Over het cognitieve endofenotype bij ADHD: orde in de chaos

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Over het cognitieve endofenotype bij ADHD orde
in de chaos?

• Jan K. BuitelaarDept. of Psychiatry, UMC St
  Radboud, Karakter, University Centre for Child
  and Adolescent Psychiatry, Nijmegen, NL

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ADHD - Core Symptom Areas
Inattention
Impulsivity/Hyperactivity
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A General Problem is Our Clinically Defined
Syndromes Are Not Discrete And Are Frequently
Overlapping
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Co-occurring Disorders in Children (n579)
Oppositional Defiant Disorder 40
Tics 11
ADHD alone 31
Conduct Disorder 14
Anxiety Disorder 34
Mood Disorders 4
MTA Cooperative Group. Arch Gen Psychiatry 1999
56 1088-96
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Sources of complexity and heterogeneity

• Clinical
• Heterogeneity (symptom profile, course)
• Comorbidity
• Aetiological heterogeneity

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Etiologies of ADHDFrom Joel Nigg (2006), What
Causes ADHD?
Other
Perinatal
Smoking
Lead
FASD
LBW
Heritable (Genetics)
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A possible solution one underlying cognitive
deficit ?
Multiple symptoms
Core deficit
Multiple causes
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ADHD and Executive Functions
Conceptual model linking behavioral inhibition
with performance of executive functions
Motor control, fluency, syntax
Barkley RA. Psychol Bull 199712165-94 Barkley
RA, et al. J Abnorm Child Psychol 200129541-56
Pennington BF, et al. Child Psychol Psychiatry
19963751-87.
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Traditional case-control design
External variable
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Diagnostic Efficiency of Neuropsychological Test
Scores for Discriminating Boys With and Without
ADHD

• Doyle et al. (2000) Journal of Consulting and
  Clinical Psychology, 68, 477-488

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Tests

• Stroop Color-Word Test
• Wisconsin Card Sorting Test
• California Verbal Learning Test
• Auditory Continuous Performance Test
• Letter Cancellation Task
• Rey-Osterreith Complex Figure
• Freedom from Distractibility Index (WISC/WAIS)

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Diagnostic Efficiency of Neuropsychological Test
Scores in ADHD
of cases
ADHD
Control
Number of tests
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Do EF tasks separate ADHD children from
controls? Meta-analysis findings
Yes, but.
To discriminate 80 of the two groups we need an
Effect Size of 2.0!
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Do EF tasks separate ADHD adults from controls?
(meta)
Yes, but
Poor clinical discrimination
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EF discrimination of ADHD subgroups
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EF discrimination ADHD and other externalizing
disordersMeta and Single study comparisons
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EF discrimination of ADHD and Reading
Disability Single study comparisons
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ADHD v HFA EF measuresSingle study comparisons
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• Is a common aspect aggregated over all tasks,
  variability of reaction time, perhaps a better
  discriminator?

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Is variability the greater discriminator?
Poor clinical discrimination
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• Are measures of functional brain imaging,
  showing the brain in action, more powerful?

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ADHDNeurobiologic Basis
Attention Networks
EXECUTIVE CONTROL
ORIENTING (SELECTIVE ATTENTION)
ALERTING
Posner and Raichle. Images of Mind. Scientific
American Books 1996.
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Paradigm shift

• From one to multiple core deficits
• From between-group to within-group analyses
• Cognitive functional measures as a way to
  partition clinical and aetiological heterogeneity
  and to describe more homogeneous subtypes

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Traditional case-control design
External variable
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Research
Brain
Genes
Behavior
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Endophenotype latent trait that

• Is indirectly related to clinical symptoms
  (disease phenotype)
• Reflects underlying genetic susceptibility to
  disease phenotype
• Can be measured on a neurophysiological /
  neuropsychological / neurochemical / behavioral
  level
• May be used to define genetically homogeneous
  samples

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Gene - Environment
Genes
Complex Traits / Disorders
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Gene - Environment
Genes
Brain abnormalities
Cognitive dysfunctions
Complex Traits / Disorders
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Gene - Environment
Genes
Genotype
Brain abnormalities
Endophenotype Intermediate phenotype
Cognitive dysfunctions
Complex Traits / Disorders
Phenotype
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Gene - Environment
Genes
Genotype
Brain abnormalities
Endophenotype Intermediate phenotype
Environment
Cognitive dysfunctions
Complex Traits / Disorders
Phenotype
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Gene - Environment
Gene
Gene
Gene
Gene
Gene
Gene
Gene
BrAbn
BrAbn
BrAbn
BrAbn
BrAbn
CogDys
CogDys
CogDys
CogDys
CogDys
Complex Traits / Disorders
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Genotype and endophenotype
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Genotype and endophenotype
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Dual pathway model of ADHD
Sonuga-Barke, 2003
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Environment and compensation DeAv
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Environment and compensation - EF
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Testing external validity of this model

• Differential relations with external variables
• Genes / Environments
• Course / Developmental precursors
• Clinical severity
• Risk for comorbidities
• Response to treatment
• Type of treatment

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Cognitive Endophenotype of ADHD Results from the
Dutch IMAGE Cohort

• 238 ADHD-families (545 children)
• 238 probands (combined subtype),
• 112 affected siblings (64 combined subtype, 28
  inattentive subtype and 20 with
  hyperactive-impulsive subtype)
• 195 non-affected siblings
• 147 control-families (271 children, 90 sibling
  pairs)
• Multiple executive functions
• Inhibition stop task
• visuo-spatial memory
• verbal working memory
• intelligence (performal and verbal IQ)

Nanda Rommelse, Marieke E. Altink, Ellen Fliers,
Cathelijne Buschgens, Steve Faraone, Jan
Buitelaar, Jaap Oosterlaan, Joe Sergeant
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Inhibition - Stop-signal reaction-time
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Mean reaction time
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Standard Deviation Reaction time
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Inhibition - errors
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Spatial working memory
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Verbal working memory
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Intelligence
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Mutual influence model of behavioral control
(based on Nigg, 2006)
PFC-striatal
Neural/CNS
Limbic-frontal
Vagal tone Response suppression (inhibition) WM
PNS Cognitive
HR response to reward skin conductance Incentive
reactivity, speed, reinf. learning
Temperament Personality
Effortful control, flexible coping
Reactive control, behavioral inhibition
Impulsivity, hyperactivity, impulsive aggression
sx
Inattentive, disorganized sx
Pathology
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Neural Substrates of ADHD New Data

• Volumetric MRI Adults with ADHD have less gray
  matter, and more white matter largest reductions
  in anterior cingulate (14), Nc Accumbens (9),
  and DLPFC
• Cortical thickness 6 thinner cortex (particular
  ACC, DLPFC, OFC, inferior parietal lobe, temporal
  lobe)
• Diffusion Tensor Imaging (DTI) lower FA values
  in cingulum bundle and superior fasciculus
  longitudinalis (Makris et al. Cerebral Cortex,
  2007)

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Neural Substrates of ADHD New Data

• Clinical response to Concerta-MPH is correlated
  with ACC activation at an individual level

Bush et al. Arch Gen Psychiatry, 2007, in press
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Testing external validity of this model

• Differential relations with external variables
• Genes / Environments
• Course / Developmental precursors
• Clinical severity
• Risk for comorbidities
• Response to treatment
• Type of treatment

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Executive Dysfunction Syndrome
ASD
OCD
CD
EDF
MOOD
ADHD
Bipolar