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*Manuscript
Running head: CORTISOL AND CORE EXECUTIVE FUNCTIONS
1
Does Cortisol Influence Core Executive Functions?
A Meta-Analysis of Acute Cortisol Administration Effects on Working Memory, Inhibition, and SetShifting
Grant S. Shields,1 Joseph C. Bonner,1 & Wesley G. Moons2
1
University of California, Davis, CA, 95616, United States of America
2
Moons Analytics, San Diego, CA 92101, United States of America
Address correspondence to Grant S. Shields, Department of Psychology, University of California
Davis, One Shields Avenue, Davis, CA 95616; [email protected]
Word Count: 5,780
Introduction Word Count: 942
Discussion Word Count: 1,821
References (not including those used in the meta-analysis): 40
CORTISOL AND CORE EXECUTIVE FUNCTIONS
Abstract
The hormone cortisol is often believed to play a pivotal role in the effects of stress on human cognition.
This meta-analysis is an attempt to determine the effects of acute cortisol administration on core
executive functions. Drawing on both rodent and stress literatures, we hypothesized that acute cortisol
administration would impair working memory and set-shifting but enhance inhibition. Additionally,
because cortisol is thought to exert different nongenomic (rapid) and genomic (slow) effects, we further
hypothesized that the effects of cortisol would differ as a function of the delay between cortisol
administration and cognitive testing. Although the overall analyses were nonsignificant, after separating
the rapid, nongenomic effects of cortisol from the slower, genomic effects of cortisol, the rapid effects of
cortisol enhanced response inhibition, g+ = 0.113, p = .016, but impaired working memory, g+ = -0.315, p
= .008, although these effects reversed over time. Contrary to our hypotheses, there was no effect of
cortisol administration on set-shifting. Thus, although we did not find support for the idea that increases
in cortisol influence set-shifting, we found that acute increases in cortisol exert differential effects on
working memory and inhibition over time.
Keywords: Cortisol; Executive Function; Meta-analysis; Working Memory; Inhibition; SetShifting; Executive Attention; Response Inhibition; Cognitive Inhibition; Interference Control; Stress
2
CORTISOL AND CORE EXECUTIVE FUNCTIONS
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1. Introduction
1.1 Executive Function
When studying complex cognition in humans, executive function—the construct that underlies
our ability to flexibly control our thoughts and actions—comes to the forefront. Executive function is a
general ability comprised of three interrelated core processes (Miyake et al., 2000; Diamond, 2013). To
enhance clarity, we will use the term ―executive function‖ only to reference the general factor of
executive function (that is, the latent ability facilitating performance across all executive function tasks)
and use the name of each core executive function when referencing that specific function. The first core
executive function is working memory, which allows people to integrate new and old information.
Second, inhibition enables both cognitive inhibition (the ability to inhibit irrelevant information and
selectively attend to goal-relevant information) and response inhibition (the ability to inhibit a prepotent
response). Third, set-shifting allows people to flexibly shift between modes of thought.
Core executive functions are assessed using multiple tasks (cf. Diamond, 2013). For example, a
common working memory task is the n-back, which requires participants to indicate whether a given
stimulus was the same stimulus they were shown n trials previously—thus requiring constant updating of
working memory. A common inhibition task is the flanker task, which requires a participant to report the
direction of an arrow in the center of the screen, which is flanked by irrelevant arrows either pointing in
the same direction or pointing in the opposite direction as the target. The cost in reaction time when the
target is flanked by arrows pointing in the opposite direction is an inverse index of inhibition. Finally, a
typical set-shifting task is the trail-making test, which requires participants to draw a line connecting
numbered circles (e.g., 1-2-3-4-5-6) in one part of the task and a line connecting circles that alternate
between numbers and letters (e.g., 1-A-2-B-3-C) in the second part of the task. The difference in time
taken to complete the different parts of the task indicates a participant’s mental flexibility.
1.2 Stress, Cortisol, and Executive Function
Previous research consistently indicates that stress tends to impair performance on tasks that
CORTISOL AND CORE EXECUTIVE FUNCTIONS
4
make use of working memory (e.g., Schoofs et al., 2008; Schoofs et al., 2009) and set-shifting (e.g.,
Alexander et al., 2007; Plessow et al., 2011), although the effects of stress on inhibition are less clear
(Scholz et al., 2009; Schwabe et al., 2013). One promising explanation of stress-induced influences on
core executive functions is found in the stress hormone cortisol (i.e., Butts et al., 2011). Thus, a
discussion of the system governing cortisol is in order.
The stress response occurs the moment the brain detects a physical or perceived threat, resulting
in the initiation of ―allostasis,‖ or the maintenance of bodily stability through change (McEwen, 2004).
Activating one pathway of allostasis, stressors upregulate activity in the paraventricular nucleus (PVN) of
the hypothalamus, which then secretes corticotropin releasing hormone (CRH); CRH then acts on the
pituitary gland and promotes the release of adrenocorticotropin hormone (ACTH); ACTH in turn acts on
the adrenal gland to stimulate the synthesis and release of the cortisol (Ulrich-Lai and Herman, 2009).
This is known as the hypothalamic-pituitary-adrenal (HPA) axis, and it is primarily through this system
that cortisol is regulated.
Acute increases in glucocorticoids—the class of hormones to which cortisol belongs—function
primarily to mobilize the body’s resources in order to combat or evade the stress-provoking stimulus.
Receptors for glucocorticoids exist throughout the brain and, notably, they are concentrated within brain
regions supporting core executive functions (Reul and de Kloet, 1985). The effects of glucocorticoids are
variable, however, as glucocorticoids can exert both rapid-acting, nongenomic effects—effects of cortisol
brought about without modulation of gene expression—and slow, genomic effects—effects of cortisol
brought about by modulation of gene expression—(cf. Joëls et al., 2011). Thus, cortisol can act through
multiple pathways to enable the body to combat or evade the stress-inducing stimulus.
