Simulating perinodal changes observed in immune-mediated neuropathies: impact on conduction in a model of myelinated motor and sensory axons

Author:

Sleutjes Boudewijn T. H. M.1,Kovalchuk Maria O.1,Durmus Naric23,Buitenweg Jan R.2,van Putten Michel J. A. M.34ORCID,van den Berg Leonard H.1,Franssen Hessel1

Affiliation:

1. Department of Neurology, Brain Center Utrecht, University Medical Center Utrecht, Utrecht, The Netherlands

2. Biomedical Signals and Systems, MIRA, Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands

3. Department of Clinical Neurophysiology, University of Twente, Enschede, The Netherlands

4. Department of Neurology and Clinical Neurophysiology, Medisch Spectrum Twente, Enschede, The Netherlands

Abstract

Immune-mediated neuropathies affect myelinated axons, resulting in conduction slowing or block that may affect motor and sensory axons differently. The underlying mechanisms of these neuropathies are not well understood. Using a myelinated axon model, we studied the impact of perinodal changes on conduction. We extended a longitudinal axon model (41 nodes of Ranvier) with biophysical properties unique to human myelinated motor and sensory axons. We simulated effects of temperature and axonal diameter on conduction and strength-duration properties. We then studied effects of impaired nodal sodium channel conductance and paranodal myelin detachment by reducing periaxonal resistance, as well as their interaction, on conduction in the 9 middle nodes and enclosed paranodes. Finally, we assessed the impact of reducing the affected region (5 nodes) and adding nodal widening. Physiological motor and sensory conduction velocities and changes to axonal diameter and temperature were observed. The sensory axon had a longer strength-duration time constant. Reducing sodium channel conductance and paranodal periaxonal resistance induced progressive conduction slowing. In motor axons, conduction block occurred with a 4-fold drop in sodium channel conductance or a 7.7-fold drop in periaxonal resistance. In sensory axons, block arose with a 4.8-fold drop in sodium channel conductance or a 9-fold drop in periaxonal resistance. This indicated that motor axons are more vulnerable to developing block. A boundary of block emerged when the two mechanisms interacted. This boundary shifted in opposite directions for a smaller affected region and nodal widening. These differences may contribute to the predominance of motor deficits observed in some immune-mediated neuropathies. NEW & NOTEWORTHY Immune-mediated neuropathies may affect myelinated motor and sensory axons differently. By the development of a computational model, we quantitatively studied the impact of perinodal changes on conduction in motor and sensory axons. Simulations of increasing nodal sodium channel dysfunction and paranodal myelin detachment induced progressive conduction slowing. Sensory axons were more resistant to block than motor axons. This could explain the greater predisposition of motor axons to functional deficits observed in some immune-mediated neuropathies.

Funder

Prinses Beatrix Spierfonds

European Federation of Neurological Societies

Publisher

American Physiological Society

Subject

Physiology,General Neuroscience

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