Reframing ADHD in the Genomic Era

Table

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.

Reframing ADHD

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.

Genetics

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.

Neurobiology

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 activity^16-18,27 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.

Potential strengths in ADHD

The neurobiological research in ADHD suggests several neural systems that may contribute to putative strengths. For example, the atypical right/left cerebral asymmetries and a right hemisphere "bias" observed in ADHD³⁰ may contribute to insight problem solving,^31,32 intuition, or creativity,^33,34 as well as self-transcendence (a character component of personality).³⁵ Adults with ADHD have been shown to score more highly on measures of self-transcendence,³⁶ a trait associated with improved survival after illness or end-of-life stages,³⁷ although this finding requires replication. Novelty-seeking, a temperament trait, is associated with ADHD,³⁶ and this construct may be associated with creativity and innovation,³⁸ while daydreaming (a common behavioral feature of ADHD) may be associated with creativity and learning.^35,39

These traits (daydreaming, creativity, intuition, self-transcendence) require more rigorous research because they may reflect strengths of neurobiological continua associated with ADHD that may be enhanced in certain environmental settings. Further work is warranted to elucidate the relative influence of these continua with ADHD and how recognition and enhancement of these traits may serve to improve the quality of life and minimize impairment associated with ADHD.

A neurodiversity framework

Reframing ADHD as an atypical mode of neural functioning often associated with impairment takes it out of a categorical diagnosis of a medical disorder into a neurodiversity framework that highlights the relationship of our genomes to our brains and behavior and sets the foundation for change in how we, as a community, view ADHD.

This reconceptualization of ADHD as a trait does not minimize that it can be and often is "impairing" and that individuals who have ADHD may need professional help. However, it places a more significant burden of responsibility for reducing impairment within the context of the community and social networks in which the child is raised or the adult lives.

Empirical data support the strong role that family environmental stress can have on the impairment associated with ADHD but not necessarily on the development of the trait per se.⁴⁰ Reframing ADHD within the context of a neurodiversity model may shift some of the responsibility of change onto the social settings in which children are raised (school systems, family systems, health care systems) rather than the child. Specifically, providing education and discussion as a community of ADHD as an extreme on a normal continuum is important for destigmatizing the diagnosis. This approach may, in and of itself, help reduce impairment in ADHD and reduce comorbid psychiatric sequelae (low self-esteem, depression, substance abuse) because the environment within which the child, adolescent, or adult functions may be less shame-inducing and more embracing of diversity.

Recognizing the nature of impairment

The relative nature of impairment must be recognized and discussed to highlight the individual child's strengths and difficulties and to design the best programs for fostering growth of strengths and management of difficulties. The increased prevalence of ADHD over the past several decades reflects a broadening definition of a disorder, in part, because impairment is evident in a greater proportion of individuals at the extremes of population continua. This shift is, in part, due to the recognition of impairment associated with inattentive symptoms, with few or no symptoms of hyperactivity-impulsivity (ie, the inattentive subtype). The expansion of ADHD classification may reflect the increasing cultural focus on and perceived value of what might be considered simplis-tically left hemisphere, language-based, product-oriented behavior (ie, "doing") at the expense of possibly more right hemisphere–oriented activities-nonlinear, nonlanguage-based, creative, intuitive processes (ie, "being.").

The current emphasis on the former in our schools and workplaces, at the expense of the latter, is fostering greater impairment (ie, stress) at the population level in general, and particularly for those who are inherently more oriented toward "being." Most important, we need to address at a cultural level what we deem important in education, perhaps increasing the value we place on creativity, reflection, and awareness practices, to balance the emphasis on doing and producing.

Individualized treatment

Individualized medicine will become of greater importance as specific gene patterns are identified that respond differently to pharmaceutical interventions. Even with improved community, family, and self-regulatory tools (discussed below), there will be children/adults along continua associated with ADHD in whom pharmaceutical intervention will be most beneficial to manage or minimize impairment.

In the future, DNA-based diagnostics will allow more carefully designed drug interventions that target specific biochemical profiles. Ongoing pharmacogenomic studies are beginning to investigate drug efficacy as a function of specific gene variants that may lead to increased improvement or more individually tailored treatments. Yet, as of today, there are no genes sufficiently validated or specific enough to warrant their use in clinical practice.

