Evidence for Early Divergence of Thalamocortical Networks in High-Risk Siblings of Individuals with Autism Spectrum Disorder (ASD)

Background: The thalamus is an important subcortical relay structure, through which most sensory information is routed. It plays a crucial role in modulation of visual, auditory, and somatosensory functions, as well as attention and motor control. Various lines of evidence have suggested thalamic abnormalities in ASD (e.g., Chugani et al. 1997, Friedman et al. 2003).  Highly specific patterns of thalamocortical connectivity have been demonstrated in typically developing (TD) individuals using functional connectivity MRI (fcMRI; Zhang et al. 2008, 2010; Fair et al. 2010). In prior studies (Nair et al., 2013; Nair et al., 2015), we demonstrated that children and adolescents with ASD showed mostly reduced connectivity especially for prefrontal-thalamic networks, accompanied by overconnectivity within temporal-thalamic networks.

Objectives: Given the importance of early identification of biomarkers and endophenotypes of ASD, it is crucial to understand how early in the developmental process these differences in thalamocortical networks emerge.

Methods: Resting-state fcMRI (rs-fcMRI) data were acquired during natural sleep for 8 minutes on a 3T Siemens scanner for 19 infant siblings (6 weeks post-birth) of children with ASD (i.e., high-risk group; HR) and 21 infants at low risk (LR) for ASD. Data were preprocessed using AFNI and FSL, and included motion correction, spatial smoothing, isolation of low frequency fluctuations (.008<f<.08), and normalization to the UNC Infant 0-1-2 neonate atlas (Shi, 2011). The same atlas was used to obtain masks for prefrontal cortex, motor cortex, somatosensory cortex, parietal lobe, occipital lobe, temporal lobe and thalamus (see Nair et al., 2013). Time-series were extracted from each of these cortical regions, and submitted to partial correlation analyses with field of view restricted to thalamus. Results were normalized using Fisher R-to-Z transformation and submitted to paired t-test analysis for comparison between groups. Additional rs-fcMRI data were obtained for 10 HR and 11 LR participants at 9-months post-birth. Similar preprocessing and statistical analyses were used on these data, except that these data were normalized to the UNC Infant 0-1-2 1-year atlas. 

Results: Rs-fcMRI results showed aberrant patterns of thalamocortical connectivity in the HR group compared to LR groups at 6-weeks post-birth. These patterns mostly indicated underconnectivity effects for all regions in the HR group, except for the parietal lobe, which showed bilateral overconnectivity effects with the thalamus. At 9 months post-birth, the HR group showed thalamocortical patterns similar to older ASD children and adolescents in our prior studies (Nair et al., 2013; Nair et al., 2015). More specifically, as compared to the LR group, the HR group demonstrated marked bilateral underconnectivity within prefrontal-thalamic networks, and bilateral overconnectivity within temporal-thalamic networks. 

Conclusions: Our findings suggest that aberrant subcortical-cortical connectivity may be disrupted as early as the first weeks of life in infants at higher risk of developing ASD. Further longitudinal assessment is required to determine if these thalamocortical connectivity differences can predict which individuals within the HR group will later meet criteria for diagnosis of ASD.