Functional Connectivity of the Amygdala in 2- to 5-Year-Old Children with Autism Spectrum Disorder
The neuropathology of Autism Spectrum Disorder (ASD) likely involves abnormalities in white matter and neural connectivity patterns.
Functional connectivity MRI during rest reflects spontaneous synchronous neural activity between distinct brain regions. Recent studies provide evidence for altered resting state functional connectivity in various brain networks in older children and adults with ASD, but studies in very young children are lacking. There is evidence from structural MRI studies for abnormal enlargement of the amygdala in young children with ASD; however, functional connectivity patterns of the amygdala in young children have not yet been assessed.
We investigated resting state functional connectivity of the amygdala in 2- to 5-year-old children with ASD compared to typically developing peers (TYP).
We acquired high-resolution T1-weighted structural scans and resting-state EPI-BOLD scans during natural sleep in 64 male participants, aged 2-5 years (n=45 ASD, mean age 3.5 years; n=19 TYP, mean age 3.6 years). Participants were screened for medication use and excluded for any psychotropic medications. The left and right amygdala were manually traced according to an anatomically reliable protocol developed by our laboratory, and the resulting ROIs were used as seed regions for the functional connectivity analysis. Resting-state scans were pre-processed (time shifted, motion corrected, spatially smoothed, band-pass filtered) and aligned to the structural image in native individual space. The mean time-series of the left and right amygdala ROIs were extracted from each individual and correlated with all other voxels in the brain. Group comparisons were conducted in standard MNI space and significant clusters of group difference were corrected for multiple comparisons at p < .05.
Both diagnostic groups showed functional connectivity between the amygdala and several brain regions that are consistent with older healthy populations, including the striatum, inferior temporal cortex, visual cortex, and medial prefrontal cortex.
However, direct group comparison revealed that the ASD group had reduced connectivity between the amygdala and multiple brain regions, with the greatest reductions in connectivity between the amygdala and anterior striatum and between the amygdala and visual cortex.
These findings suggest that the anatomical abnormalities found in the amygdala of individuals with ASD may be associated with altered functional connectivity of the amygdala in early childhood, particularly in brain regions that may underlie some of the sensory and behavioral features of ASD.
Additional analyses will be conducted to examine the functional connectivity between the amygdala and other brain regions with known anatomical connectivity. We will also evaluate amygdala functional connectivity in previously identified phenotypic subgroups of ASD based on amygdala growth trajectories. Finally, we will evaluate whether functional connectivity between the amygdala and specific cortical regions is associated with behavioral symptoms of ASD.
Further Readings of Interest
Myeloid dendritic cells frequencies are increased in children with autism spectrum disorder and associated with amygdala volume and repetitive behaviors.
Department of Medical Microbiology and Immunology, University of California, Davis, USA
The pathophysiology of Autism Spectrum Disorder (ASD) is not yet known; however, studies suggest that dysfunction of the immune system affects many children with ASD.
Increasing evidence points to dysfunction of the innate immune system including activation of microglia and perivascular macrophages, increases in inflammatory cytokines/chemokines in brain tissue and CSF, and abnormal peripheral monocyte cell function.
Dendritic cells are major players in innate immunity and have important functions in the phagocytosis of pathogens or debris, antigen presentation, activation of naïve T cells, induction of tolerance and cytokine/chemokine production.
In this study, we assessed circulating frequencies of myeloid dendritic cells (defined as Lin-1(-)BDCA1(+)CD11c(+) and Lin-1(-)BDCA3(+)CD123(-)) and plasmacytoid dendritic cells (Lin-1(-)BDCA2(+)CD123(+) or Lin-1(-)BDCA4(+) CD11c(-)) in 57 children with ASD, and 29 typically developing controls of the same age, all of who were enrolled as part of the Autism Phenome Project (APP).
The frequencies of dendritic cells and associations with behavioral assessment and MRI measurements of amygdala volume were compared in the same participants. The frequencies of myeloid dendritic cells were significantly increased in children with ASD compared to typically developing controls (p < 0.03). Elevated frequencies of myeloid dendritic cells were positively associated with abnormal right and left amygdala enlargement, severity of gastrointestinal symptoms and increased repetitive behaviors. The frequencies of plasmacytoid dendritic cells were also associated with amygdala volumes as well as developmental regression in children with ASD.
Dendritic cells play key roles in modulating immune responses and differences in frequencies or functions of these cells may result in immune dysfunction in children with ASD. These data further implicate innate immune cells in the complex pathophysiology of ASD.