In der vorliegenden prospektiven Pilotstudie wurden die Hypothesen überprüft, dass es durch die nicht-invasive aurikuläre Vagusnervstimulation, jedoch nicht durch eine Kontrollstimulation am Ohrläppchen, zu einer Steigerung der Befindlichkeit, einer Verbesserung der Kognition und einem positiven Effekt auf die Herzratenvariabilität kommt. Zusammenfassend konnten dabei in dieser Studie geringe Effekte der t-VNS auf einen kognitiven Parameter (F%-Wert des d2-Tests) sowie einen einzelnen HRV-Parameter (pNN50) gezeigt werden, wobei es Hinweise auf eine Intensitätsabhängigkeit der einzelnen Effekte gab. Auf die übrigen erfassten kognitiven Parameter und die weiteren gemessenen HRV-Parameter sowie die Befindlichkeit konnte kein Einfluss der t-VNS nachgewiesen werden. Bestätigt werden konnte das gute Sicherheitsprofil und die gute Tolerabilität der t-VNS. / The aim of this pilot study was to investigate the effects of transcutaneous vagus nerve stimulation on well-being, cognitive parameters and heart rate variability (HRV) compared to a sham-stimulation of the ear lobe. The results showed small effects on one cognitive parameter (F%; d2-test) and one HRV-parameter (pNN50). However, there was no significant effect of transcutaneous vagus nerve stimulation on the other investigated cognitive parameters and HRV-parameters and well-being.

