cognitive failures questionnaire (broadbent)
DESCRIPTION
Vigilant attention, arousal and error processing: Lessons from TBI, ADHD and the plain absent-minded. - PowerPoint PPT PresentationTRANSCRIPT
Sustained Attention Phenotype
Vigilant attention, arousal and error processing:Lessons from TBI, ADHD and the plain absent-minded
Sustained Attention Phenotype
• If you have to drive a car on an icy road, anxiously feeling the wheels skidding under you, there is no problem staying alert and attentive, no matter how tired or drowsy you might have been feeling beforehand. Contrast this with driving down the empty M6 late at night – mile after mile of monotony presents a quite different challenge – staying alert.
Sustained Attention Phenotype
These two examples contrast exogenously and endogenously mediated vigilant attention and arousal. They also represent the interplay between a right-hemisphere-cortex mediated vigilant/sustained attention system on the one hand and a midbrain-located arousal system on the other. Successful living requires that these two systems interact in an organised way:
Sustained Attention Phenotype
Sustained Attention Phenotype
Cognitive Failures Questionnaire (Broadbent)• Do you read something and then find you haven’t
been thinking about what you’re reading?• Do you find you forgot whether you turned off a
light or fire, or locked the door?• Do you fail to hear people speaking to you when
you are doing something else?• Do you fail to hear people speaking to you when
you are doing something else?• Do you start doing one thing at home and then get
distracted into doing something else, unintentionally?
Sustained Attention Phenotype
6 4 9 1 4 2 3 5 2
X
DON’T PRESS 3
STANDARD SART (11% probability)
Sustained Attention Phenotype
9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2
FIXED-SEQUENCE SART
Preparation
Sustained Attention Phenotype
TOTAL ERRORS of COMMISSION
3020100
CF
Q
90
80
70
60
50
40
30
20
r=0.4, p<0.05
Bellgrove, Robertson et al 2004
Sustained Attention Phenotype
SART proportional error declines as no-go
probability rises (Manly, Robertson 1999)
05
101520
11%Lure
50%lure
Proportional error
Sustained Attention Phenotype
Only 11% probability Go-NoGo SART correlates with CFQ
0
5
10
11%lure
50%lure
High CFQLow CFQ
Sustained Attention Phenotype
.. But there are other factors than inhibition involved as making the task completely predictable enhances the discrimination of tbi from controls: fixed SART
0
2
4
6
8
10
12
Control errors TBI Errors
Random SARTFixed SART
1 2 3 4 5 6 7 8
9 1 2 3 4 5 6 7
Sustained Attention Phenotype
Fixed SART
0
10
20
30
40
ADHD (n=93) Controls (n=72)
Me
an
E
rro
rs
MeanCommissionErrorsMeanOmissionErrorsMean TotalErrors
P<0.001 for all comparisons
Bellgrove, Gill, Robertson et al in press
Sustained Attention Phenotype
Failure in preparatory slowing in TBI compared to Controls (Dockree and Robertson 2004)
Pre - correct withholds
TRIAL
tw osonesnines
Me
an
RT
580
560
540
520
500
480
460
440
GROUP
tbi
cnt
Sustained Attention Phenotype
Failure of TBI’s to show desynchronisation of alpha 2 power
(FCz) prior to 3 in fixed SARTChanges in lower-2 alpha power as a function of
trial in the Fixed Sequence SART (FCZ)
1.25
1.35
1.45
1.55
1.65
nine one two
Trial
low
er-
2 a
lph
a p
ow
er
(uv
2) TBIs
Controls
Sustained Attention Phenotype
ms-600.0 -350.0 -100.0 150.0 400.0 650.0 900.0 1150.0
µV
0.0
2.5
5.0
7.5
10.0
12.5
15.0
-2.5
-5.0
-7.5
*correct_press.avgcorrect_withholds.avgcommission_errors.avg
omission_errors.avg
Electrode: 22
Subject: EEG file: correct_press.avg Recorded : 11:49:19 26-Nov-2002Rate - 500 Hz, HPF - 1 Hz, LPF - 30 Hz, Notch - off
Neurosoft, Inc.SCAN 4.2Printed : 11:02:10 25-Sep-2003
Sustained Attention Phenotype
