Vagus nerve stimulation (VNS) has been increasingly used in the treatment of several health conditions. These include treatment-resistant epilepsy, obesity, pain, and incontinence. One of the main obstacles in VNS is the lack of stimulation selectivity when it comes to only activating vagus nerve fibres that produce a desired effect while avoiding activation of non-targeted fibres, the latter of which could lead to serious side effects. In electrical VNS, fibre-selectivity is currently achieved by adjusting parameters of the stimulation waveform. However, the results are less than perfect. While it is possible to selectively activate the large-diameter A-type fibres, selectively activating the small-diameter C-type fibres while avoiding the concurrent recruitment of A-type fibres, proves to be difficult. Moreover, fibre type-selectivity alone cannot always provide adequate control of VNS effects. In this case, spatially selective VNS would need to be deployed: the knowledge of the anatomical arrangement of fibre populations in the vagus nerve can be used to design a stimulator device capable of targeting a single compartment of a nerve fibre, rather than the entire fibre. Spatial targeting of specific areas of the vagus nerve, especially those that lie in the interior, may require complex stimulation waveforms, multi-contact electrodes and cathode/anode arrangements to produce clinically meaningful selectivity.
Other than electrical stimulation, focused ultrasound stimulation (FUS) has also shown potential in targeting specific neural tissue within a larger neural mass, including tissue deeper in the nerve structure. FUS thanks its spatial selectivity to the short wavelength of ultrasound in biological tissue. In ideal circumstances, FUS can achieve a spatial resolution in the order of cubic millimetres in tissue. The inherent focusing ability of ultrasound also simplifies the stimulator design compared to electrical stimulation. Ultrasound has the potential to stimulate the vagus nerve distally and non-invasively while maintaining focality (e.g., transcutaneously through the neck, Fig. 1 left).
Figure 1. Focused ultrasound for vagus nerve stimulation: (left) transducer on the neck, (right) transducers on the nerve.
The goal of this PhD research is to design a FUS system for spatially selective activation of the vagus nerve. The focus is on two usage scenarios: non-invasive transcutaneous FUS (Fig. 1 left) and minimally invasive FUS that places the transducer directly on the vagus nerve (Fig. 1 right). FUS has been rediscovered in the past 15 years and has enjoyed much attention from researchers. Despite this, the mechanisms of action of FUS are still not well-understood. For this reason, this PhD focuses on fundamental research including simulations of FUS biophysics and validation in experimental in-vitro/in-vivo setups. The first subobjective is to build extensive validated knowledge of the biophysics of FUS for VNS. The second subobjective is to formulate the requirements of a prototype FUS system for VNS, focusing on steerability of the stimulation target and low complexity of implementation.
In the first phase of the project, the PhD candidate performs numerical simulations of the acoustic pressure and particle velocity fields induced in the vagus nerve by a FUS transducer or transducer array. Both non-invasive (transducer(s) on the neck) and minimally invasive (transducer(s) on the vagus nerve) usage scenarios are considered. The goal is to design a transducer system of which the pressure focal point is aligned with the stimulation region-of-interest. In the second phase, the field simulations are combined with simulations of the electro-mechanical neuron coupling and vagus nerve fibre response. In-silico optimization of the FUS focal spot and stimulation waveform is performed to maximize fibre recruitment in the region of interest. In the third phase, the optimized design is experimentally validated in phantom models, living tissue and optionally animals. The project end result is a comprehensive set of requirements for a (pre)clinical FUS system for VNS. The end result should pave the way for a future prototype hardware realization of vagus nerve FUS.
Required background: Electrical Engineering, Engineering Physics, Biomedical Engineering