Theoretischer Hintergrund: Im Zuge der aktuellen demographischen Entwicklung konnte in den letzten Dekaden eine extreme Prävalenzzunahme der Demenz vom Alzheimertyp (AD) verzeichnet werden, die insbesondere künftige Generationen vor enorme gesundheitspolitische Herausforderungen stellen wird und zur Entwicklung früherer diagnostischer wie auch effektiver therapeutischer Verfahren drängt. Derzeit verfügbare Biomarker der AD sind entweder zu unspezifisch, invasiv oder zu teuer, um sie als breite Screeningwerkzeuge einsetzen zu können. Insbesondere die Erkenntnis, dass die pathologischen Prozesse der AD lange vor ihrer klinischen Manifestation im unteren Hirnstamm beginnen, führte zu der Entwicklung der neuen Methode der somatosensibel evozierten Potentiale des N. vagus (VSEP), die zunehmend als Marker der vagalen Hirnstammfunktion angesehen wird. Dennoch wurde in letzter Zeit die Aussagekraft der Vaguspotentiale angezweifelt, nachdem eine neuere Studie ihren muskulären Ursprung postulierte. Zur Validierung der parasympathischen Ätiologie der VSEP schien die Herzratenvariabilität (HRV) als breit anerkannter Marker der parasympathischen Aktivität besonders geeignet. Beide Methoden wurden auf ihren Zusammenhang sowie auf eine potentielle Veränderung im Rahmen eines „mild cognitive impairment“ (MCI) untersucht, um ihr diagnostisches Potenzial bezüglich eines prädementiellen Stadiums der AD zu überprüfen. Methoden: Die vorliegende Studie erfolgte als Querschnittsanalyse des ersten Untersuchungszeitpunktes der Vogel-Studie. Nach Ausschluss von Probanden mit HRV- wie VSEP-relevanten Erkrankungen (nicht Hypertonie, Medikamente) und sorgfältiger Datenbearbeitung enthielt die Gesamtstichprobe 218 ältere Probanden im Alter von 74 ± 1.4 Jahren (MCI: n=27; kognitiv gesunde Kontrollen: n=191). Die Erhebung der VSEP erfolgte nach den gängigen Methoden von Fallgatter et al. (2003) an den Elektrodenpositionen Fz-F3, Fz-F4, C3-F3, C4-F4 und T4-O1/T3-O1 bei sukzessiver Stimulation beider Innenseiten des Tragus, die Messung der HRV über 15 min mit einem Finometer® Midi. Nur VSEP-Latenzen (P1, N1, P2) und die vagal modulierten HRV-Variablen RMSSD, LF, HF, RSAnorm (natürlicher Logarithmus) wurden in die weitere Analyse eingeschlossen. Zur Gegenüberstellung von VSEP und HRV in der Kontrollgruppe wurden Korrelationen sowie univariate Varianzanlysen der Quartilgruppen HRV-korrelierter VSEP-Latenzen, zum Vergleich von VSEP und HRV in MCI- und Kontrollgruppe T-Tests für unabhängige Stichproben durchgeführt. Ergebnisse: Für die gesunde Kontrollgruppe konnten in den Korrelationsberechnungen unter Kontrolle potentieller Einflussfaktoren signifikante Ergebnisse in den Elektrodenpositionen T4-O2 (Stimulation rechts) sowie C4-F4 (Stimulation links) verzeichnet werden. Alle Latenzkomponenten des Kanals C4-F4 zeigten signifikante, negative Korrelationen mit den vagal modulierten HRV-Parametern (P1 mit ln RMSSD, ln LF, ln HF, RSAnorm; N1 mit ln RMSSD, ln LF, ln HF; P2 mit ln LF). Die jeweiligen Latenz-Quartilgruppenvergleiche bestätigten, dass längere P1-Latenzen mit einem signifikant geringeren parasympathischen Tonus (RSAnorm, Trend bei HF) und einer signifikant geringeren Funktion der Baroreflexe (LF) einhergeht, wobei letzteres auch für P2 gilt. Die Ergebnisse der VSEP im Kanal T4-O2 fielen zwar konträr aus (positive Korrelation von P2 mit ln LF, ln HF, ln RSAnorm), konnten jedoch auch in Anbetracht eines allgemein schwächeren Zusammenhanges zwischen VSEP und HRV nur unzureichend durch die Varianzanalysen untermauert werden. Die Mittelwertsvergleiche zwischen MCI- und Kontrollgruppe ergaben einerseits vergleichbare HRV-Werte in beiden Gruppen, andererseits eine signifikante P2-Latenzverlängerung im Kanal T4-O2 (Stimulation rechts) in der MCI-Gruppe im Vergleich zu kognitiv gesunden Kontrollen. Schlussfolgerung: Trotz nicht hundertprozentig kongruenter Ergebnisse konnte unter anderem anhand der P1-Latenz im Kanal C4-F4 und der in hohem Maße parasympathisch modulierten RSAnorm ein sehr signifikanter Zusammenhang zwischen HRV und VSEP-Latenzen deutlich gemacht werden. Dies legt den Ursprung der VSEP in den autonomen Strukturen des Hirnstamms nahe. So könnte sich eventuell eine Verzögerung der VSEP-Latenz P2, wie es in der vorliegenden Studie bei MCI-Patienten beobachtet wurde, als additiver, nicht-invasiver Biomarker zur Frühdiagnose von prädementiellen Phasen der AD etablieren. Bereits angelaufene Längsschnittstudien wie die Vogelstudie werden künftig genauere Aussagen über die prädiktive Aussagekraft der VSEP zur Vorhersage einer AD liefern. / Theoretical Background: In the course of the current demographic development, an extreme increase in the prevalence of Alzheimer's disease (AD) has been recorded in recent decades. This will confront particularly future generations with enormous health challenges. Therefore the development of earlier diagnostic as well as effective therapeutic procedures urges. The currently available biomarkers of AD are either non-specific, invasive or too expensive for using them as a screening tool. The insight that the pathological processes of AD start long before their clinical manifestation in the lower brainstem, led to the development of a new method called vagus somatosensory evoked potentials (VSEP), which is increasingly seen as a marker for the vagus activity in the brainstem. Nevertheless the relevance of the VSEP was questioned lately after a newer study stated its muscular origin. The heart rate variability (HRV) is a widely accepted marker of the vagal tone and seemed to be suitable for validating the parasympathetic etiology of the VSEP. The correlation of both methods (VSEP and HRV) was therefore investigated in a group of cognitive healthy participants. This study examined furthermore possible changes of VSEP and HRV in a group of participants with mild cognitive impairment (MCI) in order to validate their diagnostic potential in terms of this symptomatic predementia phase of AD. Methods: The presented study was carried out as a cross-sectional study within the first visit of the Vogel study. After exclusion of participants with diseases that might affect either HRV or VSEP (not hypertension, drugs) and after careful data processing, the total sample contained 218 elderly participants at the age of 74 ± 1.4 years (MCI: n=27, cognitive healthy participants: n=191). The VSEP were measured at the electrode positions Fz-F3, Fz-F4, C3-F3, C4-F4 und T4-O1/T3-O1 on the basis of the common methodology, which was firstly introduced by Fallgatter et al. (2003), by successive transcutaneous stimulation of the vagus nerve at the inner side of the tragus at both ears. The measurement of HRV was carried out over 15 minutes with a Finometer® Midi. Only VSEP latencies (P1, N1, P2) and the vagal modulated HRV variables RMSSD, LF, HF, RSAnorm (natural logarithm) were included in further analysis. To investigate the relationship between VSEP and HRV within the group of cognitive healthy participants, correlations as well as ANOVAs were accomplished. To compare VSEP and HRV between the groups of participants with and without MCI, T-Tests for independent samples were performed. Results: By taking potential influencing factors into account, the correlation of VSEP and HRV was significant for the electrode positions T4-O2 (right vagus stimulation) and C4-F4 (left vagus stimulation) in the group of cognitive healthy participants. All VSEP latencies of the electrode position C4-F4 showed significant, negative correlations with the vagal modulated parameters of HRV (P1 with ln RMSSD, ln LF, ln HF, ln RSAnorm; N1 with ln RMSSD, ln LF, ln HF; P2 with ln LF). As confirmed by ANOVA it could be shown that longer P1-latencies are significantly correlated with a lower vagal tone (RSAnorm, trend for HF) as well as a lower function of the baroreflex (LF) and that longer P2-latencies correlate with a lower L low frequency power of HRV. There were contrary results for the electrode position T4-O2 (positive correlation between P2 and ln LF, ln HF, ln RSAnorm), but the correlation between VSEP and HRV for this electrode position was generally weaker and furthermore insufficiently confirmed by ANOVA. As verified by T-Tests there was on the one hand no significant difference in the parameters of HRV between the MCI group and the control group, on the other hand a significant prolongation of the P2-latencies (T4-O2, right vagus stimulation) was detected in the MCI group in comparison to the group of cognitive healthy participants. Conclusion: In spite of not completely congruent results, this study revealed a significant negative correlation between HRV and VSEP particularly for the electrode position C4-F4. This suggests that the origin of the VSEP is located in the autonomous structures of the brainstem. Thus a delay in the P2-latency of the VSEP, as observed in the group of participants with MCI in this study, could possibly be established as a additive, non-invasive biomarker for an earlier diagnosis of predementia phases of AD. In future longitudinal studies like the Vogel Study will provide more precise information about the predicitve value of the VSEP in terms of the prediction of AD.

