Vagus nerve stimulation improves working memory performance

Abstract

Vagus nerve stimulation (VNS) is used for treating refractory epilepsy and major depression. While the impact of this treatment on seizures has been established, its impact on human cognition remains equivocal. The goal of this study is to elucidate the immediate effects of vagus nerve stimulation on attention, cognition, and emotional reactivity in patients with epilepsy. Twenty patients (12 male and 8 female; 45 ± 13 years old) treated with VNS due to refractory epilepsy participated in the study. Subjects performed a computer-based test of executive functions embedded with emotional distractors while their brain activity was recorded with electroencephalography. Subjects’ cognitive performance, early visual event-related potential N1, and frontal alpha asymmetry were studied when cyclic vagus nerve stimulation was on and when it was off. We found that vagus nerve stimulation improved working memory performance as seen in reduced errors on a subtask that relied on working memory, odds ratio (OR) = 0.63 (95% confidence interval, CI [0.47, 0.85]) and increased N1 amplitude, F(1, 15) = 10.17, p = .006. In addition, vagus nerve stimulation resulted in longer reaction time, F(1, 16) = 8.23, p = .019, and greater frontal alpha asymmetry, F(1, 16) = 11.79, p = .003, in response to threat-related distractors. This is the first study to show immediate improvement in working memory performance in humans with clinically relevant vagus nerve stimulation. Furthermore, vagus nerve stimulation had immediate effects on emotional reactivity evidenced in behavior and brain physiology.

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Vagus nerve stimulation improves working
memory performance
Lihua Sun, Jari Peräkylä, Katri Holm, Joonas Haapasalo, Kai Lehtimäki, Keith
H. Ogawa, Jukka Peltola & Kaisa M. Hartikainen
To cite this article: Lihua Sun, Jari Peräkylä, Katri Holm, Joonas Haapasalo, Kai Lehtimäki,
Keith H. Ogawa, Jukka Peltola & Kaisa M. Hartikainen (2017): Vagus nerve stimulation improves
working memory performance, Journal of Clinical and Experimental Neuropsychology, DOI:
10.1080/13803395.2017.1285869
To link to this article: http://dx.doi.org/10.1080/13803395.2017.1285869
Published online: 19 Feb 2017.
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Vagus nerve stimulation improves working memory performance
Lihua Sun
a
, Jari Peräkylä
a,b
, Katri Holm
a,b
, Joonas Haapasalo
c
, Kai Lehtimäki
c
, Keith H. Ogawa
d
,
Jukka Peltola
b,c
and Kaisa M. Hartikainen
a,b
a
Behavioral Neurology Research Unit, Tampere University Hospital, Tampere, Finland;
b
Faculty of Medicine and Life Sciences,
University of Tampere, Tampere, Finland;
c
Department of Neuroscience and Rehabilitation, Tampere University Hospital,
Tampere, Finland;
d
John Magaddino Neuroscience Laboratory, Saint Mary’s College of California, Moraga, CA, USA
ABSTRACT
Vagus nerve stimulation (VNS) is used for treating refractory epilepsy and major
depression. While the impact of this treatment on seizures has been established, its
impact on human cognition remains equivocal. The goal of this study is to elucidate the
immediate effects of vagus nerve stimulation on attention, cognition, and emotional
reactivity in patients with epilepsy. Twenty patients (12 male and 8 female;
45 ± 13 years old) treated with VNS due to refractory epilepsy participated in the
study. Subjects performed a computer-based test of executive functions embedded
with emotional distractors while their brain activity was recorded with electroencepha-
lography. Subjects’cognitive performance, early visual event-related potential N1, and
frontal alpha asymmetry were studied when cyclic vagus nerve stimulation was on and
when it was off. We found that vagus nerve stimulation improved working memory
performance as seen in reduced errors on a subtask that relied on working memory,
odds ratio (OR) = 0.63 (95% confidence interval, CI [0.47, 0.85]) and increased N1
amplitude, F(1, 15) = 10.17, p= .006. In addition, vagus nerve stimulation resulted in
longer reaction time, F(1, 16) = 8.23, p= .019, and greater frontal alpha asymmetry, F(1,
16) = 11.79, p= .003, in response to threat-related distractors. This is the first study to
show immediate improvement in working memory performance in humans with clini-
cally relevant vagus nerve stimulation. Furthermore, vagus nerve stimulation had
immediate effects on emotional reactivity evidenced in behavior and brain physiology.
ARTICLE HISTORY
Received 9 September 2016
Accepted 16 January 2017
KEYWORDS
Attention; Cognition;
Executive functions; Frontal
alpha asymmetry; Vagus
nerve stimulation
Pharmacoresistant neurological and psychiatric
disorders highlight the importance of novel neuro-
modulation treatments. Vagus nerve stimulation
(VNS) is an effective and safe therapy
(Grimonprez, Raedt, Baeken, Boon, & Vonck,
2015; Grimonprez, Raedt, Portelli, et al., 2015;
Vonck et al., 2014) and is reported to be successful
in treating pharmacoresistant epilepsy (Penry &
Dean, 1990). In addition to reducing seizures, the
reported improvements in mood (Elger, Hoppe,
Falkai, Rush, & Elger, 2000; Klinkenberg et al.,
2012) and verbal recognition memory following
VNS stimulation (Clark et al., 1999) have led to
its use in treating other brain disorders, including
its clinical use in depression (Marangell et al.,
2002; Rush et al., 2000) and its experimental use
in treating Alzheimer’s disease (Sjogren et al.,
2002). While there is robust evidence for the ther-
apeutic effect of VNS in reducing seizures (Ben-
Menachem et al., 1994), the evidence for VNS’s
impact on cognition remains equivocal along
with several methodological limitations (Dodrill
& Morris, 2001; Klinkenberg et al., 2012;
McGlone et al., 2008; Merrill et al., 2006;
Sackeim, Keilp, et al., 2001; Sjogren et al., 2002).
Patients treated with VNS due to refractory epi-
lepsy frequently have compromised cognitive func-
tions due to epilepsy or antiepileptic drugs, they
may have covert seizures, the type of epilepsy and
etiology vary, and double-blinded studies may not
be possible due to sensation of VNS stimulation.
To that end, there is a need for further studies to
better understand potential cognitive and affective
effects of VNS.
CONTACT Kaisa M. Hartikainen kaisa.hartikainen@uta.fi Behavioral Neurology Research Unit, Tampere University Hospital, Tampere, Finland
Lihua Sun and Jari Peräkylä contributed equally.
