Effects of transcutaneous vagus nerve stimulation (tVNS) on beta and gamma brain oscillations

Physiological and behavioral effects induced through transcutaneous vagus nerve stimulation (tVNS) are under scrutiny in a growing number of studies, yet its mechanisms of action remain poorly understood. One candidate mechanism is a modulation of γ-aminobutyric acid (GABA) transmission through tVNS. Two recent behavioral studies suggest that such a GABAergic effect might occur in a lateralized fashion, i.e., the GABA modulation might be stronger in the left than in the right brain hemisphere after tVNS applied to the left ear. Using magnetoencephalography (MEG), we tested for GABA-associated modulations in resting and event-related brain oscillations and for a lateralization of those effects in a sample of 41 healthy young adults. Our data provide substantial evidence against all hypotheses, i.e., we neither find effects of tVNS on oscillatory power nor a lateralization of effects

Transcutaneous Vagus Nerve Stimulation (tVNS) and the Dynamics of Visual Bistable Perception

Transcutaneous vagus nerve stimulation (tVNS) is widely used for clinical applications, but its mechanism of action is poorly understood. One candidate pathway that might mediate the effects of tVNS is an increase in GABAergic neurotransmission. In this study, we investigated the effect of tVNS on visual bistable perception, which is highly coupled to GABA. Participants were 34 healthy young subjects. We used a static (Necker cube) and a dynamic (structure from motion) bistable perception task. Each subject underwent tVNS as well as sham (placebo) stimulation for ∼45 min. We analyze effects of tVNS on percept durations by means of Bayesian multilevel regression. We find no evidence for a modulation of bistable perception dynamics through tVNS in either task, but the analyses do not ultimately confirm the null hypothesis either. We discuss different possible implications of our finding and propose that GABAergic effects of tVNS should be further investigated using more direct measures of GABA concentration, and, more generally, that a better understanding of the mechanisms of action of vagus nerve stimulation is needed. Finally, we discuss limitations of our study design, data analysis, and conclusions

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020)

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice

The neuropsychology of transcutaneous vagus nerve simulation

In dieser Dissertation werden neuropsychologische Effekte der transkutanen Vagusnervstimulation sowie ihr therapeutisches Potential im klinischneuropsychologischen Bereich untersucht. Die ersten beiden Studien zielen auf GABAerge Neuromodulation durch tVNS ab. Diese wird als einer der neuronalen Wirkmechanismen der tVNS diskutiert, doch die Evidenzlage ist noch ungenügend. Es wird eine Modulation der automatischen Motorinhibition durch tVNS gezeigt, welche eng mit der GABA-Konzentration im motorischen Kortex assoziiert ist. Andererseits findet sich kein Effekt von tVNS auf visuelle bistabile Perzeption, die eng mit der GABA-Konzentration im visuellen Kortex assoziiert ist. Da die Ergebnisse der beiden Studien kein konsistentes Bild ergeben, ist in dieser Arbeit ein zusätzlicher Studienentwurf enthalten, in dem per MEG gemessene Hirnoszillationen als Indikator für GABAerge Neuromodulation durch tVNS genutzt werden sollen. In der dritten Studie kommt eine Aufgabe zum Einsatz, in der Antwortkonflikte erzeugt werden. Es wird gezeigt, dass tVNS die globale und konfliktspezifische Performanz verbessern sowie frontomediale Theta-Aktivität, einen elektrophysiologischen Index für Konfliktkontrolle, verstärken kann, was das klinisch-neuropsychologische Potenzial der tVNS verdeutlicht. In der vierten Studie werden tonische Pupillengröße und ereigniskorrelierte Pupillenantworten als Indikator für noradrenerge Neuromodulation durch tVNS und als potentieller Biomarker für tVNSResponsivität untersucht. Es zeigt sich kein systematischer Einfluss der tVNS auf die Pupillenmaße. In einem zusätzlichen Bericht wird exploriert, ob Vagussensorisch evozierte Potenziale (VSEP) helfen können, Responder und Nichtresponder zu identifizieren. Im Gesamtfazit hat diese Arbeit das klinische Potenzial der tVNS bestätigt. Die Wirkmechanismen und Determinanten für erfolgreiche Anwendung der tVNS sind jedoch noch ungenügend verstanden.This thesis focuses on neuropsychological effects of transcutaneous vagus nerve stimulation (tVNS) and its potential as a prospective treatment for neuropsychological deficits. The first two studies target behavioral and electrophysiological indices that might support a GABAergic neuromodulation by tVNS. GABAergic neuromodulation is one of the assumed mechanisms of action of tVNS, but the evidence in its favor is sparse. It is shown that tVNS modulates automatic motor inhibition, a process associated to GABA in the motor cortex, but not visual bistable perception, which is associated to GABA in the visual cortex. Moreover, the former effect is restricted to the contralateral brain hemisphere relative to the stimulation, suggesting a possible lateralization of the effect. Since these findings are not fully consistent with respect to GABAergic neuromodulation, a study proposal is enclosed in which GABAergic neuromodulation will be further scrutinized using MEG. The third study investigates effects of tVNS on executive control of action. It is shown that tVNS enhances global and conflict-specific behavioral performance in a cued go-nogochange task as well as conflict-related electrophysiological frontal midline theta responses, rendering it a promising candidate treatment for executive control deficits. The fourth study probes the potential of pupillometry as a non-invasive marker for tVNS responsiveness. No systematic modulation of pupil size readouts by tVNS is found. In an additional short report, it is explored whether vagussensory evoked potentials (VSEP) can help to separate responder and nonresponder groups of individuals. It is concluded that tVNS is a promising clinical method, and its further investigation for neuropsychological applications is promising. On the other hand, its mechanisms of action are still poorly understood and warrant further investigation

