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      Different modulation effects of 1 Hz and 20 Hz transcutaneous auricular vagus nerve stimulation on the functional connectivity of the periaqueductal gray in patients with migraine


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          A growing body of evidence suggests that transcutaneous auricular vagus nerve stimulation (taVNS) may relieve symptoms of migraineurs. Frequency is one of the key stimulation parameters. The aim of this study is to investigate the modulation effect of taVNS frequency on the descending pain modulation system (DPMS) in patients with migraine.


          Twenty-four episodic migraineurs without aura (21 females) were recruited for the single-blind, crossover, functional magnetic resonance imaging (fMRI) study. Each participant attended two separate fMRI scan sessions, one for 1 Hz and another for 20 Hz taVNS, in a random order. Seed-based functional connectivity analysis was applied using the ventrolateral periaqueductal gray (PAG) as the region of interest.


          Compared with the pre-taVNS resting state, continuous 1 Hz taVNS (during) produced a significant increase in functional connectivity between the PAG and the bilateral middle cingulate cortex (MCC), right precuneus, left middle frontal gyrus (MFG), and left cuneus. Compared with 20 Hz taVNS, 1 Hz taVNS produced greater PAG connectivity increases with the MCC, right precuneus/posterior cingulate cortex, left insula, and anterior cingulate cortex (ACC). A significant negative correlation was observed between the number of migraine attacks in the previous 4 weeks and the PAG-MCC functional connectivity in the pre-taVNS resting-state before 1 Hz taVNS.


          Our findings suggest that taVNS with different frequencies may produce different modulation effects on the descending pain modulation system, demonstrating the important role of stimulation frequency in taVNS treatment.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s12967-021-03024-9.

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          Resting state functional connectivity reveals intrinsic, spontaneous networks that elucidate the functional architecture of the human brain. However, valid statistical analysis used to identify such networks must address sources of noise in order to avoid possible confounds such as spurious correlations based on non-neuronal sources. We have developed a functional connectivity toolbox Conn ( www.nitrc.org/projects/conn ) that implements the component-based noise correction method (CompCor) strategy for physiological and other noise source reduction, additional removal of movement, and temporal covariates, temporal filtering and windowing of the residual blood oxygen level-dependent (BOLD) contrast signal, first-level estimation of multiple standard functional connectivity magnetic resonance imaging (fcMRI) measures, and second-level random-effect analysis for resting state as well as task-related data. Compared to methods that rely on global signal regression, the CompCor noise reduction method allows for interpretation of anticorrelations as there is no regression of the global signal. The toolbox implements fcMRI measures, such as estimation of seed-to-voxel and region of interest (ROI)-to-ROI functional correlations, as well as semipartial correlation and bivariate/multivariate regression analysis for multiple ROI sources, graph theoretical analysis, and novel voxel-to-voxel analysis of functional connectivity. We describe the methods implemented in the Conn toolbox for the analysis of fcMRI data, together with examples of use and interscan reliability estimates of all the implemented fcMRI measures. The results indicate that the CompCor method increases the sensitivity and selectivity of fcMRI analysis, and show a high degree of interscan reliability for many fcMRI measures.
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                Author and article information

                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                17 August 2021
                17 August 2021
                : 19
                : 354
                [1 ]GRID grid.38142.3c, ISNI 000000041936754X, Department of Psychiatry, Massachusetts General Hospital, , Harvard Medical School, ; Charlestown, MA USA
                [2 ]GRID grid.411866.c, ISNI 0000 0000 8848 7685, Department of Radiology, , The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, ; Guangzhou, Guangdong China
                [3 ]GRID grid.411866.c, ISNI 0000 0000 8848 7685, Department of Neurology, , The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, ; Guangzhou, Guangdong China
                Author information
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                : 10 May 2021
                : 5 August 2021
                Funded by: Medical Scientific Research Foundation of Guangdong Province of China
                Award ID: A2017234
                Award Recipient :
                Funded by: Administration of Traditional Chinese Medicine of Guangdong Province of China
                Award ID: 20182047
                Award Recipient :
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                © The Author(s) 2021

                transcutaneous auricular vagus nerve stimulation,functional connectivity,periaqueductal gray,descending pain modulation network,frequency


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