Developmental Differences in Functional Connectivity in Autism

T. K. McAllister-Day1, T. Madhyastha1, M. Reiter1, M. K. Askren1, N. Kleinhans1, W. Art. Chaovalitwongse1,2, T. Grabowski, Jr.1,3

1
Dept. of Radiology, 2Industrial & Systems Engineering, 3Dept. of Neurology, University of Washington Seattle, WA

Introduction Results
Autism is a developmental disorder Graph Analysis
known to affect brain structure and Using a graph approach, we found that within-network connectivity declined with
function, but how it affects function- age within the DAN, FPTC, and SELF networks. Neither age nor diagnostic group
al connectivity is not well understood. predicted overall change across all networks (age pcor = 0.254, group pcor = 0.873) (Fi-
There is evidence for long-range hy- gre 4).
poconnectivity and short-range hyper-
connectivity, but results are dependent Age predicted a decline in three networks: DAN, FPTC, and SELF (pcor = 0.003, pcor <
on motion, subject age, and method- 0.001, pcor = 0.002).
Figure 1: Default mode network (orange). Fox & Raichle (2007)
ological approach. There was no main effect of diagnostic group on functional connectivy in any net-
In this study we use two methodological approaches: graph-based functional connectivity (FC) and a work after correction for multiple comparisons; however, the effect on OTHER ap-
novel method called network kernel analysis, to analyze within- and between-network connectivity of proached significance (pcor = 0.056) (Figure 5).
large-scale intrinsic functional networks.
We used literature-defined coordinates to identify nodes in the default mode network (DMN), dorsal
attention network (DAN), frontal-parietal task control network (FPTC) and networks involved in emo-
tional processing (SELF and OTHER) [4]. We censored motion-tainted frames.
Figure 4: Age vs. mean connectivity Figure 5: Age vs. connectivity within the OTHER network
Our population consists of a cross-sectional sample (N=360) drawn from the Autism Brain Imaging
Data Exchange (ABIDE) repository, selected based on root mean squared mean absolute motion < 0.5 Network Kernel Analysis
mm, and individually matched for motion, full scale IQ, and age (7-35). We identified a well-fitting model across
all age groups and diagnostic groups.
Main Objectives These networks identified by NKA are
shown in Figure 8.
How are the intrinsic networks different in ASD subjects?
Network kernel analysis of the DMN
Are numerical measures of symptom severity correlated with intrinsic con- showed both increased (yellow) and de-
creased connectivity (blue) with age (Fig-
nectivity? ure 6). The top row of Figure 6 shows in-
creasing connectivity between the DMN
Methods and the hippocampus with age. The bot-
Data analyzed in this study were taken from the Autism Brain Imaging Database Exchange (ABIDE), a tom row shows attention-related areas
Figure 6: Changes in DMN connectivity with age
publicly available data set aggregating and openly sharing 1112 existing resting-state fMRI scans that decrease in connectivity with the
(rsfMRI) along with corresponding structural MRI and phenotypic information (539 ASD / 573 TD) [1]. DMN with age.

Figure 7 shows areas where there is Figure 8: Network kernels identified using NKA
We successfully download 1108 scans from ABIDE. Downloaded
Missing scans an interaction between DX status and
from ABIDE
We then excluded subjects with RMS mean absolute displace- (N=1108) N=12
age-related slope. Blue areas show where
ment > 0.5 mm (n=253), and another 53 due to artifacts. the ASD slope is lower.
We divided the remaining data set into eight age cohorts, and each Preprocessing Bad motion Correlation to the lingual gyrus with the Symptom Severity
N=253 DMN decreases with age in ASD sub-
age cohort into ASD and TD groups matched on motion, full scale We examined three symptom scores: ADOS social and communication, and the restrictive, reptitive, and
jects, whereas it increases with age in TD
IQ , and age. The creation of the cohort is detailed in Figure 2. stereotyped patterns of behavior subscore from the Autism Diagnostic Interview-Revised (ADI-R-RRB).
Sample 1 Artifacts subjects.
To avoid oversampling from a specific age range, 116 subjects were (N=843) (N=53) Each subscore was independently evaluated with the two social networks: OTHER and SELF.
Correlation between the DMN and the
excluded in order to maintain similar group sizes. frontal pole decreases less in ASD than
Removed in TD with age. No score was significantly correlated with connectivity in either network.
ASD subjects had a DSM-IV-TR diagnosis of Autistic Disor- Matching
to maintain
(age, FIQ,
der, Aspergers Disorder, or Pervasive Developmental Disorder mean abs)
group sizes