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY, 2017
http://dx.doi.org/10.1080/13803395.2017.1285869
© 2017 Informa UK Limited, trading as Taylor & Francis Group

Previously reported beneficial effects of VNS on
human cognition and emotion are thought to arise
from increased levels of norepinephrine (NE;
Grimonprez,Raedt,Baeken,etal.,2015,
Grimonprez,Raedt,Portelli,etal.,2015;Vonck
et al., 2014). VNS innervates the nucleus tractus soli-
taries (Kalia & Sullivan, 1982), which is connected to
the locus coeruleus (LC; Aston-Jones et al., 1991;Van
Bockstaele, Peoples, & Telegan, 1999), the principal
site for the brain’ssynthesisofNE(Aston-Jones&
Cohen, 2005). However, studies of the chronic effects
of VNS provide contradictory evidence for its influ-
ence on mood (McGlone et al., 2008;Sackeim,Rush,
et al., 2001) and cognition (Merrill et al., 2006;Sjogren
et al., 2002) with either improvement or no change.
Chronic effects of VNS are typically confounded by
several factors influencing emotion and cognition
including medications and seizure burden. Improved
cognitive function due to VNS has been found in very
specific situations, thus limiting the generalizability of
the findings. For example, enhanced affective memory
in rodents (Clark, Krahl, Smith, & Jensen, 1995)and
improved verbal recognition memory in humans have
been shown (Clark, Naritoku, Smith, Browning, &
Jensen, 1999) when low-intensity VNS was delivered
during the memory consolidation phase.
In this study, we investigated the immediate
effects of VNS on human executive functions by
comparing the cognitive performance when cyclic
VNS stimulation is administered and when it is
not.Thecomparisonwithinsubjectsallows
uncovering the immediate and direct effects of
VNS on human cognition. Subjects performed
an experimental computer-based visual attention
task with emotional distractors—that is, the
Executive-Reaction Time (Executive-RT) test
(Figure 1a)—while having their electroencephalo-
gram (EEG) recorded. The task is designed to
simultaneously engage several cognitive control
functions including working memory, response
inhibition, and emotional control. The
Executive-RT test has been shown to be a sensi-
tive method in revealing alteration in executive
function performance and emotion–attention
interaction due to neuromodulation
(Hartikainen et al., 2014;Sunetal.,2015;Sun
et al., 2016), brain injury (Mäki-Marttunen
et al., 2015,2017), and cardiac surgery
(Liimatainen et al., 2016).
In addition to behavioral measures, we used
measures derived from EEG to assess the impact
of VNS on cognitive and affective brain functions.
We examined the impact of VNS on early visual
evoked potential—that is, N1. The parieto-occipital
N1 amplitude has been closely linked with atten-
tion, where enhanced visual attention is associated
with increase in N1 amplitude (Luck & Ford, 1998;
Mangun & Hillyard, 1991). Moreover, we also
studied the effect of VNS on threat-induced frontal
alpha asymmetry. Relatively increased right frontal
activity, as indicated by increased frontal alpha
asymmetry, has been associated with vigilance to
Figure 1. The experimental design. (a) The Executive-RT test (RT = reaction time; Hartikainen et al., 2010). At the onset of
each trial a triangle was presented pointing either up or down, and, relying on their working memory, subjects needed to
report the orientation of the previously presented triangle by pressing one of two buttons in case of a go-signal, the
traffic light, presented at 300 ms. The color of the traffic light was a go or a no-go signal indicating whether the subject
was supposed to respond or withhold from responding. In the middle of the traffic light an irrelevant emotional or
emotionally neutral line-drawing was presented. This distractor was either a spider-like shape conveying negative threat-
related information or an emotionally neutral nonthreatening figure as a control. The elements composing the distractors
were identical to one another, and only the configuration of the figure differed. This allows for efficient control of low-
level visual attributes such as color, brightness, contrast, and so on (Vuilleumier & Schwartz, 2001). The duration of one
trial was 2 s. (b) The stimulation protocol. Vagus nerve stimulation (VNS) status (ON and OFF) was counterbalanced, with
10 subjects beginning the task with cyclic VNS ON and the remaining 10 beginning the task with VNS OFF. Each VNS
segment started with a four-minute resting state and then four blocks of behavioral testing, where each block of test
contained sixty-four 2-s trials. To view a color version of this figure, please see the online issue of the Journal.
2L. SUN ET AL.

threat (Perez-Edgar, Kujawa, Nelson, Cole, &
Zapp, 2013).
In summary, we expected that if VNS has
immediate effects on cognitive or emotional brain
functions, these would be reflected in cognitive
performance, emotional interference, and/or fron-
tal alpha asymmetry. Furthermore, comparing N1
amplitude to targets when VNS is on to when it is
off allows evaluating potential impact of VNS on
attentional processes.
Method
Subjects
Twenty patients (12 male and 8 female;
45 ± 13 years old) treated with VNS due to refrac-
tory epilepsy participated in this study (Table 1).
VNS Therapy® System (Cyberonics, Inc.) was
implanted by neurosurgeons at the Tampere
University hospital. The implanted VNS device
consists of a helical bipolar electrode surrounding
the left cervical vagus nerve and a programmable
pulse generator at the upper left chest. The ther-
apeutic goal of VNS is to control seizure frequency
and improve general well-being. Stimulation para-
meters used for clinical treatment are adjusted and
optimized by neurologists from the hospital.
Table 1 summarizes the medical information of
the subjects, including medication, type of epilepsy,
and scores of Beck’s Depression Inventory (BDI).
We used a within-subject study design in this rather
heterogeneous clinical population in order to con-
trol for several potential factors influencing cogni-
tion and emotion–attention interaction such as
antiepileptic medication and depression.
Furthermore, we excluded subjects with poor cog-
nitive performance. Three subjects with poor cog-
nitive performance (total error rate over 15%) in the
computer-based test of executive functions were
excluded from the data analysis. Especially topira-
mate is linked with adverse cognitive effects (Javed
et al., 2015). Two patients used topiramate, and the
other one of these subjects was excluded due to
poor cognitive performance. None of the subjects
suffered from moderate or severe depression. Out of
the subjects that were included in the analysis, five
had mild depression, and 12 had no or minimal
depression at the time of testing based on the BDI
score.
All patients provided their written consent for
participation. The study was approved by the
regional ethical committee of Tampere University
Hospital, Tampere, Finland and was conducted in
accordance with the guidelines set forth in the
Declaration of Helsinki governing the treatment
of human subjects.