Unawareness of SART Errors in Traumatic Brain Injury
O’Keefe and Robertson 2004
0
5
10
15
20
25
Controls TBI
% unaware errors
Sustained Attention Phenotype
Sustained Attention Phenotype
Reduced arousal response to error in traumatic brain injury
O’Keefe, Dockree and Robertson under review
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
S1W/hold S1Err of Com
Response Type
Me
an
Sk
in R
es
po
ns
e A
mp
litu
de
(m
mh
os
)
TBI CON
Sustained Attention Phenotype
Error response in ADHD
Sustained Attention Phenotype
Reduced GSR to error in ADHD(O’Connell, Bellgrove, Robertson et al, under
review)
-1
-0.5
0
0.5
1
1.5
2
2.5
3
Time following Error
Me
an
SC
R (
μS
)
control-DOC
tbi-sm
Sustained Attention Phenotype
Improvement of vigilant attention through random alerting tones
0
5
10
15
20
25
30
35
RHStroke
Patients
Controls
No monitoring cue
Monitoring Cue
Sustained Attention Phenotype
Brain regions involved in vigilance to routine action
• Manly, Robertson et al 2003
Sustained Attention Phenotype
ADHD boys versus IQ matched controls on sustained attention versus selective attention tasks
Manly, Robertson et al Journal of Child Psychology and Psychiatry 42, 1-10
012
34
56
789
10
Sustained Attention Selective Attention
ControlADHD
Sustained Attention Phenotype
Arousal
‘…some level of non-specific neuronal excitability deriving from
the structures formerly known as the reticular formation but now generally
referred to as specific chemically defined or thalamic systems that
innervate the forebrain’
(Robbins and Everitt, 1995)
Sustained Attention Phenotype
Improvement of sustained attention through random alerting tones
0
5
10
15
20
25
30
35
RHStroke
Patients
Controls
No monitoring cue
Monitoring Cue
Sustained Attention Phenotype
Alerting Modulation of More Complex Executive Behaviours: The Hotel Task: The Hotel Task
Sorting the Sorting the charity charity collection. collection.
Sorting conference Sorting conference delegate labels into delegate labels into alphabetical orderalphabetical order
Proof-reading Proof-reading the new hotel the new hotel leafletleaflet
Looking up Looking up phone numbersphone numbers
Compiling Compiling individual bills individual bills based on till based on till rollsrolls
Manly, T., Hawkins, K., Evans, J., Woldt, K., & Robertson, (2002) Neuropsychologia 40, 271-281.
Sustained Attention Phenotype
Complex executive behaviour deficits in TBI normalised by external alert
3
3.5
4
4.5
5
Control Group Patient Group(non-alerted)
Patient Group(alerted)
Tasks Attempted
Sustained Attention Phenotype
SART vs. Control
R Middle Frontal Gyrus (BA9)
R Inferior Parietal (BA 40)
R Thalamus (MD & Pulvinar)
As predicted, R lateralized network observed with SARTO'Connor, C., Manly, T., Robertson, I. H., Hevenor, S. J. & Levine. B. (inPress).
Sustained Attention Phenotype
SART-tone vs. Control-tone
R frontal-parietal-thalamic activations
ABSENT
With tones during SART, the R lateralized network is diminished
Sustained Attention Phenotype
SART vs. SART-tone
R Middle Frontal Gyrus (BA9)
R Thalamus (MD & Pulvinar)
R Inferior Parietal (BA 40) ABSENT
Elements of R lateralized network more active during SART
Sustained Attention Phenotype
Less efficient vigilant attention linked to weaker left spatial bias in normal adults
Sustained Attention Phenotype
Etiology of ADHD?• Dysfunction to catecholamine (e.g., DA
and NA) systems seems likely, since stimulants act on these systems.
• Candidate gene approach seeks to determine whether genetic variants are associated with ADHD at a greater than chance frequency
• Candidate genes for ADHD includes those coding for receptors, enzymes or transporters, amongst others, involved in catecholamine function.
Sustained Attention Phenotype
What is a gene? What is an allele?
