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Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an

fMRI study

Article in Regional Anesthesia and Pain Medicine · December 2020

DOI: 10.1136/rapm-2020-102088

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 Original research

Reg Anesth Pain Med: first published as 10.1136/rapm-2020-102088 on 1 December 2020. Downloaded from http://rapm.bmj.com/ on January 3, 2021 at Harvard Library. Protected by
Transcutaneous auricular vagus nerve stimulation
(taVNS) for migraine: an fMRI study
Yue Zhang,1 Yiting Huang,2 Hui Li,3 Zhaoxian Yan,1 Ying Zhang,1 Xian Liu,1
Xiaoyan Hou,1 Weicui Chen,1 Yiheng Tu,2 Sierra Hodges,2 Helen Chen,2 Bo Liu,1
Jian Kong2

►► Additional material is ABSTRACT ABVN) or the neck (the cervical branch of vagus
published online only. To view Background Dysfunction of the thalamocortical nerve) can induce antinociception, which may affect
please visit the journal online
(http://​dx.​doi.o​ rg/​10.​1136/​ connectivity network is thought to underlie the peripheral and central nociception, inflammatory
rapm-​2020-​102088). pathophysiology of the migraine. This current study responses and pain-­related behavior.4 6–8 Previous
1 aimed to explore the thalamocortical connectivity studies suggest that cervical tVNS can reduce the
Department of Radiology,
The Second Affiliated Hospital changes during 4 weeks of continuous transcutaneous number of migraine attacks9–11 and relieve acute
of Guangzhou University of vagus nerve stimulation (taVNS) treatment on migraine pain in migraine patients.12–14
Chinese Medicine, Guangzhou, patients. However, there is a relative paucity of literature
Guangdong, China Methods 70 migraine patients were recruited and on auricular tVNS treatment of migraine. In the
2
Department of Psychiatry,
randomized in an equal ratio to receive real taVNS only randomized, controlled clinical trial that tested
Massachusetts General Hospital,
Harvard Medical School, Boston, or sham taVNS treatments for 4 weeks. Resting-­state the effects of taVNS by stimulating the concha of
Massachusetts, USA functional MRI was collected before and after treatment. the outer ear with different frequencies, investiga-
3
Department of Neurology, The thalamus was parceled into functional regions of tors found that patients in the 1 Hz group had a
The Second Affiliated Hospital interest (ROIs) on the basis of six priori-­defined cortical significantly larger reduction in headache days per
of Guangzhou University of
Chinese Medicine, Guangzhou, ROIs covering the entire cortex. Seed-­based functional 28 days than the patients in the 25 Hz group.15
Guangdong, China connectivity analysis between each thalamic subregion Nevertheless, the effects of tVNS at ABVN at 1 HZ
and the whole brain was further compared across groups compared with sham stimulation at the vagus free
Correspondence to after treatment. area of the outer ear in migraine patients remains
Jian Kong, Massachusetts Results Of the 59 patients that finished the study, unclear, as well as the underlying mechanism

copyright.
General Hospital, Boston, USA; those in the taVNS group had significantly reduced behind it.
​JKONG2@​mgh.h​ arvard.​edu and
Bo Liu, The Second Affiliated number of migraine days, pain intensity and migraine Although still under investigation, literature
Hospital of Guangzhou attack times after 4 weeks of treatment compared suggests that the thalamus holds an important posi-
University of Chinese Medicine, with the sham taVNS. Functional connectivity analysis tion in our understanding of allodynia, central sensi-
Guangzhou, China; revealed that taVNS can increase the connectivity tization and photophobia in migraines.16 Further
​liubogzcm@​163.​com
between the motor-­related thalamus subregion and studies indicate that circuits between the thalamus
YZ and YH contributed equally. anterior cingulate cortex/medial prefrontal cortex, and and cortex play important roles in mediating the
decrease the connectivity between occipital cortex-­ perception of pain, and that functional and anatom-
Received 6 September 2020 related thalamus subregion and postcentral gyrus/ ical alterations in the thalamocortical (TC) circuits
Revised 26 October 2020 precuneus.
Accepted 1 November 2020 are involved in the development and maintenance
Conclusion Our findings suggest that taVNS can of migraines.17–19
relieve the symptoms of headache as well as modulate In a recent study, we found that 1 Hz taVNS can
the thalamocortical circuits in migraine patients. The produce widespread brain activity changes in brain
results provide insights into the neural mechanism regions such as the solitary nucleus, the locus coeru-
of taVNS and reveal potential therapeutic targets for leus, the raphe nuclei, and the insula in patients
migraine patients. with migraines.20 In addition, investigators found
that vagal afferents can activate the ascending anti-
nociceptive pathway from the periaqueductal gray
(PAG) and raphe nuclei onto the thalamus.21 Taken
INTRODUCTION together, these findings suggest that taVNS may
Migraine is a highly prevalent neurological modulate TC circuits.
disorder1 that can impose great personal and socio- In this study, we investigate the modulation
© American Society of Regional economic burdens.2 Therapeutic strategies for effect of taVNS on clinical outcomes, TC circuits,
Anesthesia & Pain Medicine migraine are mainly based on preventive and abor- and their association in migraine patients. Specif-
2020. No commercial re-­use. tive drug therapy, which are only partially effective ically, we compare clinical outcome and resting
See rights and permissions.
Published by BMJ. and bear unpleasant side effects inevitably.3 Thus, it state functional connectivity (rsFC) using a func-
is necessary to explore a new therapy for migraines tionally parceled thalamus seed-­ based approach
To cite: Zhang Y, with better efficacy and less side effects. before and after 4 weeks of taVNS (as compared
Huang Y, Li H, et al. with sham taVNS) in patients of migraine without
The vagus nerve consists of a complex network
Reg Anesth Pain Med Epub
ahead of print: [please that regulates pain, mood, and the neuroendocrine-­ aura. We hypothesize that longitudinal treatment
include Day Month Year]. immune axis.4 5 Accumulating evidence suggests with taVNS could significantly modulate the
doi:10.1136/rapm-2020- that transcutaneous vagus nerve stimulation (tVNS) rsFC of the TC network and reduce symptoms in
102088 at the external ear (auricular branch of vagus nerve, migraine patients.
Zhang Y, et al. Reg Anesth Pain Med 2020;0:1–6. doi:10.1136/rapm-2020-102088    1
 Original research

