Brain Scans Reveal Two Distinct Biological Subtypes of Autism
核心洞察
Researchers at the Italian Institute of Technology (搜索) and Child Mind Institute (搜索) identified two distinct autism (搜索) subtypes through brain connectivity patterns, representing about 25% of individuals with autism studied.
One subtype showed reduced brain communication (hypoconnectivity) linked to synaptic pathways (搜索), while the other displayed increased connectivity (hyperconnectivity) associated with immune-related biological systems.
The findings were validated across 940 autistic individuals and multiple independent datasets, with mouse models providing biological confirmation of the underlying mechanisms.
A groundbreaking study published in Nature Neuroscience has identified two distinct biological subtypes of autism (搜索) through brain connectivity patterns, potentially paving the way for more personalized treatment approaches. The research, led by Alessandro Gozzi at the Italian Institute of Technology (搜索) and Adriana Di Martino at the Child Mind Institute (搜索), represents the first large-scale effort to systematically connect human brain imaging patterns with their underlying biological causes using mouse models.
Novel Approach Links Mouse Models to Human Brain Patterns
The research team examined functional brain connectivity in 20 different mouse models and analyzed brain scans from 940 children and young adults with autism (搜索), comparing results with scans from more than 1,000 neurotypical individuals. This cross-species approach enabled researchers to establish biological reference signatures in mice and then search for matching patterns in human brain scans.
"The mouse models gave us a biological 'Rosetta Stone,'" said Dr. Di Martino. "We could see which biological pathways drive which connectivity signatures, then search for those same patterns in humans."
Two Distinct Connectivity Patterns Emerge
The analysis revealed two consistent autism (搜索) subtypes that together represented approximately 25% of the individuals with autism included in the study. The first subtype, affecting about 7.9% of autistic participants, showed reduced communication between brain regions (hypoconnectivity) and was associated with synaptic pathways (搜索). The second subtype, found in about 17.2% of participants, displayed increased communication between brain regions (hyperconnectivity) and was linked to immune-related biological systems.
"For decades, we've observed tremendous variability in how autism (搜索) manifests, but we lacked direct evidence that these differences reflected distinct underlying biology," said Dr. Gozzi. "Our approach enabled us to isolate specific genetic and immune factors, then translate those signatures to human brain scans, showing that different connectivity patterns encode different mechanistic pathways underlying autism."
Biological Mechanisms Underlying Each Subtype
The underconnected subtype showed strong links to synaptic signaling, synaptic vesicles, and brain plasticity mechanisms. This group included mouse models such as Shank3 (搜索), En2, 22q11.2, and 16p11.2, all associated with synaptic dysfunction.
In contrast, the overconnected group was linked to immune system (搜索) pathways, involving cytokines (搜索), immune responses, and microglia (搜索) - the brain's immune cells. This subtype included models such as Fmr1 (搜索), Chd8 (搜索), Tsc2, and IL-6, pointing to immune-mediated mechanisms in autism (搜索) development.
Human Brain Imaging Validates Findings
The human imaging data, sourced from the Autism (搜索) Brain Imaging Data Exchange (ABIDE) and the Child Mind Institute (搜索), confirmed the same hyperconnectivity and hypoconnectivity patterns identified in mouse models. Additional gene expression analyses strengthened these findings, with brain regions associated with hypoconnectivity showing enrichment of synaptic genes, while hyperconnected regions were enriched for immune-related genes.
The reproducibility of these subtypes across multiple independent datasets provided critical validation. "Finding the same subtypes reproducible across dozens of independent research sites was critical validation," noted Dr. Gozzi.
Behavioral Differences Between Subtypes
The two subtypes also displayed differences in clinical presentation. Individuals in the hyperconnectivity group tended to score somewhat higher on measures of autism (搜索) severity, particularly in social affect domains including social communication and interaction. However, the groups showed no major differences in restricted and repetitive behaviors.
"Brain-based biological markers reveal distinctions that current behavioral assessments don't fully capture," observed Dr. Di Martino, highlighting the potential for more precise diagnostic and treatment approaches.
Implications for Future Autism Research
The researchers emphasize that these two connectivity patterns likely represent only part of autism (搜索)'s biological diversity, as approximately 75% of autistic participants did not fit clearly into either category. They anticipate that additional subtypes may emerge as larger datasets become available and analytical methods continue to improve.
The study's cross-species validation approach provides a foundation for future precision medicine strategies in autism (搜索), potentially enabling treatments targeted to specific biological mechanisms rather than treating autism as a single condition. The research was supported by the Simons Foundation (搜索) Autism Research Initiative, the European Research Council (搜索), the Brain and Behavior Foundation, Fondazione Telethon, and the US National Institute of Mental Health.