• Chromosome consists of a linear DNA molecule
• Gene- is a length of DNA that specifies a particular protein product
• Gene are arranged along the chromosomes with each having a precise position or locus
• Alternative forms of a gene that can occupy the same locus are called alleles
• Each chromosome bears a single allele at a given locus
• Chromosome pairs have the same genetic loci in the same order, however the alleles can differ.
Sustained Attention Phenotype
A
a
B
Imagine, two homologous chromosomes with two different genes, called DAT1 and DBH for convenience. At the DAT1 locus this individual has a Aa genotype, and at the DBH locus, a BB genotype
B
The individual is heterozygous for DAT1 (Aa) andHomozygous for DBH (BB)Genotype has consequences for the expression of the trait or phenotype
DAT1 DBH
Sustained Attention Phenotype
Rationale behind the endophenotype approach
Castellanos and Tannock (2002)
ADHD SymptomatologySymptoms
Neuropsych
Brain pathology
Genetic Factors DAT1 DBH COMT
Left-spatial inattentionSustained Attention
Response Inhibition
Right Striatal DysfunctionPrefrontal dysfunction
Neuropsychological endophenotypes should be related to symptoms but be closer to the site of gene action
DA and NA dysfunction
Sustained Attention Phenotype
Study 1: Left-spatial inattention as anattentional phenotype
• Participants:– 55 right-handed children and adolescents with ADHD,
genotyped for DAT1.– DSM-IV diagnosis-76% ADHD-CT– 75% had comorbid diagnoses
– AgeM=12.3, IQM=98.4
• Low-Risk DAT1 ADHD: none or one 10-repeat DAT1• High-Risk DAT1 ADHD: two 10-repeat DAT1
– 29 right-handed matched controls, not genotyped.
Left-spatial Inattention in ADHD
The Landmark Task
In Left-neglect, a rightwards attentional bias causes relative inattention to the left and a consequent underestimation of the left half of the line
“The right end of the line is shorter”
“The left end of the line is shorter”
In Pseudoneglect, a leftwards attentional bias causes relative inattention to the right and a consequent underestimation of the right half of the line
a)
b)
Left-spatial Inattention in ADHD
• Spatial Asymmetry Index calculated– -1 +1 (right spatial inattention left spatial
inattention)
• Asymmetry Indices compared using Univariate ANOVA (Low-risk DAT1 vs, High-Risk DAT1 vs controls).
Left-spatial Inattention in ADHD
-0.2
-0.15
-0.1
-0.05
0
0.05
0.1
0.15
0.2
Group
Mag
nit
ud
e an
d D
irec
tio
n o
f M
ean
Asy
mm
etry
In
dic
es
Controls
Low-Risk-DAT1 ADHD
High-Risk-DAT1 ADHD
High-Risk DAT1 ADHD group display left spatial inattention
Left-spatial inattention in ADHD
Results• We also asked whether
– 1) Landmark Asymmetry Indices could predict biased transmision of 10-repeat DAT1 vs other alleles using logistic regression?
• Asymmetry Indices significantly predicted biased transmission of the 10-repeat DAT1 allele
• [LR-TDT: χ2 =8.57,df=1,p=0.003]
– 2) Landmark Asymmetry Indices relate to DSM symptoms?
• DSM-IV Total (r=.34, p<0.05); Inattentive (r=.34,p<0.05); not Hyperactivity (r=.24,p=0.16)
– 3) Conner’s symptom ratings predicted biased transmission of 10-repeat DAT1 vs other alleles?
• DSM-IV Total symptoms [LR-TDT: χ2 =3.6,df=1,p=0.058]
• DSM-IV Inattentive symptoms [LR-TDT: χ2 =3.6,df=1,p=0.059]
Sustained Attention Phenotype
ADHD Inattentive SymptomsSymptoms
Neuropsych
Brain pathology
Genetic Factors DAT1
Left-spatial inattention
Right Striatal DysfunctionOveractive DAT
Left-spatial inattention is related to Inattentive symptoms butcloser to the site of gene action (DAT1)
Predicting MPH Response in ADHD
Study 2: Left-spatial inattention as predictor of therapeutic response to MPH
10-repeat DAT1 allele
Left-spatialinattention
Enhanced responseto MPH
Kirley et al, 2003Study 1
Hypothesis: Performance on the Landmark Task will predict an enhanced therapeutic response to MPH
?
