Post-implantation facial nerve stimulation is a common side-effect of cochlear electrical stimulation. Facial nerve stimulation can often be resolved through adjustments in speech processor fitting but, in some instances, exhibit limited benefit or may have a detrimental effect on speech perception. In this study, the apical reference stimulation mode was investigated as a potential intervention to facial nerve stimulation. Firstly, a model refinement software tool was developed to improve the accuracy of models created by an automated workflow. Secondly, the refined model of the human cochlea, facial nerve and electrode array, coupled with a neural model, was used to predict excitations of auditory and facial nerve fibres. Finally, psychoacoustic tests were used to determine auditory comfort and threshold levels for the apical reference stimulation mode while simultaneously capturing electromyography data. The refinement tool illustrated an improved accuracy compared to measured data. Models predicted a desirable outcome for apical reference stimulation, as facial nerve fibre thresholds were higher and auditory thresholds were lower, in direct comparison to conventional monopolar stimulation. Psychoacoustic tests illustrated decreased auditory thresholds and increased dynamic range during apical reference stimulation. Furthermore, apical reference stimulation resulted in lower electromyography energy levels, compared to conventional monopolar stimulation, which suggests a reduction in facial nerve stimulation. Subjective feedback corroborated that apical reference stimulation alleviated facial nerve stimulation. This suggests that apical reference stimulation may be a viable strategy to alleviate facial nerve stimulation considering the improvements in dynamic range and auditory thresholds, complemented with a reduction in facial nerve stimulation / Dissertation (MEng (Bioengineering))--University of Pretoria, 2019. / NRF / Electrical, Electronic and Computer Engineering / MEng (Bioengineering) / Unrestricted

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.

Indiana University-Purdue University Indianapolis (IUPUI) / The pain-controlling effects of a recently introduced electronic dental anesthesia device (CEDETA) were compared with those of local anesthesia in this study. Procedures performed involved full-coverage stainless steel crowns on maxillary primary molars, some of which required indirect pulp therapy and pulpotomies. A total of 55 children, aged 6 years to 10 1/2 years, were randomly selected to have treatment done with CEDETA or local anesthetic. Eight of these patients were treated with both CEDETA and local anesthetic at different appointments. At various times during each procedure, the patient and operator rated the patient's level of discomfort using a 6-point Visual Analog Scale. For each of the five evaluation steps, no significant differences existed in discomfort ratings between the CEDETA and local anesthetic methods for the group of eight patients or for the entire group. Operator ratings of patient discomfort did not vary significantly between the two methods of anesthesia for each of the evaluation steps, except at the step of maximum output or after injection, when the CEDETA group as a whole had significantly lower operator-rated pain. In general, patients tended to rate their perceptions of pain higher than those of the operator. Although the operator and patients in this study found CEDETA to be as effective as local anesthetic for controlling dental operative pain, a number of factors must be considered when deciding to use this type of electronic dental anesthesia. A substantial monetary investment is required to purchase the CEDETA device and the disposable electrodes and batteries to power the unit. There is an increased operating expense for each procedure done when using CEDETA, because of the additional time needed for the operator, staff, and patients to become familiar with the use of the device. Additional setup and break-down time is also needed when using CEDETA as opposed to local anesthetic.

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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