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

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Presentation on theme: "Exploring the role of response inhibition in genetic risk and functional outcomes of ADHD Tara McAuley, Ph.D., C.Psych Assistant Professor of Psychology."— Presentation transcript:

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 WHAT IS RESPONSE INHIBITION? Part 1

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

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

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

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

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 CoffeeBeerWaterTeaCoffeeBeerSodaWaterSodaCoffeeJuiceTeaSoda Coffee

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

11 Inhibitory Development 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) spatial compatibility * * * Huizinga et al., 2006McAuley & 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; Chickazoe et al., 2007)

13 IS RESPONSE INHIBITION A MARKER OF GENETIC RISK FOR ADHD? Part 2

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 Proposed Validation Criteria 1Associated with the disorder 2Present in un-affected family members 3Aggregates in families 4State-independent 5Biologically plausible 6Heritable 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; Lijffijt et 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 probands who 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 Crosbie & Schachar, 2001 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

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

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) Twin 1 ace.50 NS.50 Twin 2 ace.50 NS.50 1/.50 1

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 globus pallidus (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 Proposed Validation Criteria 1Associated with the disorder 2Present in un-affected family members 3Aggregates in families 4State-independent 5Biologically plausible 6Heritable Endophenotypes

27 IS RESPONSE INHIBITION ASSOCIATED WITH FUNCTIONAL OUTCOMES ASSOCIATED WITH THE DISORDER? Part 3

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? S1 S2 S3 Situations A1 A2 A3 Aspects M1 M2 M3 Meanings Behavioural Physiological Experiential Emotional Response ANTECEDENT FOCUSEDRESPONSE FOCUSED Situation Selection Situation Modification Attentional Deployment Cognitive Change Response Modulation Gross, 2002

31 Impact on Mental Health MeasureCognitive ReappraisalExpressive Suppression Coping – reinterpretation.43*-.13* Coping – ventingNS-.43* TMM – attentionNS-.41* TMM – clarityNS-.30* TMM – repair.36*-.26* RuminationNS.18* Positive emotional experience.35*-.58* Negative emotional experience-.47*.36* Positive emotional expression.37*-.62* Negative emotional expression-.59*NS Depressive symptoms (BDI)-.23*.25* Gross & John, 2003

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

33 EF, ER, and Mental Health BRIEF :INH BRIEF :SHFT BRIEF :EC BRIEF :MON BRIEF : WM BRIEF :PO BRIEF :OM BRIEF :TC SCL: GSI ERQ: CR ERQ: ES

34 EF, ER, and Mental Health BRIEF :INH BRIEF :SHFT BRIEF :EC BRIEF :MON BRIEF : WM BRIEF :PO BRIEF :OM BRIEF :TC SCL: GSI ERQ: CR ERQ: ES Aspects of executive functioning are related to psychological concerns

35 EF, ER, and Mental Health BRIEF :INH BRIEF :SHFT BRIEF :EC BRIEF :MON BRIEF : WM BRIEF :PO BRIEF :OM BRIEF :TC SCL: GSI ERQ: CR ERQ: ES 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 BRIEF :INH BRIEF :SHFT BRIEF :EC BRIEF :MON BRIEF : WM BRIEF :PO BRIEF :OM BRIEF :TC SCL: GSI ERQ: CR ERQ: ES 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 Multifactorial polygenetic threshold model Response Inhibition Emotion Regulation Mental Health

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


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