Transcutaneous Vagus Nerve Stimulation (tVNS) and the Dynamics of Visual Bistable Perception

Transcutaneous vagus nerve stimulation (tVNS) is widely used for clinical applications, but its mechanism of action is poorly understood. One candidate pathway that might mediate the effects of tVNS is an increase in GABAergic neurotransmission. In this study, we investigated the effect of tVNS on visual bistable perception, which is highly coupled to GABA. Participants were 34 healthy young subjects. We used a static (Necker cube) and a dynamic (structure from motion) bistable perception task. Each subject underwent tVNS as well as sham (placebo) stimulation for ∼45 min. We analyze effects of tVNS on percept durations by means of Bayesian multilevel regression. We find no evidence for a modulation of bistable perception dynamics through tVNS in either task, but the analyses do not ultimately confirm the null hypothesis either. We discuss different possible implications of our finding and propose that GABAergic effects of tVNS should be further investigated using more direct measures of GABA concentration, and, more generally, that a better understanding of the mechanisms of action of vagus nerve stimulation is needed. Finally, we discuss limitations of our study design, data analysis, and conclusions

Electrophysiological Abnormalities in Angelman Syndrome Correlate With Symptom Severity.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the absence of functional UBE3A in neurons. Excess low-frequency oscillations as measured with electroencephalography (EEG) have been identified as a characteristic finding, but the relationship of this EEG finding to the symptomatology of AS and its significance in the pathophysiology of AS remain unknown. METHODS: We used correlations and machine learning to investigate the cross-sectional and longitudinal relationship between EEG spectral power and motor, cognitive, and language skills (Bayley Scales of Infant and Toddler Development, Third Edition); adaptive behavior (Vineland Adaptive Behavior Scales, Second Edition); AS-specific symptoms (AS Clinical Severity Scale); and the age of epilepsy onset in a large sample of children (age: 1-18 years) with AS due to a chromosomal deletion of 15q11-q13 (45 individuals with 72 visits). RESULTS: We found that after accounting for age differences, participants with stronger EEG delta-band abnormality had earlier onset of epilepsy and lower performance scores across symptom domains including cognitive, motor, and communication. Combing spatial and spectral information beyond the delta frequency band increased the cross-sectional association with clinical severity on average by approximately 45%. Furthermore, we found evidence for longitudinal correlations of EEG delta-band power within several performance domains, including the mean across Bayley Scales of Infant and Toddler Development, Third Edition, scores. CONCLUSIONS: Our results show an association between EEG abnormalities and symptom severity in AS, underlining the significance of the former in the pathophysiology of AS. Furthermore, our work strengthens the rationale for using EEG as a biomarker in the development of treatments for AS, a concept that may apply more generally to neurodevelopmental disorders