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
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
McAuley & White, 2010
• 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)
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)
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
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
ADHD poor inhibitors
SSRT = 510 ms
Family members w/o ADHD
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
McAuley 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
• S1
• S2
• S3
Situations
Situation
Selection
• A1
• A2
• A3
Situation
Modification
Emotional
Response
• M1
• M2
• M3
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 BRIEF
:INH
:SHFT
BRIEF BRIEF BRIEF
:EC
:MON : WM
BRIEF BRIEF
:PO
:OM
BRIEF SCL:
:TC
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 BRIEF
:INH
:SHFT
BRIEF BRIEF BRIEF
:EC
:MON : WM
BRIEF BRIEF
:PO
:OM
BRIEF SCL:
:TC
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 BRIEF
:INH
:SHFT
BRIEF BRIEF BRIEF
:EC
:MON : WM
BRIEF BRIEF
:PO
:OM
BRIEF SCL:
:TC
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 BRIEF
:INH
:SHFT
BRIEF BRIEF BRIEF
:EC
:MON : WM
BRIEF BRIEF
:PO
:OM
BRIEF SCL:
:TC
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
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