Reg Anesth Pain Med: first published as 10.1136/rapm-2020-102088 on 1 December 2020. Downloaded from http://rapm.bmj.com/ on January 3, 2021 at Harvard Library. Protected by
METHODS
Standard protocol approvals, registration and consents
Patients with migraines were recruited between May 2017
and May 2019 from the Second Affiliated Hospital of Guang-
zhou University of Chinese Medicine. This study protocol
was registered on the Chinese Clinical Trial Registry (ChiC-
TR-­ INR-17010559, February 7 2017, http://www.​ chictr.​
org.​
cn/​hvshowproject.​aspx?​id=​11101). Informed consent was
obtained from all participants. Figure 1 Real and sham taVNS stimulation site on left ear. taVNS,
transcutaneous vagus nerve stimulation.

Study population
Migraine diagnosis was based on the International Classification dissection study which reported that the cymba concha is inner-
of Headache Disorders, second Edition by licensed neurologists. vated by the ABVN in 100% of the exposed auricle, while the
Episodic migraineurs without aura were recruited for this study, tail of helix is free of cutaneous vagal innervation.23
with inclusion criteria as follows: (1) aged 18–45 years old; (2)
right-­handed; (3) have at least 6 months of migraine duration; Clinical outcomes
(4) have at least two headache attacks per month; (5) have not All patients completed the self-­recorded headache diaries for
taken any prophylactic headache medications during the past 1 the baseline period (week 1–4) and during the treatment period
month and (6) have not taken any psychoactive or vasoactive (week 5–8). Similar to a previous study on taVNS treatment of
drugs during the past 3 months. migraine,15 we chose mean reduction in the number of migraine
Excluded criteria includes the following: (1) headache induced days as the primary outcome.
by other diseases; (2) headache attack within 48 hours prior As for secondary outcomes, we evaluated: (1) mean reduction
to the experiment or during the experiment; (3) pregnancy or in pain intensity as measured by the 0–10 VAS of each migraine;
lactation; (4) any other chronic pain conditions; (5) severe head (2) mean reduction in migraine attack times; (3) increased scores
deformity or intracranial lesions; (6) score on the Self-­Rating on the Migraine Specific Quality-­of-­Life Questionnaire (MSQ);
Anxiety Scale (SAS) or the Self-­Rating Depression Scale (SDS) (4) reduction in Zung SDS and Zung SAS. All of the staff who
>50. collected clinical measurements were blinded to the treatment
distribution of the patients.
Experimental design
A single-­blinded, randomized and controlled clinical trial was Statistical analysis for clinical outcome

