transauricular vagus nerve stimulation at auricular
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Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan(CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic corticesactivation measured by fMRI
Liyan Peng, Ketao Mu, Aiguo Liu, liangqiang Zhou, Yueyue Gao, Imrit TejvanshShenoy, Zhigang Mei, Qingguo Chen
PII: S0378-5955(17)30364-7
DOI: 10.1016/j.heares.2017.12.003
Reference: HEARES 7461
To appear in: Hearing Research
Received Date: 27 July 2017
Revised Date: 3 December 2017
Accepted Date: 5 December 2017
Please cite this article as: Peng, L., Mu, K., Liu, A., Zhou, l., Gao, Y., Shenoy, I.T., Mei, Z., Chen, Q.,Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan (CO11), Liver(CO12) and Shenmen (TF4) can induce auditory and limbic cortices activation measured by fMRI,Hearing Research (2018), doi: 10.1016/j.heares.2017.12.003.
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Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan
(CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic cortices
activation measured by fMRI
Liyan Peng1, Ketao Mu2, Aiguo Liu1, liangqiang Zhou1, Yueyue Gao1, Imrit Tejvansh Shenoy1, ZhigangMei3, Qingguo Chen1
1Department of Otorhinolaryngology, Tongji hospital, Tongji medical college, Huazhong University of Science and technology, Wuhan, China; 2Department of Radiology, Tongji hospital, Tongji medical college, Huazhong University of Science and technology, Wuhan, China.
3Yichang Hospital of Traditional Chinese Medicine, Clinical Medical College of Traditional Chinese Medicine, China Three Gorges University, Yichang, Hubei, China Liyan Peng and Ketao Mu contribute equally to this paper. Qingguo Chen and Zhigang Mei are the Corresponding authors who contribute equally to this paper.
Address correspondence to Qingguo Chen, Department of Otorhinolaryngology,Tongji medical college, Huazhong University of Science and technology, 430030, Jie Fang Avenue 1095, Wuhan, China. Email:chenqingguo1982@163.com Second correspondence to Zhigang Mei, Yichang Hospital of Traditional Chinese Medicine, Clinical Medical College of Traditional Chinese Medicine, China Three Gorges University, Yichang, Hubei, China. Email: zhigangmei@139.com
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Transauricular vagus nerve stimulation at auricular acupoints Kindey (CO10), Yidan
(CO11), Liver (CO12) and Shenmen (TF4) can induce auditory and limbic cortices
activation measured by fMRI
Abstract
The purpose of this study was to explore the central mechanism of transauricular
vagus nerve stimulation (taVNS) to human by fMRI and to find a suitable taVNS site
for potential tinnitus treatment. 24 healthy subjects aged between 28 and 38 years
were enrolled in the experiment. 8 subjects were stimulated in the auricular acupoints
Kindey (CO10), Yidan (CO11), Liver (CO12) and Shenmen (TF4) in the left ear, 8
subjects were stimulated at the anterior wall of the auditory canal and left lower limb
as an anterior stimulation group; 8 persons who were arranged in a sham group
received taVNS at the left ear lobe and tail of the helix. Functional magnetic
resonance imaging (fMRI) data from the cortices was collected and an Alphasim
analysis was performed. We found that taVNS at auricular acupoints CO10-12, TF4
can instantly and effectively generate blood oxygenation level dependent (BOLD)
signal changes in the prefrontal, auditory and limbic cortices of healthy subjects by
fMRI. When comparing the acupoints group and the sham group in the left brain, the
signals from the prefrontal cortex, the auditory ascending pathway including superior
temporal gyrus, middle temporal gyrus, thalamus and limbic system regions such as
putamen, caudate, posterior cingulate cortex, amygdala and parahippocampal gyrus
were increased under our stimulation. The difference of the BOLD signal in the left
brain between acupoints group and anterior group was in the superior temporal gyrus.
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We could also find signal differences in several regions of right brain among the
groups. In conclusion, taVNS at acupoints CO10-12, TF4 could activate the prefrontal,
auditory and limbic cortices of healthy brain and this scheme could be a promising
tool for tinnitus treatment.
