Multiple-timescale dynamics, mixed mode oscillations and mixed affective states in a model of bipolar disorder.

Mixed affective states in bipolar disorder (BD) is a common psychiatric condition that occurs when symptoms of the two opposite poles coexist during an episode of mania or depression. A four-dimensional model by Goldbeter (Progr Biophys Mol Biol 105:119-127, 2011; Pharmacopsychiatry 46:S44-S52, 2013) rests upon the notion that manic and depressive symptoms are produced by two competing and auto-inhibited neural networks. Some of the rich dynamics that this model can produce, include complex rhythms formed by both small-amplitude (subthreshold) and large-amplitude (suprathreshold) oscillations and could correspond to mixed bipolar states. These rhythms are commonly referred to as mixed mode oscillations (MMOs) and they have already been studied in many different contexts by Bertram (Mathematical analysis of complex cellular activity, Springer, Cham, 2015), (Petrov et al. in J Chem Phys 97:6191-6198, 1992). In order to accurately explain these dynamics one has to apply a mathematical apparatus that makes full use of the timescale separation between variables. Here we apply the framework of multiple-timescale dynamics to the model of BD in order to understand the mathematical mechanisms underpinning the observed dynamics of changing mood. We show that the observed complex oscillations can be understood as MMOs due to a so-called folded-node singularity. Moreover, we explore the bifurcation structure of the system and we provide possible biological interpretations of our findings. Finally, we show the robustness of the MMOs regime to stochastic noise and we propose a minimal three-dimensional model which, with the addition of noise, exhibits similar yet purely noise-driven dynamics. The broader significance of this work is to introduce mathematical tools that could be used to analyse and potentially control future, more biologically grounded models of BD.