Received: 15 May 2023 Revised: 7 September 2023 Accepted: 10 September 2023

DOI: 10.1111/ejn.16153

RESEARCH REPORT

The brain-derived neurotrophic factor Val66met

polymorphism is associated with better attention and
working memory performance and resilience to mild
chronic stress

Michelle Corrone 1 | Aleshia Nanev 1 | Isabella Amato 1 | Rowena Bicknell 1 |

Stefan Piantella 1 | Paul Maruff 2 | Maarten van den Buuse 1 | Bradley J. Wright 1

1
School of Psychology and Public Health,
La Trobe University, Melbourne, Victoria,
Australia
2
Cogstate Ltd, Melbourne, Victoria,
Australia
Correspondence
Bradley J. Wright, Plenty Road and
Kingsbury Drive, Bundoora, VIC 3086,
Australia.
Email: b.wright@latrobe.edu.au
Funding information
The authors did not receive support from
any organization for the submitted work.
Edited by: Gal Richter-Levin
Abstract
The val66met polymorphism of the brain-derived neurotrophic factor (BDNF)
gene has been identified as a potential moderator for the relationship between
chronic stress and executive functioning. However, whether the presence of
the met allele increases cognitive vulnerability or resilience to stress has yet to
be determined. Given the established effects of autonomic activity and psycho-
logical arousal on executive functioning, in the present study, 56 healthy uni-
versity students completed self-report measures of chronic stress, positive
arousal (vigour) and negative arousal (anxiety) and measured heart-rate vari-
ability to quantify autonomic activity. Participants then completed a cognitive
test battery that measured attention, decision-making, visual learning and
working memory. Regression analyses demonstrated that Val/met participants
performed better on attention and working memory tasks than Val/val partici-
pants, but no differences were seen in decision-making and visual learning.
Further, Val/met participants were protected from stress-related differences in
attention seen in Val/val participants. Val66met was not associated with physi-
ological or psychological arousal. This study demonstrates that val66met plays
an important but selective role in cognitive performance.

KEYWORDS
attention, autonomic activity, brain-derived neurotrophic factor, chronic stress, working
memory

List of abbreviations: AUDIT, Alcohol Use Disorders Identification Test; BDNF, brain-derived neurotrophic factor; BMI, body mass index; DET,
detection test; HRV, heart rate variability; IDN, Identification Test; met, methionine; OCL, One Card Learning Task; ONB, One Back Test; POMS,
Profile of Mood States; PSS, Perceived Stress Scale; sAA, salivary alpha amylase; STAI, State–Trait Anxiety Inventory; val, valine; VR, virtual reality.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2023 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Eur J Neurosci. 2023;58:3903–3916. wileyonlinelibrary.com/journal/ejn 3903