Key words
Transauricular vagus nerve stimulation; Acupoints; fMRI; BOLD
1. Introduction
Vagus nerve stimulation (VNS) in the modern literature refers to a technique where a
surgeon or researcher wraps a unidirectional wire around the vagus nerve in the neck
(George et al., 2010). With the success of several clinical trials, VNS was approved
for the treatment of refractory epilepsy and depression in 1997 (Yuan and Silberstein,
2016). To date, a wide variety of disorders were under consideration of VNS
treatment including anxiety, pain and Alzheimer’s disease. Owing to the similarities
between the pathogenesis of pain and tinnitus, scientists have recently tried to treat
tinnitus with VNS. De Ridder reported a case and demonstrated that vagus nerve
stimulation paired with tones could be an effective therapy for tinnitus (De ridder et
al., 2015).
The rationale for using the VNS therapy is based on the findings that VNS triggers the
release of several neuromodulators that are thought to enhance plastic changes in the
cerebral cortex; when paired with motor or sensory stimuli, it promotes a substantial
reorganization of cortical maps (Seol et al., 2007; Engineer et al., 2011; Hays et al.,
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2013; Yakuina et al., 2017). On the other hand, the neuromodulator pathways
involved in VNS therapy could be that stimulation of the vagus nerve activates the
nucleus tractus solitarius, which in turn activates locus coeruleus (norepinephrine) and
nucleus basalis (acetylcholine) (Lulic et al., 2009; Engineer et al., 2013).
As an easy, non-invasive and low cost technique for probing neurocircuitry and
treating illness, transauricular vagus nerve stimulation (taVNS) seems to be suitable in
dealing with the diseases mentioned above. The anatomical studies demonstrated that
the ear is the only place on the surface of the human body where there is afferent
vagus nerve distribution (Peuker et al., 2012). Thus, direct stimulation of the afferent
nerve fibers on the ear should produce an effect similar to classic VNS but without the
burden of surgical intervention (George et al., 2010; Vanneste et al., 2012; Yuan and
Silberstein, 2016).
Cymba concha is the approved taVNS stimulation position for the epilepsy,
depression and pain management in Europe (Yuan and Silberstein, 2016). Auricular
acupoints Kidney (CO10), Yidan (CO11), Liver (CO12) in traditional Chinese
medicine, primary-like or core areas of cymba chonca and triangular fossa, are usually
selected to treat mental illnesses or psychiatric disorders, such as insomnia, anxiety or
tinnitus for thousands of years. The Shenmen point (TF4) has the effect of
tranquilizing the mind (Li et al., 2015). Therefore we would like to know what kind of
effects that taVNS at CO10-12 and TF4 could induce in the brain and whether such a
method approved by traditional Chinese medicine could be used to treat tinnitus.
In this experiment we tested and compared the brain response induced by taVNS
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between traditional Chinese acupoints CO10-12, TF4 and anterior wall of the outer
auditory canal to enhance our understanding of specific auricular sites for taVNS in
potential tinnitus treatment.
2. Methods
2.1. Subjects
Totally twenty-four healthy subjects aged 28–38 years took part in this study. The
participants had a mean age of 33 ± 2.7 (mean ± SD) years and included 10 males and
14 females. All subjects were screened for their general physical condition in advance
to ensure primary health. Present or past neurological disorders, psychiatric disorders
or concurrent therapy treatment were ruled out by history talking and self evaluation.
Ethics committee approval was obtained and granted from Huazhong University of
Science and Technology (HUST). The subjects gave their written informed consents
and were instructed that they could withdraw from the experiment at any time. Eight
subjects were arranged in the acupoints stimulation group where the stimulation site
was in the area of the acupuncture points CO10-12 and TF4 (Alimi et al., 2017) (Fig.
1); eight subjects were included in the anterior stimulation group and they were
stimulated at the anterior wall of the auditory canal and left lower limb (left middle
shank). Eight subjects took part in the sham group; the stimulation electrodes were
attached to the center of the left ear lobe and tail of the helix separately.
Before performing the experiment, we performed a training session for all the subjects.
The stimulation procedure and the protocols of the MRI measurements were
explained to the participants. All subjects reported that they were used to the stimulus
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amplitude after a few seconds and then the current was increased stepwise up to a
level where a constant sensation was reached. The stimulus intensity was adjusted to a
level between detection threshold (first perceptible or tingling sensation) and pain
threshold (first pricking or unpleasant sensation). The stimulation algorithm (see
section below) was performed as in the later fMRI session. For this procedure, the
subjects laid horizontally on an examination couch. Blood pressure and heart rate
were recorded continuously before and after the fMRI scan.
