Time course of the physiological stress response to an acute stressor and its associations with the primacy and recency effect of the serial position curve
Time course of the physiological stress response to an acute stressor and its associations with the primacy and recency effect of the serial position curve
Linda BeckerID 0 1
Nicolas RohlederID 0 1
0 Editor: Bruno Bonaz, Grenoble Faculty of Medicine and Hospital , FRANCE
1 Department of Psychology, Chair of Health Psychology, Friedrich-Alexander University Erlangen-Nuremberg , Erlangen , Germany
Whether stress affects memory depends on which stress pathway becomes activated and which specific memory system is involved. The activation of the sympathetic nervous system (SNS), leads to a release of catecholamines. The activation of the hypothalamic-pituitary-adrenal (HPA) axis, leads to a release of glucocorticoids. In thus study, it was investigated whether SNS and/or HPA axis activation are associated with long-term memory (LTM) and/or working memory (WM) performance in humans. Thirty-three participants underwent the socially evaluated cold-pressor test. Salivary alpha-amylase (sAA) was used as a marker for the activation of the SNS and cortisol as marker for HPA axis activation. Memory was assessed by means of word lists with 15 words each. The primacy effect (i.e., the correctly recalled words from the beginning of the lists) of the serial position curve was considered as indicator for LTM. The recency effect (i.e., the correctly recalled words from the end of the lists) were used as estimator for WM performance. In sAA responders, the recency effect and, therefore, WM performance increased immediately after the stressor. This was not found in sAA non-responders. In cortisol responders, the primacy effect and, thus, LTM performance decreased 20 minutes after the stressor. No change in LTM performance was found in cortisol non-responders. Our study supports the assumptions that 1) SNS activation is associated with WM processes via stimulation of the prefrontal cortex, and 2) HPA axis activation is associated with LTM processes through interactions with the hippocampus.
Data Availability Statement: All relevant data are
within the manuscript and its Supporting
Funding: LB was supported by the Bavarian Equal
Opportunities Sponsorship ? Fo?rderung von
Frauen in Forschung und Lehre (FFL) ? Promoting
Equal Opportunities for Women in Research and
Teaching. The authors acknowledge support by
Deutsche Forschungsgemeinschaft and
FriedrichAlexander-Universita?t Erlangen-Nu?rnberg (FAU)
within the funding programme Open Access
Cognitive functions?especially memory?are not entirely independent of peripheral
physiological processes. Some peripherally transmitted molecules (e.g., some hormones) can pass the
blood-brain barrier (BBB) and can, therefore, affect neural activity directly. Other substances
indeed cannot pass the BBB but can still affect neural activity through indirect feedback loops
Publishing.The funders had no role in study design,
data collection and analysis, decision to publish, or
preparation of the manuscript.
by activating brain networks, which lead to the release of neuro modulators in brain regions
involved in cognitive processing (e.g. [
One prominent candidate which can trigger such effects is stress. Stress can be defined as
?an actual or anticipated disruption of homeostasis or an anticipated threat to well-being? ([
p. 397). The acute stress response is dominated by two pathways (e.g., [
]; Fig 1A). The first,
which starts immediately after the onset of the stressor is the activation of the sympathetic
nervous system (SNS). This leads to the release of the catecholamines adrenaline and
noradrenaline which both cannot pass the BBB but can affect cognitive processing through indirect
pathways . The peripherally transmitted catecholamines can activate the locus coeruleus in
the brainstem which stimulates the release of noradrenaline and dopamine in the prefrontal
cortex (PFC) via the ventral tegmental area [
]. The PFC is involved in a variety of higher
order cognitive functions, e.g., in working memory (WM) processes which are mainly
controlled by noradrenaline and dopamine [
The second stress response, which peaks with a short delay of a few minutes after the onset
of the stressor, is the activation of the hypothalamic-pituitary adrenal (HPA) axis. This leads to
the release of glucocorticoids (i.e., cortisol in humans or corticosterone in rodents) from the
adrenal cortex. After threatening socially-evaluative stressors (e.g., the Trier Social Stress Test;
]), HPA axis response peaks approximately 20 minutes after the end of the stressor (e.g.,
]). The stress hormone cortisol can pass the BBB and can, therefore, directly affect neural
]. Cortisol binds to two different receptors in the brain [
]. The first, the
mineralocorticoid receptor (MR, or type 1 receptor) can be found within the hippocampus
and the prefrontal cortex . The second, the glucocorticoid receptor (GR, or type 2
receptor) is widely distributed in different brain areas. Which cognitive processes (i.e., which
memory functions) are affected after cortisol release depends on which receptors and, therefore, in
which brain area, cortisol binds to [
]. Both receptor types have different affinity for cortisol
]. The MRs have high affinity and are, therefore, usually occupied at basal cortisol
concentrations. The GRs have a lower affinity for cortisol and are, thus, in many cases not occupied
unless cortisol levels are increased. The brain structure in which both MRs and GRs are
localized is the hippocampus which is also mainly involved in long-term memory (LTM) processes.