copyright.
applied in this study. All patients were recruited from the outpa- The effect of taVNS was estimated by comparing changes of
tient unit of the Department of Neurology in the Second Affili- migraine days using a linear mixed model with time, group
ated Hospital of Guangzhou University of Chinese Medicine and allocation and interaction between the two as fixed effects,
prescreened by neurologists between May 2017 and May 2019. patients as a random effect, and age and gender as covariates.
After passing the prescreening process, potential eligible patients The analysis was performed using R V.3.1.0, with the lme424 and
provided informed consent in the presence of a study physi- lmerTest.25 We also performed similar analysis on the secondary
cian and were randomly assigned to either the real or the sham clinical outcomes including pain intensity, frequency of migraine
taVNS treatment group based on an SPSS generated random- attack times, MSQ, SDS and SAS.
ization sequence. All participants were blinded to the treatment
(real vs sham) they received. Functional MRI data acquisition
The study lasted for 8 weeks: 4 weeks before the treatment All patients participated in identical functional MRI (fMRI) scan-
(the baseline) and 4 weeks during the treatment. Patients were ning sessions before and after 4 weeks of treatment. All MRI/
instructed to complete headache diary records after enrollment. fMRI (MRI/fMRI) scans were conducted on a 3.0 T Siemens
The diaries were collected at week four and week eight. The MRI scanner (Siemens MAGNETOM Verio 3.0 T, Erlangen,
headache diary documented the onset time, duration, pain inten- Germany) with a 24-­channel phased-­array head coil.
sity (measured by Visual Analog Scale (VAS) score), accompa- Resting state fMRI encompassing the whole brain was acquired
nying symptoms, and rescue medication use. with the following parameters: repetition time (TR)=2000 ms,
echo time (TE)=30 ms, field of view (FOV)=224 mm×224
Intervention mm, matrix=64×64, flip angle=90°, slice thickness=3.5 mm,
The stimulation was applied with an electronic acupuncture interslice gap=0.7 mm, 31 axial slices paralleled and 240 time
treatment instrument (SDZII, Huatuo, Suzhou, China) by trained points. Subjects were told to stay awake, remain motionless, and
physicians. Similar to a previous taVNS study on migraine,15 we keep their eyes closed during the 8 min resting-­state fMRI scan.
have chosen the frequency of 1 Hz with the duration of 0.2 ms. T1-­weighted high-­ resolution structural images were applied
The stimulation was continuously applied for 30 min during with the following parameters: TR=1900 ms, TE=2.27 ms,
each session. Stimulation intensity was adjusted to the strongest flip angle=9°, FOV=256 mm×256 mm, matrix=256×256 and
sensation that the patients could tolerate without pain (approx- slice thickness=1.0 mm.
imately 1.5–5 mA). All the patients included in the final anal-
ysis completed 12 treatment sessions in total during the 4-­week Data preprocessing
treatment. Functional images were preprocessed using CONN18.a.26 The
Similar to our previous studies,20 real taVNS was applied at preprocessing steps included slice timing correction, realignment,
the left cymba concha (the real stimulation site).22 The control segmentation of structural data, spatial and functional normal-
(sham) stimulation was on the left tail of the helix (figure 1). ization into standard stereotactic MNI space, and reslicing into
We chose these stimulation sites based on a previous anatomical 2×2×2 mm voxels.
2 Zhang Y, et al. Reg Anesth Pain Med 2020;0:1–6. doi:10.1136/rapm-2020-102088
 Original research

Reg Anesth Pain Med: first published as 10.1136/rapm-2020-102088 on 1 December 2020. Downloaded from http://rapm.bmj.com/ on January 3, 2021 at Harvard Library. Protected by
Figure 2 Functional parcellation map of the thalamus and seed-­based analysis result of the thalamic motor seed. (A) Left: demonstration of the
six bilateral cortical brain regions. Right: six parceled thalamus subregions corresponding to prefrontal, motor, somatosensory, parietal, temporal and
occipital cortex presented in the axial view of the brain. (B) Left: seed-­based functional connectivity result of the ‘occipital’ thalamic seed showed
decreased connectivity with bilateral postcentral gyrus in the real taVNS group after treatment compared with the sham taVNS; right: correlation
between the rsFC change (post >pre) of ‘occipital‘ thalamic seed-­bilateral POG and the mean reduction of migraine days in the real taVNS group. PoG,
postcentral gyrus; rsFC, resting state functional connectivity; taVNS, transcutaneous vagus nerve stimulation.

To minimize the effects of head motion, subjects whose mean Seed-based functional connectivity analysis
frame displacement (FD) exceeded 0.2 mm were excluded27 28 The functional connectivity analysis was performed using
(no subjects were excluded in the data analysis). We identified the CONN toolbox. In the first-­level analysis, we produced a
outlier time points in the motion parameters and global signal correlation map for each patient by extracting the BOLD time
intensity using ART implemented in CONN toolbox (https:// series from each thalamic seed and computing Pearson’s correla-
www.​nitrc.​org/​projects/​artifact_​detect/). Linear regression using tion coefficients between the time series in every thalamic seed