Despite the interconnection of stress, cortisol, and neural activity, it is unclear whether cortisol
actually influences core executive functions. Previous research has indeed found correlations between
cortisol and working memory, both at baseline (Li et al., 2006; Franz et al., 2011) and in response to stress
(Oei et al., 2006; Taverniers et al., 2010). However, these data are inconsistent: some studies have found
CORTISOL AND CORE EXECUTIVE FUNCTIONS
5
an inverse relationship between cortisol and working memory (e.g., Oei et al., 2006), whereas others have
found a positive relationship (e.g., Stauble et al., 2013). One potential reason for these discrepancies is
that cortisol may interact with other components of the stress response to exert effects on cognition (e.g.,
Schwabe et al., 2012). In contrast, the mediating effects of cortisol in the effects of stress on inhibition are
slightly more established, as one previous study found that blocking a receptor for cortisol blocked the
effects of stress on inhibition (Schwabe et al., 2013). Nonetheless, it is unclear from the prior study if
cortisol is both necessary and sufficient to improve inhibition or if it is simply necessary (and thus not a
true cause). Finally, the impairing effects of stress on set-shifting are related to salivary cortisol (Plessow
et al., 2011), but the correlational nature of these data preclude causal inferences.
Experimentally manipulating cortisol through exogenous administration is a useful method for
determining if acute increases in cortisol actually influence core executive functions. Because endogenous
cortisol is synthesized outside the brain and readily crosses the blood-brain barrier, exogenously
administered cortisol should influence neural processes in the same way as endogenously synthesized
cortisol. Indeed, a recent meta-analysis demonstrated that exogenously administered cortisol significantly
impairs long-term memory retrieval (Het et al., 2005), illustrating the validity of this methodology for
uncovering the effects of cortisol on cognitive processes.
2. Current Research
2.1 Main Hypotheses
A number of studies have already investigated the effects of cortisol administration on one or
more core executive functions. Thus, our goal in this study is to aggregate these results using metaanalytic techniques in an attempt to determine the true effect of acute cortisol administration on each of
the core executive functions. Given the heterogeneous nature of the stress and working memory or
inhibition literatures as well as the nascent stress and set-shifting or inhibition literatures, one could argue
that no strongly supported a priori hypotheses could be made regarding the effects of stress on core
executive functions. Nonetheless, drawing on both rodent and stress literature (Schoofs et al., 2009; Butts
CORTISOL AND CORE EXECUTIVE FUNCTIONS
6
et al., 2011; Plessow et al., 2011; Schwabe et al., 2013), we hypothesized that acute cortisol
administration would impair working memory and set-shifting but enhance inhibition.
2.2 Proposed Moderators
Whether or not cortisol evidences an effect on core executive functions may depend on
moderating factors. Importantly, the timing of cortisol administration relative to cognitive testing should
be considered. As previously mentioned, cortisol is thought to have differential fast and slow effects; as
such, analyses exploring the effects of cortisol should consider the delay between cortisol administration
and cognitive testing. We also considered a number of additional moderators in this meta-analysis
including cortisol dose, participant age and sex, mode of administration, whether the task included an
affective component,1 time of day for cognitive testing, outcome type (time or accuracy-based), and
study design.
We only included studies that employ a methodology of acute cortisol administration to
participants. This is in part because effects of acute increases in cortisol likely differ qualitatively from
effects of chronic elevations of cortisol (e.g., McEwen, 2004). Consequently, any inferences made from
the findings reported here should be constrained to acute increases in cortisol, not chronically high levels
of cortisol.
3. Method
3.1 Study Selection and Inclusion Criteria
3.1.1 Literature review. Our search terms for obtaining studies relevant to this meta-analysis
consisted of ―hydrocortisone‖, ―cortisol treatment‖, ―cortisol administration‖, or ―exogenous cortisol‖ and
―executive function‖, ―working memory‖, ―updating‖, ―response inhibition‖, ―set-shifting‖, ―attention‖,
―cognitive‖, or ―cognition.‖ We queried and performed an exhaustive search of the following databases:
PsycINFO, PsycArticles, PubMed, Proquest Theses and Dissertations: Social Sciences, Web of Science,
1
There was an insufficient number of studies assessing detection/activation but not suppression of emotional
material to determine differences of cortisol administration on detection vs. suppression of emotional material.
CORTISOL AND CORE EXECUTIVE FUNCTIONS
7
University of Alabama Theses and Dissertations, and U.C. Davis Theses and Dissertations. PubMed
returned 1,684 results. ProQuest was used to index PsycINFO, PsycArticles, ProQuest Theses and
Dissertations, and U.C. Davis Theses and Dissertations, which collectively returned 1,643 results.
Similarly, Web of Science returned 218 results, while the University of Alabama Theses and Dissertations
returned 64 results. References from relevant articles were reviewed, and studies that were potentially
relevant were examined from those references. For all articles considered, we followed Dickerson and
Kemeny (2004) in reviewing abstracts and examining full texts whenever an article had the potential to
include a relevant effect (that is, whenever a study within an article administered cortisol to participants,
the full-text of the article was reviewed to ensure that a relevant effect was not omitted from the abstract
and thus this analysis).
We also posted announcements to a number of listservs and reviewed conference proceedings for
an extensive number of conventions. Corresponding authors of all studies with unpublished relevant
results were emailed with a request for unpublished statistics. Authors who responded with these
unpublished statistics are listed in the acknowledgements section.
