6. Is the population of planet Earth large enough to minimize type I & type II error ? “ Millions” x “thousands” x “hundreds” (genetic variants) (voxels) (task contrasts)
7. relevance to many disorders post-natal developmental trajectory well studied anatomically well studied pharmacologically relevance to cognitive interventions that have long-term benefits TASK… VALIDITY - parsing cognition ATTENTION as a model system Psychopathology Anterior Cingulate Cortex Attention
9. Distribution of normalized scores for executive attention N = 200 normal adult volunteers Stimulus-Response conflict score TASK … RELIABILITY is there sufficient or too much variation ? 0 10 20 30 40 50 60 70 80 90 0.05 0.15 0.25 0.35 This group “ Slows down” during incongruent trials
10. TASK … VALIDITY - where in the assay does the inter-subject variability originate ? Where is the variation coming from ? baseline reaction times ? perceptual differences ? differences in motivation ? paying attention to errors ?
11. CANDIDATE GENE … anatomical & pharmacological constraints Fan et al., 2004
12. Correlation values between twin pairs of MZ and DZ twins for each network and mean RT. _______________________________________ Twin Alerting Orienting Conflict RT _______________________________________ MZ .465 * .099 .727 ** .740 ** DZ .375 .395 * .281 .659 ** _______________________________________ Note: * p < .05; ** p < .01 Heritability Alerting Orienting Conflict RT _____________________________________________ h 2 F = 2 ( r MZ – r DZ ) .18 -.59 .89 .16 h 2 H = ( r MZ – r DZ )/ .14 -.49 .62 .24 (1 – r DZ ) ML fit: h 2 .18 .00 .72 .16 TASK … HERITABILITY
13. Dopamine Transporter Dopamine Receptor Monoamine Oxidase A COMT CANDIDATE GENE … selection of polymorphism … known SYNAPTIC function ?
16. INTERPRETATION… internally & externally consistent with literature ? Low DA levels High DA levels 20 30 N = VAR00002 2.00 1.00 Mean +- 1 SE VAR00001 .24 .22 .20 .18 .16 .14 .12 Conflict ratio score COMT Val 108/158 MAOA long prom. repeat COMT Met 108/158 MAOA short prom. repeat
17. INTERPRETATION … internal & external robustness Fan et al., 2003 MAOA (4-repeat) – (3-repeat) 4-repeat, LOW MA 3-repeat, Hi MA Reaction Time Diff Red = activity biased by MAOA 4-repeat allele Blue = activity biased by MAOA 3-repeat allele
18. INTERPRETATION … is the inter-subject variation coming from a meaningful source ? DRD2 TaqA1 allele Fossella et al., 2006
19. CANDIDATE GENE … anatomy & pharmacology constraints Striatal activation is significantly increased for subjects carrying the 9R-allele of the DAT1-VNTR , whereas cerebellar vermis activation is significantly attenuated. Durston et al., 2006
20. DEVELOPMENTAL CONTEXT … diffuse to focal model system Shaw, P. et al. Arch Gen Psychiatry 2007;64:921-931. Child ANT
21. A synaptic model frames our imaging genetic research: LTP in the (mouse) anterior cingulate cortex (Zhuo et al., 2007) DA GABA GLUTAMATE +NR2B -AC1, AC8 -CaMKIV
22. Jin Fan Xun Liu Kevin Guise Liang Wang Tobias Sommer Karin Brocki Michael Posner Thanks to Jeff Newcorn
