Exploring the role of response inhibition in genetic risk and functional outcomes of ADHD

1. Exploring the role of response inhibition in genetic risk and functional outcomes of ADHD Tara McAuley, Ph.D., C.Psych Assistant Professor of Psychology University of Waterloo

2. Part 1 What is response inhibition?

3. Executive Functioning Abilities that facilitate goal-oriented behavior (Lezak, 1995)

4. Executive Functioning • Central to theories of EF (e.g., Lyon & Krasnegor, 1996) • Can be dissociated behaviourally after brain insult (e.g., Bechara et al., 1998; Hildebrandt et al., 2004) • Supported by overlapping, though distinct, neural networks (Aron et al., 2004; Cohen et al., 2004) Abilities that facilitate goal-oriented behavior (Lezak, 1995)

5. Executive Functioning Mental flexibility, working memory, and response inhibition are separable though inter-related constructs… Plus-minus Mental Flexibility Number-letter Local-global 0.56 Keep-track Working Memory 0.42 Tone monitoring Letter memory 0.63 Anti-saccade Response Inhibition Stop signal Stroop Miyake et al., 2000

6. Executive Functioning …that are differentially related to higher-order aspects of executive control Plus-minus Mental Flexibility Number-letter Local-global WCST 0.56 Keep-track Working Memory 0.42 Tone monitoring Letter memory Operation Span 0.63 Anti-saccade Response Inhibition Stop signal Stroop Tower of Hanoi Miyake et al., 2000

7. Response Inhibition Creates the space for us to stop, think, and engage in alternative behaviours, and thus avoid acting in ways that are purposeless, embarrassing, or dangerous.

8. Measurement You will see words one at a time. Clap each time you see a word, unless the word is COFFEE. If the word is COFFEE, don’t clap.

9. Coffee Beer Water Tea Coffee Beer Soda Water Soda Coffee Juice Tea Soda Coffee

10. X ↓ Measurement Overcome a prepotent response tendency ↓ Spatial Compatibility ↘ ↙ Withhold a planned response Go/No-Go Stop Signal O O Cancel an ongoing response X

11. Inhibitory Development spatial compatibility * • Response inhibition emerges in infancy (Diamond, 1985; Wellman et al., 1987) • Refinements occur during childhood (Gerstadt et al,. 1994; McAuley et al., 2011) • Improvements continue into adolescence/adulthood (Huizinga et al., 2006; McAuley & Whilte, 2010) * * 7 11 15 21 Huizinga et al., 2006 McAuley & White, 2010

12. Neural Substrates • Parallel circuits connect cortex and basal ganglia (Alexander et al., 1986) • Inhibitory deficits observed following lesions along the ventral frontostriatal circuit (Chao & Knight, 1995; Iverson & Mishkin, 1970) • IFG and basal ganglia are core components of the response inhibition network (Aron et al., 2003; Chevrier et al., 2007; Chickazoeet al., 2007)

13. Part 2 Is response inhibition a marker of genetic risk for ADHD?

14. ADHD • Phenotype consists of 6+ impairing symptoms that appear before age 7 • Genetic mechanisms remain elusive • Endophenotypes are more proximal to genetic causes and may be markers for the etiology of the disorder Multifactorial polygenetic threshold model

15. Endophenotypes

16. Association with Disorder • If response inhibition is a marker of genetic risk, deficits should be common in ADHD and relatively unique to the disorder • Meta-analytic studies have shown that ADHD is associated with deficits in response inhibition (Alderson et al., 2007; Lijffijtet al., 2005; Oosterlaan et al., 1998) • However, there are limitations to these studies: • Other clinical groups not well-represented • Near exclusive focus on children • Methodological quality not taken into account

17. Association with Disorder * * * * * Lipszyc & Schachar, 2010

18. Unaffected Family Members • If response inhibition is a marker of genetic risk, then deficits in response inhibition should be more common in unaffected family members of ADHD probands • Family members share genes, thus an endophenotype influenced by genetic factors should be observed in relatives who do not have the disorder • Implication is that the endophenotype can detect asymptomatic genetic carriers and/or those with incomplete penetrance of the disease-causing genotype