Experimental design
The Executive-RT test
Subjects performed a computer-based Executive-RT
test (Figure 1a) as described in our previous studies
Table 1. Medical information of the subjects.
Patient ID
Age at
diagnosis
(years)
Types of
epilepsy
Duration
of stimulation
(months)
BDI
score Medication
V01 25 Multifocal 6 5 Levetiracetam, oxcarbazepine, zonisamide
V02 22 Temporal 5 15 Escitalopram, lamotrigine, lacosamide, zonisamide
V03 17 Frontal 100 0 Levetiracetam, oxcarbazepine, lacosamide, zonisamide
V04
a
3 Multifocal 104 8 Valproic acid, vigabatrin, topiramate, olanzapine
V05 9 Parietal 82 14 Lamotrigine, zonisamide
V06 5 Temporal 4 11 Escitalopram, clobazam, carbamazepine, lacosamide
V07
a
25 Multifocal 99 0 Quetiapine, lamotrigine, mirtazapine, lacosamide, zonisamide
V08 1 Multifocal 108 0 Perampanel, lacosamide
V09 8 Temporal 4 6 Valproic acid, levetiracetam, lamotrigine, zonisamide
V10 1 Temporal 52 4 Pregabalin, lacosamide, eslicarbazepine acetate
V11
b
19 Temporal 86 7 Carbamazepine, zonisamide
V12
a
2 Multifocal 109 19 Gabapentin, lacosamide
V13 16 Multifocal 51 17 Clobazam, lamotrigine, zonisamide
V14 13 Fronto-temporal 61 4 Carbamazepine, lacosamide, pregabalin, perampanel
V15 9 Multifocal 38 10 Topiramate, valproic acid, clobazam
V16 18 Fronto-temporal 4 0 Carbamazepine, clobazam
V17 46 Temporal 63 4 Oxcarbazepine
V18 20 Fronto-parietal 2 18 Lamotrigine, valproic acid, perampanel, clobazam
V19 27 Multifocal 5 10 Levetiracetam, oxcarbazepine
V20 50 Unknown 130 16 Oxcarbazepine, clonazepam, levetiracetam, gabitril
Note. BDI = Beck Depression Inventory, with raw scores of 0–13 indicating no or minimal depression, 14–19 indicating mild depression.
a
Subjects excluded in all data analysis.
b
Excluded in the event-related potential data analysis.
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 3

(Hartikainen et al., 2014;Sunetal.,2015). The
participants had to store the orientation of the
triangle in their working memory and press the
corresponding button after the go signal while with-
holding from responding after a no-go signal. The
go or no-go signals were alternated so that in half of
the trials a green traffic light was a go signal, and in
half of the trials a red light was a go signal.
Within the test, orientations of the triangles,
sequence of go/no-go signals, and types of distractors
were all randomized. The behavioral test was pre-
sented and data collected with Presentation software
(Neurobehavioral System, Inc. Berkeley, CA, USA).
The patients were required to respond as fast and
accurately as possible. Behavioral outcome of the
Executive-RT test includes reaction times to different
stimuli and three error types—that is, incorrect but-
ton presses (in go trials), misses (no button press in
go trials), and commission errors (any button press
in no-go trials). In general, incorrect button presses
in go trials reflect lapses in working memory perfor-
mance, a miss signifies a failure to initiate a response
within given time and commission error in no-go
trials a failure in response inhibition.
The stimulation protocol
During the experiment, VNS ON refers to VNS
cycling with stimulation on for 30 s and off for
48 s, ensuring two duty cycles with stimulation in
each ON block of behavioral testing. When stimula-
tion was turned ON the output current was set to
1.5–1.75 mA depending on the subjects’tolerance.
If the subjects’clinical tolerance was higher than
1.75 mA, we used 1.75 mA. If their clinical tolerance
was lower than 1.75 mA, we used their clinically
used current. This approach—that is, the current is
the same as the subject’s clinical setting or less—
ensured that subjects would not have inconvenience
during the experiment that could affect their per-
formance. When VNS was OFF the current was set
to 0 mA. The stimulation frequency was 30 Hz and
pulse width 250 µs. Every time when VNS stimula-
tor status was changed there was a resting period
before the test was continued to allow for sensory
habituation (Figure 1b). In light of the potential
sensory reactions due to VNS, the study is not
eligible for blind design.
Analysis of EEG
EEG was recorded during the Executive-RT test
with actiCAP silver/silver chloride (Ag/AgCl)
electrodes and the 64-channel QuickAmp amplifier
(Brain Products GmbH, Gilching, Germany) and
was digitized at 500-Hz sampling rate. Impedance
of all electrodes was kept below 5 kΩduring the
recording. Offline EEG data were analyzed with
Brain Vision Analyzer2 software (Brain Products
GmbH, Germany). Initial processing of EEG data
included downsampling to 250 Hz and ocular
movement correction using the ICA (independent
component analysis) ocular correction function,
where one or two ICA components representing
ocular movement artifact were removed.
In the analysis of parietal-occipital N1 potential,
EEG signal was re-referenced to linked earlobe
reference. EEG signal was band-pass filtered at
0.1–30 Hz and was segmented into 1000-ms seg-
ments starting 200 ms before the onset of each
trial. Segments were baseline-corrected and then
subjected for artifact rejection where any segment
with amplitude exceeding ±80 µV was rejected.
The remaining segments were averaged to yield
the ERP (event-related potential) waveform. N1
was defined as the negative peak detected between
150 and 250 ms after trial onset in the parieto-
occipital region (electrodes P1, Pz, P2, PO1, POz,
PO2, O1, Oz, and O2). Peak amplitude of N1
component was exported for statistical analysis.
One subject was excluded due to epileptiform
activity leading to excessive artifacts and unidenti-
fiable ERPs.
In the analysis of frontal alpha asymmetry,
EEG signal was re-referenced to Cz electrode.
After band-pass filtering at 3–30 Hz, EEG signal
was segmented into 2000-ms segments starting
from the onset of each trial. Then the segments
were subjected to artifact rejection where any
segment with amplitude exceeding ±80 µV was
rejected. The remaining segments were applied
fast Fourier transform (FFT) to calculate the
power spectrum (µV
2
Hz
–1
), which was aver-
aged. Finally, the alpha (8–13 Hz) power was
analyzed at EEG electrodes F3 and F4 typically
used for assessing effects related to affect and
motivation (Davidson, 1995). Alpha power was
log-transformed, and the asymmetry was calcu-
lated by subtracting the log-transformed alpha
power at F4 by those at F3.
