In the era of genomics, psychiatry—like all areas of medicine—will likely undergo radical change. As genetic risk factors are uncovered and the dynamic nature of gene expression is elucidated, novel approaches to prevention will diminish or preempt diagnosis and treatment for many psychiatric and neurobehavioral disorders. While we are in the infant stage of this change, it is perhaps not too early to begin to investigate how such a reorientation will influence our thinking about mental disorders and well-being in general.
Attention-deficit/hyperactivity disorder (ADHD) is an ideal condition with which to begin such an investigation because of its common frequency, early onset and chronic nature, high heritability, and measurable variability outside the range of impairment. This article attempts to reframe ADHD from the view of it at the end of the 20th century to one that is emerging in the 21st century.
The reframing has 4 points as illustrated in the Table. Reframing ADHD requires a modification of the current view from a medical model of ADHD to one reflecting neurodiversity. Here, neurodiversity is used to reflect the variability of neurobiological functioning present in the human species, generally continuous and measurable at the population level, such as IQ, personality, or cognitive processes. Neurobiological functions—whether measured at the behavioral, neuropsychological, or neurophysiological level—vary in a population because of genetic differences and the diversity of environments in which genes are expressed (from the cellular to cultural level). Along any one continuum of such neurodiversity (eg, attentional processes), there is variability in the population, and extremes (less-typical modes of functioning) are often associated with impairment.
ADHD, under such a neurodiversity model, is recognized as an "atypical" mode of processing along one or more continua. By definition, it is a "disorder" because impairment is severe enough that intervention is warranted. We are beginning to see the emergence of this perspective in the current discussions of development of DSM-V and ICD-11 criteria, in which the introduction of continuous mea- surement of psychiatric diagnoses is being considered for inclusion with categorical criteria.1 Reframing ADHD under a neurodiversity model, rather than a medical model, has important ramifications:
- First, when the continuous nature of ADHD, as a trait, is recognized, the categorical distinction of "affected" versus "unaffected" will become less important because the underlying liability does not match this clinical distinction.
- Second, the continua underlying ADHD may be distinguished from the "disorder" in that the trait continua may be impairing in some environmental contexts and less impairing or even advantageous in others.
- Third, because genes influence neurodiversity, genetic blueprints of individuals will enable diag- nosis and treatment to be more individualized.
- Fourth, detection of genetic blueprints of neurobiology in individuals—before the onset of behavioral symptoms—will likely move intervention to prevention.
The empiric evidence supporting this reframing of ADHD arises from research on genetics and neurobiological correlates of ADHD over the past several decades.
It is clear that ADHD runs in families and that it is a highly heritable condition, with estimates at about 76% of the liability to ADHD being genetic.2 Excellent reviews are available summarizing genetic findings in ADHD based on such research.3-5 Genetic research has moved into molecular investigations with multiple groups working to define specific gene variants that contribute to ADHD liability using genome-wide and candidate gene approaches.
The first genome-wide scan was published by our group just following the first rough draft of the human genome; follow-up studies and 3 additional genome-wide scans occurred within 4 years.6-12 Several large-scale scans are currently under way by a number of other groups. These stud-ies support multiple gene locations and heterogeneity across populations. Candidate gene studies (as opposed to genome-wide approaches) lend support to multiple gene variants at several dopamine genes (receptors DRD4, DRD5, DRD2, dopamine transporter, and dopamine b-hydroxylase, to name a few), as well as genes involved in serotonin and other neurotransmitters.2 However, while excitement has been generated in this area, it should be stressed that none of the gene effects are large, generally with odds ratios of less than 1.5, and there are always positive and negative findings across different study populations.
Given the complex nature of ADHD, neurobiological research is focused on identifying the underlying continua that influence liability to ADHD, including various levels of measurement of brain functioning—from neuropsychological testing, electroencepha-lography (EEG), neurophysiological measurements, and neurochemistry, to anatomical and functional brain studies using MRI or functional MRI.
Various terms have been used to describe associated neurobiolog-ical continua, including "subclinical markers," "biomarkers," and "endophenotypes," the last term perhaps more specifically reserved for those measures that demonstrate heritable influences and are reflective of a subset of genes that influence liability.13 There are excellent reviews of neurobiological continua associated with ADHD,14-18 including cognitive functioning, temperament and affect regulation, and brain functioning as assessed by imaging techniques or EEG. Cognitive processes associated with ADHD include areas of language processing (eg, verbal fluency, reading, spelling), working memory, arousal, inhibition (the ability to inhibit a response), time estimation, and attention.14,15,19-22
In addition to cognitive processes, affect dysregulation is evident in ADHD from studies directly assessing emotional regulation or labeling and from studies of temperament differences.23,24 Several structural and functional brain regions are associated with ADHD,16,17,24,25 with brain size and prefrontal cortical structures perhaps being most prominent, followed by atypical right/left hemisphere asymmetries, and then by cerebellum and subcortical structure involvement (eg, basal ganglia, anterior cingulate, hippocampus, amygdala). Recent imaging studies support group differences in limbic structures (amygdala, hippocampus) involved in emotional response and frontal cortical modulation of such limbic structures.24,26 Functional imaging and EEG studies support underactive frontal cortical activity16-18,27 coupled with neurochemical findings of neurotransmitter systems (dopamine, serotonin, noradrenergic) that are known to be enriched in such regions.28,29
Taken together, the research supports multiple neural system involvement in ADHD, with differing com- positions of underlying factors contributing to the diverse clinical and subclinical variability observed in this condition. While most of the research, under a medical model of ADHD, has centered on deficits and problems that are associated with the condition, under a neurodiversity model, there is a need for more research on putative strengths associated with the atypical patterns of neural functioning. Future research may help to clarify the extent of such strengths, and environments in which strengths are enhanced, in ADHD.
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