Collins, Roberts, Dias, Everitt, & Robbins (1998) Behavioral Task Delayed Response Self-Ordered Pointing Type of Lesion to working memory + inhibition requires working memory Frontal Cortex Excitotoxic Performance Performance (cell bodies destroyed) IMPAIRED IMPAIRED Performance Performance 6-OHDA (dopamine depleted) IMPAIRED SPARED Collins, Roberts, Dias, Everitt, & Robbins (1998)

This is the pattern we saw in treated PKU children: Behavioral Task Delayed Response Self-Ordered Pointing Type of Lesion to working memory + inhibition requires working memory Frontal Cortex Excitotoxic Performance Performance (cell bodies destroyed) IMPAIRED IMPAIRED 6-OHDA Performance Performance (dopamine depleted) IMPAIRED SPARED This is the pattern we saw in treated PKU children: Diamond, Prevor, Callender, & Druin (1997)

Congruent Incongruent HEARTS & FLOWERS Push Left Push Right Push Right 3 3

PRESS ON THE SAME SIDE AS THE HEART HEARTS – CONGRUENT Each time you see a HEART, press with the thumb or forefinger on the SAME side as the stimulus. For example, if the heart appears on the left, press with your left hand. Remember: PRESS ON THE SAME SIDE AS THE HEART

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PRESS ON THE SIDE OPPOSITE THE FLOWER FLOWERS - INCONGRUENT Now you’ll see a flower. Press on the side OPPOSITE the flower. For example, if a flower appears on the left, press with your right hand. (Here, you’ll need to inhibit on every trial the natural tendency to respond on the same side as the stimulus) Remember: PRESS ON THE SIDE OPPOSITE THE FLOWER

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The rules stay the same: For HEARTS, press on the SAME side. HEARTS & FLOWERS-MIXED: Now you will sometimes see a heart and sometimes a flower. On only half the trials will you have to inhibit the tendency to press on the same side as the stimulus, BUT you’ll have to switch between the same-side and opposite-side rules. The rules stay the same: For HEARTS, press on the SAME side. For FLOWERS, press on the OPPOSITE side. HEARTS – SAME SIDE FLOWERS – OPPOSITE SIDE

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Dots Conditions: Accuracy 100 90 80 Percent Correct 70 60 4 5 6 6 7 8 9 10 11 13 26 Stimuli presented for 2500 ms Stimuli presented for 750 ms Age in Years Davidson et al. (2006). Neuropsychologia, 44, 2037 - 2078

Adults have little difficulty exercising inhibition in steady-state in single-task blocks, but children of all ages demonstrate a cost in doing so.

At every age studied, without exception, children were slower & less accurate at Dots-Incongruent block than at Dots-Congruent. Adults may not appreciate how inordinately difficult inhibition is for young children because it is less taxing for us.

Increasing demands on inhibition are more difficult for children (ages 4-9 years) than increasing demands on how much information they must hold in mind (2 to 6 items). Not until 10 years of age does increased memory demands (holding in mind 2 versus 6 arbitrary, hard-to-verbalize rules) take a greater toll on accuracy than does consistently inhibiting the tendency to respond on the same side as the stimulus (Dots-Incongruent vs. Dots-Congruent).

The opposite is true for young adults: Increasing memory load is disproportionately more difficult for adults than increasing inhibitory demands. The inhibitory demand of Dots- Incongruent feels minimal for adults while the memory demands of 6- Abstract-Shapes feels very substantial. 

How come Danny Weinberger and I didn’t get bigger effects?

Perhaps, the methionine variant of the COMT gene results in too much dopamine in PFC for some children and young adults.

Levels of dopamine in the brain decrease with aging. Therefore, the methionine variant might be more UNIVERSALLY beneficial to older adults, as it would be more likely to help a larger percentage of them reach the optimal point on the DA curve, rather than going past it. Hence, hypothesis: the relation of COMT genotype to Executive Function should be even stronger among older adults than already observed among children & young adults.

Art Kramer Paige Scaile John Fossella

No effect!

But, Females far outnumber males among the elderly. Males perform better if slightly stressed but females perform worse under stress, even if slight stressed (Tracey Shors; Amy Arnsten)

Effect of Stress on Trace Eyeblink Conditioning in Male and Female Rats 100 NO Stress STRESSED 80 60 % of Conditioned Responses 40 20 Males Females Shors & Leuner, 2003

Hypothesis: Baseline levels of DA may be higher in females than males. Baseline DA levels may be optimal in females & slightly too low in males. (Hence slight stress helps males by raising their DA levels to the optimum level but hurts female performance because it pushes their DA levels past the optimum level.)

Hypothesis: Females with the V-V version of COMT should perform better. Males with the M-M version of COMT should perform better.

Percent of Perseverative Errors on the WCST WORST 16 14 Percent 12 10 BEST Gender: Males Females COMT genotype: V-V M-M V-V M-M

Percent of Perseverative Errors on the WCST WORST 16 14 Percent 12 10 BEST Gender: Males Females COMT genotype: V-V M-M V-V M-M

The presence of sex hormones during gestation and development organize how stress affects learning in adulthood. Female rats given testosterone at birth perform like males; their performance is facilitated by stress (Shors & Miesegeas, 2002). Male rats, whose mothers were injected with a testosterone antagonist for several days when testosterone levels are normally elevated in fetal males, do NOT show the male enhanced in learning when stress (though not impaired either; Shors & Miesegeas, 2002).

Would expect these gender differences to be even stronger in young adults comparing males with females during the point in their menstrual cycles when their estrogen levels are elevated….

The higher a female rat’s current level of estrogen, the more impaired she is on PFC-mediated tasks in the face of natural or pharmacological stress (benzodiazepine inverse agonist).

Estrogen down-regulates human COMT transcription (Ho, 2006). COMT activity is 30% lower in women than men. Varies with estrus cycle in rats; inverse relation between COMT activity and estrogen levels.

Stress & PFC Delayed Alternation (Shansky et al., 2004)

Stress & PFC Delayed Alternation (Shansky et al., 2004)

Stress & PFC (Females only) Delayed Alternation (Shansky et al., 2004)