3904
1 | INTRODUCTION
Because of the high density of glucocorticoid receptors in
the prefrontal cortex (Patel et al., 2000; Perlman
et al., 2007), stress exposure and its associated high levels
of circulating glucocorticoids can alter cognition and
have long-lasting effects on executive functioning (Jett
et al., 2017; Smith et al., 2018). However, these stress
effects have been found to be highly variable, even within
healthy populations, and this variability has been linked
to genetic, physiological and psychological factors.
Brain-derived neurotrophic factor (BDNF) is involved
in neuronal maturation, growth and survival and binds
to tropomyosin-related kinase B receptors (TrkB; Notaras
et al., 2015) with high levels of BDNF found within the
prefrontal cortex (Ernfors, Ib
añez et al., 1990; Ernfors,
Wetmore et al., 1990; Hofer et al., 1990). Glucocorticoids
directly and indirectly influence BDNF signalling and
expression (Gourley et al., 2009; Jeanneteau et al., 2008;
Pradhan et al., 2019; Smith et al., 1995), whereas BDNF
can regulate the stress response through modulation of
corticotrophin-releasing factor (CRF) gene expression
(Givalois et al., 2004; Jeanneteau et al., 2012). Animal
studies have shown that increased BDNF signalling
induced by administration of an agonist at the BDNF
receptor, TrkB, protected against stress-induced deficits
in executive functioning (Barfield & Gourley, 2017). Con-
versely, TrkB deactivation impaired cortical neuroplasti-
city following stress by blocking glucocorticoid receptor
phosphorylation (Arango-Lievano et al., 2015). For these
reasons, BDNF may be central in the relationship
between stress and executive functioning.
The val66met polymorphism is a common BDNF gene
variant, where a single nucleotide substitution at codon
66 causes an amino acid substitution of valine (val) for
methionine (met), resulting in reductions in activity-
dependent release of BDNF (Notaras et al., 2015;
Notaras & van den Buuse, 2018). Compared with val
homozygous (Val/val) carriers, neuronal BDNF release is
reduced by 13% in single allele met (Val/met) carriers
and 23% in met homozygous (Met/met) carriers (Chen
et al., 2006, 2004; Egan et al., 2003). Although the pres-
ence of the val66met polymorphism has been associated
with disrupted cognitive performance, the role of val66-
met in executive functioning is less clear (Barha
et al., 2019; Erickson et al., 2008; Gabrys et al., 2017;
Krueger et al., 2011; Wiłko
s
c et al., 2016). Specifically, it
remains unclear whether val66met increases an individ-
ual’s vulnerability or resilience to stress-induced changes
in executive functioning and which components of these
cognitive processes are most affected. Both human and
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CORRONE ET AL.
animal studies have provided evidence that individuals
carrying the met allele are more vulnerable to stress-
induced impairments in core executive functions, such as
working memory and cognitive flexibility (Gabrys
et al., 2017; Gatt et al., 2009; Yu et al., 2012), but few
studies have been published on higher order executive
functions such as decision-making and problem-solving,
despite evidence that BDNF expression is associated
with decision-making in stressful situations (Smith
et al., 2014). Moreover, the cognitive load of the neuro-
cognitive tasks administered may account for some of the
variability in the literature, with our recent work demon-
strating that complex, top-down cognitive tasks were
more strongly associated with val66met than simpler,
bottom-up cognitive tasks (Corrone et al., 2021). There-
fore, this study will extend our previous findings and
assess data taken from the same participants at the same
time as the earlier work (Corrone et al., 2021) and mea-
sure a core executive function (working memory), a
higher order executive function (decision-making) and
a non-executive cognitive function (attention). Visual
learning was also included to determine whether the lack
of relationship between val66met and visual processing
speed observed in our previous study (Corrone
et al., 2021) extends to other visual-based cognitive
functions.
Heart rate variability (HRV) provides a proxy measure
of autonomic activity, and although associations between
HRV and val66met have been identified, the direction of
this relationship is unclear. For example, some studies
have found that carriers of the Met/met genotype had
reduced parasympathetic activity, resulting in sympa-
thetic dominance, compared with Val/val and Val/met
individuals (Tsuru et al., 2014; Yang et al., 2010), whereas
others have found increased sympathetic activity in
Val/met individuals compared with Val/val individuals,
but no resultant sympathetic dominance (Corrone
et al., 2021). Another study found that although individ-
uals carrying the met allele had reduced parasympathetic
activity compared with Val/val individuals, the effect was
only present in male participants, suggesting that the
relationship between val66met and HRV may be
gender-specific (Chang et al., 2014). However, both Yang
et al. (2010) and Corrone et al. (2021) found no
interactions between genotype and gender in their HRV
analysis.
Mood state is also associated with cognitive perfor-
mance during neuropsychological testing (Bolte
et al., 2003; Rowe et al., 2007). A positive mood state is
typically associated with better cognition than negative
mood states (Bolte et al., 2003; Schuch & Pütz, 2018), and

