Synergistic effects of simultaneous transcranial direct current stimulation (tDCS) and transcutaneous auricular vagus nerve stimulation (taVNS) on the brain responses

Transcranial direct current stimulation (tDCS) has been extensively used to modulate cognitive function in both healthy and disease populations [[1]Chase H.W. et al.Transcranial direct current stimulation: a roadmap for research, from mechanism of action to clinical implementation.Mol Psychiatr. 2020; 25: 397-407Crossref PubMed Scopus (58) Google Scholar]. Although the underlying neural mechanism of tDCS is still unclear, recent studies have found that the modulation effect of tDCS is highly dependent on the brain state and tDCS mainly impacts on network-level neural function such as oscillatory dynamics [1Chase H.W. et al.Transcranial direct current stimulation: a roadmap for research, from mechanism of action to clinical implementation.Mol Psychiatr. 2020; 25: 397-407Crossref PubMed Scopus (58) Google Scholar, 2Ghobadi-Azbari P. et al.fMRI and transcranial electrical stimulation (tES): a systematic review of parameter space and outcomes.Prog Neuro-Psychopharmacol Biol Psychiatry. 2020; : 110149PubMed Google Scholar, 3Li L.M. et al.Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation.Hum Brain Mapp. 2019; 40: 904-915Crossref PubMed Scopus (57) Google Scholar]. Besides, another possible and important mechanism of tDCS is that the electric field affects the excitability of the peripheral nerves of the scalp which could modulate cognitive functions through the bottom-up pathway [[4]Adair D. et al.Electrical stimulation of cranial nerves in cognition and disease.Brain Stimulat. 2020; 13: 717-750Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,[5]van Boekholdt L. et al.tDCS peripheral nerve stimulation: a neglected mode of action?.Mol Psychiatr. 2021; 26: 456-461Crossref PubMed Scopus (10) Google Scholar]. Therefore, the effects of tDCS (especially prefrontal tDCS) may be concurrently mediated by a range of different transcranial and potentially transcutaneous mechanisms, which are difficult to distinguish [[4]Adair D. et al.Electrical stimulation of cranial nerves in cognition and disease.Brain Stimulat. 2020; 13: 717-750Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,[5]van Boekholdt L. et al.tDCS peripheral nerve stimulation: a neglected mode of action?.Mol Psychiatr. 2021; 26: 456-461Crossref PubMed Scopus (10) Google Scholar]. The concurrent effects from combination of tDCS and peripheral nerves stimulation (PNS) were directly explored on the motor recovery after stroke in several studies, but there was no consensus [6Rizzo V. et al.Increased transcranial direct current stimulation after effects during concurrent peripheral electrical nerve stimulation.Brain Stimulat. 2014; 7: 113-121Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar, 7Sattler V. et al.Anodal tDCS combined with radial nerve stimulation promotes hand motor recovery in the acute phase After ischemic stroke.Neurorehabilitation Neural Repair. 2015; 29: 743-754Crossref PubMed Scopus (56) Google Scholar, 8Schabrun S.M. et al.Interaction between simultaneously applied neuromodulatory interventions in humans.Brain Stimulat. 2013; 6: 624-630Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar]. As we know, whether frontal tDCS combined with PNS can enhance the modulation effect on cognitive-related brain networks has not been reported. Considering that auricular vagus nerve stimulation (taVNS), a promising cranial nerve stimulation method which belonging to PNS, can modulate multiple cognitive functions in both healthy and disease populations [[4]Adair D. et al.Electrical stimulation of cranial nerves in cognition and disease.Brain Stimulat. 2020; 13: 717-750Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar,[9]Neuser M.P. et al.Vagus nerve stimulation boosts the drive to work for rewards.Nat Commun. 2020; 11Crossref PubMed Scopus (27) Google Scholar], we explored the immediate physiological effects of simultaneous prefrontal tDCS and taVNS by functional MRI (fMRI) in this study. Thirty healthy subjects were recruited (See supplementary material for inclusion criteria). Before the experiment, all participants were provided with information about the stimulation procedure, and wrote the informed consents. The research was conducted according to the Declaration of Helsinki and was approved by the local ethics committee. The stimulator powered by a current source was produced by Xi’an Bashui Health Technology Co., Ltd., model MMSTI_B. The stimulator with two channels was placed outside the MRI scanning room throughout the experiment. One channel was for taVNS and the other for tDCS. Each channel passed through 12-m MRI-compatible cable (without any artifacts) in a twisted pair which were connected to the radio frequency filter and electromagnetically shielded to avoid interference from radio frequency radiation. The taVNS channel was connected to two silver chloride electrodes (outer diameter 7 mm). The anode and cathode of taVNS were both placed in the left cymba conchae with the anode inside and 0.5 cm apart from the cathode. The current intensity was set at 150% of the sensory threshold of each subject (See the supplementary material for detailed procedures). The electrical