No description available.

No description available.

Background: The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact.

<p>Current challenges in neuronal tract tracing include sacrificing the animal, detailed sectioning of the brain, and cumbersome reconstruction of slices to gather information, which are very tedious, time consuming, and have low-throughput. In this regard, Manganese-enhanced Magnetic Resonance Imaging (MEMRI) has been an emerging methodology for fiber tract tracing <i>in vivo</i>. <i></i>The manganese ion (Mn²⁺) is paramagnetic and is analogous to calcium ions (Ca²⁺), which allows it to enter excitable cells through voltage-gated calcium channels, thereby reporting cellular activity in T₁-weighted MR images<i>. </i>Moreover, once the Mn²⁺enters the cell, it will move along the axon by microtubules, release at the synapse, and then uptake by post-synaptic neurons, hence revealing the pathway of Mn²⁺transportation. While most MEMRI neuronal tracing studies have focused on mapping circuitries within the brain, MEMRI has rarely been applied to trace peripheral nerve projections into the brain. </p><p>In this thesis, I will propose the use of MEMRI to trace vagal nerve projections into the central nervous system by showing enhancement of neuronal pathways with an optimized protocol. This protocol demonstrates <i>in vivo </i>monitoring of manganese transport into the brain from the nodose ganglion and shows how the enhancement in MR images can be promoted with vagus nerve stimulation (VNS). Additionally, I will present preliminary findings, for the very first time, that show the downstream projection of the sympathetic pathway from the brainstem. In sum, the technique presented in this thesis will shed light on the use of MEMRI to study the functional results of using clinically-based VNS settings</p>

