ArticlePDF Available

Transcutaneous auricular vagus nerve stimulation enhances learning of novel letter-sound relationships in adults

Authors:
  • Spark Biomedical Inc.

Abstract and Figures

Background Reading is a critical skill in modern society but is significantly more difficult to acquire during adulthood. Many adults are required to learn a new orthography after this window closes for personal or vocational reasons and while many programs and training methods exist for learning to read in adulthood, none result in native-like fluency. Implantable cervical vagus nerve stimulation is capable of driving neural plasticity but is invasive and not practical as a reading intervention. Objective The goal of the current study was to evaluate whether non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) is effective at enhancing novel orthography acquisition in young adults. Methods We enrolled 37 typically developing participants and randomly assigned them to a computer control, device sham control, earlobe stimulation control, or experimental transcutaneous auricular stimulation (taVNS) group. Participants then learned novel letter-sound correspondences in Hebrew over five training lessons. Performance was assessed using three measures to evaluate various aspects of reading: Letter ID, Automaticity, and Decoding. Results The taVNS group significantly outperformed the three control groups on both the Automaticity and Decoding tasks. There was no difference on the Letter ID task. Conclusions These results demonstrate, for the first time, that taVNS is capable of improving aspects of reading acquisition in adults. These findings have potential implications for a wide range of cognitive tasks.
Content may be subject to copyright.
Transcutaneous auricular vagus nerve stimulation enhances learning
of novel letter-sound relationships in adults
Vishal J. Thakkar
a
, Abby S. Engelhart
a
, Navid Khodaparast
b
,
1
, Helen Abadzi
c
,
Tracy M. Centanni
a
,
*
a
Department of Psychology, Texas Christian University, Fort Worth, TX, 76129, USA
b
Nexeon MedSystems, Inc., Dallas, TX, 75231, USA
c
Department of Psychology, University of Texas Arlington, Arlington, TX, 76019, USA
article info
Article history:
Received 18 January 2020
Received in revised form
22 September 2020
Accepted 21 October 2020
Available online 27 October 2020
Keywords:
Plasticity
Reading
Automaticity
Decoding
Intervention
Fluency
abstract
Background: Reading is a critical skill in modern society but is signicantly more difcult to acquire
during adulthood. Many adults are required to learn a new orthography after this window closes for
personal or vocational reasons and while many programs and training methods exist for learning to read
in adulthood, none result in native-like uency. Implantable cervical vagus nerve stimulation is capable
of driving neural plasticity but is invasive and not practical as a reading intervention.
Objective: The goal of the current study was to evaluate whether non-invasive transcutaneous auricular
vagus nerve stimulation (taVNS) is effective at enhancing novel orthography acquisition in young adults.
Methods: We enrolled 37 typically developing participants and randomly assigned them to a computer
control, device sham control, earlobe stimulation control, or experimental transcutaneous auricular
stimulation (taVNS) group. Participants then learned novel letter-sound correspondences in Hebrew over
ve training lessons. Performance was assessed using three measures to evaluate various aspects of
reading: Letter ID, Automaticity, and Decoding.
Results: The taVNS group signicantly outperformed the three control groups on both the Automaticity
and Decoding tasks. There was no difference on the Letter ID task.
Conclusions: These results demonstrate, for the rst time, that taVNS is capable of improving aspects of
reading acquisition in adults. These ndings have potential implications for a wide range of cognitive
tasks.
©2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Introduction
Reading is a critical skill for modern life, as daily communication
relies on print. The development of the brains reading network is a
protracted process, requiring many years of practice, lasting into
early adulthood [1e3]. The sensitive period for reading closes
around the age of 18e19 [4,5], possibly due to the long trajectory for
reading network acquisition and the amount of practice needed to
achieve expertise. One marker of expertise is uency, the ability to
read and comprehend a word without decoding individual letters
[6,7]. Although adults learning to read in a novel orthography may
achieve a level of speed that allows for comprehension, they may
never achieve native-like uency. In spite of this obstacle, there are
many situations in which an adult may need to achieve native-like
uency in a new orthography. Some examples include business
professionals needing to review documents during international
meetings, subsequent generations of immigrant families wanting
to read historical scriptures, and military ofcers needing to
communicate with local residents during deployment and times of
critical events. Prior research on literacy programs suggests that
adults can learn to read when provided adequate training, but the
learning time is long and retention performance is poor [4,5]. It is
therefore clear that current behavioral programs are insufcient to
induce long-term uency. Thus, the goal of the current study was to
*Corresponding author. 2800 South University Drive, TCU Box 298920, Fort
Worth, TX, 76129, USA.
E-mail addresses: vishalthakkar0415@gmail.com (V.J. Thakkar), abby.mason@
tcu.edu (A.S. Engelhart), navid.khodaparast@sparkbiomedical.com
(N. Khodaparast), habadzi@gmail.com (H. Abadzi), tmcentanni@gmail.com
(T.M. Centanni).
1
Navid Khodaparasts current afliation is Spark Biomedical Inc. (18208 Preston
Road Ste D9-531, Dallas, TX 75252).
Contents lists available at ScienceDirect
Brain Stimulation
journal homepage: http://www.journals.elsevier.com/brain-stimulation
https://doi.org/10.1016/j.brs.2020.10.012
1935-861X/©2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/
).
Brain Stimulation 13 (2020) 1813e1820
evaluate a novel method for re-opening the brains sensitive win-
dow for orthography learning.
One established method involves stimulating the vagus nerve to
activate the nucleus tractus solitarius (NTS), which has projections
to the nucleus basalis (NB) and locus coeruleus (LC). Together, they
release key neurotransmitters important for driving brain plasticity
and learning and memory: acetylcholine [8] and norepinephrine
[9], respectively. In mice, stimulation of NE was found to aid in long
term potentiation for an extended period of time [10] and stimu-
lation of the LC aided rats in an auditory perception task [11].
Further, disruption of norepinephrine release in rats blocked plas-
ticity driven by vagus nerve stimulation (VNS) [12,13]. These re-
gions are also tied to learning in humans, as higher LC activation is
associated with improved memory on a delayed gratication task
[14]. VNS allows for targeted release of norepinephrine and
acetylcholine without invasive direct brain stimulation (i.e., deep
brain stimulation), providing easier access to this neural plasticity
mechanism in patient populations.
Cervical vagus nerve stimulation (cVNS) is FDA approved for the
treatment of epilepsy [15,16] and depression [17 ] and is in clinical
trials for stroke [18] and tinnitus [19 ]. This approach involves sur-
gically implanting a cuff electrode around the vagus nerve, located
in the neck, and a pulse generator positioned subcutaneously below
the clavicle or axilla. Pairing the timing of cVNS with an external
stimulus (e.g., sound or movement) drives long-lasting and
meaningful neural plasticity [20e22]. For example, cVNS paired
with a specic tone drives sensory plasticity in primary auditory
cortex (A1) of a rat, specic to the frequency of the paired tone [21].
This approach led to a novel tinnitus treatment, now in clinical
trials [19]. cVNS is also capable of driving plasticity in the motor
cortex when paired with specic movements both in the rat model
[23e25] and in clinical trials with patients experiencing upper limb
motor decits [18].
In the cognitive domain, cVNS, has increased performance on
tasks relying on working memory [26e28]. For example, delivering
cVNS after paragraph reading improved recognition of highlighted
words [26]. In another study, participants receiving cVNS had
decreased error rates during a delayed recall task [27]. cVNS also
improved performance on digit-symbol and verbal uency tasks
[28]. Together, results demonstrate that cVNS can increase perfor-
mance and decrease error rates in cognitive tasks, suggesting it may
also aid in other cognitive tasks, such as reading.
In spite of the success with cVNS, such an invasive and expensive
procedure is not a practical intervention for cognitive skills like
reading. The auricular branch of the vagus nerve (ABVN) projects to
the outer earand can be accessed at either the cymba conchae region
of the pinna [29e31] or the posterior surface of the tragus [32]. fMRI
studies have demonstrated that transcutaneous auricular vagus
nerve stimulation (taVNS) activates similar medullary and deep
brain structures as cVNS, without the need for an invasive surgery
[29,31]. Growing evidence suggests that taVNS may also provide a
comparable neural plasticity effect compared to cVNS. For example,
taVNS improved rehabilitation of post-stroke motor function re-
covery in humans [30] and increased performance on a memory task
in older adults [33]. Given the comparable success of taVNS and
cVNS on improving motor control after stroke and improving
cognitive tasks, we hypothesized that taVNS paired with training
would signicant improve orthography acquisition in ve days.
Methods
Participants
In total, 122 participants were screened for eligibility, with 37
participants meeting these criteria. To be eligible for the study,
participants needed to: (a) be a native English speaker, (b) be be-
tween the ages of 18 and 35, (c) achieve a standard score of 85 or
higher on the KBIT-2 Matrices, (d) achieve standard reading scores
of 90 or higher on each of the four measures described below, (e)
have no history of neurological disorders, diagnoses, or medica-
tions, (f) have no medical implants, and (g) not been previously
exposed to Hebrew or a language of similar orthography. We
screened 122 individuals, but 4 were excluded for a low IQ score, 44
for low reading scores on one or more measures, 8 for exclusionary
medications, 8 for medical implants, procedures, or diagnoses, 2 for
previous exposure to a similar orthography, 3 for being outside of
the age range, and 14 for issues in scheduling or withdrawing from
the study. Two participants were trained but errors were made
during administration of outcome assessments. Thus, our nal
sample included 37 participants. Participant characteristics and
assessment scores (mean ±SD) by group are provided in Table 1.
