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Even Very Mild Stress Impairs the Executive Functions of Most People

Zareyan*, S., Zhang*, H., Wang, J., Song, W., Hampson, E., Abbott, D., & Diamond, A. (2020). First demonstration of double dissociation between COMT-Met158 and COMT-Val158 cognitive performance when stressed and when calmer. Cerebral Cortex, xx, 1-16. https://doi.org/10.1093/cercor/bhaa276  (pdf)

We present here the first evidence of the much-predicted double dissociation between the effect of stress on cognitive skills [executive functions (EFs)] dependent on prefrontal cortex (PFC) by catechol-O-methyltransferase (COMT) genotype. The COMT gene polymorphism with methionine (Met) at codon 158 results in more dopamine (DA) in PFC and generally better EFs, while with valine (Val) at codon 158 the result is less PFC DA and generally poorer EFs. Many have predicted that mild stress, by raising PFC DA levels should aid EFs of COMT-Vals (bringing their PFC DA levels up, closer to optimal) and impair EFs of COMT-Mets (raising their PFC DA levels past optimal).We tested 140 men and women in a within-subject crossover design using extremely mild social evaluative stress. On trials requiring EFs (incongruent trials) of the Flanker/Reverse Flanker task, COMT-Val158 homozygotes performed better when mildly stressed than when calmer, while COMT-Met158 carriers performed worse when mildly stressed. Two other teams previously tried to obtain this, but only found stress impairing EFs of COMT-Mets, not improving EFs of COMT-Vals. Perhaps we found both because we used a much milder stressor. Evidently, the bandwidth for stress having a facilitative effect on EFs is exceedingly narrow.

Sex Differences in the Effects of Mild Stress on Executive Functions

Prefrontal cortex (PFC)-dependent EFs are critical for reasoning, problem-solving, self-control and planning. The PFC dopamine (DA) level has been demonstrated to modulate EFs in an inverted U-shaped curve, where an intermediate level of DA is optimal. Unlike in other brain regions, PFC DA systems: 1) relies highly on the catechol-O-methyltransferase (COMT) enzyme for clearing released DA; and 2) can be activated even by mild stress. Estradiol (E2) has been shown to down-regulate COMT gene transcription, causing the activity of COMT enzyme to be ~30% less in women than in men.

Animal studies have repeatedly shown that stress facilitates cognitive functions dependent on the hippocampus and / or PFC in males, but impairs them in females. Therefore, based on Diamond’s hypothesis that baseline PFC DA levels are higher and closer to the optimal level in women during menstrual phases when their circulating E2 are elevated, than in men, we predicted that mild stress would facilitate EF performance in men but impair it in women when their circulating E2 levels are high.

In a crossover design, healthy young adults (both men and women), all COMT Val158Met heterozygotes, were each tested twice (once with social-evaluative stress and once without, order counterbalanced) on five EF tasks which tapped on the core EFs of inhibitory control, working memory and cognitive flexibility, and one higher-level EF, reasoning. Women were randomly assigned to the low-E2 (F-L) group or high-E2 (F-H) group. Women in the F-L group were tested during the early follicular phase (low E2 level). Women in the F-H group were tested during the midluteal phase (high E2 level).

Our social-evaluative procedure was shown to succeed in inducing physiological and subjective stress responses and significantly impaired the performance of the F-H group on one index of inhibitory control, whereas the performance of the M and F-L groups showed a trend towards enhancement. Similar trends (M and F-L: stress-induced enhancement; F-H: stress-induced impairments) were found for some other indices in the first two tasks. These results emphasized that the ways of improving EFs need to be considered in a sex-specific and hormone-dependent manner.

Pharmacologically Modelling Individual Differences in the Effects of Mild Stress on Executive Functions using MPH

Following our studies on the modulation of the effects of mild stress on EFs by COMT genotype and estradiol, we pharmacologically modeled this. If mild stress impairs EFs because it pushes dopamine (DA) levels in prefrontal cortex (PFC) past optimal, then increasing PFC DA levels artificially in the absence of stress should produce the same effect. We tested this using a low dose of Methylphenidate (MPH; which increases PFC DA levels), in a double-blind crossover design with a placebo (Vitamin C; results in analyses). We predict that MPH + COMT-Met genotype or MPH + higher estradiol levels will result in worse EFs than placebo.

What's Best for Men is Not Always what's Best for Women: Sex Differences
in the Effects of COMT Genotypes in Older Adults

Adele Diamond, Paige Scaile, Arthur Kramer, John Fossella, David Abbott, & Jennie Kim. (manuscript in prep.) What’s best for men is not always what’s best for women: Gender differences in the effects of COMT genotypes.

