The Emergence of Network Inefficiencies in Infants With Autism Spectrum Disorder

Abstract

Background: Autism spectrum disorder (ASD) is a developmental disorder defined by behavioral features that emerge during the first years of life. Research indicates that abnormalities in brain connectivity are associated with these behavioral features. However, the inclusion of individuals past the age of onset of the defining behaviors complicates interpretation of the observed abnormalities: they may be cascade effects of earlier neuropathology and behavioral abnormalities. Our recent study of network efficiency in a cohort of 24-month-olds at high and low familial risk for ASD reduced this confound; we reported reduced network efficiencies in toddlers classified with ASD. The current study maps the emergence of these inefficiencies in the first year of life.

Methods: This study uses data from 260 infants at 6 and 12 months of age, including 116 infants with longitudinal data. As in our earlier study, we use diffusion data to obtain measures of the length and strength of connections between brain regions to compute network efficiency. We assess group differences in efficiency within linear mixed-effects models determined by the Akaike information criterion.

Results: Inefficiencies in high-risk infants later classified with ASD were detected from 6 months onward in regions involved in low-level sensory processing. In addition, within the high-risk infants, these inefficiencies predicted 24-month symptom severity.

Conclusions: These results suggest that infants with ASD, even before 6 months of age, have deficits in connectivity related to low-level processing, which contribute to a developmental cascade affecting brain organization and eventually higher-level cognitive processes and social behavior.

Keywords: Autism; Connectivity; Development; Efficiency; Infant siblings; Network analysis.

Figure 1

The group differences in nodal local efficiency for HRPOS infants vs HRNEG and LRNEG infants assessed at 6, 9, and 12 months of age. The t-statistic is shown in the top half of the figure; the p-statistic is shown in the bottom half. Reduced efficiency in the HRPOS infants yields a negative t-statistic (blue); increased efficiency yields a positive t-statistic (red). The p-statistic maps show both the p-values that survive an FDR correction for multiple comparisons (purple), as well as those that are significant uncorrected, but do not survive multiple comparison correction (blue). Each row shows the results for the left hemisphere on the left, and the right hemisphere on the right. The medial views for the left hemisphere are furthest to the left; the medial views for the right hemisphere are furthest to the right. Age is indicated in the center of each row. Notice that FDR significant reductions in nodal local efficiency in HRPOS infants are seen at 6 months of age in the right primary auditory cortex, and superior and middle temporal gyri; reductions in the left primary auditory cortex become significant by 9 months of age, followed by reductions in the left insula by 12 months of age.

Figure 2

The group differences in nodal global efficiency for HRPOS infants vs HRNEG and LRNEG infants assessed at 6, 9, and 12 months of age. The t-statistic is shown in the top half of the figure; the p-statistic is shown in the bottom half. Reduced efficiency in the HRPOS infants yields a negative t-statistic (blue); increased efficiency yields a positive t-statistic (red). The p-statistic maps show both the p-values that survive an FDR correction for multiple comparisons (purple), as well as those that are significant uncorrected, but do not survive multiple comparison correction (blue). Each row shows the results for the left hemisphere on the left, and the right hemisphere on the right. The medial views for the left hemisphere are furthest to the left; the medial views for the right hemisphere are furthest to the right. Age is indicated in the center of each row. Notice that FDR significant reductions in nodal global efficiency in HRPOS infants are seen in Broca’s area at 12 months of age.

Figure 3

The relation of autism severity scores to nodal local efficiency in the high-risk infants, assessed within linear mixed effects models at 6, 9, and 12 months of age. The t-statistic is shown in the top half of the figure; the p-statistic is shown in the bottom half. A positive correlation between efficiency and severity yields a positive t-statistic (red); an inverse relation between efficiency and severity yields a negative t-statistic (blue). The p-statistic maps show both the p-values that survive an FDR correction for multiple comparisons (purple), as well as those that are significant uncorrected, but do not survive multiple comparison correction (blue). Each row shows the results for the left hemisphere on the left, and the right hemisphere on the right. The medial views for the left hemisphere are furthest to the left; the medial views for the right hemisphere are furthest to the right. Age is indicated in the center of each row. Notice that there are FDR significant inverse relations between autism severity and nodal local efficiency at 6 months of age in primary auditory cortex, and that by 12 months of age there are also inverse relations in visual and somatosensory regions, as well as the insula.

Figure 4

The relation of autism severity scores to nodal global efficiency in the high-risk infants, assessed within linear mixed-effects models at 6, 9, and 12 months of age. The t-statistic is shown in the top half of the figure; the p-statistic is shown in the bottom half. A positive correlation between efficiency and severity yields a positive t-statistic (red); an inverse relation between efficiency and severity yields a negative t-statistic (blue). The p-statistic maps show both the p-values that survive an FDR correction for multiple comparisons (purple), as well as those that are significant uncorrected, but do not survive multiple comparison correction (blue). Each row shows the results for the left hemisphere on the left, and the right hemisphere on the right. The medial views for the left hemisphere are furthest to the left; the medial views for the right hemisphere are furthest to the right. Age is indicated in the center of each row. Notice that there are FDR significant inverse relations between autism severity and nodal global efficiency by 9 months of age in areas involved in somatosensory processing, and language processing, and that by 12 months of age there are inverse relations in a more extensive set of language areas, including Broca’s area and its right hemisphere homologue, as well as areas involved in motor processing, and more abstract aspects of cognition.