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The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) has been associated with a reduction in resting state functional connectivity, though this assertion has recently been challenged by reports of increased connectivity in ASD. To address these contradictory findings, we examined both inter- and intrahemispheric functional connectivity in several resting state data sets acquired from adults with high-functioning ASD and matched control participants. Our results reveal areas of both increased and decreased connectivity in multiple ASD groups as compared to control groups. We propose that this heterogeneity stems from a previously unrecognized ASD characteristic: idiosyncratic distortions of the functional connectivity pattern relative to the typical, canonical template. The magnitude of an individual's pattern distortion in homotopic interhemispheric connectivity correlated significantly with behavioral symptoms of ASD. We propose that individualized alterations in functional connectivity organization are a core characteristic of high-functioning ASD, and that this may account for previous discrepant findings.

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Figure 1: Pooled homotopic interhemispheric group maps and between-groups difference map.
Figure 2: Schematic illustration of the spatial-distortion origins of the ‘regression to the mean’ effect.
Figure 3: Idiosyncratic distortions of homotopic interhemispheric connectivity patterns in ASD groups.
Figure 4: Quantification of individual pattern distortions and correlation with ASD symptoms.
Figure 5: Idiosyncratic distortions of heterotopic interhemispheric connectivity patterns in ASD groups.
Figure 6: Idiosyncratic distortions of intrahemispheric connectivity patterns in ASD groups.

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Acknowledgements

The authors would like to thank H. Dubossarsky and T. Golan for numerous discussions and suggestions that contributed greatly to this work, and Y. Cohen for assistance with illustrations. This study was supported by the Israeli Presidential Bursary for outstanding PhD students in brain research (A.H.); the Simons Foundation SFARI award 298640 and the Pennsylvania Department of Health SAP grant 4100047862 (M.B.); and a European Union Future Emerging Technologies -7 – Virtual Embodiment and Robotic Re-Embodiment, Israeli Science Foundation, and Israeli Center of Research Excellence grant 51/11, European Union Flagship The Human Brain Project and the Helen and Martin Kimmel award (R.M.). Funding sources for the ABIDE data sets are listed at http://fcon_1000.projects.nitrc.org/indi/abide/index.html.

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Authors

Contributions

A.H. conducted the data analyses; A.H., M.B. and R.M. interpreted the results and wrote the manuscript; R.M. supervised the project.

Corresponding author

Correspondence to Rafael Malach.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Comparison of typical interhemispheric connectivity and group differences in interhemispheric connectivity by data set

(a) The bottom map of each column is the unthresholded between-group inter-hemispheric t-test map for each specific dataset (control>ASD). The top map of each column is the group inter-hemispheric connectivity map of control participants from all datasets, excluding participants of the specific dataset for which the t-map is presented below. The number of participants contained in each dataset is denoted in the title of each column. Arrows demonstrate the correspondence between directionalities of group-differences and variation in homotopic inter-hemispheric connectivity magnitudes; the ASD groups show reduced homotopic inter-hemispheric connectivity in regions of typically high inter-hemispheric connectivity (orange arrows), and increased inter-hemispheric connectivity in areas of reduced connectivity in the typical brain (blue arrows). Note the spatial similarity between disparity directionalities across datasets. (b) Top: Homotopic inter-hemispheric group map of all control and ASD participants combined across datasets. Bottom: Unthresholded pooled between-group t-test map (controls>ASD). Since homotopic inter-hemispheric maps are symmetrical across the midline, only the right hemisphere is presented. CAL, California Institute of Technology; CMU, Carnegie Mellon University; PBG, University of Pittsburgh; Utah-1, University of Utah – first half; Utah-2, University of Utah – second half; LOC, lateral occipital cortex; ITG, inferior temporal gyrus; PCG, post central gyrus; MFG, middle frontal gyrus.

Supplementary Figure 2 Pooled analysis versus meta-analysis of homotopic interhemispheric connectivity group differences

Left: t-test map (control>ASD) created for the pooled cohort of participants. Right: Meta-analysis map showing effect sizes (control>ASD) measured using Hedges' g. White contours represent areas found to show a significant difference between groups using 95% confidence intervals. Note the spatial similarity between the two maps in areas showing either over- or under-connectivity in ASD participants in comparison to controls.

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Hahamy, A., Behrmann, M. & Malach, R. The idiosyncratic brain: distortion of spontaneous connectivity patterns in autism spectrum disorder. Nat Neurosci 18, 302–309 (2015). https://doi.org/10.1038/nn.3919

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