Relationship between cingulo-insular functional connectivity and autistic traits in neurotypical adults

Abstract

Objective: The Social Responsiveness Scale-Adult Version (SRS-A) measures autistic traits that are continuously distributed in the general population. Based on increased recognition of the dimensional nature of autistic traits, the authors examined the neural correlates of these traits in neurotypical individuals using the SRS-A and established a novel approach to assessing the neural basis of autistic characteristics, attempting to directly relate SRS-A scores to patterns of functional connectivity observed in the pregenual anterior cingulate cortex, a region commonly implicated in social cognition.

Method: Resting state functional magnetic resonance imaging scans were collected for 25 neurotypical adults. All participants provided SRS-A ratings completed by an informant who had observed them in natural social settings. Whole brain-corrected connectivity analyses were then conducted using SRS-A scores as a covariate of interest.

Results: Across participants, a significant negative relationship between SRS-A scores and the functional connectivity of the pregenual anterior cingulate cortex with the anterior portion of the mid-insula was found. Specifically, low levels of autistic traits were observed when a substantial portion of the anterior mid-insula showed positive connectivity with the pregenual anterior cingulate cortex. In contrast, elevated levels of autistic traits were associated with negative connectivity between these two regions.

Conclusions: Resting state functional connectivity of the pregenual anterior cingulate cortex-insula social network was related to autistic traits in neurotypical adults. Application of this approach in samples with autism spectrum disorders is needed to confirm whether this circuit is dimensionally related to the severity of autistic traits in clinical populations.

Figure 1. Surface maps for the pregenual anterior cingulate cortex (pgACC) functional connectivity across all participants (n=25)(a)

(a) Significant positive (orange) and negative (blue) connectivity for the pgACC (Z > |2.3|, cluster significance: p < .05, corrected). Surface maps were generated using the Analysis of Functional NeuroImages Surface Mapper (AFNI SUMA) package. The bottom axial and sagittal figures show the location of the pgACC region of interest (ROI) used to map functional connectivity (x=0, y=47, z=9 in Montreal Neurological Institute standard space).

Figure 2. Pregenual anterior cingulate (pgACC) functional connectivity (FC) related to the Social Responsiveness Scale –Adult version (SRS-A)(b)

(b) Surface maps depict regions for which pgACC FC is related to the SRS-A scores across participants (n=25) (Z > |2.3|, cluster significance: p< .05, corrected). Connectivity between pgACC and a cluster centered in anterior mid-insula (red) was negatively related to SRS-A bilaterally, while a cluster centered in the left hemisphere parietal/occipital cortices (green) was positively related to SRS-A. Scatter plots depict relationships between individual SRS-A scores and the parameter estimates of pgACC FC for (A) left anterior mid-insula, (B) left parietal/occipital cortices, and (C) right anterior mid-insula, and (R²=0.56; 0.51, 0.44; for A, B, C, respectively; p < 0.001).

Figure 3. Inter-individual differences in pregenual anterior cingulate (pgACC) functional connectivity (FC) with anterior mid-insula (aMI)(c)

(c) Tricolor bar-plots depict the percentage of voxels within the aMI cluster mask showing significantly positive pgACC FC (red), negative pgACC FC (blue), or no significant connectivity (gray), for participants scoring in the lowest (n=8), intermediate (n=9) and highest (n=8) Social Responsiveness Scale –Adult (SRS-A) tercile. Scatter plots depict the difference between the percentage of voxels positively connected minus the percentage of voxels negatively connected to pgACC in the aMI masks for each of the three SRS-A terciles. Significantly ordered differences between the three SRS-A groups were found, such that the more positive the difference (i.e., more voxels in the mask positively connected to pgACC) the lower the SRS-A rating (Jonckheere-Terpstra based Z-score = −3.4 and −2.7, for left and right hemispheres, respectively; p< 0.01).

Figure 4. Pregenual anterior cingulate cortex (pgACC) connectivity in the lowest and highest terciles per the Social Responsiveness Scale-Adult version (SRS-A)(d)

(d) Surface maps showing voxels with positive (orange) and negative (blue) pgACC FC for SRS-A subgroups (lowest tercile, highest tercile; n=8 for each group; mean age 26.7 ± 3.5 and 26.9 ± 3.3; 2 and 3 males; mean SRS-A Score 11.8 ± 5.2 and 48.9 ± 6.8, respectively). Bottom panel represents statistical surface maps for direct comparisons between the two SRS-A-based subgroups. The group of participants in the lowest SRS-A tercile showed greater positive connectivity between anterior mid-insula (red) in the left hemisphere and pgACC. In contrast, the highest SRS-A tercile group showed greater positive connectivity in parietal/occipital cortices (green) in the left hemisphere (Z > |2.3|, cluster significance: p < .05, corrected). LH: left hemisphere; RH= right hemisphere.

Figure 5. Test-retest reliability for pregenual anterior cingulate cortex (pgACC) functional connectivity (FC)(e)

(e) Surface maps depicting voxel-wise intraclass correlation (ICC) values for the pgACC FC over the long-term/intersession (scans 1 and 2 separated by 5–16 months) and short-term/intra-session (scans 2 and 3 separated by 45 minutes) in the 20 participants who completed three scans. The upper map depicts the stability of parameter estimates for pgACC/left anterior mid-insula (aMI) FC across scans 1 and 2; the lower map shows the intrasession stability across scans 2 and 3 (R² = .45 and .60; p< 0.01 and p < .001, respectively). At the top left of the figure are the sagittal and axial images of the pgACC ROI (x=0, y=47, z=9 in Montreal Neurological Institute standard space); at the top right are sagittal and axial images of the left aMI mask (x=34, y=0, z=−2 in Montreal Neurological Institute standard space).