Therefore, there has been a long research history in the evaluation of the effects of cortisol
binding on GRs in the hippocampus and its associations with LTM processes (e.g., [
Fig 1. a) Stress pathways that are activated after an acute stress situation, affected brain regions through indirect (dashed arrow) or direct pathways, and b) a simplified
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A classical model which involves both WM and LTM, was proposed by Atkinson and
]. According to this model, any new information first enters?after it has passed the
socalled sensory register?WM. After this, the information is either forgotten or it is stored in
LTM from where it can be retrieved at later time points (Fig 1B). One easy way to assess both
WM and LTM within one experiment is to investigate the so-called serial position effects
]. A typical experimental procedure is to present word lists of approximately 15 words to
the participants and to let them recall as many words as they can remember immediately after
the last word was presented. The classical observation is that words from the beginning as well
as from the end of the word list can be better recalled than words from the middle of the list.
The first effect is called the primacy effect (PE) which is associated with LTM processes. The
second is called recency effect (RE) and it is associated with WM [
]. The effects of acute
stress on the serial position effects have not been investigated so far.
The aims of the present study were to investigate whether SNS activation is associated with
WM and whether HPA axis activation is associated with LTM performance in humans after
an acute stressor. As measures of the functioning of the memory systems, the PE and the RE of
the serial position curve were examined. The hypotheses were that 1) SNS activation would
start immediately after the stressor and would be related with the RE and, thus, with WM and
2) that HPA axis activation would peak with a time delay of approximately 20 minutes and
would be associated with the PE and, therefore, with LTM performance. It was assumed that
these effects will only be found in participants who show indeed a SNS or HPA axis response,
respectively (the so-called responders). Furthermore, it was hypothesized that such effects will
not be found in the non-responder groups.
Materials and methods
Thirty-three healthy, German-speaking adults participated (mean age: 24.0 ? 5.7 years; eight
male; BMI = 22.2 ? 2.8 kg/m2). None of them reported endocrinological, neurological, or
psychological diseases. This was checked during a pre-screening. Persons with a psychiatric
diagnosis (currently or in the past) were screened out. All participants gave their written and
informed consent. The study was carried out in accordance with the Code of Ethics of the
World Medical Association (Declaration of Helsinki) and was approved by the local ethics
committee of the Friedrich-Alexander University Erlangen-Nuremberg (protocol # 6_18 B).
The time course of the experiment is shown in Fig 2. The whole session?including
instructions?lasted 60 minutes. For memory assessment, participants were presented three word lists
with 15 words each with inter-stimulus intervals of one second. The words were simple neutral
words with a short pronunciation time (e.g., the German words for ?dog?, ?coffee?, ?bus?, or
?door?). After the presentation of each list, the participants were asked to immediately recall as
many words as they had remembered. As measure for LTM performance, the PE was used
which was defined as the sum of correctly recalled words from the first three words of the lists.
Accordingly, the RE, which was used as a measure for WM performance, was defined as the
sum of correctly recalled words from the last three words of the lists. Memory testing was
repeated three times throughout the experimental session with three lists each time. The order
of the word lists was counterbalanced between the participants and between the memory
assessment time points.
