Intrinsic functional connectivity variance and state-specific under-connectivity in autism

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with altered brain connectivity. Previous neuroimaging research demonstrates inconsistent results, particularly in studies of functional connectivity in ASD. Typically, these inconsistent findings are results of studies using static measures of resting-state functional connectivity. Recent work has demonstrated that functional brain connections are dynamic, suggesting that static connectivity metrics fail to capture nuanced time-varying properties of functional connections in the brain. Here we used a dynamic functional connectivity approach to examine the differences in the strength and variance of dynamic functional connections between individuals with ASD and healthy controls (HCs). The variance of dynamic functional connections was defined as the respective standard deviations of the dynamic functional connectivity strength across time. We utilized a large multicenter dataset of 507 male subjects (209 with ASD and 298 HC, from 6 to 36 years old) from the Autism Brain Imaging Data Exchange (ABIDE) to identify six distinct whole-brain dynamic functional connectivity states. Analyses demonstrated greater variance of widespread long-range dynamic functional connections in ASD (P < 0.05, NBS method) and weaker dynamic functional connections in ASD (P < 0.05, NBS method) within specific whole-brain connectivity states. Hypervariant dynamic connections were also characterized by weaker connectivity strength in ASD compared with HC. Increased variance of dynamic functional connections was also related to ASD symptom severity (ADOS total score) (P < 0.05), and was most prominent in connections related to the medial superior frontal gyrus and temporal pole. These results demonstrate that greater intraindividual dynamic variance is a potential biomarker of ASD. Hum Brain Mapp 38:5740-5755, 2017. © 2017 Wiley Periodicals, Inc.

Keywords: autism spectrum disorder; dynamic functional connectivity; intraindividual variance; state-specific under-connectivity.

Figure 1

Flowchart of the dynamic FC analysis. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Decreased sFC strength in ASD. (A) The mean sFC networks of HC and ASD groups; (B) decreased sFCs in ASD, red points represent connections with lower sFC strength in ASD compared to HC. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Hypervariant dFCs in ASD. (A) Hypervariant connections in ASD. Red blocks represent hypervariant connections in ASD and blue blocks represent connections with no significant difference of dFCvar between HC and ASD. The numbers below represent the numbers of atypical connections with corresponding regions divided by the number of total atypical connections. (B) Hypervariant regions. The length of the bars represents the number of hypervariant connections of the corresponding regions. Only regions with hypervariant connections greater than the mean + SD are shown. Abbreviations of the regions are listed in Supporting Information. (C) Severity‐related hypervariant connections. The hypervariant connections significantly positively correlated with ADOS total score in ASD. The size of nodes represents the number of connections. Red regions represent the areas with the most connections. PFR, prefrontal regions; FR, other regions of frontal lobe; PR, parietal regions; TR, temporal regions; OR, occipital regions; SUB, subcortical regions [Wang et al., 2007]. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Length distribution of hypervariant connections in ASD. (A) Overview of the long‐range, middle‐range, and short‐range hypervariant connections in ASD: blue lines represent long‐range atypical connections, green lines represent middle‐range atypical connections, and yellow lines represent short‐range atypical connections. (B) Counts of long‐range, middle‐range, and short‐range hypervariant connections in ASD. Abbreviations of the regions are listed in Supporting Information. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

State‐specific difference of the dFC network between ASD and HC. (A) Top row represents the dFC networks at 6 states. (B) Second row represents the hubs of the dFC networks at 6 states. For display, we defined the significant connections as the connections whose absolute strength is greater than the mean + SD, and hub regions as the nodes whose degree is above mean + 2 SD. (C) The third row represents the distribution of the decreased connections in ASD for each state while red represents the distribution of decreased dFC in ASD for each state. For display, we also compared the sFC between ASD and HC (blue). No decreased dFC in ASD at States 3 and 5 were found. The values of the radar map are the ratio of the decreased connections related to corresponding regions divided by the total decreased connections. (D) Fourth row represents the dFC strength of the hypervariant connections. Red bars represent the dFC strength for the ASD group and blue bars represent the dFC strength for the HC group. * represents P < 0.05 (Bonferroni corrected). Bi, bilateral; SOG, superior occipital gyrus; ORBmid, middle frontal gyrus, orbital part; IPL, inferior parietal; ORBsupmed, superior frontal gyrus, medial orbital; PCC, posterior cingulate gyrus; ANG, angular; ROL, rolandic operculum; HIP, hippocampus; PHG, parahippocampus; TPOmid, temporal pole, middle temporal gyrus. [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 6

Different relationships between FC variance and age and in ASD and HC. (A) Relationship between FC variance and age in ASD and HC. The FC variance of the whole‐brain and hypervariant FCs showed significant negative correlation with age in the HC group, but not in the ASD group. (B) Diagrammatic drawing of the dFC development curve in ASD and HC. Red solid lines represent the linear fitting curve of mean dFC strength in ASD while the blue lines represent the HC. The upper and lower dashed lines represent the linear fitting curve of mean dFC strength plus and minus the dFCvar in ASD and HC. [Color figure can be viewed at http://wileyonlinelibrary.com]