Statistical analysis
RTs, ERPs, and the frontal alpha asymmetry were
analyzed using repeated measures analysis of
4L. SUN ET AL.

variance (ANOVA). In the analysis of reaction
time, VNS status (ON vs. OFF) and emotional
valence (negative vs. neutral) were used as factors.
In the analysis of N1 amplitude and the frontal
alpha asymmetry, VNS status, emotional valence,
and response types (go vs. no-go) were used as
factors. Interaction effects were followed by further
post hoc analysis.
All data analyzed with repeated measures
ANOVA were checked for normality and trans-
formed if necessary. RTs were skewed to the right
and thus log-transformed. N1 amplitudes were nor-
mally distributed and did not need transformation.
Frontal alpha asymmetry data were not normally
distributed and were transformed by subtracting
personal mean from each data point, thus shifting
the personal mean of all subjects to zero.
Errors were analyzed using a generalized mixed
effects logistic regression model. Separate models
were made for each error type predicting probabil-
ity to make an error of a given type using subject,
VNS status, and emotional valence as predictors.
Subject was a random effect, while VNS status and
emotional valence were fixed effects. Trial outcomes
were dichotomized into either “error”or “other”
classes. In the incorrect button press model,
“error”class included incorrect button presses, and
“other”class included correct and missing button
presses. In the missing response model, “error”
included missing button presses, and “other”class
included correct and incorrect button presses. In
the commission error model, “error”class included
any button presses during no-go trials, and “other”
class included no response cases that were correct
responses in no-go trials.
All statistical analysis was done using R statistics
(Version 3.1.1., the R Foundation for Statistical
Computing). Repeated measures ANOVA was
done using ez package (Version 4.2–2) and regres-
sion analysis using lme4 package (Version 1.1–10).
Results
VNS, working memory, and visual attention
Subjects were required to hold the orientation of
the triangle in working memory and indicate the
orientation of the triangle by pressing the correct
button after a go signal. Analysis of incorrect but-
ton presses revealed a main effect of VNS status,
where cyclic VNS ON reduced the probability of
making such errors, odds ratio (OR) = 0.63 (95%
confidence interval, CI [0.47, 0.85]) (Figure 2a). In
addition to improved cognitive performance,
increase in N1 event-related brain potential ampli-
tude to targets over the parieto-occipital region
was observed, F(1, 15) = 10.17, p= .006,
η
2G
= .01 (Figures 2b and 2c). VNS status had no
effect on other error types. Emotional valence of
the distractor had no effect on any errors.
VNS and emotional reactivity
Analysis of RTs revealed an interaction between
VNS status and emotional valence, F(1, 16) = 5.15,
p= .04. Post hoc analysis revealed that cyclic VNS
ON led to increased RTs only when there were
negative threat-related distractors, F(1, 16) = 8.23,
p= .019, η
2G
= .004 (Figure 3a). VNS status had no
effect on RTs in the context of neutral distractors,
F(1, 16) = 0.48, p= .50.
We also investigated the impact of VNS on the
task-related frontal alpha asymmetry in the context
of negative threat-related and neutral non-threat-
related distractor. There was a main effect of VNS
status, F(1, 16) = 7.37, p= .02, η
2G
= .17, where
VNS increased frontal alpha asymmetry (cyclic
VNS ON −0.082 ± 0.33, VNS OFF
−0.055 ± 0.35). There was also an interaction
between VNS status and emotional valence, F(1,
16) = 7.13, p= .02. Post hoc analysis revealed that
cyclic VNS ON increased frontal alpha asymmetry
only when there were negative threat-related dis-
tractors, F(1, 16) = 11.79, p= .003, η
2G
= .35.
(Figure 3b). VNS status did not affect frontal
alpha asymmetry with neutral nonthreatening dis-
tractors, F(1, 16) = 0.54, p= .47.
In order to assess potential impact of depression
underlying the emotion-related effects of VNS, we
conducted separate subgroup analysis on the sub-
jects with BDI scores lower than 13 (no or minimal
depression) and those higher than 13 (mild depres-
sion). Similar to the results obtained from the
whole group analysis, the subgroup analysis of
the 12 subjects with no or minimal depression
resulted in an interaction between VNS status
and emotional valence, F(1, 11) = 5.26, p= .004,
for frontal alpha-asymmetry. Post hoc analysis
revealed that cyclic VNS ON increased frontal
alpha asymmetry only when there were negative
threat-related distractors, F(1, 11) = 5.55, p= .04,
η
2G
= .29, but not when there were neutral dis-
tractors, F(1, 11) = 0.002, p= .97. We conducted a
separate analysis for the subgroup of five subjects
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 5

Figure 3. Vagus nerve stimulation (VNS) increased threat-related behavioral and brain responses. (a) In trials with
emotionally negative threat-related distractors, VNS increased reaction times compared to when VNS was turned off.
VNS status had no effect on reaction times in trials with neutral distractors. (b) VNS increased frontal alpha asymmetry
when there were emotionally negative threat-related distractors but not when there were neutral distractors. Error bar
indicates Fisher’s least significant difference Significance indicators: p< .05 (*), p< 0.01 (**), not significant (n.s.).
Figure 2. Vagus nerve stimulation (VNS) improved working memory performance and enhanced visual attention. (a)
When cyclic VNS was ON, subjects made fewer errors in a subtask that depended on working memory performance—that
is, in responding whether a previously presented triangle was up or down. Also, VNS increased parieto-occipital N1
amplitude. (b) Grand average event-related potentials (ERPs) over the parieto-occipital brain region (covering electrodes
P1, Pz, P2, PO1, POz, PO2, O1, Oz, and O2). (c) VNS difference waveform VNS ON –VNS OFF illustrates the topography of
the increased negativity during N1 time window (150–250 ms) due to VNS. Significance indicators: p< .01 (**).01. To view
a color version of this figure, please see the online issue of the Journal.
6L. SUN ET AL.

with higher than 13 BDI score. The interaction
effect did not reach significance, but analyzing
separately the impact of VNS stimulation on nega-
tive and neutral distractors, a similar significant
result was found as for the whole group and for
the nondepressed subgroup analysis. Cyclic VNS
ON increased frontal alpha asymmetry only when
there were negative threat-related distractors, F(1,
4) = 13.66, p= .002, η
2G
= .54, and not when there
were emotionally neutral distractors, F(1, 4) = 1.70,
p= .26. For RTs there were no significant results
for either subgroup analysis.