Prevention

Intervention for the most part will shift to prevention of impairment. It is clear from emerging work in gene expression that genetic does not mean fixed. While we are born with a genetic blueprint, the diversity of gene expression stemming from that blueprint is largely a function of environmental influences. The 21st century will likely yield radically new insights into a range of diversity based on gene regulation and what we as parents, clinicians, and individuals can do to modify gene expression.

While psychosocial and behavioral interventions have yet to be shown to be strong factors in ADHD treatment, they may prove to be extremely valuable-perhaps in a cumulative way-for promoting resiliency and prevention of impairment if initiated early. There is a need to invest in more research of behavioral tools that are likely to be more conducive to prevention than pharmaceutical interventions, since taking medications before the onset of symptoms is highly unlikely.

Self-regulatory practices, such as exercise, attention and memory training, meditation, and biofeedback, may provide small but positive effects on particular brain and body networks involved in ADHD.^41-43 Perhaps, just as diet and exercise promote a healthy heart, multiple behavioral changes will be necessary to promote emotional and learning well-being. Furthermore, as with dyslexia, the earlier the introduction of behavioral tools, the better the outcome.⁴⁴ These behavioral tools may help children and adults with ADHD learn to self-regulate. There is a need for extensive and rigorous research in this area.

One area of increasing interest is the role of "self-regulatory" tools in biological and brain change. Biofeedback, neurofeedback, meditation, and brain-training tools may prove more beneficial to neural regulation (and self-regulation of gene expression) as we move from intervention to prevention. Exciting research on such mechanisms with neural circuits underlying attention, memory, and emotional regulation has emerged in the past decade, suggesting that this is an important area of research in ADHD.^45-48 Our laboratory recently applied a mindfulness meditation program in a small, uncontrolled study in adults and teens and found beneficial effects,⁴⁹ and research on neural structures and networks underlying attention have shown that mindfulness meditation does lead to significant cognitive brain changes in non-ADHD populations.^50,51 These sorts of studies, while intriguing, require large database study, because other small studies of alternative approaches have not-in large study designs-proved to be effective.⁵² It is imperative, nevertheless, that research begins to target more programs that may be easily translated into impairment prevention models that maximize strengths, as genetic risk detection becomes possible. Basic research investigating the mechanisms of action of such tools is needed to provide the scientific rational for their application in ADHD.

Limitations of the model

Notwithstanding the advantages of a neurodiversity model, there are potential pitfalls with this conceptual framework. First and foremost is the impact such a model might have on treatment services. Under a medical model, ADHD is recognized as a disorder that warrants medical attention. The absence of such a framework might make access to services more limited instead of creating increased attention and access to resources by a broader range of individuals, families, and programmatic services. Introducing quantitative criteria into the diagnostic classification of ADHD¹ may be a first step in a transition from categorical "medical model" classification to a more hybrid approach (continuous and categorical) that better reflects the continuous nature of the underlying condition.

Second, interpretation of ADHD as a variant along continua may be misinterpreted as implying that there is a single underlying genetically mediated continuum accounting for ADHD. This is definitely not the case, as is reflected by both molecular and neuropsychological research to date. As with other complex traits-such as heart disease-there are likely to be multiple genes influencing ADHD liability-genes that contribute to emotional regulation, attention, right/left hemisphere asymmetry, or temperament-all of which may be expected to vary in intensity across individuals with ADHD. Heterogeneity will likely be the norm, and as genes are uncovered that contribute to ADHD liability, they will differ in effect size from small to medium across individuals, families, and populations and also as a function of environment experience.

Conclusion and summary

Reframing ADHD in the genomic era means shifting our view of it as solely a medical disorder to viewing it as a complex and heritable trait composed of 1 or more continua of neural functioning in the population. Impairment arises as a function of the less common (atypical) nature of neural functioning and the subsequent difficulties arising within cultural or social norms. Different genes and environments contribute to these continua and vary across individuals and populations. Reframing ADHD from this perspective means:

• A greater emphasis toward treatment and prevention in the social networks of the child or adult.
• Increased research on strengths associated with ADHD as well as difficulties.
• Individual treatment tailored toward high-risk genes.
• The development of preventive modalities to reduce the impairment associated with atypical neural processing.

Hazards associated with a shift away from a medical model of ADHD include potential reduced services and misunderstanding of the heterogeneous nature of the condition. Inclusion of both continuous and categorical criteria for diagnoses may be a first step in recognizing the continuous nature of the disorder itself.

