The validity of ADHD as a clinical diagnosis has long excited debate and controversy in both lay and scientific circles. An expert panel convened and sponsored by the National Institutes of Health recently reviewed and documented extensively within a Consensus Statement the validity of ADHD as a clinical disorder, its public health importance for children and families, and the effectiveness of its treatments (NIH, 2000). Among their many conclusions, the conference panelists concurred that ADHD meets or exceeds the standards for validity established by most other disorders defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Still unclear, however, is whether the disorder represents a behavioral syndrome that is qualitatively and etiologically distinct from the range of ADHD-like symptoms present in children within the general population.
Attention deficit hyperactivity disorder comprises the symptomatic triad of inatten-tiveness, hyperactivity, and impulsivity, although predominantly inattentive (i.e., without prominent hyperactivity or impulsivity) and predominantly hyperactive/impulsive subtypes are recognized. Symptoms usually begin early in childhood, decrease gradually in adolescence (particularly symptoms of hyperactivity), and then reach some stable level by early adulthood (Biederman et al., 2000). ADHD affects approximately 3 to 9 percent of children in the general population (Szatmari et al., 1989; Taylor et al., 1991), with boys being 2 to 8 times more likely to be diagnosed than girls. Clinical, epidemiological, and family-genetic studies have shown ADHD to be a strong predictor of conduct disorder, depression, anxiety disorders, and substance abuse both in temporal cross section and in later life (McArdle et al., 1995; Peterson et al., 2001a). ADHD is widely believed to be a heterogeneous condition having multiple biological subtypes. This heterogeneity has probably helped to dilute the specificity of findings in biological studies.
Genetics. Family studies suggest that ADHD is highly familial (Biederman et al., 1992). A parent with ADHD has a 57 percent chance of having a child who also has ADHD (Biederman et al., 1995a). Adoption studies suggest that genetic factors contribute importantly to this familial predisposition (Morrison and Stewart, 1973; Cantwell, 1975), and twin studies indicate that genetic variance accounts for 70 to 90 percent of the phenotypic variance (Levy et al., 1997; Sherman et al., 1997). Quantitative analyses of family data sets have suggested a single gene mode of transmission (Faraone et al., 1992). Several candidate genes have been associated with ADHD, with varying degrees of reproducibility. These include the genes for the D2 dopamine receptor (DRD2), the dopamine transporter (DAT1) (Cook et al., 1995; Gill et al., 1997), the seven repeat allele of the D4 dopamine receptor (DRD4) (Faraone et al., 2001; Roman et al., 2001), and recently studies of other dopamine receptors and other neurotransmitter systems (Fisher et al., 2002; Roman et al., 2002). Even if the association of these genes with ADHD is indisputably established, the evidence suggests that the overall effects of these genes coding for transmitter systems in ADHD are likely to be modest at best.
Despite the demonstrated importance of genetic determinants in ADHD, nongenetic influences also contribute to its pathophysiology. Premature birth, other obstetrical complications, maternal smoking during pregnancy, pediatric head trauma, and chaotic family environments in particular are all thought to predispose to the later development of ADHD (Hinshaw et al., 2000; Roy et al., 2000).
Neurochemistry. Many studies of neurotransmitter metabolite levels in the blood and urine of ADHD children have been reported, both at baseline and after pharmacological treatments or challenges. Dopamine metabolite levels have been most extensively studied, but their variable and often contradictory findings have not yielded conclusive evidence for or against the involvement of dopamine in the pathophysiol-ogy of ADHD (Zametkin and Rapoport, 1987). Baseline measures of norepinephrine in serum, as well as MHPG (a norepinephrine metabolite) in plasma and 5-HIAA in platelets do not differ in ADHD children compared with controls. Findings for the levels of these compounds in urine have been inconsistent, and responses of these levels to pharmacological agents do not seem to differ across diagnostic groups. CSF studies in ADHD are relatively rare, but likewise do not clearly indicate the presence of disturbances in these neurotransmitter systems.
Neurobiological Substrate. Animal models, human in vivo imaging studies, and electrophysiological studies all suggest that anatomical and functional disturbances of frontostriatal components of CSTC circuits subserve the symptoms of ADHD. These circuits, moreover, are the primary sites of action for the dopaminergic properties of stimulant medication, the most robustly effective pharmacotherapy for ADHD.