Sex Difference in which polymorphism of the COMT Gene is more Beneficial
for Executive Functions varies with the Menstrual Cycle

Jeanette Evans, John Fossella, Elizabeth Hampson, Clemens Kirschbaum, & Adele Diamond. (manuscript in prep.) Gender differences in the cognitive functions sensitive to the level of dopamine in prefrontal cortex. Poster presented at the Association for Psychological Science annual meeting, San Francisco, CA.

Estrogen down-regulates catechol-o-methyltransferase (COMT) gene transcription. The COMT enzyme is 30% less active in women than men (a less active COMT enzyme clears dopamine more slowly, leaving more dopamine around longer in PFC). With estrogen resulting in a slower COMT enzyme, further slowing of the enzyme by the COMT gene polymorphism with methionine at codon 158 could result in too much dopamine in PFC (too much or too little dopamine in PFC impairs EFs). Hence the COMT gene variant usually associated with better EFs for men (COMT-Met158) is not the variant associated with better EFs for women, at least when their estrogen levels are high (instead COMT-Val158 is).

Since the sex difference is estrogen-mediated, which variant of the COMT gene is most beneficial for women varies with the menstrual cycle.

Review of All the Different Methods Use to Improve Executive Functions (Cognitive Training, Physical Activity, etc.) and at All Ages (Not Just in Children or Just in Older Adults)

Diamond, A., & Ling*, D. S. (2020). Review of the evidence on, and fundamental questions about, efforts to improve executive functions, including working memory. In J. Novick, M.F. Bunting, M.R. Dougherty & R. W. Engle (Eds.), Cognitive and working memory training: Perspectives from psychology, neuroscience, and human development, (pp.143-431). New York, NY: Oxford University Press. ISBN:978-0199974467. (pdf)

Diamond, A., & Ling, D.S., (2015). Conclusions about interventions, programs, and approaches for improving executive functions that appear justified and those that, despite much hype, do not. Developmental Cognitive Neuroscience. (pdf)

This systematic review of EF interventions is the largest such review thus far, including 179 studies from all over the world, reported in 193 papers. It covers all the ways that have been tried to improve EFs, including computerized and noncomputerized cognitive training, neurofeedback, school programs, physical activities, mindfulness practices, and miscellaneous approaches (e.g., drama and Experience Corps), at all ages. A little studied approach—mindfulness practices involving movement (such as taekwondo and t’ai chi)—shows the best results for improving EFs. Promising school programs are second. Both approaches show better results than any cognitive training. Third best at improving EFs is noncomputerized cognitive training. Perhaps these three approaches show better results than computerized training because they involve more in-person trainer-trainee interaction. The best-performing computerized cognitive-training method for improving EFs is Cogmed®. Support was lacking for claims that N-back training improves fluid intelligence. Resistance training and “plain” aerobic-exercise interventions (e.g., running or walking) show the least evidence of benefit to EFs of all methods. Results for aerobic exercise with more cognitive or motor-skill challenges are only slightly better. This probably reflects how physical-activity interventions have been structured, rather than that physical activity does not benefit EFs. For any intervention, trainers’ ability to make the training activity enjoyable and to communicate their unwavering faith in participants and the program plus the activity being personally meaningful and relevant, inspiring commitment and emotional investment in participants to the activity and to one another is probably what is most important.

A Randomized Control Trial of Tools of the Mind in Kindergartens in the Lower Mainland

Diamond, A., Lee*, C., Senften*, P., Lam*, A. & Abbott, D. (2019). Randomized control trial of Tools of the Mind: Marked benefits to kindergarten children and their teachers. PLOS ONE, 14, 1-27. doi:10.1371/journal.pone.0222447    (pdf)

The kindergarten program, Tools of the Mind (Tools), has been shown to improve EFs (as assessed by laboratory measures) and academic performance. The objective here was to see if Tools can improve EFs in the real world (in the classroom), academic outcomes not previously investigated, reduce bullying and peer ostracism, and increase teachers' and students' joy in being in the classroom. This first randomized controlled trial of Tools in Canada included 351 kindergarten children (mean age 5.2 years at entry; 51% female) in 18 public schools. Stratified randomization resulted in teachers and students in both groups being closely matched. Teachers in both groups received the same number of training hours and same funds for new materials. Outcome measures were pre and post standardized academic skill assessments and teacher online survey responses.

