Differences in the physical shape and wiring of the brain can directly contribute to the development of attention and social deficits. Recent genetic studies have mapped how the size of certain brain folds and the organization of brain wiring alter the risk of developing autism and attention-deficit hyperactivity disorder. The results of this study were published in the journal Progress in Neuropsychopharmacology & Biological Psychiatry.
Autism spectrum disorder and attention deficit hyperactivity disorder are developmental disorders that can persist throughout a person’s life. These influence how individuals process information, regulate their attention spans, and participate in social interactions. People dealing with these neurological differences often face increased emotional strain and negative health outcomes compared to other populations.
Medical experts have been using brain scans to study these populations for decades. These imaging tests frequently show that neurodivergent people have slightly different brain structures than neurotypical people. But simple observational brain scans cannot tell researchers which event happened first.
Differences in brain structure may cause this condition, or living with it may cause the physical brain to slowly form as the person grows. It is also entirely possible that a third, unrelated environmental factor causes both brain changes and behavioral symptoms.
To solve this timing puzzle, researchers rely on large genetic datasets. Researchers Yilu Zhao, Yamin Zhang, and Tao Li from China’s Zhejiang University designed a study to systematically test whether differences in brain structure actually influence the onset of these neurodevelopmental conditions.
The research team focused their investigation on two major physical components of the human brain. Gray matter is made up of small bodies of nerve cells where the actual processing of sensory information takes place. This tissue covers the outside of the brain with deep folds and ridges, maximizing the total processed surface area within the limited space of the human skull.
White matter lies beneath this outer processing shell. It consists of axons, long insulated fibers that extend between distant nerve cell bodies. These biological cables act like communication highways, allowing different specialized areas of gray matter to coordinate their electrical activity.
To understand how these organizations are associated with developmental disorders, the researchers used an approach called Mendelian randomization. When medical professionals want to know if a drug is effective, they conduct a randomized clinical trial and assign patients to either the active drug or a placebo. Mendelian randomization uses similar logic, but uses the natural genetic shuffle that occurs before birth.
Humans inherit natural variations in their genetic code from their parents. Some of these small genetic variations reliably determine the physical characteristics of the brain. By examining vast population databases, scientists are able to isolate the precise genetic markers that lead to slightly thicker brain folds and highly organized white matter fascicles.
Analysts can then see whether those exact same genetic blueprints are overrepresented in populations diagnosed with neurological diseases. If the genes that build a particular brain shape match the diagnosis perfectly, researchers can deduce the sequence of events. Genes determine the structure of the brain, and that structure serves as a biological precursor to behavioral symptoms.
Following this method, Zhao and colleagues collected the genetic profiles of tens of thousands of individuals. They cross-referenced genes known to alter the dimensions of gray and white matter with a separate database containing DNA from people diagnosed with autism or attention-deficit hyperactivity disorder. They discovered specific regions in the frontal lobe of the brain that directly structurally contribute to these symptoms.
The frontal lobe is a large area located behind the forehead that is deeply involved in decision-making, social behavior, and attention span. When it comes to attention-deficit hyperactivity disorder, the team found that increasing the surface area of the superior frontal gyrus increases the risk of developing the condition. The superior frontal gyrus is a piece of brain tissue near the top of the frontal lobe.
Previous imaging studies have linked the superior frontal gyrus to executive function and the ability to suppress impulsive responses. These are common cognitive challenges for people with Attention Deficit Hyperactivity Disorder. The finding that excessive growth of surface area in this specific region causes the disorder is in good agreement with behavioral observations and suggests that normal tissue maturation is altered.
Researchers have identified vastly different patterns of autism spectrum disorders. They took a closer look at the orbitofrontal gyrus, an area located just above the eyes. This neural region processes incoming sensory information and helps us interpret other people’s emotional states.
Genetic analysis shows that a larger surface area of the orbitofrontal gyrus inherently protects against autism risk. People with genetic markers for a more expanded orbitofrontal gyrus were less likely to be diagnosed with autism. The region’s larger treatment area appears to provide a buffer against the social and communication challenges associated with this condition.
The research team then moved on to investigating white matter connectivity within the brain. They analyzed tissue properties that explain the physical complexity and orientation of nerve fibers as they pass deep into the brain. Highly organized structural pathways are essential for efficient integration of thought and sensation over long distances.
In attention-deficit hyperactivity disorder, altered structural connectivity called the inferior fronto-occipital bundle has emerged as a contributing factor. This pathway is a bundle of fibers that connects the visual center in the back of the brain with the language processing center in the front. The data showed that the developmental organization of this visual-to-frontal relay directly influences risk for attention disorders.
Additional white matter tracts are thought to be involved in autism risk. Researchers have discovered that physical changes in a deep brain junction called the internal capsule contribute to the diagnosis of autism. Decreased structural integrity of certain pathways that carry visual sensory data to the cortex increased the likelihood that a child would be diagnosed with autism.
The scientists also ran the mathematical model in reverse to scan for reverse connections. Researchers wanted to know whether inheriting genetic markers for attention deficit hyperactivity disorder or autism ultimately causes physical changes in brain structure over time. This reverse progression result was not statistically significant. Rather than conditions driving architecture, it appears that physical brain shape drives behavioral conditions.
The physical structure of the brain is only one part of a broader puzzle. The way these physical structures actively interact with each other represents the brain’s functional network. Magnetic resonance imaging can capture this living activity by measuring small changes in blood oxygen levels as different tissues emit electrical signals.
The Zhejiang University team performed additional tests using live functional image data to see how physical shape translates into behavioral symptoms. They discovered that resting brain connections act as functional bridges. For example, expanding the surface area of the superior frontal gyrus changes how that frontal tissue communicates with areas that control body movement on a daily basis.
This altered real-time communication causes recognizable physical and behavioral symptoms of attention disorders. This is similar to how a city’s road network determines daily traffic congestion. The abnormally wide road structure permanently changes the propensity of vehicles to travel, and the altered traffic flow eventually causes visible congestion.
When the data was broken down by demographic details, the scientists noticed a clear trend. For attention-deficit hyperactivity disorder, the structural causes are very clear when it comes to childhood onset. However, when researchers looked at data from individuals diagnosed later in life, these specific anatomical causes were not statistically significant.
When the researchers analyzed the genetic information by gender, they found that the association between white matter and attention disorders was strong in boys, but not in girls. This physiological difference is consistent with global clinical observations, as men have historically been diagnosed with attention disorders at much higher rates than women. Conversely, structural shape factors associated with autism risk were universally present in both male and female genetic profiles.
Although the genetics approach provides strong evidence of causation, the study authors acknowledge that the data have some limitations. The large DNA database used in the analysis was collected primarily from individuals of European descent. This lack of genetic diversity means that the identified anatomical pathways may not be fully representative of the world’s population.
Future research efforts will need to incorporate genetic profiles from a wide range of ethnic backgrounds around the world to obtain robust results. Larger genetic tracing projects could also test for similar structural factors in other developmental variations, such as specific learning differences or communication delays.
The study, “Causal relationships among ADHD, ASD, and brain structures: A Mendelian randomized study,” was authored by Yilu Zhao, Yamin Zhang, and Tao Li.
