Four Subtypes of Autism Spectrum Disorder Are Distinguished, Helping to Explain Individual Differences in Symptoms

Four Subtypes of Autism Spectrum Disorder Are Distinguished, Helping to Explain Individual Differences in Symptoms

Posted: May 4, 2023
Four Subtypes of Autism Spectrum Disorder Are Distinguished, Helping to Explain Individual Differences in Symptoms

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Researchers used neuroimaging and genetics data to discover that a cohort of 299 individuals with autism spectrum disorder (ASD) “clustered” in four subgroups, each with distinct patterns of atypical functional connectivity in ASD-related neural networks. The findings promise to advance the search for new treatments.


Researchers led by a BBRF grantee have used a large set of neuroimaging data to identify distinct sets of alterations in functional connectivity that may help explain differences among individuals with autism spectrum disorder (ASD). The finding could have implications for the development of new treatments.

The autism “spectrum” refers to wide variations in the types of symptoms that affect those diagnosed, as well as the degree to which symptoms impact individual function. Social communication and interaction skills are usually affected, although to varying degrees. As noted by the U.S. Centers for Disease Control, people with ASD also may have restricted or repetitive behaviors or interests. In addition, some patients may have delays in acquiring language skills, movement skills, or cognitive and learning skills. Some may exhibit hyperactive, impulsive, or inattentive behavior; or have unusual eating or sleeping habits, gastrointestinal issues, or issues with mood, anxiety or fear.

“Our limited understanding of the neural mechanisms underlying ASD variability has impeded the development of therapeutic interventions,” notes a research team led by 2013 BBRF Young Investigator Conor Liston, M.D., Ph.D., of Weill Cornell Medicine, reporting in Nature Neuroscience. Dr. Liston’s team sought to discover consistently identifiable subtypes of ASD as a way of generating testable theories “about how different biochemical genetic, and cellular processes may shape” the wide range of ASD’s clinical manifestations.

There was good reason to use neuroimaging data to try to discern ASD subgroups. Past functional magnetic resonance imaging (fMRI) studies have found that impaired social cognition and language processing in ASD are associated with atypical activity in the thalamus and visual areas of the brain, as well as in the salience network, composed of several brain regions that work together to determine which stimuli should command attention. Repetitive and ritualistic behaviors also have been linked in imaging studies with specific brain circuitry.

Dr. Liston and colleagues sought to discover how atypical connectivity contributes to individual differences in ASD symptoms and behaviors. They drew upon two large-scale fMRI datasets curated by the Autism Brain Imaging Data Exchange. The data analyzed was derived from 299 individuals with ASD and 907 neurotypical controls. The analysis enabled the team to relate functional connectivity patterns to three “dimensions” of ASD symptoms—those affecting verbal ability, social affect, and repetitive behaviors and restricted interests.

When study subjects with ASD were assessed according to this schema, the team found that they “clustered” in four subgroups, each with distinct patterns of functional connectivity in ASD-related neural networks. The same four subgroups emerged when the team applied the same functional-connectivity analysis to an independent sample of ASD patients.

The next step was to consider the connectivity data for the four ASD subgroups in the light of data on gene expression patterns in the brain. Of the approximately 21,000 human genes, many, but not all, are activated at different moments in brain cells in different regions, and activation patterns vary depending on what tasks the brain is performing. The team hypothesized that distinct genetic pathways may be important in subsets of ASD patients, and may confer risk for specific symptoms by impacting functional connectivity in ASD-related brain networks.

That is what the analysis revealed. Each of the four ASD subtypes was associated with distinct gene expression patterns and the biological processes they affect. This led to a number of interesting observations. Individuals in two of the subgroups, for example, were alike in being “highly impaired” by core ASD symptoms, the team noted, but differed notably in verbal ability, and had dissimilar patterns of atypical connectivity and gene expression. The other two subgroups “had average verbal ability” but differed in the degree to which they were impaired by two of the core ASD symptoms, social affect and repetitive and restricted behaviors.

The four ASD subgroups identified by Dr. Liston and colleagues provide insight into the biological mechanisms “that may regulate changes brain function that lead to ASD behaviors,” the team said. The analysis also makes it possible, they said, to form “multiple testable hypotheses that could be explored in future studies.”

In ASD subgroup 4 for example, which is characterized by strong repetitive and restrictive behaviors and notably diminished “social affect,” i.e., signals to others about how one is feeling, atypical connectivity was linked with decreased expression of a gene called HTR1A. That gene encodes a cellular receptor for the neurotransmitter serotonin that has been associated in past research with severe repetitive behaviors and restricted interests. Expression of HTR1A is known to be reduced in people with ASD, which in turn is associated with stress and anxiety. Problems with serotonin signaling have also been implicated in altered reward processing in the brain, as well as impairments of the sensorimotor system during development—which contribute to repetitive and restrictive behaviors. These linkages suggest that drugs targeting the serotonin system could potentially be beneficial for reducing these behaviors in some people with ASD, the researchers note.

More broadly, the researchers say their results can generate testable ideas that can be explored in animal models of ASD and in future clinical studies. “They suggest distinct alterations in brain function that could be targeted using circuit-based neuromodulation” such as TMS or other brain-stimulation technologies. They also “predict distinct biological pathways that could help inform studies of drug targets specific to each ASD subtype,” the team said.