Mediastinal nerve stimulation (MNS) reproducibly evokes atrial fibrillation (AF) by excessive and heterogeneous activation of intrinsic cardiac (IC) neurons. This study evaluated whether preemptive vagus nerve stimulation (VNS) impacts MNS-induced evoked changes in IC neural network activity to thereby alter susceptibility to AF. IC neuronal activity in the right atrial ganglionated plexus was directly recorded in anesthetized canines (n = 8) using a linear microelectrode array concomitant with right atrial electrical activity in response to: 1) epicardial touch or great vessel occlusion vs. 2) stellate or vagal stimulation. From these stressors, post hoc analysis (based on the Skellam distribution) defined IC neurons so recorded as afferent, efferent, or convergent (afferent and efferent inputs) local circuit neurons (LCN). The capacity of right-sided MNS to modify IC activity in the induction of AF was determined before and after preemptive right (RCV)- vs. left (LCV)- sided VNS (15 Hz, 500 μs; 1.2× bradycardia threshold). Neuronal (n = 89) activity at baseline (0.11 ± 0.29 Hz) increased during MNS-induced AF (0.51 ± 1.30 Hz; P ˂ 0.001). Convergent LCNs were preferentially activated by MNS. Preemptive RCV reduced MNS-induced changes in LCN activity (by 70%) while mitigating MNS-induced AF (by 75%). Preemptive LCV reduced LCN activity by 60% while mitigating AF potential by 40%. IC neuronal synchrony increased during neurally induced AF, a local neural network response mitigated by preemptive VNS. These antiarrhythmic effects persisted post-VNS for, on average, 26 min. In conclusion, VNS preferentially targets convergent LCNs and their interactive coherence to mitigate the potential for neurally induced AF. The antiarrhythmic properties imposed by VNS exhibit memory.

Using vagus nerve stimulation (VNS), we sought to determine the contribution of vagal afferents to efferent control of cardiac function. In anesthetized dogs, the right and left cervical vagosympathetic trunks were stimulated in the intact state, following ipsilateral or contralateral vagus nerve transection (VNTx), and then following bilateral VNTx. Stimulations were performed at currents from 0.25 to 4.0 mA, frequencies from 2 to 30 Hz, and a 500-μs pulse width. Right or left VNS evoked significantly greater current-and frequency-dependent suppression of chronotropic, inotropic, and lusitropic function subsequent to sequential VNTx. Bradycardia threshold was defined as the current first required for a 5% decrease in heart rate. The threshold for the right vs. left vagus-induced bradycardia in the intact state (2.91 ± 0.18 and 3.47 ± 0.20 mA, respectively) decreased significantly with right VNTx (1.69 ± 0.17 mA for right and 3.04 ± 0.27 mA for left) and decreased further following bilateral VNTx (1.29 ± 0.16 mA for right and 1.74 ± 0.19 mA for left). Similar effects were observed following left VNTx. The thresholds for afferent-mediated effects on cardiac parameters were 0.62 ± 0.04 and 0.65 ± 0.06 mA with right and left VNS, respectively, and were reflected primarily as augmentation. Afferent-mediated tachycardias were maintained following β-blockade but were eliminated by VNTx. The increased effectiveness and decrease in bradycardia threshold with sequential VNTx suggest that 1) vagal afferents inhibit centrally mediated parasympathetic efferent outflow and 2) the ipsilateral and contralateral vagi exert a substantial buffering capacity. The intact threshold reflects the interaction between multiple levels of the cardiac neural hierarchy.