2.2. TaVNS stimulation procedure
Two electrodes were applied in the following taVNS procedure simultaneously. The
stimulation electrodes which were MRI compatible consisted of a silver plate (5 mm
in diameter) and an elongated cylindrical silver stimulation electrode (8 mm in length,
3mm in diameter). In the acupoints group, the silver plate was placed in the left ear
triangular fossa; the cylindrical electrode was placed in the left cymba concha. In the
anterior stimulation group, the plate electrode was placed in the left external acoustic
meatus on the inner side of the tragus; the cylindrical electrode was placed on the left
lower limb (left middle shank). In the sham group, the stimulation electrodes were
attached to the center of the left ear lobe and tail of the helix. All electrodes were
connected to the stimulation device by copper cables. The stimulus was a
monophasic-modified rectangle impulse with a pulse width of 250 µs. Typically, the
electrical current amplitude threshold was around 5 mA on the acupuncture points
(varied individually between 4 and 8 mA). Stimulation frequency was kept at 20 Hz,
which was known to activate nerve fibers. The individual thresholds of perception and
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pain were determined for each subject. Electrical stimulus was applied from a widely
used transcutaneous electrical nerve stimulation device (TENS200, HUATUO GmbH,
Hangzhou, China).
2.3. Experimental protocol
Functional MRI sessions were performed using the following protocol: the
experiment lasted for 420 seconds and was started with a baseline lasting for 60
seconds. This was followed by a first stimulation period of 30 seconds and a
break/baseline of 60 seconds. Four alternating stimulation and baseline sequences
were performed in total.
2.4. Functional magnetic resonance imaging of the brain
Functional MRI was performed with a three dimensional 3.0-Tesla MRI scanner (GE
Medical Systems, Milwaukee, WI) at the institute of Radiology Department, Tongji
hospital, Wuhan, China. The head of the subject was fixed in a head coil by rubber
pads and both ears were plugged and eyes were closed. Three dimensional (3D) Fast
Imaging Employing FSPGR was performed with the following parameters: repetition
time (TR)=6.6ms; echo time (TE)=2.8ms; flip angle=60; contiguous 1.0mm slice
thickness; FOV=16cm/image; matrix=256*256; number of excitation (NEX)=1.
Possible head movements of the subjects were corrected using the motion correction
function of the SYNGO scanner software (Siemens Medical Solutions).
2.5. Functional MRI Data processing
Standard professional data post-processing software, Data Processing Assistant for
Resting-state fMRI (DPARSF 3.2 advanced edition,
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http://restfmri.net/forum/DPARSF), was used for data analysis. DPARSF is a plug-in
software based on statistical parametric mapping (SPM 8,
http://www.fil.ion.ucl.ac.uk/spm), which runs on a matrix laboratory platform
(MATLAB R2012a). Preprocessing included data format conversion, slice timing,
realignment, normalization, smoothing with a 6mm full width at half-maximum
gaussian kernel, and filtering (0.06–0.11Hz). Then dcm2nii package of MRIcroN
software was used to transfer each 4D.nii file to 150 paired .img and .hdr files which
could be distinguished by SPM 8. After specifying 1st-level analysis, .mat file were
generated, followed by the step of “estimate” and “results”. Finally, .con files were
extracted and reorganized into group A, group B and group C. ANOVA was used to
analyze inter-group differences among group A, group B and group C, and the
significantly different brain area was picked up to be set as a mask. Two-sample t-test
was further used to analyze the inter-group differences between group A & group B,
group C & group B and group A & group C, based on the mask extracted in the
ANOVA. Set cluster size > 54 voxel, volume > 1458 mm3, rmm=4 (surface connected)
and correct thresholds by AlphaSim, when viewing the result files.
