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Background: Evidence suggests that vagus nerve stimulation can modulate heart rate variability (HRV). However, there is a lack of mechanistic studies in healthy subjects assessing the effects of bilateral transcutaneous auricular vagus nerve stimulation (taVNS) on HRV. Our study aims to investigate how taVNS can influence the HRV response, including the influence of demographic variables in this response. Methods: Therefore, we conducted a randomized controlled study with 44 subjects, 22 allocated to active and 22 to sham taVNS. Results: Our results showed a significant difference between groups in the high-frequency (HF) metric. Active taVNS increased the HF metric significantly as compared to sham taVNS. Also, we found that age was a significant effect modifier of the relationship between taVNS and HF-HRV, as a larger increase in HF-HRV was seen in the older subjects. Importantly, there was a decrease in HF-HRV in the sham group. Conclusions: These findings suggest that younger subjects can adapt and maintain a constant level of HF-HRV regardless of the type of stimulation, but in the older subjects, only the active taVNS recipients were able to maintain and increase their HF-HRV. These results are important because they indicate that taVNS can enhance physiological regulation processes in response to external events.

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BACKGROUND: The discovery of effective treatments for major depressive disorder (MDD) may help target different brain pathways. Invasive vagus nerve stimulation (VNS) is an effective neuromodulation technique for the treatment of MDD; however, the effectiveness of the noninvasive technique, transauricular VNS (taVNS), remains unknown. Moreover, a mechanistic understanding of the neural effects behind its biological and therapeutic effects is lacking. This review aimed to evaluate the clinical evidence and the neural and anti-inflammatory effects of taVNS in MDD. METHODS: Two searches were conducted using a systematic search strategy reviewed the clinical efficacy and neural connectivity of taVNS in MDD in humans and evaluated the changes in inflammatory markers after taVNS in humans or animal models of depression. A risk of bias assessment was performed in all human studies. RESULTS: Only 5 studies evaluated the effects of taVNS in patients with depression. Although the studies demonstrated the efficacy of taVNS in treating depression, they used heterogeneous methodologies and limited data, thus preventing the conduct of pooled quantitative analyses. Pooled analysis could not be performed for studies that investigated the modulation of connectivity between brain areas; of the 6 publications, 5 were based on the same experiment. The animal studies that analyzed the presence of inflammatory markers showed a reduction in the level of pro-inflammatory cytokines or receptor expression. CONCLUSIONS: Data on the clinical efficacy of taVNS in the treatment of MDD are limited. Although these studies showed positive results, no conclusions can be drawn regarding this topic considering the heterogeneity of these studies, as in the case of functional connectivity studies. Based on animal studies, the application of taVNS causes a decrease in the level of inflammatory factors in different parts of the brain, which also regulate the immune system. Therefore, further studies are needed to understand the effects of taVNS in patients with MDD.

Assuntos

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INTRODUCTION: Seed-based analysis has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can modulate the dysfunctional brain network in patients with major depressive disorder (MDD). However, the voxel-based neuropsychological mechanism of taVNS on patients with first-episode MDD is poorly understood. The objective of this study was to assess the effects of an 8-week course of taVNS on patients with first-episode MDD. METHODS: Twenty-two patients with first-episode MDD accepted an 8-week course of taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment. Voxel-based analyses were performed to characterize spontaneous brain activity. Healthy controls (n=23) were recruited to minimize test-retest effects. Analysis of covariance (ANCOVA) was performed to ascertain treatment-related changes. Then, correlations between changes in brain activity and the Hamilton Depression Rating Scale (HAM-D)/Hamilton Anxiety Scale (HAM-A) remission rate were estimated. RESULTS: Significant group-by-time interactions on voxel-based analyses were observed in the inferior ventral striatum (VSi) and precuneus. Post-hoc analyses showed that taVNS inhibited higher brain activity in the VSi, while upregulating it in the precuneus. Functional connectivity (FC) between the VSi and precuneus decreased. Positive correlations were found between the HAM-D remission rate and changes in brain activity in the VSi. CONCLUSION: taVNS reduced the FC between VSi and precuneus by normalizing the abnormal spontaneous brain activity of VSi in first-episode MDD patients.

