found maternal depression to be associated with undesirable parenting practices such as intrusiveness, unresponsiveness, and inept discipline. In addition, their review supported the idea that depressed mothers had negative perceptions of their children.
Other work shows that ADHD in children predicts depression in mothers, but maternal depression provides no additional information for predicting ADHD in siblings of ADHD probands. This finding suggests that maternal depression is a heterogeneous disorder. It may be that some mothers have a disorder that is genetically linked to ADHD, whereas others may experience depression resulting from the stress of raising a child with ADHD (and perhaps living with an ADHD-affected or antisocial husband). Further- more, it is possible that maternal depression exacerbates family conflict and poor parenting, both of which could exacerbate ADHD symptoms.
Notably, although many studies provide strong evidence of the importance of psychosocial adversity for ADHD, these factors tend to emerge as universal predictors of chil- dren’s adaptive functioning and emotional health, not pre- dictors that are specific to ADHD. Thus, they can be con- ceptualized as nonspecific triggers of an underlying predisposition or as modifiers of the course of illness.
SUMMARY AND CONCLUSIONS
It is not yet possible to describe the origin and pathophysiol- ogy of ADHD completely. Nevertheless, converging evi- dence from the studies reviewed in this chapter supports several empiric generalizations, which should be useful in guiding future research and theory.
Much research supports the idea that catecholaminergic sys- tems mediate the onset and expression of ADHD symp- toms. The key data supporting this idea are as follows: (a) anti-ADHD medications have noradrenergic and dopami- nergic effects; (b) lesion studies in mouse and monkey models implicate dopaminergic pathways; (c) the SHR rat shows deficits in catecholaminergic systems; (d) D2, D3, and D4 knockout mice studies show that these genes regu- late locomotor activity; and (e) human studies implicate the DRD4 and DAT genes in the origin of ADHD.
Although the role of catecholamine systems cannot be disputed, future work must also consider other neurotrans- mitter systems that exert upstream effects on catechola- mines. Two prime candidates are nicotinic and serotonergic systems. Nicotinic agonists help to control the symptoms of ADHD, and nicotinic activation enhances dopaminergic neurotransmission. Serotonergic drugs have not been shown to be effective anti-ADHD agents, but knockout mice stud- ies suggest that the paradoxical effects of stimulants on hy-
Chapter 43: Pathophysiology of ADHD
peractivity are mediated by serotonergic neurotransmission. Moreover, SNAP-25, which has been implicated in studies of the coloboma mouse, leads to striatal dopamine and sero- tonin deficiencies. These data call for further studies of sero- tonergic and nicotinic systems.
Several types of study provide information about the locus of ADHD’s pathophysiology in the brain: neuropsychologi- cal studies, neuroimaging studies, and animal models. Taken together, these studies support the idea that ADHD arises from the dysregulation of frontal cortex, subcortical structures, and networks connecting them. This idea fits with the pharmacotherapy of ADHD because a plausible model for the effects of stimulants is that, through dopami- nergic or noradrenergic pathways, these drugs increase the inhibitory influences of frontal cortical activity on subcorti- cal structures.
Additional data supporting frontal-subcortical involve- ment in ADHD are as follows: (a) neuropsychological stud- ies implicate orbitofrontal and dorsolateral prefrontal cortex or regions projecting to these regions; (b) the monkey model of ADHD implicates frontal-striatal neural networks; (c) studies of the SHR rat implicate caudate, putamen, nucleus accumbens, and frontal cortex; patients with frontal lobe damage show ADHD-like behaviors; (d) structural neu- roimaging implicates frontal cortex, usually limited to the right side, cerebellum, globus pallidus, caudate, and corpus callosum; (e) the I/LnJ mouse strain shows total callosal agenesis along with behavioral features that resemble ADHD; (f) functional neuroimaging finds hypoactivity of frontal cortex, anterior cingulate cortex, and subcortical structures, usually on the right side; (g) ADHD secondary to brain injury shows lesions in right putamen, right caudate nucleus, and right globus pallidus; (h) disabling the D4 gene in mice leads to increased dopamine synthesis in dorsal striatum; (i) mice without D2 genes also show decreased striatal DAT functioning, abnormal synaptic plasticity at corticostriatal synapses, and long-term changes in synaptic efficacy in the striatum; and (j) the coloboma mouse shows deficient dopamine release in dorsal striatum.
In a word, the origin of ADHD is complex. Although rare cases may have a single cause such as lead exposure, general- ized resistance to thyroid hormone, head injury, and frontal lobe epilepsy, most cases of ADHD are probably caused by a complex combination of risk factors.
From the many twin studies of ADHD, we know for certain that genes mediate susceptibility to ADHD. Molec- ular genetic studies suggest that two of these genes may be the DRD4 gene and the DAT gene. To confirm these find- ings, we need much more work because, even if the positive