Exploring the role of response inhibition in genetic

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

Part 1 WHAT IS RESPONSE INHIBITION?

Executive Functioning Mental Flexibility Organization Self-regulation Monitoring Abilities that facilitate goal-oriented behavior Initiation (Lezak, 1995) Response Inhibition Fluency Working Memory Planning

Executive Functioning • Central to theories of EF Mental Flexibility Selfregulation Monitoring Organization Abilities that facilitate goal-oriented behavior Initiation Response Inhibition Working Memory Planning • Can be dissociated behaviourally after brain insult (e. g. , Bechara et al. , 1998; Hildebrandt et al. , 2004) (Lezak, 1995) Fluency (e. g. , Lyon & Krasnegor, 1996) • Supported by overlapping, though distinct, neural networks (Aron et al. , 2004; Cohen et al. , 2004)

Executive Functioning Mental flexibility, working memory, and response inhibition are separable though inter-related constructs… Plus-minus Number-letter Mental Flexibility Local-global 0. 56 Keep-track Tone monitoring Working Memory 0. 42 Letter memory 0. 63 Anti-saccade Stop signal Stroop Response Inhibition Miyake et al. , 2000

Executive Functioning …that are differentially related to higher-order aspects of executive control Plus-minus Number-letter Mental Flexibility WCST Local-global 0. 56 Keep-track Tone monitoring Working Memory 0. 42 Operation Span Letter memory 0. 63 Anti-saccade Stop signal Stroop Response Inhibition Tower of Hanoi Miyake et al. , 2000

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.

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.

Coffee Water Soda Juice Beer Tea

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

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

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 components of the response inhibition network (Aron et al. , 2003; Chevrier et al. , 2007; Chickazoe et al. , 2007)

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

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

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

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

Association with Disorder 0, 9 * 0, 8 0, 7 0, 6 * * 0, 5 * 0, 4 0, 3 * Weighted Mean ES 0, 2 0, 1 TS SC SU Z BS T OD D/ CD GA M B RD D OC D M AS D AD HD AN X 0 Lipszyc & Schachar, 2010

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

Unaffected Family Members 400 350 300 250 200 SSRT 150 100 50 0 ADHD Proband Affected Sibling Non-Affected Healthy Control Sibling Schachar et al. , 2005

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

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

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

State-independence 450 400 SSRT (msec) Remitted Persistently Symptomatic 350 Persistently Impaired Fully Persistent 300 250 200 Time: F(1, 126) = 52. 38** Group: NS Time x Group: NS Time 1 Time 2 Mc. Auley et al. (submitted)

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. 50 NS Twin 1 e. 50 a c. 50 NS Twin 2 e. 50

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)

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

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

ADHD and Comorbidity

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

Emotion Regulation? Aspects • S 1 • S 2 • S 3 Situations Situation Selection • A 1 • A 2 • A 3 Situation Modification Emotional Response • M 1 • M 2 • M 3 Meanings Attentional Deployment ANTECEDENT FOCUSED Cognitive Change • Behavioural • Physiological • Experiential Response Modulation RESPONSE FOCUSED Gross, 2002

Impact on Mental Health Measure Coping – reinterpretation Cognitive Reappraisal Expressive Suppression . 43* -. 13* Coping – venting NS -. 43* TMM – attention NS -. 41* TMM – clarity NS -. 30* TMM – repair . 36* -. 26* NS . 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* Rumination Gross & John, 2003

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

EF, ER, and Mental Health BRIEF : INH BRIEF : SHFT BRIEF : EC BRIEF : MON : WM BRIEF : PO BRIEF : OM BRIEF : TC SCL: GSI . 78 . 85 . 72 ERQ: CR -. 05 . 02 -. 12 ERQ: ES . 47 . 31 . 20 SCL: GSI . 69 . 45 . 04 . 75 --- . 09 -. 29 -. 32 -. 21 . 11 -. 24 . 09 -. 02 -. 09 . 00 . 22 . 49

EF, ER, and Mental Health BRIEF : INH BRIEF : SHFT BRIEF : EC BRIEF : MON : WM BRIEF : PO BRIEF : OM BRIEF : TC SCL: GSI . 78 . 85 . 72 ERQ: CR -. 05 . 02 -. 12 ERQ: ES . 47 . 31 . 20 SCL: GSI . 69 . 45 . 04 . 75 --- . 09 -. 29 -. 32 -. 21 . 11 -. 24 . 09 -. 02 -. 09 . 00 . 22 . 49 • Aspects of executive functioning are related to psychological concerns

EF, ER, and Mental Health BRIEF : INH BRIEF : SHFT BRIEF : EC BRIEF : MON : WM BRIEF : PO BRIEF : OM BRIEF : TC SCL: GSI . 78 . 85 . 72 ERQ: CR -. 05 . 02 -. 12 ERQ: ES . 47 . 31 . 20 SCL: GSI . 69 . 45 . 04 . 75 --- . 09 -. 29 -. 32 -. 21 . 11 -. 24 . 09 -. 02 -. 09 . 00 . 22 . 49 • 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

EF, ER, and Mental Health BRIEF : INH BRIEF : SHFT BRIEF : EC BRIEF : MON : WM BRIEF : PO BRIEF : OM BRIEF : TC SCL: GSI . 78 . 85 . 72 ERQ: CR -. 05 . 02 -. 12 ERQ: ES . 47 . 31 . 20 SCL: GSI . 69 . 45 . 04 . 75 --- . 09 -. 29 -. 32 -. 21 . 11 -. 24 . 09 -. 02 -. 09 . 00 . 22 . 49 • 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

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

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

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