Attention-deficit hyperactivity disorder pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Charmaine Patel, M.D. [2], Haleigh Williams, B.S.

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Overview

ADHD appears to be highly heritable, although one-fifth of all cases are estimated to be caused by trauma or exposure to toxins. Evidence suggests that ADHD is a heterogeneous disorder, meaning that several causes could create very similar symptomology. Although there is evidence for dopamine abnormalities in ADHD, it is not clear whether abnormalities of the dopamine system are a molecular abnormality of ADHD or a secondary consequence of ADHD.

Pathophysiology

Pathogenesis

The exact pathogenesis of ADHD is not fully understood. It is believed that ADHD is caused by a complex interaction between genetic and environmental factors.

Genetics

• Common genetic variation accounts for around 75% of cases of ADHD. Loci on chromosomes 7, 11, 12, 15, 16, and 17 are associated with ADHD, likely indicating that ADHD does not follow the traditional model of an hereditary disease.

• Norepinephrine and dopamine play a critical role in modulating attention in ADHD patients. Norepinephrine seems to have more of an effect on executive function, whereas dopamine may be more important in maintaining attention. A variety of dopamine and serotonin receptors (e.g., dopamine 4 and 5, serotonin 1B) are associated with ADHD.

• Mutations in the PTCHD1 gene, which is active in the thalamus, are associated with attention deficit, hyperactivity, and learning disability. Lack of a functional copy of the gene in the thalamic reticular nucleus (TRN) results in attention deficit, hyperactivity, and disrupted sleep.

Dopamine Levels and Blood Circulation

• People with ADHD have reduced blood circulation and a significantly higher concentration of dopamine transporters in the striatum, a part of the brain that plays a role in executive function.

• It is likely not the dopamine transporter levels that indicate the presence of ADHD, but the brain's ability to produce dopamine itself. ADHD patients show lower levels of dopamine than healthy subjects across the board. Further, plasma homovanillic acid, an index of dopamine levels, is inversely related not only to childhood ADHD symptoms in adult psychiatric patients, but to "childhood learning problems" in healthy subjects as well.

Glucose Metabolism

• An early PET scan study found that global cerebral glucose metabolism was 8.1% lower in medication-naive adults who had been diagnosed as ADHD while children. The image on the left illustrates glucose metabolism in the brain of a "normal" adult while doing an assigned auditory attention task; the image on the right illustrates the areas of activity in the brain of an adult who had been diagnosed with ADHD as a child when given that same task. (These are not pictures of individual brains, which would contain substantial overlap, but rather images constructed to illustrate group-level differences.)
• Additionally, the regions with the greatest deficit of activity in the ADHD patients (relative to the controls) included the premotor cortex and the superior prefrontal cortex. A second study in adolescents failed to find statistically significant differences in global glucose metabolism between ADHD patients and controls, but did find statistically significant deficits in 6 specific regions of the brains of the ADHD patients (relative to the controls). Most notably, lower metabolic activity in one specific region of the left anterior frontal lobe was significantly inversely correlated with symptom severity. These findings strongly imply that lowered activity in specific regions of the brain, rather than a broad global deficit, is involved in ADHD symptoms. However, these readings are of subjects doing an assigned task. They could be found in ADHD diagnosed patients because they simply were not attending to the task. Hence the parts of the brain used by others doing the task would not show equal activity in the ADHD patients.

PET scans of glucose metabolism in the brains of a normal adult (left) compared to an adult diagnosed with ADHD (right). "This PET scan was taken from Zametkin's landmark 1990 study, which found lower glucose metabolism, in the brains of patients with ADHD who had never taken medication. Scans were taken while patients were engaging in tasks requiring focused attention. The greatest deficits were found in the premotor cortex and superior prefrontal cortex."

Associated Conditions

ADHD is associated with many of the same inherited genetic variations as clinical depression. Other conditions, such as learning disabilities, anxiety disorder, conduct disorder, depression, and substance abuse, are common in people with ADHD.