Scientists Identify Two Distinct Biological Subtypes of Autism Based on Brain Connectivity

New research suggests that autism may include at least two distinct biological subtypes, each characterized by a different pattern of communication across the brain. One subtype shows unusually strong connections between brain regions, while the other is marked by weaker connectivity. The findings could help pave the way for more personalized approaches to autism diagnosis and treatment.

The study, published in Nature Neuroscience, was led by researchers from the Istituto Italiano di Tecnologia in Italy and the Child Mind Institute in New York, in collaboration with the University of Trento and several international research centers. Their goal was to connect patterns seen in brain imaging with the biological mechanisms underlying autism.

How the Brain Connectivity Study Worked

The researchers analyzed functional brain connectivity in 20 different mouse models associated with autism. They combined brain imaging with genetic and biochemical analyses to investigate how molecular changes influence communication between different brain regions. Using functional MRI (fMRI), they measured how brain areas interact while at rest.

The team then compared these findings with brain scans from 940 children and young adults diagnosed with autism and more than 1,000 neurotypical participants. The human data came from the Autism Brain Imaging Data Exchange and several other large neuroimaging initiatives, allowing researchers to determine whether the connectivity patterns observed in mice also appeared in people.

Their analysis identified two consistent subtypes among autistic participants. One subtype displayed reduced communication between brain regions, known as hypoconnectivity, while the other showed increased communication, or hyperconnectivity, across several major brain networks.

Distinct Biological Signatures Emerge

In the mouse models, hypoconnectivity was associated with disruptions in synaptic pathways that regulate communication between neurons. Hyperconnectivity, on the other hand, was linked to immune-related biological processes within the brain. These patterns appeared consistently across multiple mouse models, suggesting they reflect fundamental biological mechanisms.

Researchers then used these connectivity and molecular signatures as reference patterns when analyzing the human brain scans. They found that subsets of autistic participants closely matched either the hypoconnected or hyperconnected profiles identified in mice. Together, these two subgroups accounted for approximately 25% of the autism sample.

Gene expression analyses further supported these findings. Brain regions showing hypoconnectivity were enriched for genes involved in synaptic function, whereas hyperconnected regions were enriched for immune-related genes. These human findings closely mirrored the biological mechanisms observed in the animal models.

Implications for Diagnosis and Treatment

The two biological subtypes differed not only in brain connectivity but also in broader patterns of brain organization. Individuals within the hyperconnectivity group tended to score slightly higher on standard measures of autism severity, although both groups remained within the current autism spectrum diagnosis.

The researchers say these findings demonstrate the limitations of relying solely on behavioral assessments when diagnosing autism. Brain-based biomarkers may reveal important biological differences that cannot be distinguished through symptoms alone. In the future, such information could help guide more personalized treatments and improve the design of clinical trials.

The authors emphasize that these two subtypes likely represent only part of autism's biological diversity. As larger imaging databases become available and analytical techniques continue to improve, additional biological patterns may emerge. They argue that combining brain imaging, genetics, and behavioral assessment will be essential for developing precision medicine approaches to autism.

The study was supported by the Simons Foundation Autism Research Initiative, the European Research Council, the Brain and Behavior Research Foundation, Fondazione Telethon, and the U.S. National Institute of Mental Health. The findings highlight the growing value of combining animal research with human brain imaging to better understand the biological mechanisms underlying autism.