O nervo vago exerce um papel importante na regulação da homeostase, e seus ramos eferentes emitem sinais capazes de atenuar a resposta inflamatória através da via do reflexo inflamatório. Nossa hipótese foi de que esta via pode também alterar a função das células dendríticas (DCs), uma vez que estas células possuem receptores colinérgicos e podem ser reguladas pelas citocinas inflamatórias. Sendo assim, DCs esplênicas e DCs geradas a partir de células precursoras da medula óssea de animais vagotomizados unilateralmente foram analisadas quanto aos marcadores fenotípicos CD11c e MHC-II e as moléculas co-estimuladoras CD80 e CD86. As DCs derivadas da medula óssea ainda foram avaliadas quanto a função fagocítica, a apresentação de antígenos, bem como, a produção de citocinas do cocultivo destas com linfócitos de camundongos OT-II. Um ensaio de reação de hiperensibilidade tardia (DTH) para se avaliar a resposta imune celular também foi realizado, mas não mostrou alterações significantes. A análise dos marcadores fenotípicos revelou um aumento da expressão de CD80 em DCs esplênicas de animais vagotomizados unilateralmente, mas não houveram alterações nas DCs derivadas da medula óssea. A avaliação da capacidade fagocítica revelou uma diminuição significante em DCs derivadas da medula óssea de animais vagotomizados unilateralmente enquanto no ensaio de proliferação de linfócitos OTII não houve efeito significante. Entre as citocinas avaliadas, a IL-6 e IFN-&#978; se apresentaram aumentadas nos animais vagotomizados unilateralmente. Portanto, o presente trabalho foi capaz de evidenciar que as DCs também estão sujeitas à modulação do sistema nervoso parassimpático, e que, uma vez moduladas, estas células são capazes de exercer influências sobre outras células do sistema imunológico. / The vagus nerve plays an important role in the regulation of homeostasis and its efferent branches emit signals capable of attenuating the inflammatory response via the inflammatory reflex. Our hypothesis was that this pathway may also alter the function of dendritic cells (DCs), since these cells have cholinergic receptors and can be regulated by the inflammatory cytokines. Thus, splenic DCs and DCs generated from bone marrow precursor cells unilaterally vagotomized animals were analyzed for phenotypic markers CD11c and MHC-II and co-stimulatory molecules CD80 and CD86. The bone marrow-derived DCs were also evaluated for phagocytic function, antigen presentation, as well as the production of cytokines such co-culture with lymphocytes from mice OT-II. A delayed type hypersensitivity test (DTH) twas also performed to evaluate the cellular immune response was also performed, but showed no significant changes. The analysis of phenotypic markers showed increased CD80 expression in splenic DCs from unilaterally vagotomized animals but there were no changes in bone marrow-derived DCs. The evaluation of phagocytic ability showed a significant decrease in DCs from unilaterally vagotomized animals while in the OT-II lymphocyte proliferation assay there was no significant effect. Among the cytokines evaluated, IL-6 and IFN-&#978; were increased in unilaterally vagotomized animals. Therefore, this study was able to demonstrate that DCs are also subject to modulation of the parasympathetic nervous system, which, once modulated, these cells are able to exert influence on other cells.