CORRONE ET AL.
memory retrieval is enhanced when the stimuli’s emo-
tional valence is congruent with the mood state of the
individual at the time of encoding (Bower, 1981). In
the present study, the relationship between val66met,
mood state (i.e., vigour and anxiety) and potential inter-
action effects on cognition was examined in a healthy
population.
The overall aim of this study was to elucidate the
role of val66met in the relationship between chronic
stress and attention, decision-making, visual learning
and working memory after considering the role of
physiological (autonomic activity) and psychological
(mood states) arousal. It was hypothesized that carriers
of the met allele would be more likely to have impair-
ments in working memory associated with high stress
compared to Val/val individuals but would perform
better on cognitive tests of attention and decision-
making than individuals homozygous for the val allele
regardless of stress levels. No associations between
val66met, stress and visual learning were anticipated.
Further, it was hypothesized that val66met would be
associated with heightened sympathetic reactivity
because of the mild stress elicited by the cognitive
testing in Val/met participants compared with Val/val
participants, but these changes would not be strong
enough to alter autonomic dominance. It was further
predicted that the relationship between val66met and
autonomic activity would not be gender specific. Lastly,
it was hypothesized that val66met would be associated
with higher self-reported state anxiety, but no
association with vigour was expected.
2 | METHODS
2.1 | Participants
Participants were healthy young adults (N = 56,
females = 31), aged 18 to 28 years (M = 20.7, SD = 2.1).
Participants were invited to participate face-to-face on
the grounds of La Trobe University, Melbourne,
Australia, using a recruitment script. Participants were
included if they were currently full-time students (crite-
rion for a related study) and could read English. Exclu-
sion criteria included a self-reported history of
concussion in the previous 6 months; psychiatric, cardiac,
or neurological illness; dementia, head injury, insomnia
or other sleep disorders; and the use of medications that
may affect concentration. Candidates were also excluded
if they reported feeling physically fragile or acutely
unwell (cold, flu), or if they reported regular illicit drug
or alcohol consumption. Participants provided written
informed consent in line with institutional ethics
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3905
(HEC19036) and were compensated for their time with a
$100 shopping voucher.
2.2 | Materials
2.2.1 | Chronic stress
The Perceived Stress Scale (PSS; Cohen et al., 1983) is a
10-item self-report measure that assesses perceived
chronic stress on a 5-point Likert scale (0 = never to
4 = very often). An example item is ‘In the last month,
how often have you felt that things were going your
way?’ (Cohen et al., 1983, p. 394). High scores denote
high levels of perceived stress. In this study, the PSS had
high internal consistency (α = 0.82).
2.2.2 | Vigour—Positive mood state
The Profile of Mood States (POMS; McNair et al., 1971) is
a 65-item self-report questionnaire that measures short-
term mood states on a 5-point Likert scale (0 = not at all
to 4 = extremely). To assess the participants’ positive
mood states, the 7-item vigour subscale was used. High
scores on the vigour subscale denote a positive mood
state. The POMS vigour subscale showed high internal
consistency (α = 0.89).
2.2.3 | Anxiety—Negative mood state
The six-item short-form of the State–Trait Anxiety Inven-
tory (STAI-6; Marteau & Bekker, 1992) was used to assess
participants’ state anxiety levels. The STAI-6 is a self-
report questionnaire that utilizes a 4-point Likert scale
(0 = not at all to 4 = very much so), where high scores
denote a negative mood state. The STAI-6 showed high
internal consistency (α = 0.78).
2.2.4 | Alcohol consumption screening
The Alcohol Use Disorders Identification Test (AUDIT;
Saunders et al., 1993) was used to screen for frequent
alcohol use. The 10-item self-report scale assesses alcohol
consumption, drinking behaviour and consequences
related to drinking. An AUDIT score of ≥8 indicates
risky/hazardous levels of alcohol use. The AUDIT
has high internal consistency (α = 0.81; Shields &
Caruso, 2003) and strong test–retest reliability
(Selin, 2003). No participants were excluded based on this
criterion.

3906
2.2.5 | Heart rate variability
HRV measures heartbeat fluctuations, which are primar-
ily controlled by autonomic activity. Dysregulated HRV is
commonly associated with alteration in cognitive perfor-
mance (Collins et al., 2012; Forte et al., 2019). Continu-
ous heart rate was measured using a digital ambulatory
ECG recorder (AR12plus, Medilog, Schiller AG,
Switzerland). The ECG recorder has five leads that attach
to the chest and records ECG signals at a sampling rate
of 1000 Hz. Recordings were examined using Darwin V2
software (Medilog, Schiller AG, Switzerland) to deter-
mine R-R peak intervals during the baseline and cogni-
tive testing phases. Non-sinus intervals were excluded.
The duration of the baseline and testing periods were
both approximately 10 min and were analysed using a
Poincaré plot, a non-linear method of measuring HRV
where each data point refers to the relative change
between one R-R interval and the consecutive R-R
interval (Roy & Ghatak, 2013). Non-linear methods of
analysing ECG data were developed to identify non-
linear patterns in HRV that occur because of the com-
plexity of the autonomic nervous system (Roy &
Ghatak, 2013; Shaffer & Ginsberg, 2017). There is
insufficient evidence of non-linear HRV in val66met
populations, as studies have predominantly been
analysed by linear, time- and frequency-domain methods.
However, in a previous study, it was seen that stress-
induced alterations in HRV were identified in Val/met
participants but not Val/val participants (Corrone
et al., 2021), highlighting that further examining
non-linear patterns could elucidate the relationship
between HRV and val66met.
The Poincaré plot provides three indices of HRV:
SD1, SD2 and SD12. SD1 is a measure of parasympathetic
activity and refers to the standard deviation of instanta-
neous beat-to-beat interval variability. SD2 is a measure
of sympathetic activity, which refers to the standard devi-
ation of the continuous long-term R-R interval variabil-
ity. SD12 is the ratio of SD1/SD2 and indicates
autonomic balance. An SD12 change variable was calcu-
lated by subtracting the baseline phase measure from the
cognitive testing phase measure. Higher SD12 change
values denote increases in sympathetic dominance
between baseline and cognitive testing phases.
2.2.6 | Genotyping
Participants provided an unstimulated saliva sample dur-
ing the baseline period by moving a cotton swab
(Salivette®, Sarstedt, Chur, Switzerland) around their
mouth in a circular motion for 1 minute. The Salivettes®
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CORRONE ET AL.
were placed in a centrifuge tube and immediately stored
in a freezer (
20 C). Samples were sent on dry ice to the
Australian Genome Research Facility for DNA extraction
and were analysed using Agena Mass Array for the single
nucleotide polymorphism rs6265 (BDNF val66met).
2.2.7 | Cognitive test battery
The cognitive test battery consisted of a collection of
4 Cogstate computerized neurocognitive tests: the Detec-
tion test (DET), the Identification test (IDN), the One
Card Learning test (OCL) and the One Back test (ONB).
These tests measure attention, decision-making, visual
learning and working memory, respectively. Participants
were provided with a practice test and began each trial
when they selected the ‘enter’ button on the computer
keyboard. The tests have moderate to high test–retest
reliability (DET, r = 0.90; IDN, r = 0.69; OCL, r = 0.45;
ONB, r = 0.76) and have been validated for use in
healthy young people (Collie et al., 2003). More informa-
tion can be found at https://www.cogstate.com/clinical-
trials/computerized-cognitive-assessment/
The DET uses simple reaction time as a measure of
attention and psychomotor function. Participants are pre-
sented with a face-down playing card on screen with the
question ‘Has the card turned over?’ to which they can
only respond by selecting the on-screen ‘Yes’ button by
pressing the left button on the computer mouse. Partici-
pants are instructed to respond as quickly and accurately
as possible when the card turns over. The test is typically
administered in 3 min for healthy participants.
The IDN uses choice reaction time as a measure of
decision-making. Participants are presented with a
face-down playing card on the screen with the question
‘Is the card red?’ to which they can respond by pressing
the ‘Yes’ or ‘No’ (left or right respectively) buttons with
the computer mouse. When the card turns over, the face
will either be red or black, and participants are required
to respond as quickly and accurately as possible. The
test is typically administered in 3 min for healthy
participants.
The OCL uses a pattern separation paradigm as a
measure of visual learning and memory. Participants are
presented with a face-down playing card on the screen
with the question ‘Have you seen this card before?’ to
which the participant can respond by selecting either
‘Yes’ or ‘No’. When the card turns over, the face will dis-
play a standard card face and the participants are
required to recall whether the card has been previously
presented throughout the test, responding as quickly and
accurately as possible. The test is typically administered
in 4 min for healthy participants.