copyright.
white matter (WM) and cerebrospinal fluid (CSF) signals, linear and all other voxels of the whole brain, respectively. Correlation
trend, subject motion (six rotation/translation motion param- coefficients were Fisher transformed into ‘Z’ scores to increase
eters and six first-­ order temporal derivatives), and outliers normality. Seed-­to-­voxel second-­level analyses were performed
(scrubbing) was conducted to remove any confounding factors. using a mixed-­ designed analysis of variance with treatment
After that, the residual BOLD time series was band-­pass filtered (real taVNS vs sham taVNS) entered as the between-­ subject
with a frequency window of 0.008–0.09 Hz. Preprocessed data factor, time (pretreatment vs post-­ treatment) as the within-­
remained unsmoothed for further winner-­take-­all thalamic func- subject factor, and age and gender as covariates. A threshold of
tional parcellation. Data were smoothed at a Gaussian kernel voxel-­wise p<0.005 uncorrected and cluster-­level p<0.05 false
of 6 mm Full Width at Half Maximun (FWHM) for seed-­based discovery rate (FDR) corrected was applied for comparison.
analysis.
RESULTS
Parcellation of thalamus
29 30 Participants and baseline characteristics
Similar to the procedure in previous studies, the cortex of
Seventy patients were randomized after screening and base-
the whole brain was partitioned into six bilateral cortical subre-
line assessment (35 in the taVNS group, 35 in the sham taVNS
gions: the prefrontal, motor, somatosensory, parietal, temporal
group). Fifty-­nine patients (33 in the taVNS group, 26 in the
and occipital cortex (figure 2A, see online supplemental table
sham taVNS group) completed the two fMRI scans (baseline
e1 for detailed region components) based on a priori-­defined
and after 4-­week treatment). See figure 3 for reasons for drop-
nonoverlapping Harvard-­ Oxford probabilistic cortical atlas
ping out in each group. No patients were excluded due to head
threshold at 25% (https://​fsl.​fmrib.​ox.​ac.​uk/​fsl/​fslwiki/​Atlases).
motion under the previously defined standard.
We also localized the entire thalamus based on the Harvard-­
Baseline characteristics of the two groups were shown in
Oxford subcortical atlas.
online supplemental table e2. There was no significant differ-
Then, the BOLD signals of six bilateral cortical subregions
ence between the real and sham group in age, gender, number
and the entire thalamus were extracted. Partial correlations
of migraine days, pain intensity, MSQ, SAS and SDS at baseline.
between the mean BOLD signal of each cortical subregion
and the signal in each thalamic voxel were applied, adjusting
the signal variance from other cortical subregions. After that, Clinical outcome
custom winner-­take-­all strategy31–33 was applied, that is, partial The clinical outcome measurements and corresponding statistics
correlations were averaged across all patients and each thalamic are summarized in table 1. Significant time ×group interaction
voxel was labeled according to the cortical subregion with the effects were found in the primary outcome variable (mean reduc-
highest partial correlation value. Thus, we functionally parceled tion in numbers of migraine days [F (1,57)=5.41, p=0.024]), two
the thalamus into six regions corresponding to the predefined of the secondary outcome variables (mean reduction in headache
cortical regions. The six thalamic subregions were used as seeds pain intensity [F (1,57)=7.52, p=0.008], and migraine attack
(regions of interest) in the following seed-­based rsFC analysis. times [F (1,57)=6.29, p=0.015]). For the primary outcome
Zhang Y, et al. Reg Anesth Pain Med 2020;0:1–6. doi:10.1136/rapm-2020-102088 3
 Original research

Reg Anesth Pain Med: first published as 10.1136/rapm-2020-102088 on 1 December 2020. Downloaded from http://rapm.bmj.com/ on January 3, 2021 at Harvard Library. Protected by
thalamic seed and the right supramarginal gyrus (SMG); (2) the
‘temporal’ thalamic seed and the right superior parietal lobule
(SPL); (3) the ‘occipital’ thalamic seed and the bilateral post-
central gyrus (PoG), right SMG and right precuneus (PCu)/SPL.
Given the important role of the rACC/mPFC and somato-
sensory cortex in the TC network of vagus nerve stimulation,35
we extracted the Fisher z value of the connectivity between the
rACC/mPFC-‘motor’ thalamic seed and the connectivity between
the PoG-‘occipital’ thalamic seed, and explored the association
between the functional connectivity change and corresponding
clinical improvement (reduction of number of days, pain inten-
sity, and attack times).
Pearson’s correlation showed that the FC change of the ‘occip-
ital’ thalamic seed and the bilateral PoG is significantly correlated
with the reduction of the migraine days (left: R=−0.39,
p=0.026; right: R=−0.42, p=0.016) in the real taVNS group
after treatment (figure 2B), and no significant correlations were
found in sham group (left: R=−0.2, p=0.33; right: R=−0.19,
p=0.36). There is no significant correlation between the FC
change of rACC/mPFC and the corresponding clinical improve-
ments in both real and sham groups.

DISCUSSION
In this study, we investigated the modulation effect of taVNS in
migraine patients. We found significant alleviation in the number
Figure 3 Flow chart of screening, randomization and intervention. of migraine days, pain intensity and attack times after real taVNS
fMRI, functional MRI; taVNS, transcutaneous vagus nerve stimulation. treatment when compared with sham taVNS treatment. The
taVNS significantly modulated the TC functional connectivity.
In particular, we found that the thalamic subregions associated
measure, the intra-­group difference was an absolute reduction with the motor and occipital cortex had a significant functional

