Pathophysiology

People with ADHD have problems with inattention, hyperactivity, and/or impulsivity. Children and adults with ADHD perform more poorly on tasks requiring cessation of motor activity, organization of information, planning, complex problem solving, and learning and recalling oral instructions.

Studies of neurochemistry and metabolism, brain imaging, epidemiological risk factors, and genetics, support the concept that ADHD is a polymorphic genetic disorder involving CNS neurotransmitter and receptor regulation. No single gene, neurotransmitter, altered pathway, or mechanism has been found to account for the observed patterns of dysfunction and co-morbidities.

The available evidence points towards involvement of multiple factors involving inheritance, amounts of neurotransmitters in specific brain areas, and deficits in specific neurocircuits. In addition to genetics, environmental and psychosocial factors also contribute to brain development, and the complexities of self-image, personality, character, and compensatory styles can influence individual manifestations of symptomatology [Faraone and Doyle, 2001].

An International Consensus Statement (ICS) on ADHD was issued in January 2002 [ICS, 2002] and signed by over 80 international researchers and clinicians. The ICS notes, "ADHD involves a serious deficiency in a set of psychological abilities and that these deficiencies pose serious harm to most individuals possessing the disorder. Current evidence indicates that deficiencies in behavioral inhibition and sustained attention are central to this disorder."

The ICS states, "The central psychological deficits in those with ADHD have now been linked through numerous studies using various scientific methods to several specific brain regions (the frontal lobe, its connections to the basal ganglia, and their relationship to the cerebellum). Most neurological studies find that as a group, those with ADHD have less brain electrical activity and show less reactivity to stimulation in one or more of these regions. Neuroimaging studies of groups of those with ADHD also demonstrate relatively smaller areas of brain matter and less metabolic activity of this brain matter than is the case in control groups used in these studies."

Neuroimaging Studies

Results of neuroimaging studies on large numbers of people with ADHD have yet to be presented and published. Neuroimaging studies are expensive to conduct and the results have not always been consistent. They are currently considered tools for basic brain research including studying the effects of drugs. Magnetic Resonance Imaging (MRI) studies have found slight decreases in total cerebral volume, smaller anterior regions in the corpus callosum, smaller areas of the right prefrontal cortex, caudate nucleus, globus pallidus region of the basal ganglia, cerebellar hemispheres, and vermis, particularly the posterior-inferior lobules.

Positron Emission Tomography (PET) scans show people with ADHD often have reduced perfusion to the bilateral frontal areas (adults more so than adolescents), the caudate nuclei, and the basal ganglia. Administration of stimulants may increase cerebral perfusion to these areas [Faraone et al, 2000; Giedd et al, 2001].

Genetics

ADHD has characteristics of a polygenic inheritance rather than being an autosomal dominant, recessive, or mixed disorder. The exact number of genes involved and their overall relative contributions are not known. The genetic basis of ADHD and its relationship to other disorders with genetic components are the subject of ongoing research studies. There is probably a combined effect from several different genes, each of which makes a small contribution [Faraone, 2002]. In families with a child with ADHD, there is about a 15-25% likelihood that a sibling also has ADHD. Approximately 15-40% of children with ADHD have a parent with ADHD.

Conclusions from studies of families, adopted children, and fraternal vs. identical twins, indicate that about 70-95% of the variance in symptoms of ADHD is genetic. In identical twins with ADHD, there is about a 70-80% concordance compared with a co-occurrence of 30-40% in fraternal twins. Several distinct neuropsychiatric disorders that run in families, probably genetically related to ADHD and with relatively high co-morbidities with ADHD, are indicative of some shared genes. More research needs to be done, however, to conclusively prove these shared gene associations. These neuropsychiatric disorders include depression, anxiety, tic disorders, learning disorders, substance abuse, and conduct disorders [Comings, 2001; Faraone and Doyle, 2001; Wilens et al 2002].

Evidence from molecular genetic studies and response to drugs that affect brain dopaminergic and noradrenergic activity, including changes in cerebral blood flow, suggests that there are multiple genes involved in ADHD which involve the neurotransmitters, receptors, and/or transporters for dopamine and norepinephrine. Some of the specific dopaminergic genes implicated by some researchers include, but are not limited to, the dopamine receptor genes DRD2 and DRD5, the dopamine transport gene DAT1, and defective alleles of the dopamine beta hydroxylase enzyme (DBH) responsible for conversion of dopamine to norepinephrine [Comings, 2001].

Some of the involved adrenergic genes include the receptors ADRA2A, ADRA2C, and the norepinephrine transporter (NET) [Comings, 2001]. Conflicting results have been seen in defective gene identification studies including the DRD4 dopamine receptor gene; it can bind both dopamine and norepinephrine. Researchers generally agree that serotonin, glycine, and GABA do not play a major role in ADHD. Researchers differ on the emphasis of the relative importance of dopaminergic vs. noradrenergic factors [Comings, 2001; Biederman and Spencer 1999; Faraone et al, 2002; Solanto, 2002].

Dopaminergic Activity

There are measurable clinical benefits from stimulants on inattentive, hyperactive, and impulsive behaviors. These results, seen in numerous short-term, placebo-controlled, double-blinded clinical studies for approval of stimulants to treat ADHD in children and adolescents, as well as other studies, have paved the way for a more scientific understanding of ADHD [Elia et al, 1999; Smucker and Hedayat, 2001; Swanson and Volkow, 2002].

The precise mechanisms of action of stimulants are still unknown. The paradoxical calming effect on hyperactive children was recognized in the 1930s [Reviewed by Spencer, 2002]. Pharmacokinetic and pharmacodynamic studies with some stimulants indicate that tachyphylaxis or acute tolerance may develop and dissipate rapidly during a single dose. Stimulants may facilitate dopaminergic activity in cognitive centers but reduce dopaminergic stimulation in areas responsible for hyperactivity and impulsivity. People with ADHD generally have increased dopamine transporter density and activity.

There is some evidence that there are different pathophysiological mechanisms involved in the different subtypes of ADHD. The hyperactive-motor vs. the emotional/cognitive-impulsive/inattentive features of ADHD may have different underlying mediators, pathways, and familial patterns. Intriguingly, there are differences in the time effects and dose-response relationships to stimulants. In general, hyperactive symptoms, which may be considered more primitive than cognitive dysfunctions, respond more favorably to lower doses of stimulants and/or less frequent dosing than do cognitive symptoms.

ADHD in adults is more associated with cognitive dysfunction than motor hyperactivity. Various data, including animal models and PET scans suggest that hyperactivity may result from excess dopaminergic activity in the striatum and/or nucleus accumbens [Solanto, 2002].

References

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