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. 2022 Aug;179(8):562-572.
doi: 10.1176/appi.ajp.21090896. Epub 2022 Mar 25.

Subcortical Brain Development in Autism and Fragile X Syndrome: Evidence for Dynamic, Age- and Disorder-Specific Trajectories in Infancy

Mark D Shen  1 , Meghan R Swanson  1 , Jason J Wolff  1 , Jed T Elison  1 , Jessica B Girault  1 , Sun Hyung Kim  1 , Rachel G Smith  1 , Michael M Graves  1 , Leigh Anne H Weisenfeld  1 , Lisa Flake  1 , Leigh MacIntyre  1 , Julia L Gross  1 , Catherine A Burrows  1 , Vladimir S Fonov  1 , D Louis Collins  1 , Alan C Evans  1 , Guido Gerig  1 , Robert C McKinstry  1 , Juhi Pandey  1 , Tanya St John  1 , Lonnie Zwaigenbaum  1 , Annette M Estes  1 , Stephen R Dager  1 , Robert T Schultz  1 , Martin A Styner  1 , Kelly N Botteron  1 , Heather C Hazlett  1 , Joseph Piven  1 ; IBIS Network  1
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Subcortical Brain Development in Autism and Fragile X Syndrome: Evidence for Dynamic, Age- and Disorder-Specific Trajectories in Infancy

Mark D Shen et al. Am J Psychiatry. 2022 Aug.

Abstract

Objective: Previous research has demonstrated that the amygdala is enlarged in children with autism spectrum disorder (ASD). However, the precise onset of this enlargement during infancy, how it relates to later diagnostic behaviors, whether the timing of enlargement in infancy is specific to the amygdala, and whether it is specific to ASD (or present in other neurodevelopmental disorders, such as fragile X syndrome) are all unknown.

Methods: Longitudinal MRIs were acquired at 6-24 months of age in 29 infants with fragile X syndrome, 58 infants at high likelihood for ASD who were later diagnosed with ASD, 212 high-likelihood infants not diagnosed with ASD, and 109 control infants (1,099 total scans).

Results: Infants who developed ASD had typically sized amygdala volumes at 6 months, but exhibited significantly faster amygdala growth between 6 and 24 months, such that by 12 months the ASD group had significantly larger amygdala volume (Cohen's d=0.56) compared with all other groups. Amygdala growth rate between 6 and 12 months was significantly associated with greater social deficits at 24 months when the infants were diagnosed with ASD. Infants with fragile X syndrome had a persistent and significantly enlarged caudate volume at all ages between 6 and 24 months (d=2.12), compared with all other groups, which was significantly associated with greater repetitive behaviors.

Conclusions: This is the first MRI study comparing fragile X syndrome and ASD in infancy, demonstrating strikingly different patterns of brain and behavior development. Fragile X syndrome-related changes were present from 6 months of age, whereas ASD-related changes unfolded over the first 2 years of life, starting with no detectable group differences at 6 months. Increased amygdala growth rate between 6 and 12 months occurs prior to social deficits and well before diagnosis. This gradual onset of brain and behavior changes in ASD, but not fragile X syndrome, suggests an age- and disorder-specific pattern of cascading brain changes preceding autism diagnosis.

Keywords: Amygdala; Autism Spectrum Disorder; Caudate; Fragile X Syndrome; Neurodevelopmental Disorders; Neuroimaging.

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Figures

FIGURE 1.
FIGURE 1.
Cognitive ability from 6 to 24 months in infants at high or low likelihood for ASD who did or did not develop ASD and infants with fragile X syndromea a ASD=autism spectrum disorder; FXS=fragile X syndrome; HL-ASD=infants at high likelihood for ASD who were later diagnosed with ASD; HL-negative=high-likelihood infants who were negative for ASD; LL-negative=low-likelihood infants who were negative for ASD. Compared with all other groups, the infants with fragile X syndrome had significantly lower cognitive ability (Mullen Early Learning composite score) starting at 6 months of age and remaining significantly lower at 12 and 24 months. The HL-ASD group showed no differences in cognitive ability at6 months relative to HL- and LL-negative control infants but showed significantly lower cognitive ability by 12 months of age. Error bars indicate standard error of the mean.
FIGURE 2.
FIGURE 2.
Amygdala growth between 6 and 24 months in infants at high or low likelihood for ASD who did or did not develop ASD and infants with fragile X syndromea a ASD=autism spectrum disorder; FXS=fragile X syndrome; HL-ASD=infants at high likelihood for ASD who were later diagnosed with ASD; HL-negative=high-likelihood infants who were negative for ASD; LL-negative=low-likelihood infants who were negative for ASD. Infants who developed ASD had faster amygdala growth between 6 and 24 months; there were no group differences at 6 months, followed by significantly larger amygdala volume in the ASD group at 12 and 24 months, compared with all other groups; there was a significant group-by-age interaction (p<0.0001). Plots of the model-adjusted least-squares means are overlaid onto the raw data points of all participants. Percent differences in least-squares means are in relation to the LL-negative group. Effect sizes for the HL-ASD group relative to the LL-negative group: d=0.15 at 6 months; d=0.56 at 12 months; d=0.40 at 24 months. (Note that the LL-negative (blue) and HL-negative (purple) lines are overlapping.) Error bars indicate standard error of the mean. Asterisks indicate p values (corrected) compared with all other groups; n.s.=not significant. *p<0.05. **p<0.005.
FIGURE 3.
FIGURE 3.
Caudate growth between 6 and 24 months in infants at high or low likelihood for ASD who did or did not develop ASD and infants with fragile X syndromea a ASD=autism spectrum disorder; FXS=fragile X syndrome; HL-ASD=infants at high likelihood for ASD who were later diagnosed with ASD; HL-negative=high-likelihood infants who were negative for ASD; LL-negative=low-likelihood infants who were negative for ASD. Infants with fragile X syndrome had larger caudate volume at all ages between 6 and 24 months; there was a significant main effect of group (p=0.001). Plots of the model-adjusted least-squares means are overlaid onto the raw data points of all participants. Percent differences in least-squares means are in relation to the LL-negative group. Effect sizes for the FXS group relative to the LL-negative group: d=2.12 at 6 months; d=2.04 at 12 months; d=1.49 at 24 months. (Note that the lines for the LL-negative (blue) and HL-negative (purple) lines are overlapping.) Error bars indicate standard error of the mean. Asterisks indicate p values (corrected) compared with all other groups. ***p<0.0001.
FIGURE 4.
FIGURE 4.
Relationship between amygdala growth between 6 and 12 months and social deficits and restricted and repetitive behaviors at 24 months in infants who developed ASDa a ASD=autism spectrum disorder. Faster amygdala growth rate in the ASD group between 6 and 12 months was associated with greater social deficits at 24 months (based on the Autism Diagnostic Observation Schedule [ADOS] social affect calibrated severity score; panel A), but not restricted and repetitive behaviors at 24 months (based on the ADOS restricted, repetitive behavior calibrated severity score; panel B).
FIGURE 5.
FIGURE 5.
Relationship between caudate volume at 12 months and repetitive behaviors at 24 months in infants with fragile X syndromea a In infants with fragile X syndrome (FXS), caudate enlargement at 12 months was associated with greater repetitive behaviors at 24 months (based on the overall score on the Repetitive Behavior Scale–Revised, RBS-R).
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