The pathology of ADHD is not clear. Psychostimulants (which facilitate dopamine release) and noradrenergic tricyclics used to treat this condition have led to speculation that certain brain areas related to attention are deficient in neural transmission. PET scan imaging indicates that methylphenidate acts to increase dopamine. The neurotransmitters dopamine and norepinephrine have been associated with ADHD.

The underlying brain regions predominantly thought to be involved are frontal and prefrontal; the parietal lobe and cerebellum may also be involved. In one functional MRI study, children with ADHD who performed response-inhibition tasks were reported to have differing activation in frontostriatal areas compared with healthy controls. A 2010 study again indicated the presence of frontostriatal malfunctioning in the etiology of ADHD.  Although ADHD has been associated with structural and functional alterations in the frontostriatal circuitry, recent studies have further demonstrated changes just outside that region and more specifically in the cerebellum and the parietal lobes.  Another study using proton magnetic spectroscopy demonstrated right prefrontal neurochemical changes in adolescents with ADHD. 

Work by Sobel et al has demonstrated deformations in the basal ganglia nuclei (caudate, putamen, globus pallidus) in children with ADHD. The more prominent the deformations, the greater the severity of symptoms. Furthermore, Sobel et al have shown that stimulants may normalize the deformations. 

Adults with ADHD also have been reported to have deficits in anterior cingulate activation while performing similar tasks.

In a longitudinal analysis, Shaw et al used 389 neuroanatomic MRI images to compare 193 typically developing children with varying levels of symptoms of hyperactivity and impulsivity (measured with the Conners’ Parent Rating Scale) with 197 children with ADHD (using 337 imaging scans).  Children with higher levels of hyperactivity/impulsivity had a slower rate of cortical thinning. This was most notable in prefrontal cortical regions, bilaterally in the middle frontal/premotor gyri, extending down the medial prefrontal wall to the anterior cingulate. It was also noted in the orbitofrontal cortex and the right inferior frontal gyrus. Slower cortical thinning during adolescence is characteristic of ADHD and provides neurobiological evidence for dimensionality.

A PET scan study by Volkow et al revealed that in adults with ADHD, depressed dopamine activity in caudate and preliminary evidence in limbic regions was associated with inattention and enhanced reinforcing responses to intravenous methylphenidate. This concludes that dopamine dysfunction may be involved with symptoms of inattention but may also contribute to substance abuse comorbidity. 

Individuals with ADHD have inhibition impairment, which is difficulty stopping their responses. 

According to a study of young children, there is evidence of early brain structural chages in pre-schoolers with ADHD. Researchers used high resolution anatomical (MPRAGE) images and cognitive and behavioral measures in a cohort of 90 medication-naïve preschoolers, aged 4–5 years (52 with ADHD, 38 controls; 64.4% boys). Results show reductions in bilateral frontal, parietal, and temporal lobe gray matter volumes in children with ADHD relative to typically developing children. The largest effect sizes were noted for right frontal and left temporal lobe volumes. Examination of frontal lobe sub-regions revelated that the largest between group effect sizes were evident in the left orbitofrontal cortex, left primary motor cortex (M1), and left supplementary motor complex (SMC). ADHD-related reductions in specific sub-regions (left prefrontal, left premotor, left frontal eye field, left M1, and right SMC) were significantly correlated with symptom severity, such that higher ratings of hyperactive/impulsive symptoms were associated with reduced cortical volumes. 

Narad et al. explored the relationship between traumatic brain injury (TBI) in children and development of secondary attention-deficit/hyperactivity disorder (SADHD). ^[11] They looked at concurrent cohort/prospective studies of children aged 3 to 7 years who were hospitalized overnight for TBI or orthopedic injury (OI; used as control group). A total of 187 children and adolescents were included in the analyses: 81 in the TBI group and 106 in the OI group. According to the results, early childhood TBI was associated with increased risk for SADHD. This finding supports the need for post-injury monitoring for attention problems. Consideration of factors that may interact with injury characteristics, such as family functioning, will be important in planning clinical follow-up of children with TBI.

Researchers in Denmark conducted a population-based cohort study to determine the association of prenatal exposure to antiepileptic drugs and risk of ADHD in offspring. Of more than 900,000 children, 580 were identified as having been exposed to valproate during pregnancy. Of them, 49 (8.4%) had ADHD. Among the children not exposed to the drug, approximately 30,000 (3.2%) had the disorder. This suggests that maternal use of valproate, but not other AEDs, during pregnancy is associated with an increased risk of ADHD in the offspring.

There has been concern about the association of maternal smoking during pregnancy and the development of ADHD in offspring. In a Finnish population-based study, researchers analyzed prenatal cotinine levels and offspring ADHD. Cotinine is a product formed after the chemical nicotine enters the body. Nicotine is a chemical found in tobacco products, including cigarettes and chewing tobacco. Measuring cotinine in people’s blood is the most reliable way to determine exposure to nicotine for both smokers and nonsmokers exposed to environmental tobacco smoke (ETS). Measuring cotinine is preferred to measuring nicotine because cotinine remains in the body longer. The study measured maternal cotinine levels using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy. Results showed a dose-dependent relationship between nicotine exposure during pregnancy and offspring ADHD. ^]

Evidence of a neurobiologic contribution to the cause of ADHD continues to grow. A 12-year historical prospective nationwide cohort study examined whether adherence to methylphenidate (MPH) during early childhood predicts the initiation of antidepressants during adolescence. Researchers looked at children enrolled in an integrated care system who were first prescribed MPH between the ages of 6 and 8 years (N = 6830). They found that patients with higher adherence to MPH had a 50% higher risk (95% CI 1.16-1.93) of receiving antidepressants during adolescence when controlling for other comorbid psychiatric conditions and parental use of antidepressants.