In this paper, we consider networks of reaction-diffusion systems of Hodgkin-Huxley type. We give a general mathematical framework, in which we prove existence and unicity of solutions as well as the existence of invariant regions and of the attractor. Then, we illustrate some relevant numerical examples and exhibit bifurcation phenomena and propagation of bursting oscillations through one and two coupled non-homogeneous systems.

Our aim is to propose a new robust and manageable technique, called multi-base harmonic balance method, to detect and characterize the periodic solutions of a nonlinear dynamical system. Our case test is the Hodgkin-Huxley model, one of the most realistic neuronal models in literature. This system, depending on the value of the external stimuli current, exhibits periodic solutions, both stable and unstable.

Quantitative systems pharmacology (QSP) proved to be a powerful tool to elucidate the underlying pathophysiological complexity that is intensified by the biological variability and overlapped by the level of sophistication of drug dosing regimens. Therapies combining immunotherapy with more traditional therapeutic approaches, including chemotherapy and radiation, are increasingly being used. These combinations are purposed to amplify the immune response against the tumor cells and modulate the suppressive tumor microenvironment (TME). In order to get the best performance from these combinatorial approaches and derive rational regimen strategies, a better understanding of the interaction of the tumor with the host immune system is needed. The objective of the current work is to provide new insights into the dynamics of immune-mediated TME and immune-oncology treatment. As a case study, we will use a recent QSP model by Kosinsky et al. [J. Immunother. Cancer 6, 17 (2018)] that aimed to reproduce the dynamics of interaction between tumor and immune system upon administration of radiation therapy and immunotherapy. Adopting a dynamical systems approach, we here investigate the qualitative behavior of the representative components of this QSP model around its key parameters. The ability of T cells to infiltrate tumor tissue, originally identified as responsible for individual therapeutic inter-variability [Y. Kosinsky et al., J. Immunother. Cancer 6, 17 (2018)], is shown here to be a saddle-node bifurcation point for which the dynamical system oscillates between two states: tumor-free or maximum tumor volume. By performing a bifurcation analysis of the physiological system, we identified equilibrium points and assessed their nature. We then used the traditional concept of basin of attraction to assess the performance of therapy. We showed that considering the therapy as input to the dynamical system translates into the changes of the trajectory shapes of the solutions when approaching equilibrium points and thus providing information on the issue of therapy.

The Hodgkin-Huxley equations constitute one of the more realistic neuronal models in literature and the most accepted one. It is well known that, depending on the value of the external stimuli current, it exhibits periodic solutions, both stable and unstable.Our aim is to detect and characterize such periodic solutions, exploiting a robust and manageable technique, mainly based on harmonic balance method.

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