Vigilant attention, arousal and error processing: Lessons from TBI, ADHD and the plain absentminded

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Vigilant attention, arousal and error
processingLessons from TBI, ADHD and the plain
absent-minded
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• 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.

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• 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

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Cognitive Failures Questionnaire (Broadbent)

• Do you read something and then find you havent
  been thinking about what youre 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?

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STANDARD SART (11 probability)
6 4 9 1 4 2 3 5 2
X
DONT PRESS 3
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FIXED-SEQUENCE SART
9 1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7
8 9 1 2

Preparation
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90
80
70
60
50
40
30
CFQ
20
30
20
10
0
TOTAL ERRORS of COMMISSION
r0.4, plt0.05
Bellgrove, Robertson et al 2004
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SART proportional error declines as no-go
probability rises (Manly, Robertson 1999)
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Only 11 probability Go-NoGo SART correlates with
CFQ
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.. But there are other factors than inhibition
involved as making the task completely
predictable enhances the discrimination of tbi
from controls fixed SART
1 2 3 4 5 6 7 8 9 1 2 3 4 5 6 7
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Plt0.001 for all comparisons
Bellgrove, Gill, Robertson et al in press
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Failure in preparatory slowing in TBI compared to
Controls (Dockree and Robertson 2004)
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Failure of TBIs to show desynchronisation of
alpha 2 power (FCz) prior to 3 in fixed SART
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Unawareness of SART Errors in Traumatic Brain
InjuryOKeefe and Robertson 2004
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Reduced arousal response to error in traumatic
brain injuryOKeefe, Dockree and Robertson
under review
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Error response in ADHD
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Reduced GSR to error in ADHD(OConnell,
Bellgrove, Robertson et al, under review)
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Improvement of vigilant attention through random
alerting tones
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Brain regions involved in vigilance to routine
action

• Manly, Robertson et al 2003

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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
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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)

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Improvement of sustained attention through random
alerting tones
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Alerting Modulation of More Complex Executive
Behaviours The Hotel Task
Manly, T., Hawkins, K., Evans, J., Woldt, K.,
Robertson, (2002) Neuropsychologia 40, 271-281.
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Complex executive behaviour deficits in TBI
normalised by external alert
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SART vs. Control
R Middle Frontal Gyrus (BA9) R Inferior Parietal
(BA 40) R Thalamus (MD Pulvinar)
As predicted, R lateralized network observed with
SART
O'Connor, C., Manly, T., Robertson, I. H.,
Hevenor, S. J. Levine. B.  (in Press).
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SART-tone vs. Control-tone
R frontal-parietal-thalamic activations
ABSENT
With tones during SART, the R lateralized network
is diminished
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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
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Less efficient vigilant attention linked to
weaker left spatial bias in normal adults
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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.

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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.

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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
DBH
DAT1
A
B
a
B
The individual is heterozygous for DAT1 (Aa)
and Homozygous for DBH (BB) Genotype has
consequences for the expression of the trait or
phenotype
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Rationale behind the endophenotype
approachCastellanos and Tannock (2002)
Neuropsychological endophenotypes should be
related to symptoms but be closer to the site of
gene action
DA and NA dysfunction
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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
• AgeM12.3, IQM98.4
• 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.

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The Landmark Task
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• 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).

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High-Risk DAT1 ADHD group display left spatial
inattention
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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 ?2 8.57,df1,p0.003
• 2) Landmark Asymmetry Indices relate to DSM
  symptoms?
• DSM-IV Total (r.34, plt0.05) Inattentive
  (r.34,plt0.05) not Hyperactivity (r.24,p0.16)
• 3) Conners symptom ratings predicted biased
  transmission of 10-repeat DAT1 vs other alleles?
• DSM-IV Total symptoms LR-TDT ?2
  3.6,df1,p0.058
• DSM-IV Inattentive symptoms LR-TDT ?2
  3.6,df1,p0.059

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Left-spatial inattention is related to
Inattentive symptoms butcloser to the site of
gene action (DAT1)
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Study 2 Left-spatial inattention as predictor
of therapeutic response to MPH
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Hypothesis Performance on the Landmark Task will
predict an enhanced therapeutic response to MPH
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Study 2 Left-spatial inattention as predictor
of therapeutic response to MPH

• Participants
• 49 right-handed children and adolescents with
  ADHD, genotyped for DAT1.
• AgeM12.4, IQM98.4
• All children currently receiving or had received
  MPH
• Medication response retrospectively rated on a
  three point scale 1No response, 2Mediocre
  Response, 3Very Good Response.
• Parents completed the CPRS-RL twice,
  retrospectively rating symptoms on and off MPH.
• All children were withdrawn from medication 24
  hours prior to completing the Landmark Task.

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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 ?23.981,df1, p.046
• Asymmetry Indices correlated with rating of
  Inattentiveness when un-medicated but not
  medicated.

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10-repeat DAT1 homozygotes who achieved a Very
GoodResponse to MPH, displayed left-spatial
inattention
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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

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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).

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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

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The Sustained Attention to Response Test (SART)
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Fixed SART ADHD vs Controls
All pslt0.02
Age p.49 IQ p.38
pgt0.05
plt0.05
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Fixed SART and DAT1 Genotype

• High-Risk DAT1 ADHDgtControls
• High-Risk DAT1 not different to Low-Risk DAT1
• Low-Risk DAT1 not different to controls

• High-Risk DAT1 ADHDgt Low-Risk DAT1
• High-Risk DAT1 ADHDgt Controls

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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

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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

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Fixed SART and DBH Genotype
ADHDs with2 high-risk DBH Alleles, compared to
none, had sustained attention deficits on the
Fixed SART
Age pgt0.05 IQ plt0.05
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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)

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The Prior Entry Task

SOA varied between 50ms,100ms 200ms
Side of firststimulus onsetvaried Left/Right
Left came first!
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Sustained Attention in relation to DBH genotype

• Hypotheses
• 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
• 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).
• 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.

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Results

• ADHD (n42) compared to Controls (n23)
• 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.

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DBH Group by SOA interaction

• DBH group effect
• Interaction driven bythe difference between
  theTwo-High Risk DBH and No-High Risk DBH
  groupsat the 50ms and 100ms SOAs

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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)

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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

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• 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 Dont Walk
• Score Dual Task
• Sky Search Dual Task

All load on a Sustained Attention factor
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Effect of COMT genotype on Sustained Attention

• Val allele is thoughtto impair prefrontal
  cognition
• However, children withthe Met allele
  underperform those withthe Val allele on
  sustainedattention tasks

• DLPFC cortex is compromised in ADHD (Sowell et
  al, 2003)
• Too much as well as too little DA impairs
  cognition
• Perhaps given neuronal reduction in DLPFC, the
  Met allele impairs cognition because DA supply
  is in excess of demands

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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.

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• 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