A11 ASD / Autism Spectrum Disorder (atypical connectivity)

Topic

The cortical network organizes its activity through a characteristic pattern of connectivity among its various regions. In autism spectrum disorder, this cortical network connectivity pattern is altered in a characteristic way: connectivity between nearby cortical regions increases—a phenomenon known as short-range hyperconnectivity—while connectivity between distant cortical regions decreases—known as long-range hypoconnectivity. Both changes are quantified as extensions of the same connectivity matrix previously used to describe cortical network connections in another model.

The ratio between this short-range hyperconnectivity and long-range hypoconnectivity defines a segregation-integration index for the cortical network: the greater the short-range hyperconnectivity relative to the long-range hypoconnectivity, the more segregated and less integrated the cortical network becomes as a whole.

Within the cortical network, at the cellular level, this altered connectivity pattern is driven by two developmental mechanisms: first, a relative excess of excitation over inhibition emerges—the same type of imbalance previously described for other cortical circuits; second, synaptic pruning—which normally eliminates excess connections during development—occurs at an atypically reduced rate, following the same pruning dynamics previously used to model cortical network development. The more reduced this developmental synaptic pruning is, the higher the synaptic density remaining in the cortical network by adulthood.

This higher-than-expected synaptic density in adulthood is precisely what underlies, at the cellular level, the aforementioned short-range hyperconnectivity of the cortical network: the more synapses the cortical network retains due to a lack of pruning during development, the stronger the connectivity between nearby cortical regions becomes. Clinically, this alteration in the cortical network's connectivity pattern is associated with sensory hyper-reactivity—that is, an increased gain in the cortical network's response to stimuli—and with greater intra-individual variability in the cortical network's neural response when the same stimulus is presented repeatedly. Taken together, it is the combination of atypical cortical network connectivity and the elevated synaptic density resulting from reduced developmental pruning that explains both the connectivity profile and the clinical manifestations of autism spectrum disorder.

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