Attention-Deficit Hyperactivity Disorder (ADHD)

Kytja K. S. Voeller, MD

Disclosures

J Child Neurol. 2004;19(10):798-814. 

In This Article

Etiology of ADHD

ADHD is a highly heritable disorder. However, it can also be acquired, and some individuals have a combination of genetic and acquired ADHD. At the present time, it is not possible to distinguish between these two types of ADHD—they both look the same, and both usually respond to treatment with the same psychostimulant medication.

ADHD is, in most cases, of familial origin. Parents with ADHD have a better than 50% chance of having a child with ADHD, and about 25% of children with ADHD have parents who meet the formal diagnostic criteria for ADHD.[83] Twin studies have placed the heritability of ADHD in the range of 80%.[84] In a longitudinal twin study examining the size of genetic and environmental effects on ADHD behaviors based on maternal report at the ages of 3, 7, 10, and 12 years, the estimate of heritability was nearly 75% at each age, with hyperactivity at age 3 years being somewhat less related to later inattention and inattention at age 7 years being quite stable. The genetic factors explained 76% and 92% of the covariance between hyperactivity and inattention.[85] This provides another line of support for the observation that behaviors related to ADHD (inattention to a greater extent than hyperactivity) do not improve with maturation.

ADHD can be considered a disorder of neurotransmitter function, with particular focus on the neurotransmitters dopamine and norepinephrine. There has been extensive research conducted that demonstrates that dopamine is critical in the regulation of learning, as well as maintaining trained or conditioned responses and motivated (goal-directed) behaviors.[86,87,88,89,90] Dopamine also plays an important role in working memory, the ability to "keep something in mind" for a brief period of time.[91,92] Thus, dopamine can modulate neuronal activity related to motor activity that is guided by external cues and is goal directed.[93] Dopamine plays an important role in the function of the prefrontal-subcortical system. Norepinephrine (noradrenaline) is involved in maintaining alertness and attention. Norepinephrine neurons are triggered by novel and important stimuli and are quiescent during sleep. Psychostimulant medications that increase the amount of central dopamine and norepinephrine are typically the most effective way to treat ADHD.

To summarize, dopamine is the neurotransmitter that regulates the system that plays an important function in learning, motivation, goals, drives, and emotion—all of which are crucial to survival. Norepinephrine is the neurotransmitter involved in the detection of those stimuli that are important or novel and maintains the organism in a state of alertness and readiness as needed to process these stimuli. This system appears to be impaired in children with ADHD who have difficulty regulating their own level of alertness and awareness of important stimuli.[94]

Genetic studies of ADHD have focused on genes involved in the regulation of neurotransmitter function, mainly related to dopamine, although some studies have also examined the role of norepinephrine and other neurotransmitters. Many different processes are involved in neurotransmission. These and a list of candidate genes for ADHD are summarized in Table 1 . It is unlikely that a single gene will be linked to ADHD; rather, ADHD might be due to the interaction of several different genes involved in the function of several different neurotransmitters. In addition, individuals' genetic makeup will determine how they will respond to specific medications used to treat ADHD. Thus, we are at the beginning of a process that will not only make it possible to carry out more sophisticated diagnostic processes but will also make it possible to develop more sophisticated and effective approaches to treatment.

The behaviors associated with ADHD can also arise from environmental factors that disrupt normal brain growth, before, during, and after birth. Such insults give rise to behaviors that are indistinguishable from the behaviors seen in ADHD of genetic origin. It is not unusual to see individuals who have both a genetic and an acquired form.

Multiple pre- and perinatal factors can result in ADHD.[95] One such factor is fetal alcohol syndrome, which results in significant inattention, impulsivity, and hyperactivity in the child. Exposure of the fetus to alcohol is associated with a reduction in the volume of the prefrontal and temporal cortices—the brain areas involved in regulation of attention and control of impulsivity.[96,97] Maternal smoking has been linked with ADHD.[98,99] Even though women with ADHD are at increased risk of becoming smokers and the child's ADHD might be genetic, exposure of the fetus to cigarette smoking confers an increased risk.[100] One study found a fourfold higher risk of ADHD in the offspring of smokers, even after controlling for maternal ADHD.[101] Metabolic disorders of the mother (eg, diabetes, phenylketonuria) can also result in an ADHD-like picture in the infant.[102]

The dopamine system is exquisitely sensitive to hypoxia, particularly in the fetus or infant. Thus, any events pre- or postnatally that disrupt the flow of blood or oxygen to the brain might set the stage for later ADHD behaviors. This observation is supported both by laboratory studies[103,104] and a study of ex-premature infants who had documented cerebral ischemia at birth and were re-examined in early adolescence.[105]

Iron deficiency is associated with disruption of the dopamine system and more extensive neurodevelopmental problems.[106] It is rarely a cause of ADHD because most children in the United States receive diets with adequate iron.

Injury to the medial temporal lobe during early development is also associated with ADHD-like behaviors later in development, possibly because of the disruption of dopamine regulation in the dorsolateral prefrontal cortex. This has been shown in nonhuman primates[107,108] and children with temporal lobe cysts.[109]

Hyperbilirubinemia (jaundice) in the newborn period can evolve into an ADHD-like picture later in childhood. In the past, before effective treatments were developed, neonatal hyperbilirubinenia resulted in severe and irreversible damage to the basal ganglia (specifically the globus pallidus and subthalamic nucleus). (Bilirubin is a mitochondrial poison and affects calcium homeostasis, resulting in neuronal death.) However, it has become apparent that even moderate levels of bilirubin in otherwise healthy infants might not be as benign as previously believed.[110,111]

Any injury to the brain that affects the prefrontal-subcortical circuits can result in an ADHD-like picture. Traumatic injury often involves damage to the tips of the frontal lobes or shearing of white-matter tracts and often results in ADHD-like behaviors.[112,113,114,115,116] In one study comparing monozygotic twins who were discordant for ADHD, caudate lesions were observed in the twin with ADHD.[117] Similarly, children who have suffered strokes, particularly those involving subcortical areas in the prefrontal-subcortical circuits, not infrequently manifest ADHD-like behaviors. In one study, nearly half of the children developed ADHD following stroke,[118] and there was a strong correlation between lesions of the putamen and ADHD symptomatology.[119] Meningitis and encephalitis are also associated with ADHD-like behaviors. Autoimmune disorders have also been implicated in triggering ADHD-like symptoms in susceptible patients. Pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) is linked to Tourette syndrome, obsessive-compulsive disorder, and ADHD.[120] Lyme disease has also been associated with a number of neuropsychiatric symptoms, including those of ADHD.[121]

The role that environmental factors play in ADHD should not be minimized. Early deprivation can result in ADHD symptoms in later childhood (increased rates of attention deficit and hyperactivity have been observed in children who were raised in institutions). These children also have a somewhat different set of associated psychiatric disorders than children with genetic ADHD and have disturbed attachment.[122,123] Children who grow up in chaotic environments often have difficulty regulating attention, impulsivity, and emotionality. The risk of ADHD is proportional to the number of adverse factors (eg, poverty, maternal psychopathology, paternal criminality) that are present.[124]

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