O nervo vago exerce um papel importante na regulação da homeostase, e seus ramos eferentes emitem sinais capazes de atenuar a resposta inflamatória através da via do reflexo inflamatório. Nossa hipótese foi de que esta via pode também alterar a função das células dendríticas (DCs), uma vez que estas células possuem receptores colinérgicos e podem ser reguladas pelas citocinas inflamatórias. Sendo assim, DCs esplênicas e DCs geradas a partir de células precursoras da medula óssea de animais vagotomizados unilateralmente foram analisadas quanto aos marcadores fenotípicos CD11c e MHC-II e as moléculas co-estimuladoras CD80 e CD86. As DCs derivadas da medula óssea ainda foram avaliadas quanto a função fagocítica, a apresentação de antígenos, bem como, a produção de citocinas do cocultivo destas com linfócitos de camundongos OT-II. Um ensaio de reação de hiperensibilidade tardia (DTH) para se avaliar a resposta imune celular também foi realizado, mas não mostrou alterações significantes. A análise dos marcadores fenotípicos revelou um aumento da expressão de CD80 em DCs esplênicas de animais vagotomizados unilateralmente, mas não houveram alterações nas DCs derivadas da medula óssea. A avaliação da capacidade fagocítica revelou uma diminuição significante em DCs derivadas da medula óssea de animais vagotomizados unilateralmente enquanto no ensaio de proliferação de linfócitos OTII não houve efeito significante. Entre as citocinas avaliadas, a IL-6 e IFN-&#978; se apresentaram aumentadas nos animais vagotomizados unilateralmente. Portanto, o presente trabalho foi capaz de evidenciar que as DCs também estão sujeitas à modulação do sistema nervoso parassimpático, e que, uma vez moduladas, estas células são capazes de exercer influências sobre outras células do sistema imunológico. / The vagus nerve plays an important role in the regulation of homeostasis and its efferent branches emit signals capable of attenuating the inflammatory response via the inflammatory reflex. Our hypothesis was that this pathway may also alter the function of dendritic cells (DCs), since these cells have cholinergic receptors and can be regulated by the inflammatory cytokines. Thus, splenic DCs and DCs generated from bone marrow precursor cells unilaterally vagotomized animals were analyzed for phenotypic markers CD11c and MHC-II and co-stimulatory molecules CD80 and CD86. The bone marrow-derived DCs were also evaluated for phagocytic function, antigen presentation, as well as the production of cytokines such co-culture with lymphocytes from mice OT-II. A delayed type hypersensitivity test (DTH) twas also performed to evaluate the cellular immune response was also performed, but showed no significant changes. The analysis of phenotypic markers showed increased CD80 expression in splenic DCs from unilaterally vagotomized animals but there were no changes in bone marrow-derived DCs. The evaluation of phagocytic ability showed a significant decrease in DCs from unilaterally vagotomized animals while in the OT-II lymphocyte proliferation assay there was no significant effect. Among the cytokines evaluated, IL-6 and IFN-&#978; were increased in unilaterally vagotomized animals. Therefore, this study was able to demonstrate that DCs are also subject to modulation of the parasympathetic nervous system, which, once modulated, these cells are able to exert influence on other cells.

abstract: Vagus nerve stimulation (VNS) has shown benefits beyond its original therapeutic application, though there is a lack of research into these benefits in healthy and athletic populations. To address this gap in the VNS literature, the present study addresses the feasibility and possible efficacy of transcutaneous VNS (tVNS) in improving performance and various biometrics during two athletic tasks: golf tee shots and baseball pitching. Performance, cortical dynamics, anxiety measures, muscle excitation, and heart rate characteristics were assessed before and after stimulation using electroencephalography (EEG), the State-Trait Anxiety Inventory (STAI), and electrocardiography (ECG) during the baseball and golf tasks as well as electromyography (EMG) for muscle excitation in the golf participants. Golfers exhibited increased perceived quality of each repetition (independent from outcome) and an improvement in state and trait anxiety after stimulation. Golfers in the active stimulation group also showed a greater reduction in right upper trapezius muscle excitation when compared to the sham stimulation group. Baseball pitchers exhibited an increase in perceived quality of each repetition (independent from outcome) after active stimulation but not an improvement of state and trait anxiety. No significant effects of stimulation Priming, stimulation Type, or the Priming×Type interaction were seen in heart rate, EEG, or performance in the golf or baseball tasks. The present study supports the feasibility of tVNS in sports and athletic tasks and suggests the need for future research to investigate further into the effects of tVNS on the performance, psychologic, and physiologic attributes of athletes during competition. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2019

abstract: Stroke remains a leading cause of adult disability in the United States. In recent studies, chronic vagus nerve stimulation (VNS) has been proven to enhance functional recovery when paired with motor rehabilitation training after stroke. Other studies have also demonstrated that delivering VNS during the onset of a stroke may elicit some neuroprotective effects as observed in remaining neural tissue and motor function. While these studies have demonstrated the benefits of VNS as a treatment or therapy in combatting stroke damage, the mechanisms responsible for these effects are still not well understood or known. The aim of this research was to further investigate the mechanisms underlying the efficacy of acute VNS treatment of stroke by observing the effect of VNS when applied after the onset of stroke. Animals were randomly assigned to three groups: Stroke animals received cortical ischemia (ET-1 injection), VNS+Stroke animals received acute VNS starting within 48 hours after cortical ischemia and continuing once per day for three days, or Control animals which received neither the injury nor stimulation. Results showed that stroke animals receiving acute VNS had smaller lesion volumes and larger motor cortical maps than those in the Stroke group. The results suggest VNS may confer neuroprotective effects when delivered within the first 96 hours of stroke. / Dissertation/Thesis / Masters Thesis Electrical Engineering 2019