3.1.2 Inclusion criteria. Our seven inclusion criteria for this study were as follows: studies had to
(1) acutely (2) administer (3) hydrocortisone—without coadministration of another substance—and/or a
placebo to (4) healthy (5) human participants, who then completed (6) a task utilizing one of the core
executive functions. (7) If a study used a within-subjects, crossover design, performance on the task
utilizing one of the core executive functions had to be separated by at least one day (to reduce
confounding the effects of cortisol on learning and practice from the effects of cortisol on core executive
functions). We chose these inclusion criteria to best isolate the relationship between cortisol and core
executive functions.2
2
Inclusion criterion (1) was chosen to avoid confounding acute increases in cortisol and likely interactions with
extant glucocorticoid receptor resistance. We chose criterion (2) because we were interested in the effects of
exogenous cortisol administration, not endogenous changes due to other factors. We chose criterion (3) because this
allows direct comparison of cortisol administration alone to a control condition. We chose criterion (4) because
CORTISOL AND CORE EXECUTIVE FUNCTIONS
8
3.1.3 Selected studies. Our search and study inclusion criteria led to the incorporation of 30
studies,3,4 27 of which were published.5
3.2 Coding of Covariates and Moderators
Tasks that make use of executive function were coded as one of the three core executive functions
based upon previous empirical or theoretical literature suggesting that a given task loaded on one of the
factors (working memory, inhibition, or set-shifting) primarily. See Table S3 in the online Supplementary
Material for a complete description of task coding. Tasks were considered including an affective
component if the task employed affective characteristics or if the task incorporated faces as stimuli. The
covariate of dose of hydrocortisone required some conversion between studies, as studies using an
intravenous drip provided doses in μg/kg rather than the more common single dosages given in oral form.
We thus converted doses given in μg/kg to the equivalent mg dose for typical individuals.
To test for differences among moderators, most potential moderators were dummy-coded,
including whether the task included an affective component, whether the effect size was derived from
repeated measures, mode of cortisol administration, and whether the outcome was a reaction-time or
performance-based measure. One potential moderator was contrast-coded—time of cortisol
administration—because none of the three groups (morning, early afternoon, and late afternoon) could
suitably serve as a reference for the others. Finally, average age of participants, percentage of males, dose
of hydrocortisone, and delay in minutes from hydrocortisone administration to cognitive testing6 were
mental and physical illness has been linked to glucocorticoid receptor dysregulation. We chose inclusion criterion (5)
because executive function in animals, which is an extensively trained ability, may be influenced in different ways
than executive function in humans, which is a natural ability.
3
One study was reported in two separate papers (Henckens et al., 2011; Henckens et al., 2012) and was treated as
one study for this analysis.
4
One study (Newcomer et al., 1999) explored the effects of chronic cortisol administration. However, we used only
the data presented for the effects of cortisol on day 1, presented in a table within the paper.
5
6
A study was considered ―unpublished‖ if the effect was not reported in a published paper.
Adding 15 minutes (or similar values) to studies employing intravenous rather than oral cortisol administration did
not alter any of the findings presented here.
CORTISOL AND CORE EXECUTIVE FUNCTIONS
9
treated as continuous variables and centered their respective lowest obtained values, making the intercept
(which is the effect size estimate at the lowest value of the covariate) interpretable while controlling for
the covariate. If the average participant age was not given in the article, the median participant age was
used if it was reported; if neither of these statistics were listed, the midpoint of the reported participant
age range was used.
3.3 Analytic Strategy
Standardized mean differences were used as the effect size measure of interest. For effect size
estimates, we used Hedges’ g rather than Cohen’s d, given that the former is a relatively unbiased estimate
of the population standardized mean difference effect size while the latter is a biased estimate. To obtain
Hedges’ g, we calculated the effect size from the means, standard deviations, and sample sizes presented
in the article. If means and standard deviations were not reported and the design was between-studies, we
used t or one-way F statistics to calculate the effect size. If none of these statistics were reported, we
emailed corresponding authors for these statistics. If we were unable to contact the corresponding authors
for necessary statistics for a study, that study was excluded. For within-studies designs, we converted
effect size estimates and their variances into the between-study effect size metric following Morris and
DeShon (2002).7
Given the multifaceted nature of executive function, most studies often report more than one
outcome for any given task that makes use of a core executive function.8 Multiple outcomes are a
7
We emailed the authors of studies using a repeated-measures design with a request for the correlation of the
outcomes under cortisol with the outcomes under placebo. Multiple authors responded with these statistics, but not
all. We used RVE to estimate the population correlation from the coefficients emailed to us and used the estimate as
the correlation between measures for the repeated-measures studies in which we had not obtained the correlation
coefficients. The estimated correlation between all tasks utilizing a core executive function under cortisol with all
tasks utilizing a core executive function under placebo was .69, 95% CI [.50, .81]. We conducted sensitivity analyses
by using the upper and lower bounds of the 95% confidence interval as the correlation between repeated measures
for which we had not obtained the actual correlation. None of the results were significantly from those using the
point estimate.
8
Some might suggest that instead of incorporating all reported effect sizes we should select only the critical effect
size from each study. However, this approach is only valid if a strong case can be made for doing so (Scammacca et
al., 2014). In our meta-analysis this case cannot be made; many of these studies found effects within different
CORTISOL AND CORE EXECUTIVE FUNCTIONS
10
problem for conventional meta-analytic methods, as averaging effect sizes within studies without
accounting for their correlations can alter or obscure true effect size estimates (Scammacca et al., 2014).
Thus, we employed the meta-analytic technique of robust variance estimation, a random-effects metaregression that can account for dependence between effect size estimates (Hedges et al., 2010; TannerSmith et al., 2013). This technique robustly estimates effect size weights and standard errors for the given
effects, allowing for multiple outcomes within studies (Hedges et al., 2010). We employed the robu()
function of the robumeta package in R, version 3.1.1, to conduct these analyses, using the small sample
corrections suggested by Tipton (2014) and the correlated weights given by Hedges et al. (2010). To
account for dependency between the effect sizes, ρ was set to the recommended .80 (Tanner-Smith and
Tipton, 2014).9 Because we were more interested in understanding factors that influenced the relationship
between cortisol administration and core executive functions than we were in understanding factors
contributing to heterogeneity, covariate analyses do not separate covariates into within- and betweenstudy covariates.
Degrees of freedom for all analyses were estimated using the Satterwaite approximation, where
df=2/cv2 and cv represents the coefficient of variation, as simulation studies have indicated that this
method of estimating degrees of freedom is most analytically valid with the RVE meta-analytic technique
(Tipton, 2014). Because of how the degrees of freedom are estimated, if the degrees of freedom are less
than four, then there is a heightened risk of a Type I error and the analysis results cannot be trusted to
represent population values (Tipton, 2014).
