(A) Transcutaneous auricular vagus nerve stimulation using millimeter wave

Abstract

The vagus nerve (VN), the 10th cranial nerve, is the longest of the 12 cranial nerves. It is involved in parasympathetic nervous system, which manages control of mood, immune response, digestion, and heart rate. The vagal afferents, account for 80 % of all fibers, send information about the state of the organs to the brain. Whereas, the vagal efferents, account for 20 % of all fibers, send the signals from brain to the organs. The vagus nerve stimulation (VNS) modulates different brain regions through controlling biofeedback to the brain by stimulation of the vagal afferents. The VNS, which uses a device to stimulate the VN with electrical impulses, has been approved by the US Food and Drug Administration (FDA) for refractory epilepsy, depression. Furthermore, it has been used for various studies and preclinical research including, migraine, heart failure, in inflammation, and Alzheimer's disease. Although 100,000 VNS devices had been implanted in 75,000 patients worldwide (as of 2014), the invasive stimulation of the cervical branch of the vagus nerve, which need the inevitable surgical incision of the neck surgical causes surgical complications and additional costs such as periodic replacement of the stimulation-device batteries. Electric stimulation of auricular vagus nerve is an alternative approach for the invasive stimulation of the cervical branch of the vagus nerve. As a non-invasive neuromodulation technique, the transcutaneous auricular vagus nerve stimulation (ta-VNS) has been used for various conditions, including depression, epilepsy, headaches, and cerebral ischemia. However, unwanted non-vagal nerve stimulation could occur due to diffuse stimulation. This thesis proposes millimeter wave (MMW) as a stimlus source of ta-VNS with a millimeter-square fine spatial resolution without needle electrode penetration. This thesis describes work on the modeling, finite element analysis, and animal test for validating the MMW-based ta-VNS. The main focus of this study is to determine whether MMW could stimulate the focal area within the cymba conchae of the human outer ear. A 60 GHz continuous wave (CW) is selected as a region-specific ta-VNS source to overcome the challenge of diffuse stimulation resulting from ta-VNS using an electric pulse. Electromagnetic simulation results show that the CW propagating the outer ear model at 60 GHz formed the stimulation field whose dimension was 4.79 mm x 4.42 mm, which could be within the region of the cymba conchae (15.8 mm × 6.8 mm) suggesting MMW-based ta-VNS could develop stimulation fields that affect only regions innervated by the auricular branch of vagus nerve (ABVN). Additionally, the electric pulse produced the stimulation field whose dimension was 20.3 mm x 12.1 mm. The MMW-induced neuronal responses of seven mice were evaluated. Transcutaneous auricular VNS (ta-VNS) was applied to the cymba conchae innervated by the AVBN using a 60-GHz continuous wave (CW). As the control, the auricle’s exterior margin was stimulated and referred to as the transcutaneous auricular non-vagus nerve stimulation (ta-nonVNS). During the stimulations, the local field potential (LFP) in the nucleus tractus solitarii (NTS), an afferent vagal projection site, was simultaneously recorded. As the incident power of the MMW-based ta-VNS increased to 7, 10, and 13 dBm, in order, powers in the NTS tended to increase gradually. In particular, the ta-VNS with the stimulus level of 13 dBm showed a significant increase of the LFP power in the NTS. The mean increases in power (n = 7) in the gamma high and gamma very high bands were 8.6 ± 2.0 % and 18.2 ± 5.9 % respectively. However, the ta-nonVNS with the stimulus level of 13 dBm showed significant decrease of the LFP power in the NTS. The mean decreases in power in the beta and gamma low bands were 11.0 ± 4.4 % and 10.8 ± 2.8 %, respectively. These findings suggest that MMW stimulation clearly induced the different response according to the existence of ABVN stimulation. To the best of the author’s knowledge, these results constitute the first demonstration of the impact of an MMW on the central projections of the ABVN. The results also provide a basis for the development of a new modality in the MMW-based stimulation of the ta-VNS with a square-mm spatial resolution.