Predicting MPH Response in ADHD
Study 2: Left-spatial inattention as predictor of therapeutic response to MPH
• Participants:– 49 right-handed children and adolescents with ADHD,
genotyped for DAT1.
– AgeM=12.4, IQM=98.4
– All children currently receiving or had received MPH
– Medication response retrospectively rated on a three point scale: 1=No response, 2=Mediocre Response, 3=Very Good Response.
– Parents completed the CPRS-R:L twice, retrospectively rating symptoms on and off MPH.
– All children were withdrawn from medication 24 hours prior to completing the Landmark Task.
Predicting MPH Response in ADHD
Results
• Since numbers were low in the No-Response category we combined the No-response and Very Good Response categories
• Using logistic regression we asked whether Landmark Asymmetry Indices could predict a Very Good vs. Mediocre Response to MPH.– Indeed the Asymmetry Index predicted an enhanced
response to MPH [χ2=3.981,df=1, p=.046]
• Asymmetry Indices correlated with rating of Inattentiveness when un-medicated but not medicated.
Predicting MPH Response in ADHD
-0.4
-0.3
-0.2
-0.1
0
0.1
0.2
0.3
0.4
Mea
n A
sym
met
ry I
nd
ices Low-Risk DAT1/
Mediocre Response
Low-Risk DAT1/ Verygood response
High-Risk DAT1/ Mediocre response
High-Risk DAT1/ Verygood response
10-repeat DAT1 homozygotes who achieved a Very GoodResponse to MPH, displayed left-spatial inattention
Sustained Attention Phenotype
Conclusions of Studies 1 and 2
• Results support the existence of a subgroup of ADHD that is associated with the 10-repeat DAT1 allele and is defined
– 1) in neuropsychological terms, by left-spatial inattention.
– 2) in symptomatological terms, by inattentive symptomatology
– 3) in pharmacogenomic terms, by an enhanced therapeutic response to MPH.
• Left spatial inattention might predict therapeutic response to MPH because it acts as a proxy for DAT1 genotype and so transporters that are overactive, perhaps within the right striatum.
• MPH might be most efficacious for those children presenting with left-spatial inattention, because it indexes a hypodopaminergic state
Sustained Attention Phenotype
Study 3: Sustained Attention as anattentional phenotype
• Sustained attention may be defined as the active maintainenance of an alert state in the absence of exogenous support (Robertson et al, 1997)
• Neuroimaging suggests sustainedattention relies heavily upon activitywithin right dorsolateral prefrontal and inferior parietal regions (Manly et al, 2003)– Posner and Peterson (1990) argued for NA modulation
of sustained attention via projections from Locus Coerleus (LC) to temporo-parietal junction (TPJ).
Sustained Attention Phenotype
Study 3: Sustained Attention as anattentional phenotype
• Existence of a sustained attention deficit in ADHD remains controversial– Loo et al (2003) found greater sustained attention deficit
in 10-repeat DAT1 homozygotes. Role for dopamine?