CORRONE ET AL.
The ONB uses the n-back paradigm as a measure of
working memory. Participants are presented with a face-
down playing card on the screen with the question ‘is the
previous card the same?’ to which they can respond by
using the computer mouse to select either ‘Yes’ or ‘No’.
When the card turns over, the face will display a standard
card face and the participants are required to recall the
previous card and respond as quickly and accurately as
possible. The test is typically administered in 4 min for
healthy participants.
2.3 | Statistical analysis
IBM SPSS statistics computer software package (version
26) was used for all statistical analyses. An independent
samples t-test was used to compare Val/val or Val/met
genotype groups on age and BMI. Chi-square was used to
examine relationships between BDNF genotypes and
gender. A one-sample t-test was used to compare partici-
pants’ self-reported chronic stress (PSS), vigour (POMS)
and state anxiety (STAI) with age-matched normative
samples. A paired t-test compared HRV (i.e., SD1, SD2
and SD12) differed across baseline and testing phases. A
2 (phase; baseline, testing)  2 (genotype; val/val, Val/-
met) analysis of variance (ANOVA) assessed if changes
in HRV between phases differed by genotype. A one-way
analysis of covariance (ANCOVA) assessed whether vig-
our, anxiety or chronic stress differed by genotype after
controlling for age and gender. Associations between par-
ticipant characteristics (genotype, gender, age and BMI),
self-report measures of mental state (PSS, vigour and anx-
iety), HRV (change in SD12) and cognitive measures
(DET, IDN, OCL and ONB) were assessed with Pearson
and Spearman correlations as appropriate. Four moder-
ated regression analyses were conducted using the SPSS
PROCESS macro (Hayes, 2013) with bootstrapping
(N = 5000 resamples) to assess whether genotype inter-
acted with PSS to predict performance on the cognitive
test battery after controlling for age, gender, vigour and
changes in autonomic arousal.
3 | R E SUL T S
3.1 | Data management
One participant carried the Met/met genotype, and there-
fore, data for this subject were removed from the study.
Data were free from outliers as assessed by Mahalanobis
distance and violations of normality (z-skewness > 2.58),
multicollinearity in the regression tests (all tolerance
statistics > .10) and homoscedasticity. To be consistent
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3907
and directly comparable with previous research using
Cogstate tests, all cognitive measures were transformed
using either logarithmic transformation (IDN, DET,
ONB) or arcsine transformation (OCL).
3.2 | Demographic equivalence and
normative comparisons
The descriptive statistics are provided for each genotype
and the entire sample for gender, age and BMI data
(Table 1). The genotype groups did not differ in gender
distribution (X 2[1, N = 56] = 0.30, p = .420), mean age (t
[54] =
0.51, p = .610), or mean BMI (t[54] = 0.136,
p = .892). Participants reported lower perceived chronic
stress and state anxiety and higher vigour than age-
matched normative samples (Table 2).
3.3 | Effect of testing and genotype on
autonomic activity
Increases in autonomic activity were observed in the test-
ing phase for all variables except SD1 (Table 3). The effect
size for SD2 was very large (Cohen, 1988), indicating a
substantial change in sympathetic activity during cogni-
tive testing. Changes in autonomic arousal did not differ
between genotypes (Figure 1; SD1: F(1,52) = 0.50,
p = 0.49; SD2: F(1,52) = 0.54, p = 0.47; SD12: F(1,52)
= 0.12, p = 0.73), nor genders; SD1: F(1,52) = 0.98,
p = 0.33; SD2: F(1,52) = 0.07, p = 0.79; SD12: F(1,52)
= 1.50, p = 0.23). No interaction effects were identified
between genotype and gender (SD1: F(1,52) = 0.21,
p = 0.65; SD2: F(1,52) = 2.09, p = 0.16; SD12: F(1,52)
= 2.32, p = 0.13).
3.4 | Effect of genotype on perceived
mood states
The differences in self-reported state vigour and anxiety
between genotypes after controlling for age and gender
were assessed. Neither vigour (F(1,52) = 0.77, p = 0.38)
nor anxiety (F(1,52) = 0.25, p = 0.62) differed between
genotypes (Figure 2).
3.5 | Associations between key variables
The associations between participant characteristics, self-
report measures of stress, vigour and anxiety, physiological
arousal and cognitive measures were assessed (Table 4).
Individuals carrying the met allele were associated with
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3908 CORRONE ET AL.

