Two mechanisms on the autism spectrum: A new study published in the scientific journal Nature Neuroscience found that among some people with autism, there are at least two different biological patterns of brain activity. In one of them, different regions of the brain communicate with each other with higher intensity than usual, and in the other, communication between them is weaker. The discovery may explain why autism manifests so differently from person to person, and lay a foundation in the future for developing treatments tailored to the biological mechanism of each patient.
The study was conducted by an international team led by researchers from the Italian Institute of Technology in the city of Rovereto and the Child Mind Institute in New York, in collaboration with the University of Trento and other research centers. The researchers examined brain scans of 940 children and young people with autism and compared them to scans of 1,036 people without autism.
The examination was based on functional magnetic resonance imaging, a brain scan that measures changes in blood flow and thus makes it possible to assess which areas work together. The researchers focused on functional connectivity, meaning the degree of coordination between the activity of different brain regions during rest.
The central challenge in autism research is the immense variance among those diagnosed. Two children who received the same diagnosis may present completely different communication, language, learning, movement, and sensory processing abilities. The intensity of the need for support also varies greatly, from children who require little assistance to people who need extensive accompaniment throughout their lives.
To decipher the biological meaning of the scan patterns, the researchers used 20 different mouse models that underwent genetic changes related to autism. Since in these models it is possible to know which genes and cellular pathways were altered, they served as a sort of key to deciphering the findings seen in the human scans.
<br>Two patterns, two groups
Analysis of the mouse scans revealed two main patterns. In one group, hyperconnectivity was observed, a state in which brain networks communicated with each other more than usual. In the second group, hypoconnectivity was found, where the coordination between brain regions was lower.
The researchers found that the patterns were not just a statistical division. The hypoconnectivity was linked mainly to changes in pathways related to synapses, the connection points through which nerve cells transmit signals to one another. The hyperconnectivity was linked to gene expression pathways and to mechanisms related to the immune system.
After the reference patterns were built in mice, the researchers looked for similar signatures in human brain scans. Among the children and young people with autism, two parallel groups also appeared: A group with reduced connectivity and a group with increased connectivity. The patterns were found again in independent databases collected at dozens of research centers, a finding that strengthened the assumption that this is not an accidental result of a single research site.
The two subtypes together represented about 24% of the participants with autism in the main study group. About 7% were classified in the hypoconnectivity group and about 17% in the hyperconnectivity group. This means that the study did not divide all autism cases into just two types. In about three–quarters of the participants, no clear fit was found to one of the two patterns, and the researchers estimate that additional biological types exist that have not yet been identified.
Further analysis of gene expression in the brain supported the results. Regions characterized by hypoconnectivity presented a relative abundance of genes related to synaptic function, whereas regions with hyperconnectivity were linked more to genes involved in immune activity. The similarity between the findings in mice and humans gave the researchers a possible clue to the molecular mechanisms underlying the scan patterns.
Moderate differences were also found in behavioral assessments. Participants in the hyperconnectivity group tended to score slightly higher on standard measures for assessing autism characteristics. However, the overlap between the groups was wide, and it was not possible to identify the subtype based on behavior alone.
<br>The implications
According to the researchers, the future implication may be a transition from a broad diagnosis based mainly on behavior to an approach that also integrates biological measures. If it turns out that synaptic mechanisms and immune mechanisms are involved in different groups, it is possible that a treatment that helps one group will not affect the other. Biological division may also improve drug trials, where a positive response from a small group might disappear within the average of a diverse population.
The road to medical application is still long. Functional brain scanning is sensitive to movements, the subject's age, state of alertness, and differences between scanning devices and research centers. It is also not currently used for routine diagnosis of autism, and the study did not show that it is possible to determine through a single scan which group a specific child belongs to.
The link to immune system pathways also does not prove that an immune disease causes autism or that a treatment that suppresses the immune system will be beneficial. The term describes a statistical relationship between connectivity patterns and the expression of certain genes and biological pathways, rather than a proven therapeutic target. Providing treatment based on the findings at this stage would be premature and unfounded.
Autism is a neurodevelopmental condition that begins in childhood and manifests in various combinations of difficulties in communication and social interaction, repetitive patterns of behavior and interest, and sensory sensitivities. Diagnosis is based on child development, clinical observation, conversations with the parents, and assessments by professional teams. There is currently no blood test, single genetic test, or brain scan that can diagnose the condition on its own.
Existing treatments are not intended to change the person's identity or personality, but rather to assist in areas where they struggle. They include communication and developmental interventions, occupational therapy, speech–language pathology, educational accommodations, and treatment for accompanying symptoms such as anxiety, ADHD, sleep disorders, or behavior that impairs functioning.
The researchers plan to examine whether the subtypes can also be identified using more accessible methods, to track their stability throughout childhood, and to check whether they predict response to specific interventions. Only future studies will be able to determine whether the findings will turn from a research tool into a medical measure that enables more precise treatment selection.