Simulating focal demyelinating neuropathies: membrane property abnormalities

Abstract

Membrane properties such as potentials (intracellular, extracellular, electrotonic) and axonal excitability indices (strength-duration and charge-duration curves, strength-duration time constants, rheobasic currents, recovery cycles) can now be measured in healthy subjects and patients with demyelinating neuropathies. They are regarded here in two cases of simultaneously reduced paranodal seal resistance and myelin lamellae in one to three consecutive internodes of human motor nerve fiber. The investigations are performed for 70 and 96% myelin reduction values. The first value is not sufficient to develop a conduction block, but the second leads to a block and the corresponding demyelinations are regarded as mild and severe. For both the mild and severe demyelinations, the paranodally internodally focally demyelinated cases (termed as PIFD1, PIFD2, and PIFD3, respectively, with one, two, and three demyelinated internodes) are simulated using our previous double-cable model of the fiber. The axon model consists of 30 nodes and 29 internodes. The membrane property abnormalities obtained can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome (GBS) and multifocal motor neuropathy (MMN). The study confirms that focal demyelinations are specific indicators for acquired demyelinating neuropathies. Moreover, the following changes have been calculated in our previous papers: (1) uniform reduction of myelin thickness in all internodes (Stephanova et al. in Clin Neurophysiol 116: 1153-1158, 2005); (2) demyelination of all paranodal regions (Stephanova and Daskalova in Clin Neurophysiol 116: 1159-1166, 2005a); (3) simultaneous reduction of myelin thickness and paranodal demyelination in all internodes (Stephanova and Daskalova in Clin Neurophysiol 116: 2334-2341, 2005b); and (4) reduction of myelin thickness of up to three internodes (Stephanova et al., in J Biol Phys, 2006a,b, DOI: 10.1007/s10867-005-9001-9; DOI: 10.1007/s10867-006-9008-x). The membrane property abnormalities obtained in the homogeneously demyelinated cases are quite different and abnormally greater than those in the case investigated here of simultaneous reduction in myelin thickness and paranodal demyelination of up to three internodes. Our previous and present results show that unless focal demyelination is severe enough to cause outright conduction block, changes are so slight as to be essentially indistinguishable from normal values. Consequently, the excitability-based approaches that have shown strong potential as diagnostic tools in systematically demyelinated conditions may not be useful in detecting mild focal demyelinations, independently of whether they are internodal, paranodal, or paranodal internodal.

Sensory root demyelination: Transforming touch into pain

“…Meanwhile, the propagation of action potentials along LTMRs should be hindered at the demyelinated axons in sensory roots, since myelin sheaths insulate the corresponding axons from their surroundings and assist in the rapid and salutatory conduction of action potentials (Damasio & Carvalho, 2013;Naud & Longtin, 2019;Reutskiy et al, 2003). As a result, ionic exchanges between the demyelinated axons and their surroundings are locally increased here (Damasio & Carvalho, 2013;Stephanova et al, 2007). Both close axolemmal apposition and local increase of ionic exchanges provide the basis for ephaptic axon-axon coupling between demyelinated LTMRs and nociceptive Aδ/C primary afferents in the demyelinated sensory roots F I G U R E 4 Sensory root demyelination would be necessary for the development of painful touch after mice nerve injuries.…”

Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling

“…The challenge lies in interpreting those observations. To this end, the group of Stephanova has simulated progressively greater degrees of systematic and focal demyelination of motor fibers to try to explain the observed physiological changes [ 26 , 27 , 28 , 29 , 30 , 31 ] (see Modeling section below).…”