Ephaptic Activity

There is evidence that sometimes electrical activity in one axon can excite activity in another axon, which is presumed to lie adjacent to the first. Such cross-excitation at a

Figure 11 Spike triggered bursting record exhibited by the same central demyelinated axon as shown in Fig. 5. After 30 seconds of stimulation at 200 Hz, stimulation at only 1 Hz (indicated by the downward deflections of the stimulus artefacts, which are seemingly superimposed in time with the action potentials they evoked) resulted in the formation of short bursts of impulses triggered by the passage of the first impulse in the train. Calibration bar = 0.5 sec. (Reproduced from Felts et al. 1995.)

Figure 11 Spike triggered bursting record exhibited by the same central demyelinated axon as shown in Fig. 5. After 30 seconds of stimulation at 200 Hz, stimulation at only 1 Hz (indicated by the downward deflections of the stimulus artefacts, which are seemingly superimposed in time with the action potentials they evoked) resulted in the formation of short bursts of impulses triggered by the passage of the first impulse in the train. Calibration bar = 0.5 sec. (Reproduced from Felts et al. 1995.)

Figure 12 Recording from a cutaneous nerve in the wrist of a patient with MS and Lhermitte's phenomenon. Neck flexion (vertical arrow) evoked a nonpainful electric tingling sensation in all the fingers of her hands, indicated by the peak in the lower grip force record. The middle record shows the evoked multiunit burst of activity, which coincides with the paraesthesia, and the upper record shows the integrated neurogram (time constant 0.5 sec). (Reproduced from Nordin et al., 1984.)

Neck flexion

Figure 12 Recording from a cutaneous nerve in the wrist of a patient with MS and Lhermitte's phenomenon. Neck flexion (vertical arrow) evoked a nonpainful electric tingling sensation in all the fingers of her hands, indicated by the peak in the lower grip force record. The middle record shows the evoked multiunit burst of activity, which coincides with the paraesthesia, and the upper record shows the integrated neurogram (time constant 0.5 sec). (Reproduced from Nordin et al., 1984.)

site other than a synapse is termed ephaptic transmission, and the phenomenon has been convincingly demonstrated in the "dystrophic" mutant mouse (Rasminsky, 1978, 1980). In this model, impulses traveling in an amyelinated axon ephaptically excited daughter impulses in a normal axon;

the daughter impulses traveled away from the ephapse in both directions (Fig. 13) (Rasminsky, 1980). This demonstration involved peripheral amyelinated axons, but it is reasonable to suppose that a similar phenomenon might occur in central and peripheral demyelinated axons. This view is encouraged by a host of peculiar phenomena in patients (e.g., Kapoor et al., 1992; Hartmann et al., 1999) that have reasonably been attributed to ephaptic transmission occurring by the lateral spread of excitability across different, but anatomically adjacent, spinal or brainstem tracts.

IV Remyelination

Demyelination can be repaired by remyelination, even in MS (Prineas and Connell, 1979; Prineas et al., 1993), namely by the formation of new internodes of myelin across the demyelinated gap. The new internodes are both thinner and shorter than normal (Gledhill and McDonald, 1977; Harrison et al., 1972), and this latter consideration means that new nodes are formed at sites along the axon that were previously covered by myelin. These sites will, initially at least, lack nodal specializations such as the accumulation of sodium channels, and so it was not inevitable that remyeli-nated axons would be able to conduct impulses. Indeed, conduction block could theoretically be favored by the thinness of the myelin, especially in the early stages of remyelination,

5 msec

to 2

Ephapse

* Exciting Excited

Distance (mm)

Figure 13 Plots showing ephaptic transmission from a nonmyelinated axon to a myelinated axon in the ventral root of a dystrophic mouse (illustrated in B). (A) Ladder plot of external longitudinal currents recorded at intervals of200 mm from proximal (top) to distal. The directions of travel of the exciting and excited action potentials are indicated by the dashed and open arrows, respectively. (C) Graph of the latency of the exciting and excited action potentials. The slow conduction velocity of the exciting impulse (dashed arrows) indicates the nonmyelinated characteristics of the exciting axon. (Reproduced from Rasminsky, 1980.)

as this will be associated with a raised internodal capacitance and reduced resistance, both of which will impair conduction. However, studies that have serially monitored conduction in central axons as they underwent demyelina-tion and remyelination have established that remyelination is accompanied by the restoration of fast conduction, probably in all remyelinated axons (Fig. 14) (Smith et al., 1979. 1981). The conduction is as secure as in normal axons, as judged by the restoration of the RPT to within normal limits, and the ability of the axons to conduct high frequency trains (Smith et al., 1979, 1981). Studies in peripheral remyelinated axons (Smith et al., 1982) have established that each new node is excited in turn as impulses conduct along remyelinated regions, and it seems safe to assume that a similar pattern will occur in central remyelinated axons. Certainly the new nodes can express high densities of sodium channels (Craner et al., 2003; Dugandzija-Novakovic et al., 1995).

Figure 14 Records obtained over 5 months showing the changes in conduction occurring along dorsal columns containing a central demyelinating lesion. On the left are shown records obtained excluding the lesion from the conduction pathway, and these were quite stable throughout. Conduction was also stable (top 3 records on the right) in records obtained including the site of the lesion, but before the lesion was induced. At day 0, the demyeli-nating lesion was induced by the intraspinal injection of lysolecithin, and this blocked conduction for about 2 weeks in most axons. Conduction was progressively restored during the period of repair by remyelination. Remyelination also restored the security of conduction (not shown). (Reproduced from Smith et al., 1979.)

Figure 14 Records obtained over 5 months showing the changes in conduction occurring along dorsal columns containing a central demyelinating lesion. On the left are shown records obtained excluding the lesion from the conduction pathway, and these were quite stable throughout. Conduction was also stable (top 3 records on the right) in records obtained including the site of the lesion, but before the lesion was induced. At day 0, the demyeli-nating lesion was induced by the intraspinal injection of lysolecithin, and this blocked conduction for about 2 weeks in most axons. Conduction was progressively restored during the period of repair by remyelination. Remyelination also restored the security of conduction (not shown). (Reproduced from Smith et al., 1979.)

Using different techniques, it has been found that remyelinated axons can conduct when invested with only thin new myelin sheaths, composed of only five lamellae of myelin (Felts et al., 1997). The robustness of conduction in remyelinated axons is in accord with the observation that remyelination is associated with the restoration of function at the behavioral level (Jeffery and Blakemore, 1997), and it is reasonable to assume that remyelination will contribute to remissions in MS.

Given the preceding observations it is not surprising that the promotion of remyelination continues to be a major goal of research in MS (see Chapter 28), and a number of different strategies have been used, including immunological (Warrington et al., 2000; Asakura and Rodriguez, 1998) and, especially, transplantation strategies (Blakemore and Franklin, 2000; Baron-Van et al., 1997). It is encouraging that conduction has now been demonstrated in axons remyelinated primarily by oligodendrocytes (Smith et al., 1979, 1981), Schwann cells (Felts and Smith, 1992), transplanted Schwann cells (Honmou et al., 1996), olfactory ensheathing cells (Imaizumi et al., 1998, 2000; Utzschneider et al., 1994), human neural precursor cells (Akiyama et al., 2001), bone marrow cells (Akiyama et al., 2002), and human frozen Schwann cells (Kohama et al., 2001). Given the wide range of strategies that result in successful conduction, the prospect for achieving meaningful improvements in axonal function in MS is good.

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