copyright.
of −2.5 days (95% CI −3.3 to −1.6; p<0.001) in the group connectivity change with two important cortical regions in the
treated with real taVNS compared with −0.7 days (95% CI −2.1 vagus afferent network- the rACC/mPFC and somatosensory
to 0.6; p=0.267) in the sham group. There were no significant cortex respectively. When compared with the sham group, the
interactions or between-­group effects on other clinical outcome real taVNS group showed increased connectivity between the
measurements (MSQ, SAS, SDS). ‘motor’ thalamic subregion and the rACC/mPFC, and decreased
connectivity of the ‘occipital’ thalamic subregion with bilateral
Functional connectivity results PoG. Furthermore, this decreased connectivity is significantly
Six functionally parceled thalamic subregions corresponding to associated with the primary variable (mean reduction of migraine
the prefrontal, motor, somatosensory, parietal, temporal and days) in the taVNS group.
occipital cortex were shown in figure 2A (see online supple- Consistent with the previous studies, we found that 1 Hz
mental figure e1 for details). Functional subdivisions of the taVNS can significantly relieve the symptoms of migraine when
thalamus were similar to the previous studies using the winner-­ compared with sham taVNS. Straube et al15 showed that patients
take-­all parcellation strategy.31 34 who had received 1 Hz taVNS had a significant reduction in
The result of seed-­based analysis using six functionally parceled headache days compared with patients who had received 25
thalamic subregions is shown in online supplemental table e3. Hz after 3 months of treatment, highlighting the potential of
Compared with the sham group, the real taVNS group showed 1 Hz taVNS for migraine treatment. Our findings are also in
increased connections between ‘motor’ thalamic seed with the line with studies using other non-­invasive vagus nerve stimula-
rostral anterior cingulate cortex/medial prefrontal cortex (rACC/ tion (at the neck), which demonstrated the potential of VNS for
mPFC) after treatment. Also, real taVNS, compared with sham migraine treatment. For instance, two multicenter clinical trials
taVNS, showed decreased connectivity between (1) the ‘parietal’ have shown that self-­administered neck VNS three times per day

Table 1 Clinical outcome measurements in the real and sham taVNS groups
taVNS group, n=33 Sham group, n=26
Pretreatment mean Post-­treatment Post-­pre Pretreatment mean Post-­treatment Post-­pre
(SD) mean (SD) (95% CI) (SD) mean (SD) (95% CI) Interaction effect
Migraine days 4.0 (1.9) 1.5 (1.4) −2.5 (−3.3 to −1.6) 4.0 (3.2) 3.2 (2.3) −0.7 (−2.1 to 0.6) F(1,57)=5.41, p=0.024
Pain intensity 50.2 (14.5) 32.8 (20.7) −17.4 (−25.2 to −9.7) 51.6 (15.2) 47.6 (18.2) −4.1 (−9.4 to 1.3) F(1,57)=7.52, p=0.008
Attack times 4.0 (2.3) 2.5 (2.3) −1.5 (−2.3 to −0.6) 3.8 (2.4) 4.3 (3.4) 0.4 (−0.9 to 1.7) F(1,57)=6.29, p=0.015
MSQ 57.1 (9.7) 70.8 (10.6) 13.6 (9.1 to 18.2) 55.9 (10.9) 67.3 (11.6) 11.4 (7.0 to 15.8) F(1,57)=0.51, p=0.479
SAS 43.3 (6.2) 40.2 (7.1) −3.0 (−4.5 to −1.6) 43.2 (5.0) 40.3 (7.4) −2.7 (−4.7 to −0.7) F(1,57)=0.08, p=0.773
SDS 43.9 (6.2) 41 (6.1) −2.9 (−4.5 to −1.4) 44.6 (5.1) 43.5 (8.6) −1.0 (−4.0 to 2.1) F(1,57)=1.57, p=0.215
MSQ, Migraine Specific Quality-­of-­Life Questionnaire; SAS, Self-­Rating Anxiety Scale; SDS, Self-­Rating Depression Scale; taVNS, transcutaneous vagus nerve stimulation.

