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ADHD pathophysiologic research has focused on neural circuits centered in the prefrontal cortex and striatum, as well as on the brain stem catecholamine systems that innervate these circuits.
The prefrontal cortex and the striatum are part of a com-plex neural system that mediates inhibitory control processes. The prefrontal cortex receives higher-order sensory input and inhibits the processing of irrelevant sensory stimuli through reciprocal con-nections with temporal and parietal association cortices. In turn, the prefrontal cortex exerts inhibitory control over motor functions through well-organized connections with the caudate nucleus, and indirectly with the globus pallidus. The globus pallidus feeds back to the prefrontal cortex via thalamic nuclei. Emerging data from neuroimaging studies suggest that impairments in these prefrontal– striatal regions play a central role in the pathophysiology of ADHD.
Morphological studies using magnetic resonance imaging (MRI) have identified a smaller right prefrontal cortex, caudate nu-cleus and globus pallidus in children with ADHD which suggests that ADHD may be associated with fewer prefrontal corticostriatal fibers and less pallidal feedback to prefrontal regions. In addition, reduced area in the corresponding anterior genu region of the corpus callosum in children with ADHD indicates the presence of fewer inter-hemispheric fibers in prefrontal regions. Anomalies have also been found in ADHD in regions that project to the prefrontal cortex, including in the parietal–occipital region (i.e., reduced white mat-ter) and the cerebellum (i.e., smaller posterior vermis). The latter findings raise the possibility that brain anomalies in ADHD extendbeyond the prefrontal cortex and striatum to the posterior and sub-cortical regions that innervate these frontal circuits.
Studies with single photon emission computerized tomog-raphy (SPECT) and positron emission tomography (PET) have re-ported lower basal activity in the prefrontal cortex and striatum of children (Zametkin et al., 1990), but not adolescents with ADHD (Zametkin et al., 1993). More recent studies employing functional MRI (fMRI) have tentatively linked altered prefrontal–striatal acti-vation with deficits in inhibitory control. Reduced striatal activation during response inhibition tasks has been consistently reported in children and adolescents with ADHD. However, prefrontal activa-tion during the same tasks was enhanced in children, but reduced in adolescents with the disorder. Normal age-related declines in prefrontal activation may account for the disparate findings.
The fact that virtually all medications that are efficacious in ADHD affect noradrenaline (NA) and dopamine (DA) trans-mission strongly suggest that perturbations of these catechol-amine inputs play a significant role in the pathophysiology of ADHD, although studies of catecholamine function in ADHD have yielded highly inconsistent findings (Zametkin and Rapo-port, 1987). Only more recent studies that used central indices of catecholamine function or that examined more homogeneous subgroups of children with ADHD have provided evidence of DA and NA dysfunction associated with ADHD. For example, cerebrospinal (CSF) levels of the DA metabolite homovanillic acid were positively correlated with ratings of hyperactivity and stimulant response in boys with ADHD (Castellanos et al., 1996). Further, dividing boys with ADHD based on the presence or absence of reading disabilities revealed differences in plasma levels of the NA metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) that correlated with differences in clinical characteristics (Halperin et al., 1997).
A promising recent development has been the use of PET and SPECT imaging in combination with DA-selective radiotrac-ers to examine localized DA function in vivo. These studies have revealed preliminary evidence of increased striatal DA trans-porter binding in adults with ADHD (Dougherty et al., 1999; Krause et al., 2000) and altered DA synthesis in the prefrontal cortex and right midbrain of children and adults with ADHD. These data point to localized DA deficits in the nigrostriatal and mesocortical fiber systems in ADHD.
The neurobiologic basis of CD has focused primarily on the neu-rochemical substrates of aggressive behaviors. An early body of literature pointed to a role for reduced noradrenergic func-tion. Several studies found negative correlations between plasma and CSF concentrations of MHPG and aggression and conduct problems (Kruesi et al., 1990; Rogeness et al., 1987). Children with CD were also reported to exhibit low activity of the enzyme dopamine-beta-hydroxylase, which converts DA into NA. These data suggest that NA dysfunction may play a role in aggression through its involvement in the regulation of behavioral arousal.
More recent research has focused on the role of central serotonergic (5-HT) function in aggression and antisocial behav-ior (Markowitz and Coccaro, 1995). Aggressive and antisocial adults have consistently been shown to have reduced CSF levels of 5-HT metabolites and blunted responses to 5-HT challenge agents. Studies examining central 5-HT function in aggressive children have had mixed results. Reduced central 5-HT function is associated with numerous risk factors for persistence in ag-gressive children, including affective lability, adverse child-rear-ing and parental history of aggression
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