Primary paranode demyelination modulates slowly developing axonal depolarization in a model of axonal injury

Abstract

Neurological sequelae of mild traumatic brain injury are associated with the damage to white matter myelinated axons. In vitro models of axonal injury suggest that the progression to pathological ruin is initiated by the mechanical damage to tetrodotoxin-sensitive voltage-gated sodium channels that breaches the ion balance through alteration in kinetic properties of these channels. In myelinated axons, sodium channels are concentrated at nodes of Ranvier, making these sites vulnerable to mechanical injury. Nodal damage can also be inflicted by injury-induced partial demyelination of paranode/juxtaparanode compartments that flank the nodes and contain high density of voltage-gated potassium channels. Demyelination-induced potassium deregulation can further aggravate axonal damage; however, the role of paranode/juxtaparanode demyelination in immediate impairment of axonal function, and its contribution to the development of axonal depolarization remain elusive. A biophysically realistic computational model of myelinated axon that incorporates ion exchange mechanisms and nodal/paranodal/juxtaparanodal organization was developed and used to study the impact of injury-induced demyelination on axonal signal transmission. Injured axons showed alterations in signal propagation that were consistent with the experimental findings and with the notion of reduced axonal excitability immediately post trauma. Injury-induced demyelination strongly modulated the rate of axonal depolarization, suggesting that trauma-induced damage to paranode myelin can affect axonal transition to degradation. Results of these studies clarify the contribution of paranode demyelination to immediate post trauma alterations in axonal function and suggest that partial paranode demyelination should be considered as another "injury parameter" that is likely to determine the stability of axonal function.

3D finite element formulation for mechanical–electrophysiological coupling in axonopathy

“…Other future applications of the model include the study of membrane related injury mechanisms such as mechanoporation [7,11,9,6], coupled left shift of voltage gated ion channels [10] and re-organisation of paranodal junctions [17]. Further development of this framework will also allow for the modelling of electrophysiological driven membrane morphology change observed during patch clamp studies [18].…”

“…The model described above is used as such with E N a = E 0 N a and E K = E 0 K , i.e., no damage is considered. In this case, as the area of the membrane is changing during deformation, the electrophysiological properties vary accordingly, i.e., the integrals in Equation (17) are done with respect to the deformed configuration. This model is in agreement with the fact that growing axons retain their electrophysiological properties per unit membrane area [33].…”

“…Computational studies explicitly modelling electrophysiological alterations are often used to rationalise experimentally observed damage mechanisms [15,16,17]. Babbs and Shi [15] used increasing node width to computationally simulate mild retraction of myelin caused by stretch and crush injuries, while more severe retraction and detachment of paranodal myelin were generalised by decreasing paranodal resistance in their simulation.…”

“…Boucher et al [16] modelled the trauma induced coupled left shift dynamics of N a V 1.6 channels observed experimentally by Wang et al [10] by displacing the membrane potential towards a more hyperpolarised state. Volman and Ng [17] proposed a compartmentalised axon model to consider separately nodes of Ranvier, paranodes and juxtaparanodes, and focussed their investigation on the electrophysiological alteration caused by the nodal junction demyelination observed experimentally [9]. While the studies mentioned above all capture electrophysiological alterations arising from geometrical alterations, they fall short of directly relating the electrophysiological alterations to mechanical deformation (i.e., any mechanical deformation automatically affects the electrophysiolgical model), hence limiting the ability to model graded damage under varying degrees of deformation with one unique model [18,10,7].…”

A Mechanistic End-to-End Concussion Model That Translates Head Kinematics to Neurologic Injury

“…A one-dimensional multi-compartmental cable model with cylindrical geometry was used for describing the myelinated axon. The model myelinated axon consisted of a series of interconnected compartments, with compartmental properties matched to the known biophysical parameters for different axonal segments (nodes, paranodes connecting to nodes and juxtaparanodes, juxtaparanodes connecting to paranodes and internodes, and internodes connecting to juxtaparanodes) (25, 41, 42) (Figure 3A). The axon was ~10 mm long (although the length could be easily adjusted), with 100 fully myelinated internodal segments (length, 80 μm), interspersed by 101 non-myelinated nodes of Ranvier (length, 1 μm).…”