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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.

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Presentation on theme: "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."— Presentation transcript:

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

2 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.

3 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:

4 Sustained Attention Phenotype

5 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 start doing one thing at home and then get distracted into doing something else, unintentionally? Sustained Attention Phenotype

6 Sustained Attention Phenotype
STANDARD SART (11% probability) X DON’T PRESS 3 Sustained Attention Phenotype

7 Sustained Attention Phenotype
FIXED-SEQUENCE SART Preparation Sustained Attention Phenotype

8 Sustained Attention Phenotype
90 80 70 60 50 40 30 CFQ 20 10 20 30 TOTAL ERRORS of COMMISSION r=0.4, p<0.05 Bellgrove, Robertson et al 2004 Sustained Attention Phenotype

9 Sustained Attention Phenotype
SART proportional error declines as no-go probability rises (Manly, Robertson 1999) Sustained Attention Phenotype

10 Only 11% probability Go-NoGo SART correlates with CFQ
Sustained Attention Phenotype

11 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 Sustained Attention Phenotype

12 Sustained Attention Phenotype
P<0.001 for all comparisons Bellgrove, Gill, Robertson et al in press Sustained Attention Phenotype

13 Sustained Attention Phenotype
Failure in preparatory slowing in TBI compared to Controls (Dockree and Robertson 2004) Sustained Attention Phenotype

14 Sustained Attention Phenotype
Failure of TBI’s to show desynchronisation of alpha 2 power (FCz) prior to 3 in fixed SART Sustained Attention Phenotype

15 Sustained Attention Phenotype

16 Sustained Attention Phenotype
Unawareness of SART Errors in Traumatic Brain Injury O’Keefe and Robertson 2004 Sustained Attention Phenotype

17 Sustained Attention Phenotype

18 Sustained Attention Phenotype
Reduced arousal response to error in traumatic brain injury O’Keefe, Dockree and Robertson under review Sustained Attention Phenotype

19 Error response in ADHD

20 Sustained Attention Phenotype
Reduced GSR to error in ADHD (O’Connell, Bellgrove, Robertson et al, under review) Sustained Attention Phenotype

21 Improvement of vigilant attention through random alerting tones
Sustained Attention Phenotype

22 Brain regions involved in vigilance to routine action
Manly, Robertson et al 2003 Sustained Attention Phenotype

23 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 Sustained Attention Phenotype

24 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

25 Improvement of sustained attention through random alerting tones
Sustained Attention Phenotype

26 Sustained Attention Phenotype
Alerting Modulation of More Complex Executive Behaviours: The Hotel Task Looking up phone numbers Compiling individual bills based on till rolls Proof-reading the new hotel leaflet Sorting conference delegate labels into alphabetical order Sorting the charity collection. Manly, T., Hawkins, K., Evans, J., Woldt, K., & Robertson, (2002) Neuropsychologia 40, Sustained Attention Phenotype

27 Sustained Attention Phenotype
Complex executive behaviour deficits in TBI normalised by external alert Patients became indistinguishable from the control participants Sustained Attention Phenotype

28 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 SART O'Connor, C., Manly, T., Robertson, I. H., Hevenor, S. J. & Levine. B.  (in Press). Sustained Attention Phenotype

29 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

30 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

31 Sustained Attention Phenotype
Less efficient vigilant attention linked to weaker left spatial bias in normal adults Sustained Attention Phenotype

32 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.

33 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.

34 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 DAT1 DBH 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

35 Rationale behind the endophenotype approach Castellanos and Tannock (2002)
Neuropsychological endophenotypes should be related to symptoms but be closer to the site of gene action ADHD Symptomatology Symptoms Neuropsych Brain pathology Genetic Factors DAT1 DBH COMT Left-spatial inattention Sustained Attention Response Inhibition Right Striatal Dysfunction Prefrontal dysfunction DA and NA dysfunction

36 Study 1: Left-spatial inattention as an attentional 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.

37 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

38 Left-spatial Inattention in ADHD
Spatial Asymmetry Index calculated (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

39 Left-spatial Inattention in ADHD
High-Risk DAT1 ADHD group display left spatial inattention Left-spatial Inattention in ADHD

40 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] Left-spatial inattention in ADHD

41 ADHD Inattentive Symptoms
Left-spatial inattention is related to Inattentive symptoms but closer to the site of gene action (DAT1) ADHD Inattentive Symptoms Symptoms Neuropsych Brain pathology Genetic Factors DAT1 Left-spatial inattention Right Striatal Dysfunction Overactive DAT

42 Predicting MPH Response in ADHD
Study 2: Left-spatial inattention as predictor of therapeutic response to MPH 10-repeat DAT1 allele Left-spatial inattention Enhanced response to MPH Kirley et al, 2003 Study 1 ? Hypothesis: Performance on the Landmark Task will predict an enhanced therapeutic response to MPH Predicting MPH Response in ADHD

43 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

44 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

45 Predicting MPH Response in ADHD
10-repeat DAT1 homozygotes who achieved a Very Good Response to MPH, displayed left-spatial inattention Predicting MPH Response in ADHD

46 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

47 Study 3: Sustained Attention as an attentional 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 sustained attention relies heavily upon activity within 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

48 Study 3: Sustained Attention as an attentional 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

49 Sustained Attention Phenotype
The Sustained Attention to Response Test (SART) Mask Digit Press Sustained Attention Phenotype

50 Fixed SART: ADHD vs Controls
All p’s<0.02 Age: p=.49 IQ: p=.38 p>0.05 p<0.05

51 Fixed SART and DAT1 Genotype
High-Risk DAT1 ADHD>Controls High-Risk DAT1 not different to Low-Risk DAT1 Low-Risk DAT1 not different to controls High-Risk DAT1 ADHD> Low-Risk DAT1 High-Risk DAT1 ADHD> Controls Sustained Attention Phenotype

52 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

53 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

54 Fixed SART and DBH Genotype
ADHDs with 2 high-risk DBH Alleles, compared to none, had sustained attention deficits on the Fixed SART Age: p>0.05 IQ: p<0.05

55 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

56 Prior Entry and DBH Genotype
The Prior Entry Task + SOA varied between 50ms,100ms &200ms + * Side of first stimulus onset varied Left/Right Left came first! Prior Entry and DBH Genotype

57 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. Prior Entry and DBH Genotype

58 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

59 Prior Entry and DBH Genotype
DBH Group by SOA interaction DBH group effect Interaction driven by the difference between the Two-High Risk DBH and No-High Risk DBH groups at the 50ms and 100ms SOAs Prior Entry and DBH Genotype

60 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)

61 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

62 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 Sustained Attention factor COMT and Sustained Attention

63 Effect of COMT genotype on Sustained Attention
Val allele is thought to impair prefrontal cognition However, children with the Met allele underperform those with the Val allele on sustained attention 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

64 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.

65 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 acting within the inferior parietal lobe DAT1 acting sub-cortically Conclusions and Further Issues


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