Discussion
To our knowledge this is the first study to show
immediate improvement of working memory per-
formance with VNS stimulation in humans.
Subjects made fewer errors on a subtask that relied
on working memory when cyclic VNS was turned
on than when it was turned off. Improved working
memory performance lays the foundation for bet-
ter cognitive performance in general.
The current results provide evidence for the
beneficial cognitive effects of VNS in treatment of
epilepsy patients whose cognitive performance
may be otherwise compromised due to epilepsy
or antiepileptic drugs. However, the patients ana-
lyzed in the current study were able to perform a
rather demanding cognitive task, tapping into
attention and executive function, at a high level,
indicating relatively intact cognition. Three of the
subjects with poor performance suggesting com-
promised cognitive functioning were excluded
from the analysis. Thus, with results obtained
from patients with good cognitive performance
these results are not limited only to patients with
epilepsy but may be generalizable to other subjects
as well.
VNS increased early visual N1 amplitude similar to
what is seen with increased level of attention (Luck &
Ford, 1998;Mangun&Hillyard,1991). Our findings
suggest that attentional mechanisms might contribute
to improved working memory performance due to
VNS. Attention allows for selecting information for
further processing while working memory allows for
information to be kept in an accessible state. Attention
and working memory are interacting constructs and
tightly intertwined, attention providing the basis for
selecting what information will be encoded in working
memory (Awh, Vogel, & Oh, 2006). Along with this
electrophysiological attention-related brain response,
the performance of the subjects improved in a task
where subjects were supposed to indicate the orienta-
tion of a previously presented triangle by a corre-
sponding button press. Greater N1 in response to
triangles, whose orientation was maintained in work-
ing memory, suggests deeper processing and better
fidelity of information encoding into working mem-
ory. In other words, improved selective attention
allows for better working memory performance.
General level of attention and performance remained
unchanged with no other performance measures
showing impact of VNS such as reaction times, miss-
ing responses, or commission errors. With improved
general attention or higher arousal levels, one might
expect speeded reaction times or overall improvement
in performance. However, specific improvement of
working memory performance along with electrophy-
siological markers suggesting greater attention to tar-
gets encoded into working memory was observed due
to VNS.
Besides the cognitive modulation of VNS, emo-
tional effects were observed. When VNS was on,
task-irrelevant threat-related distractors slowed
reaction times and increased frontal alpha asym-
metry in comparison to when stimulation was
turned off. There seemed to be an increased vigi-
lance to threat-related stimuli as an immediate
effect of VNS stimulation. Whether emotional dis-
tractors have an impact on performance and on
brain responses depends on several factors includ-
ing task and subject-related factors (Hartikainen,
Ogawa, & Knight, 2000,2010; Hartikainen, Ogawa,
Soltani, & Knight, 2007; Hartikainen, Siiskonen, &
Ogawa, 2012; Mäki-Marttunen et al., 2014).
Subject-related factors include mood, with depres-
sion and anxiety typically increasing attention allo-
cation to threat (Bishop, 2008; Dalgleish & Watts,
1990; MacLeod & Mathews, 1988). Increased
attention allocation to threat is also seen in patient
groups with predisposition to depression such as
mild head injury (Mäki-Marttunen et al., 2015),
patients with orbitofrontal injury (Mäki-
Marttunen et al., 2017), and epilepsy patients trea-
ted with deep brain stimulation (Hartikainen et al.,
2014; Sun et al., 2015). In the current study, 12
subjects had no or minimal depression, and five
subjects had mild depression based on BDI. We
made additional subgroup analysis that revealed
that the impact of VNS on emotion–attention
interaction was not driven by subjects with symp-
toms of depression. Furthermore, when comparing
immediate effects of cyclic VNS stimulation, the
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 7

mood can be controlled for, as it is likely to remain
relatively stable over the short time periods of
stimulation on and off and thus should cancel
out in within-subject design.
The increased vigilance to threat as seen in
greater impact of threat-related distractors on
behavior and brain responses may seem paradox-
ical to the use of VNS in treatment of depression.
Greater attention to threat is a hallmark of anxiety
(Kindt & Van Den Hout, 2001). Meanwhile, both
depression and anxiety are linked with dysregula-
tion of NE (Goddard et al., 2010), and VNS is
thought to modulate NE levels in the brain
(Roosevelt, Smith, Clough, Jensen, & Browning,
2006). NE is known to have both anxiolytic and
anxiogenic effects depending on several factors
including the time course (Goddard et al., 2010).
Thus, the time course of NE release and VNS
stimulation, whether short term or chronic, is
likely to be critical on the neuromodulatory impact
of VNS on emotional responses and mood. While
the relationship between the immediate effects of
VNS observed in the current study and the
mechanism of VNS alleviating depression remains
speculatory, the observed effects may provide
objective biomarkers of VNS’s effect on emotion
system that could be used in future studies linking
effects of VNS on emotional processes and mood.
The current study shows that VNS has instant
and direct effects on human cognitive and affective
brain functions. These immediate effects on
human working memory performance and brain’s
affective responses are probably linked to increased
brain level of NE due to VNS (Vonck et al., 2014).
It has been previously shown that VNS stimulation
activates neurons in the LC and increases NE levels
in neocortex, hippocampus, amygdala, and other
parts of the brain with efferent projections from
LC (Hassert, Miyashita, & Williams, 2004; Raedt
et al., 2011). According to the adaptive gain theory
by Aston-Jones & Cohen (2005), LC is normally
driven by the utility assessment function processed
in the orbitofrontal cortex and the anterior cingu-
late cortex, which have direct connections to LC.
The outcome of the utility assessment drives pha-
sic firing of LC neurons increasing its instanta-
neous norepinephrine production, thus
improving task performance (Aston-Jones &
Cohen, 2005). In rats’brains, high-density VNS
(1 mA) leads to transient increase of NE in both
cortical and limbic brain areas in comparison to
the baseline NE level—that is, the level of NE when
VNS was off (Roosevelt et al., 2006). Increased NE
level in the hippocampus is reported to facilitate
long-term potentiation, which facilitates memory
formation (O’Dell, Connor, Guglietta, & Nguyen,
2015). NE is also implicated in arousal-related
emotional memory and working memory func-
tions (Chamberlain, Muller, Blackwell, Robbins,
& Sahakian, 2006). In line with our current find-
ings of VNS improving working memory, moder-
ate levels of NE may improve cognitive functions
dependent on prefrontal networks such as working
memory (Chamberlain et al., 2006). Increased NE
level has been linked with increase in the amygdala
activation while processing emotional pictures
(Chamberlain et al., 2006; Van Stegeren, 2008).
