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

Tara McAuley, Ph.D., C.PsychAssistant Professor of PsychologyUniversity of Waterloo

WHAT IS RESPONSE INHIBITION?Part 1

Mental Flexibility

Organization

Initiation

Response Inhibition

Planning Working Memory

Fluency

Monitoring

Self-regulation

Abilities that facilitate goal-oriented

behavior (Lezak, 1995)

Executive Functioning

Mental Flexibility

Organization

Initiation

Response Inhibition

Planning Working Memory

Fluency

Monitoring

Self-regulation

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

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

0.42

0.56

0.63

Mental flexibility, working memory, and response inhibition are separable though inter-related constructs…

Executive Functioning

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

0.42

0.56

0.63

WCST

Operation Span

Tower of Hanoi

…that are differentially related to higher-order aspects of executive control

Executive Functioning

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.

CoffeeBeerWaterTeaCoffeeBeerSodaWaterSodaCoffeeJuiceTeaSodaCoffee

Measurement

Go/No-Go Withhold a planned response

XStop Signal O O X Cancel an ongoing response

↓Spatial Compatibility

↘ ↙Overcome a prepotent response tendency

↓

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)

02468101214161820

EC LC A YA

spatial compatibility

7 11 15 21

*

*

*

Huizinga et al., 2006 McAuley & White, 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 core components of the response inhibition network (Aron et al., 2003; Chevrier et al., 2007; Chickazoe et al., 2007)

IS RESPONSE INHIBITION A MARKER OF GENETIC RISK FOR ADHD?

Part 2

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

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

Endophenotypes

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

ADHDANX

ASD MDOCD

ODD/CD

GAMB RD SCZSU

BST TS0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Weighted Mean ES

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

ADHD Proband

Affected Si

bling

Non-Affected Si

bling

Healthy C

ontrol

050

100150200250300350400

SSRT

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

Crosbie & Schachar, 2001

Family members with ADHD Family members w/o ADHD

ADHD poor inhibitorsSSRT = 510 ms

ADHD good inhibitorsSSRT = 205 ms

Healthy controlsSSRT = 232 ms

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

McAuley et al. (submitted)

Time 1 Time 2200

250

300

350

400

450

RemittedPersistently Symp-tomaticPersistently ImpairedFully Persistent

SSRT

(mse

c)

Time: F(1, 126) = 52.38**Group: NSTime x Group: NS

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

a c e

.50 NS .50

Twin 2

a c e

.50 NS .50

1/.50 1

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)

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

Endophenotypes

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

Part 3

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?

• S1• S2• S3

Situations

ANTECEDENT FOCUSED RESPONSE FOCUSED

Situation Selection

Situation Modification

Attentional Deployment

Cognitive Change

Response Modulation

Gross, 2002

Impact on Mental HealthMeasure Cognitive Reappraisal Expressive Suppression

Coping – reinterpretation .43* -.13*

Coping – venting NS -.43*

TMM – attention NS -.41*

TMM – clarity NS -.30*

TMM – repair .36* -.26*

Rumination 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*

Gross & John, 2003

Role of Executive Functioning

Multifactorial polygenetic threshold model

Response Inhibition

Emotion Regulation

Mental Health

EF, ER, and Mental Health

BRIEF:INH

BRIEF:SHFT

BRIEF:EC

BRIEF:MON

BRIEF: WM

BRIEF:PO

BRIEF:OM

BRIEF:TC

SCL: GSI

SCL: GSI .78 .85 .72 .72 .69 .45 .04 .75 ---

ERQ: CR -.05 .02 -.12 .09 -.29 -.32 -.21 .11 -.24

ERQ: ES .47 .31 .20 .09 -.02 -.09 .00 .22 .49

EF, ER, and Mental Health

BRIEF:INH

BRIEF:SHFT

BRIEF:EC

BRIEF:MON

BRIEF: WM

BRIEF:PO

BRIEF:OM

BRIEF:TC

SCL: GSI

SCL: GSI .78 .85 .72 .72 .69 .45 .04 .75 ---

ERQ: CR -.05 .02 -.12 .09 -.29 -.32 -.21 .11 -.24

ERQ: ES .47 .31 .20 .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

BRIEF: WM

BRIEF:PO

BRIEF:OM

BRIEF:TC

SCL: GSI

SCL: GSI .78 .85 .72 .72 .69 .45 .04 .75 ---

ERQ: CR -.05 .02 -.12 .09 -.29 -.32 -.21 .11 -.24

ERQ: ES .47 .31 .20 .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

BRIEF: WM

BRIEF:PO

BRIEF:OM

BRIEF:TC

SCL: GSI

SCL: GSI .78 .85 .72 .72 .69 .45 .04 .75 ---

ERQ: CR -.05 .02 -.12 .09 -.29 -.32 -.21 .11 -.24

ERQ: ES .47 .31 .20 .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

Multifactorial polygenetic threshold model

Response Inhibition

Emotion Regulation

Mental Health

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

CollaboratorsDesiree White

Russell SchacharJennifer CrosbieChristine Purdon

CAN LabAmi Rints

Siobhan Torrie