This study replicated that Tools improves reading and shows for the first time that it improves writing (far exceeding levels the school districts had seen before), self-control and attention-regulation in the real world (e.g., time on task without supervision), reduces teacher burnout and children being ostracized or excluded, and increases the joy students and teachers experience in school. By Spring, Tools teachers were still enthusiastic about teaching; control teachers were exhausted. These results were not only better than the control group but also better than Tools teachers experienced the year before Tools. Thus, children in a kindergarten curriculum that emphasized play, improving self-regulation, working together and helping one another, and hands-on learning performed better academically, showed less bullying and peer ostracism and more kindness and helping behavior than students in more traditional classes, and teacher enthusiasm for teaching soared. Tools reduced initial disparities separating children, schools, and teachers.

The Effect of Storytelling vs. Story Reading on the Executive Functions
of Fourth Graders

Bachmann, E. & Diamond, A. (May 10, 2022). Tell me a story: The effects of storytelling vs. story-reading on the executive functions of fourth graders. Poster presented at the International Science and Engineering Fair, Atlanta, GA.

We found that mutual storytelling between fourth graders improved auditory sustained attention more than did mutual story-reading.

Integrating Color and Shape aids Conditional Discrimination even though Separating them aids Card Sorting

Ling, D. S., Wong, C. D., & Diamond, A. (2021). Children only 3 years old can succeed at conditional “if, then” reasoning much earlier than anyone had thought possible. Frontiers in Psychology, 11: 57189. https://doi.org/10.3389/fpsyg.2020.571891 (pdf)

That conditional, if-then reasoning does not emerge until 4-5 years has long been accepted. Here we show that children barely 3 years old can do conditional reasoning. All that was needed was a superficial change to the stimuli: When color was a property of the shapes (line drawings of a star and truck) rather than of the background (as in all past conditional discrimination [CD] testing), 3-year-olds could deduce that red meant the star was correct and blue that the truck was correct, thus succeeding at conditional discrimination. Three-year-olds do not seem to use color to inform them which shape is correct in CD unless color is a property of the shapes themselves, suggesting they have difficulty mentally integrating dimensions that are not part of the same object.

While CD requires integrating color and shape information, the dimensional change card sort (DCCS) task requires keeping those dimension cognitively separate – inhibiting attention to one (e.g., shape) when sorting by the other (e.g., color). For DCCS, a superficial change to the stimuli that is the inverse of what helps on CD enables 3-year-olds to succeed when normally they do not until ~4½ years. As we and others have previously shown, 3-year-olds can succeed at DCCS when color is a property of the background (e.g., a white truck on a red background), instead of a property of the stimulus (e.g., a red truck on a white background, as in standard DCCS; Diamond et al.,2005).

Our findings on CD and DCCS suggest that scaffolding preschoolers’ emerging conceptual skills by changing the way stimuli look (perceptual bootstrapping) enables 3-year-olds to demonstrate reasoning abilities long thought beyond their grasp. Evidently, children of 3 years have difficulty mentally separating dimensions (e.g., color and shape) of the same object and difficulty mentally integrating dimensions not part of the same object. Our present CD findings plus our earlier DCCS findings provide strong evidence against prominent cognitive complexity, conditional reasoning, and graded memory theories for why 3-year-olds fail these two tasks. The ways we have traditionally queried children may have obscured the budding reasoning competencies present at 3 years of age.

Assuming the Same Normal Body Temperature for Everyone is Not Justified

Diamond, A., Lye*, C.T., Prasad*, D., & Abbott, D. (2021) One size does not fit all: Assuming the same normal body temperature for everyone is not justified. PLoS ONE, 16: e0245257. doi:10.1371/journal.pone.0245257 PMID: 33534845

We found wide individual differences in normal body temperature with the mean temperature across those studied being 36.1°C (97.0°F). Using temperature for Covid screening wouldn't detect 98.6° as a fever, but for persons with a normal temperature of 36.1°C (96°F) or 97°F, that's a fever.

Despite the increasing personalization of medicine, surprisingly ~37.0°C (~98.6°F) continues as the estimate of normal temperature. We found that individual differences in body temperature were large; mean temperatures ranged from 35.2°C (95.4°F) to 37.4°C (99.3°F). Assuming 37.0°C (98.6°F) is the normal temp can result in failing to detect a serious fever in people who have a low normal temperature or obtaining false negatives for such people when using temperature to screen for COVID-19, mistaking what for them is an elevated temperature as normal. Although temperature varied widely across individuals, it showed marked stability within individuals over days.

Any standardized “normal” temperature will lead to errors for many people. Individual differences are simply too great. Personalizing body temperature is needed.

A Powerful Example of how Biological and Environmental Factors Interact to produce a behavior

Weikum, W. M. T, Grunau, R. E., Brain, U., Chau, C. M. Y., Boyce, W. T., Diamond, A., & Oberlander, T. F. (2013). Prenatal serotonin reuptake inhibitor (SRI) antidepressant exposure and serotonin transporter promoter genotype (SLC6A4) influence executive functions at 6 years of age. Frontiers in Cellular Neuroscience, 7, 1-12. doi:10.3389/fncel.2013.00180

We found that it is not possible to say which genotype of the serotonin-regulatory gene (SLC6A4) is associated with better EFs without taking into account an environmental factor (mother’s mood).

