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Neuropsychopharmacology: The Fifth Generation of Progress

find children with ADHD to be impaired on this measure (1).

stimulate hypotheses about the role of specific brain regions in the pathophysiology of ADHD.

Children with ADHD also perform poorly on tasks re- quiring inhibition of motor responses, organization of cog- nitive information, planning, complex problem solving, and the learning and recall of verbal material (49). Examples of tests that measure these functions are the Stroop Test, the Wisconsin Card Sorting Test, the Rey-Osterrieth Test, the Freedom from Distractibility factor from Wechsler’s Tests of Intelligence, and the California Verbal Learning Test.

Some studies suggest that the impairments found in chil- dren with ADHD cannot be accounted for by psychiatric comorbidity (50). Moreover, having a family history of ADHD may predict a greater degree of neuropsychological impairment. This latter finding suggests that familial ADHD and neuropsychological impairment identify a more biologically based type of ADHD. In contrast, nonfa- milial cases of ADHD with lesser neuropsychological im- pairments may have other etiologic factors. Children with ADHD do not appear to be impaired on simple motor speed, verbal fluency, or visual spatial accuracy, findings that suggest that observed neuropsychological impairments are caused by specific, not generalized, deficits (51).

Notably, neuropsychological studies have consistently found adults with ADHD to be impaired on measures of vigilance using the continuous performance test (52,53). These studies have also shown adults with ADHD to be impaired in other functions known to affect children with ADHD. These include the following: perceptual-motor speed as assessed by the digit symbol/coding tests (54,55); working memory as assessed by digit span tests (53,56); verbal learning, especially semantic clustering (52,56); and response inhibition as assessed by the Stroop Color-Word Test (57,58). Because neuropsychological tests are free of the potential biases of self-reported symptoms, the finding that the neurocognitive profiles of adults with ADHD are similar to those of children with ADHD suggests that the diagnosis of ADHD is valid as applied in adulthood.

Our description of neuropsychological dysfunction in ADHD describes trends that have emerged in the research literature, not findings that have been consistently repli- cated. Although there are inconsistencies among studies, it is notable that the pattern of deficits that has emerged is similar to what has been found among adults with frontal lobe damage. Thus, the neuropsychological data tend to support the hypothesis that the frontal cortex or regions projecting to the frontal cortex are dysfunctional in at least some children with ADHD.

With this considerations in mind, we view the pattern of neuropsychological impairment in children with ADHD as consistent with Satterfield and Dawson’s (46) idea that symptoms of ADHD derive from abnormalities of prefron- tal cortex or its neural connections to subcortical structures. This inference derives from the clinical and behavioral fea- tures that have been linked to regions of the prefrontal cor- tex (59). Notably, orbital frontal lesions predict social disin- hibition and impulsivity, and dorsolateral lesions affect organizational abilities, planning, working memory, and at- tention. Studies of children with ADHD find impairment in all these neuropsychological domains. Thus, the neuro- psychological test data—along with the clinical features of the disorder—implicate both orbitofrontal and dorsolateral prefrontal dysfunction in ADHD. In contrast, the mesial prefrontal region, where lesions predict dysfluency and the slowing of spontaneous behavior, is not implicated in ADHD.

Given the complexity of prefrontal circuitry (60), along with the limitations of neuropsychological inference, we cannot endorse a simple lesion model of ADHD. The ‘‘pre- frontal’’ abnormalities in ADHD may result from abnor- malities of prefrontal cortex, but they may also reflect the dysfunction of brain areas with projections to prefrontal cortex. Given the known role of subcortical networks as modulators of prefrontal functioning, the term frontosubcor- tical seems appropriate for ADHD. This term denotes a behavioral or cognitive dysfunction that looks ‘‘frontal’’ but may be influenced by subcortical projections.

The neuropsychological findings in ADHD provide a fertile resource for speculations about the role of subcortical structures. For example, the cingulate cortex influences mo- tivational aspects of attention and in response selection and inhibition. The brainstem reticular activating system regu- lates attentional tone and reticular thalamic nuclei filter in- terference. Working memory deficits implicate a distributed network including anterior hippocampus, ventral anterior and dorsolateral thalamus, anterior cingulate, parietal cor- tex, and dorsolateral prefrontal cortex. Moreover, the atten- tional problems of children with ADHD may implicate a wider distribution of neural networks. A system mainly in- volving right prefrontal and parietal cortex is activated dur- ing sustained and directed attention across sensory modali- ties. The inferior parietal lobule and superior temporal sulcus are polymodal sensory convergence areas that provide a representation of extrapersonal space and play an impor- tant role in focusing on and selecting a target stimulus.

Because neuropsychological tests provide indirect mea- sures of brain function, we must be cautious in using them to make inferences about the locus of brain impairment in ADHD. Yet because many of these tests have been standard- ized on normative populations and administered extensively to brain-damaged populations, observed deficits tests can

Neuroimaging Studies

Fortunately, hypotheses based on neuropsychological infer- ence can be tested with neuroimaging paradigms. Because neuroimaging studies provide direct assessments of brain

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