The protocol was approved by the Texas Christian University
Institutional Review Board, and participants provided written
informed consent prior to enrollment.
Participants were assessed using a background survey and a
standardized battery to ensure they were uent readers in their
native English. The battery included the matrices subtest of the KBIT-
2[34], as a measure of nonverbal IQ, as well as four reading mea-
sures: the Sight Word Efciency and Phonemic Decoding Efciency
subtests of the TOWRE-2 [35] and the Word ID and Word Attack
subtests of the WRMT-3 [36]. In addition to these eligibility mea-
sures, we administered additional assessments, including the pas-
sage comprehension and oral uency subtests of the WRMT-3 [36],
rapid automatized naming (RAN) of digits and letters (CTOPP-2) [37],
and working memory and attention subtests from the WRAML-2
[38]. A second researcher reviewed all scoring, and discrepancies
were resolved by a consensus between both researchers. Participants
also completed a brief Hebrew Letter ID pre-test to conrm no prior
knowledge of to-be-learned letters. All participants scored less than
5% accuracy, with no group differences (Table 1).
taVNS device settings
Prior to placing the auricular neurostimulation device on the left
ear (Fig. 1), participants cleaned the skin on and around the ear
with an alcohol wipe to remove any excess oils and ensure optimal
conductivity. Conductive hydrogels were placed on the earpiece to
control current ow and ensure participant comfort. A 1-cm long
cylindrical stimulating electrode was placed either at the left cymba
conchae or the left earlobe, depending on group assignment. There
are well-demonstrated differences in the effect of stimulating the
left versus right branches of the vagus [39]. The right branch is
connected to the sinoatrial node [40], making this branch more
effective at driving cardiac change. To ensure activation of the NTS,
which is critical for neural plasticity [20e22], and to avoid cardiac
change, we chose to stimulate only the left ear [29,31]. The earlobe
was used as a control location as fMRI studies demonstrated
stimulation of the earlobe does not activate the NTS [29,31]. The
current return electrode (1 cm 3 cm) was located behind the ear
over the mastoid bone. Current was delivered as a square, biphasic
pulse, at 5 Hz, and a 200
m
s pulse width. These parameters and
electrode placement were chosen based on prior work [41,42].
Stimulation intensity was determined for each participant indi-
vidually, as described below. The device was controlled by custom
Python programming to ensure precise timing of the stimulation.
taVNS group assignment and thresholding
Eligible participants were randomized into one of four experi-
mental groups: computer control, device sham control, earlobe
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1814
stimulation control, or experimental taVNS. The computer control
group (n¼7) participants completed the automated training pro-
gram without any interaction with or knowledge of the stimulator.
The remaining participants went through a taVNS thresholding
procedure, wore the earpiece, and were told they would receive
stimulation during training. To account for placebo effects or beliefs
about wearing the earpiece, the device sham control group (n¼7)
wore the earpiece at the left cymba concha (the same anatomical
location as the taVNS group) and was told stimulation would occur,
but the device was turned off without the participantsknowledge.
All sham participants were told that our thresholding procedure
was designed to determine a comfortable stimulation intensity for
each individual, and that each person may experience that current
differently. At the end of the study, no participants reported being
suspicious of their stimulation group.
To determine whether the sensation of stimulation anywhere on
the left ear increased performance, the earlobe stimulation control
group (n¼9) wore the device and received active stimulation to the
left earlobe, as earlobe stimulation does not activate the NB or LC
[29,31]. Finally, the taVNS group (n¼14) wore the earpiece during
all training sessions and received stimulation to the left cymba
concha.
All participants who wore the device, regardless of the elec-
trodes location, completed a thresholding procedure in which a
trained researcher determined a customized amount of current for
each participant. Thresholding took place in the location the
stimulator would be worn. To determine comfortable current for
each participant, we obtained two measurements at minimum
threshold and two at the upper level of comfort (Table 2)[31]. The
upper level of comfort was dened as the point when stimulation
became distracting and uncomfortable but prior to the onset of
pain. The average of these four measurements was calculated and
used as the current intensity setting during the training sessions.
There were no group differences between the device sham control
(2.04 ±1.18 mA), earlobe stimulation control (1.51 ±0.35 mA), and
taVNS groups (1.68 ±0.87 mA) in thresholding current intensity (F
(2, 27) ¼0.81, p¼0.46).
Training program
Eligible participants returned to the lab on ve separate days for
30-min training sessions, which were conducted individually in
sound-dampened testing rooms in the lab. We chose to train par-
ticipants over several days to ensure we could measure higher-
Table 1
Summary of participant demographics and standard scores (M ±SD) from baseline English assessments (N ¼37). There were no main effects of group on any measure.
Group Computer Control n¼7 Device Sham Control n¼7 Earlobe Stimulation Control n¼9 taVNS
n¼14
F-Value
# Females 4 6 8 9
Age 22.60 ±4.88 20.31 ±1.22 20.05 ±1.46 21.26 ±2.81 1.23
KBIT-2 Matrices 106.71 ±16.00 111.86 ±12.29 102.44 ±9.61 107.71 ±7.84 0.99
TOWRE-2 SWE 109.14 ±10.96 108.71 ±12.24 113.13 ±13.40 106.71 ±10.91 0.51
TOWRE-2 PDE 109.00 ±6.95 103.42 ±5.56 114.25 ±11.17 107.14 ±8.35 2.23
WRMT-3 Word ID 111.57 ±6.58 105.43 ±8.77 109.78 ±6.44 108.07 ±7.25 0.94
WRMT-3 Word Attack 101.43 ±9.20 100.43 ±10.31 106.00 ±10.56 104.57 ±8.71 0.61
WRMT-3 Passage Comprehension 101.00 ±9.26 97.29 ±16.82 95.89 ±19.97 105.85 ±9.21 1.12
WRMT-3 Oral Fluency 118.71 ±13.17 112.57 ±16.84 118.89 ±11.05 115.71 ±7.53 0.50
CTOPP-2 Digits 10.86 ±2.34 12.29 ±2.29 11.33 ±2.00 11.43 ±1.74 0.61
CTOPP-2 Letters 11.14 ±1.68 11.71 ±1.50 10.22 ±1.48 10.71 ±3.22 0.58
WRAML-2 Design Memory Core 11.86 ±2.54 8.86 ±3.24 10.78 ±2.44 9.71 ±2.67 1.73
WRAML-2 Verbal Learning Core 11.14 ±1.35 11.29 ±3.82 10.89 ±2.82 11.43 ±1.83 0.09
WRAML-2 Finger Windows 11.43 ±3.41 10.29 ±3.77 9.56 ±2.65 9.86 ±3.16 0.51
WRAML-2 Number Letter 12.14 ±1.22 11.57 ±3.82 12.00 ±2.69 11.43 ±2.65 0.15
WRAML-2 Design Memory Recognition 9.71 ±4.54 8.43 ±3.55 11.33 ±2.74 10.86 ±2.48 1.33
WRAML-2 Verbal Learning Recall 10.43 ±2.76 11.57 ±3.31 9.78 ±3.31 11.43 ±1.95 0.88
Hebrew Pre-Test 0.74 ±1.97% 0.00 ±0.00% 0.00 ±0.00% 0.34 ±1.27% 0.70
Fig. 1. Electrode location in groups wearing the device. The earpiece was placed on participantsleft ear at locations shown by the gray bar. For the device sham and taVNS groups, the
electrode was placed at the cymba concha region of the left ear (A). For the earlobe stimulation control group, the electrode was placed at the earlobe of the left ear (B).
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1815
order reading skills, such as decoding. Lesson length was modeled
after commonly used orthography training programs such as
DuoLingo. At the beginning of each session, a brief test was con-
ducted to ensure that the participants customized level of
thresholding current was comfortable. Then, the participant
completed a self-paced lesson, presented through custom PsychoPy
programming [43]. All instructions and feedback were provided by
a pre-recorded, female native-English speaker. Participants were
instructed to practice reading letters out loud and point along to the
letters both during practice as well as during feedback. A trained
researcher was always present in the room to ensure participant
safety and compliance with instructions. No adverse events
occurred during training.
Training lessons were structured in a uniform manner and were
designed to mimic best practices for new orthography learning in
adults [44]. Each training lesson began with a review of the letters
learned on previous days. Next, one or two new letters were
introduced and practiced individually (Fig. 2A), followed by prac-
tice in series of letters (Fig. 2B). For certain trials, font size and angle
were varied to improve generalizability of learned letters. Partici-
pants verbally sounded out the sequence of letters and pressed a
button when nished. After the participant read the series out loud,
the correct responses to the same sequence were presented in the
auditory domain while the participant pointed along, ensuring
attention to the feedback. Those in the earlobe stimulation control
and taVNS groups received stimulation during this multi-sensory
auditory and visual feedback to ensure that only correct pairings
were reinforced. Stimulation lasted approximately 6e8 s per
sequence and occurred during approximately 215 letter-sound
pairings per session. Finally, each training session concluded with
participants practicing sequences of letters arranged as real or
pseudowords, with the instruction to blend the sounds together
(Fig. 2C). As in series practice, stimulation was only paired with
feedback. After ve training lessons, participants had learned two
consonants and eight vowels in Hebrew using closely approxi-
mated English phonemes (Table 3).
Hebrew assessments
After ve lessons, participants were assessed on their knowl-
edge of trained Hebrew graphemes through three assessments:
Letter ID, Automaticity, and Decoding. These measures were
generated in-house and based on standard English assessments.