Increased amygdala activation may be one of the
mechanisms of increased vigilance to threat due to
VNS as observed in the current study.
Compared to previous studies, the current study
on immediate effects of VNS on human executive
functions holds methodological merits. Firstly,
immediate comparison between stimulation ON
and OFF allowed for controlling potential con-
founding factors including chronic effects of med-
ication or alterations in seizure burden. Therefore,
any observed difference can be attributed to the
immediate and direct effect of VNS on cognitive
and affective brain functions. Secondly, we used a
relatively sensitive behavioral task—that is, the
Executive-RT test—which mimics everyday situa-
tions and engages several executive functions
including working memory and emotional control
(Hartikainen, Wäljas, et al., 2010). Combination of
EEG measurement and a computer-based cogni-
tive test with rapid presentation of stimuli along
with challenging task allows for good control over
general level of attention, making it feasible to
repeat the test over several cycles of stimulation
on and off, thus providing a sensitive and reliable
method for assessing the immediate effects of neu-
romodulation on brain functions (Hartikainen
et al., 2014; Sun et al., 2016; Sun et al., 2015).
Third, using clinically relevant VNS parameters
in the current study extends the impact of the
current findings beyond theoretical interest. In
contrary, previous findings reporting direct bene-
ficial effects of VNS on cognition used relatively
lower current not commonly used in clinical treat-
ment, and timing of VNS was linked to a specific
phase of cognitive task (Clark et al., 1999), which
in real-life setting is not feasible. Furthermore,
although subjects were not completely blinded to
8L. SUN ET AL.

VNS settings, any modulatory effect between ON
and OFF conditions reflects the real-life effects of
VNS. With vulnerable cognitive functions in these
patients and with other treatments such as antie-
pileptic drugs frequently associated with compro-
mised cognitive functions, evidence for positive
effect of VNS on cognition is of significant clinical
importance. It is also noteworthy that these cogni-
tive benefits are immediate to the stimulation and
can be dissociated from the long-term chronic
effects depending on multiple factors and often
linked with plasticity. Additional relevance of the
current findings relates to generalizability of the
results to the actual clinical population using VNS
as their treatment for epilepsy since the results are
obtained from a rather heterogeneous group of
patients in regard to a variety of factors including
medication and type of epilepsy. Subgroup analysis
further supported fairly robust effects.
In conclusion, we found that VNS has immediate
and direct beneficial effects on human cognition.
The use of clinically relevant VNS settings in this
study extends the impact of these findings beyond
theoretical interest. VNS increased early visual brain
responses similar to enhanced attention and
improved working memory performance. In addi-
tion to showing immediate beneficial effects of VNS
on cognition in epilepsy patients, whose cognition
may be slightly compromised due to antiepileptic
drugs or the brain pathology related to epilepsy,
beneficial effect of VNS on cognition might not be
limited to patients with epilepsy. To that end, these
findings call for future research on the potential
benefit of VNS on cognitive enhancement or as a
clinical intervention in cognitive dysfunction or
attentional deficits in other patient groups.
Disclosure statement
No potential conflict of interest was reported by the
authors.
Funding
This work was supported by the Academy of Finland
and the Competitive Research Fund of Pirkanmaa
Hospital District.
References
Aston-Jones, G., & Cohen, J. D. (2005). An integrative
theory of locus coeruleus-norepinephrine function:
Adaptive gain and optimal performance. Annual
Review of Neuroscience,28, 403–450. doi:10.1146/
annurev.neuro.28.061604.135709
Aston-Jones, G., Shipley, M. T., Chouvet, G., Ennis, M.,
van Bockstaele, E., Pieribone, V., . . . Charlety, P.
(1991). Afferent regulation of locus coeruleus neu-
rons: Anatomy, physiology and pharmacology.
Progress in Brain Research,88,47–75. Retrieved
from http://www.ncbi.nlm.nih.gov/pubmed/1687622
Awh, E., Vogel, E. K., & Oh, S. H. (2006). Interactions
between attention and working memory.
Neuroscience,139(1), 201–208. doi:10.1016/j.
neuroscience.2005.08.023
Ben-Menachem, E., Manon-Espaillat, R., Ristanovic, R.,
Wilder, B. J., Stefan, H., Mirza, W., . . . Wernicke, J. F.
(1994). Vagus nerve stimulation for treatment of par-
tial seizures: 1. A controlled study of effect on sei-
zures. First international vagus nerve stimulation
study group. Epilepsia,35(3), 616–626. doi:10.1111/
epi.1994.35.issue-3
Bishop, S. J. (2008). Neural mechanisms underlying
selective attention to threat. Annals of the New York
Academy of Sciences,1129, 141–152. doi:10.1196/
annals.1417.016
Chamberlain, S. R., Muller, U., Blackwell, A. D., Robbins,
T. W., & Sahakian, B. J. (2006). Noradrenergic mod-
ulation of working memory and emotional memory in
humans. Psychopharmacology (Berl),188(4), 397–407.
doi:10.1007/s00213-006-0391-6
Clark, K. B., Krahl, S. E., Smith, D. C., & Jensen, R. A.
(1995). Post-training unilateral vagal stimulation
enhances retention performance in the rat.
Neurobiology of Learning and Memory,63(3), 213–
216. doi:10.1006/nlme.1995.1024
Clark, K. B., Naritoku, D. K., Smith, D. C., Browning, R.
A., & Jensen, R. A. (1999). Enhanced recognition
memory following vagus nerve stimulation in
human subjects. Nature Neuroscience,2(1), 94–98.
doi:10.1038/4600
Dalgleish, T., & Watts, F. N. (1990). Biases of attention
and memory in disorders of anxiety and depression.
Clinical Psychology Review,10(5), 589–604.
doi:10.1016/0272-7358(90)90098-U
Davidson, R. J. (1995). Cerebral asymmetry, emotion,
and affective style. Brain asymmetry (pp. 361–387).
Canmbridge, MA: MIT.
Dodrill, C. B., & Morris, G. L. (2001). Effects of vagal
nerve stimulation on cognition and quality of life in
epilepsy. Epilepsy & Behavior: E&B,2(1), 46–53.
doi:10.1006/ebeh.2000.0148
Elger, G., Hoppe, C., Falkai, P., Rush, A. J., & Elger, C.