stimulation waveform was a single-phase rectangular pulse with a pulse width of 500 microseconds and frequency of 25 Hz. The tDCS channel was connected to two standard wet sponge electrodes (5 × 7 cm). The anode and cathode of tDCS were placed at the left frontal lobe and right orbitofrontal region (F3 and Fp2 in the 10–20 system) respectively. The current intensity of tDCS was set at 1mA. fMRI data were collected using a 3-T MRI system (EXCITE; General Electric, Milwaukee, WI) in the Department of Radiology of Xijing Hospital. Each subject underwent four fMRI sessions in 4 h. Each session included a task-fMRI run under one of the four stimulation conditions: tDCS (the taVNS electrodes well-placed but taVNS channel shut down), taVNS (the tDCS electrodes well-placed but tDCS channel shut down), simultaneous tDCS and taVNS (simultaneous joint stimulation, SJS) or sham (the taVNS and tDCS electrodes well-placed but both channels shut down). The time interval between any two continuous sessions was about 1 h for each subject (they waited for their next scanning session outside the scanning room), and the order of the stimulation conditions was counterbalanced across subjects. Each task-fMRI run had a block design with a total length of 462 seconds, starting with 66 seconds of rest/OFF and followed by three applications of 66 seconds of stimulation/ON and 66 seconds of OFF. Preprocessing and statistical analysis were performed using FSL version 5.0.9. The detailed description of fMRI scanning parameters, data processing, and individual-level statistical analysis was shown in the supplementary material. The mean effects of the BOLD responses during tDCS, taVNS, and SJS, the between-condition effects of SJS versus tDCS, and SJS versus tDCS + taVNS were calculated. All higher-level analysis were corrected for multiple comparisons based on voxel threshold at Z = 2.3 and cluster-corrected at P = 0.05. The whole-brain regions were localized using the Harvard-Oxford Cortical and Subcortical Structural Atlas and brainstem regions were localized using Duvernoy’s brainstem atlas. Five subjects were excluded because of the MRI scanner failure or excessive head movement. The mean age of the final twenty-five subjects was 19.96 ± 2.26 (range 18–24 years; 13 males). There was no significant difference in the subjective sensation (See supplementary material for details). The frontal pole, inferior frontal gyrus, insular, and somatosensory cortex were activated, while the posterior cingulate cortex, precuneous cortex, parahippocampal gyrus, hippocampus, amygdala, and temporal fusiform cortex were deactivated during F3-Fp2 tDCS (TableS1), which were consistent with previous findings [[3]Li L.M. et al.Brain state and polarity dependent modulation of brain networks by transcranial direct current stimulation.Hum Brain Mapp. 2019; 40: 904-915Crossref PubMed Scopus (57) Google Scholar,[10]Stagg C.J. et al.Widespread modulation of cerebral perfusion induced during and after transcranial direct current stimulation applied to the left dorsolateral prefrontal cortex.J Neurosci. 2013; 33: 11425-11431Crossref PubMed Scopus (182) Google Scholar]. No significant result evoked by taVNS was found, which may result from short stimulation time, small sample size, or the selection of threshold. To our best knowledge, this is the first study to explore the brain responses during simultaneous tDCS and taVNS. The SJS evoked extensive activation in cortical and subcortical regions, and deactivation in default mode network (TableS1, Fig. 1B). Particularly, significant synergistic effects (the activation by SJS were stronger than the numerical summation of the activation by tDCS and taVNS) were found in bilateral thalamus, pallidum, parahippocampal gyrus, dorsal raphe nucleus, substantia nigra and periaqueductal gray matter (TableS2 and Fig. 1D). These results indicated that simultaneous tDCS and taVNS might have the potential to modulate multiple brain network in a more effective way. Considering that the effect of tDCS or taVNS is highly dependent on brain state, we infer that taVNS may modulate brain activity into a state in which tDCS is easier to work, or vice versa. In conclusion, the ability to modulate specific cognitive function by tDCS combined with taVNS needs to be further explored in both healthy and disease populations. Author contributions included conception and study design (Jin-Bo Sun, Qun Yang and Wei Qin), data collection or acquisition (Jin-Bo Sun, Nan Li, Ling-Xia Meng, Qian-Qian Tian, Yuan-Qiang Zhu and Yi-Bin Xi), statistical analysis (Jin-Bo Sun, and Qian-Qian Tian), interpretation of results (Jin-Bo Sun, Xue-Juan Yang, and Hui Deng), drafting the manuscript work or revising it critically for important intellectual content (Jinbo Sun, Xue-Juan Yang, Hui Deng, and Zi-Xuan Zhao) and approval of final version to be published and agreement to be accountable for the integrity and accuracy of all aspects of the work (All authors). This study was funded by the Key Research and Development Program of Shaanxi (Program No. 2020ZDLSF04-05), the Science and Technology Projects of Xi’an, China (Grant No, 201809170CX11JC12), and the Fundamental Research Funds for the Central Universities (XJS201209).

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.