19. Unaffected Family Members Schachar et al., 2005

20. Familial Aggregation • If response inhibition is a marker of genetic risk, then response inhibition should predict family history of the disorder in ADHD probandswho are poor inhibitors • Family members share genes, thus an endophenotype influenced by genetic factors should give rise to the clinical manifestations of the disorder in some relatives

21. Familial Aggregation Family members with ADHD Family members w/o ADHD ADHD poor inhibitors SSRT = 510 ms ADHD good inhibitors SSRT = 205 ms Healthy controls SSRT = 232 ms Crosbie & Schachar, 2001

22. State-independence • If response inhibition is a marker of genetic risk, then deficits in response inhibition should persist irrespective of disease progression • Although ADHD behaviour may vary, response inhibition remains stable (Soreni et al., 2007) • Deficits in response inhibition have been identified in ADHD individuals of every age, but we don’t know if it persists in those who outgrow the disorder

23. State-independence Time: F(1, 126) = 52.38** Group: NS Time x Group: NS McAuley et al. (submitted)

24. Heritability • If response inhibition is a marker of genetic risk, then individual differences should at least partly reflect genetic factors • Twin studies provide compelling evidence of a significant genetic contribution (e.g., Kuntsi et al., 2006; Schachar et al., 2011; Young et al., 2009) 1 1/.50 a c e a c e .50 .50 .50 .50 NS NS Twin 1 Twin 2

25. Biological Plausibility • If response inhibition is a marker of genetic risk, then it should be related to the biological basis of ADHD • ADHD associated with reduced prefrontal cortical volumes, especially IFG (Castellanos et al., 2002; Sowell et al., 2003) • ADHD is associated with smaller volumes in the caudate and globuspallidus(Bush et al., 1999; Valera et al., 2003) • ADHD show less activation in frontal brain regions during inhibitory tasks (Rubia et al., 2000, 2002; Shulz et al., 2004) • Inhibitory tasks also give rise to group differences in activation of basal (Durston et al., 2003)

26. Endophenotypes

27. Part 3 Is response inhibition associated with functional outcomes associated with the disorder?

28. ADHD and Comorbidity

29. ADHD and Emotion Regulation Problems with emotion regulation may look like: • Being easily frustrated • Being touchy or easily annoyed • Arguing with others • Easily losing one’s temper • Being resentful • Prone to tears

30. Emotion Regulation? Response Modulation Situation Selection Situation Modification Attentional Deployment Cognitive Change ANTECEDENT FOCUSED RESPONSE FOCUSED Gross, 2002

31. Impact on Mental Health Gross & John, 2003

32. Role of Executive Functioning Mental Health Emotion Regulation Response Inhibition Multifactorial polygenetic threshold model

33. EF, ER, and Mental Health

34. EF, ER, and Mental Health • Aspects of executive functioning are related to psychological concerns

35. EF, ER, and Mental Health • Aspects of executive functioning are related to psychological concerns • Working memory and planning are related to cognitive reappraisal, whereas inhibition and shifting are related to suppression

36. EF, ER, and Mental Health • Aspects of executive functioning are related to psychological concerns • Working memory and planning are related to cognitive reappraisal, whereas inhibition and shifting are related to suppression • Suppression, but not reappraisal, is related to psychological symptoms and impairment

37. Role of Executive Functioning Mental Health Emotion Regulation Response Inhibition Multifactorial polygenetic threshold model

38. Summary • Response inhibition is a key executive skill that enables us to effectively navigate an ever-changing environment • Response inhibition has a protracted course of development and is supported by maturation of a frontostriatal network featuring IFG and basal ganglia • Response inhibition is implicated in ADHD and has been identified as a candidate endophenotype of the disorder, meaning that it is a possible marker of genetic risk • Response inhibition may also play a role in outcomes that are frequently associated with ADHD, such social-emotional concerns, though this is an area in need of more research

39. Acknowledgments Collaborators Desiree White Russell Schachar Jennifer Crosbie Christine Purdon CAN Lab Ami Rints Siobhan Torrie