For all of the following analyses, a positive effect size indicates that cortisol improved
performance on the outcome relative to placebo, whereas a negative performance indicates that cortisol
subgroups, and many of these effect sizes reflect a study’s use of multiple measures assessing core executive
functions with multiple outcomes. As such, a justification cannot be given for the use of a single effect size from a
given study.
9
Because of how the RVE meta-analytic method estimates effect size weights, the designation of ρ at .80 is largely
non-consequential; indeed, sensitivity analyses with values of ρ ranging from 0 to 1.0 evidenced no change greater
than 0.0001 in absolute value in estimates.
CORTISOL AND CORE EXECUTIVE FUNCTIONS
11
impaired performance on the outcome relative to placebo. In addition, because the outcome in these
analyses is the standardized mean difference between groups (the effect size), a significant covariate
means that the effect size estimate depends upon levels of that covariate. In other words, if a covariate is
significant, it means that as the covariate increases or decreases, the mean difference between the effect of
cortisol compared to placebo on core executive functions increases or decreases.
4. Results
4.1 Preliminary Analyses
4.1.1 Study characteristics. The final sample consisted of 30 studies, each of which is
represented by m. Twenty-seven of these studies were published. There were 260 total effect sizes,10 each
of which is represented by k. Of these studies, 18 assessed working memory, with k=119. Similarly, 12 of
these studies assessed inhibition, with k=59. Finally, 6 of these studies assessed set-shifting, with k=23.
4.1.2 Assessment of publication bias. To assess publication bias, we first compared effect sizes
from unpublished work (m=3,k=11) to those of published work (m=27,k=249). This analysis indicated
that unpublished studies were of the same magnitude as published studies, t(2.5)=-1.49, p=.25. Second we
conducted Egger’s test (Egger et al., 1997) for funnel plot asymmetry on both the overall study set and
each core executive function individually. Egger’s test returned nonsignificant results when looking at the
overall study set, t(28)=-0.17, p=.87, working memory, t(16)=0.04, p=.97, inhibition, t(21)=-0.45, p=.66,
and set-shifting, t(4)=0.61, p=.57, indicating a lack of bias. These results therefore indicate that any
effects observed in this meta-analysis are unlikely to be due to publication bias.
4.2 Primary Analyses
4.2.1 Working memory. The overall effect of cortisol administration on tasks primarily utilizing
working memory (m=18,k=119) was nonsignificant, g+=-0.043, t(15.4)=-0.69, p=.50, 95% CI [-0.175,
0.090] (Figure 1). There was substantial heterogeneity within studies, I2=67.91, albeit with relatively low
10
Although this may seem like a large number of effects per study, the number of effect sizes per study we obtained
is relatively common in social science research (Scammacca et al., 2014).
CORTISOL AND CORE EXECUTIVE FUNCTIONS
12
between-study heterogeneity, τ2=0.08. This heterogeneity illustrates that the effects exhibited within-study
discrepancies that did not translate into between-study differences, as the effect was relatively
homogenous between studies.
Despite a nonsignificant overall effect, however, after separating the genomic effects of cortisol
from its nongenomic effects by controlling for the delay between cortisol administration and cognitive
testing, the non-genomic effects of cortisol significantly impaired working memory, g+=-0.315, t(3.8)=5.15, p=.008, 95% CI [-0.488, -0.142]. Although the degrees of freedom in the previous analysis do not
quite reach 4.0, the likelihood of making a Type I error only increases at most twofold with df<4 (Tipton,
2014), and given that p<.025 (half of .05) in the previous analysis, inferences are applicable. Similarly, a
longer delay between cortisol and cognitive testing improved working memory, B=0.005, t(1.8)=6.07,
p=.03 (cf. Figure 2); thus, the unstandardized slope estimate indicates that 74 minutes after cortisol
administration, cortisol begins to improve working memory, whereas from 15 to 73 minutes following
cortisol administration, cortisol impairs working memory. In the previous significance test, however, the
restricted degrees of freedom preclude definitive inference—given an increased likelihood of a Type I
error.
Notably, however, the effects of cortisol dose did not influence the effect size of cortisol
administration on working memory, B=-.001, t(2.1)=-0.78, p=.51. Similarly, there was no evidence for a
quadratic relationship between cortisol dose and the effects of cortisol on working memory, B<-.001,
t(9.3)=-0.15, p=.88. This lack of association held even when controlling for the time of cortisol
administration. Moderator analyses determined that cortisol administration impaired accuracy relative to
reaction time outcomes, t(9.9)=2.22, p=.051, as accuracy was significantly impaired after cortisol
administration, g+=-0.12, t(12.3)=-2.91, p=.01, while reaction times were not significantly affected,
g+=0.13, t(7.5)=0.56, p=.60. However, even when only considering accuracy-based outcomes, the dose of
cortisol did not influence the effect size of cortisol on working memory, B=.001, p=.44, nor was there any
evidence of a quadratic effect, B<.001, p=.58, indicating that cortisol lacked a dose-response effect for
CORTISOL AND CORE EXECUTIVE FUNCTIONS
13
influencing accuracy-based working memory performance. Further analyses did not reveal any additional
significant covariates (Table 1) or moderators (Table 2) with df>4.
4.2.2 Inhibition. The effect of cortisol administration on tasks primarily utilizing inhibition
(m=12,k=61) was nonsignificant, g+=0.055, t(12.9)=1.6, p=.138, 95% CI [-0.020, 0.130] (Figure 3). There
was low heterogeneity within the effects, I2=30.80, and low between-study heterogeneity, τ2=0.01,
indicating that effect sizes were fairly consistent between studies.
