Pharmacological modulation of response
inhibition – target identification using fMRI
Mitul Mehta
UCL – Nov 15 2013
Imaging at Denmark Hill
Maurice Wohl Clinical
Neuroscience Institute
Clinical Research
Facility
C.N.S.
Maudsley
Hospital
Institute of
Psychiatry
James Black Centre
St. Thomas’
PET Centre
Response inhibition
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The ability to inhibit a motor
response
Or the ability to not respond in a
task appropriate manner
A key component of cognitive
control
Impaired in many psychiatric
conditions, neurological disorders
and following brain injury
Measuring response inhibition
GO/NO-GO
Design
STOP SIGNAL
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Inhibitory
performance
e.g., Aron et al. (2006)
e.g., Konishi et al. (1999)
percent of responses to
no-go stimuli
The stop signal task
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Stop signals are required to be:
+
+
Thanks to P Boulinguez for the horse pic!
•
Unpredictable
•
(Infrequent)
•
Able to trigger a process
independent of the go signal
Meta-analysis of stop signal tasks
Rae et al. (2013) Neuroimage in press
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Problem #1
If stop signals are infrequent they will
be salient, attention grabbing and
arousing
To what extent are brain activations
to the stop signal due to response
cancellation?
Sharp et al. (2010) PNAS
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IFG – stop AND continue
SMA – STOP AND slow
Sharp et al. 2010 PNAS
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Identical stop signal tasks
Different instructions
Inhibit – cancel response
Target detect – count no of
up arrows
Sharp et al. 2010 PNAS
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•
16 healthy volunteers
•
40mg methylphenidate or placebo
•
Double blind crossover
Go signal
Stop trials 20%
Time
Continue trials 20%
•
Hypotheses:
The effect of methylphenidate on right IFG activation
would be associated with attentional capture, and
would hence be observed during both successful
inhibition and attentional capture trials
methylphenidate will modulate performance-monitoring
networks during failed inhibition
Pauls et al. (2012) Biological Psychiatry
Overview of mechanism of action of stimulant
treatments
Methylphenidate / amphetamine
The effects of methylphenidate on IFG activity
STOP versus GO
Reductions on methylphenidate
1
2
Pauls et al. (2012) Biological Psychiatry
Regions modulated show different connectivity
Continue vs go
2
Go signal
Stop trials 20%
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Stop vs go
1
Time
Continue trials 20%
1
2
Pauls et al. (2012) Biological Psychiatry
What happens during errors?
Pauls et al. 2012 Biol Psych; Hester et al. 2012 J Neurosci
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Neuroimaging studies of ATX (published)
• Also increased activation in right IFG during failed + successful
response inhibition trials (Chamberlain et al, 2009)
• ATX increases activity in bilateral IFG and SMA (Graf et al. 2011)
Chamberlain et al. (2009) Biol Psychiatry
Response inhibition & drug effects
•
Stop signal tasks require multiple processes for
success and these can be separated along lines of
stimulus capture and outright inhibition (at least)
•
Effects of methylphenidate reveal the IFG role to be
complex and multifactorial
•
Additional roles of other brain regions (e.g.
putamen) may be related to other aspect of
inhibitory tasks
•
The concepts of behavioural inhibition as measures
by SSRT are insufficiently precise in earlier studies
and our findings suggest that a reappraisal of
deficits and treatment effects in ADHD is warranted
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Go / nogo
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Effects of methylphenidate during a go/no-go task
Costa et al. (2013) Cereb Cortex
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Varieties of go/no-go
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GO/NO-GO
The STANDARD MODEL
The ALTERNATIVE MODEL
PROACTIVE
REACTIVE
PROACTIVE INHIBITORY CONTROL
How to do to get this true
unbiased control condition?
180
Go
Go
control
Number of trials
NoGo
Go control
Go
20
0.5
1
Normalized Reaction Time
The proactive inhibition model
Proactive
Inhibition
External
Stimulus
Motor Output
Trigger
Automatic
Motor Activation
Identification
Internal
Control
Impulse
activation
inhibition
default state
Internal
Stimulus
Volitional
Response Preparation
Noradrenergic modulation
See Robbins and Arnsten for recent review.
Annual Review of Neuroscience (2013)
Does NA manipulation modulate the activity of the proactive network?
