Neurobiology
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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