Chapter 43: Pathophysiology of ADHD
TABLE 43.1. STRUCTURAL NEUROIMAGING STUDIES OF ADHD
Shaywitz et al. (199) Nasrallah et al. (200) Lou et al. (201) Hynd et al. (202)
ADD HYP ADD ADD/H
CT CT CT MRI
No abnormalities found Sulcal widening, cerebellar atrophy Slight frontal cortex atrophy Smaller frontal cortex Loss of normal asymmetry in frontal cortex Smaller corpus callosum Smaller left globus pallidus Smaller left globus pallidus Small corpus callosum Small corpus callosum Smaller right prefrontal cortex, right caudate, and globus pallidus Smaller inferior posterior vermis of cerebellum Neural migration anomalies and excess cerebrospinal fluid in the
Hynd et al. (203) Aylward et al. (204) Singer et al. (205) Baumgardner (206) Semrud-Clikeman et al. (207) Castellanos et al. (208) Mostofsky et al. (209) Nopoulos et al. (70)
ADHD ADHD ADHD+TS ADHD ADHD ADHD ADHD ADHD
MRI MRI MRI MRI MRI MRI MRI MRI
Overmeyer et al. (210) Mataro et al. (211) Kayl et al. (212)
ADHD ADHD ADHDa
MRI MRI MRI
posterior fossa but no differences in cavum septi pellucidi No corpus callosum abnormalities Larger right caudate nucleus Increased severity of attention problems was associated with small
Berquin et al. (213) Casey et al. (214)
total callosal areas Smaller inferior posterior vermis of cerebellum Poor response inhibition associated with right sided abnormalities
Filipek et al. (215)
prefrontal cortex, caudate, and globus pallidus, but not putamen Smaller left caudate, right frontal cortex, and bilateral peribasal
ganglia and parietal-occipital regions
ADD, DSM-III attention-deficit disorder; ADD/H, DSM-III ADD with hyperactivity; ADHD, DSM-III-R attention-deficit hyperactivity disorder; CT, computed tomography; HYP, DSM-II hyperkinesis; MRI, magnetic resonance imaging; TS, Tourette syndrome. aIn this study, ADHD was secondary to neurofibromatosis.
structure and function, they are ideal for testing hypotheses about the locus of brain dysfunction. Table 43.1 reviews 18 structural neuroimaging studies of children, adolescents, and adults with ADHD that used computed tomography or magnetic resonance imaging. Among these studies, the most consistent findings implicated frontal cortex, usually limited to the right side, cerebellum, globus pallidus, cau- date, and corpus callosum. Several other regions were less consistently implicated. Consistent with these findings, the I/LnJ mouse strain shows total callosal agenesis along with behavioral features that resemble ADHD (61). These mice show learning impairments, impulsiveness, and hyperactiv- ity. Metabolic mapping studies suggest that their behavioral deficits are associated with lower 2-deoxyglucose uptake in the left striatum and the frontal and parietal cortex (61).
Table 43.2 reviews 14 functional neuroimaging studies of ADHD using regional cerebral blood flow, positron emis- sion tomography, single photon emission tomography, functional magnetic resonance imaging, or electroencephal- ography. The most consistent findings were hypoactivity of frontal cortex and subcortical structures, usually on the right side. Because Ernst et al. found significant brain dysfunction for girls, but not boys, with ADHD (62), and Baving et al. found gender differences in lateralization (63), future stud- ies will need to assess gender differences and to determine how they may be related to the male predominance of the disorder.
Ernst et al. noted that findings of frontal hypoactivity are stronger in adult ADHD compared with adolescent ADHD (64). They offered two explanations for this finding. First, the adolescent samples studied may have been more hetero- geneous than the adult samples. Although all the adults had persistent ADHD, some of the adolescent cases may have remitted by adulthood. Thus, frontal dopaminergic hypoac- tivity may be associated with persistent ADHD only. Alter- natively, Ernst et al. speculated that, because of brain matu- ration, the locus of ADHD’s dopamine abnormality may shift from the midbrain in childhood to the prefrontal cor- tex in adults.
Anterior cingulate cortex, lying on the medial surface of the frontal lobe, has strong connections to dorsolateral prefrontal cortex. Bush et al. used a Stroop task to compare anterior cingulate cortex activation in adults with ADHD and those who did not have ADHD (65). In contrast to controls, the adults with ADHD failed to activate the ante- rior cingulate cortex. Notably, in the prior study by Zamet- kin et al. (66), cingulate cortex was one of only four (of 60) regions evaluated that still showed regional hypoactivity after global normalization.
The neurochemical basis of brain dysfunction in ADHD was studied by Dougherty et al. (67). They measured DAT density by single photon emission computed tomography with the radiopharmaceutical iodine 123–labeled altropane. Their findings were consistent with the catecholamine hy-