Combining genetics and brain imaging to understand ADHD
Attention deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children. It is characterized by difficulty in paying attention and focusing, impulsivity, and an inability to sit still. ADHD begins when children are school aged and can continue into early adulthood.
“ADHD affects young people in the formative years of their life. They often miss out on school or work due to their symptoms,” says Dr. Lena Palaniyappan, Lawson Associate Scientist, Endowed Tanna Schulich Chair of Neurosciences & Mental Health at Western University's Schulich School of Medicine & Dentistry, and Scientist at Robarts Research Institute. “This makes early diagnosis and treatment critically important.”
Accurately diagnosing ADHD can be difficult. There are no objective biomarkers and misdiagnosis is common.
“Many people suffering from ADHD go undiagnosed and do not get the proper treatment. Meanwhile, those who don’t have ADHD can be misdiagnosed and prescribed stimulants,” explains Dr. Palaniyappan, who is also Medical Director at the Prevention & Early Intervention Program for Psychoses (PEPP) at London Health Sciences Centre (LHSC).
Drugs called stimulants are the most common treatment for ADHD. They work by targeting a chemical in the brain called dopamine, which is responsible for sending signals between neurons. Dopamine is important to human decision-making, feelings of pleasure and motor functioning.
“While stimulants are a highly effective treatment for persons with ADHD, they can be harmful for some and even cause psychosis. Accurate diagnosis is therefore important for treatment decisions.”
In a new study, Dr. Palaniyappan and collaborators at the University of Nottingham discovered that genetics may be influencing detailed folding in the brain of individuals with ADHD. The research suggests that genetics and brain imaging may hold promise for accurately diagnosing a specific group of ADHD patients who will respond well to stimulants.
Above: Dr. Lena Palaniyappan
The study included 49 children, 25 who had been diagnosed with ADHD and 24 in a control group. All participants were from the United Kingdom and between the ages of 9 and 15 years old. The researchers obtained genetic samples and structural brain scans using magnetic resonance imaging (MRI).
The researchers tested for the presence of a genetic abnormality of a gene called dopamine DRD4 7R allele (DRD4-7r). This genetic abnormality is a known risk factor for ADHD and other psychiatric disorders. It affects the gene that controls dopamine and is present in 20 per cent of the general population.
“While we suspect there are many genes that can play a role in ADHD, this gene has been reliably associated with the mechanism of this disorder. In particular, we think patients with this genetic risk factor will respond best to stimulants since the drugs affect dopamine,” states Dr. Palaniyappan. “But the presence of this genetic abnormality alone is not enough to diagnose someone with ADHD. There are many people who will have the abnormality but no ADHD.”
The team also looked at the brain structure of participants through MRI scans. They wanted to see whether participants with ADHD, particularly those who also carry the genetic abnormality, had any structural changes in the frontal area of the brain called the prefrontal cortex. The prefrontal cortex is associated with speech and helps to control impulsivity, a common symptom in ADHD.
The researchers found that participants with ADHD who carry the genetic risk factor were much more likely to have abnormal brain folding, suggesting that the genetic risk factor can lead to abnormal development in the brain.
“The folds in our brain are a bit like fingerprints. While we all have lines that are similar, the actual complexity of minor folds is unique to each person. They develop by the age of two and do not change much over time,” explains Dr. Palaniyappan. “Our findings therefore highlight that ADHD is a developmental disorder influenced by genetics from an early age.”
The findings suggest that a combination of the genetic risk factor and abnormal brain folding is indicative of ADHD. The combined testing might potentially identify those with ADHD who will likely respond to stimulants, though this is yet to be tested.
Dr. Palaniyappan notes the importance of identifying patients who will respond to stimulants to reduce unwarranted prescriptions. For patients who don’t have ADHD, taking stimulants can be harmful. Certain types of prescribed stimulants can increase the risk of psychosis. ADHD and psychosis also share similar symptoms, and some patients with ADHD may be at risk for psychosis later in life.
“It’s important that patients with suspected ADHD are assessed for risk of psychosis before beginning stimulant therapy. If the risk is high, clinicians should consider a different second-line therapy.”
Dr. Palaniyappan hopes to expand this research in future by studying the combined genetic testing and brain imaging in a larger group of participants from London, Ontario and surrounding areas.
The study, “Reduced Prefrontal Gyrification in Carriers of the Dopamine D4 Receptor 7-Repeat Allele with Attention Deficit/Hyperactivity Disorder: A Preliminary Report,” is published in Frontiers in Psychiatry.