The following is an abstract of the presentation of James Swanson, Ph.D., and F. Xavier Castellanos, M.D. on the biological bases of Attention Deficit Hyperactivity Disorder: Neuoranatomy, Genetics, and Pathophysiology. The abstract is designed for the use of panelists and participants in the conference and as a reference document for anyone interested in the conference deliberations. We are grateful to the authors, who have summarized their materials and made them available in a timely fashion. (Graphics and tables version available for easier reading)

In a multistage process for validation of a psychiatric disorder (Jensen, Martin, Cantwell, 1997), two preliminary steps have been taken for attention deficit hyperactivity disorder (ADHD): (1) a partial consensus has been reached in the two primary diagnostic manuals, DSM-IV and ICD-9, about an ADHD phenotype that can be reliably assessed (Swanson, Sergeant, Taylor, et al., 1998) and (2) in followup studies of children with the disorder from several different geographical locations, adverse adolescent outcome in social adjustment and educational attainment has been documented (e.g., Mannuzza, Klein, Bessler, et al., 1993; Satterfield, Swanson, Schell, et al., 1994; Taylor, Chadwick, Heptinstall, et al., 1996). In this process, a critical next step is the delineation of biological bases of ADHD by laboratory tests. We will review recent pivotal studies from neuroanatomy and molecular biology that address this issue.

Recent investigations of a refined phenotype defined by the ICD-10/DSM-IV consensus criteria (ADHD-combined type without serious comorbidities present in childhood) (ADHD/hyperkinetic disorder [HKD]) have produced some converging evidence about biological bases of this disorder. Multiple causes have been assumed (see Conners, 1998, this volume), and both neurological damage and genetic variation have been proposed as likely biological etiologies. We will discuss research exemplifying both proposals.

Recent Research on Neuroanatomical Abnormalities

One of the most important current developments has been the convergence of findings from magnetic resonance imaging studies of brain anatomy (aMRI). We will present a meta-analysis of studies from several independent laboratories that have reported ADHD/HKD abnormalities in two specific but still coarsely defined brain regions of the frontal lobes and basal ganglia. For example, Filipek and colleagues (1997) reported that a group of children with ADHD/HKD had brain volumes about 10 percent smaller than normal in anterior superior regions (posterior prefrontal, motor association, and midanterior cingulate) and anterior inferior regions (anterior basal ganglia), and Castellanos and colleagues (1996) reported that right anterior frontal, caudate, and globus pallidus regions were about 10 percent smaller in an ADHD/HKD group than in a control group.

The convergence of findings within and across investigators has not emerged for functional imaging studies using positron emission tomography (PET) (Ernst, Zametkin, 1995) as it has for aMRI studies. We will discuss possible reasons for this, as well as a variety of findings from studies based on other methods of functional imaging, such as single photon emission tomography (SPECT), EEG event-related potentials (ERP), and functional magnetic resonance imaging (fMRI).

The reported aMRI findings may be localized in theoretical frameworks of neural networks, such as the parallel segregated circuits described by Alexander and colleagues (1986) and the neuroanatomical networks of attention described by Posner and Raichle (1996). We will discuss attempts to use these theories to organize the empirical findings from brain imaging studies of ADHD/HKD, and we will review some of the proposals that have been offered to account for executive function deficits of ADHD/HKD children documented by neuropsychological tests (see Tannock, 1998, in this volume).

Recent Molecular Genetic Investigations

Many family (e.g., Faraone, Biederman, Chen, et al., 1992), twin (e.g., Gjone, Stevenson, Sundet, 1996), and adoption (e.g., Deutsch, Matthysse, Swanson, et al., 1990) studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies are necessary to identify allelic variations of specific genes that are functionally associated with ADHD/HKD. Dopamine genes have been the initial candidates for application of advances in molecular biology, based on the site of action of the stimulant drugs (Wender, 1971; Volkow, Ding, Fowler, et al., 1995), the primary pharmacological treatment for ADHD/HKD (see Greenhill, 1998, in this volume).

Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene (Cook, Stein, Krasowski, et al., 1995; Gill, Daly, Heron, et al., 1997) and the dopamine receptor D4 (DRD4) gene (LaHoste, Swanson, Wigal, et al., 1996; Swanson, Sunohara, Kennedy, et al., 1998). The associated polymorphisms of these genes are defined by variable numbers of tandem repeats (VNTR), which for the DAT1 gene is a 40-bp repeat sequence on chromosome 5p15.3 and for the DRD4 gene is a 48-bp repeat sequence on chromosome 11p15.5. Speculative hypotheses have been based on the notions that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g., that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). However, the literature on this topic is sparse, and not all studies agree about the association of ADHD/HKD with DAT1 (Sunohara, Kennedy, 1998) or DRD4 (Castellanos, Lau, Tayebi, et al., in press). This is an emerging area of research; so we will discuss its status at the time of the conference.