3. Results
3.1. Psychophysics
The psychophysiological parameters (heart rate and blood pressure) were evaluated
during training session. After the stimulation, all subjects reported a relaxed yet
focused condition. Heart rate, systolic blood pressure and diastolic blood pressure
were measured immediately before and after taVNS. A one-sample
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Kolmogorov-Smirnov test was used to compare the distributions of our data to the
normal distribution. Paired Student T-test was used to compare the results before and
after the stimulation. The mean values and standard deviations of heart rate, systolic
blood pressure and diastolic blood pressure before the stimulation were 72 ± 6
beats/min, 105 ± 7 mmHg and 68 ± 5 mmHg, respectively. After the stimulation, the
mean values and standard deviations of heart rate, systolic blood pressure and
diastolic blood pressure were 70 ± 5 beats/min, 102 ± 5 mmHg and 67 ± 3 mmHg,
respectively. When comparing the data before and after the stimulation, the P values
of the heart rate (p=0.836), systolic blood pressure (p=0.696) and diastolic blood
pressure (p=0.410) showed no statistical differences (p > 0.05).
3.2. Cortical activation
The results were summarized in table 1 and table 2. In general, stimulation of the
acupoints CO10-12 and TF4 in the left ear led to activations of certain brain regions,
especially of left temporal and limbic areas. Almost the same results were found in the
anterior stimulation group. The only difference between these two groups was the
superior temporal gyrus of the left cerebrum. This region was not activated in anterior
stimulation group.
3.2.1. Acupoints vs. sham stimulation (Fig. 2 - 4)
There were significant activations in the left superior temporal gyrus, left and right
middle temporal gyrus, left and right thalamus in our experiment. The left and right
amygdala, left caudate, left posterior cingulum cortex, left parahippocampal gyrus and
left putamen, which were thought to be part of the limbic system, were also activated.
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We also found the left and right prefrontal cortex activated. Notably, there was
significant activation in Brodmann area 41 (MNI coordinates: -45, -46, 14) (Fig. 10),
which was the primary auditory cortex in the auditory pathway.
3.2.2. Anterior vs. sham stimulation (Fig. 5 - 7)
We could find significant activations in anterior stimulation compared with sham
stimulation group in the ascending auditory pathway regions such as the left middle
medial temporal gyrus, the left and right thalamus. The putamen and amygdala on
both sides, caudate, posterior cingulum cortex and parahippocampal gyrus in the left
side were also activated. The left side of the prefrontal cortex was activated.
3.2.3. Acupoints vs. anterior stimulation (Fig. 8 and 9)
The only different brain region between these two groups was the superior temporal
cortex. In the anterior stimulation group, this area was not significantly activated
compared to the acupoints group.
4. Discussion
The most significant finding of this study was that taVNS at auricular acupoints
Kidney (CO10), Yidan (CO11), Liver (CO12) and TF4 can instantly and effectively
generate BOLD signal changes in the auditory, limbic and prefrontal cortices of
healthy subjects as shown by fMRI. In our experiment the signals from the left
temporal gyrus including primary auditory cortex and the limbic system region such
as left putamen, left caudate and left posterior cingulate cortex, amygdala, left
parahippocampal gyrus were obviously increased following stimulation.
Firstly, left ear taVNS induced activations of the cortices in the ascending auditory
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transduction pathway. The signals from the left superior temporal gyrus, left middle
temporal gyrus and left thalamus increased robustly (Fig. 2 and 5). In the right brain,
the activated areas were the middle temporal gyrus (Fig. 3). Primary and auditory
association cortex (Brodmann Area 21, 22, 41, 42) (Fig. 4 and 10), or near medial
Heschl’s gyrus, were significantly activated in our experiments. Primary auditory
cortex region, which increased stimulus-evoked BOLD responses were demonstrated
in tinnitus patients in many human neuroimaging investigations (Gu et al., 2010;
Leaver et al., 2011, 2012), was thought to be an important area where the neural
synchrony and neural plasticity occurred to generate tinnitus (Wienbruch et al., 2006;
Weisz et al., 2007). The neural plasticity was evidenced by excitation and inhibition in
the receptive field of primary auditory cortical neurons after limited receptor organ
damage, which causes cortical map modifications that may result in tinnitus (Rajan et
al., 1998; Roberts et al., 2008). The secondary auditory cortex was involved in the
auditory non-classical pathway, which was the anatomical basis of the cross modal
interaction that provides the input of the somatosensory system to the auditory
pathway (Dehmel et al., 2008). These meant that taVNS was an effective input that
directly regulates the central auditory pathway. Therefore, we inferred that taVNS
could be a useful method to arouse the neural changes in auditory cortex of tinnitus
patients.