During the Letter ID task, participants were presented with
sixteen consonant-vowel (CV) combinations, presented individu-
ally, and instructed to provide the correct sound, with no time
pressure. This measure was based on the Letter ID task from the
WRMT-3 [36]. An incorrect answer earned 0 points, a partially
correct answer (i.e., getting the consonant or vowel correct, but not
both) earned 0.5 points, and a correct answer earned 1 point. Scores
were added together and converted to a percentage, where a higher
score indicated better performance.
The Automaticity task was based on the RAN subtest of the
CTOPP-2 [37]. Participants saw an eight-by-four grid of Hebrew CV
combinations. The participant sounded out every CV combination
on the entire card as quickly and accurately as possible. A
researcher timed the task, rounded the time to the nearest second,
and added a 1 s penalty per error made. Thus, better performance
was indicated by faster times on this task.
Finally, the Decoding task was based on the Phonemic Decoding
Efciency subtest of the TOWRE-2 [35]. Participants viewed a card
of pseudowords written in Hebrew and read through the list as
quickly and accurately for 45 s. Performance on this measure was
scored as percent correct. Higher performance was indicated by a
higher percent correct.
Statistical analysis
A one-way ANOVA was used to evaluate whether there were
effects of control condition on performance across the three
dependent measures. No group differences were found, so control
groups were combined to test our a priori hypothesis that taVNS
would improve performance on letter-sound learning using one-
Table 2
taVNS thresholding measurements. Thresholding procedure used with all participants in the device sham control, earlobe stimulation control, and experimental
taVNS groups. Four measurements were acquired during thresholding for each participant. The average of these four measurements was used in subsequent
training sessions and checked for comfort each day.
Value Dialogue Intensity (0e10 mA)
1Tell me when you feel anything unusual in your ear.
2Tell me when the stimulation feels uncomfortable, but not painful.
3Tell me when you cannot feel any stimulation in your ear.
4Tell me when the stimulation feels uncomfortable, but not painful.
TTI Average of Values 1-4
Fig. 2. Structure of the training program.A. Following review of previously learned graphemes, particip ants learned 1e2 new letters. For example, the vowel sound eh,shown here
by two dots below the consonant, in the context of previously learned consonants (הand ִִי). B. Participants then practiced all combinations learned to date in a series by reading
from right to left. C. At the end of each session, participants completed word-like practice. Participants in the earlobe and taVNS groups received stimulation during feedback of
series trials and word-like trials (BeC).
Table 3
Hebrew letters and pronunciations learned over the ve-day training period. Sixteen
letter-sound correspondences were taught over the course of the ve training days.
Two consonants (h and y) were taught on the rst day, and vowels were added each
day throughout the training.
Hebrew Letter היְִֵֶַָֹֻ
Approximate English Translation h y ah ah eh eh ee oo uh oh
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1816
tailed independent-samples t-tests. Descriptive statistics for all
outcome measures are presented as mean ±SEM.
Additionally, we conducted analyses to evaluate the relation-
ships between English reading measures and performance on He-
brew outcome assessments. Spearman correlations (r
s
) were used
for the Letter ID task, as participants exhibited a ceiling effect, and
Pearsons correlations (r) were used for the Automaticity and
Decoding tasks. The Bonferroni correction was used to control for
multiple comparisons within each set of correlations comparing
English assessments to a single outcome measure (6 comparisons
per set).
Results
taVNS improves novel orthography acquisition
Thirty-seven participants completed training and outcome as-
sessments. We rst evaluated performance across the control
groups to determine whether there was evidence of a placebo effect
in any of these conditions. There was no signicant main effect of
group for the Letter ID task (F(2, 20) ¼0.43, p¼0.65; Fig. 3A), the
Automaticity task (F(2, 19) ¼0.52, p¼0.60; Fig. 3B) or the
Decoding task (F(2, 19) ¼0.83, p¼0.45; Fig. 3C). The control groups
were therefore combined for all subsequent analyses (see Supple-
ment for additional analyses).
There was no signicant difference in Letter ID performance
between the combined control group (96.51 ±1.20%) and the taVNS
group (97.47 ±1.44%; t(35) ¼0.52, p¼0.30; Fig. 4A). On the
Automaticity task, the taVNS group completed the task signicantly
faster (33.14 ±2.32 s) than the combined control group
(46.27 ±4.34 s; t(34) ¼2.28, p¼0.014; Fig. 4B). On the Decoding
task, the taVNS group had a higher percent correct (66.45 ±3.68%)
than the combined control group (57.49 ±3.14%; t(34) ¼1.72,
p¼0.048; Fig. 4C).
Correlations between English and Hebrew reading measures
Secondary analyses were then conducted to examine the rela-
tionship between the six English reading measures (Sight Word
Efciency, Phonemic Decoding Efciency, Word Identication,
Word Attack, Rapid Digit Naming, and Rapid Letter Naming),
administered in the initial assessment session and the Hebrew
outcome assessments administered after training.
Across all control group participants (n¼23), there were
nominally signicant positive relationships between Rapid Digit
Naming with Hebrew Letter ID (r
s
¼0.49, p¼0.02) and Hebrew
Automaticity (r¼0.49, p¼0.02), such that faster digit naming
times were related to a higher percent correct on identifying He-
brew letters and on a timed decoding task. None of these com-
parisons survived correction (Table 4).
To determine whether English measures were predictive of
benets conferred by taVNS, we evaluated the same relationships
in the taVNS group alone (n¼14). There was a nominally signicant
relationship such that higher scores on the Phonemic Decoding
task in English were related to a higher percent correct on identi-
fying Hebrew letters (r
s
¼0.59, p¼0.03). In these analyses, the
English Word Attack measure signicantly correlated with all of the
Hebrew assessments, such that higher scores on an untimed
pseudoword task was related to a nominally higher percent correct
on identifying Hebrew letters (r
s
¼0.60, p¼0.02), faster times on a
Hebrew Automaticity task (r¼0.58, p¼0.03), and a higher
percent correct on the Hebrew Decoding task (r¼0.56, p¼0.04).
No comparisons survived correction (Table 5).
Discussion
In the current study, we tested the hypothesis that taVNS paired
with novel letter-sound correspondence training in Hebrew would
improve performance on outcome measures. We observed a sig-
nicant effect of taVNS paired with training on both Automaticity
and Decoding, with no effect on Letter ID. These ndings support
the hypothesis that taVNS is effective at improving letter-sound
learning in young adults.
Relationships between native and novel orthographies
Baseline measures of reading in young children, such as rapid
naming and phoneme awareness measures, are predictive of future
reading abilities [45]. In the current study, we found various
nominally signicant correlations between baseline English
Fig. 3. Performance on three measures across control groups. There was no effect of control condition on Letter ID (A), Automaticity (B), and Decoding (C) after ve days of training.
Error bars represent standard error of the mean.
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1817
assessments and post-training Hebrew assessments. It is important
to note that none of these correlations survived correction, so the
interpretation of these results should be considered with caution,
and future well-powered studies are needed to conrm these
ndings.
Across the control groups, there were nominally signicant
positive relationships between rapid digit naming and Letter ID and
Decoding in the novel orthography. RAN is a common measure of
naming speed and is associated with future reading outcomes in
children [45,46]. Thus, it is not surprising that in our sample, in-
dividuals with better rapid automatized naming in English per-
formed better on tasks in the novel orthography. It is interesting to
note, however, that the relationship was limited to digits, perhaps
suggesting that in the short time window of training, novel letters
were processed more like symbols than letters. Early in reading
acquisition, letter symbols are processed largely by right hemi-
sphere regions as objects, with a leftward lateralization occurring
only with practice [3,47]. The brains reading network is not hard-
wired and develops with practice and instruction. The brain may
therefore need more practice than provided in our training in order
for the VWFA to process a novel orthography as print rather than as
symbols. When other symbols, such as houses [48] and faces [49]
are used as a system of print, ten training sessions were used to
evoke activation in the left VWFA for trained versus untrained
stimuli. Future well-powered studies should investigate such
training programs over a longer trajectory to determine whether
novel orthography symbols are ever processed in the same brain
region as native orthographies.
In the subset of participants receiving taVNS, a different pattern
of relationships emerged. Interestingly, the relationships between
rapid digit naming and the novel orthography measures were no
longer signicant. Instead, timed decoding was signicantly
correlated with Hebrew Letter ID, and performance on an untimed
pseudoword reading measure (Word Attack) was signicantly
correlated with every outcome measure. The Word Attack measure
in English requires knowledge of the letters, an automatic
connection between the letter and the phoneme, and the ability to
blend sounds together to decode non-words. It is interesting that
the rapid naming measures were not correlated with outcomes in
the taVNS group. If RAN scores predict learning of a novel orthog-
raphy using purely behavioral methods as discussed above, it may
suggest that such training approaches encourage the brain to
follow the same trajectory as in initial reading acquisition, with
novel letters processed as symbols prior to being recognized as
print. The lack of relationship between RAN and outcome measures
in the taVNS group suggest that taVNS may push the brain to
bypass this process and instead take advantage of existing left-
hemisphere circuits already well suited for the task at hand.
Future work, including neural imaging, is needed to determine
whether taVNS accelerates the normal trajectory for orthography
acquisition or pushes the brain to use existing circuits more effec-
tively. As discussed above, no correlations survive corrections, so
future well-powered studies are needed to see if the ndings are
replicated.
Applications for non-invasive stimulation
The ability to read uently in a novel orthography is increasingly
important in the modern developed world. Well-known and highly
used programs, such as Rosetta Stone and DuoLingo are useful in
second language learning and contain an orthography component,
but the effects are dubious [50]. The addition of a non-invasive
stimulation component may improve orthography learning in
typical readers, as our results demonstrate a signicant benetof
taVNS on orthography learning in ve days.
