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

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.

A mathematical model of neuroimmune interactions in epileptogenesis for discovering treatment strategies.

The development of epilepsy (epileptogenesis) involves a complex interplay of neuronal and immune processes. Here, we present a first-of-its-kind mathematical model to better understand the relationships among these processes. Our model describes the interaction between neuroinflammation, blood-brain barrier disruption, neuronal loss, circuit remodeling, and seizures. Formulated as a system of nonlinear differential equations, the model reproduces the available data from three animal models. The model successfully describes characteristic features of epileptogenesis such as its paradoxically long timescales (up to decades) despite short and transient injuries or the existence of qualitatively different outcomes for varying injury intensity. In line with the concept of degeneracy, our simulations reveal multiple routes toward epilepsy with neuronal loss as a sufficient but non-necessary component. Finally, we show that our model allows for in silico predictions of therapeutic strategies, revealing injury-specific therapeutic targets and optimal time windows for intervention.

Implantable Closed-Loop System for Restoration of Blinking in Case of Unilateral Facial Nerve Paralysis.

BACKGROUND: In facial nerve (FN) paralysis, a critical task is to restore the orbicularis oculi muscle (OOM) function to prevent corneal atrophy and vision deterioration. In this study, we present the application of a fully implantable bioelectrical closed-loop system for the restoration of blinking in a rabbit model of unilateral FN paralysis. We test the hypothesis that blinking events on the healthy side of a face could be used to trigger an electrical stimulation of eyelid muscles on the impaired side of the face resulting in functional simultaneous blinking. METHODS: We developed and tested in an animal model a functional prototype of a fully implantable closed-loop device for the restoration of blinking in patients with unilateral FN paralysis. The study was performed on 14 rabbits after complete transection of the FN on 1 side. The animals were divided into 2 groups. In the first group, the subcutaneous electrodes were implanted for functional electrical stimulation of the upper eyelid on the side of the damaged OOM, and the electromyographic signals (EMG) from the healthy OOM were recorded. Two-phase stimulation pulses with adjustable parameters were delivered between electrodes in the medial and lateral corners of a palpebral fissure. Animals from the second group had not received any treatment and were used as a control for facial paralysis. RESULTS: Stimulation parameters that were sufficient to cause complete eyelid closure were estimated. These parameters included pulse current amplitude, pulse width, and stimulation frequency. We also report the modulation of stimulation parameters during the stimulation period (days 8-30 post transection of the FN). The absence of the eyelid closure in the control group after 1 month of denervation was confirmed. CONCLUSION: Our study confirmed the possibility of restoration of simultaneous complete eyelid closure by a pre-pain threshold electrical stimulation using a fully implantable closed-loop device in animals with unilateral FN paralysis.

How Repair-or-Dispose Decisions Under Stress Can Initiate Disease Progression.

Glia, the helper cells of the brain, are essential in maintaining neural resilience across time and varying challenges: By reacting to changes in neuronal health glia carefully balance repair or disposal of injured neurons. Malfunction of these interactions is implicated in many neurodegenerative diseases. We present a reductionist model that mimics repair-or-dispose decisions to generate a hypothesis for the cause of disease onset. The model assumes four tissue states: healthy and challenged tissue, primed tissue at risk of acute damage propagation, and chronic neurodegeneration. We discuss analogies to progression stages observed in the most common neurodegenerative conditions and to experimental observations of cellular signaling pathways of glia-neuron crosstalk. The model suggests that the onset of neurodegeneration can result as a compromise between two conflicting goals: short-term resilience to stressors versus long-term prevention of tissue damage.