TABLE 1 Demographics of study sample compared with genotype.

Genotype

Variable Total sample Val/val Val/met

Gender (Male: Female) M = 25: F = 31 M = 11: F = 18 M = 14: F = 13
Age M (SD) 20.66 (2.15) 20.52 (2.22) 20.81 (2.22)
BMI M (SD) 24.02 (3.99) 24.10 (4.07) 23.95 (3.98)

TABLE 2 Age-matched normative comparisons of means and standard deviations for self-report measures.

Sample data Normative data

Scale M SD M SD t d
PSS 15.47 5.78 19.62 7.49
4.08*** 0.56
POMS–Vigour 17.16 4.29 15.00 6.90 2.17* 0.35
STAI 10.98 3.12 12.96 3.26
3.81*** 0.62

Note: Normative data: PSS (Örücü & Demir, 2009), n = 508, age 15–29; POMS–Vigour (Nyenhuis et al., 1999), n = 132, age 18–24; STAI (Taylor &
Deane, 2002), n = 122, age = 19–80.
Abbreviations: POMS, Profile of Mood States; PSS, Perceived Stress Scale; STAI, State–Trait Anxiety Inventory.
*p < .05.
***p < .001.

TABLE 3 Comparison of autonomic activity measures at baseline and cognitive testing.

Baseline M (SD) Testing M (SD) Cohen’s d p

SD1 28.77 (18.09) 25.65 (12.17) 0.413 .14
SD2 76.16 (26.34) 95.93 (39.89) 1.029 <.001
SD12 0.38 (0.17) 0.27 (0.09) 1.26 <.001

higher chronic stress (PSS) and better attention (DET) and
working memory (ONB). Genotype was not associated
with mood state or physiological arousal.
3.6 | Effect of chronic stress on the
relationships between genotype and
cognitive performance
A series of multivariable regressions were conducted to
assess if any of the demographic, psychological, or physi-
ological measures were associated with cognition (DET,
IDN, OCL and ONB). Given that anxiety was not corre-
lated with any cognitive measure but was correlated with
both chronic stress and vigour (Table 4), anxiety was not
included as a measure of state affect in any regression
model to preserve statistical power and potential issues of
multicollinearity.
The regression models identified that genotype was
associated with attention (DET; Table 5) and working
memory (ONB; Table 6) but not decision-making (IDN;
Table 5) or visual learning (OCL; Table 6). Specifically,
participants with the Val/met genotype demonstrated fas-
ter/better attention and working memory performance
than participants with the Val/val genotype. Lower vig-
our was also a significant predictor of attention and
decision-making performance (Table 5).
Genotype did not moderate the association between
chronic stress and IDN; b =
0.01 [
0.01, 0.01], p = 0.07,
ONB; b = 0.00 [
0.02, 0.01], p = 0.85 or OCL; b = 0.00
[
0.01, 0.01], p = 0.85 as outcomes. The attention (DET)
model, however, demonstrated an association between
genotype and chronic stress (PSS); b = 0.01 [0.01, 0.02],
p = 0.04. Specifically, the association revealed that for the
Val/val genotype, higher chronic stress was associated
with poorer attention performance; b = 0.01, p = 0.05,
whereas for the Val/met group, perceived stress was not
related to attention scores (Figure 3).
4 | DISCUSSION
In line with our hypotheses, Val/met individuals demon-
strated better attention than Val/val participants and