References:

References

1. Helzer JE, Kraemer HC, Krueger RF. The feasibility and need for dimensional psychiatric diagnoses. Psychol Med. 2006;36:1671-1680.

2. Faraone SV, Perlis RH, Doyle AE, et al. Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005;57:1313-1323.

3. Khan SA, Faraone SV. The genetics of ADHD: a literature review of 2005. Curr Psychiatry Rep. 2006;8: 393-397.

4. Waldman ID, Gizer IR. The genetics of attention deficit hyperactivity disorder. Clin Psychol Rev. 2006;26: 396-432.

5. Thapar A, O'Donovan M, Owen MJ. The genetics of attention deficit hyperactivity disorder. Hum Mol Genet. 2005;14:R275-R282.

6. Fisher SE, Francks C, McCracken JT, et al. A genome- wide scan for loci involved in attention-deficit/ hyperactivity disorder. Am J Hum Genet. 2002;70:1183-1196.

7. Venter JC, Adams MD, Myers EW, et al. The sequence of the human genome [published correction appears in Science. 2001;292:1838]. Science. 2001;291: 1304-1351.

8. Ogdie MN, Macphie IL, Minassian SL, et al. A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet. 2003;72:1268-1279.

9. Ogdie MN, Fisher SE, Yang M, et al. Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. Am J Hum Genet. 2004;75:661-668.

10. Bakker SC, van der Meulen EM, Buitelaar JK, et al. A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet. 2003;72:1251-1260.

11. Arcos-Burgos M, Castellanos FX, Pineda D, et al. Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet. 2004;75:998-1014.

12. Hebebrand J, Dempfle A, Saar K, et al. A genome-wide scan for attention-deficit/hyperactivity disorder in 155 German sib-pairs. Mol Psychiatry. 2006;11: 196-205.

13. Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003;160:636-645.

14. Nigg J. Neuropsychologic theory and findings in attention deficit/hyperactivity disorder: the state of the field and salient challenges for the coming decade. Biol Psychiatry. 2005;57:1424-1435.

15. Doyle AE, Faraone SV, Seidman LJ, et al. Are endophenotypes based on measures of executive functions useful for molecular genetic studies of ADHD? J Child Psychol Psychiatry. 2005;46:774-803.

16. Giedd JN, Blumenthal J, Molloy E, Castellanos FX. Brain imaging of attention deficit/hyperactivity disorder. Ann N Y Acad Sci. 2001;931:33-49.

17. Bush G, Valera EM, Seidman LJ. Functional neuroimaging of attention-deficit/hyperactivity disorder: a review and suggested future directions. Biol Psychiatry. 2005;57:1273-1284.

18. Snyder SM, Hall JR. A meta-analysis of quantitative EEG power associated with attention-deficit hyperactivity disorder. J Clin Neurophysiol. 2006;23: 440-455.

19. Seidman LJ, Biederman J, Valera EM, et al. Neuropsychological functioning in girls with attention-deficit/hyperactivity disorder with and without learning disabilities. Neuropsychology. 2006;20:166-177.

20. Nigg JT, Blaskey LG, Stawicki JA, Sachek J. Evaluation the endophenotypes model of ADHD neuropsychological deficit: results for parents and siblings of children with ADHD combined and inattentive subtypes. J Abnorm Psychol. 2004;113:614-625.

21. Verte S, Geurts HM, Roeyers H, et al. The relationship of working memory, inhibition, and response variability in child psychopathology. J Neurosci Methods. 2006;151:5-14.

22. Toplak ME, Dockstader C, Tannock R. Temporal information processing in ADHD: findings to date and new methods. J Neurosci Methods. 2006;151:15-29.

23. Panzer A, Viljoen M. Supportive neurodevelopmental evidence for ADHD as a developmental disorder. Med Hypotheses. 2005;64:755-758.

24. Plessen KJ, Bansal R, Zhu H, et al. Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder. Arch Gen Psychiatry. 2006;63:795-807.

25. Krain AL, Castellanos FX. Brain development and ADHD. Clin Psychol Rev. 2006;26:433-444.

26. Cardinal RN, Winstanley CA, Robbins TW, Everitt BJ. Limbic corticostriatal systems and delayed reinforcement. Ann N Y Acad Sci. 2004;1021:33-50.

27. Loo SK, Barkley RA. Clinical utility of EEG in attention deficit hyperactivity disorder. Appl Neuropsychol. 2005; 12:64-76.