Not-Otherwise-Specified, supported by the Autism Diagnostic

(N=116)
Results are presented in radiological con-
Observation Schedule (ADOS) and/or the Autism Diagnostic In- vention (R=L).
Figure 7: DMN diagnostic group X age interaction
Final sample
terview-Revised (ADI-R). (N ASD = 180,
N TD = 180)
Participants were predominately male, the final ratio was 6.35:1.
Figure 2: Preprocessing
Demographics Conclusions
The seed regions for DMN, DAN, and FPTC were taken Bin DX Age range Mean age n % male FIQ Mean Abs. Motion [mm]
First five frames Motion parameter The existing literature describes findings of both increased and decreased functional connectivity
from Power et al., 2011 [5], for the salience network from discarded regression ASD 9.76 (1.12) 37 81 109.27 (16.24) 0.24 (0.11)
1 7.13 - 11.55 across multiple systems and networks. We found no significant differences in changes in connectivity
TD 9.76 (1.11) 35 77 111.25 (15.25) 0.24 (0.11)
Sridharan et al., 2008 [6], and the SELF and OTHER net- between diagnostic group in the DMN, DAN, FPTC, and the SELF network. We did find that connec-
ASD 13.49 (0.99) 35 91 108.66 (12.97) 0.21 (0.08)
works from Murray et al., 2015 [4]. 2
TD
11.56 - 15.14
13.4 (1.02) 37 81 108.64 (11.76) 0.23 (0.11) tivity in the OTHER network declined more rapidly with age in ASD patients.
Motion correction Registration to
We calculated the correlation between age and network ASD 16.77 (0.9) 36 92 107.69 (12.52) 0.2 (0.09)
with FSL MNI space (1 3 15.22 - 18.74 Network kernel analysis was more sensitive to developmental and group differences. We show devel-
connectivity using a linear model, controlling for the ef- mm) with ANTS TD 16.79 (1.02) 36 86 107.14 (13.24) 0.2 (0.09)
fects of diagnostic group on the slope. ASD 21.1 (1.47) 38 92 112.08 (12.33) 0.22 (0.11) opmental changes in the DMN that involve age-related integration of the HC and differentiation of at-
4 18.8 - 24 tention-related networks. We also show that these age-related changes interact with diagnostic status.
We also performed a network kernel analysis (NKA) on AFNI despiking TD 20.96 (1.35) 34 85 114.22 (10.01) 0.22 (0.09)
the identified regions. Network kernels are small groups Quality assurance
ASD 29.44 (3.2) 34 85 108.68 (13.84) 0.22 (0.09) We conclude that the age group being studied and methodological approaches confound findings of
5 24 - 35
of potentially overlapping regions of interest whose time- TD 28.87 (3.24) 38 92 111.74 (8.98) 0.21 (0.1)
functional connectivity in ASD.
Table 1: Subject demographics
courses are correlated in time. They are analogous to com- Spatial smoothing
ponents obtained by an independent component analy- with Gaussian In working with such a large dataset, we were able to create matched groups that had very little varia-
sis, but are obtained from a factor analysis of the BOLD
kernel (FSL) tion within an age group (Table 1). Subjects were also compared on maximum absolute motion, mean
signal in a set of ROIs from large-scale intrinsic networks
= 3mm relative motion and maximum relative motion. References
Figure 3: Image processing Table 2 shows the (uncorrected) p-values for the between-group criteria we examined.
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Table 2: P-values for between-group differences doi:10.1073/pnas.0800005105

Support: NSF CMMI-1333841