Stress was induced by means of the socially evaluated cold-pressor test (SECPT, [
groups of two participants. The participants stood in front of a table on which transparent
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Fig 2. Time course of the experimental procedure. Stress was induced by means of the socially evaluated cold-pressor test (SECPT).
boxes filled with ice water were placed. Participants were instructed to immerse their hands in
the ice water as long as possible for up to three minutes. Mean immersion time was 2:20 ? 1:06
min (min. 0:18, max: 3:00). The hand of each participant was directly opposite of the hand of
the other person with the aim to introduce a competitive situation. Remaining time was
displayed on a large-display digital clock that was visible for both participants. An auditory
countdown announced the last five seconds. Therefore, our protocol slightly differed from that
reported by Schwabe and colleagues (2008, [
]) and by Minkley and colleagues (2014) who
introduced the first group version of the SECPT [
]. One experimenter who wore a medical
uniform was present during the SECPT and was instructed to behave distanced and to keep a
Salivary alpha-amylase (sAA) and salivary cortisol were used as measures of SNS and HPA
axis activity [
]. Saliva was collected by means of salivettes (Sarstedt, Nu?mbrecht,
Germany) at seven time points during the experimental session. The first saliva sample (s0) was
collected immediately prior to the presentation of the first word list. The following samples
were collected immediately prior (s1) and immediately after (s2) the SECPT. The following
four samples were collected five (s3), ten (s4), 20 (s5), and 35 (s6) minutes after the end of the
SECPT. The participants were instructed not to eat, drink (except water), smoke, or brush
their teeth two hours before the start of the experimental session. Additionally, subjective stress
perception was rated on a ten-point Likert-scale with the anchors ?not stressed at all? and
?totally stressed? during saliva collection.
Furthermore, some demographic and psychological variables were collected by means of
questionnaires during waiting time between the saliva samples (when no memory tests were
performed). Demographic variables that were assessed were sex, age, weight, and height. The
amount of regular physical activity was measured by means of the short form of the
International Physical Activity Questionnaire (IPAQ; [
]). Chronic stress was assessed by means
of the screening scale of the Trier Inventory of Chronic Stress (TICS-SSCS; ) and the
Perceived Stress Scale (PSS; [
]). Additionally, burnout and depression were measured by means
of the Maslach Burnout Inventory [
] and the German version of the depression scale from
the Center for Epidemiological Studies (CES-D, [
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Saliva samples were stored at -30?C after collection for later analyses. After the study was
completed, samples were sent to Dresden LabService GmbH (Dresden, Germany) where they were
analyzed by means of high performance liquid chromatography.
For statistical analyses, IBM SPSS Statistics (version 25) was used. For evaluation of the
memory test, the number of recalled words for each position (1 to 15) was summed for the three
word lists at each the three measurement time points. First, only the memory tests were
analyzed to ensure that primacy and recency effects were actually found.
Therefore, an analysis of variance for repeated measurement (rmANOVA) with the
withinsubject factors ?position? (?1?, . . ., ?15?) and ?time point (?pre SECPT?, ?post SECPT?, and ?SECPT
+ 20 min.?) was calculated. The number of correctly recalled words was averaged over the
percentiles (1st to 3rd, 4th to 6th, . . ., 13th to 15th word position; P1, . . ., P5) to make the following
post-hoc analysis easier to interpret. Only the percentiles were used for further statistical
analysis. If necessary, sphericity violations (determined by Mauchly?s test of sphericity; [
corrected by adjusting the degrees of freedom with the procedure by 36. As post-hoc tests, t-tests
with adjusted alpha levels according to the Bonferroni correction were calculated. Partial
etasquares (?p2) for ANOVAs and Cohen?s d for t-tests are reported for effect sizes. If necessary,
Cohen?s d was corrected according to the method that was proposed by Morris (2008; [
further analysis (after the occurrence of an PE and RE was revealed), P1 was considered as a
measure of the primacy effect and, therefore, for long-term memory, and P5 was considered as a
measure for the recency effect and, thus, for working memory performance. To test whether the
PE and the RE differed between the three time points (?pre SECPT?, ?post SECPT?, and ?SECPT
+ 20 min.?) and whether they were, therefore, related to the stress induction, a further
rmANOVA with the factors ?time point? and ?memory effect? (?PE? and ?RE?) was calculated.
Because of positive skewness, cortisol levels were transformed by means of the natural
logarithm prior to further statistical analysis. Participants were classified as responders or
nonresponders, separately for sAA and cortisol. Participants with an increase of more than 10
percent between s1 and s2 for sAA and between s1 and s5 for cortisol were classified as responders.
