Linking demyelination to compound action potential dispersion with a spike-diffuse-spike approach

Area of Science:

• Neuroscience
• Computational Biology
• Biophysics

Background:

• Demyelinating diseases necessitate understanding axonal propagation for biomarker discovery.
• Axonal function is critical for neurological health and disease pathology.

Purpose of the Study:

• To develop and utilize a novel computational framework to investigate the impact of demyelination on axonal signal transmission.
• To explore how demyelination affects action potential propagation, transmission probability, delay, and jitter.

Main Methods:

• Introduction of the stochastic spike-diffuse-spike (SSDS) model, simulating nodal and internodal axonal compartments.
• Modeling nodal excitability via stochastic integrate-and-fire operations and internodal propagation using linear filtering.
• Incorporation of sodium channel remodeling to simulate homeostatic control of nodal excitability.

Main Results:

• Demyelination-induced impedance mismatch impedes action potential propagation primarily upon exiting demyelinated segments.
• Increased nodal excitability can compensate for mild demyelination, restoring transmission probability and reducing delay.
• Spike timing jitter consistently reflects demyelination levels, regardless of compensatory excitability changes.
• Accumulated jitter contributes to compound action potential broadening, linking microscopic demyelination to macroscopic changes.

Conclusions:

• Action potential jitter and compound action potential dispersion are potential biomarkers for detecting weak and sporadic demyelination.
• The SSDS model provides mechanistic insights into how demyelination affects axonal function.
• Understanding these effects is crucial for developing diagnostic tools for demyelinating diseases.