Vigilant attention, arousal and error processing: Lessons from TBI, ADHD and the plain absent-minded

Sustained Attention Phenotype

Vigilant attention, arousal and error processing:Lessons from TBI, ADHD and the plain absent-minded


• 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.


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:



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?


6 4 9 1 4 2 3 5 2

X

DON’T PRESS 3

STANDARD SART (11% probability)


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


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


SART proportional error declines as no-go

probability rises (Manly, Robertson 1999)

05

101520

11%Lure

50%lure

Proportional error


Only 11% probability Go-NoGo SART correlates with CFQ

0

5

10

11%lure

50%lure

High CFQLow CFQ


.. 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


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


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


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


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


Unawareness of SART Errors in Traumatic Brain Injury

O’Keefe and Robertson 2004

0

5

10

15

20

25

Controls TBI

% unaware errors



Reduced arousal response to error in traumatic brain injury

O’Keefe, Dockree and Robertson under review

0

0.2

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Response Type

Me

an

Sk

in R

es

po

ns

e A

mp

litu

de

(m

mh

os

)

TBI CON


Error response in ADHD


Reduced GSR to error in ADHD(O’Connell, Bellgrove, Robertson et al, under

review)

-1

-0.5

0

0.5

1

1.5

2

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3

Time following Error

Me

an

SC

R (

μS

)

control-DOC

tbi-sm


Improvement of vigilant attention through random alerting tones

0

5

10

15

20

25

30

35

RHStroke

Patients

Controls

No monitoring cue

Monitoring Cue


Brain regions involved in vigilance to routine action

• Manly, Robertson et al 2003


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


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)


Improvement of sustained attention through random alerting tones

0

5

10

15

20

25

30

35

RHStroke

Patients

Controls

No monitoring cue

Monitoring Cue


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.


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


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).


SART-tone vs. Control-tone

R frontal-parietal-thalamic activations

ABSENT

With tones during SART, the R lateralized network is diminished


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


Less efficient vigilant attention linked to weaker left spatial bias in normal adults


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.


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.


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


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


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)


• 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).


-0.2

-0.15

-0.1

-0.05

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0.05

0.1

0.15

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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]


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

?


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.


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.


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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


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


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).


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


Mask

Fixation

Response

1

3

Don’t Press

Mask

Digit

Press

The Sustained Attention to Response Test (SART)


0

5

10

15

20

25

30


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

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510


Fix

ed S

AR

T M

ean

Go

RT

Fixed SART MeanVariability (SD/GoRT) by Group

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0.39

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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


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


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


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


0

2

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6

8

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14

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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




Fixed SART Mean GoRT by Group

Fixed SART Mean Variability (SD/GoRT) by Group

0

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0.1

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0.25

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0.35

0.4

0.45




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)


+

+

+

*

**

The Prior Entry Task

SOA varied between50ms,100ms &200msSide of first

stimulus onsetvaried Left/Right

Left came first!


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.


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.


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


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)


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


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


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

Documents

Vigilant attention, arousal and error processing: Lessons from TBI, ADHD and the plain absent-minded