CORRONE ET AL.
F I G U R E 1 Changes in autonomic activity between baseline
and cognitive testing phases between genotypes. Panels show SD1, a
measure of parasympathetic activity that refers to the standard
deviation of instantaneous beat-to-beat interval variability; SD2, a
measure of sympathetic activity that refers to the standard deviation
of the continuous long-term R-R interval variability; and SD12, the
ratio of SD1/SD2 and indicates autonomic balance. Box plots show
the 5th and 95th percentiles, the interquartile range and the median.
genotype was not associated with visual learning. How-
ever, contrary to our hypotheses, Val/met individuals
showed better working memory than Val/val participants
but val66met was not associated with decision-making,
physiological arousal, or psychological arousal. Further,
Val/val individuals with higher self-reported stress levels
demonstrated poorer attention, but this effect was not
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3909
F I G U R E 2 No difference in mood states between genotypes.
Top panel: vigour; bottom panel: anxiety. Box plots show the 5th
and 95th percentiles, the interquartile range and the median.
present in Val/met participants. The results of this study
suggest that, after controlling for gender, age, autonomic
arousal and mood state at baseline, Val/met participants
demonstrate better attention and working memory than
Val/val individuals and are protected against stress-
induced impairments to attention.
4.1 | The Val/met genotype is associated
with better attention and working memory
Val/met participants performed better on working mem-
ory and attention tests than Val/val participants, but no
differences between genotypes were observed for
decision-making or visual learning in the unadjusted
analyses. In our previous study, we explained the discrep-
ancies between val66met and various cognitive tasks as
 14609568, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/ejn.16153 by Nat Prov Indonesia, Wiley Online Library on [20/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
3910 CORRONE ET AL.

T A B L E 4 Correlations comparing genotype, gender, age, self-report measures of stress, vigour and anxiety, physiological arousal, and
cognitive measures.

Variable Genotype Gender Age PSS Vigour Anxiety SD12Δ IDN DET OCL
Gender
0.14 a

Age 0.07
0.09

PSS 0.28* 0.21
0.13
Vigour
0.07
0.28* 0.12
0.28*
Anxiety
0.10 0.22
0.05 0.26*
0.50**
Δ
SD12
0.07
0.15
0.09 0.02 0.00 0.09
IDN
0.18 0.24 0.01 0.11
0.39**
0.05
0.05
DET
0.31*
0.05 0.02 0.02
0.23
0.02 0.00 0.63**
OCL 0.03
0.16 0.04 0.08
0.02 0.11 0.17
0.16
0.29*
ONB
0.35** 0.29* 0.02 0.00
0.27*
0.05 0.09 0.70** 0.52**
0.01
Δ
Note: PSS, Perceived Stress Scale; SD12 , change in SD12 between baseline and testing phases; IDN, decision-making; DET, attention; OCL, visual learning;
ONB, working memory. Gender: male = 1, female = 2, Genotype 1 = Val/val, 2 = Val/met.
a
Spearman’s correlation.
*p < 0.05.
**p < 0.01.

TABLE 5 Linear regression model of predictors of attention and decision-making.

DET IDN

B (95% CI) SE B t p B (95% CI) SE B t p

Genotype
0.06 (
0.01–0.02) 0.01
3.06 <0.01
0.03 (
0.07–0.01) 0.02
1.69 0.10
PSS 0.02 (
0.06–0.17) 0.06 0.98 0.33 0.01 (
0.00–0.02) 0.01 1.88 0.07
Gender
0.03 (
0.07–0.01) 0.02
1.52 0.13 0.01 (
0.01–0.05) 0.02 0.65 0.52
Age 0.00 (
0.01–0.01) 0.00 0.65 0.52 0.00 (
0.01–0.01) 0.00 0.72 0.48
Vigour
0.01 (
0.01–0.00) 0.00
2.78 0.01
0.01 (
0.01–0.00) 0.00
3.28 < 0.01
SD12Δ
0.01 (
0.17–0.14) 0.08
0.15 0.88
0.01 (
0.15–0.14) 0.07
0.10 0.93

Note: PSS, Perceived Stress Scale; SD12Δ, change in SD12 between baseline and testing phases; DET, attention; IDN, decision-making. Total model: DET
R 2 = .27, p = .03; Total model: IDN R 2 = .27, p = .03. Genotype: 1 = Val/val, 2 = Val/met; Gender: 1 = male, 2 = female.

TABLE 6 Linear regression model of predictors of visual learning and working memory.