• Here we examined performance on the Sustained Attention to Response Test (SART), as function of DAT1 genotype
– Hypothesis: Sustained attention would relate to DAT1 genotype
Sustained Attention Phenotype
Mask
Fixation
Response
1
3
Don’t Press
Mask
Digit
Press
The Sustained Attention to Response Test (SART)
Sustained Attention Phenotype
0
5
10
15
20
25
30
ADHD (n=47) Controls (n=37)
Mea
n F
ixed
SA
RT
Err
ors
Mean Fixed SARTCommission Errors
Mean Fixed SARTOmission Errors
Mean Fixed SART TotalErrors
Fixed SART Mean Go RT by Group
420
430
440
450
460
470
480
490
500
510
ADHD (n=47) Controls (n=37)
Fix
ed S
AR
T M
ean
Go
RT
Fixed SART MeanVariability (SD/GoRT) by Group
0.29
0.3
0.31
0.32
0.33
0.34
0.35
0.36
0.37
0.38
0.39
0.4
ADHD (n=47) Controls (n=37)Fix
ed S
AR
T M
ean
Var
iab
ilit
y (S
D/G
oR
T)
p>0.05
All p’s<0.02
p<0.05
Age: p=.49 IQ: p=.38
Fixed SART: ADHD vs Controls
Sustained Attention Phenotype
Fixed SART and DAT1 Genotype
Mean Fixed SART Total Errors by Group
0
2
4
6
8
10
12
14
16
High-Risk DAT1 ADHD Low-Risk DAT1 ADHD ControlsMea
n F
ixed
SA
RT
To
tal
Err
ors
Mean Fixed SART Variability (SD/Go RT) by Group
0
0.1
0.2
0.3
0.4
0.5
0.6
High-Risk DAT1ADHD
Low-Risk DAT1ADHD
Controls
Mea
n F
ixed
SA
RT
Var
iab
ility
(S
D/G
o R
T)
1. High-Risk DAT1 ADHD>Controls
2. High-Risk DAT1 not different to Low-Risk DAT1
3. Low-Risk DAT1 not different to controls
1. High-Risk DAT1 ADHD> Low-Risk DAT1
2. High-Risk DAT1 ADHD> Controls
Sustained Attention Phenotype
Conclusions of Study 3
• The SART shows specificity for indexing the sustained attention deficit in ADHD– Effects are unlikely to reflect a response inhibition deficit.
• High-Risk DAT1 ADHD group committed more errors on the SART than controls
• High-Risk DAT1 ADHD group were more variable than both Low-Risk DAT1 ADHD group and controls (see also Loo et al, 2003)
– Variability may be a marker for executive dysfunction (Stuss et al)
– Variability may reflect the moment-to-moment fluctuations in attention that clinically characterise ADHD (see also Castellanos and Tannock, 2002)
• Data support an hypothesis of right-hemisphere dysfunction mediated in part by DAT1 genotype
Sustained Attention Phenotype
Study 4: Sustained Attention in relation to DBH genotype
• Studies 1-3 showed that spatial and sustained attention may be influenced to a degree by DA genotype– What about the role of NA-related candidate
genes in sustained attention?
• NA projections particularly strong to the right temporo-parietal junction of inferior parietal lobe– Thought to be involved in both sustained and
spatial attention
Sustained Attention Phenotype
0
2
4
6
8
10
12
14
16
18
20
no high riskDBH (n=15)
one high riskDBH (n=24)
two high riskDBH (n=20)
Mea
n F
ixed
SA
RT
Err
ors
Mean Fixed SARTCommission Errors
Mean Fixed SARTOmission Errors
Mean Fixed SART TotalErrors
Fixed SART and DBH Genotype
Fixed SART Mean Go RT by Group
440
450
460
470
480
490
500
510
520
530
540
no high riskDBH (n=15)
one high riskDBH (n=24)
two high riskDBH (n=20)
Fixed SART Mean GoRT by Group
Fixed SART Mean Variability (SD/GoRT) by Group
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
no high riskDBH (n=15)
one high riskDBH (n=24)
two high riskDBH (n=20)
Fix
ed S
AR
T M
ean
Var
iab
ilit
y (S
D/G
oR
T)
Fixed SART MeanVariability (SD/GoRT)by Group
Age: p>0.05
IQ: p<0.05
ADHDs with2 high-risk DBHAlleles, compared to none, had sustained attention deficits on the Fixed SART
Prior Entry and DBH Genotype
Sustained Attention in relation to DBH genotype
• We asked participants to perform a “Prior Entry” task– Based upon the observation that events perceived
at an attended location reach awareness before events occurring at unattended locations
– Primarily been used to index the degree of pathological spatial bias in unilateral neglect (Rorden et al,1997)
Prior Entry and DBH Genotype
+
+
+
*
**
The Prior Entry Task
SOA varied between50ms,100ms &200msSide of first
stimulus onsetvaried Left/Right
Left came first!
Prior Entry and DBH Genotype
Sustained Attention in relation to DBH genotype
• Hypotheses:1. If DBH plays a role in left-spatial inattention in ADHD, then
those carrying the high-risk allele should make more errors on left-first, relative to right-first, trials
2. Temporal order judgements, irrespective of side of first presentation, will relate to sustained attention performance on the SART
– Activations within right TPJ are independent of visual field of targets
– Right TPJ may play a role in sustained attention (see Corbetta et al, 2000).