Intracardiac pathways mediating the parasympathetic control of various cardiac functions are incompletely understood. Several intracardiac ganglia have been demonstrated to potently influence cardiac rate [the sinoatrial (SA) ganglion], atrioventricular (AV) conduction (the AV ganglion), or left ventricular contractility (the cranioventricular ganglion). However, there are numerous ganglia found throughout the heart whose functions are poorly characterized. One such ganglion, the posterior atrial (PA) ganglion, is found in a fat pad on the rostral dorsal surface of the right atrium. We have investigated the potential impact of this ganglion on cardiac rate and AV conduction. We report that microinjections of a ganglionic blocker into the PA ganglion significantly attenuates the negative chronotropic effects of vagal stimulation without significantly influencing negative dromotropic effects. Because prior evidence indicates that the PA ganglion does not project to the SA node, we neuroanatomically tested the hypothesis that the PA ganglion mediates its effect on cardiac rate through an interganglionic projection to the SA ganglion. Subsequent to micro-injections of the retrograde tracer fast blue into the SA ganglion, >70% of the retrogradely labeled neurons found within five intracardiac ganglia throughout the heart were observed in the PA ganglion. The neuroanatomic data further indicate that intraganglionic neuronal circuits are found within the SA ganglion. The present data support the hypothesis that two interacting cardiac centers, i.e., the SA and PA ganglia, mediate the peripheral parasympathetic control of cardiac rate. These data further support the emerging concept of an intrinsic cardiac nervous system.

Background Autonomic regulation therapy involving either vagus nerve stimulation (VNS) or spinal cord stimulation (SCS) represents emerging bioelectronic therapies for heart disease. The objective of this study was to determine if VNS and/or SCS modulate primary cardiac afferent sensory transduction of the ischemic myocardium. Methods Using extracellular recordings in 19 anesthetized canines, of 88 neurons evaluated, 36 ventricular-related nodose ganglia sensory neurons were identified by their functional activity responses to epicardial touch, chemical activation of their sensory neurites (epicardial veratridine) and great vessel (descending aorta or inferior vena cava) occlusion. Neural responses to 1 min left anterior descending (LAD) coronary artery occlusion (CAO) were then evaluated. These interventions were then studied following either: i) SCS [T1-T3 spinal level; 50 Hz, 90% motor threshold] or ii) cervical VNS [15–20 Hz; 1.2 × threshold]. Results LAD occlusion activated 66% of identified nodose ventricular sensory neurons (0.33 ± 0.08–0.79 ± 0.20 Hz; baseline to CAO; p < 0.002). Basal activity of cardiac-related nodose neurons was differentially reduced by VNS (0.31 ± 0.11 to 0.05 ± 0.02 Hz; p < 0.05) as compared to SCS (0.36 ± 0.12 to 0.28 ± 0.14, p = 0.59), with their activity response to transient LAD CAO being suppressed by either SCS (0.85 ± 0.39–0.11 ± 0.04 Hz; p < 0.03) or VNS (0.75 ± 0.27–0.12 ± 0.05 Hz; p < 0.04). VNS did not alter evoked neural responses of cardiac-related nodose neurons to great vessel occlusion. Conclusions Both VNS and SCS obtund ventricular ischemia induced enhancement of nodose afferent neuronal inputs to the medulla.