E. (2000). Vagus nerve stimulation is associated with
mood improvements in epilepsy patients. Epilepsy
Research,42(2–3), 203–210. doi:10.1016/S0920-1211
(00)00181-9
Goddard, A. W., Ball, S. G., Martinez, J., Robinson, M.
J., Yang, C. R., Russell, J. M., & Shekhar, A. (2010).
Current perspectives of the roles of the central nor-
epinephrine system in anxiety and depression.
Depression and Anxiety,27(4), 339–350. doi:10.1002/
da.20642
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 9

Grimonprez, A., Raedt, R., Baeken, C., Boon, P., &
Vonck, K. (2015). The antidepressant mechanism of
action of vagus nerve stimulation: Evidence from
preclinical studies. Neuroscience & Biobehavioral
Reviews,56,26–34. doi:10.1016/j.
neubiorev.2015.06.019
Grimonprez, A., Raedt, R., Portelli, J., Dauwe, I., Larsen,
L. E., Bouckaert, C., . . . Vonck, K. (2015). The anti-
depressant-like effect of vagus nerve stimulation is
mediated through the locus coeruleus. Journal of
Psychiatric Research,68,1–7. doi:10.1016/j.
jpsychires.2015.05.002
Hartikainen, K. M., Ogawa, K. H., & Knight, R. T.
(2000). Transient interference of right hemispheric
function due to automatic emotional processing.
Neuropsychologia,38(12), 1576–1580. doi:10.1016/
S0028-3932(00)00072-5
Hartikainen, K. M., Ogawa, K. H., & Knight, R. T.
(2010). Trees over forest: Unpleasant stimuli compete
for attention with global features. Neuroreport,21(5),
344–348. doi:10.1097/WNR.0b013e328336eeb3
Hartikainen, K. M., Ogawa, K. H., Soltani, M., & Knight,
R. T. (2007). Emotionally arousing stimuli compete
for attention with left hemispace. Neuroreport,18(18),
1929–1933. doi:10.1097/WNR.0b013e3282f1ca18
Hartikainen, K. M., Siiskonen, A. R., & Ogawa, K. H.
(2012). Threat interferes with response inhibition.
Neuroreport,23(7), 447–450. doi:10.1097/
WNR.0b013e3283531e74
Hartikainen, K. M., Sun, L., Polvivaara, M., Brause, M.,
Lehtimäki, K., Haapasalo, J., . . . Peltola, J. (2014).
Immediate effects of deep brain stimulation of ante-
rior thalamic nuclei on executive functions and emo-
tion-attention interaction in humans. Journal of
Clinical and Experimental Neuropsychology,36(5),
540–550. doi:10.1080/13803395.2014.913554
Hartikainen, K. M., Wäljas, M., Isoviita, T., Dastidar, P.,
Liimatainen, S., Solbakk, A.-K., . . . Öhman, J. (2010).
Persistent symptoms in mild to moderate traumatic
brain injury associated with executive dysfunction.
Journal of Clinical and Experimental
Neuropsychology,32(7), 767–774. doi:10.1080/
13803390903521000
Hassert, D. L., Miyashita, T., & Williams, C. L. (2004).
The effects of peripheral vagal nerve stimulation at a
memory-modulating intensity on norepinephrine
output in the basolateral amygdala. Behavioral
Neuroscience,118(1), 79–88. doi:10.1037/0735-
7044.118.1.79
Javed, A., Cohen, B., Detyniecki, K., Hirsch, L. J., Legge,
A., Chen, B., . . . Choi, H. (2015). Rates and predictors
of patient-reported cognitive side effects of antiepi-
leptic drugs: An extended follow-up. Seizure: The
Journal of the British Epilepsy Association,29,34–40.
doi:10.1016/j.seizure.2015.03.013
Kalia, M., & Sullivan, J. M. (1982). Brainstem projections
of sensory and motor components of the vagus nerve in
the rat. The Journal of Comparative Neurology,211(3),
248–264. doi:10.1002/cne.902110304
Kindt, M., & Van Den Hout, M. (2001). Selective atten-
tion and anxiety: A perspective on developmental
issues and the causal status. Journal of
Psychopathology and Behavioral Assessment,23(3),
193–202. doi:10.1023/A:1010921405496
Klinkenberg, S., Majoie, H. J., van der Heijden, M. M.,
Rijkers, K., Leenen, L., & Aldenkamp, A. P. (2012).
Vagus nerve stimulation has a positive effect on
mood in patients with refractory epilepsy. Clinical
Neurology and Neurosurgery,114(4), 336–340.
doi:10.1016/j.clineuro.2011.11.016
Liimatainen, J., Perakyla, J., Jarvela, K., Sisto, T., Yli-
Hankala, A., & Hartikainen, K. M. (2016). Improved
cognitive flexibility after aortic valve replacement sur-
gery. Interact Cardiovasc Thorac Surg,23, 630–636.
doi:10.1093/icvts/ivw170
Luck, S. J., & Ford, M. A. (1998). On the role of selective
attention in visual perception. Proceedings of the
National Academy of Sciences of the United States of
America,95(3), 825–830. doi:10.1073/pnas.95.3.825
MacLeod, C., & Mathews, A. (1988). Anxiety and the
allocation of attention to threat. The Quarterly
Journal of Experimental Psychology,40(4), 653–670.
doi:10.1080/14640748808402292
Mangun, G. R., & Hillyard, S. A. (1991). Modulations of
sensory-evoked brain potentials indicate changes in
perceptual processing during visual-spatial priming.
Journal of Experimental Psychology. Human
Perception and Performance,17(4), 1057–1074.
doi:10.1037/0096-1523.17.4.1057
Marangell, L. B., Rush, A. J., George, M. S., Sackeim, H.
A., Johnson, C. R., Husain, M. M., . . . Lisanby, S. H.