At the same time, left cingulate gyrus, left putamen, left caudate, left
parahippocampal gyrus, left and right amygdala were activated (Fig. 2 and 5). These
regions are known to be of importance in the pathophysiology of depressive states
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where limbic activity might underlie abnormal emotional processing (Drevets et al.,
2008; Cole et al., 2011). Many models of tinnitus pathophysiology proposed that
negative or emotional reactions to tinnitus may be involved in the progress of tinnitus.
It was considered that dysregulation of the auditory system by specific structures of
the limbic system converted subjective tinnitus to chronic form (Rauschecker et al.,
2010; De Ridder et al., 2011; Leaver et al., 2012). Typically, transient tinnitus can be
assessed by limbic frontostriatal networks as an unwanted stimulus and thus
suppressed. In patients with chronic tinnitus, this regulatory mechanism does not
function properly: the initial tinnitus signal could enter limbic networks via
projections from the auditory thalamus (MGN, medial geniculate nucleus) and/or
auditory cortex to the amygdala and nucleus accumbens. Similarly, limbic structures
could suppress auditory activity via projections between ventromedial prefrontal
cortex and MGN (Leaver et al. 2016). Although the specific methods and mechanisms
for the associated brain junctions need to be further defined, it was certain that the
auditory center of the tinnitus patient interacts with the limbic system. Combined with
our finding that taVNS could activate limbic system of normal subjects, we deduce
that taVNS could make changes to the limbic network of tinnitus patients.
It is interesting to note that our experiments also found activation of the prefrontal
cortex, which plays an important role in the cognitive and attention process (Fig. 4
and 7). Cognitive and attention processes beyond stress and affection are clearly
relevant to tinnitus. Patients must deal with the tinnitus percept as it interferes with
incoming auditory stimulus in their daily lives. Tinnitus signal may be under
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attentional control and some therapies such as cognitive behavior therapy train patient
to lessen the impact of tinnitus by attentional and cognitive strategies (Jastreboff,
2007; Roberts et al., 2013). Neuroimaging findings in regions outside the ascending
auditory pathway may support these processes. Sdywell et al had reported correlations
between patient-reported tinnitus loudness and increases in stimulus-evoked fMRI
signal in lateral prefrontal cortex (Seydell-Greenwald et al., 2012).
Auricular acupoints mentioned above are distributed in the regions supplied by
auricular branch of vagus nerve and trigeminal nerve. They have been used to treat
tinnitus for thousands of years in China (Chen, 2010). Putting new wine in old bottles,
we scientifically deduced that taVNS at CO10-12, TF4 could be a prospective
treatment for tinnitus patients through these ways: 1. TaVNS can activate primary and
secondary auditory cortex where the neural synchrony and plasticity occurred to
produce tinnitus; 2. Limbic network can be influenced by taVNS, a place which
causes subjective tinnitus to become chronic; 3. Prefrontal cortex activation was
changed under taVNS treatment, here cognitive and attentional processes are clearly
relevant to tinnitus process. 4. There are currently several clinical studies on taVNS
for the treatment of tinnitus and their results are promising.
Some results of our experiments differed from previous similar experiments. Kraus
and Stefan had reported that the signal from the limbic system was deactivated, but
our experiment showed that the limbic system was activated (Kraus et al., 2007, 2013;
Dietrich et al., 2008). In these observations, brain regions like left amygdala, middle
temporal gyrus were deactivated. But our findings showed the opposite. Yakunina et
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al summed up all the BOLD fMRI studies on vagus nerve stimulation (VNS) since
September 2016, with a total of seven VNS and four taVNS literatures included
(Yakunina et al., 2017). The results showed that the activation or deactivation status of
each brain region were not exactly the same in these studies. For example, about the
amygdala, kraus et al found it was deactivated after taVNS, but Frangos study
reported that it was activated (Frangos et al., 2015); secondly, about the cingulate
gyrus posterior, kraus reported deactivation and Dietrich and Frangos found it was
activated (Dietrich et al., 2008; Frangos et al., 2015); lastly, about the middle temporal
gyrus, most of the taVNS experiments did not report this area; Kraus reported and
found it was deactivated, but Bohning and Nahas found this region was activated after
VNS (Bohning et al., 2001; Nahas et al., 2007).