Fig. 4. Effect of taVNS on three outcome measures.A. There was no effect of taVNS on Letter ID due to a ceiling effect. B. taVNS signicantly improved speed on the Automaticity task
compared to controls. C. taVNS signicantly improved percent correct on the Decoding task as compared to controls. *p<0.05. Error bars represent standard error of the mean.
Table 4
Correlations between six English reading measures and the three Hebrew assessments in control group participants (n ¼23).
Sight Word Efciency Phonemic Decoding Efciency Word Identication Word Attack Rapid Digit Naming Rapid Letter Naming
Letter ID 0.36 0.31 0.04 0.15 0.49*0.07
Automaticity 0.06 0.03 0.26 0.30 0.41 0.28
Decoding 0.23 0.17 0.22 0.17 0.49*0.28
Note.*signies p<0.05. No correlations remain signicant after adjusting for multiple comparisons.
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1818
In some countries, many individuals never acquire reading as
children and are therefore learning to read for the rst time as
adults. Despite efforts by many international organizations to
generate evidence-based literacy programs, most individuals never
achieved native-like uency [4,5,44], and a lack of practice leads to
regression into illiteracy [5]. taVNS devices are small and portable
and may be useful additives to literacy programs in regions of the
world that are difcult to access. In the current study, all partici-
pants were well-educated, native readers in English, so it is un-
known whether this approach will be effective in novice adults or
struggling readers. Future research in these populations is needed
to determine whether this approach is effective in illiterate adults.
Limitations
There are three main limitations of the current study. First,
while the results were robust, a small sample size recruited from a
pool of undergraduate students stunts the ability to generalize
ndings. Future studies should evaluate this approach in a larger
group of individuals, to account for effects of gender, varied back-
grounds and occupations, and a range of baseline reading abilities.
Second, taVNS is a new technology, so future work is needed to
understand parameters and interactions with neurotransmitters
like norepinephrine, acetylcholine, and serotonin [12,13]. We chose
a stimulation frequency based on previous research in epilepsy,
migraine [51], and anti-inammatory [52] models which demon-
strated that lower stimulation frequencies (1e10 Hz) were more
effective at activating associated neural structures than higher
stimulation frequencies (20e30 Hz). However, VNS may also be
effective at other current intensities [41,42] or frequencies,
including 25 Hz [30e32], or 30 Hz [26], as well as in subthreshold
conditions [53]. Our effect may be muted by the choice of a lower
stimulation frequency. Future work should evaluate frequency
optimization [41,42] and a comparison of stimulation at and below
sensory threshold [53]. Third, we did not investigate whether the
addition of taVNS improves retention of learned relationships after
training ends. For taVNS to be relevant for the general public, the
effects must be long-lasting. Therefore, future studies should
include a measure of retention after training.
CRediT authorship contribution statement
Vishal J. Thakkar: Investigation, Formal analysis, Writing -
original draft, preparation, Writing - review &editing. Abby S.
Engelhart: Investigation, Writing - review &editing. Navid Kho-
daparast: Conceptualization, Methodology, Writing - review &
editing. Helen Abadzi: Methodology, Writing - review &editing.
Tracy M. Centanni: Conceptualization, Methodology, Software,
Data curation, Supervision, Funding acquisition, Writing - review &
editing.
Declaration of competing interest
The authors have no conicts of interest to declare.
Acknowledgments
Aspects of this research were supported by the TCU Science &
Engineering Research Center (SERC) [grant numbers 170306,
180535, and 180536 (awarded to Tracy Centanni)]. The authors
would like to thank Nexeon MedSystems (https://www.
nexeonmedsystems.com/) for the use of their stimulators, pro-
vided materials, and technical support. We would also like to thank
Caiden Berry, Annie (Danyang) Dang, Jared Fox, Alexis Jefferson,
Trinton Kahland, Nick Mattox, Grace Mortenson, Grace Pecoraro,
Madeline Pitcock, Zoe Richardson, Rosie Robinson, Carly Stacey,
Courtney Weeks, and Katheryn Wisely for their help in data
collection and scoring. We would also like to thank Carly Stacey for
recording the stimuli and instructions for the training program.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.brs.2020.10.012.
References
[1] Cohen L, Lehericy S, Chochon F, Lemer C, Rivaud S, Dehaene S. Language-
specic tuning of visual cortex? Functional properties of the visual word form
area. Brain 2002;125:1054e69. https://doi.org/10.1093/brain/awf094.
[2] Dehaene S, Cohen L. Cultural recycling of cortical maps. Neuron 2007;56:
384e98. https://doi.org/10.1016/j.neuron.2007.10.004.
[3] Centanni TM, King LW, Eddy MD, Whiteld-Gabrieli S, Gabrieli JDE. Devel-
opment of sensitivity and specicity for print in the visual word form area.
Brain Lang 2017;170:62e70. https://doi.org/10.1016/j.bandl.2017.03.009.
[4] Abadzi H. Does age diminish the ability to learn uent reading? Educ Psychol
Rev 1996;8:373e95. https://doi.org/10.1007/BF01463940.
[5] Abadzi H. Can adults become uent readers in newly learned scripts? Educ
Res Int 2012:710785. https://doi.org/10.1155/2012/710785.
[6] Christodoulou JA, Del Tufo SN, Lymberis J, Saxler PK, Ghosh SS, Triantafyllou C,
et al. Brain bases of reading uency in typical reading and impaired uency in
dyslexia. PloS One 2014;9(7):e100552. https://doi.org/10.1371/
journal.pone.0100552.
[7] Wolf M, Katzir-Cohen T. Reading uency and its intervention. Sci Stud Read
2001;5(3):211e39. https://doi.org/10.1207/S1532799XSSR0503_2.
[8] Picciotto MR, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator:
cholinergic signaling shapes nervous system function and behavior. Neuron
2012;76(1):116e29. https://doi.org/10.1016/j.neuron.2012.08.036.
[9] Tully K, Volshakov VY. Emotional enhancement of memory: how norepi-
nephrine enables synaptic plasticity. Mol Brain 2010;3:15. https://doi.org/
10.1186/1756-6606-3-15.
[10] Maity S, Rah S, Sonenberg N, Gkogkas CG, Nguyen PV. Norepinephrine triggers
metaplasticity of LTP by increasing translation of specic mRNAs. Learn Mem
2015;22:499e508. https://doi.org/10.1101/lm.039222.115.
[11] Glennon E, Carcea I, Martins ARO, Multani J, Shehu I, Svirsky MA, Froemke.
Locus coeruleus activation accelerates perceptual learning. Brain Res
2019;1709:39e49. https://doi.org/10.1016/j.brainres.2018.05.048.
[12] Hulsey DR, Shedd CM, Sarker SF, Kilgard MP, Hays SA. Norepinephrine and se-
rotonin are required for vagusnerve stimulation directed cortical plasticity. Exp
Neurol 2019;320:112975. https://doi.org/10.1016/j.expneurol.2019.112975.
[13] Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RL, et al. Reor-
ganization of motor cortex by vagus nerve stimulation requires cholinergic
innervation. Brain Stimul 2016;9(2):174e81. https://doi.org/10.1016/
j.brs.2015.12.007.
[14] Clewett D, Schoeke A, Mather M. Locus coeruleus neuromodulation of
memories encoded during negative or unexpected action outcomes. Neuro-
biol Learn Mem 2014;111:65e70. https://doi.org/10.1016/j.nlm.2014.03.006.
[15] DeGiorgio CM, Schachter SC, Handforth A, Salinsky M, Thompson J, Uthman B,
et al. Prospective long-term study of vagus nerve stimulation for the treat-
ment of refractory seizures. Epilepsia 2000;41(9):1195e200. https://doi.org/
10.1111/j.1528-1157.2000.tb00325.x.
Table 5
Correlations between six English reading measures and three Hebrew assessments in the taVNS group (n ¼14) .
Sight Word Efciency Phonemic Decoding Efciency Word Identication Word Attack Rapid Digit Naming Rapid Letter Naming
Letter ID 0.16 0.59*0.48 0.60*0.17 0.17
Automaticity 0.24 0.51 0.44 0.59*0.09 0.05
Decoding 0.21 0.41 0.28 0.56*0.11 0.10
Note.*signies p<0.05. No correlations remain signicant after adjusting for multiple comparisons.
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1819
[16] Morris GL, Mueller W. Vagus Nerve Stimulation Study Group. Long-term
treatment with vagus nerve stimulation in patients with refractory epilepsy.
Neurology 1999;53(8):1731e5. https://doi.org/10.1212/wnl.53.8.1731.
[17] Sackeim HA, Rush AJ, George MS, Marangell LB, Husain MM, Nahas Z, et al.
Vagus nerve stimulation (VNS) for treatment-resistant depression: efcacy,
side effects, and predictors of outcome. Neuropsychopharmacology
2001;25(5):713e28. https://doi.org/10.1016/S0893-133X(01)00271-8.
[18] Dawson J, Pierce D, Dixit A, Kimberley TJ, Robertson M, Tarver B, et al. Safety,
feasibility, and efcacy of vagus nerve stimulation paired with upper-limb
rehabilitation after ischemic stroke. Stroke 2016;47:143e50. https://doi.org/
10.1161/strokeaha.115.010477.
[19] De Ridder D, Vanneste S, Engineer ND, Kilgard MP. Safety and efcacy of vagus
nerve stimulation paired with tones for the treatment of tinnitus: a case se-
ries. Neuromodulation 2014;17:170e9. https://doi.org/10.1111/ner.12127.
[20] Borland MS, Vrana WA, Moreno NA, Fogarty EA, Buell EP, Sharma P, et al.