3. If DBH plays a role in sustained attention, then its effects should be most pronounced at shorter SOAs since briefly separated targets would require a vigilant state for detection.
Prior Entry and DBH Genotype
Results
• ADHD (n=42) compared to Controls (n=23)• ADHD group showed significantly higher
error rates than controls across conditions– No interaction between Group and SOA or
Group and Side
• SART performance was a significant predictor of errors across SOAs and Side– Total Error and Variability explained up to 25%
of the variance in errors of temporal order judgement
• Temporal order judgements may be underpinned by sustained attention.
Prior Entry and DBH Genotype
SOA
200ms100ms50ms
Num
ber
of P
rior
Ent
ry E
rror
s
7
6
5
4
3
2
1
0
DBH Group
no high risk DBH
one high risk DBH
two high risk DBH
DBH Group by SOA interaction
1. DBH group effect2. Interaction driven by
the difference between theTwo-High Risk DBH and No-High Risk DBH groups
at the 50ms and 100ms SOAs
Sustained Attention Phenotype
Conclusions of Study 4
• Study provides the first evidence that a NA-related genotype can affect sustained attention processes– Provides support for the model of alertness proposed by
Posner and Peterson (1990)
• Functional sig of DBH genotype not fully understood– Some evidence that the high-risk allele may related to
reduced NA • DBH-related reductions in NA may impact on
regions within the inferior parietal lobe, such as TPJ, compromising sustained attention capacity– May interact with structural changes within the inferior
parietal lobe in ADHD (Sowell et al, 2003)
Sustained Attention Phenotype
Study 5: Effect of COMT genotype on sustained attention/ response inhibition
• COMT Val allele is known to degrade DA in prefrontal cortex 4x a rapidly as the Met allele.
• COMT degradation is the main mechanism of DA regulation in the prefrontal cortex
• Genetic association studies have not found robust evidence for associations with the COMT Val allele– Qian et al even found evidence for association of the
Met allele
COMT and Sustained Attention
• Given functional role of COMT and frontal hypotheses of ADHD, we investigated its influence on sustained attention– Hypothesis: Val allele would be associated with
impaired sustained attention
• Assessed 61 children on the Test of Everyday Attention for Children (TEA-Ch) (Manly et al 2001)– Walk Don’t Walk– Score Dual Task– Sky Search Dual Task
All load on a SustainedAttention factor
Sustained Attention Phenotype
0
2
4
6
8
10
12
Met-Met Met-Val Val-Val
Walk Don't Walk
Score DT
Sky Search DT
Effect of COMT genotype on Sustained Attention
1. Val allele is thoughtto impair prefrontal cognition
2. However, children withthe Met allele underperform those withthe Val allele on sustainedattention tasks
1. DLPFC cortex is compromised in ADHD (Sowell et al, 2003)2. Too much as well as too little DA impairs cognition3. Perhaps given neuronal reduction in DLPFC, the Met allele impairs
cognition because DA supply is in excess of demands
Sustained Attention Phenotype
Conclusions and Further Issues
• Left-spatial inattention and sustained attention both related to DAT1 genotype, but there was no relationship between Landmark scores and SART performance– This relationship has been observed in parietal neglect
suggesting that the left spatial inattention in ADHD could arise from dysfunction outside the parietal lobe
– We suggest the striatum as the locus of this dysfunction• We hypothesise that performance on endogenous
orienting tasks will relate to DAT1 genotype, since imaging studies of endogenous, relative to exogenous, show sub-cortical activation.
Conclusions and Further Issues
• DBH genotype affected sustained visual attention but did not influence spatial attention– We suggest that DBH genotype, perhaps interacting
with frontal and parietal brain changes, impairs sustained attention
– Indeed, we find that COMT genotype, presumably acting on dorsolateral prefrontal cortex, impairs sustained attention in ADHD
COMT acting prefrontally
DBH actingwithin theinferior parietallobe
DAT1 acting sub-cortically