Studies in Selective Reinnervation

In a study of denervated canine laryngeal muscles following RLN neurorrhaphy, Zealear et al. found that the basic nature of reinnervation could be manipulated by electrical stimulation of the target muscle. Specifically, stimulation of the denervated posterior cricoarytenoid (PCA) muscle promoted selective reinnervation by native inspiratory motoneurons over foreign adductor motoneurons [54]. Eight animals were implanted with a planar array of 36 electrodes for chronic stimulation and recording of spontaneous and evoked electromyographic (EMG) potentials across the entire muscle surface. The PCA muscle in four experimental animals was stimulated during the 11-month experiment, using a i-s, 30-pps, biphasic pulse train composed of l-ms pulses 2-6 mA in amplitude and repeated every 10 s. The remaining four animals served as non-stimulated controls. Appropriate reinnervation by native inspiratory motoneurons was indexed behaviorally by the magnitude of vocal fold opening, and elec-tromyographically by the averaged potential across all electrode sites (Fig. 2.5A). Inappropriate reinnervation by foreign reflex glottic closure motoneurons was quantitated by recording EMG potentials following stimulation of the internal branch of the SLN (Fig. 2.5D). All four experimental animals showed a greater level of correct (¿><0.0064) and a lesser level of incorrect reinnervation (¿<0.0084) than controls. These findings are consistent with a previous report [55] and suggest that stimulation

Fig. 2.5. Recordings from same PCA muscle electrode site, a Inspiratory activity at beginning of C02/air delivery. b EEMG following RLN stimulation, c EEMG following inadvertent stimulation of RLN motor fibers within vagus nerve just posterior to the superior laryngeal nerve, d The reflex glottic closure motor units activated polysynaptically via superior laryngeal nerve stimulation. Note latency increased from b to c, and c to d, due to increased conduction path. Response due to direct activation of PCA motor fibers in c could be distinguished from indirect response evoked in d on the basis of latency and waveform differences, as illustrated.

Fig. 2.5. Recordings from same PCA muscle electrode site, a Inspiratory activity at beginning of C02/air delivery. b EEMG following RLN stimulation, c EEMG following inadvertent stimulation of RLN motor fibers within vagus nerve just posterior to the superior laryngeal nerve, d The reflex glottic closure motor units activated polysynaptically via superior laryngeal nerve stimulation. Note latency increased from b to c, and c to d, due to increased conduction path. Response due to direct activation of PCA motor fibers in c could be distinguished from indirect response evoked in d on the basis of latency and waveform differences, as illustrated.

of a mammalian muscle may profoundly affect its receptivity to reinnervation by a particular motoneuron type.

Although induction of specificity in mo-toneuron-muscle reconnection by electrical stimulation has not been described by other investigators, there are reports that regenerating motoneurons are influenced by trophic factors in distal nerve stumps. In the invertebrate, Wigston and Donahue described selective reinnervation of surgically exchanged axolotl muscles by their native motoneurons [56]. In the mammal, Brushart et al. observed that collaterals of single motor axons often regenerate down both sensory and motor pathways at a nerve bifurcation. Subsequently, the collaterals in the sensory pathway are pruned, while those in the motor pathway are maintained [57]. This process, termed "preferential motor reinnervation," is believed to be triggered by Schwann cell tube neurotropins and directed by motoneuron cell bodies. In particular, brief electrical stimulation of motoneurons has been found to accelerate the speed and accuracy of regeneration [58]. Politis reported preferential regeneration of peroneal and tibial components of the sciatic nerve down their native branches [59]. These branches each contain motor fibers; however, preferential regeneration down individual muscle pathways in the mammal cannot be inferred from these studies. Indeed, although target muscle recognition may occur in the invertebrate, reinnervation in the adult mammal is believed to be random, with high probability of a synkinetic outcome. With regard to laryngeal muscles, any neurotrophic effect on regeneration is inadequate to prevent misdirected regeneration of adductor fibers in the RLN and inappropriate reinnervation of the PCA muscle. Apparently, reinnervation specificity may be conferred only when muscle fibers or their reconnecting motoneurons are electricallyactivated [54].