Cortical map plasticity as a function of vagus nerve stimulation intensity.
Brain Stimul 2016;9(1):117e23. https://doi.org/10.1016/j.brs.2015.08.018.
[21] Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, et al.
Reversing pathological neural activity using targeted plasticity. Nature
2011;470:101e6. https://doi.org/10.1038/nature09656.
[22] Shetake JA, Engineer ND, Vrana WA, Wolf JT, Kilgard MP. Pairing tone trains with
vagus nerve stimulation induces temporal plasticity in auditory cortex. Exp
Neurol 2012;233:342e9. https://doi.org/10.1016/j.expneurol.2011.10.026.
[23] Khodaparast N, Hays SA, Sloan AM, Hulsey DR, Ruiz A, Pantoja RL, et al. Vagus
nerve stimulation during rehabilitative training improves forelimb strength
following ischemic stroke. Neurobiol Dis 2013;60:80e8. https://doi.org/
10.1016/j.nbd.2013.08.002.
[24] Khodaparast N, Hays SA, Sloan AM, Fayyaz T, Hulsey DR, Rennaker RL, et al.
Vagus nerve stimulation delivered during motor rehabilitation improves re-
covery in a rat model of stroke. Neurorehabilitation Neural Repair 2014;28(7):
698e706. https://doi.org/10.1177/1545968314521006.
[25] Porter BA, Khodaparast N, Fayyaz T, Cheung RJ, Ahmed SS, Vrana WA, et al.
Repeatedly pairing vagus nerve stimulation with a movement reorganizes
primary motor cortex. Cerebr Cortex 2012;22(10):2365e74. https://doi.org/
10.1093/cercor/bhr316.
[26] Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recog-
nition memory following vagus nerve stimulation in human subjects. Nat
Neurosci 1999;2(1):94e8. https://doi.org/10.1038/4600.
[27] Sun L, Perakyla J, Holm K, Haapasalo J, Lehtimaki K, Ogawa KH, et al. Vagus nerve
stimulation improves working memory performance. J Clin Exp Neuropsychol
2017;39(10):954e64. https://doi.org/10.1080/13803395.2017.1285869.
[28] Sackeim HA, Keilp JG, Rush AJ, George MS, Marangell LB, Dormer JS, et al. The
effects of vagus nerve stimulation on cognitive performance in patients with
treatment-resistant depression. Neuropsychiatry, Neuropsychology, and
Behavioral Neurology 2001;14(1):53e62.
[29] Frangos E, Ellrich J, Komisaruk BR. Non-invasive access to the vagus nerve
central projections via electrical stimulation of the external ear: fMRI evi-
dence in humans. Brain Stimul 2015;8(3):624e36. https://doi.org/10.1016/
j.brs.2014.11.018.
[30] Redgrave JN, Moore L, Oyekunle T, Ebrahim M, Falidas K, Snowdon N, et al.
Transcutaneous auricular vagus nerve stimulation with concurrent upper
limb repetitive task practice for poststroke motor recovery: a pilot study.
J Stroke Cerebrovasc 2018;27(7):1998e2005. https://doi.org/10.1016/
j.jstrokecerebrovasdis.2018.02.056.
[31] Yakunina N, Kim SS, Nam E-C. Optimization of transcutaneous vagus nerve
stimulation using functional MRI. Neuromodulation 2016;20(3):290e300.
https://doi.org/10.1111/ner.12541.
[32] Badran BW, Dowdle LT, Mithoefer OJ, LaBate NT, Coatsworth J, Brown JC, et al.
Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation
(taVNS) via electrical stimulation of the tragus: a concurrent taVNS/fMRI
study and review. Brain Stimul 2018;11(3):492e500. https://doi.org/10.1016/
j.brs.2017.12.009.
[33] Jacobs HIL, Riphagen JM, Razat CM, Wiese S, Sack AT. Transcutaneous vagus
nerve stimulation boosts associative memory in older individuals. Neurobiol
Aging 2015;36:1860e7. https://doi.org/10.1016/j.neurobiolaging.2015.02.023.
[34] Kaufman AS, Kaufman NL. KBIT-2 Kaufman brief intelligence test. second ed.
Bloomington, MN: Pearson; 2004.
[35] Torgesen J, Wagner R, Rashotte C. Test of word reading efciency. second ed.
Austin, TX: ProEd, Inc; 2012.
[36] Woodcock RW. Woodcock reading mastery tests. third ed. Bloomington, MN:
American Guidance Service Circle Pines; 2011.
[37] Wagner RK, Torgesen JK, Rashotte CA. CTOPP-2: comprehensive test of
phonological processing. second ed. Austin, TX: ProEd, Inc; 2013.
[38] Sheslow D, Adams W. Wide range assessment of memory and learning. sec-
ond ed. Austin, TX: ProEd, Inc; 2009.
[39] Brown GL, Eccles JC. The action of a single vagal volley on the rhythm of the
heartbeat. J Physiol 1934;82(2):211e41.
[40] Muppidi S, Gupta PK, Vernino S. Reversible right vagal neuropathy. Neurology
2011;77:1577e9.
[41] Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al.
Current directions in the auricular vagus nerve stimulation I- A physiological
perspective. Front Neurosci 2019;13:854. https://doi.org/10.3389/
fnins.2019.00854.
[42] Kaniusas E, Kampusch S, Tittgemeyer M, Panetsos F, Gines RF, Papa M, et al.
Current directions in the auricular vagus nerve stimulation II- an engineering
perspective. Front Neurosci 2019;13:772. https://doi.org/10.3389/
fnins.2019.00772.
[43] Peirce JW, Gray JR, Simpson S, MacAskill MR, Hochenberger R, Sogo H, et al.
PsychoPy2: experiments in behavior made easy. Behav Res Methods
2019;51(1):195e203. https://doi.org/10.3758/s13428-018-01193-y.
[44] Abadzi H, Prouty R. Discerning shapes, reading words like faces: the current
science of literacy and its implications for low-income countries. Int Forum
2012;15(1):5e28.
[45] Norton ES, Wolf M. Rapid automatized naming (RAN) and reading uency:
implications for understanding and treatment of reading disabilities. Annu
Rev Psychol 2012;63:427e52. https://doi.org/10.1146/annurev-psych-
120710-100431.
[46] Lervag A, Hulme C. Rapid automatized naming (RAN) taps a mechanism that
places constraints on the development of early reading uency. Psychol Sci
2009;20(8):1040e8. https://doi.org/10.1111/j.1467-9280.2009.02405.x.
[47] Centanni TM, Pantazis D, Truong DT, Gruen JR, Gabrieli JDE, Hogan TP.
Increased variability of stimulus-driven cortical responses is associated with
genetic variability in children with and without dyslexia. Dev Cogn Neuros
2018;34:7e17. https://doi.org/10.1016/j.dcn.2018.05.008.
[48] Martin L, Durisko C, Moore MW, Coutanche MN, Chen D, Fiez JA. The VWFA is
the home of orthographic learning when houses are used as letters. eNeuro
2019;6(1):e0425. https://doi.org/10.1523/ENEURO.0425-17.2019. 17.
[49] Moore MW, Durisko C, Perfetti CA, Fiez JA. Learning to read an alphabet of
human faces produces left-lateralized training effects in the fusiform gyrus.
J Cognit Neurosci 2014;26(4):896e913. https://doi.org/10.1162/jocn_a_
00506.
[50] Nielson K. Self-study with language learning software in the work place: what
happens? Lang Learn Technol 2011;15(3):110e29.
[51] Straube A, Ellrich J, Eren O, Blum B, Ruscheweyh R. Treatment of chronic
migraine with transcutaneous stimulation of the auricular branch of the vagal
nerve (auricular t-VNS): a randomized, monocentric clinical trial. J Headache
Pain 2015;16:63. https://doi.org/10.1186/s10194-015-0543-3.
[52] Clarencon D, Pellissier S, Sinniger V, Kibleur A, Hoffman D, Vercueil L, et al.
Long term effects of low frequency (10 Hz) vagus nerve stimulation on EEG
and heart rate variability in Crohns disease: a case report. Brain Stimul
2014;7:914e5. https://doi.org/10.1016/j.brs.2014.08.001.
[53] Llanos F, McHaney JR, Schuerman WL, Yi HG, Leonard MK, Chandrasekaran B.
Non-invasive peripheral nerve stimulation selectively enhances speech cate-
gory learning in adults. NPJ Sci 2020;5:12. https://doi.org/10.1038/s41539-
020-0070-0.
V.J. Thakkar, A.S. Engelhart, N. Khodaparast et al. Brain Stimulation 13 (2020) 1813e1820
1820
... Our stimulation parameters are based on a published study showing that TAVNS can help enhance adults' ability to learn novel letter-sound relationships. 58 In their study, Thakkar et al reported that TAVNS at 5 Hz and 200 μs can improve automaticity and decoding task performance. 58 As participants vary in the stimuli intensity they can perceive and tolerate, 4-6 mA stimulus frequency will be used herein, adjusted below participants' pain tolerance levels. ...
... 58 In their study, Thakkar et al reported that TAVNS at 5 Hz and 200 μs can improve automaticity and decoding task performance. 58 As participants vary in the stimuli intensity they can perceive and tolerate, 4-6 mA stimulus frequency will be used herein, adjusted below participants' pain tolerance levels. ...
