more pervasive task-independent dysfunction. other-relevant statements. Even with these explicit tasks, we Although the above described abnormalities of default observed abnormality in the vMPFC/vACC region of the regions were found, perhaps equally interesting are the default network, supporting the idea that such functional functional similarities between groups. With the exception of abnormality of this region might be task-independent and the vMPFC/vACC, the responses of the dMPFC, RSC/PCC pervasive. Importantly, such pervasive dysfunction of the and lANG were indistinguishable between groups during vMPFC/vACC could also explain the introspective difficul- SELF and OTHER judgments. In the dMPFC, both groups ties described earlier. had similar levels of activity in the SELF and OTHER Group differences were also observed in the dMPFC conditions, a finding consistent with several previous studies and RSC/PCC, although the nature of these abnormalities of self and close other person reflection in control subjects was quite different from the vMPFC/vACC abnormality (Schmitz et al., 2004; Ochsner et al., 2005; however, also see described earlier. In these regions, group differences were Heatherton et al., 2006). Furthermore, in the RSC/PCC and found in the relative pattern of activity between INTERNAL lANG, both groups had greater activity in OTHER relative to and EXTERNAL conditions, rather than group differences in the SELF condition. This typical pattern of RSC/PCC activity overall levels of activity when collapsed across these tasks in autism, given the abnormal pattern of RSC/PCC activity (as found in the vMPFC/vACC). In other words, group across INTERNAL/EXTERNAL judgments, further under- differences in the dMPFC and RSC/PCC were task-specific scores the task-specific, as opposed to task-independent, (i.e. group by condition interactions), rather than reflecting dysfunction of this region. These findings suggest that, at a a more general, non-specific and pervasive dysfunction (i.e. neural level, high functioning individuals with autism and main effects of group). For both regions, this interaction Asperger’s syndrome are able to differentiate between seems to have been driven primarily by reduced activity judgments of themselves and others, and, with the exception during the INTERNAL condition in the autism group, while of the vMPFC/vACC, recruit the same default network exhibiting similar or slightly increased activity during the regions to do so. EXTERNAL condition. Such functional differences between While the importance of using explicitly defined and well- groups cannot be accounted for simply by differences in controlled experimental conditions is clear, we should reliability of judgments, because using this performance emphasize the importance of also measuring brain activity 188 SCAN (2008) D. P. Kennedy and E.Courchesne during unconstrained or underspecified tasks, since each group differences reported here. Additional studies will be necessary to further explore this possibility. approach provides a unique perspective on brain function- In sum, the present experiment gives further insight into ing. On the one hand, using a non-task resting state or an underspecified experimental task can reveal what the autistic the nature of default network functionality and abnormality brain does naturally (i.e. what it defaults to) when in autism. We provide evidence for task-specific deficits unconstrained by often artificial, rigidly defined and exter- within particular default network regions (dMPFC and RSC/PCC) as well as evidence for more pervasive nally imposed task demands. On the other hand, studies using task-independent abnormalities (vMPFC/vACC). Such experimentally constrained tasks with explicit instructions distinctions between the type of functional abnormality in and explicit requirements can reveal what the autistic brain is these and other brain regions involved in social, capable of doing when challenged with a particular task or emotional and introspective processes will likely be impor- situation. Although it is possible that brain activity (and tant for understanding the nature of such difficulties underlying mental processes) can be similar during both in autism. unconstrained and constrained contexts, this relationship cannot be assumed, especially in patient populations. 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P. Kennedy and E.Courchesne Appendix A Complete list of stimuli used in the present experiment. Statements for the OTHER condition were modified by replacing ‘I’ with ‘My mother’ and modifying the verb appropriately (e.g., I am ...’ becomes ‘My mother is ...’). SELF, INTERNAL SELF, EXTERNAL I am a quiet person I usually wear white socks I am an emotional person I eat pizza often I am a loving person I use computers often I am generous I usually eat breakfast I am a relaxed person I often make my bed I am a good listener I drive on highways often I am funny I drive a car I am talkative I eat fruit often I am polite I read books often I am honest I eat at restaurants a lot I am competitive I eat chicken often I am a patient person I watch a lot of TV I am a quick learner I go shopping often I am friendly I drink coffee often I am a moody person I talk on the phone a lot I am a happy person I take showers in the morning I am easily upset I go to the movies often I am easily stressed I read the newspaper I am a focused person I spend a lot of money I am easily distracted I listen to music often I am a demanding person I wash dishes I am very thoughtful I talk to my family often I am very observant I wear jeans often I am a confident person I am a deep sleeper I am a curious person I usually wake up early I am compassionate I listen to the radio I am a nurturing person I usually go to bed early I am creative I take naps often I am easily bored I usually cook dinner I am easily scared I dance often I am shy I go to the beach sometimes I am dependable I read books often I am kind I watch sports games I am outgoing I swim sometimes I am helpful I check my email often I am sensitive I have a dog I am hard-working I buy a lot of CDs I am easily frustrated I eat burritos often I am a silly person I go to the mall a lot I am a caring person I drink juice often I am lazy I go on walks often I am a selfish person I rent a lot of movies I am controlling I read magazines I am a rude person I eat a lot of candy I am respectful I go to the bank often I am smart I play video games often I am a serious person I work out a lot I am easily disappointed I do my laundry often

Journal

Social Cognitive and Affective Neuroscience – Oxford University Press

Published: Jun 28, 2008

Keywords: autism spectrum disorders retrosplenial cortex posterior cingulate cortex default mode rest

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