Assuntos

RESUMO

Introduction: Seed-based analysis has shown that transcutaneous auricular vagus nerve stimulation (taVNS) can modulate the dysfunctional brain network in patients with major depressive disorder (MDD). However, the voxel-based neuropsychological mechanism of taVNS on patients with first-episode MDD is poorly understood. The objective of this study was to assess the effects of an 8-week course of taVNS on patients with first-episode MDD. Methods: Twenty-two patients with first-episode MDD accepted an 8-week course of taVNS treatment. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were performed before and after treatment. Voxel-based analyses were performed to characterize spontaneous brain activity. Healthy controls (n=23) were recruited to minimize test-retest effects. Analysis of covariance (ANCOVA) was performed to ascertain treatment-related changes. Then, correlations between changes in brain activity and the Hamilton Depression Rating Scale (HAM-D)/Hamilton Anxiety Scale (HAM-A) remission rate were estimated. Results: Significant group-by-time interactions on voxel-based analyses were observed in the inferior ventral striatum (VSi) and precuneus. Post-hoc analyses showed that taVNS inhibited higher brain activity in the VSi, while upregulating it in the precuneus. Functional connectivity (FC) between the VSi and precuneus decreased. Positive correlations were found between the HAM-D remission rate and changes in brain activity in the VSi. Conclusion: taVNS reduced the FC between VSi and precuneus by normalizing the abnormal spontaneous brain activity of VSi in first-episode MDD patients.

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Transcutaneous auricular vagus nerve stimulation (taVNS) is a newer delivery system using a non-invasive stimulation device placed at the ear. taVNS research is focused on clinical trials showing potential therapeutic benefits, however the neurophysiological effects of this stimulation on brain activity are still unclear. We propose a systematic review that aims to describe the effects of taVNS on EEG measures and identify taVNS parameters that can potentially lead to consistent EEG-mediated biomarkers for this therapy. A systematic literature review was carried out following the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes (PRISMA) and the Cochrane handbook for systematic reviews. Clinical trials examining EEG parameters were considered, including absolute and relative power, coherence, degree of symmetry, evoked potentials, and peak frequency of all bands. According to our criteria, 18 studies (from 122 articles) were included. Our findings show a general trend towards increased EEG power spectrum activity in lower frequencies, and changes on early components of the ERP related to inhibitory tasks. This review suggests that quantitative electroencephalography can be used to assess the effects of taVNS on brain activity, however more studies are needed to systematically establish the specific effects and metrics that would reflect the non-invasive stimulation through the auricular branch of the vagus nerve.

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Background: Novel coronavirus disease (COVID-19) morbidity is not restricted to the respiratory system, but also affects the nervous system. Non-invasive neuromodulation may be useful in the treatment of the disorders associated with COVID-19. Objective: To describe the rationale and empirical basis of the use of non-invasive neuromodulation in the management of patients with COVID-10 and related disorders. Methods: We summarize COVID-19 pathophysiology with emphasis of direct neuroinvasiveness, neuroimmune response and inflammation, autonomic balance and neurological, musculoskeletal and neuropsychiatric sequela. This supports the development of a framework for advancing applications of non-invasive neuromodulation in the management COVID-19 and related disorders. Results: Non-invasive neuromodulation may manage disorders associated with COVID-19 through four pathways: (1) Direct infection mitigation through the stimulation of regions involved in the regulation of systemic anti-inflammatory responses and/or autonomic responses and prevention of neuroinflammation and recovery of respiration; (2) Amelioration of COVID-19 symptoms of musculoskeletal pain and systemic fatigue; (3) Augmenting cognitive and physical rehabilitation following critical illness; and (4) Treating outbreak-related mental distress including neurological and psychiatric disorders exacerbated by surrounding psychosocial stressors related to COVID-19. The selection of the appropriate techniques will depend on the identified target treatment pathway. Conclusion: COVID-19 infection results in a myriad of acute and chronic symptoms, both directly associated with respiratory distress (e.g., rehabilitation) or of yet-to-be-determined etiology (e.g., fatigue). Non-invasive neuromodulation is a toolbox of techniques that based on targeted pathways and empirical evidence (largely in non-COVID-19 patients) can be investigated in the management of patients with COVID-19.