New research implicates genetically altered dopamine transporters in ADHD.

New Insights into ADHD Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder with consequences that diminish academic and occupational achievement and increase the risk of depression, substance abuse, and accidental injury or even death. ADHD is characterized by restlessness and distractibility, believed to be caused by an impaired ability to inhibit certain impulses inside the brain. ADHD can, in most cases, be successfully treated with medications that increase the availability of an inhibiting neurotransmitter, called dopamine, inside the brain. Scientists have long suspected that having too little dopamine might produce ADHD. Recent evidence suggests that this is the case and points to defects in “dopamine transporters” in the brain as the main culprit: the transporters take up too much dopamine before it can be passed from one brain cell to another. A research team led by Donald Gilbert, a pediatric neurologist at Cincinnati Children's Hospital Medical Center, tested how the brain’s motor cortex inhibits movement in 16 children and adolescents with ADHD, both before and after they were given medications that increase the availability of dopamine inside the brain.5 The resultant increased amounts of dopamine inhibited motor cortex activity in all children tested, but the medicine had a much greater effect in children with a genetic variation called DAT1, which ordinarily causes too much dopamine transporter activity. The result is too little inhibitory dopamine. This research implicates genetically altered dopamine transporters in ADHD. In a related development, Katya Rubia of the Institute of Psychiatry at King's College in London and colleagues found similar deficiencies in brain regions responsible for motor inhibition and switching of behavior in a group of 19 boys with ADHD who had never taken any medication for the disorder.6 This is significant, the researchers point out, because previous research has been undertaken in children who had been taking ADHD medications, which might have confounded the results. Using functional magnetic resonance imaging, Rubia's team found abnormal brain activation in these "medication-naive" children and adolescents with ADHD during tasks that involved motor inhibition and task switching (which requires cognitive flexibility). The finding suggests that under activation in this patient group is unrelated to long-term stimulant exposure. Under activation was evident during both tasks in prefrontal brain regions, as well as in temporal and parietal regions, which in the past have not been implicated in ADHD. Brain thickness as an indicator of brain development has been studied in ADHD, just as it has been studied in autism. National Institute of Mental Health researchers led by Philip Shaw measured cortical thickness in a group of 166 children with ADHD.7 The researchers obtained magnetic resonance images approximately every two years in these children and compared them with scans of healthy children. An analysis of the images revealed that children with ADHD had a thinner cortex in parts of the brain that are important for the control of attention. Subsequent scans of these children revealed that those with worse clinical outcomes had a particularly thin cortex at the front of the brain, near a region that controls aspects of attention, such as inhibiting inappropriate behaviors. Moreover, the children with ADHD who had better clinical outcomes showed a distinctive pattern of cortical change in the right parietal cortex, which controls some of the most fundamental aspects of attention. Here, by late adolescence, the cortex reached the same thickness in these children as in healthy children. However, this "normalization" did not occur in the children with worse clinical outcomes. These results were unaffected by whether the children had been taking medication for ADHD. This work gives a very detailed picture of the cortex in children with ADHD and highlights brain changes that may reflect, or even drive, recovery from the disorder, the researchers suggest. As in autism, imaging studies are suggesting what is going wrong in brain functions in ADHD. These types of studies may be useful in both diagnosis and treatment.