28. Arnsten AF. Fundamentals of attention-deficit/ hyperactivity disorder: circuits and pathways. J Clin Psychiatry. 2006;67:7-12.

29. Levy F, Swanson JM. Timing, space and ADHD: the dopamine theory revisited. Aust N Z J Psychiatry. 2001; 35:504-511.

30. Hale TS, Zaidel E, McGough JJ, et al. Atypical brain laterality in adults with ADHD during dichotic listening for emotional intonation and words. Neuropsychologia. 2006;44:896-904.

31. Jung-Beeman M, Bowden EM, Haberman J, et al. Neural activity when people solve verbal problems with insight. PLoS Biol. 2004;2:e97.

32. Beeman MJ, Bowden EM. The right hemisphere maintains solution-related activation for yet-to-be-solved problems. Mem Cognit. 2000;28:1231-1241.

33. Brugger P, Graves RE. Right hemispatial inattention and magical ideation. Eur Arch Psychiatry Clin Neurosci. 1997;247:55-57.

34. Weinstein S, Graves RE. Are creativity and schizotypy products of a right hemisphere bias? Brain Cogn. 2002;49:138-151.

35. Cloninger CR. Feeling Good: The Science of Well-Being. New York: Oxford University Press, Inc; 2004.

36. Lynn DE, Lubke G, Yang M, et al. Temperament and character profiles and the dopamine D4 Receptor gene in ADHD. Am J Psychiatry. 2005;162:906-913.

37. Coward DD, Reed PG. Self-transcendence: a resource for healing at the end of life. Issues Ment Health Nurs. 1996;17:275-288.

38. Schweizer TS. The psychology of novelty-seeking, creativity and innovation: neurocognitive aspects within a work-psychological perspective. Creativity and Innovation Management. 2006;15:164-172.

39. Mueller ET, Dyer MG. Daydreaming in humans and computers. Proceedings of the Ninth International Joint Conference on Artificial Intelligence. University of California, Los Angeles: August 18-24, 1985.

40. Pressman LJ, Loo SK, Carpenter EM, et al. Relationship of family environment and parental diagnosis to impairment in ADHD. J Am Acad Child Adolesc Psychiatry. 2006;45:346-354.

41. Arnold LE. Alternative treatment for adults with attention-deficit hyperactivity disorder (ADHD). Ann N Y Acad Sci. 2001;931:310-341.

42. Haffner J, Roos J, Goldstein N, et al. The effectiveness of body-oriented methods of therapy in the treatment of attention-deficit hyperactivity disorder (ADHD): results of a controlled pilot study [in German]. Z Kinder Jugendpsychiatr Psychother. 2006;34:37-47.

43. Klingberg T, Fernell E, Olsen PJ, et al. Computerized training of working memory in children with ADHD-a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2005;44:177-186.

44. Foorman BR, Breier JI, Fletcher JM. Interventions aimed at improving reading success: an evidence-based approach. Dev Neuropsychol. 2003;24:613-639.

45. Schwartz JM, Begley S. The Mind and the Brain: Neuroplasticity and the Power of Mental Force. New York: Regan Books; 2002.

46. Davidson R. Meditation and neuroplasticity: training your brain. Interview by Bonnie J. Horrigan. Explore (NY). 2005;1:380-388.

47. Davidson RJ, Kabat-Zinn J, Schumacher J, et al. Alterations in brain and immune function produced by mindfulness meditation. Psychosom Med. 2003;65: 564-570.

48. Brown KW, Ryan RM, Creswell JD. Mindfulness: theoretical foundations and evidence for its salutary effects. Psychological Inquiry. In press.

49. Zylowska L, Ackerman DL, Yang MH, et al. Behavioral and cognitive changes in attention deficit hyperactivity disorder using mindfulness meditation approach. J Atten Disord. In press.

50. Jha AP, Krompinger J, Baime MJ. Mindfulness training modifies subsystems of attention. Cogn Affect Behav Neurosci. 2007;7:109-119.

51. Lazar SW, Kerr CE, Wasserman RH, et al. Meditation experience is associated with increased cortical thickness. Neuroreport. 2005;16:1893-1897.

52. Ospina MB, Bond K, Karkhaneh M, et al. Meditation Practices for Health: State of the Research. AHRQ Publication: Evidence Report/Technology Assessment. No. 155. 2007;07-E010:1-472.