4 Zhang Y, et al. Reg Anesth Pain Med 2020;0:1–6. doi:10.1136/rapm-2020-102088

 Original research

Reg Anesth Pain Med: first published as 10.1136/rapm-2020-102088 on 1 December 2020. Downloaded from http://rapm.bmj.com/ on January 3, 2021 at Harvard Library. Protected by
may reduce the number of migraine days in chronic migraine functional network connectivity with the visual cortex and PCu
patients.9 10 in migraine patients.50 In a more recent study, we found that the
The role of the thalamus in migraine pathology has been well occipital cortex may play an important role in the pathophys-
documented. A previous positron emission tomographic study iology of migraines.51 We speculate that this may indicate that
showed posterior/lateral thalamus activation during a migraine taVNS can modulate the interaction among key sensory regions,
attack.36 Hodkinson et al found increased low-­frequency oscil- including the somatosensory cortex and the visual cortex
lations (as measured by fractional amplitude of low frequency through the thalamus.
fluctuation, fALFF) in the TC network of patients with migraines There are several limitations in this study. First, the sample
during their interictal phase. This increased fALFF in the thal- size is relatively small, so a randomized and sham-­controlled
amus was selectively associated with headache frequency.37 clinical trial/study with a large sample size is needed to validate
More recently, investigators found alteration of thalamic func- our findings of taVNS. Second, this is a single-­blinded study. The
tional connectivity in brain regions associated with pain modu- physicians who administered the taVNS were not blinded to
lating and pain encoding networks during migraine attacks when the treatment modality. Thus, there may be some potential bias.
compared with their interictal period.18 These findings demon- Nevertheless, the patients and staff members involved in clinical
strate the important role of the TC circuits in the pathophysi- and imaging data collection were blinded to the randomization.
ology of migraines. In addition, we are not able to report the magnitude to which
In this study, we found that taVNS can significantly modu- the blinding is maintained during the study course as we did not
late the TC circuits. Specifically, real 4-­week taVNS treatment
perform a blinding assessment.52 A further study with a double-­
produced increased rsFC between the ‘motor’ thalamic subre-
blinded design and a blindness assessment is needed to further
gion with the rACC/mPFC when compared with sham taVNS
validate our findings. Third, three multicenter, double-­blinded,
treatment.
randomized, sham-­controlled studies using non-­invasive vagus
Literature suggests that the motor cortex may play an
nerve stimulation at the neck included migraine patients with
important role in pain modulation. For instance, motor cortex
or without aura.9 10 14 One reported a greater therapeutic gain
stimulation has shown particular promise in the treatment of
in migraine patients with aura than those without aura.10 In the
refractory pain.38 39 Non-­ invasive motor cortex stimulation
current study, we only recruited migraine patients without aura.
has been used to treat different chronic pain disorders.40 41
Timothy et al showed anodal M1 tDCS enhanced activation in It remains an interesting topic to investigate/compare the effects
brain regions such as the mPFC, ACC and PAG, leading to the of taVNS in migraine patients with and without aura. Future
descending inhibition of pain.42 studies regarding this topic are needed.
The rACC/mPFC are key regions in the descending pain modu-
lation system.43 In previous studies, we found that compared

copyright.
CONCLUSION
with healthy controls, migraine patients showed reduced rsFC
In summary, in this single-­ blinded placebo controlled clin-
between the rACC/mPFC and PAG, another key region in the
ical study, we investigated the modulation effect of taVNS
descending pain modulatory system.44 We also found that the
and its underlying mechanism. We found that real taVNS can
rACC/mPFC had decreased functional connectivity with brain
significantly improve clinical outcomes compared with sham
regions within the default mode network and increased rsFC
taVNS after 4 weeks of treatment. Using functionally parceled
with sensorimotor and salience networks in chronic low back
pain patients.45 methods, we found that taVNS can increase the connectivity
The rACC/mPFC are also important targets for the antinoci- between the motor-­ related thalamic subregion and rACC/
ceptive effects of opioids. A human positron emission tomog- mPFC, and decrease the connectivity between the ‘occipital’
raphy study demonstrated that the opioid receptors were thalamic subregion and brain regions associated with pain
enriched in cortical projections of the medial pain system in the sensitivity (postcentral gyrus/PCu). Furthermore, the rsFC
cingulate and prefrontal cortex.46 Alexandre et al found that change between the occipital related thalamic subregion and
migraine patients had abnormal activation of opioid receptors in the bilateral postcentral gyrus was significantly correlated with
the prefrontal cortex during migraine attacks.47 Taken together, the reduction of migraine days in the real taVNS treatment
our findings suggest that the descending pain modulation system group. The current study may further our understanding of
may be involved in the modulation effect produced by taVNS. migraine pathophysiology and identify potential new targets
We also found that taVNS could significantly decrease the for intervention in the form of electrical stimulation for
connectivity between the ‘occipital’ thalamic seed and the migraine patients.
bilateral PoG as well as the right PCu after taVNS treatment.
Specifically, the decreased functional connectivity between the Contributors Design and conceptualized study: YZ, BL and JK; Analyze and
‘occipital’ thalamic seed and the bilateral PoG is significantly interpret the data: YH, JK and YT; Acquisition of data: YZ, HL, ZY, YZ, XL, XYH and
WC; Manuscript preparation: YH, SH, HC and JK; Funding acquisition: YZ and BL.
associated with the reduction of migraine days.
The anatomical profile of the functionally parceled ‘occip- Funding This study was supported by the Medical Scientific Research Foundation
of Guangdong Province of China (A2017234) and the Administration of Traditional
ital’ thalamic subregions located in an area around the medial Chinese Medicine of Guangdong Province of China (20182047).
and posterior group of thalamic nuclei. In particular, pulvinar
Competing interests None declared.
nucleus from the posterior group of the thalamus has a strong
connection with the visual cortex and is recognized as a proto- Patient consent for publication Obtained.
typic association nucleus involved in reciprocal cortico–cortical Ethics approval This study protocol was approved by the Institutional Review
interactions.48 A neural anatomy study showed that the pulvinar Board of the Second Affiliated Hospital of Guangzhou University of Chinese
nuclei in this region send projections to V1, V2, auditory and Medicine.
somatosensory cortices, and that these projections are implicated Provenance and peer review Not commissioned; externally peer reviewed.
in the clinical features of migraines.49 In a previous study, we Data availability statement Data are available on reasonable request. Data are
found abnormal posterior thalamic (pulvinar nuclei) dynamic available on reasonable request, contact email: ​liubogzcm@​163.​com