Article
Full-text available
Background As one of the most common stroke sequelae, poststroke cognitive impairment significantly impacts 17.6%–83% of survivors, affecting their rehabilitation, daily living and quality of life. Improving cognitive abilities among patients in stroke recovery is therefore critical and urgent. Transcutaneous auricular vagus nerve stimulation (TAVNS) is a non-invasive, safe, cost-effective treatment with great potential for improving the cognitive function of poststroke patients. This clinical research will evaluate the effectiveness, and help elucidate the possible underlying mechanisms, of TAVNS for improving poststroke cognitive function. Methods and analysis A single-centre, parallel-group, allocation concealment, assessor-blinded randomised controlled clinical trial. We will allocate 88 recruited participants to the TAVNS or sham group for an intervention that will run for 8 weeks, 5 days per week with twice daily sessions lasting 30 min each. Blood tests will be performed and questionnaires issued at baseline and 8-week and 12 week follow-ups. Primary outcomes will be changes in cognitive function scores. Secondary outcomes will be changes in activities of daily living, quality of life and serum oxidative stress indicators. Ethics and dissemination The Ethics Committee of the First Affiliated Hospital of Hunan University of Chinese Medicine has approved the protocol (No. HN-LL-YJSLW-2022200). Findings will be published in peer-reviewed academic journals and presented at scientific conferences. Trial registration number ChiCTR2200057808.
... However, despite the anatomical and physiological plausibility of the indirect effects of taVNS on HRV, many steps to validation remain before HRV may be considered a relevant index of taVNS efficacy. Considering the evidence provided for both mental health and cognitive functions of taVNS (Colzato, Ritter & Steenbergen, 2018b;Thakkar et al., 2020) and HRV (Forte, Favieri & Casagrande, 2019;Forte et al., 2021;Forte et al., 2022a;Forte et al., 2022b), these results open the way to potential clinical trials. ...
Article
Background Transcutaneous auricular vagus nerve stimulation (taVNS) stimulating the auricular branch of the vagus nerve along a well-defined neuroanatomical pathway, has promising therapeutic efficacy. Potentially, taVNS can modulate autonomic responses. Specifically, taVNS can induce more consistent parasympathetic activation and may lead to increased heart rate variability (HRV). However, the effects of taVNS on HRV remain inconclusive. Here, we investigated changes in HRV due to brief alteration periods of parasympathetic-vagal cardiac activity produced by taVNS on the cymba as opposed to control administration via the helix. Materials and Methods We compared the effect of 10 min of active stimulation ( i.e ., cymba conchae) to sham stimulation ( i.e ., helix) on peripheral cardiovascular response, in 28 healthy young adults. HRV was estimated in the time domain and frequency domain during the overall stimulation. Results Although active-taVNS and sham-taVNS stimulation did not differ in subjective intensity ratings, the active stimulation of the cymba led to vagally mediated HRV increases in both the time and frequency domains. Differences were significant between active-taVNS and both sham-taVNS and resting conditions in the absence of stimulation for various HRV parameters, but not for the low-frequency index of HRV, where no differences were found between active-taVNS and sham-taVNS conditions. Conclusion This work supports the hypothesis that taVNS reliably induces a rapid increase in HRV parameters when auricular stimulation is used to recruit fibers in the cymba compared to stimulation at another site. The results suggest that HRV can be used as a physiological indicator of autonomic tone in taVNS for research and potential therapeutic applications, in line with the established effects of invasive VNS. Knowledge of the physiological effect of taVNS short sessions in modulating cardiovagal processing is essential for enhancing its clinical use.
... In recent years, studies have reported that tVNS can be used as a potential treatment for improving cognitive function (Cai et al., 2019;Hakon et al., 2020;Thakkar et al., 2020). However, the potential mechanism of tVNS on cognitive performance in populations, including healthy individuals, remains unclear. ...
Article
Full-text available
Transcutaneous vagus nerve stimulation, which involves the application of electrical currents to the cervical (tcVNS) or auricular (taVNS) branches of the vagus nerve, may be a potential treatment for improving cognitive dysfunction. taVNS may improve cognitive performance in healthy adults, and fewer studies have been performed on the effects of tcVNS on cognition in healthy subjects. We conducted a randomized, single-blind, crossover-controlled trial to investigate the effects of tcVNS stimulation on cognitive function and neural activity in the brains of healthy adults. This study provides support for further tcVNS studies for the treatment of cognitive impairment. Twenty-one participants were randomly divided into two groups, A and B. Group A received tcVNS first and then sham-tcVNS, while group B received the intervention in the reverse order, receiving sham stimulation first and then true stimulation. All subjects were required to perform cognitive function tests before and after receiving intervention, and functional magnetic resonance imaging (fMRI) was performed concurrently during the intervention. We hypothesized that tcVNS would have an effect on the cognitive performance of the subjects and alter the neural activity of the brain. The present study showed that tcVNS had beneficial effects on cognitive performance, mainly improving memory and language skills and attention. tcVNS intervention produced significant spontaneous neural activity in the calcarine gyrus, fusiform gyrus, lingual gyrus, and parahippocampal gyrus of the brain. Future tcVNS/fMRI trials will need to explore the effects of changes in stimulus parameters on the neural activity response of the brain.
... While in the sham taVNS group, another pair of auricular acupoints were stimulated, including elbow (scaphoid fossa, SF 3 ) and shoulder (SF 4,5 ), out of the distribution of vagus nerve. The scaphoid fossa was the stimulated site as the sham control in this study, which was different from the stimulation of the ear lobe as the sham stimulation in some studies [22][23][24]. The interventions were illustrated in Fig.1. ...
Article
Full-text available
Background: There are 9.9 million new cases of dementia in the world every year. Short-term conversion rate from mild cognitive impairment (MCI) to dementia is between 20% and 40%, but long-term in 5-10 years ranges from 60% to 100%. It is particularly important to prevent or prolong the development of MCI into dementia. Both auriculotherapy and vagus nerve stimulation are effective on improving cognitive functions. However, there is no double blinded randomized clinical trial to support the effectiveness of transcutaneous electrical stimulation of auricular acupoints in patients with MCI. Methods: This randomized controlled trial involved patients with MCI, aged from 55 to 75 years old. Patients were randomly allocated to transcutaneous auricular vagus nerve stimulation (taVNS) group or sham taVNS group. In the taVNS group, two auricular acupoints were stimulated, including heart (concha, CO15) and kidney (CO10), which are in the distribution of vagus nerve. While in the sham taVNS group, two other auricular acupoints were stimulated, including elbow (scaphoid fossa, SF3) and shoulder (SF4,5), which are out of the distribution of vagus nerve. The primary outcome was the Montreal cognitive assessment-basic, MOCA-B. The secondary outcomes included auditory verbal learning test-HuaShan version (AVLT-H), shape trails test A&B (STT-A&B), animal fluence test (AFT), Boston naming test (BNT), Pittsburgh sleep quality index (PSQI), rapid eye movement sleep behavior disorder screening questionnaire (RBDSQ), Epworth sleepiness scale (ESS) and functional activities questionnaire (FAQ). These outcome measures were taken at baseline, 24 weeks later. Results: After 24 weeks of intervention, the data of 52 patients were intended for analysis. After intervention, there was significant difference in the overall scores of MoCA-B between taVNS group and sham taVNS group (p = 0.033 < 0.05). In taVNS group, compared with before intervention, the overall scores of MOCA-B increased significantly after intervention (p < 0.001). As for N5 and N7, the two sub-indicators of AVLT-H, in taVNS group, compared with before intervention, both N5 and N7 increased significantly after intervention (both ps < 0.001). As for STTB, in taVNS group, compared with before intervention, STTB was significantly reduced after intervention (p = 0.016). For BNT, in taVNS group, compared with before intervention, BNT increased significantly after intervention (p < 0.001). In taVNS group, compared with before intervention, PSQI, RBDSQ, ESS and FAQ decreased significantly after intervention (p = 0.002, 0.025, <0.001, 0.006 respectively). 1 patient with a history of tympanic membrane perforation in taVNS group was reported with mild adverse reactions which disappeared a week after termination of taVNS. The intervention of taVNS is effective on increasing the overall scores of MoCA-B, N5 and N7. Conclusion: The clinical trial demonstrated that taVNS can improve cognitive performance in patients with MCI. This inexpensive, effective and innovative method can be recommended as a therapy for more patients with MCI in the prevention or prolonging of its development into dementia, but it is still required to be further investigated. Trial registration: http://www.chictr.org.cn. (ID: ChiCTR2000038868).
... This mechanism of action can be strengthened over multiple sessions of pairing to produce long-term permanent reorganization of sensory pathways that alters perception. Taken together, these works suggest phasic VNS has great potential as a next generation neuromodulation technology for rehabilitative motor and sensory therapies (Neuhaus et al., 2007;Kreuzer et al., 2014;Engineer et al., 2015;Tyler et al., 2017;Vanneste et al., 2017;Kilgard et al., 2018;Adcock et al., 2020;Llanos et al., 2020;Thakkar et al., 2020;Altidor et al., 2021;Phillips et al., 2021). ...
Article
Full-text available
After sensory information is encoded into neural signals at the periphery, it is processed through multiple brain regions before perception occurs (i.e., sensory processing). Recent work has begun to tease apart how neuromodulatory systems influence sensory processing. Vagus nerve stimulation (VNS) is well-known as an effective and safe method of activating neuromodulatory systems. There is a growing body of studies confirming VNS has immediate effects on sensory processing across multiple sensory modalities. These immediate effects of VNS on sensory processing are distinct from the more well-documented method of inducing lasting neuroplastic changes to the sensory pathways through repeatedly delivering a brief VNS burst paired with a sensory stimulus. Immediate effects occur upon VNS onset, often disappear upon VNS offset, and the modulation is present for all sensory stimuli. Conversely, the neuroplastic effect of pairing sub-second bursts of VNS with a sensory stimulus alters sensory processing only after multiple pairing sessions, this alteration remains after cessation of pairing sessions, and the alteration selectively affects the response properties of neurons encoding the specific paired sensory stimulus. Here, we call attention to the immediate effects VNS has on sensory processing. This review discusses existing studies on this topic, provides an overview of the underlying neuromodulatory systems that likely play a role, and briefly explores the potential translational applications of using VNS to rapidly regulate sensory processing.
