Adele Diamond - US grants

[unreadable] DESCRIPTION (provided by applicant): This is part of a larger endeavor whose aim is to systematically investigate executive control functions, studying their development, neural bases, and genetic & neurochemical modulation from infancy through old age. The focus here is on inhibition of attention, inhibition of action, and cognitive flexibility during early development. It is hypothesized that: (1) Errors made by children of 3-10 years reflect problems with flexibly switching. Even 3-year-olds will succeed at steady-state attentional inhibition (selective attention) and steady-state action inhibition (inhibition of old stimulus-response mappings). Lags of up to 3-6 years will be found, however, between when children can first show inhibition in steady-state and when they can switch back and forth. (2) This progression does not depend on improved memory; even the younger children will be able to state the correct rule on each trial. It does depend, though, on improvements in the ability to execute the mental computations necessary to translate abstract rules into practice. The core problems in the development of executive control functions are the abilities to flexibly switch mental settings and to flexibly manipulate information in one's mind, not inhibition or memory per se. (3) Many of the errors made by infants and preschoolers reflect difficulty in grasping that two things are conceptually connected if they are not physically connected (e.g., not part of the same entity), and the flip side, difficulty grasping that attributes of a single entity can be separated and the entity conceptually redescribed from different perspectives. Thus, while switching attentional focus and response mappings is difficult, when the stimulus dimensions are separated, children will succeed at such switching at a very young age. The proposed research will test these and other hypotheses, charting the development of inhibitory control and cognitive flexibility in the early years of life. This will provide valuable insights into why children have difficulties, conditions for optimizing their performance, and benchmarks by which to assess children's development or deficits. A more refined understanding of executive control functions will assist efforts to understand how these are differentially affected in disorders such as Attention Deficit Hyperactivity Disorder, Obsessive Compulsive Disorder, schizophrenia, addictions, and autism. Insights into the conditions under which children can succeed may yield procedures that might prove helpful to those afflicted with disorders affecting these critical functions. [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This project will investigate the hypothesis that: (a) children with autism have unusual difficulty grasping the relation between one thing & another (e.g., between a stimulus object & reward object) that cannot be attributed to cognitive delay, (b) critical advances in this fundamental ability to perceive conceptual connections between physically unconnected things occur during the 2nd year of life, and (c) children with autism can show rule-learning and can grasp abstract concepts when fairly simple modifications are made in how the relation between objects is presented to them. Typically-developing (TD) infants under 21 months and children with autism have inordinate difficulty acquiring the "delayed nonmatching to sample [DNMS]" rule even with minimal delays, when the rewards are placed in shallow wells just beneath the stimuli; though once they've learned the rule, they succeed at long delays. Since children with autism appear to fail DNMS in the same ways as do infants, they may be failing for the same reasons and may succeed under the same conditions. If the reward is velcroed to the base of the stimulus (reward still hidden when stimulus is atop a well), infants of 12 months readily grasp the nonmatching rule. We predict that children with autism will similarly succeed when the rewards are attached to (though detachable from) the base of the stimuli. If children with autism are able to grasp the abstract rule and the connection between stimulus and reward in the velcro condition, the implications for intervention are exciting. Most behavioral training with children with autism has not considered whether cue and referent are physically connected. The ability to form abstract concepts and grasp the relation between cue and referent is critical for diverse facets of cognitive and social development. Thus, we expect our findings will have direct and immediate implications for teaching some concepts to some young children with autism more efficiently, earlier, and with greater real acquisition than previously thought possible. To better understand the ability of children with autism to relate one thing to another, and the importance of physical connectivity to their ability to do that, 3 tasks, each with 2-3 conditions, will be used. To determine whether this is specific to children with autism, at what developmental level children with autism are performing, and the typical developmental progression in the unfolding of this ability, these tasks will be given to mildly developmentally-delayed preschoolers with (a) autism and (b) Down syndrome (each group with a mean age of 45 months and mean mental age of 27 months), and TD children of 27, 24, 21,18, 15, and 12 months. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The unusual properties of the prefrontal cortex (PFC) dopamine (DA) system contribute to the unusual sensitivity of PFC and the cognitive functions that depend on it to environmental and genetic variations. (Those cognitive functions are called 'executive functions' [EFs] and are important for reasoning, planning, problem-solving, and self-control.) We propose to study the effects of an environmental factor (mild stress) on EFs, testing our predictions of how and why those effects differ by biological factors (hormones and genotype). To test our hypotheses concerning the underlying mechanism, we will try to model the effects of mild stress on EFs pharmacologically. Two ways in which the DA system in PFC is unusual are: (1) It relies heavily on the catechol-O-methyltransferase (COMT) enzyme for clearing released DA (other brain regions rely heavily on the dopamine transporter). (2) Mild stress markedly increases DA in PFC (but not in other brain regions). Animal studies find a sex difference in that mild stress aids performance on cognitive tasks that require PFC in males, but hinders it in females. We propose (a) a new interpretation of that, (b) to see if this sex differene is also true in humans, and (c) to put our new interpretation to the test. We hypothesize that mild stress exerts its effect on cognition, and produces the sex difference in that, by increasing DA in PFC (rather than the mechanism being solely by increasing cortisol and affecting hippocampal functioning). If we are correct, then if we model this by pharmacologically increasing DA in PFC, we should be able to replicate the sex difference. There are two common variants of the gene that codes for the COMT enzyme, one codes for a much slower COMT enzyme than the other, clearing DA from PFC much more slowly. With a slower enzyme increasing the level of DA in PFC, the increase in PFC DA due to stress could well result in too much DA in PFC, impairing EFs. Thus we predict opposite effects of stress on cognition by COMT genotype, and we predict that by pharmacologically increasing DA in PFC, we should be able to replicate that (those homozygous for the gene coding for the faster enzyme should benefit, but those homozygous for the other version should show impaired EFs). We thus hope to put our causal model to the test by attempting to reproduce the opposing effects of mild stress in males and females and by genotype without stress but just by increasing DA in PFC. If our hypotheses are borne out, gender and genotype should be taken into account when considering the best environment and best drug dosage for aiding a person's self-control and creative problem-solving, and for minimizing a person's impulsive tendencies when trying to prevent or treat mental health disorders (such as addictions) in which EFs and the DA system in PFC are implicated and when teaching or designing a work environment.