Despite a nonsignificant overall effect, however, after separating genomic from nongenomic
effects by controlling for the delay between administration and inhibition testing, the fast, nongenomic
effects of cortisol administration significantly improved inhibition, g+=0.113, t(9.5)=2.92, p=.016, 95% CI
[0.026, 0.201]. Conversely, a longer delay in minutes between cortisol administration and inhibition
testing marginally impaired inhibition, B=-0.001, t(1.5)=-4.49, p=.080 (cf. Figure 4). The unstandardized
slope estimate is centered at 15 minutes (the lowest obtained value for the delay between cortisol
administration and inhibition testing), and it represents the change in the effect size for each minute
increase between cortisol administration and inhibition testing. As such, this slope estimate indicates that
cortisol improves inhibition from 15 to 135 minutes post-administration, but cortisol begins to impair
inhibition after 136 minutes post-administration. However, the restricted degrees of freedom preclude
definitive inferences regarding the effect of the delay between cortisol and cognitive testing—given an
increased likelihood of Type I error. Notably, however, cortisol dose did not influence the effect size
estimate, B=-.003, t(7.0)=-1.89, p=.10, nor was there a quadratic relation between cortisol dose and the
effect size, B<-.001, t(3.5)=-0.26, p=.81. This lack of association held even when controlling for the time
of cortisol administration. Further analyses did not reveal any additional significant covariates (Table 1)
or moderators (Table 2) with df>4.
4.2.3 Set-shifting. Analyzing only the effect sizes related to set-shifting (m=6,k=23) revealed a
negligible effect, g+=-0.011, t(4.2)=-0.12, p=.91, 95% CI [-0.266, 0.244] (Figure 5) with low
heterogeneity between effects, I2=31.53, τ2=0.03, indicating that the effects of cortisol administration was
CORTISOL AND CORE EXECUTIVE FUNCTIONS
14
relatively consistent both within and between studies. There were no significant covariates (Table 1) or
moderators (Table 2) of the effect size.
4.3 Supplementary Analyses
Analyses exploring the effects of cortisol administration over all tasks utilizing one of the core
executive functions are presented within the online Supplementary Material.
5. Discussion
This is the first comprehensive meta-analysis of the effects of cortisol administration on core
executive functions. As hypothesized, we found that acute increases in cortisol impaired working memory
but enhanced inhibition, and these effects reversed over time. Contrary to our hypothesis, though, there
was no effect of cortisol administration on set-shifting. There was little heterogeneity between effect sizes
in analyses of inhibition, and although there was moderate heterogeneity between effect sizes in analyses
of working memory and set-shifting, most of this heterogeneity was due to within-study (not betweenstudy) variability—likely reflecting the variety of tasks used within studies—illustrating that the observed
effects were largely consistent across studies. Thus, we observed remarkable consistency in the effects of
cortisol administration on core executive functions across various studies.
We found that the rapid, nongenomic effects of cortisol enhanced inhibition, but the slow,
genomic effects of cortisol impaired inhibition. Similarly, the rapid, nongenomic effects of cortisol
impaired working memory, whereas the slow, genomic effects of cortisol enhanced working memory.
These effects coincide with stress research, which has linked the rapid effects of acute increases in
cortisol to enhancements in inhibition (Schwabe et al., 2013) and impairments in working memory
(Schoofs et al., 2008). Additionally, the observation that the effect of cortisol on these processes reverses
over time may also help to explain some inconsistencies in stress literature, given that some studies have
found stress-induced cortisol predicts enhanced working memory (Stauble et al., 2013) or that stress
impairs inhibition (Scholz et al., 2009). Thus, the overlap of our working memory and inhibition results
with stress literature validates the assumption in much of this literature that cortisol is causally related to
CORTISOL AND CORE EXECUTIVE FUNCTIONS
15
the effects observed in those studies.
5.1 Discussion of Moderators
Despite the overlap with stress research, there was no significant effect of cortisol dose. Although
the reasons for this lack of dose-dependent effect are unclear, one potential explanation is that the lack of
dose-dependent effects is due to a lack of dose-response studies (with only five included in the above
analyses); however, a meta-analysis allows comparisons of effects across studies with different doses of
cortisol. Thus, the lack of a dose-response effect is likely as reliable as other potential moderators, such as
delay between cortisol administration and cognitive testing. An alternative explanation is that the dosages
given in this study do not approximate endogenous cortisol increases following exposure to a stressor.
This explanation may have some validity. Although a dose of 10mg produces an increase that
approximates a mild stressor (Taylor et al., 2011)—illustrating that the lower range of cortisol doses
obtained in this meta-analysis index relatively typical endogenous levels following mild stress—the upper
range of dosages given in this meta-analysis are much larger than dosages that approximate moderate to
severe stress (i.e., 30mg‒ 40mg). Indeed, after a post hoc restriction of cortisol dose to the upper range
approximating a moderate to severe stressor (less than 40mg), marginally significant linear or quadratic
(i.e., inverted U shaped) effects emerged for inhibition and working memory, respectively (data not
shown). Thus, although this distinction was post hoc, it may be the case that cortisol exerts dosedependent effects to the extent that the increase is relatively typical of an endogenous increase, and,
moreover, these dose-dependent effects are eliminated with enormous cortisol increases, potentially due
to aberrant recruitment of additional processes to dampen the enormous cortisol response.
Other proposed moderators that were not related to the effects of cortisol on core executive
functions this study included age, sex, or time of day during cortisol administration. This lack of
association was surprising, given how many of these variables influence the effects of cortisol on
cognition (e.g., Het et al., 2005). It is tempting to offer speculative explanations for this (e.g., age may
interact with health status to alter the association between cortisol and cognition), but these explanations
CORTISOL AND CORE EXECUTIVE FUNCTIONS
16
go beyond our data. Future research could address this finding by attempting to determine additional
moderators influencing another given moderator’s effects on the association between cortisol and working
memory or inhibition.