... (2) Due to the characteristics of athlete management, the control group members who get along day and night may inquire about learning related content in the experimental group members; this is a phenomenon similar to "stealing." (3) Although some mindfulness exercises will be done in the training class, the team members rarely did mindful breathing and body scanning exercises after class, so, at most, it is just a clarification of cognition in class, or the guidance of some adjustment methods is working, and the athletes did not experience the process of actively internalizing mindfulness practice, so as shown in Figure 1, in the follow-up test, the mindfulness level of the experimental group decreased, while that of the control group hardly changed [9]. This time between mindfulness and the fluency of shooting athletes introduce emotion regulation selfefficacy as a regulation variable, and the interaction with mindfulness affects the fluency state [10]. ...
Article
Full-text available
Introduction: Mindfulness cognitive therapy is based on mindfulness decompression, integrating the elements of cognitive behavioral therapy and related psychological education components, a set of mindfulness group courses designed. Objective: In order to explore the influence of mindfulness training on fluency and anxiety in shooting sports training. Methods: There are 22 athletes in a provincial shooting team, 12 in the experimental group and 10 people in the control group, grouped according to the random principle. A single-participant experiment design with multiple baseline levels of ABA was adopted. Results: The fluency state of the athletes has increased from 28.75 to 30.63; the average value before the intervention increased by 6.5%, PEM = 88%, explaining that the previous intervention has a moderate-intensity effect. The average value of athletes' sports competition anxiety state 205 before intervention was reduced to 171.25, reduced by 16.5%, PEM = 100%, showing that the intervention effect is very effective. Conclusions: After the shooting athletes received the intervention of the mindfulness cognitive intervention method MBCT, the state of fluency is improved, the level of competition anxiety is reduced, and the experimental intervention basically confirmed the research hypothesis. This study confirms the moderating role of emotion regulation self-efficacy between mindfulness and the fluency of shooters and provides further impetus for the refinement and development of a push-up spiral model that explains mindfulness mechanisms.
... Enhancing specific cognitive functions and learning via VNS likely depends on a complex interplay of these neuromodulatory circuits (Hulsey, Shedd, Sarker, Kilgard, & Hays, 2019;Hulsey et al., 2016) and the degree to which each system contributes to plasticity and learning may depend on VNS timing. It has been found that taVNS improves associative memory when delivered continuously during encoding and consolidation phases of an association memory task ( Jacobs et al., 2015) and L2 lettersound mapping when paired with learning feedback (Thakkar, Engelhart, Khodaparast, Abadzi, & Centanni, 2020). In a study of Mandarin lexical tone perception, perceptual categorization was improved for tones that were paired with taVNS during training but not for tones that occurred in the same training task but were not paired with taVNS (Llanos et al., 2020), which parallels findings in animal models of iVNS affecting auditory processing only when temporally coupled to stimuli (Engineer, Engineer, Riley, Seale, & Kilgard, 2015). ...
Article
Difficulty perceiving phonological contrasts in a second language (L2) can impede initial L2 lexical learning. Such is the case for English speakers learning tonal languages, like Mandarin Chinese. Given the hypothesized role of reduced neuroplasticity in adulthood limiting L2 phonological perception, the current study examined whether transcutaneous auricular vagus nerve stimulation (taVNS), a relatively new neuromodulatory technique, can facilitate L2 lexical learning for English speakers learning Mandarin Chinese over 2 days. Using a double-blind design, one group of participants received 10 min of continuous priming taVNS before lexical training and testing each day, a second group received 500 msec of peristimulus (peristim) taVNS preceding each to-be-learned item in the same tasks, and a third group received passive sham stimulation. Results of the lexical recognition test administered at the end of each day revealed evidence of learning for all groups, but a higher likelihood of accuracy across days for the peristim group and a greater improvement in response time between days for the priming group. Analyses of N400 ERP components elicited during the same tasks indicate behavioral advantages for both taVNS groups coincided with stronger lexico-semantic encoding for target words. Comparison of these findings to pupillometry results for the same study reported in Pandža, Phillips, Karuzis, O'Rourke, and Kuchinsky (2020) suggest that positive effects of priming taVNS (but not peristim taVNS) on lexico-semantic encoding are related to sustained attentional effort.
Article
Full-text available
Non-invasive transcutaneous auricular vagus nerve stimulation (taVNS) as a newly developed technique involves stimulating the cutaneous receptive field formed by the auricular branch of the vagus nerve in the outer ear, with resulting activation of vagal connections to central and peripheral nervous systems. Increasing evidence indicates that maladaptive neural plasticity may underlie the pathology of several pediatric neurodevelopmental and psychiatric disorders, such as autism spectrum disorder, attention deficit hyperactivity disorder, disruptive behavioral disorder and stress-related disorder. Vagal stimulation may therefore provide a useful intervention for treating maladaptive neural plasticity. In the current review we summarize the current literature primarily on therapeutic use in adults and discuss the prospects of applying taVNS as a therapeutic intervention in specific pediatric neurodevelopmental and other psychiatric disorders. Furthermore, we also briefly discuss factors that would help optimize taVNS protocols in future clinical applications. We conclude from these initial findings that taVNS may be a promising alternative treatment for pediatric disorders which do not respond to other interventions.
Article
Expert reading acquisition is marked by fluent, effortless decoding and adequate comprehension skills and is required for modern daily life. In spite of its importance, many individuals struggle with reading comprehension even when decoding skills are adequate. Unfortunately, effective reading comprehension interventions are limited, especially for adults. A growing body of research suggests that non-invasive transcutaneous stimulation of the auricular vagus nerve (taVNS) may drive neural plasticity for low-level reading skills such as speech sound perception and letter-sound learning, but it is unknown whether taVNS can improve higher level skills as well. Thus, the current pilot study was designed to evaluate the effect of taVNS paired with passage reading on reading comprehension performance. Twenty-four typically developing young adults were recruited and screened for baseline reading and working memory skills. Participants received either sham or active taVNS while reading short passages out loud. Immediately following each passage, participants answered a series of test questions that required either direct recall of passage details or more complete comprehension of the passage content. While taVNS did not improve the mechanics of reading (e.g., reading rate or accuracy), there was a significant effect of active taVNS on test performance. This effect was driven by significant improvement on accuracy for memory questions while there was no effect of taVNS on comprehension question accuracy. These findings suggest that taVNS may be beneficial for enhancing memory, but its efficacy may be limited in higher cognitive domains.
Article
Objectives: To evaluate the autonomic function in specific learning disorder (SLD) and comorbid SLD attention-deficit hyperactivity disorder (SLD-ADHD). Methods: A cross-sectional study was conducted in a tertiary care hospital with 20 adolescent subjects each of confirmed SLD, SLD-ADHD, and healthy control (mean age 15.32 y). Heart-rate variability and autonomic-function tests were carried out using standard protocols. Results: Heart-rate variability parameters, viz., mean RR interval, number of RR intervals which differ by ≥ 50 ms (NN50), percentage NN50, standard deviation of differences between adjacent RR intervals, root square of mean of the sum of the squares of differences between adjacent RR intervals, coefficient of variance and absolute power of high-frequency band (HF) recorded apparently lower levels in SLD and SLD-ADHD as compared to healthy control indicating lower parasympathetic tone. Whereas, higher absolute power of low- frequency band (LF) in SLD and SLD-ADHD than healthy control indicated enhanced sympathetic activity. Higher LF/HF and lower SD1/SD2 ratios in SLD and SLD-ADHD than healthy control indicated higher sympathetic tone over parasympathetic tone. Values of autonomic-function tests such as E:I ratio, change in heart rate during deep-breathing test, 30:15 ratio, and Valsalva ratio showed a decrease in SLD and SLD-ADHD as compared to healthy control implying reduction in parasympathetic reactivity. Increased values for rise in diastolic blood pressure in the isometric handgrip test and cold pressor test recorded in SLD as compared to healthy control, revealed the increased sympathetic reactivity. Conclusion: Overall, results of heart-rate variability and autonomic-function tests imply dysregulation of sympathetic and parasympathetic activities with sympathetic dominance in SLD and SLD-ADHD.
Article
Full-text available
Adults struggle to learn non-native speech contrasts even after years of exposure. While laboratory-based training approaches yield learning, the optimal training conditions for maximizing speech learning in adulthood are currently unknown. Vagus nerve stimulation has been shown to prime adult sensory-perceptual systems towards plasticity in animal models. Precise temporal pairing with auditory stimuli can enhance auditory cortical representations with a high degree of specificity. Here, we examined whether sub-perceptual threshold transcutaneous vagus nerve stimulation (tVNS), paired with non-native speech sounds, enhances speech category learning in adults. Twenty-four native English-speakers were trained to identify non-native Mandarin tone categories. Across two groups, tVNS was paired with the tone categories that were easier- or harder-to-learn. A control group received no stimulation but followed an identical thresholding procedure as the intervention groups. We found that tVNS robustly enhanced speech category learning and retention of correct stimulus-response associations, but only when stimulation was paired with the easier-to-learn categories. This effect emerged rapidly, generalized to new exemplars, and was qualitatively different from the normal individual variability observed in hundreds of learners who have performed in the same task without stimulation. Electroencephalography recorded before and after training indicated no evidence of tVNS-induced changes in the sensory representation of auditory stimuli. These results suggest that paired-tVNS induces a temporally precise neuromodulatory signal that selectively enhances the perception and memory consolidation of perceptually salient categories.