OCL ONB

B (95% CI) SE B t p B (95%CI) SE B t p

Genotype
0.01 (
0.21–0.24) 0.04
0.11 0.92
0.06 (
0.10–0.01) 0.02
2.45 0.02
PSS 0.00 (
0.02–0.03) 0.01 0.39 0.70 0.00 (
0.02–0.01) 0.01
0.21 0.84
Gender
0.04 (
0.12–0.03) 0.04
1.12 0.27 0.03 (
0.01–0.08) 0.02 1.47 0.15
Age 0.00 (
0.01–0.02) 0.01 0.40 0.69 0.00 (
0.01–0.01) 0.01 0.80 0.43
Vigour
0.00 (
0.01–0.01) 0.00
0.32 0.75
0.00 (
0.01–0.00) 0.00
1.73 0.09
SD12Δ 0.15 (
0.14–0.45) 0.15 1.05 0.30 0.07 (
0.11–0.26) 0.09 0.83 0.41

Note: PSS, Perceived Stress Scale; SD12Δ, change in SD12 between baseline and testing phases; OCL, visual learning; ONB, working memory. Total model: OCL
R 2 = .07, p = .85; Total model: ONB R 2 = .26, p = .04. Genotype: 1 = Val/val, 2 = Val/met; Gender: 1 = male, 2 = female.

potentially related to cognitive load of the tasks (Corrone presence of val66met than low cognitive load tasks, this
et al., 2021). However, where we found that tasks with study found that relatively low and high cognitive load
high cognitive load are more likely to be affected by the tasks (but not moderate) were performed better by

CORRONE ET AL.
F I G U R E 3 Association between chronic stress and attention
between genotypes. The perceived stress scale was mean centred
prior to analysis but the untransformed values are presented on the
X-axis to assist interpretation.
participants with the Val/met genotype. Yet, the atten-
tion and decision-making tasks of this cognitive battery,
simple and choice reaction time tasks, are analogous to
the simple and choice reaction time tasks used in the
Corrone et al. (2021) study and therefore should demon-
strate similar findings. The discrepancies between the
current and previous study (Corrone et al., 2021) may be
explained by the increased level of arousal (HRV and
heart rate) elicited by the CONVIRT virtual-reality test-
ing environment compared to the Cogstate computer-
based testing (Horan et al., 2020). Additionally, carriers
of the met allele are less likely to be distracted by irrele-
vant stimuli during goal-directed behaviour than Val/val
individuals (Getzmann et al., 2013). Therefore, Val/met
participants may have been advantaged in our previous
study using the CONVIRT virtual-reality task because of
better tolerance to distractors, whereas the Val/met par-
ticipants had no such advantage during the present
study’s standard computerized cognitive testing.
Although the positive association between val66met
and working memory is in line with the theory that high
cognitive load tasks elicit differences between genotypes,
the result that Val/met participants had better working
memory than Val/val participants differs from previous
val66met research, where no association was found
between val66met and working memory (Cerasa
et al., 2010; Chen et al., 2015; Gatt et al., 2009; LeMoult
et al., 2015). However, these studies generally focus on
working memory accuracy and capacity, rather than
choice reaction time (Cerasa et al., 2010; Chen
et al., 2015; LeMoult et al., 2015). Where choice reaction
time was measured (Gatt et al., 2009), these results were
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3911
not reported independently and were incorporated in an
information processing factor score. Therefore, it is possi-
ble that choice reaction time measures in isolation are
more specific than accuracy or capacity measures and
therefore better demonstrate the cognitive differences
between val66met genotypes.
This study supports previous evidence that val66met
is not an important predictor of visual learning. Although
very few studies have investigated the role of val66met in
visual learning, neither an effect of val66met nor serum
BDNF levels have been established (Pitts et al., 2020;
Wheeler et al., 2020).
4.2 | The Val/met genotype buffers the
association between stress and poor
attention
The association between higher perceived stress and
poorer attention observed in Val/val participants could
be the result of heightened dopaminergic activity in the
prefrontal cortex (PFC). This is supported by evidence
that stress increases dopaminergic activity in the PFC to
the point of cognitive impairment (Finlay et al., 1995;
Murphy et al., 1996; Oh et al., 2021; Roth et al., 1988) and
dopaminergic hyperfunctioning throughout mesocortico-
limbic pathways has been linked to inattention (Viggiano
et al., 2003; Zhuang et al., 2001). Although studies of a
direct role of val66met in the mesocortical pathway are
limited, there is evidence that met-carrying individuals
exhibit reduced dopamine transmission in the nucleus
accumbens (Pecina et al., 2014). However, it is possible
that the observed relationship between val66met, stress
and attention may be related to a more direct action of
TrkB, independent of dopamine activity. Suppressed
TrkB activity is associated with reduced glucocorticoid
receptor phosphorylation and has been seen to block
stress-induced changes in cortical dendritic growth
(Arango-Lievano et al., 2015). Given the val66met-
associated decrease in activity-dependent BDNF secre-
tion, carriers of the met allele have less BDNF available
to bind to TrkB receptors (Egan et al., 2003).
4.3 | The potential role of ventral and
dorsal attention networks
The ventral attention network is important for inhibition
and filtering out distractors but is suppressed during
multi-elemental tasks (Zhao et al., 2022), whereas the
dorsal attention network is related to spatial attention
and working memory (Vossel et al., 2014; Zhao
et al., 2022). It is likely that the more complex measures