Further rmANOVAS with the within-subject factors ?memory type? and ?time point? and the
between-subject factor ?respondence? were calculated. If necessary, post-hoc rmANOVAS with
the factors ?time point? and ?respondence? were calculated, separately for the PE and RE.
Stress effects on memory
A main effect of the factor position (F(6.011, 192.35) = 24.80, p < .001, ?p2 = .44), a main effect of
time point (F(2, 64) = 4.08, p = .022, ?p2 = .11), and an interaction position time (F(14.17, 453.42)
= 4.83, p < .001, ?p2 = .13) were found (Fig 3A?3C). A further rmANOVA, in which the
percentiles P1, P3, and P5 were compared, revealed a significant main effect of the factor time
point (F(1.61, 51.76) = 58.0, p < .001, ?p2 = .64), a marginally significant main effect of the factor
percentile (F(2, 64) = 2.84, p = .066, ?p2 = .08), and a significant interaction time point
percentile (F(4, 128) = 13.19, p < .001, ?p2 = .29). Post-hoc t-tests showed that both the primacy effects
(i.e., P1 > P3) and recency effects (i.e., P5 > P3) were found for all three time points (all p <
.001) in this sample.
For further analysis, the first (P1) and the last (P5) three words were used as measures for
the PE and RE. A further rmANOVA revealed main effects of the factors time point (F(2, 64) =
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Fig 3. Number of correctly recalled words in dependence of the word position, a) before the SECPT, b) immediately after SECPT, c) 20 minutes after the SECPT, and d)
strength of the primacy and recency effect in dependence of the measurement time-point.
5.76, p = .005, ?p2 = .15) and memory effect (F(1, 32) = 17.15, p < .001, ?p2 = .35) and an
interaction time point memory effect (F(1.67, 53.4) = 20.76, p < .001, ?p2 = .39, Fig 3D). Post-hoc
ttests showed that the strength of the PE and RE was the same before the SECPT and different
after the SECPT (i.e., the RE was stronger than the PE; both p < .001). Immediately after
SECPT, the PE was the same as before (p = .236). The PE was significantly weaker 20 minutes
after the SECPT than immediately after it (t(32) = 3.65, p = .001, d = -0.71). Therefore, LTM
performance did not differ immediately after SECPT, but decreased 20 minutes after the stress
induction. The RE was significantly stronger immediately after the SECPT than before
(prepost: t(32) = -5.43, p < .001, d = 0.86), but did not change further in the following 20 minutes (p
= .122). Therefore, WM performance increased immediately after the SECPT, but did not
Subjective stress perception
Subjective stress perception significantly differed between the seven time points (F(3.68, 117.75) =
13.56, p < .001, ?p2 = .30). Post-hoc t-tests revealed that subjective stress perception was higher
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immediately after the SECPT (s2) than before it (s1-s2: t(32) = -2.97, p = .006, d = 0.56) and
further declined until 20 minutes after the SECPT (s5, all p < .230, Fig 4A).
Salivary alpha-amylase concentration significantly differed between the seven time points (F(6,
192) = 2.32, p = .034, ?p2 = .07, Fig 4B). Post-hoc t-tests revealed that sAA concentration
increased immediately after the SECPT (s1-s2: t(32) = -2.20, p = .035, d = 0.49) and then
decreased until it reached a minimum ten minutes after the SECPT (s3-s4: t(32) = 1.91, p = .033,
d = -0.32). Amylase concentration did not change further after s4.
Twenty-two participants were classified as sAA-responders with an sAA-increase of more
than ten percent between s1 and s2. Eleven participants were classified as sAA non-responders.
A further rmANOVA with the within-subject factors memory type and time and the
betweensubject factor sAA respondence was calculated. This revealed a main effect of memory type
(F(1, 31) = 24.25, p < .001, ?p2 = .44), a main effect of time (F(2, 62) = 4.49, p = .015, ?p2 = .13), a
memory type sAA respondence interaction (F(1, 1) = 5.29, p = .028, ?p2 = .15), and a memory
type time interaction (F(2, 62) = 15.41, p < .001, ?p2 = .33).
