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Cognitive Failures Questionnaire (Broadbent)

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

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Cognitive Failures Questionnaire (Broadbent)

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  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 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. STANDARD SART (11% probability) 6 4 9 1 4 2 35 2 X DON’T PRESS 3 Sustained Attention Phenotype

  7. FIXED-SEQUENCE SART 9 1 2 34 5 6 7 8 9 1 2 3 4 5 6 7 8 9 1 2 Preparation Sustained Attention Phenotype

  8. 90 80 70 60 50 40 30 CFQ 20 0 10 20 30 TOTAL ERRORS of COMMISSION r=0.4, p<0.05 Bellgrove, Robertson et al 2004 Sustained Attention Phenotype

  9. 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. .. 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 Sustained Attention Phenotype

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

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

  14. 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. Unawareness of SART Errors in Traumatic Brain InjuryO’Keefe and Robertson 2004 Sustained Attention Phenotype

  17. Sustained Attention Phenotype

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

  19. Error response in ADHD

  20. 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. ADHD boys versus IQ matched controls on sustained attention versus selective attention tasksManly, Robertson et al Journal of Child Psychology and Psychiatry 42, 1-10 Sustained Attention Phenotype

  24. 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. Looking up phone numbers Compiling individual bills based on till rolls Sorting the charity collection. Sorting conference delegate labels into alphabetical order Proof-reading the new hotel leaflet Alerting Modulation of More Complex Executive Behaviours: The Hotel Task Manly, T., Hawkins, K., Evans, J., Woldt, K., & Robertson, (2002) Neuropsychologia 40, 271-281. Sustained Attention Phenotype

  27. Complex executive behaviour deficits in TBI normalised by external alert Sustained Attention Phenotype

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

  29. 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. 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. 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 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

  35. Symptoms ADHD Symptomatology Left-spatial inattention Neuropsych Sustained Attention Response Inhibition Right Striatal Dysfunction Brain pathology Prefrontal dysfunction Genetic Factors DAT1 COMT DBH 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

  36. 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.

  37. a) In Pseudoneglect, a leftwards attentional bias causes relative inattention to the right and a consequent underestimation of the right half of the line “The right end of the line is shorter” b) “The left end of the line is shorter” 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 Landmark Task Left-spatial Inattention in ADHD

  38. 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

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

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

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

  43. 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. 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. 10-repeat DAT1 homozygotes who achieved a Very GoodResponse 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 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

  48. 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

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

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