Article
Full-text available
Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging technology in the field of bioelectronic medicine with applications in therapy. Modulation of the afferent vagus nerve affects a large number of physiological processes and bodily states associated with information transfer between the brain and body. These include disease mitigating effects and sustainable therapeutic applications ranging from chronic pain diseases, neurodegenerative and metabolic ailments to inflammatory and cardiovascular diseases. Given the current evidence from experimental research in animal and clinical studies we discuss basic aVNS mechanisms and their potential clinical effects. Collectively, we provide a focused review on the physiological role of the vagus nerve and formulate a biology-driven rationale for aVNS. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the framework of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on physiological aspects-a discussion of engineering aspects is Frontiers in Neuroscience | www.frontiersin.org 1 August 2019 | Volume 13 | Article 854 Kaniusas et al. Auricular Vagus Nerve Stimulation-Physiology provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.
Article
Full-text available
Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve-a powerful entrance to the brain-affects a large number of physiological processes implicating interactions between the brain and body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, in silico modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope of EU COST Action "European network for innovative uses of EMFs in biomedical applications (BM1309)." Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on engineering aspects-a discussion of physiological aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.
Article
Full-text available
Electrical stimulation of the auricular vagus nerve (aVNS) is an emerging electroceutical technology in the field of bioelectronic medicine with applications in therapy. Artificial modulation of the afferent vagus nerve – a powerful entrance to the brain – affects a large number of physiological processes implicating interactions between the brain and body. Engineering aspects of aVNS determine its efficiency in application. The relevant safety and regulatory issues need to be appropriately addressed. In particular, in silico modeling acts as a tool for aVNS optimization. The evolution of personalized electroceuticals using novel architectures of the closed-loop aVNS paradigms with biofeedback can be expected to optimally meet therapy needs. For the first time, two international workshops on aVNS have been held in Warsaw and Vienna in 2017 within the scope of EU COST Action “European network for innovative uses of EMFs in biomedical applications (BM1309).” Both workshops focused critically on the driving physiological mechanisms of aVNS, its experimental and clinical studies in animals and humans, in silico aVNS studies, technological advancements, and regulatory barriers. The results of the workshops are covered in two reviews, covering physiological and engineering aspects. The present review summarizes on engineering aspects – a discussion of physiological aspects is provided by our accompanying article (Kaniusas et al., 2019). Both reviews build a reasonable bridge from the rationale of aVNS as a therapeutic tool to current research lines, all of them being highly relevant for the promising aVNS technology to reach the patient.
Article
Full-text available
PsychoPy is an application for the creation of experiments in behavioral science (psychology, neuroscience, linguistics, etc.) with precise spatial control and timing of stimuli. It now provides a choice of interface; users can write scripts in Python if they choose, while those who prefer to construct experiments graphically can use the new Builder interface. Here we describe the features that have been added over the last 10 years of its development. The most notable addition has been that Builder interface, allowing users to create studies with minimal or no programming, while also allowing the insertion of Python code for maximal flexibility. We also present some of the other new features, including further stimulus options, asynchronous time-stamped hardware polling, and better support for open science and reproducibility. Tens of thousands of users now launch PsychoPy every month, and more than 90 people have contributed to the code. We discuss the current state of the project, as well as plans for the future.
Article
Full-text available
Neural representations of the external world are constructed and updated in a manner that depends on behavioral context. For neocortical networks, this contextual information is relayed by a diverse range of neuromodulatory systems, which govern attention and signal the value of internal state variables such as arousal, motivation, and stress. Neuromodulators enable cortical circuits to differentially process specific stimuli and modify synaptic strengths in order to maintain short- or long-term memory traces of significant perceptual events and behavioral episodes. One of the most important subcortical neuromodulatory systems for attention and arousal is the noradrenergic locus coeruleus. Here we report that the noradrenergic system can enhance behavior in rats performing a self-initiated auditory recognition task, and optogenetic stimulation of noradrenergic locus coeruleus neurons accelerated the rate at which trained rats began correctly responding to a change in reward contingency. Animals successively progressed through distinct behavioral epochs, including periods of perseverance and exploration that occurred much more rapidly when animals received locus coeruleus stimulation. In parallel, we made recordings from primary auditory cortex and found that pairing tones with locus coeruleus stimulation led to a similar set of changes to cortical tuning profiles. Thus both behavioral and neural responses go through phases of adjustment for exploring and exploiting environmental reward contingencies. Furthermore, behavioral engagement does not necessarily recruit optimal locus coeruleus activity.
Article
Full-text available
Individuals with dyslexia exhibit increased brainstem variability in response to sound. It is unknown as to whether increased variability extends to neocortical regions associated with audition and reading, extends to visual stimuli, and whether increased variability characterizes all children with dyslexia or, instead, a specific subset of children. We evaluated the consistency of stimulus-evoked neural responses in children with (N = 20) or without dyslexia (N = 12) as measured by magnetoencephalography (MEG). Approximately half of the children with dyslexia had significantly higher levels of variability in cortical responses to both auditory and visual stimuli in multiple nodes of the reading network. There was a significant and positive relationship between the number of risk alleles at rs6935076 in the dyslexia-susceptibility gene KIAA0319 and the degree of neural variability in primary auditory cortex across all participants. This gene has been linked with neural variability in rodents and in typical readers. These findings indicate that unstable representations of auditory and visual stimuli in auditory and other reading-related neocortical regions are present in a subset of children with dyslexia and support the link between the gene KIAA0319 and the auditory neural variability across children with or without dyslexia.
Article
Vagus nerve stimulation (VNS) paired with forelimb training drives robust, specific reorganization of movement representations in the motor cortex. This effect is hypothesized to be mediated by VNS-dependent engagement of neuromodulatory networks. VNS influences activity in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), but the involvement of these neuromodulatory networks in VNS-directed plasticity is unknown. We tested the hypothesis that cortical norepinephrine and serotonin are required for VNS-dependent enhancement of motor cortex plasticity. Rats were trained on a lever pressing task emphasizing proximal forelimb use. Once proficient, all rats received a surgically implanted vagus nerve cuff and cortical injections of either immunotoxins to deplete serotonin or norepinephrine, or vehicle control. Following surgical recovery, rats received half second bursts of 0.8 mA or sham VNS after successful trials. After five days of pairing intracortical microstimulation (ICMS) was performed in the motor cortex contralateral to the trained limb. VNS paired with training more than doubled cortical representations of proximal forelimb movements. Depletion of either cortical norepinephrine or serotonin prevented this effect. The requirement of multiple neuromodulators is consistent with earlier studies showing that these neuromodulators regulate synaptic plasticity in a complimentary fashion.
Article
Learning to read specializes a portion of the left mid-fusiform cortex for printed word recognition, the putative visual word form area (VWFA). This study examined whether a VWFA specialized for English is sufficiently malleable to support learning a perceptually atypical second writing system. The study utilized an artificial orthography, HouseFont, in which house images represent English phonemes. House images elicit category-biased activation in a spatially distinct brain region, the so-called parahippocampal place area (PPA). Using house images as letters made it possible to test whether the capacity for learning a second writing system involves neural territory that supports reading in the first writing system, or neural territory tuned for the visual features of the new orthography. Twelve human adults completed two weeks of training to establish basic HouseFont reading proficiency and underwent functional neuroimaging pre and post-training. Analysis of three functionally defined regions of interest (ROIs), the VWFA, and left and right PPA, found significant pre-training versus post-training increases in response to HouseFont words only in the VWFA. Analysis of the relationship between the behavioral and neural data found that activation changes from pre-training to post-training within the VWFA predicted HouseFont reading speed. These results demonstrate that learning a new orthography utilizes neural territory previously specialized by the acquisition of a native writing system. Further, they suggest VWFA engagement is driven by orthographic functionality and not the visual characteristics of graphemes, which informs the broader debate about the nature of category-specialized areas in visual association cortex.
Background: Invasive vagus nerve stimulation (VNS) has the potential to enhance the effects of physiotherapy for upper limb motor recovery after stroke. Noninvasive, transcutaneous auricular branch VNS (taVNS) may have similar benefits, but this has not been evaluated in stroke recovery. We sought to determine the feasibility of taVNS delivered alongside upper limb repetitive task-specific practice after stroke and its effects on a range of outcome measures evaluating limb function. Materials and methods: Thirteen participants at more than 3 months postischemic stroke with residual upper limb dysfunction were recruited from the community of Sheffield, United Kingdom (October-December 2016). Participants underwent 18 × 1-hour sessions over 6 weeks in which they made 30-50 repetitions of 8-10 arm movements concurrently with taVNS (NEMOS; Cerbomed, Erlangen, Germany, 25 Hz, .1-millisecond pulse width) at maximum tolerated intensity (mA). An electrocardiogram and rehabilitation outcome scores were obtained at each visit. Qualitative interviews determined the acceptability of taVNS to participants. Results: Median time after stroke was 1.16 years, and baseline median/interquartile range upper limb Fugl-Meyer (UFM) score was 63 (54.5-99.5). Participants attended 92% of the planned treatment sessions. Three participants reported side effects, mainly fatigue, but all performed mean of more than 300 arm repetitions per session with no serious adverse events. There was a significant change in the UFM score with a mean increase per participant of 17.1 points (standard deviation 7.8). Conclusion: taVNS is feasible and well-tolerated alongside upper limb repetitive movements in poststroke rehabilitation. The motor improvements observed justify a phase 2 trial in patients with residual arm weakness.