5.2 Caveats
One important caveat in interpreting these results is that the effects of cortisol in this metaanalysis are considered in isolation, whereas in the typical stress response cortisol exerts its effects in
tandem with alterations in catecholamines, the sympathetic nervous system, and the immune system
(Allen et al., 2014). Thus, it may be the case that cortisol interacts with other biological processes to
further influence core executive functions. Indeed, there is preliminary support for the idea that cortisol
may interact with stress-induced increases in noradrenergic (one type of catecholamine) activity to exert
its effects on cognitive processes (Roozendaal et al., 2006; cf. Lupien et al., 2007), perhaps due to effects
of noradrenergic activity on attention (cf. Robbins and Arnsten, 2009). For example, studies investigating
the conjoint effects of cortisol administration with a noradrenergic agonist have found synergistic effects
of administration of these substances on decision-making (Schwabe et al., 2012), although similar
interactive effects were not observed for memory encoding or, notably, inhibition (Vasa et al., 2009; van
Stegeren et al., 2010). Similarly, stress also increases dopaminergic activity (Robbins and Arnsten, 2009),
and dopamine both interacts with cortisol (Mizoguchi et al., 2004) and follows an inverted U to enhance
or impair working memory (Robbins and Arnsten, 2009). Put together, these studies provide preliminary
support for the idea that the effects of cortisol on core executive functions may be more complex in vivo
than is captured in studies of cortisol administration, and therefore the true effects of cortisol on core
executive functions may be stronger in magnitude than effects of cortisol administration given in
isolation. Thus, it is possible that cortisol may indeed influence set-shifting when considered within the
context of the typical stress response. Nonetheless, it is important to note that many studies (i.e., Oei et
al., 2006; Plessow et al., 2011) have found associations between cortisol and performance on tasks that
make use of core executive functions in the absence of noradrenergic activity. Moreover, the effects
CORTISOL AND CORE EXECUTIVE FUNCTIONS
17
obtained in our meta-analysis show that cortisol can exert effects on working memory and inhibition
independent of other interactive effects.
It is also important to note that the effects of cortisol considered here are specific to acute
increases. Chronically elevated levels of cortisol contribute to dysregulation of the immune system,
multiple hormonal systems, and neural function (McEwen, 2004; Silverman and Sternberg, 2012). This
multiple-system dysregulation is thought to bring about structural alterations in neural systems
contributing to cognitive impairments (McEwen, 2004; Silverman and Sternberg, 2012). Thus, it is quite
likely that chronically elevated cortisol may influence core executive functions, presumably through
different pathways than acute elevations in cortisol. Currently, only two studies exist that have considered
the effects of chronic cortisol administration in healthy individuals, and they have presented mixed results
regarding effects on working memory (Young et al., 1999; Newcomer et al., 1999). Thus, future research
should attempt to examine whether sustained stress-related elevations in cortisol might contribute to
impairments in core executive functions.
Finally, altered performance on tasks that make use of core executive functions does not
necessarily imply that performance on tasks that make use of global executive resources, such as
planning, playing chess, dieting, or going Christmas shopping will be altered. It is interesting to speculate
how the differential influences of cortisol on working memory and inhibition may contribute to
performance in tasks common to everyday life. For example, our data could suggest that cortisol may
produce a more phenotype of more control (enhanced inhibition) but less capacity (impaired working
memory), resulting in perhaps a more cautious action orientation, which may increase success in things
such as dieting but decrease success in things such as winning a game of chess. However, these
speculations go beyond our data. Future research could thus extend these findings by examining effects of
cortisol on tasks common to daily life.
5.3 Limitations
This meta-analysis has limitations. First, the substantial heterogeneity of within-study effect sizes
CORTISOL AND CORE EXECUTIVE FUNCTIONS
18
in working memory and set-shifting analyses coupled with the paucity of evidence for significant
covariates or effect size moderators indicates that important covariates may have not been considered.
Although both the small heterogeneity in inhibition analyses and small between-study heterogeneity in
working memory and set-shifting analyses alleviates the concern of this limitation inasmuch as the
inferences made are pertinent to this meta-analysis, this limitation highlights the need to understand
additional factors that may influence the relationships of cortisol and the core executive functions of
working memory and set-shifting. Second, the diversity of tasks that make use of core executive functions
throughout the various studies may have obscured potential effects on a specific task. Third, the study set
size of 30 might be thought to lack power to detect an effect. However, the low between-study
heterogeneity illustrates remarkable consistency in the observed effects (indicating that more studies
would not produce an effect unobserved here), and a study set size of 30 is relatively large in comparison
to other similar meta-analyses (e.g., Het et al., 2005; Steptoe et al., 2007). As such, while 30 studies is less
than ideal, it represents a sizeable number of studies that can be used to make inferences about effects of
cortisol administration. Fourth, the neural substrates underpinning core executive functions may be more
sensitive to the effects of cortisol administration than are tasks that make use of core executive functions,
and these neural substrates may evidence an effect that is hidden by performance on broad cognitive
tasks—given that the neural substrates are closer to the source of potential modulation. Fifth, this metaanalysis could not assess potential differences in detection versus suppression of emotional material
following cortisol administration due to an insufficient number of studies assessing detection of emotional
information without also assessing suppression of that information; thus, this meta-analysis cannot
determine whether cortisol differentially modulates detection versus suppression of emotional
information. Sixth, some might suggest that different core executive functions should have been chosen
for analysis, since it is possible a different analytic strategy would have returned different results.
However, the core executive functions chosen for analysis are each and every core executive function
discussed in a major recent review of executive function (Diamond, 2013; see also Miyake et al., 2000);
CORTISOL AND CORE EXECUTIVE FUNCTIONS
19
as such, while a different strategy may have produced different results, the strategy chosen for analysis is
the most theoretically supported strategy. Finally, the effects examined in this study were restricted to
acute administrations of cortisol given in isolation. As discussed previously, cortisol may interact with
other components of the stress response to modulate cognitive function, which is not something this metaanalysis can address.
6. Conclusion
We found that acute increases in cortisol impair working memory and enhance inhibition, and
these effects reverse over time. Contrary to our hypothesis, however, there was no effect of cortisol
administration on set-shifting. These findings inform future research by suggesting a timescale in which
experiments should assess working memory and inhibition following stress, depending upon the effect of
cortisol desired.
CORTISOL AND CORE EXECUTIVE FUNCTIONS
Acknowledgments
This research was supported by a U.C. Davis Provost’s Fellowship to Grant S. Shields and a
Hellman Foundation Fellowship to Wesley G. Moons.