The possible reasons of the discrepancies among these results of the taVNS fMRI
studies, besides the different stimulus schemes, stimulation instruments and small
samples in the experiments, could be that the stimulus in these experiments induced
only transient responses which may be different from the long term stable changes of
the brain. For example, Henry et al published papers on acute and prolonged effects of
brain blood flow alterations induced by therapeutic vagus nerve stimulation in partial
epilepsy in 1998 and 2004 respectively (Henry et al., 1998, 2004). The results showed
that during immediate-effect studies, VNS decreased bilateral hippocampal, amygdala,
and cingulate cerebral blood flow and increased bilateral insular cerebral blood flow;
but no significant cerebral blood flow changes were observed in these regions during
prolonged studies. Therefore, our opinions on these discrepancies were that this
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deactivation or activation status was only a transient unstable brain reaction under
taVNS; the final effect of taVNS on brain determined by the BOLD should be based
on the fMRI results after long period treatment of taVNS.
There are several limitations to this pilot study that should be noted. Firstly, the
samples used in the current study were not large and our observations solely reflected
the acute changes in brain induced by taVNS. Parallel studies of VNS were inclined
to involve in the long-term effects, which will be addressed in our future taVNS
studies. Another limitation was that acupoint group and anterior stimulation group
were conducted in two different series, so inter-individual anatomical diversity has to
be taken into consideration when estimating the difference. Third, we didn’t show
brainstem activations (for example, locus coeruleus and solitary tract) that are
considered as mandatory for further subcortical and cortical activities. Last, it remains
unclear whether vagal afferences were the decisive cause of the displayed fMRI
hyperactivations by taVNS. Alternatively, nerves other than the vagus nerve, such as
the great auricular nerve or the auriculotemporal nerve, might also be responsible for
the observed effects, because the outer ear has several innervations. Therefore, further
studies are necessary to confirm taVNS induced activations of brain stem nuclei like
the tractus nucleus solitaries.
5. Conclusions
TaVNS at acupoints CO10-12, TF4 could activate primary and secondary auditory
cortex, limbic cortices and prefrontal cortices of healthy brain and this scheme could
be a promising tool for tinnitus treatment.
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Disclosure
The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the paper.
Funding information
This study was supported by grants from the National Natural Science Foundation of
China (project number: 81700909).
Acknowledgment
We are grateful to doctor Hui Dai for image processing and data statistics.
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Legend
Fig. 1.
Top left: This illustration of the right anterior ear was labeled to indicate the
anatomical terminology used for different regions of the auricle. Top right: This
drawing of the external ear showed the broad projection of three cranial nerves to
three different territories of auricle. Below left: The ear acupuncture nomenclature
system developed in China after the WHO international conference in 1990 and the
whole concha region of the ear is represented by the letters “CO”. Below right:
Sketch showing the positions of the specific auricular acupoints CO10-12, TF4 and
the innervation of the human auricle, including auricular vagus nerve and trigeminal
nerve (blue grid), great auricular nerve (green grid) and auriculotemporal nerve (red
grid). The first three pictures came from Auriculotherapy manual 4rd written by Terry
Oleson.
Fig. 2. Activation map which showed the contrasts of acupoints vs. sham stimulation
group of the left brain. Brain regions of red color meant the differentially activated
areas between two groups. MNI coordinate of the activated brain slices were recorded
below the MRI pictures respectively and marked by red crosshairs in the pictures.
Fig. 3. Activation map which showed the contrasts of acupoints vs. sham stimulation
group of the right brain. Brain regions of red color meant the differentially activated
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areas between two groups. MNI coordinate of the activated brain slices were recorded
below the MRI pictures respectively and marked by red crosshairs in the pictures.
Fig. 4. The results of figure 2 were comprehensively analyzed in axial, coronal and
sagittal slices, the numbers denote the respective region in the Brodmann Area (BA).
Middle temporal gyrus (BA21) corresponded to green color and superior temporal
gyrus (BA22) meant pink, primary and auditory association cortex (BA41, 42) was
brown and red. Cingulate cortex (BA23) was green. Prefrontal gyrus (BA9)
corresponded to yellow. Parahippocampal gyrus (BA34) was showed in purple.
Fig. 5. Activation map which showed the contrasts of anterior vs. sham stimulation
group of the left brain. Brain regions of red color meant the differentially activated
areas between two groups. MNI coordinate of the activated brain slices were recorded
below the MRI pictures respectively and marked by red crosshairs in the pictures.