Zhang Y, et al. Reg Anesth Pain Med 2020;0:1–6. doi:10.1136/rapm-2020-102088 5

 Original research

Reg Anesth Pain Med: first published as 10.1136/rapm-2020-102088 on 1 December 2020. Downloaded from http://rapm.bmj.com/ on January 3, 2021 at Harvard Library. Protected by
REFERENCES 26 Whitfield-­Gabrieli S, Nieto-­Castanon A. Conn: a functional connectivity toolbox for
1 Jensen R, Stovner LJ. Epidemiology and comorbidity of headache. Lancet Neurol correlated and anticorrelated brain networks. Brain Connect 2012;2:125–41.
2008;7:354–61. 27 Jenkinson M, Bannister P, Brady M, et al. Improved optimization for the robust and
2 Stewart WF, Ricci JA, Chee E. Lost productive time and cost due to common pain accurate linear registration and motion correction of brain images. Neuroimage
conditions in the US workforce. JAMA 2003;290:2443–54. 2002;17:825–41.
3 Whyte CA, Tepper SJ. Adverse effects of medications commonly used in the treatment 28 Yan C-­G, Cheung B, Kelly C, et al. A comprehensive assessment of regional variation
of migraine. Expert Rev Neurother 2009;9:1379–91. in the impact of head micromovements on functional connectomics. Neuroimage
4 Yuan H, Silberstein SD. Vagus nerve and vagus nerve stimulation, a comprehensive 2013;76:183–201.
review: Part III. Headache 2016;56:479–90. 29 Behrens TEJ, Johansen-­Berg H, Woolrich MW, et al. Non-­Invasive mapping of
5 Yuan H, Silberstein SD. Vagus nerve and vagus nerve stimulation, a comprehensive connections between human thalamus and cortex using diffusion imaging. Nat
review: Part I. Headache 2016;56:71–8. Neurosci 2003;6:750–7.
6 Busch V, Zeman F, Heckel A, et al. The effect of transcutaneous vagus nerve stimulation 30 Giraldo-­Chica M, Rogers BP, Damon SM, et al. Prefrontal-­Thalamic anatomical
on pain perception--an experimental study. Brain Stimul 2013;6:202–9. connectivity and executive cognitive function in schizophrenia. Biol Psychiatry
7 Butt MF, Albusoda A, Farmer AD, et al. The anatomical basis for transcutaneous 2018;83:509–17.
auricular vagus nerve stimulation. J Anat 2020;236:588–611. 31 Zhang D, Snyder AZ, Fox MD, et al. Intrinsic functional relations between human
8 Kaniusas E, Kampusch S, Tittgemeyer M, et al. Current directions in the auricular cerebral cortex and thalamus. J Neurophysiol 2008;100:1740–8.
vagus nerve stimulation I – a physiological perspective. Front Neurosci 2019;13:854. 32 Fair DA, Bathula D, Mills KL, et al. Maturing thalamocortical functional connectivity
9 Silberstein SD, Calhoun AH, Lipton RB, et al. Chronic migraine headache across development. Front Syst Neurosci 2010;4:10.
prevention with noninvasive vagus nerve stimulation: the event study. Neurology 33 Hwang K, Bertolero MA, Liu WB, et al. The human thalamus is an integrative hub for
2016;87:529–38. functional brain networks. J Neurosci 2017;37:5594–607.
10 Diener H-­C, Goadsby PJ, Ashina M, et al. Non-­Invasive vagus nerve stimulation (nVNS) 34 Woodward ND, Heckers S. Mapping thalamocortical functional connectivity in chronic
for the preventive treatment of episodic migraine: the multicentre, double-­blind, and early stages of psychotic disorders. Biol Psychiatry 2016;79:1016–25.
randomised, sham-­controlled premium trial. Cephalalgia 2019;39:1475–87. 35 Hachem LD, Wong SM, Ibrahim GM. The vagus afferent network: emerging role in
11 Chaudhry SR, Lendvai IS, Muhammad S, et al. Inter-­ictal assay of peripheral translational connectomics. Neurosurg Focus 2018;45:E2.
circulating inflammatory mediators in migraine patients under adjunctive cervical 36 Afridi SK, Giffin NJ, Kaube H, et al. A positron emission tomographic study in
non-­invasive vagus nerve stimulation (nVNS): a proof-­of-­concept study. Brain Stimul spontaneous migraine. Arch Neurol 2005;62:1270–5.
2019;12:643–51. 37 Hodkinson DJ, Wilcox SL, Veggeberg R, et al. Increased amplitude of
12 Barbanti P, Grazzi L, Egeo G, et al. Non-­Invasive vagus nerve stimulation for acute thalamocortical low-­frequency oscillations in patients with migraine. J Neurosci
treatment of high-­frequency and chronic migraine: an open-­label study. J Headache 2016;36:8026–36.
Pain 2015;16:61. 38 Tsubokawa T, Katayama Y, Yamamoto T, et al. Chronic motor cortex stimulation in
13 Lai Y-­H, Huang Y-­C, Huang L-­T, et al. Cervical noninvasive vagus nerve stimulation patients with thalamic pain. J Neurosurg 1993;78:393–401.
for migraine and cluster headache: a systematic review and meta-­analysis. 39 Levy R, Deer TR, Henderson J. Intracranial neurostimulation for pain control: a review.
Neuromodulation 2020;23:721–31. Pain Physician 2010;13:157–65.
14 Tassorelli C, Grazzi L, de Tommaso M, et al. Noninvasive vagus nerve stimulation 40 Mylius V, Borckardt JJ, Lefaucheur J-­P. Noninvasive cortical modulation of experimental
as acute therapy for migraine: the randomized PRESTO study. Neurology pain. Pain 2012;153:1350–63.
2018;91:e364–73. 41 Quesada C, Pommier B, Fauchon C, et al. New procedure of high-­frequency repetitive
15 Straube A, Ellrich J, Eren O, et al. Treatment of chronic migraine with transcutaneous transcranial magnetic stimulation for central neuropathic pain: a placebo-­controlled

