exploring the role of response inhibition in genetic risk and functional outcomes of adhd tara...
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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
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.
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)
0
2
4
6
8
10
12
14
16
18
20
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)
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 MD
OCD
ODD/CD
GAMB RD SC
ZSU
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 Proban
d
Affected Si
bling
Non-Affecte
d Siblin
g
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
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