Internodal conduction in undissected demyelinated nerve fibres

Abstract

SUMMARY1. A new method is described for recording external longitudinal currents from single undissected nerve fibres in rat ventral roots. The method permits identification of the sites of fifteen or more successive nodes of Ranvier in a given single fibre and the measurement of internodal conduction times between them.2. Average internodal conduction time for normal ventral root fibres of internodal length between 0*75 and 1-45 mm is 19-7 + 4.6 (S.D.) ,usec at 370 C. Internodal conduction time appeared to show a minimum for fibres of internodal length 1 0 mm.3. Ventral roots were demyelinated by focal application of diphtheria toxin. Although conduction is markedly slowed in demyelinated fibres, sites of inward membrane current remain spatially separated indicating that conduction remains saltatory to the point of conduction block rather than becoming continuous as in unmyelinated fibres.4. Slowing of conduction appears to be due to changes in the passive electrical properties of the internodal myelin. Evidence is presented suggesting that there is an increase in internodal capacitance and a decrease in internodal transverse resistance at internodes of demyelinated fibres; such changes would have the effect of delaying excitation at the nodes. The changes in passive electrical properties, which appear to be primarily in the vicinity of the nodes, would be consistent with the pathological changes observed in demyelinated fibres. 6. As in normal fibres, nodes of demyelinated fibres generate less current when excited by the second of two closely spaced impulses. This results in an increased internodal conduction time for the second impulse and, at a critically short interstimulus interval, conduction block of the second impulse.7. The increased refractory period of transmission of internodes with increased internodal conduction times is a consequence of the decreased ability of such internodes to sustain propagation in the face of small decreases in nodal current.8. During tetanic stimulation, increases in internodal conduction time are associated with corresponding decreases in nodal current generated by the node proximal to the internode in question.9. It is suggested that changes in the magnitude of the nodal current during repetitive activity are due to changes in transmembrane concentration gradients of sodium, the increased internodal conduction time and eventual conduction block during tetanic stimulation being caused by intracellular sodium accumulation.10. Intracellular sodium accumulation is also offered as the explanation for the post-tetanic depression seen in demyelinated fibres.

Conduction in Segmentally Demyelinated Mammalian Central Axons

“…The RP Ts of the ionophoresed axons, as illustrated in Figure 3, were much longer in the lesioned than in the unlesioned portion of the axon, in agreement with previous studies (McDonald and Sears, 1970a,b;Rasminsky and Sears, 1972;Smith et al, 1979Smith et al, , 1981Smith and Hall, 1980;Felts and Smith, 1992). It should be noted, however, that axons were selected for study on the basis of a prolonged RPT, and so any demyelinated axon with a short RPT (theoretically unlikely) will have been excluded.…”

“…Our results demonstrate conclusively that some central axons can conduct even if they are segmentally demyelinated for lengths of several internodes, and even if they are entirely devoid of glial contacts for lengths up to 126 m. Conduction is with a reduced velocity and a prolonged RP T, as predicted from previous studies of axons passing through regions of central demyelination Sears, 1969a,b, 1970a,b;Smith et al, 1979Smith et al, , 1981Kaji et al, 1988;Black et al, 1991;Felts and Smith, 1992), and in common with the conduction properties of peripheral demyelinated axons (McDonald, 1963;Mayer and Denny-Brown, 1964;Rasminsky and Sears, 1972;Bostock andSears, 1976, 1978;Smith and Hall, 1980;Smith et al, 1982;Pender and Sears, 1984;Shrager et al, 1987;Pender, 1988;Shrager and Rubinstein, 1990).…”

“…Such silent lesions may sometimes be explained by the utilization or unmasking of alternative pathways that avoid the demyelinated site, but such a phenomenon cannot explain recovery when lesions occur in structures where no alternative pathway exists, such as within the optic nerves (Wisniewski et al, 1976). Such observations could be explained if the demyelinated axons were able to acquire the ability to conduct even if not repaired by remyelination, but experimental studies have so far failed to provide any conclusive direct evidence that conduction can occur in central demyelinated axons, although there is good evidence that conduction can occur in their peripheral counterparts (McDonald, 1963;Mayer and Denny-Brown, 1964;Rasminsky and Sears, 1972;Bostock and Sears, 1976, 1978;Smith and Hall, 1980;Smith et al, 1982;Shrager et al, 1987;Shrager and Rubinstein, 1990). In the CNS, the classic studies of Sears (1969a,b, 1970a,b) established that some axons that passed through an experimental demyelinating lesion could conduct and did so with abnormal conduction properties [e.g., decreased conduction velocity and increased refractory period of transmission (RPT)], but it was not clear whether these axons were segmentally demyelinated.…”

Axonal dwindling in early experimental diabetes. II. A study of isolated nerve fibres

“…However, in another well known neuropathy, that of diphtheria, a similar widening of the Ranvier node is observed at the light microscropic level [3,10], without changes in conduction time [10]. Furthermore, studies of single diphtheritic nerve fibres did not demonstrate electrical abnormalities of the axon membrane at the Ranvier node [11].…”

Density of sodium channels in mammalian myelinated nerve fibers and nature of the axonal membrane under the myelin sheath.

“…This "saltatory" mode of conduction results from a discontinuity in the excitability properties of the axon: excitable regions (nodes) alternate with nonexcitable passive core conductors (myelinated internodes). Although definitive proof of saltatory conduction has been long available (1)(2)(3)(4)(5)(6)(7)(8), it has remained unclear whether the inexcitability of the internode is primarily a result of the internode being insulated by the myelin sheath or whether it reflects an inherent inexcitability of the internodal axonal membrane itself (4). The answer to this question, apart from its intrinsic interest, is crucial for an understanding of the pathophysiology of demyelinating disease such as multiple sclerosis.…”