Key points: The evoked cardiac response to bipolar cervical vagus nerve stimulation (VNS) reflects a dynamic interaction between afferent mediated decreases in central parasympathetic drive and suppressive effects evoked by direct stimulation of parasympathetic efferent axons to the heart. The neural fulcrum is defined as the operating point, based on frequency–amplitude–pulse width, where a null heart rate response is reproducibly evoked during the on-phase of VNS. Cardiac control, based on the principal of the neural fulcrum, can be elicited from either vagus. Beta-receptor blockade does not alter the tachycardia phase to low intensity VNS, but can increase the bradycardia to higher intensity VNS. While muscarinic cholinergic blockade prevented the VNS-induced bradycardia, clinically relevant doses of ACE inhibitors, beta-blockade and the funny channel blocker ivabradine did not alter the VNS chronotropic response. While there are qualitative differences in VNS heart control between awake and anaesthetized states, the physiological expression of the neural fulcrum is maintained. Abstract: Vagus nerve stimulation (VNS) is an emerging therapy for treatment of chronic heart failure and remains a standard of therapy in patients with treatment-resistant epilepsy. The objective of this work was to characterize heart rate (HR) responses (HRRs) during the active phase of chronic VNS over a wide range of stimulation parameters in order to define optimal protocols for bidirectional bioelectronic control of the heart. In normal canines, bipolar electrodes were chronically implanted on the cervical vagosympathetic trunk bilaterally with anode cephalad to cathode (n = 8, ‘cardiac’ configuration) or with electrode positions reversed (n = 8, ‘epilepsy’ configuration). In awake state, HRRs were determined for each combination of pulse frequency (2–20 Hz), intensity (0–3.5 mA) and pulse widths (130–750 μs) over 14 months. At low intensities and higher frequency VNS, HR increased during the VNS active phase owing to afferent modulation of parasympathetic central drive. When functional effects of afferent and efferent fibre activation were balanced, a null HRR was evoked (defined as ‘neural fulcrum’) during which HRR ≈ 0. As intensity increased further, HR was reduced during the active phase of VNS. While qualitatively similar, VNS delivered in the epilepsy configuration resulted in more pronounced HR acceleration and reduced HR deceleration during VNS. At termination, under anaesthesia, transection of the vagi rostral to the stimulation site eliminated the augmenting response to VNS and enhanced the parasympathetic efferent-mediated suppressing effect on electrical and mechanical function of the heart. In conclusion, VNS activates central then peripheral aspects of the cardiac nervous system. VNS control over cardiac function is maintained during chronic therapy.

Vagus nerve stimulation (VNS) currently treats patients with drug-resistant epilepsy, depression, and heart failure. The mild intensities used in chronic VNS suggest that primary visceral afferents and central nervous system activation are involved. Here, we measured the activity of neurons in the nucleus of the solitary tract (NTS) in anesthetized rats using clinically styled VNS. Our chief findings indicate that VNS at threshold bradycardic intensity activated NTS neuron discharge in one-third of NTS neurons. This VNS directly activated only myelinated vagal afferents projecting to second-order NTS neurons. Most VNS-induced activity in NTS, however, was unsynchronized to vagal stimuli. Thus, VNS activated unsynchronized activity in NTS neurons that were second order to vagal afferent C-fibers as well as higher-order NTS neurons only polysynaptically activated by the vagus. Overall, cardiovascular-sensitive and -insen-sitive NTS neurons were similarly activated by VNS: 3/4 neurons with monosynaptic vagal A-fiber afferents, 6/42 neurons with monosynaptic vagal C-fiber afferents, and 16/21 polysynaptic NTS neurons. Provocatively, vagal A-fibers indirectly activated C-fiber neurons during VNS. Elevated spontaneous spiking was quantitatively much higher than synchronized activity and extended well into the periods of nonstimulation. Surprisingly, many polysynaptic NTS neurons responded to half the bradycardic intensity used in clinical studies, indicating that a subset of myelinated vagal afferents is sufficient to evoke VNS indirect activation. Our study uncovered a myelinated vagal afferent drive that indirectly activates NTS neurons and thus central pathways beyond NTS and support reconsideration of brain contributions of vagal afferents underpinning of therapeutic impacts. NEW & NOTEWORTHY Acute vagus nerve stimulation elevated activity in neurons located in the medial nucleus of the solitary tract. Such stimuli directly activated only myelinated vagal afferents but indirectly activated a subpopulation of second- and higher-order neurons, suggesting that afferent mechanisms and central neuron activation may be responsible for vagus nerve stimulation efficacy.