copyright.
stimulation of the auricular branch of the vagal nerve (auricular t-­VNS): a randomized, randomized crossover study. Pain 2020;161:718–28.
monocentric clinical trial. J Headache Pain 2015;16:543. 42 Meeker TJ, Keaser ML, Khan SA, et al. Non-­Invasive motor cortex neuromodulation
16 Younis S, Hougaard A, Noseda R, et al. Current understanding of thalamic structure reduces secondary hyperalgesia and enhances activation of the descending pain
and function in migraine. Cephalalgia 2019;39:1675–82. modulatory network. Front Neurosci 2019;13:467.
17 Magon S, May A, Stankewitz A, et al. Morphological abnormalities of 43 Ong W-­Y, Stohler CS, Herr DR. Role of the prefrontal cortex in pain processing. Mol
thalamic subnuclei in migraine: a multicenter MRI study at 3 tesla. J Neurosci Neurobiol 2019;56:1137–66.
2015;35:13800–6. 44 Li Z, Liu M, Lan L, et al. Altered periaqueductal gray resting state functional
18 Amin FM, Hougaard A, Magon S, et al. Altered thalamic connectivity during connectivity in migraine and the modulation effect of treatment. Sci Rep
spontaneous attacks of migraine without aura: a resting-­state fMRI study. Cephalalgia 2016;6:20298.
2018;38:1237–44. 45 Tu Y, Jung M, Gollub RL, et al. Abnormal medial prefrontal cortex functional
19 Martucci KT, Mackey SC. Neuroimaging of pain: human evidence and clinical connectivity and its association with clinical symptoms in chronic low back pain. Pain
relevance of central nervous system processes and modulation. Anesthesiology 2019;160:1308–18.
2018;128:1241–54. 46 Jones AKP, Qi LY, Fujirawa T, et al. In vivo distribution of opioid receptors in man in
20 Zhang Y, Liu J, Li H, et al. Transcutaneous auricular vagus nerve stimulation at 1 Hz relation to the cortical projections of the medial and lateral pain systems measured
modulates locus coeruleus activity and resting state functional connectivity in patients with positron emission tomography. Neurosci Lett 1991;126:25–8.
with migraine: An fMRI study. Neuroimage Clin. 2019;24:101971. 47 DaSilva AF, Nascimento TD, DosSantos MF, et al. μ ‐Opioid activation in the prefrontal
21 Nishikawa Y, Koyama N, Yoshida Y, et al. Activation of ascending antinociceptive cortex in migraine attacks – brief report I. Ann Clin Transl Neurol 2014;1:439–44.
system by vagal afferent input as revealed in the nucleus ventralis posteromedialis. 48 Benarroch EE. Pulvinar: associative role in cortical function and clinical correlations.
Brain Res 1999;833:108–11. Neurology 2015;84:738–47.
22 Badran BW, Brown JC, Dowdle LT, et al. Tragus or cymba conchae? investigating the 49 Goadsby PJ, Holland PR, Martins-­Oliveira M, et al. Pathophysiology of migraine: a
anatomical Foundation of transcutaneous auricular vagus nerve stimulation (taVNS). disorder of sensory processing. Physiol Rev 2017;97:553–622.
Brain Stimul 2018;11:947–8. 50 Tu Y, Fu Z, Zeng F, et al. Abnormal thalamocortical network dynamics in migraine.
23 Peuker ET, Filler TJ. The nerve supply of the human auricle. Clin Anat 2002;15:35–7. Neurology 2019;92:e2706–16.
24 Bates D, Mächler M, Bolker B, et al. Fitting linear mixed-­effects models using lme4 51 Tu Y, Zeng F, Lan L, et al. An fMRI-­based neural marker for migraine without aura.
2015;67:48. Neurology 2020;94:e741–51.
25 Kuznetsova A, Brockhoff PB, Christensen RHB. lmerTest Package: Tests in Linear Mixed 52 Bang H, Ni L, Davis CE. Assessment of blinding in clinical trials. Control Clin Trials
Effects Models. J Stat Softw 2017;82:26. 2004;25:143–56.

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