Several animal models for ADHD have been proposed. One particularly attractive model is the spontaneously hypertensive rat (SHR). SHRs are hyperactive, and they exhibit inattention on certain behavioral tasks. They have lower metabolism of their medial and lateral frontal cortices (Papa et al., 1998), and lower basal levels of transcription factors in their nucleus accumbens (Papa et al., 1997), a region within the ventral striatum subserving learning and reward. Dopaminergic activity is reduced and noradrenergic activity is increased in the frontal cortices of SHRs (Russell, 2002), and catecholamine innervation of frontal cortices depends on perinatal androgen levels, possibly accounting for the higher prevalence of ADHD in males (King et al., 2000). Methylphenidate attenuates hyperactivity and inattention in these animals (Ueno et al., 2002).
Consistent with findings in this animal model, human imaging studies have most consistently reported abnormalities in the dorsal prefrontal cortex and basal ganglia of subjects with ADHD. Smaller volumes of the right prefrontal cortex have been reported in children with ADHD compared with normal controls (Castellanos et al., 1996a), a finding that has generally been replicated, although not always with regard to laterality (Aylward et al., 1996; Filipek et al., 1997). In an anatomical imaging study of 152 children with ADHD and 139 controls, cortical volume reductions were not specific to frontal regions, but were instead generalized to all cortical regions (Castellanos and Tannock, 2002). Additionally, smaller right globus pallidus nuclei have been detected in a subset of these children (Castellanos et al., 1996).
Positron emission tomography studies have reported reduced metabolic rates in, among other regions, the left anterior frontal area, where metabolism correlated inversely with measures of symptom severity (Zametkin et al., 1993). Functional MRI studies have reported abnormal activation of the striatum (Vaidya et al., 1998; Rubia et al., 1999), prefrontal cortex (Rubia et al., 1999), and anterior cingulate cortex (Bush et al., 1999). SPECT studies of ADHD adults have reported marked elevations of dopamine transporter levels in the basal ganglia (Dougherty et al., 1999; Krause et al., 2000), which, after a month of daily methylphenidate treatment, decreased to control levels (Krause et al., 2000). Additional findings in ADHD imaging studies include a smaller cerebellum (Castellanos and Tonnock, 2002), a region thought to be important in attentional processing (Middleton and Strick, 1994).
Electrophysiological studies support these findings from other brain imaging modalities. Event-related potential recordings during attentional tasks produces smaller P300s over parietal cortices, suggesting that parietal dysfunction may contribute to inattentive symptoms in ADHD (Overtoom et al., 1998). Quantitative EEG studies of large samples of ADHD children suggest abnormal activity of the frontal cortices (Chabot and Serfontein, 1996). Disordered brainstem involvement in ADHD is suggested by delayed latencies in components of the brainstem auditory evoked response (Lahat et al., 1995).
Psychostimulants. Countless studies have demonstrated that psychostimulants, methylphenidate and amphetamine in particular, improve ADHD symptoms (Green-hill et al., 2002). Indeed, such agents improve attentional functioning even in normal children and animals. A large and definitive multisite clinical trial has shown that stimulant medications generally are far superior to behavioral management alone, and that behavioral management added to treatment with stimulant medications provides little additional benefit (Group 1999a). Nonmedical treatments are most helpful for ADHD children who also have clinically significant anxiety symptoms (Group, 1999b). Many clinicians continue to believe that consistently and appropriately implemented parent management training alone can be effective for some children with ADHD, especially for younger children. Suggestions for early psychosocial interventions, including increased play, remain to be evaluated, although preliminary data from animal models are encouraging (Panksepp et al., 2002; Panksepp et al., 2003).
Stimulant medications are usually well tolerated. The most common side effects include impaired sleep, poor appetite, headaches, or irritability. Although several preliminary animal studies of these medications suggest the possibility of neurotoxic effects (Moll et al., 2001) or potential longer-term behavioral effects (Nocjar and Panksepp, 2002; Panksepp et al., 2002), long-term neuroimaging studies of children with ADHD have thus far not provided evidence of anatomical changes associated with chronic stimulant use (Castellanos and Tannock 2002). Moreover, behavioral studies in humans suggest that psychostimulants may reduce the long-term risks of substance abuse associated with the presence of ADHD earlier in life (Biederman et al., 1999; Barkley et al., 2003; Wilens et al., 2003). Stimulants also seem to improve peer, parent, and teacher ratings of the child's social skills (Group, 1999a, b). These longer-term benefits of stimulant medications for children with ADHD would seem likely to have important and enduring positive effects on self-esteem and adaptive functioning.
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