Summary: A new study has broken through decades of clinical ambiguity by proving that autism can be split into at least two distinct biological subtypes based on brain connectivity. The research represents the first systematic effort to decode human functional magnetic resonance imaging (fMRI) data by mapping it directly against the molecular landscapes of animal models.
By evaluating over 1,900 human brain scans alongside 20 distinct mouse models, investigators successfully isolated a “hypoconnectivity” subtype tied to altered synaptic pathways and a “hyperconnectivity” subtype driven by immune-related systems.
Key Facts
- Dismantling Spectrum Variability: Autism spectrum disorder has long been characterized by immense behavioral and clinical variability, making generalized treatments highly ineffective. This study establishes a foundation for precision medicine by proving that these superficial differences are driven by fundamentally distinct, underlying biological mechanisms.
- The fMRI Rosetta Stone: Co-led by Dr. Alessandro Gozzi (IIT) and Dr. Adriana Di Martino (Child Mind Institute), the research team used genetic and biochemical analyses of mouse models as a biological “Rosetta Stone.” They mapped how specific molecular flaws alter cellular functions, establishing reference patterns that allowed them to successfully isolate matching mechanistic pathways in human brains.
- The Hypoconnectivity Synaptic Subtype: The first reproducible subtype identified is characterized by a widespread reduction in communication between brain regions (hypoconnectivity). Gene expression analyses confirmed that the human brain areas displaying this dampening effect are heavily enriched for genes regulating synaptic pathways and cellular connections.
- The Hyperconnectivity Immune Subtype: The second reproducible subtype exhibits the exact opposite architecture, presenting an over-communication or flooding of signals between brain regions (hyperconnectivity). This subtype is heavily associated with immune-related biological systems and scored moderately higher on standardized measures of autism severity.
- Massive Scale Validation: To verify their findings, investigators cross-analyzed fMRI data from 20 mouse models with brain scans of 940 autistic individuals and over 1,000 neurotypical controls sourced from the global Autism Brain Imaging Data Exchange (ABIDE). Together, these two profiles accounted for roughly 25% of the individuals examined, maintaining perfect biological reproducibility across dozens of independent international research sites.
- Beyond Behavioral Assessments: Standardized behavioral evaluations are unable to capture the deep neurological architecture of the spectrum. By uncovering clear brain-based biomarkers, this international collaboration creates a diagnostic framework that allows clinicians to look past external symptoms and target the exact cellular or immune environments of the patient.
Source: Child Mind Institute
An international research team led by Istituto Italiano di Tecnologia (IIT Italian Institute of Technology) in Rovereto (Trento, Italy) and the Child Mind Institute in New York (USA), and in collaboration with researchers from the University of Trento, Italy, has shown that it is possible to identify at least two distinct subtypes of autism, defined by their patterns of brain connectivity.
In the “hyperconnectivity” subtype, brain areas communicate more than usual; in the “hypoconnectivity” subtype, communication between brain areas is reduced. The study aims to develop tools for precise, personalized autism care and support.
The research paper was published in the international journal Nature Neuroscience.
The research study was coordinated by Alessandro Gozzi, PhD, director of the Center for Neuroscience and Cognitive Systems (CNCS) at the IIT and Adriana Di Martino, MD, founding director of the Autism Center at the Child Mind Institute, and it represents the first systematic effort to decode human brain imaging patterns (via fMRI) by tracing them back to their molecular underpinnings in mouse models. By linking patterns of connectivity to specific biological pathways, the findings offer a foundation for precision medicine approaches.
Therefore, the researchers analyzed functional connectivity across 20 mouse models and brain scans from 940 children and young adults with autism and over 1,000 neurotypical individuals. The findings revealed two reproducible autism subtypes: one characterized by reduced brain connectivity (hypoconnectivity) linked to synaptic pathways, the other by increased connectivity (hyperconnectivity) associated with immune-related systems. Together, these subtypes accounted for approximately 25% of individuals with autism examined in the study.
“For decades, we’ve observed tremendous variability in how autism manifests, but we lacked direct evidence that these differences reflected distinct underlying biology,” said Dr. Alessandro Gozzi, at Italian Institute of Technology.
“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.”
The team combined brain imaging with genetic and biochemical analyses in mouse models, linking connectivity patterns to specific alterations in cellular function. This revealed how specific molecular pathways, including synaptic and immune-related mechanisms, manifest as distinct connectivity patterns observable with fMRI. The study established biological reference patterns from mice that guided subtype identification in human brain scans.
“The mouse models gave us a biological ‘Rosetta Stone,” said Dr. Adriana Di Martino at the Child Mind Institute. “We could see which biological pathways drive which connectivity signatures, then search for those same patterns in humans.”