Investigations of Nongenetic Etiologies

Specific genetic models have incorporated a high phenocopy rate to account for a sporadic as well as a genetic form of the disorder (Faraone, Biederman, Chen, et al., 1992; Deutsch, Matthysse, Swanson, et al., 1990). In addition to rare genetic mutations, sporadic cases may be due to nongenetic etiologies such as acquired brain damage. For decades, theories of minimal brain damage and minimal brain dysfunction (MBD) have been proposed and rejected (e.g., Wender, 1971; Brown, Chadwick, Shaffer, et al., 1981) because of the lack of empirical evidence of suspected brain damage in children manifesting behavioral soft signs and the lack of specificity of the behavioral consequences of traumatic brain injury. However, recent theories based on animal models and brain damage have revived this approach. For example, Lou (1996) proposed that during fetal development, bouts of hypoxia and hypotension could selectively damage neurons located in some of the critical regions of the anatomical networks implicated in ADHD/HKD (i.e., the striatum). Fetal exposure to alcohol, lead, nicotine, and other substances may produce similar neurotoxic effects. Also, severe traumatic brain injury may produce selective interneuron damage in the frontal lobes, which Max and colleagues (1998) suggest may produce new-onset symptoms of inattention and impulsivity, though often not hyperactivity (Brown, Chadwick, Shaffer, et al., 1981). We will discuss these new developments in the context of the historical questions about documentation of specific neuroanatomical abnormalities (which may be addressed with modern imaging methods) and selective expression of ADHD/HKD symptoms (which may be addressed by prospective followup investigations).

Neurobiological Bases for Pharmacological Treatment

The abnormalities in neuroanatomical networks associated with ADHD/HKD (smaller frontal and basal ganglia regions) and the biochemical pathways (specific alleles of dopamine genes) suggest a possible theoretical basis (e.g., a dopamine deficit) for the standard pharmacological treatments of ADHD/HKD with dopamine agonist drugs (see Greenhill, 1998, in this volume). Primary treatment with the stimulant medication methylphenidate has stood the test of time and the scrutiny of controlled research (Wilens, Biederman, 1992; Swanson, McBurnett, Wigal, et al., 1993). Recent investigations (Volkow, Ding, Fowler, et al., 1995) have identified the site of action of methylphenidate, which blocks the dopamine transporter. This increases the temporal and spatial presence of synaptic dopamine when it is released in the basal ganglia (e.g., putamen, caudate, and ventrostriatum) and cortex (e.g., temporal, insula, and cingulate gyri) for approximately the post-peak length of action following oral administration (2 to 3 hours). We will discuss site-of-action hypotheses that have been proposed to account for effects of clinical doses of stimulant medication. For example, Castellanos (1997) proposed that presynaptic effects may predominate in D2-rich subcortical regions where presynaptic receptors are abundant, producing decreased synaptic dopamine, and postsynaptic effects may predominate in D4-rich cortical regions, which lack presynaptic receptors, producing increased synaptic dopamine. Also, Seeman and Madras (in press) have proposed that clinically relevant doses of stimulants may increase extracellular background levels of dopamine more than action-potential released dopamine, which may account for why these dopamine agonist drugs result in a reduction in psychomotor activity.

Other etiologies of ADHD/HKD have been proposed (e.g., adverse reactions to foods or food additives, cortical underarousal, muscular tension), and on the basis of these proposals, specific nonpharmacological treatments have been suggested (e.g., special diets, EEG biofeedback, EMG relaxation training). These proposals and treatments have testimonial support, but empirical support from controlled studies is lacking. Since these areas will be covered by Arnold (1998, this volume), they will not be discussed here.

Summary

Recent investigations provide converging evidence that a refined phenotype of ADHD/HKD is characterized by reduced size in specific neuroanatomical regions of the frontal lobes and basal ganglia. These specific deficits suggest abnormalities in neural networks that affect input-output processing and attention (alerting and executive function). These neural networks are modulated by catecholamines, which are affected by stimulant drugs. The site of action of methylphenidate (the primary stimulant now used to treat ADHD/HKD) suggests that dopamine is the principal neurotransmitter involved, although norepinephrine has also been implicated. Recent molecular genetic studies have documented significant association of a refined phenotype of ADHD/HKD with polymorphisms in dopamine genes, which may alter the functions of the implicated neural networks. Recent investigations of brain development and brain injury also suggest that damage to these specific neural networks may produce symptoms of ADHD/HKD. Overall, the recent investigations in these areas have provided considerable evidence of multiple biological bases of ADHD/HKD.

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