A Longitudinal MRI Study of Subcortical Brain Development in Infants Who Develop Autism and Infants with Fragile X Syndrome

Background: Previous research has shown that the caudate is enlarged in preschool-aged children with fragile X syndrome (FXS) (Hazlett, 2009; 2012). The amygdala is enlarged in young children with ASD (Hazlett, 2009; Mosconi, 2009; Nordahl, 2012; Schumann, 2009; Sparks, 2002) and exhibits neuronal abnormalities (Amaral, 2008; Schumann, 2006). However, it is unknown whether altered growth trajectories of the caudate and amygdala can be detected prior to age 2.

Objectives: We conducted a longitudinal MRI study and hypothesized that infants with FXS would show caudate enlargement, while infants who develop ASD would show amygdala enlargement, compared to age-matched control infants.

Methods: Longitudinal MRIs were collected at 6, 12, and 24 months in N=21 infants with FXS, N=50 high-risk infants who were later diagnosed with idiopathic ASD, N=227 high-risk infants who were not diagnosed with ASD (HR-neg), and N=134 low-risk control infants (LR-neg). Between 6-24 months, 50 scans were acquired in the FXS group, 153 in the ASD group, 611 in the HR-neg group, and 330 in the LR-neg group. Multi-atlas subcortical segmentation generated volumes for left and right caudate, amygdala, globus pallidus, putamen, thalamus, and hippocampus. A repeated-measures mixed-effects model tested main effects and interactions with group, while controlling for age, sex, and total cerebral volume (TCV).

Results: For the caudate, there was a significant main effect of group (F_3,456=16.33, p<.0001), as well as TCV, age and sex, but no group interactions. Pairwise comparisons revealed that the FXS group had larger caudate volume at 6, 12, and 24 months, compared to all other groups (p<.0001). The FXS group had 16% larger caudate volume at 6 months (vs. all other groups), 20% larger at 12 months, and 17% larger at 24 months (Fig. 1). For the amygdala, there was a significant group x age interaction (F_3,494=6.35, p<.05) with the ASD group having a steeper trajectory, such that by 12 months the ASD group had significantly larger amygdala volume (5% larger vs. HR-neg and LR-neg) and the FXS group had significantly smaller amygdala (5% smaller vs. HR-neg and LR-neg), after controlling for TCV, age and sex (Fig. 2). The globus pallidus showed a significant main effect of group (F_3,494=4.45, p<.05) with the FXS group having larger volume at 6-24 months. There were no significant group differences in the thalamus, putamen, or hippocampus. No group x laterality interactions were observed in any structure. Behavioral analyses revealed that caudate enlargement in the FXS group was significantly associated with greater motor stereotypies (r=.55, p<.05).

Conclusions: Infants with FXS have a striking enlargement of the caudate present by 6 months of age, whereas infants who develop ASD have amygdala enlargement that emerges between 6 and 24 months. While FXS shares some behavioral characteristics with idiopathic ASD, it appears that longitudinal brain imaging can delineate distinct brain trajectories early in life. Caudate enlargement has a pathological effect on motor behavior, consistent with findings in preschoolers (Wolff, 2013). We will examine the association between amygdala size and behaviors regulated by this brain region, including sensory function and social ability.