We have been following a cohort of children since before birth whose mothers were moderately depressed during pregnancy. At the age of 6 years, the EFs of children with at least 1 short allele of the gene stayed fine even if their mom reported many depressive symptoms (i.e., they showed resilience and relative insensitivity to the environmental risk of a sad mom). But the EFs of children with 2 long forms of the SLC6A4 gene were very affected by their mom’s mood. If their mom was sadder, these children displayed worse EFs than any other group; but if their mom was happier, these children’s EFs were better than any other group. Thus, given a sadder mother, children with = 1 short allele of the SLC6A4 gene showed the best EFs, but given a mom who wasn’t sad, children with 2 long alleles of the gene showed the best EFs.

A Dramatically Larger, more Robust, and Developmentally More-Sensitive Flanker Effect

Sarah Munro, Cecil Chau, Karine Gazarian, Nancy Wang, & Adele Diamond. (manuscript in prep.) Dramatically larger Flanker effects (6-fold elevation). Poster presented at the Cognitive Neuroscience Society annual meeting, San Francisco, CA.

On our Flanker Task there are 3 blocks. Block 1 is the standard Flanker paradigm (where the stimuli are blue and subjects are to attend to the center stimulus and ignore the flanking stimuli).  Block 2 is Reverse Flanker (attend to the flankers, ignore the center stimulus; the stimuli are pink). In Block 3, Flanker (blue stimuli trials) and Reverse Flanker (pink stimuli trials) trials are randomly intermixed. 
Results with our Flanker paradigm reveal:

     The Flanker effect is 6-10 larger in the context of switching (Block 3) than we or others find on the standard Flanker paradigm. (In Block 3, only trials comparable to standard Flanker trials were used for this comparison, i.e., only Flanker, non-switch trials.)

      Unlike on the standard Flanker task, in the context of switching (Block 3), the Flanker effect is robust in the face of variations in stimulus characteristics (e.g., whether the stimuli are larger or smaller or closer together or farther apart).

The developmental progression extends for far longer in the context of switching (Block 3) than on the standard Flanker task.

The Social Simon Effect is seen as Early as the Simon Effect

Yvette Wu, Sarah Munro, & Adele Diamond (manuscript in prep.) Development of the social ‘Simon’ effect. Poster presented at the Jean Piaget Society annual meeting, Amsterdam, Netherlands

Perception of a stimulus on one side of space tends to activate the hand on that same side. To respond with the other hand requires inhibition of that prepotent response. Hence people are slower to act on the rule, “Press the right hand button whenever you see astar,” if the star appears on the left than if it appears on the right. This “Simon Effect” is copiously documented in adults. Recently it has been demonstrated in adults that if the task is shared with another person, so that the person sitting beside you is responsible for the right hand button and so should always press when the star appears and you are responsible for the left hand button and so should always press when the frog appears, adults still show the Simon Effect. However if the interpersonal dimension is removed and the task is presented as a Go/No-go (press for the frog, do nothing when a star appears), the Simon Effect is NOT found, even though what you do here is exactly the same as in the interpersonal situation.

We wanted to see if this was true in children, and if so, how early it would be seen.

We tested 4 age groups: mean age in years= 3.6 (range= 3.4-3.8), 4.1 (range= 3.9-4.3), 4.7 (range= 4.5-4.9), and 20.7 (range= 18.5-22.7), 16 subjects per group (50% female).

We replicated the findings previously reported in adults: longer RTs when a stimulus appeared on the side opposite its associated response than when it appeared on the same side (the Simon effect) in the basic and team conditions, but not in go/no-go. We also replicated that the earliest age for the Simon effect is 4 years. Our 4.1-year-old group showed the Simon effect, but our 3.6-year-old group did not. The task was too difficult for them and they responded randomly.

Would children show the Social Simon effect and how early? From the earliest age that children can perform the task (4 years) they showed the Social Simon effect (a Simon effect in the Team but not the Go/No-go condition -- and comparable Simon effect in the Team and Basic conditions) and it was completely as robust as that for adults. This was true (a) if the Simon effect was determined by the usual formula: RT on incongruent trials minus RT on congruent trials. It was also true when we corrected for children’s slower RTs: (b) (RT incongruent trials minus RT congruent trials) divided by the child’s average RT in that condition.

These results imply that children as young as 4.1 years are treating the other person in Team Simon as an extension of themselves. It’s as if they themselves were pressing the other button.