Fig. 6. Activation map which showed the contrasts of anterior vs. sham stimulation
group of the right brain. Brain regions of red color meant the differentially activated
areas between two groups. MNI coordinate of the activated brain slices were recorded
below the MRI pictures respectively and marked by red crosshairs in the pictures.
Fig. 7. The results of figure 5 were comprehensively analyzed in axial, coronal and
sagittal slices, the numbers denote the respective region. Prefrontal gyrus (BA46)
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corresponded to green and precuneus (AAL67) corresponded to crimson in
Anatomical Automatic Labeling (AAL) space.
Fig. 8. Activation map which showed the contrasts of anterior vs. acupoints
stimulation group. MNI coordinate of the differentially activated brain slices were
recorded below the MRI pictures and marked by red crosshairs in the pictures.
Fig. 9. The results of figure 8 were comprehensively analyzed in axial, coronal and
sagittal slices, the numbers denote the respective region in the Brodmann Area (BA).
Middle temporal gyrus (BA21) corresponded to green color.
Fig. 10. MNI cordinate of Brodmann Area 41 (primary and auditory association
cortex) in axial, coronal and sagittal slices.
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Table 1 Changes in BOLD signal of left brain by acupoints vs. anterior vs. sham stimulation
Acupoints VS Sham Anterior VS Sham Acupoints VS Anterior
Brain region Voxel Tvalue MNI coordinate
Voxel Tvalue MNI coordinate
Voxel Tvalue MNI coordinate
X Y Z X Y Z X Y Z
superior Temporal gyrus 165 2.849 -59 -47 15 - - - - - 94 3.1301 -45 -48 15 middle temporal gyrus 137 4.369 -46 -47 15 24 2.39 -42 -68 21 - - - - - thalamus 93 4.385 -7 -26 7 51 2.67 -7 -17 -1 - - - - - putamen 89 2.1443 -22 20 6 89 2.75 -14 10 -9 - - - - - caudate 65 2.1783 -19 20 6 62 3.46 -17 22 8 - - - - - posterior cingulum cortex 143 3.4609 -9 -46 35 50 4.33 -10 -49 33 - - - - - amygdala 2 3.5988 -25 1 -12 5 2.75 -20 0 -11 - - - - - parahippocampal gyrus 13 2.119 -23 -3 -7 6 2.35 -16 4 -18 - - - - - prefrontal cortex 169 3.630 -14 52 35 4 4.09 -14 64 20 - - - - -
Note: Results of taVNS in the left ear. Voxel number, t-values and p-values (p < 0.05) were obtained from the statistical parametric mapping of the Alphasim analysis.
Positive t-values represented an increase of the BOLD signal during stimulation in the respective brain region. The MNI coordinates reflected the center of gravity of
the cluster as found by the AlphaSim analysis. The minimum cluster size was 1458mm3 during the fMRI data analysis.
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Table 2 Changes in BOLD signal of right brain by acupoints vs. anterior vs. sham stimulation
Acupoints VS Sham Anterior VS Sham Acupoints VS Anterior
Brain region Voxel Tvalue MNI coordinate
Voxel Tvalue MNI coordinate
Voxel Tvalue MNI coordinate
X Y Z X Y Z X Y Z
middle temporal gyrus 90 3.559 53 -66 15 - - - - - - - - - - thalamus 48 3.35 7 -26 5 24 2.82 7 -11 -1 - - - - - amygdala 4 3.075 25 4 -12 2 3.6 18 0 -12 - - - - - prefrontal cortex 87 3.23 14 58 35 - - - - - - - - - -
Note: Results of taVNS in the left ear. Voxel number, t-values and p-values (p < 0.05) were obtained from the statistical parametric mapping of the alphasim analysis.
Positive t-values represented an increase of the BOLD signal during stimulation in the respective brain region. The MNI coordinates reflected the center of gravity of
the cluster as found by the AlphaSim analysis. The minimum cluster size was 1458mm3 during the fMRI data analysis.
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HIGHLIGHTS TaVNS at acupoints CO10-12, TF4 can arouse BOLD signals by fMRI in temporal gyrus and limbic cortices TaVNS at acupoint CO10-12, TF4 can induce signals from the prefrontal cortex TaVNS at acupoint CO10-12, TF4 could be a potential treatment for tinnitus.
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