Two postulates are offered as to how electrical stimulation could confer neuromuscular specificity. The first idea holds that muscle stimulation maintains the motoneuron-muscle fiber specificity that was established during development [60] and prevents its loss upon denervation. The second idea assumes that the concept of muscle plasticity extends to the synapse, and that electrical stimulation can modulate not only contractile protein synthesis and muscle fiber properties, but receptivity of the endplate for a particular motoneuron type.

Evidence in support of the first hypothesis comes from basic studies in neurophysiology. The specificity between a single neuron and its endplate is established during development with the competitive elimination of redundant innervation [60, 61]. Following denervation in the adult, motoneurons revert to a more embryonic or dedifferentiated state but retain some specificity for their original muscle target [57, 62]. Denervation induces formation of ex-trajunctional (de novo) receptors on each muscle fiber; however, the original endplate may be distinguished from these de novo receptors by its recognition and affinity for the original motoneuron [63]. Stimulation of a muscle represses the formation of extrajunctional receptors without making the original endplate refractory to reinnervation [64]; thus, stimulation may favor reconnection between an original endplate and its nerve fiber, and foster restoration of the synapse which was competitively selected in development.

The second hypothesis, that electrical stimulation can modulate endplate receptivity, originated from basic studies in neuromuscular plasticity. In an early landmark study by Buller et al., it was discovered that fast and slow muscles cross-reinnervated by each others nerves switched their contraction speeds [65,66], This led to the dogma that the trophic influence of a nerve is needed in order to maintain the integrity and characteristic contractile properties of a muscle; however, in a later study, Salmons and Sreter opposed the putative chemotrophic effects of a nerve on its muscle's contraction speed with patterned electrical stimulation of the nerve [67]. Whether a muscle was innervated by its intrinsic nerve or cross-reinnervated by a nerve of opposite type, the contraction speed was determined by the pattern of electrical stimulation. Finally, Lomo and West-gaard demonstrated that denervated muscles, chronically stimulated with different electrical patterns, varied their contraction speeds in accordance with the pattern with which they were stimulated [68], Apparently, the activity induced by electrical stimulation can maintain a muscle's characteristics in the absence of nerve supply. More recent studies have supported the idea that there is some feature of electrically induced activity which influences both the synthesis of contractile proteins (myosin heavy chain, MHC) and the contractile properties of muscle [69-71].

Regardless of which hypothesis is responsible for induction of selective reinnervation, it is probable that this event is genetically controlled. If the second hypothesis is true, some of the genes that control muscle transformation may also regulate receptivity to regrowing motor axons. The PCA muscle is distinguished from the adductor antagonists in having a slower contraction speed and higher abundance of type-I (slow-twitch) muscle fibers [10]. Following PCA denervation and reinnervation by the RLN, there is a change in muscle composition to favor type-II (fast-twitch) fibers and a corresponding acceleration of muscle contraction speed. Transformation of the muscle from slow to fast fibers can be prevented or reversed in the presence of electrical stimulation using the paradigm found to induce selective reinnervation [72]. These findings are consistent with reports of activity-dependent changes on muscle contraction in other motor systems [73, 74]. Apparently, the muscle transformation is controlled at a transcriptional level. Recent reports have identified specific genes and their promoters responsible for changes in MHC expression, paralleled by changes in muscle contraction speed induced by alteration in muscle activity [75,76].

A recent report provides strong evidence that the MHC composition of a laryngeal muscle is correlated with the appropriateness of reinnervation [70]. In case of a nerve-crush injury, there was observed a transient shift in MHC expression characteristic of a denervated muscle. In particular, there was a consistent increase in type-IIA/IIX MHC and a decrease in type-IIB MHC, with a tendency toward a decrease in type-I MHC. Some weeks later upon appropriate reinnervation, the MHC composition reverted to that of the normally innervated control muscle of the same type (i.e., PCA vs

Table 2.1. Normal myosin heavy chain composition in rat laryngeal muscles (%). PCA posterior cricoarytenoid, TA thyroarytenoid, VOC vocalis, CT cricothyroid, LCA /ateral cricoarytenoid, MHC myosin heavy chain. (From Shiotani and Flint [71])

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