Degeneracy in epilepsy: multiple routes to hyperexcitable brain circuits and their repair

Abstract

Due to its complex and multifaceted nature, developing effective treatments for epilepsy is still a major challenge. To deal with this complexity we introduce the concept of degeneracy to the field of epilepsy research: the ability of disparate elements to cause an analogous function or malfunction. Here, we review examples of epilepsy-related degeneracy at multiple levels of brain organisation, ranging from the cellular to the network and systems level. Based on these insights, we outline new multiscale and population modelling approaches to disentangle the complex web of interactions underlying epilepsy and to design personalised multitarget therapies.

Fig. 1. Degeneracy in the context of epilepsy spans various levels across different brain regions.

a In this article we exemplify degeneracy in epilepsy across the cellular, network and system level. Levels and sub-components are highlighted. This list reflects the organisation and scope of the article and is not intended to be exhaustive. There are likely to be other levels of organisation that express degeneracy in the context of epilepsy. b The concept of degeneracy, e.g. different changes leading to a similar outcome, can be visualized by a many-to-one relationship between the parametric and the functional space. Diverse changes in the parametric space can lead to a similar pathological outcome in the functional space. Green/violet spheres represent the healthy/pathological case in functional space and in the corresponding parametric space. Black thin arrows symbolise the many-to-one relationship, violet arrows the corresponding pathological transition. c Epilepsy is often multicausal: Pathological changes at the cellular, network and system levels can interact across multiple brain regions. d Thus, similar pathology indices in multiple animals can be caused by degenerate modifications of multiple properties across various levels. Some elements of a and c were adapted from, published under CC BY license http://creativecommons.org/licenses/by/4.0/.

Fig. 2. Ion channel degeneracy explains why epilepsy is typically associated with mutations in multiple risk genes.

a Genetic analysis reveals that both healthy and pathological individuals commonly carry multiple mutations in the 17 known ion channel risk genes for familial human epilepsy. Data reproduced from ref. . b To illustrate why the combined effect of multiple mutations may sometimes, but not always, be detrimental, we create a hypothetical scenario with three voltage-gated ion channels, which are all equally effective. Let us assume, that a healthy state requires that the peak of the combined activation remains in a certain voltage band, green zone. In contrast, if the peak of the combined activation is shifted to a lower or higher voltage a pathological situation may occur, violet zone. In the upper row, all three channels are present. Due to their symmetric activation profiles, the combined activation will be strongest at the center, dashed line, and thus remains in the healthy zone. If both channel 2 and channel 3 are lost, middle row, peak activation shifts to the left and pathology ensues. In contrast, if channel 1 and channel 3 are deleted, lower row, the healthy state is maintained. Modified from ref. . c The combined effect of multiple mutations depends on their specific trajectory in the abstract functional space: Multiple mutations can be neutral if the function simply remains in the healthy zone, upper left green trajectory, or if a detrimental mutation is compensated by a second mutation, right green trajectory. Mutations can be pathological, if they together cause the functional state to leave the healthy zone, violet trajectory.

Fig. 3. Degenerate interactions at the system level during epileptogenesis.

a Complex interactions at the system level illustrate why multiple distinct pathomechanisms may be sufficient but not necessary for epileptogenesis. b Experiments and simulations show that different causes, such as blood-brain barrier (BBB) disruption or neuroinflammation, can lead to a similar epileptic outcome.

Fig. 4. Ion channel degeneracy indicates a need for personalized single- or multitarget pharmacological therapy.

Epileptic hyperexcitability or restoration of normal excitability can be achieved by individual or combined changes in ion channels. The transition between normal excitation (green) and pathological hyperexcitability (violet) occurs when a tipping line is crossed. This transition can be induced for example by variation of sodium (horizontal axis) and potassium (vertical axis) conductance. Decrease in potassium conductance (a), increase in sodium conductance (c), or combining both (b) induces a transition from normal to pathological firing behavior of neurons. Increasing both conductances (d) maintains normal excitability. Conversely, reversal of epileptic hyperexcitability can be achieved by increasing potassium conductance (e), decreasing sodium conductance (f), or applying both changes simultaneously (g). Combined modification (g) moves the system farther away from the dangerous tipping point than isolated modification (e) or (f). For this reason, drugs might treat certain forms of epilepsy better if they modulate two or more types of ion channels simultaneously. This illustrates the potential advantage of multi-target therapy. Modified from refs. ^,.