Restricted and Repetitive Behavior and Brain Functional Connectivity in Infants at Risk for Developing Autism Spectrum Disorder

Abstract

Background: Restricted and repetitive behaviors (RRBs), detectable by 12 months in many infants in whom autism spectrum disorder (ASD) is later diagnosed, may represent some of the earliest behavioral markers of ASD. However, brain function underlying the emergence of these key behaviors remains unknown.

Methods: Behavioral and resting-state functional connectivity (fc) magnetic resonance imaging data were collected from 167 children at high and low familial risk for ASD at 12 and 24 months (n = 38 at both time points). Twenty infants met criteria for ASD at 24 months. We divided RRBs into four subcategories (restricted, stereotyped, ritualistic/sameness, self-injurious) and used a data-driven approach to identify functional brain networks associated with the development of each RRB subcategory.

Results: Higher scores for ritualistic/sameness behavior were associated with less positive fc between visual and control networks at 12 and 24 months. Ritualistic/sameness and stereotyped behaviors were associated with less positive fc between visual and default mode networks at 12 months. At 24 months, stereotyped and restricted behaviors were associated with more positive fc between default mode and control networks. Additionally, at 24 months, stereotyped behavior was associated with more positive fc between dorsal attention and subcortical networks, whereas restricted behavior was associated with more positive fc between default mode and dorsal attention networks. No significant network-level associations were observed for self-injurious behavior.

Conclusions: These observations mark the earliest known description of functional brain systems underlying RRBs, reinforce the construct validity of RRB subcategories in infants, and implicate specific neural substrates for future interventions targeting RRBs.

Keywords: Autism spectrum disorder; Brain development; Functional connectivity; Functional magnetic resonance imaging; Infant; Restricted and repetitive behavior.

Figure 1.. Restricted and repetitive behaviors and functional connectivity in infants

The number of items endorsed for each RBS-R factor at both 12 months old (mo; blue) and 24 mo (red): (A) the restricted behavior factor includes four items pertaining to limited range of focus, interest, or activity (e.g., preoccupation with part of object); (B) the stereotyped behavior factor includes six items relating to repeated, purposeless movements (e.g., arm flapping); (C) the self-injurious factor includes eight items relating to repeated actions that can cause injury to the body (e.g., hair pulling); (D) the ritualistic/sameness factor includes seventeen items relating to performing activities of daily living in a similar manner or resistance to change (e.g., arranging/ordering). Also see Supplemental Table S1. (E) An Infomap-sorted mean fcMRI matrix derived from the correlation structure between 230 functionally-defined regions of interest (ROIs). See Supplemental Figure S1. (F) Left lateral view of the ROIs on the brain surface, colored according to network assignment (see Materials and Methods for details and definition of network abbreviations). For clarity, ROIs in the cerebellum are displayed without the cerebellar structure.

Figure 2.. Connections showing a strong relationship to restricted behavior are concentrated in temporal default mode—dorsal attention and temporal default mode—posterior frontoparietal control network pairs at 24 months.

(A) Strong positive and negative brain-behavior relationships cluster by sign, within a subset of network blocks (note the visually striking red clustering at 24 mo but not at 12 mo indicated by the arrow). (B) Functional connections showing a strong relationship to restricted behavior are defined as those with p ≤ 0.05. Quantifying the level of clustering with enrichment analyses (see Materials and Methods and Supplemental Figure S2) reveals that strong brain-behavior relationships are constrained to a minority of network pairs that differ across age (enriched network pairs outlined in black). (C) Only two functional network pairs significantly enriched at either age ( 12 mo; 24 mo) also exhibit significant differences across age groups (• ; tested via McNemar χ²): tDMN-DAN and tDMN-pFPC, (see Supplemental Table S3). (D) For each primary result, ROI pairs contributing to enrichment are visualized on a surface representation of the cortex. Ball color denotes functional network membership and line color joining ROI pairs denotes the sign of brain-behavior relationship (red-positive; blue-negative). The signs of brain-behavior relationships are largely consistent within network pairs. See Supplemental Figure S2 for more detailed analysis of the fc underlying these brain-behavior relationships.

Figure 3.. Strong fc-stereotyped relationships cluster within temporal default mode—visual network connections at 12 months and dorsal attention—subcortex and temporal default mode—posterior frontoparietal control network connections at 24 months.

Analyses are as outlined in Figure 2. (A) Negative binomial regression based relationships between fc and stereotyped behavior scores. (B) Significant clustering of strong brain-behavior associations (p ≤ 0.05) is restricted to a subset of network pairs (outlined in black). (C) Primary findings include tDMN-Vis enrichment at 12 mo (but not 24 mo) and DAN-SubCtx and tDMN-pFPC enrichment at 24 mo (but not 12 mo;). See Supplemental Figure S3 for enrichment and McNemar (age group comparison) analyses. See Supplemental Table S3 for statistics. (D) At 12 mo, the Vis-tDMN network pair showed primarily negative fc-stereotyped relationships while at 24 mo both network pairs showed primarily positive fc-stereotyped relationships. See Supplemental Figure S3 for more detailed analysis of the fc underlying these brain-behavior relationships.

Figure 4.. Strong fc-ritualistic/sameness relationships cluster within visual-temporal default mode network connections at 12 months and visual—posterior frontoparietal control network connections at 12 and 24 months. Analyses follow those outlined in Figure 2.

(A)Note the particularly visually striking cluster of negative fc-ritualistic/sameness behavior relationships in the Vis-tDMN network pair at 12 mo. (B) Significant clustering of strong brain-behavior associations (p ≤ 0.05) is restricted to a subset of network pairs. (C) Primary findings included tDMN-Vis enrichment at 12 mo (but not 24 mo; indicated with dot in a blue box) and Vis-pFPC pair enrichment at both 12 mo and 24 mo (indicated with a green box). See Supplemental Figure S4 for McNemar (age group differences) analysis and Supplemental Table S3 for statistics. (D) Both Vis-tDMN (at 12 mo) and Vis-pFPC (at 12 mo and 24 mo) showed primarily negative fc-stereotyped relationships: higher ritualistic and sameness scores are associated with less positive fc between Vis and both tDMN and pFPC. See Supplemental Figure S4 for more detailed analysis of the fc underlying these brain-behavior relationships.

Figure 5.. Global patterns of RRB-fc relationships across age and behavior.

The first column depicts the nature of the brain-behavior relationship, that is, whether the relationship is positive or negative and whether it spans primarily positive or negative fc values. The second column contains the network pair in question. The third column emphasizes whether greater behavior scores were associated with increasing or decreasing fc between the network pair. The last three columns catalogue implicated behavior and time point combinations for the given network pairs. See Supplemental Figure S5 for more detailed analysis of the self-injurious RBS-R subcategory. See Supplemental Figure S6 for the global RRB-fc relationships as derived using adult-based functional networks.

Figure 6.. ROIs contributing to enrichment across behavior factors.

Analyses revealed two network pairs, one at 12 mo and one at 24 mo, implicated with multiple behaviors. (A) Functional connections between Vis and tDMN that showed a strong relationship to both stereotyped and ritualistic/sameness behavior at 12 mo. (B) Functional connections between the pFPC-tDMN that showed a strong relationship to both restricted and stereotyped behavior at 24 mo are visualized on the brain. As above, the color of the ROI denotes the functional network, and the color of the connecting bar denotes the sign of the brain-behavior relationship.