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Aberrant brain network and eye gaze patterns during natural social interaction predict multi-domain social-cognitive behaviors in girls with fragile X syndrome

Molecular Psychiatry volume 27, pages 3768–3776 (2022)Cite this article

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Abstract

Girls with fragile X syndrome (FXS) often manifest significant symptoms of avoidance, anxiety, and arousal, particularly in the context of social interaction. However, little is currently known about the associations among neurobiological, biobehavioral such as eye gaze pattern, and social-cognitive dysfunction in real-world settings. In this study, we sought to characterize brain network properties and eye gaze patterns in girls with FXS during natural social interaction. Participants included 42 girls with FXS and 31 age- and verbal IQ-matched girls (control). Portable functional near-infrared spectroscopy (fNIRS) and an eye gaze tracker were used to investigate brain network alterations and eye gaze patterns associated with social-cognitive dysfunction in girls with FXS during a structured face-to-face conversation. Compared to controls, girls with FXS showed significantly increased inter-regional functional connectivity and greater excitability within the prefrontal cortex (PFC), frontal eye field (FEF) and superior temporal gyrus (STG) during the conversation. Girls with FXS showed significantly less eye contact with their conversational partner and more unregulated eye gaze behavior compared to the control group. We also demonstrated that a machine learning approach based on multimodal data, including brain network properties and eye gaze patterns, was predictive of multiple domains of social-cognitive behaviors in girls with FXS. Our findings expand current knowledge of neural mechanisms and eye gaze behaviors underlying naturalistic social interaction in girls with FXS. These results could be further evaluated and developed as intermediate phenotypic endpoints for treatment trial evaluation in girls with FXS.

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Fig. 1: Overview of the experiment design.
Fig. 2: Overview of the two-layer behavior prediction model.
Fig. 3: Between-group comparison (FXS vs. control) and within-FXS group comparison (Prompt vs. non-prompt) of inter-ROI functional connectivity and ROI strength.
Fig. 4: Between-group difference (FXS vs. Control, independent t test) and within-group difference (prompt vs. nonprompt, paired t test) in the eye gaze measures.
Fig. 5: Predictive model performance (r) and optimal feature set (top 10) for each domain of FXS-linked social deficits.

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Acknowledgements

We thank the families who participated in this study and many members of the laboratory who assisted with this project. This work was supported by National Institute of Mental Health Grant Nos. R01MH050047 and T32MH019908 (to A.L.R.), the Kelvin Foundation and the Canel Family Fund.

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Authors and Affiliations

  1. Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 94305, USA

    Rihui Li, Jennifer L. Bruno, Cindy H. Lee, Kristi L. Bartholomay, Jamie Sundstrom, Aaron Piccirilli, Tracy Jordan, Jonas G. Miller, Amy A. Lightbody & Allan L. Reiss

  2. Departments of Radiology and Pediatrics, Stanford University, Stanford, CA, 94305, USA

    Allan L. Reiss

  3. Department of Pediatrics, Stanford University, Stanford, CA, 94305, USA

    Allan L. Reiss

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  1. Rihui Li
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Contributions

RL conceived the idea, preprocessed the data, performed the main analysis, and wrote the article. JB, CL and KB collected the data and revised the article. JS and AP preprocessed the eye tracking data and revised the article. TJ, JG and AL conceived the idea and revised the article. AR obtained funding, conceived the idea, and critically revised the article.

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Correspondence to Rihui Li.

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Li, R., Bruno, J.L., Lee, C.H. et al. Aberrant brain network and eye gaze patterns during natural social interaction predict multi-domain social-cognitive behaviors in girls with fragile X syndrome. Mol Psychiatry 27, 3768–3776 (2022). https://doi.org/10.1038/s41380-022-01626-3

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