Genetic and Environmental Influences on Prefrontal Cortex: Relevance of what we know to what can be done to help children Adele Diamond Canada Research Chair Professor of Developmental Cognitive Neuroscience University of British Columbia (UBC)

The “Executive Functions” (EF), which depend on prefrontal cortex, include 3 core abilities:

(a) Inhibitory control (self-control) is the ability to resist a strong inclination to do one thing and instead do what is most appropriate or needed

Being able to… (1) pay attention despite distraction e.g., suppressing attention to what others are saying so that you can concentrate on what the the lecturer is saying or screening out all but one voice at a cocktail party

Being able to… (2) act appropriately when tempted to act otherwise e.g., staying on task despite boredom or tantalizing temptations -- such as resisting the temptation to do something more fun and instead finish a task, or resisting a luscious chocolate dessert and instead going for the fresh fruit if you want to lose weight

Being able to… (3) not giving in to your first impulse and giving a more considered response instead e.g., resisting saying something socially inappropriate (or hurtful) and saying the polite remark instead

Why is INHIBITION important? The ability to inhibit attention to distractors makes possible selective and sustained attention. The ability to inhibit a strong behavioral inclination helps make self-discipline and change possible, as well as social politeness. Inhibition, thus, allows us a measure of control over our attention and our actions, rather than simply being controlled by external stimuli, our emotions, or engrained behavioral tendencies.

(b) Working Memory: Holding information in mind while mentally working with or updating it

such as  relating one idea to another  relating what you read earlier to what you are reading now  doing mental arithmetic (e.g., adding or subtracting)

or Holding information in mind while working on something else for example, holding in mind where something was hidden despite being given something else to do during the delay

Why is WORKING MEMORY important? WM makes it possible to  consider things from different perspectives,  understand a story – relating the beginning, middle, & end  relate the present to the future or past  translate instructions into action plans. It is critical to our ability to see connections between seemingly unconnected things, and hence to creativity, for the essence of creativity is to be able to disassemble and re-combine elements in new ways.

being able to flexibly switch perspectives or the focus of attention, flexibly adjusting to changed demands or priorities. (c) COGNITIVE FLEXIBILITY Note that shifting mental sets involves both: activating the new set & de-activating the old one

This is critical for creative problem- solving… for considering something from a fresh or different perspective, and for ‘thinking outside the box.’ Why is COGNITIVE FLEXIBILITY important?

STUDY YEAR METHOD AGES FACTORS Miyake et al. (2000) confirmatory adults 3: inhibition, updating (WM), factor analysis shifting (cog flex) Lehto et al. (2003) exploratory 8-13 years 3: inhibition, working & confirmatory memory, set shiifting factor analysis Used a completely different set of tasks than Miyake Again, a CFA indicated that the best fit was a model with three dissociable but moderately intercorrelated latent variables. Huizinga et al. (2006) confirmatory 7-21 years 3: inhibition, working factor analysis memory, shifting St. Clair- Thompson exploratory yrs 2: inhibition, working & Gathercole (2006) factor analysis memory WM and inhibition were found to be completely uncorrelated. Verbal & visuospatial measures of complex WM shared a common association with updating, but were completely uncorrelated with inhibition. Failed to identify a distinct factor for shifting - but prob.s w/ their tasks Senn et al. (2004) suggested that mental flexibility may be less differentiated from WM & inhibition in young children than in adults.

Want to be able to use PFC whenever you….. are presented with the unexpected,.. need to think outside the box,.. need to concentrate particularly hard,.. need to adapt to change… BUT

Want most tasks to be so familiar and well learned that PFC is NOT used. Instead, those tasks are handed off to subcortical regions that have had 100,000s of more years of evolutionary time to perfect their functioning and can subserve task performance ever so much more efficiently than can PFC.

TT NS MT DO DC KO RB The DLPFC Slice for 8 Individuals (A/P=+45) CB LR

Stress impairs Executive Function and can cause someone to look as if he or she has ADHD.

Even mild stress increases DA release in PFC Stress and Prefrontal Cortex (Roth et al., 1988)

People often mistake the symptoms of unmanaged stress. Children may be reprimanded by teachers or parents for actions that are really stress reactions, rather than intentional misbehavior.

Yerkes – Dodson Curve Task Performance Anxiety Level

But that may be true only for males! But that may only be true for males!

NO StressSlight Stress Males Females % of Conditioned Responses Effect of Stress on Trace Eyeblink Conditioning in Male and Female Rats Shors & Leuner, 2003

PFC Stress

Putting Feelings Into Words Produces Therapeutic Effects on the Brain When you put feelings into words, you increase activation in prefrontal cortex and that produces a reduced response in the amygdala.

Matt Lieberman et al., 2007

If you can get people to talk or write about their problems, their psychological and physical health improves. --- James Pennebaker, Opening Up: The Healing Power of Expressing Emotions

Translating an emotional experience into language, talking or writing about, alters the way it is represented and understood in our mind and our brain (gets prefrontal cortex more involved).

Special Properties of the Dopamine Neurons that Project to PFC

Striatum = DA Transporter = DA Receptor

Prefrontal Cortex = DA Transporter = DA Receptor

This makes prefrontal cortex more dependent on secondary mechanisms (such as the COMT [catechol-O- methyltransferase] enzyme) for clear- ing dopamine from extracellular space than are other brain regions, such as the striatum.

COMT Gene catechol-O-methyltransferase gene codes for the COMT enzyme, which methylates released dopamine. It’s located on chromosome 22.

A single base pair substitution: CGTG to CATG translates into a substitution of Methionine for Valene at codon 108/158: leads to AGVKD vs. AGMKD

Catechol-O-methyltransferase (COMT) Val158 Met affects catabolism of catecholamine neurotransmitters COMT Val-Val COMT Met-Met High dopamine Zalsman et al. Low activity enzyme High activity enzyme Low dopamine SYNAPSE

The low-activity M allele breaks down DA more slowly. It is associated with better PFC function. Adults homozygous for the Methionine variant of the COMT gene perform better on WCST, & need less PFC activation to show the same level of performance on the N-back task.

val/valval/metmet/met WCST Perseverative Errors (t-scores) patients controls COMT Genotype Egan, Goldberg, Kolachana, Callicott, Mazzanti, Straub, Goldman, & Weinberger (2001) Proceedings of the National Academy of Science, 98:

This effect is specific to PFC function: There is no relation between the M vs. V allele of the COMT gene with IQ or other non-PFC functions.

Genetic and Neurochemical Modulation of Prefrontal Cognitive Functions in Children Adele Diamond, Lisa Briand, John Fossella, & Lorrie Gehlbach (2005) American Journal of Psychiatry vol 16, pages

Prediction: Although the COMT genotype, which affects the level of dopamine in PFC, should correlate with performance on the Dots task, IT SHOULD NOT CORRELATE with performance on self- ordered pointing.

Dots - Congruent Push Left Push Right Push Left Push Right Dots - Incongruent

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

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Performance on Self-Ordered Pointing has been linked specifically to dorsolateral PFC by work with…. … lesioned monkeys … brain-damaged patients … functional neuroimaging in normal adults