The authors wish to thank Heather Abercrombie, Claudia Buss, Mark Ellenbogen, Dirk
Hellhammer, Robert Kumsta, Sonia Lupien, Christopher Monk, Peter Putman, Catherine Symonds,
Veronique Taylor, Marieke Tollenaar, Oliver Wolf, and Stefan Wüst for providing us with requested
unpublished or additional statistics from their work.
20
CORTISOL AND CORE EXECUTIVE FUNCTIONS
21
Studies Included in the Meta-Analysis
Abercrombie, H.C., Kalin, N.H., Thurow, M.E., Rosenkranz, M.A., Davidson, R.J., 2003. [Unpublished
data referenced in the published paper, ―Cortisol variation in humans affects memory for
emotionally laden and neutral information‖]. Unpublished raw data.
Bertsch, K., Böhnke, R., Kruk, M.R., Richter, S., Naumann, E., 2011. Exogenous cortisol facilitates
responses to social threat under high provocation. Horm. Behav. 5, 428-434.
Breitberg, A., Drevets, W.C., Wood, S.E., Mah, L., Schulkin, J., Sahakian, B.J., Erickson, K., 2013.
Hydrocortisone infusion exerts dose- and sex-dependent effects on attention to emotional
stimuli. Brain Cogn. 81, 247-255.
Buss, C., Wolf, O.T., Witt, J., Hellhammer, D.H., 2004. [Unpublished data referenced in the published
paper, ―Autobiographic memory impairment following acute cortisol administration‖].
Unpublished raw data.
Carvalho Fernando, S., Beblo, T., Schlosser, N., Terfehr, K., Wolf, O.T., Otte, C., . . . Wingenfeld, K.,
2013. Acute glucocorticoid effects on response inhibition in borderline personality disorder.
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memory to the acute effects of corticosteroids: a dose–response study in humans. Behav.
Neurosci. 113, 420-430.
Monk, C.S., Nelson, C.A., 2002. The effects of hydrocortisone on cognitive and neural function: a
behavioral and event-related potential investigation. Neuropsychopharmacology 26, 505-519.
Newcomer, J.W., Selke, G., Melson, A.K., Hershey, T., Craft, S., Richards, K., Alderson, A.L., 1999.
Decreased memory performance in healthy humans induced by stress-level cortisol
treatment. Arch. Gen. Psychiatry. 56, 527-533.
Oei, N.Y., Tollenaar, M.S., Spinhoven, P., Elzinga, B.M., 2009. Hydrocortisone reduces emotional
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Porter, R.J., Barnett, N.A., Idey, A., McGuckin, E.A., O’Brien, J.T., 2002. Effects of hydrocortisone
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Putman, P., Hermans, E.J., Koppeschaar, H., Van Schijndel, A., Van Honk, J., 2007. A single
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Putman, P., Hermans, E.J., Van Honk, J., 2010. Cortisol administration acutely reduces threat-selective
spatial attention in healthy young men. Physiol. Behav. 99, 294-300.
Schlosser, N., Wolf, O.T., Fernando, S.C., Terfehr, K., Otte, C., Spitzer, C., . . . Wingenfeld, K., 2013.
Effects of acute cortisol administration on response inhibition in patients with major depression
and healthy controls. Psychiatry Res. 209, 439-446.
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Table(s)
Table 1. Covariate effects on the relation between cortisol and core executive functions.
Variable
B
β
.001
.02
g+ (SE)
Controlling for
Covariate
t
df
p
0.37
11.4
.72
-1.24
6.6
.24
6.07
1.8
.03
-5.15
3.83
.008
0.76
2.1
.52
-1.86
2.6
.17
-0.78
2.1
.51
-0.17
10.8
.87
-0.15
9.3
.88
-0.21
7.2
.84
-2.2
2.6
.13
0.57
12.6
.58
0.14
11.1
.89
0.86
4.9
.43
-4.49
1.5
.08
2.92
9.5
.02
0.73
3.6
.51
2.10
8.5
.07
-1.89
7.0
.10
2.85
7.6
.02
-0.26
3.5
.81
2.12
5.1
.09
0.97
3.4
.40
0.51
16.1
.62
0.95
2.4
.43
-0.75
1.4
.56
Working Memory
Percent Male Participants
Range: 0‒100
Delay Between Cortisol and Test
-.07 (.06)
.005
.12
Range: 15‒240
Quadratic Delay
-.32 (.06)
< .001
-.05
-.24 (.13)
Cortisol Dose
-.001
-.03
Range: 3.567‒120
Quadratic Cortisol Dose
-.01 (.08)
< -.001
-.04
-.03 (.14)
Participant Age
-.006
-.05
Range: 20.4‒75.5
.05 (.09)
Inhibition
Percent Male Participants
< .001
< .01
Range: 0‒100
Delay Between Cortisol and Test
.05 (.05)
-.001
-.12
Range: 15‒540
Quadratic Delay
.11 (.04)
< .001
.10
.14 (.07)
Cortisol Dose
-.003
-.08
Range: 10-100
Quadratic Cortisol Dose
.11 (.04)
< -.001
-.10
.10 (.05)
Participant Age
.002
.02
Range: 20.1‒75.5
.03 (.05)
Set-Shifting
Percent Male Participants
Range: 0‒100
.003
.13
-.20 (.27)
Delay Between Cortisol and Test
< .001
.06
Range: 60‒540
Quadratic Delay
-.04 (.11)
< .001
NAa
.14 (.10)
Cortisol Dose
-.004
-.13
Range: 13.33‒120
Quadratic Cortisol Dose
.11 (.06)
< -.001
-.25
.06 (.14)
Participant Age
Range: 22.2‒75.5
.001
.01
-.03 (.19)
0.56
1.2
.66
-0.36
3.4
.74
1.62
2.2
.24
1.37
1.0
.40
-2.54
1.8
.14
1.87
2.4
.18
-0.40
2.1
.73
0.45
2.5
.69
0.19
2.7
.86
-0.13
3.0
.90
Note: B = unstandardized slope; β = standardized slope; g+ = effect size; SE = standard error of the effect
size; t = t test statistic for test determining whether the effect size differs from zero; df = degrees of
freedom for t test; p = p value for t test. Marginal or significant p values are in boldface. If df < 4, there is
up to an 10% risk of Type I error, given how df are estimated. Linear associations are reported without
controlling for quadratic effects. Superscript a entails that the model was unsolvable.