Transcutaneous auricular vagal nerve stimulation (taVNS) is a non-invasive method of activating axons in the auricular branch of the vagus nerve through the concha of the outer ear. taVNS is under investigation as an alternative treatment option for a wide range of disorders. Vagal afferent fibers terminate in the nucleus of the solitary tract (NTS) where information is processed and relayed to higher brain regions influencing sympathetic and parasympathetic systems. Due to extensive neuronal connections, it is likely that taVNS could serve as a treatment option for many disorders, specifically cardiac, migraine, and gastric motility disorders. Human fMRI studies have indicated that taVNS elicits neuronal responses within NTS and spinal trigeminal nucleus (Sp5c). Studies have indicated that caudal NTS (cNTS) has substantial connections with the cardiac system, rostral NTS (rNTS) is relevant for gastric motility, and Sp5c is likely involved in migraine disorders due to meningeal connections. Aberrant neuronal signaling is likely responsible for the development of these disorders, and taVNS has the potential to modulate neuronal activity to reestablish homeostatic signaling. In this study, electrophysiological methods were used to interrogate neuronal activity of 50-70 neurons within cNTS, rNTS, and Sp5c following taVNS. A high-impedance tungsten electrode was placed stereotaxically in 15 male Sprague-Dawley rats anesthetized with chloralose. Changes in neuronal firing rates were investigated during and immediately following taVNS by comparing changes in neuronal activity to baseline levels using the software Spike 2 v9.14. Neurons were classified as negative responders if activity decreased more than 20%, positive responders if activity increased more than 20%, or non-responders if activity changes were less than 20%. Six different taVNS parameters were investigated using three frequencies (20, 100, 250Hz) at two intensity levels (0.5, 1.0mA). Data from this study suggest that taVNS can modulate neuronal activity in a frequency and intensity-dependent manner. The greatest positive activation for all 3 brain regions occurred at 20Hz, 1.0mA stimulation where an average of 46% ± 9% neurons showed increased firing compared to 29% ± 2% positive responders for other paradigms. The greatest negative activation for all 3 regions occurred at 100Hz, regardless of intensity, where an average of 33% ± 1% neurons showed reduced firing compared to 15% ± 2% negative responders for remaining paradigms. Based on what is known about cardiac, migraine, and gastric motility disorders, it is likely that taVNS can be used to modulate activity in NTS and Sp5c to provide beneficial treatment options to patients. Specifically, using paradigms yielding decreased activity in Sp5c could improve migraine symptoms, and paradigms increasing activity in cNTS and rNTS could improve cardiac and gastric motility disorders, respectively.

Die vorliegende Studie beschreibt eine neuartige Methode der Auslösung eines Blinkreflexes (BR), welcher ein unwillkürliches Zusammenkneifen der Augenringmuskulatur darstellt, wie sie nach elektrophysiologischer Reizung des somatosensiblen Anteils des Vaguskernkomplexes am äußeren Gehörgang am Ramus auricularis nervi vagi (RANV) und anderen Stimulationsorten auftritt. Durch den Vergleich dieser neuen Methode mit ähnlichen, bereits etablierten Methoden wurde diese validiert. Etablierte Methoden sind dabei die Stimulation des Nervus (N.) trigeminus (NT) über dem Auge oder des N. medianus (NM) am Handgelenk. Darüber hinaus wurde geklärt, ob diese Methode geeignet ist, bei Patienten mit idiopathischem Parkinsonsyndrom (IPS) Veränderungen im Bereich des Hirnstammes abzubilden, wie sie bereits durch histopathologische Untersuchungen gezeigt werden konnten und diskutiert, in wie weit ausbleibende Veränderungen Rückschlüsse