Region
BA
Side
p(FWE-
k
corrected)
Putamen
Insula
48
48
R
R
0,020
61
Cerebellum
Middle occipital gyrus
Middle occipital gyrus
SMA
Posterior temporal
lobe
Superior parietal gyrus
Superior parietal gyrus
Middle occipital gyrus
Inferior occipital gyrus
Middle occipital gyrus
Superior occipital gyrus
Superior parietal gyrus
Superior occipital gyrus
PCC
PCC
ACC
Superior frontal gyrus
Thalamus
*
Putamen
19
19
39
6
L
R
R
L
0,000
1719
0,035
53
21
*
*
19
19
37
19
7
*
23
23
32
32
*
*
*
L
L
L
L
L
L
L
L
L
L
R
R
R
L
L
L
0,000
369
0,001
114
0,000
295
0,027
57
0,055
47
0,001
108
zscore
4,76
4,01
x
y
z
24
36
9
12
-12
0
4,58
4,56
4,44
4,44
-18
45
39
-9
-66
-78
-72
6
-24
6
18
54
4,34
4,33
4,20
4,19
4,01
3,59
4,12
4,08
3,81
4,11
3,25
3,93
3,67
3,90
3,84
3,75
-42
-18
-15
-51
-45
-42
-21
-27
-24
-6
6
12
18
-9
-12
-24
-48
-45
-51
-78
-75
-72
-81
-57
-93
-15
-6
42
45
-6
-3
6
6
33
27
3
-3
12
45
51
27
39
42
12
18
12
3
-6
Clonidine
Stop signal and preparatory inhibition
Hu and Li (2012) HBM
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Warm colours show preparatory
activity for successful
inhibition
Areas include midline frontal
and parietal structures and
lateral frontal areas
A proactive inhibition model
A general, early, elementary and nonselective inhibitory mechanism supported by the SMC is
involved in response control when the situation is unpredictable.
STIMULUS

Executive
setting
Automatic motor
activations
Response
Automatic
inhibition
time
Summary
Successful inhibition involves elemental of
- executive setting (proactive)
- attentional capture (saliency)
- action cancellation (reactive)
AND their links
Few studies have attempted to parcellate in patients
their impairments in inhibitory behaviour
Amelioration strategies must take into account the
precise nature of inhibitory deficit and use tasks
sensitive to these features
Neuroimaging studies are beginning to combine
psychopharmacology and novel inhibitory control
tasks
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Thanks
Phillipe Boulinguez – for sharing data on unpublished
clonidine study and some slides on proactive
inhibition
MRC, IoP – for funding
Astrid Pauls and Owen O’Daly – for their work on the
MPH study
David Sharp and team – for development of the
attentional capture version of SST
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Psychological
models
Neuroimaging
methods
Molecular
investigations
Clinical issues
Why is it so tricky?
 The psychological model that has thus far guided studies on the
neural and neurochemical bases of inhibitory control is likely
incomplete, or even invalid in some instances.
 Neuroimaging methods are constrained by the psychological
model, and by the compromises that have to be found between
spatial and temporal resolution.
 Current methods do not allow tracking the activity of all
neurotransmitters systems.
Clinical issues
 Proactive inhibition: A gate to the understanding of executive
disorders in various neurological and psychiatric conditions?
bis Open up new horizons regarding the pharmacotherapeutic
strategies for various diseases associated with inhibitory
disorders?
Psychological
models
Neuroimaging
methods
Molecular
investigations
WHAT TO LOOK FOR? (with fMRI)
Clinical issues
Reactive activity
Proactive activity
Tonic activity
- implements the inhibitory
 Non-selective (context-dependent)
set,
STIM
- modulates the prestimulus
activity of the motor brake
circuitry
- involves essentially a medial
fronto-parietal network
Evoked (phasic) activity
-is
not specifically triggered by
 Selective (No-Go)
no-go signals
 Non-selective (context-dependent)
- is rather
automatic and nonSTIM
selective
- depends on the context
(inhibitory set)
- is limited to SMA
Psychological
models
Neuroimaging
methods
Molecular
investigations
Clinical issues
Proactive inhibitory control
dysfunctions: Issues and questions
for future research
Proactive Inhibitory Control arouses growing interest in the field
e.g., Aron (2011) From Reactive to Proactive and Selective Control: Developing a Richer Model for Stopping Inappropriate Responses. Biol.
Psychiatry
Boy , Husain and Sumner (2010). Unconscious inhibition separates two forms of cognitive control. PNAS
Verbruggen and Logan (2009) Proactive adjustments of response strategies in the stop-signal paradigm. JEP:HPP
Lo et al. (2009) Proactive inhibitory control and attractor dynamics in countermanding action: a spiking neural circuit model. J Neurosci
Proactive Inhibitory Control may provide new insights and clinical perspectives into
the issue of the mysterious intrinsic brain activity (Default Mode Network)
e.g., SCZ: Increased deactivation of anterior DMN and precuneus related to positive symptoms (Garrity et al (2007) Am. J. Psychiatry)
SCZ: Disconnectivity of the low-frequency oscillatory activity in the PCC, mPFC and lateral parietal cortex. Bluhm et al. (2007) Schizophr. Bull.
PD: Increased deactivation of PCC/precuneus in cognitive tasks, reduced connectivity between mPFC and precuneus. Van Eimeren et al (2009)
Arch. Neurol.
Proactive Inhibitory Control should be considered when establishing the neural
basis for the efficacy of existing treatments
e.g., ADHD: Much is known about the effects of the most common medications prescribed for ADHD on reactive inhibition (Cubillo et al. Cerebral
Cortex 2012), nothing about their effects on proactive control.
Measuring
Inhibitory
Control: significance
for diagnosis?
« considering Proactive
the utility of ‘neurocognitive
endophenotypes’,
such as
impulsivity
and compulsivity, derived from measures of brain as well as behavior, and
using them ‘transdiagnostically’ across disorders, such as substance abuse,
obsessive-compulsive
disorder (OCD) and attention deficit /hyperactivity disorder (ADHD) to discern
possible commonalities that may highlight new genetic or therapeutic
avenues.”