Post-hoc analysis for the PE revealed only a main effect of time (F(2, 62) = 7.55, p = .001, ?p2
= .20; Fig 5A). Thus, the PE and, therefore, long-term memory performance was not associated
with the sAA response. For the RE, a main effect of time was found (F(2, 62) = 18.24, p < .001,
?p2 = .37) and a main effect of sAA respondence were found (F(1, 31) = 4.77, p = .037, ?p2 = .13;
Fig 5B). Only the sAA responders showed a main effect of the factor time effect (F(2, 42) =
23.37, p < .001, ?p2 = .53), but not the sAA non-responders. Therefore, WM performance only
increased in sAA responders. However, it should be noted that the sAA-non responders had
higher baseline REs than the sAA-responders which might have prevented a further increase
(t(31) = -2.28, p = .030, d = -0.84).
Cortisol concentration also differed significantly between the seven time points (F(2.02, 164.48) =
7.08, p = .001, ?p2 = .20, Fig 4C). Post-hoc t-tests revealed that cortisol concentration did not
differ between before and immediately after the SECPT (p = .368). Afterwards cortisol
concentration increased until it reached a maximum 20 minutes after the SECPT (s4-s5: t(32) = -3.35, p
= .002, d = 0.45).
Twenty-three participants were classified as cortisol-responders with a cortisol increase of
more than ten percent between s1 and s5. Ten participants were assigned to the cortisol
nonresponders group. A further rmANOVA with the within-subject factors memory type and
time and the between-subject factor cortisol respondence was calculated. This revealed a main
effect of memory type (F(1, 31) = 16.51, p < .001, ?p2 = .35), a main effect of time (F(2, 62) = 7.01,
p = .002, ?p2 = .18), a memory type time interaction (F(2, 62) = 13.12, p < .001, ?p2 = .30), and
a memory type time cortisol respondence interaction (F(2, 1) = 4.07, p = .022, ?p2 = .12).
Post-hoc analysis for the PE revealed a main effect of time (F(2, 62) = 4.92, p = .01, ?p2 = .14)
and a time cortisol respondence interaction (F(2, 31) = 11.79, p = .005, ?p2 = .16). Post-hoc
analyses showed that, for the PE, a time effect was found only for the cortisol responders (F(2,
44) = 18.28, p < .001, ?p2 = .45), but not for the cortisol non-responders (Fig 5C). Therefore,
long-term memory performance only decreased in cortisol responders after the SECPT, but
not in cortisol non-responders. For the RE, only a main effect of time (F(2, 62) = 15.44, p <
.001, ?p2 = .51), but no interaction time cortisol respondence or a main effect of cortisol
respondence were found (Fig 5D).
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Fig 4. Time course of subjective stress ratings (a), sAA concentration (b), and cortisol concentration (c) at different
time points before and after the SECPT.
In this study, we investigated the time course of the physiological stress response and its
associations with WM and LTM performance. The latter were operationalized by means of the PE
and the RE of the serial position curve. Our first finding was that WM performance increased
immediately after the stressor in participants who showed a sAA response. No changes in WM
performance were found in sAA non-responders. This is in line with our hypothesis and with
previous findings, in which improvements in WM performance after an acute stressor were
found as well [
]. However, other studies also found the opposite, i.e. impaired WM
functioning after an acute stressor (e.g., [
]). However, in contrast to our study, in most cases
spatial WM and not verbal WM was investigated in these previous studies. One explanation
that has been proposed to explain the different findings was that WM improves for simple
tasks, but that it is impaired for complex tasks [
]. This explanation fits well to the results of
Fig 5. Primacy and recency effects for sAA (a, b) as well as for cortisol (c, d) responders and non-responders, before, after and 20 minutes after the SECPT.
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our study because we used simple word lists with only 15 non-emotional words, and it can be
assumed that this was an easy task for our participants.
Our second finding was that LTM performance did not change immediately after the
stressor, but decreased 25 minutes after its onset in cortisol responders. This was also the time
point of the maximal cortisol response. This decrease in LTM performance was not found in
cortisol non-responders. Our finding is in line with many previous studies in which a drop in
LTM performance and a relation with glucocorticoids was found (e.g., [
there are also a few studies which cannot support this conclusion [
]. It has been proposed
that the timing of the glucocorticoid release (or injection for pharmacological studies), is the
critical factor for the diversity of the findings [
]. This could also explain why we did not
find an effect on LTM performance immediately after the stressor.