(2002). Vagus nerve stimulation (VNS) for major
depressive episodes: One year outcomes. Biological
Psychiatry,51(4), 280–287. doi:10.1016/S0006-3223
(01)01343-9
McGlone, J., Valdivia, I., Penner, M., Williams, J.,
Sadler, R. M., & Clarke, D. B. (2008). Quality of life
and memory after vagus nerve stimulator implanta-
tion for epilepsy. The Canadian Journal of
Neurological Sciences,35(3), 287–296. doi:10.1017/
S0317167100008854
Merrill, C. A., Jonsson, M. A., Minthon, L., Ejnell, H.,
Hans, C., Blennow, K., . .. Sjogren, M. J. (2006). Vagus
nerve stimulation in patients with Alzheimer’s disease:
Additional follow-up results of a pilot study through 1
year. The Journal of Clinical Psychiatry,67(8), 1171–
1178. doi:10.4088/JCP.v67n0801
Mäki-Marttunen, V., Kuusinen, V., Brause, M.,
Peräkylä, J., Polvivaara, M., Dos Santos Ribeiro, R.,
. . . Hartikainen, K. M. (2015). Enhanced attention
capture by emotional stimuli in mild traumatic
brain injury. Journal of Neurotrauma,32(4), 272–
279. doi:10.1089/neu.2014.3557
Mäki-Marttunen, V., Kuusinen, V., Perakyla, J., Ogawa,
K., Brause, M., Brander, A., & Hartikainen, K. (2017).
Greater attention to task-relevant threat due to orbi-
tofrontal lesion. Journal of Neurotrauma, 34(2), 400-
413. doi:10.1089/neu.2015.4390
Mäki-Marttunen, V., Pickard, N., Solbakk, A. K.,
Ogawa, K. H., Knight, R. T., & Hartikainen, K. M.
(2014). Low attentional engagement makes attention
network activity susceptible to emotional
10 L. SUN ET AL.

interference. Neuroreport,25(13), 1038–1043.
doi:10.1097/WNR.0000000000000223
O’Dell, T. J., Connor, S. A., Guglietta, R., & Nguyen, P.
V. (2015). beta-Adrenergic receptor signaling and
modulation of long-term potentiation in the mamma-
lian hippocampus. Learning & Memory (Cold Spring
Harbor, N.Y.),22(9), 461–471. doi:10.1101/
lm.031088.113
Penry, J. K., & Dean, J. C. (1990). Prevention of intract-
able partial seizures by intermittent vagal stimulation
in humans: Preliminary results. Epilepsia,31(Suppl
2), S40–43. doi:10.1111/j.1528-1157.1990.tb05848.x
Perez-Edgar, K., Kujawa, A., Nelson, S. K., Cole, C., &
Zapp, D. J. (2013). The relation between electroence-
phalogram asymmetry and attention biases to threat
at baseline and under stress. Brain and Cognition,82
(3), 337–343. doi:10.1016/j.bandc.2013.05.009
Raedt, R., Clinckers, R., Mollet, L., Vonck, K., El Tahry,
R., Wyckhuys, T., . . . Meurs, A. (2011). Increased
hippocampal noradrenaline is a biomarker for effi-
cacy of vagus nerve stimulation in a limbic seizure
model. Journal of Neurochemistry,117(3), 461–469.
doi:10.1111/j.1471-4159.2011.07214.x
Roosevelt, R. W., Smith, D. C., Clough, R. W., Jensen, R.
A., & Browning, R. A. (2006). Increased extracellular
concentrations of norepinephrine in cortex and hip-
pocampus following vagus nerve stimulation in the
rat. Brain Research,1119(1), 124–132. doi:10.1016/j.
brainres.2006.08.048
Rush, A. J., George, M. S., Sackeim, H. A., Marangell, L. B.,
Husain, M. M., Giller, C., ... Goodman, R. (2000).
Vagus nerve stimulation (VNS) for treatment-resistant
depressions: A multicenter study. Biological Psychiatry,
47(4), 276–286. doi:10.1016/S0006-3223(99)00304-2
Sackeim, H. A., Keilp, J. G., Rush, A. J., George, M. S.,
Marangell, L. B., Dormer, J. S., . . . Zboyan, H. (2001).
The effects of vagus nerve stimulation on cognitive
performance in patients with treatment-resistant
depression. Neuropsychiatry, Neuropsychology, and
Behavioral Neurology,14(1), 53–62. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/11234909
Sackeim, H. A., Rush, A. J., George, M. S., Marangell, L.
B., Husain, M. M., Nahas, Z., . . . Goodman, R. R.
(2001). Vagus nerve stimulation (VNS) for treat-
ment-resistant depression: Efficacy, side effects, and
predictors of outcome. Neuropsychopharmacology,25
(5), 713–728. doi:10.1016/S0893-133X(01)00271-8
Sjogren, M. J., Hellstrom, P. T., Jonsson, M. A.,
Runnerstam, M., Silander, H. C., & Ben-Menachem,
E. (2002). Cognition-enhancing effect of vagus nerve
stimulation in patients with Alzheimer’s disease: A
pilot study. The Journal of Clinical Psychiatry,63
(11), 972–980. doi:10.4088/JCP.v63n1103
Sun, L., Peräkylä, J., Polvivaara, M., Öhman, J., Peltola,
J., Lehtimäki, K., . . . Hartikainen, K. M. (2015).
Human anterior thalamic nuclei are involved in emo-
tion-attention interaction. Neuropsychologia,78,88–
94. doi:10.1016/j.neuropsychologia.2015.10.001
Sun, L., Peräkylä, J., Kovalainen, A., Ogawa, K. H.,
Karhunen, P. J., & Hartikainen, K. M. (2016).
Human brain reacts to transcranial extraocular light.
PLoS One,11(2), e0149525. doi:10.1371/journal.
pone.0149525
Van Bockstaele, E. J., Peoples, J., & Telegan, P. (1999).
Efferent projections of the nucleus of the solitary tract
to peri-locus coeruleus dendrites in rat brain:
Evidence for a monosynaptic pathway. The Journal
of Comparative Neurology,412(3), 410–428.
doi:10.1002/(ISSN)1096-9861
van Stegeren, A. H. (2008). The role of the noradrener-
gic system in emotional memory. Acta Psychologica,
127(3), 532–541. doi:10.1016/j.actpsy.2007.10.004
Vonck, K., Raedt, R., Naulaerts, J., De Vogelaere, F.,
Thiery, E., Van Roost, D., . . . Boon, P. (2014).
Vagus nerve stimulation25 years later! What do we
know about the effects on cognition? Neuroscience &
Biobehavioral Reviews,45,63–71. doi:10.1016/j.
neubiorev.2014.05.005
Vuilleumier, P., & Schwartz, S. (2001). Beware and be
aware: Capture of spatial attention by fear-related
stimuli in neglect. Neuroreport,12(6), 1119–1122.
doi:10.1097/00001756-200105080-00014
JOURNAL OF CLINICAL AND EXPERIMENTAL NEUROPSYCHOLOGY 11