auf anatomische Besonderheiten in den Reflexbahnen der einzelnen Blinkreflexe zulassen und ob derartige Blinkreflexuntersuchungen in Zukunft einen Stellenwert in der Diagnostik von Hirnstammläsionen haben könnten. Das Studienprotokoll inklusive geeigneter Testparameter wurden für den neuen Blinkreflex an einem Kollektiv aus 9 Studenten erprobt, der gesamte Studienablauf unter Hinzunahme der etablierten Blinkreflexe an weiteren 11 Studenten erneut getestet. Nach Abschluss dessen wurden für die Hauptversuchsreihe über die Klinik und Poliklinik für Neurologie 30 Patienten mit IPS rekrutiert, der Schweregrad der motorischen Symptome wurde dabei erhoben (Unified Parkinsons Disease Rating Scale Part III, UPDRS-3). Als Vergleichsgruppe wurden 30 altersentsprechende Kontrollprobanden angeworben, welche nicht an IPS erkrankt waren. Allen Teilnehmern wurde zudem ein Fragebogen bezüglich der subjektiven Schlafqualität (REM-Schlafverhaltens-Fragebogen, RSBDQ) ausgehändigt und ein Demenzscreening wurde durchgeführt (Montreal Cognitive Assessment, MoCA). Neben Area-Under-Curve (AUC) und Latenzwerten nach Stimulation wurde zudem erfasst, wie oft ein Blinkreflex auslösbar war. Stimuliert wurde pro Nerv jeweils fünfmal mit einem zufälligem Inter-Stimulus-Intervall von mindestens 20 Sekunden, nachdem für jede Stimulationsart und -seite eine sensible Reizschwelle manuell bestimmt wurde. Der neuartige RANV-BR konnte in dieser Studie in beiden Vergleichsgruppen wesentlich zuverlässiger als der NM-, aber etwas weniger zuverlässig als der NT-BR ausgelöst werden. Nach statistischen Vergleichen konnte in den Latenz- und AUC-Werten zwischen den IPS Patienten und Kontrollprobanden in keinem der BR-Varianten ein signifikanter Unterschied ermittelt werden. Dies galt auch, durch multiple Regressionsanalyse bestätigt, nach Anpassung an die Ergebnisse des RBDSQ Fragebogens und des MoCA. Darüber hinaus fand sich auch keinen Zusammenhang zwischen Latenzen bzw. AUC und dem Alter, der Krankheitsdauer, UPDRS-3-Score oder dem RBDSQ Ergebnis innerhalb der Gruppe der IPS Patienten. Diese Ergebnisse zeigen, dass der RANV-BR eine zuverlässige Methode zum Auslösen eines BR ist. Er ist nicht geeignet, um Pathologien entsprechend der anatomisch angenommenen Läsionsorte im Hirnstammbereich bei motorisch mäßig schwer betroffenen IPS Patienten nachzuweisen. Auch die etablierten BR-Varianten des NT und NM konnten keine Unterschiede aufdecken. Dies könnte beim RANV-BR an der unterschiedlichen sensiblen Versorgung des äußeren Gehörgangs liegen, welche aufgrund der embryonalen Entwicklung verschiedene Hirnnerven involviert. Eine weitere Begründung liegt daran, dass die Läsionsorte zwar in anatomischer Nähe zu bekannten Reflexbahnen liegen, aber diese nicht involvieren, da von einer Entwicklung des IPS entlang synaptischer Bahnen ausgegangen wird. Somit wären die Blinkreflexbahnen nicht unmittelbar betroffen. In weiterführenden Studien muss geklärt werden, ob schwerer betroffenen Patienten in Phasen ohne Medikation (sog. OFF-Phase) Anomalien der BR zeigen. Ein nicht untersuchter Aspekt stellte die Habituation an wiederkehrende BR dar, welche bei IPS verändert sein könnte. Hinweise auf eine gewisse Lateralität des N. vagus geben Studien, welche unterschiedliche Volumina des sonographisch dargestellten Nervens zeigten, zudem ein reduziertes Volumen bei Patienten mit IPS. Dieser Aspekt könnte in weiterführenden Studien ebenfalls in Zusammenhang mit BR evaluiert werden. Zudem muss erforscht werden, ob BR-Untersuchungen geeignete Tools darstellen, um zwischen IPS und atypischen Parkinsonsyndromen zu unterscheiden.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20755号 / 医博第4285号 / 新制||医||1024(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 宮本 享, 教授 井上 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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