Our findings support the view that peripherally transmitted noradrenaline leads via indirect
pathways to a release of noradrenaline and dopamine in the PFC (e.g., [
]). Furthermore, our
results are in line with previous findings that have shown that peripherally released cortisol
passes the BBB and binds to receptors that are located in the hippocampus (e.g., [
However, in the PFC GRs can be found as well [
] and the hippocampus also receives
noradrenaline and dopamine input [
]. However, the association between PFC functioning
and peripheral glucocorticoid release can be found for longer time delays only .
Furthermore, associations between hippocampal dopamine release and memory have been found for
chronic stress and late long-term potentiation only [
In our study, we investigated SNS and HPA axis response to an acute stressor. However,
there are further peripheral-physiological stress responses which occur with a longer time
delay, but which might be related with memory processes as well (e.g., parasympathetic
activation and activation of inflammatory processes; e.g., [
]). This should be investigated in future
research (e.g., by means of heart-rate variability analyses and collection of blood samples).
It is important to point out that neutral words were used in our study. There is an extensive
literature on the effects of (e.g., emotional) arousal or stress on emotional memory (e.g.,
]). It was found that emotional LTM is enhanced?and not impaired as it is for neutral
stimuli . For memory formation of emotional stimuli, the amygdala plays a critical role
]. Emotional memory is indeed affected by SNS activity [
]. For example, it has been
found that the enhancement in emotional LTM is eliminated through a blockade of
betaadrenergic receptors in humans [
]. Furthermore, it was shown that a noradrenaline
injection after learning enhances LTM for emotional stimuli [
]. In animal studies, it has been
found that noradrenaline can have long-term effects on the hippocampus [
glucocorticoids are also involved in LTM enhancement for emotional stimuli. For example,
Buchanan and Lovallo  found that a cortisol injection during learning enhanced recall one
week later. To combine these manifold findings, it has been suggested that both, the
glucocorticoid and the noradrenaline pathway, interact in emotional memory formation [
Furthermore, it should be noted that, in previous studies, LTM was assessed in a different
way than in our study. In most previous paradigms, participants were presented the material
on one day and the recall took place on another day. Thus, the elapsed time was much longer
than in our study. Our design has the advantage that learning as well as retrieval of the items
could both be tested at all three time points within one person. Therefore, our design offers
new insights in the effects of acute stress on memory performance.
Our study does not allow us to draw conclusions about the reasons for the sAA- or
cortisolnon respondence. It has been shown previously that stress responsiveness is associated with
childhood traumata and adversity (e.g., [
]). These might be factors underlying the
nonresponsiveness in our study as well. Unfortunately, we did not ask our participants for this.
But, this should be investigated in future research.
10 / 15
Moreover, our design should be repeated with emotional stimuli in future studies.
Furthermore, it should be combined with imaging techniques to get more insight into the underlying
neural processes. Besides, our design should be supplemented by the collection of blood
samples, because the use of sAA as marker for SNS activity is well-established [
], there are
still some valid concerns that need to be taken into account . Furthermore, our design
should be supplemented by pharmacological treatments, which block either the MR or the GR,
because to understand the underlying mechanisms both receptor types should be taken into
Our study supports the assumption that SNS activation after an acute stressor immediately
improves WM function. This is probably related with noradrenergic and dopaminergic
activation of the PFC. Furthermore, we showed that HPA axis activity is associated with LTM
processes?probably through interactions with the hippocampus. Using the serial position effects
to measure both WM and LTM performance within one test seems to be a very good means
for further research on the effects of acute stress on memory.
S1 File. Data file.
S2 File. Codebook.
Conceptualization: Linda Becker.
Formal analysis: Linda Becker.
Investigation: Linda Becker.
Methodology: Linda Becker.
Project administration: Linda Becker.
Supervision: Nicolas Rohleder.
Visualization: Linda Becker.
Writing ? original draft: Linda Becker.
Writing ? review & editing: Nicolas Rohleder.
We thank Aylin Go?gsen, Kristin von Majewski, and Yvonne Daichendt for data collection.
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