The human data came from the Autism Brain Imaging Data Exchange (ABIDE) — a pioneering neuroimaging initiative co-founded by Dr. Di Martino that aggregates datasets from research laboratories worldwide — and the Child Mind Institute.
The analyses identified corresponding hypo- and hyperconnectivity subtypes in the human data. Gene expression analyses confirmed that human brain regions showing hypoconnectivity were enriched for synaptic genes, while hyperconnected regions showed enrichment for immune-related genes — mirroring the mechanisms identified in mouse models. Importantly, the subtypes were reproducible across independent datasets, validating their biological consistency.
“Finding the same subtypes reproducible across dozens of independent research sites was critical validation,” added Dr. Gozzi.
The two subtypes exhibited different functional brain architecture and showed modest differences on standardized autism assessments, with the hyperconnectivity subtype scoring moderately higher on autism severity measures.
“Brain-based biological markers reveal distinctions that current behavioral assessments don’t fully capture,” noted Dr. Di Martino.
The researchers emphasize that while the current findings capture two dominant patterns of brain connectivity in autism, the full diversity of the spectrum likely encompasses additional subtypes that larger datasets and refined analytical approaches may reveal.
Funding: The research was made possible by an international collaboration coordinated by the Italian Institute of Technology and the Child Mind Institute, with funding from the Simons Foundation Autism Research Initiative, the European Research Council through the #DISCONN and #BRAINAMICS projects, the Brain and Behavior Foundation, the Fondazione Telethon, and the US National Institute of Mental Health.
Key Questions Answered:
A: Because autism is not a single condition; it is a highly diverse umbrella masking completely different biological realities. For decades, medicine relied entirely on surface-level behavioral observations, treating everyone on the spectrum under a single framework. This breakthrough study proves that beneath the surface, patients have entirely different brain wiring profiles driven by completely unrelated biological systems, requiring personalized, precision care.
A: Mice served as the ultimate genetic blueprint. While an fMRI scan of a child’s brain can show lines of communication lighting up, it cannot reveal the microscopic genes causing that behavior. By studying 20 mouse models, scientists could precisely trace how specific genetic and immune changes alter brain tissue, creating a biological “Rosetta Stone” that allowed them to look at a human brain scan and instantly identify the exact molecular pathways at play.
A: They are absolute polar opposites in how the brain talks to itself. In the hypoconnectivity subtype, communication between brain areas is dialed down and restricted, a state driven by alterations in synaptic genes. In the hyperconnectivity subtype, brain regions over-communicate and flood the system, an architecture deeply linked to immune-related biological pathways that often correlates with moderately higher scores on autism severity assessments.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this autism research news
Author: Media Office
Source: Child Mind Institute
Contact: Media Office – Child Mind Institute
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“Autism subtypes identified using cross-species functional connectivity analyses” by Marco Pagani, Valerio Zerbi, Silvia Gini, Filomena Grazia Alvino, Abhishek Banerjee, Andrea Barberis, M. Albert Basson, Yuri Bozzi, Alberto Galbusera, Jacob Ellegood, Michela Fagiolini, Jason P. Lerch, Michela Matteoli, Caterina Montani, Davide Pozzi, Giovanni Provenzano, Maria Luisa Scattoni, Nicole Wenderoth, Ting Xu, Michael V. Lombardo, Michael P. Milham, Adriana Di Martino & Alessandro Gozzi. Nature Neuroscience
DOI:10.1038/s41593-026-02287-z
Abstract
Autism subtypes identified using cross-species functional connectivity analyses
It is often assumed that phenotypic heterogeneity in autism reflects underlying pathobiological variation. However, direct evidence supporting this link is lacking.
Leveraging cross-species functional neuroimaging, we show that brain dysconnectivity patterns in autism can be parsed into biologically dissociable subtypes. Specifically, we found that functional magnetic resonance imaging (fMRI) connectivity alterations in 20 distinct genetic mouse models of autism cluster into hypoconnectivity-dominant and hyperconnectivity-dominant subtypes.
These subtypes are linked to distinct biological pathways, with hypoconnectivity being associated with synaptic dysfunction and hyperconnectivity reflecting transcriptional and immune-related alterations.
Here we identified analogous hypoconnectivity and hyperconnectivity subtypes in a multicenter human fMRI dataset of n = 940 individuals with idiopathic autism and n = 1,036 neurotypical individuals.
The human autism subtypes are highly replicable, are associated with distinct functional network architectures and behavioral profiles and recapitulate the synaptic and immune-related pathways identified in the rodent dataset.
Our work provides a new empirical framework for targeted subtyping of the autism spectrum.