3912
of decision-making, working memory and visual learning
require more dynamic attentional control than the atten-
tion measure (simple reaction time) and therefore would
rely on the dorsal attention network while suppressing
the ventral attention network. Further, it has been dem-
onstrated that chronic stress increases PFC connectivity
to and activation of both attention networks (Ginty
et al., 2019; Soares et al., 2013). However, although few
studies have compared differences in the dorsal and ven-
tral attention networks between val66met genotypes, pre-
liminary evidence suggests met carriers may have
stronger ventral attention networks than individuals
homozygous for the val allele (Hashimoto et al., 2016),
and no functional differences have been identified in the
dorsal attention network (Li et al., 2016; Pietzuch
et al., 2021). Therefore, it is possible that the met allele
protects against stress-induced deficits in attention due
to a more robust ventral attention network, but once
the dorsal attention network plays a more dominant
role during decision-making, working memory and
visual learning tasks, this effect can no longer be
seen behaviourally.
4.4 | Psychological and physiological
arousal are not associated with Val66met
Although positive psychological arousal (vigour) was
associated with better attention and working memory
performance, no interactions between val66met and psy-
chological or physiological arousal were found. Previous
studies have found that Val/met participants report
higher levels of vigour and respond to emotional stimuli
differently than Val/val individuals (Tsuru et al., 2014;
Wang et al., 2012). However, the results of the current
study are consistent with evidence derived from clinical
samples that have also found no relationship between
val66met and mood states (Surtees et al., 2007; Verhagen
et al., 2010). Further, the lack of relationship between
val66met and HRV differs from previous research, which
has found that individuals carrying the met allele have
altered autonomic activity compared to Val/val partici-
pants (Chang et al., 2014; Corrone et al., 2021; Tsuru
et al., 2014; Yang et al., 2010). It is possible that the par-
ticipants of this study did not reach an adequate level of
arousal during computer-based testing to elicit differ-
ences between genotypes.
4.5 | Limitations
A limitation of this study was that although the working
memory assessment involves hippocampal input, it is
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CORRONE ET AL.
primarily driven by the PFC. Additionally, participants
with the Met/met genotype were not included, with gen-
otyping conducted after recruitment and only one
Met/met carrier identified. This meant we could not fully
examine the effects of all val66met genotypes. Further,
there have been some concerns surrounding the use of a
candidate gene approach (Sullivan, 2007). However,
genome-wide association studies are limited when asses-
sing genotypes that are moderated by environmental fac-
tors (Moore, 2017). Therefore, evaluation of the
relationship between val66met and stress was best
addressed using a candidate gene approach.
Although our sample size was modest, it was
adequately powered and the study controlled for several
potential confounds that are not typically considered
in val66met research (e.g., psychological arousal).
Additionally, a pre-post design strengthened this study by
allowing for analysis of autonomic change within
participants, whereas direct comparisons could be drawn
between genotypes. Nonetheless, the results of this
study should be replicated in a larger and higher
stressed sample.
5 | CONCLUSION
In conclusion, this study provides evidence that val66met
plays an important role in cognitive performance, dem-
onstrating better attention and working memory perfor-
mance in Val/met participants compared with Val/val
participants. We demonstrated, when controlling for age,
gender and psychological and physiological arousal, that
Val/met participants are protected from chronic stress-
related decreases in attention. This study provides a foun-
dational basis for animal model studies to establish a
direct role of val66met in the mesocortical dopamine
pathway and the ventral attention network.
A C KN O WL ED G EME N T S
N/A.
C O N F L I C T O F I N T E R E S T S T A TE M E N T
P.M. is an employee and equity holder in CogState Ltd.
The other authors have nothing to disclose.
PE ER RE VI EW
The peer review history for this article is available at
https://www.webofscience.com/api/gateway/wos/peer-
review/10.1111/ejn.16153.
DA TA AVAI LA BI LI TY S T ATE ME NT
Data will be available from the Open Science Foundation
platform at OSF j Cogstate Val/Met.

CORRONE ET AL.
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How to cite this article: Corrone, M., Nanev, A.,
Amato, I., Bicknell, R., Piantella, S., Maruff, P., van
den Buuse, M., & Wright, B. J. (2023). The
brain-derived neurotrophic factor Val66met
polymorphism is associated with better attention
and working memory performance and resilience
to mild chronic stress. European Journal of
Neuroscience, 58(8), 3903–3916. https://doi.org/10.
1111/ejn.16153