Table 2. Moderator analyses of the effects of cortisol on executive function.
g+
SE
df
p
m
k
Nonemotive
-.03
.05
15.0
.57
18
107
Emotive
.11
.56
2.0
.86
3
12
Reaction Time
.13
.23
7.5
.60
9
74
Accuracy
-.12*
.04
12.3
.01
15
45
Repeated Measures
-.05
.03
3.9
.15
12
38
Between Groups
.11
.24
5.0
.67
6
81
Intravenous/Injection
-.15
.09
3.1
.19
5
68
Oral
-.01
.08
11.1
.86
13
51
Morning
-.12
.11
3.4
.33
5
53
Mid-Afternoon
.09
.17
4.9
.60
6
38
Late Afternoon
-.06
.09
5.3
.52
7
28
Nonemotive
.01
.05
10.5
.89
14
72
Emotive
.12†
.05
6.0
.06
11
46
Reaction Time
.07
.04
6.6
.13
15
58
Accuracy
-.03
.05
11.5
.58
15
60
Repeated Measures
.07†
.04
6.9
.07
14
73
Between Groups
-.05
.10
7.5
.64
9
45
Intravenous/Injection
-.02
.06
2.4
.82
4
42
Oral
.06
.04
11.0
.13
19
76
Variable
Working Memory
Emotive Task
Reaction Time vs. Accuracy
a
Study Design
Mode of Administration
Time of Treatment
Inhibition
Emotive Task
Reaction Time vs. Accuracy
Study Design
Mode of Administration
Time of Treatment
Morning
.03
.03
1.2
.42
4
16
Mid-Afternoon
-.05
.10
5.2
.63
7
41
Late Afternoon
.08
.05
7.7
.13
12
61
Nonemotive
-.02
.09
3.1
.86
5
7
Emotive
<.01
.07
1.0
.96
1
16
Reaction Time
.04
.18
1.9
.83
3
10
Accuracy
-.08
.11
3.6
.49
5
13
Repeated Measures
-.08
.11
2.8
.54
4
20
Between Groups
.22
.06
3.9
.16
2
3
Intravenous/Injection
<.01
<.01
1.0
.56
2
17
Oral
-.02
.15
2.5
.91
4
6
Morning
.04
.04
1.0
.51
2
2
Mid-Afternoon
<.01
.07
1.0
.96
1
16
Late Afternoon
-.04
.24
1.9
.88
3
5
Set-Shifting
Emotive Task
Reaction Time vs. Accuracy
Study Design
Mode of Administration
Time of Treatment
Note: †p<.10; *p<.05; Superscript a indicates that the two groups differ at p = .051. g+ = effect size of the
respective group; SE = standard error of the effect size; ; t = t test statistic for test determining whether the
effect size differs from zero; df = degrees of freedom for t test; p = p value for t test; m = number of
studies in the analysis, k = number of effect sizes in the analysis. If df < 4, there is up to an 10% risk of
Type I error, given how df are estimated.
Figure(s)
Working Memory
Figure 1. Forest plot of working memory study-average effect sizes by weight. The grand effect was
nonsignificant, g+= -.04, p=.50. Numbers on the Y axis correspond to the studies listed below.
1
7
13
2
8
14
Breitberg et al. (2013)
Entringer et al. (2009)
3
Henckens et al. (2011; 2012)
4
Kuhlmann and Wolf (2005)
5
Kuhlmann et al. (2005)
6
Kumsta et al. (2010)
Lupien et al. (1999)
Monk and Nelson (2002)
9
Oei et al. (2009)
10
Porter et al. (2002)
11
Symonds et al. (2012)
12
Terfehr et al. (2011)
Tollenaar et al. (2009)
Tops et al. (2006)
15
Vaz et al. (2011)
16
Wingenfeld et al. (2011)
17
Wolf et al. (2001)
18
Yehuda et al. (2007)
Figure 2. Association between the study-average, non-centered delay of cortisol administration and the
study-average effect size for working memory. Size of point represents the effect size weight. Cortisol
administration impaired working memory at short delays but enhanced working memory over long
delays.
Inhibition
Figure 3. Forest plot of inhibition study-average effect sizes by weight. The grand effect was
nonsignificant, g+=.05, p=.14. Numbers on the Y axis correspond to the studies listed below.
1
9
17
2
10
18
Abercrombie et al. (2003)
Bertsch et al. (2011)
3
Breitberg et al. (2013)
4
Buss et al. (2004)
5
Carvalho Fernando et al. (2013)
6
Henckens et al. (2011)
7
Hsu et al. (2003)
8
Kuhlmann and Wolf (2005)
Kuhlmann et al. (2005)
Monk and Nelson (2002)
11
Newcomer et al. (1999)
12
Porter et al. (2002)
13
Putman and Berling (2011)
14
Putman et al. (2007)
15
Putman et al. (2010)
16
Schlosser et al. (2013)
Taylor et al. (2011)
Tollenaar et al. (2009)
19
Tops et al. (2006)
20
Vasa et al. (2009)
21
Vaz et al. (2011)
22
Wolf et al. (2001)
23
Yehuda et al. (2007)
Figure 4. Association between the study-average, non-centered delay of cortisol administration and the
study-average effect size for inhibition. Size of point represents the effect size weight. Cortisol
administration enhanced inhibition at short delays but impaired it over long delays. Removing the
outlying study did not influence the results; this outlying study thus provides a nice illustration of the
accuracy of the slope estimate.
Set-Shifting
Figure 5. Forest plot of set-shifting study-average effect sizes by weight. The grand effect was
nonsignificant, g+= -.01, p=.91. Numbers on the Y axis correspond to the studies listed below.
1
Breitberg et al. (2013)
2
Newcomer et al. (1999)
3
Porter et al. (2002)
4
Vaz et al. (2011)
5
6
Wingenfeld et al. (2011)
Yehuda et al. (2007)