The impact of motor and sensory nerve architecture on nerve regeneration

Sensory nerve autografting is the standard of care for injuries resulting in a nerve gap. Recent work demonstrates superior regeneration with motor nerve grafts. Improved regeneration with motor grafting may be a result of the nerve's Schwann cell basal lamina tube size. Motor nerves have larger SC basal lamina tubes, which may allow more nerve fibers to cross a nerve graft repair. Architecture may partially explain the suboptimal clinical results seen with sensory nerve grafting techniques. To define the role of nerve architecture, we evaluated regeneration through acellular motor and sensory nerve grafts. Thirty-six Lewis rats underwent tibial nerve repairs with 5 mm double-cable motor or triple-cable sensory nerve isografts. Grafts were harvested and acellularized in University of Wisconsin solution. Control animals received fresh motor or sensory cable isografts. Nerves were harvested after 4 weeks and histomorphometry was performed. In 6 animals per group from the fresh motor and sensory cable graft groups, weekly walking tracks and wet muscle mass ratios were performed at 7 weeks. Histomorphometry revealed more robust nerve regeneration in both acellular and cellular motor grafts. Sensory groups showed poor regeneration with significantly decreased percent nerve, fiber count, and density (p < 0.05). Walking tracks revealed a trend toward improved functional recovery in the motor group. Gastrocnemius wet muscle mass ratios show a significantly greater muscle mass recovery in the motor group (p < 0.05). Nerve architecture (size of SC basal lamina tubes) plays an important role in nerve regeneration in a mixed nerve gap model.     

Motor nerve biopsy studies in motor neuropathy and motor neuron disease

The clinical presentation of motor neuropathy often resembles that of motor neuron disease, sometimes leading to an erroneous diagnosis. Moreover, the underlying pathological process in motor neuropathy has been rarely investigated and there are no systematic studies of the affected motor nerves. We describe a new motor nerve biopsy procedure, performed in 15 patients: 6 with motor neuropathy and 9 with motor neuron disease. The motor branch from the anterior division of the obturator nerve to the gracilis muscle in the thigh was biopsied. In both groups of patients the motor nerves exhibited depletion of myelinated nerve fibers. In motor neuropathy there was a significantly higher density of regenerative clusters of small myelinated fibers in comparison to motor nerves from patients with motor neuron disease. In addition, in 3 patients with motor neuropathy there was evidence for demyelination with thinly myelinated axons and small onion bulb formations. These pathological studies of motor nerve biopsies can help to differentiate motor neuropathy from motor neuron disease. © 1997 John Wiley & Sons, Inc.     

Motor nerve graft is better than sensory nerve graft for survival and regeneration of motoneurons after spinal root avulsion in adult rats

In the present study, we compared the effects of implanting peripheral sensory nerve and motor nerve on motoneuron survival and regeneration after spinal root avulsion in adult rats. Our results showed that 116% more motoneurons regenerated axons into the motor than the sensory nerve graft and 59% of motoneurons survived in the motor nerve-implanted group compared to 48% in the sensory nerve-implanted group. We demonstrated by real time PCR that levels of BDNF and GDNF mRNA were significantly higher in the motor than the sensory nerve five days after implantation into the spinal cord. This may account for the superiority of motor over sensory nerve in promoting motor axon regeneration and motoneuron survival. Lastly, we also showed that implanting two sensory nerves enhances motoneuron regeneration over implanting a single nerve.     

F response and somatosensory and brainstem auditory evoked potential studies in HMSN type I and II.

To evaluate conduction along the proximal and distal segments of motor and sensory long limb nerves, as well as along the very short acoustic nerve, F response and somatosensory and brainstem auditory evoked potential were studied in a series of patients with hereditary motor and sensory neuropathy (HMSN) types I and II. A diffuse and comparable slowing of conduction in proximal and distal nerve segments, as well as along the acoustic nerve, seems to favour a primary myelin defect in HMSN I. F response and motor conduction velocity showed a similar derangement in both proximal and distal motor segments. Latencies of somatosensory evoked potentials were symmetrically prolonged and correlated with motor nerve impairment. Central conduction times were normal. Studies of brainstem auditory evoked potentials showed a high incidence of acoustic nerve involvement, the most evident abnormality being a statistically significant increase in the latency of the I wave. Our data seem to support the presence of primary myelinopathic damage in HMSN I.     

A motor neuron-specific epitope and the low-affinity nerve growth factor receptor display reciprocal patterns of during development,axotomy, and regeneration

Somatic motor neurons begin to express the transmitter synthesizing enzyme, choline acetyltransferase (ChAT) and the low-affinity nerve growth factor receptor (NGFR) during embryonic development. However, as motor neurons mature in postnatal life, they lose immunoreactivity for NGFR and acquire a motor neuron-specific epitope that is recognized by the monoclonal antibody, MO-1. The present study was undertaken to examine the effect of nerve injury in adult rats on these three developmentally regulated markers in two populations of somatic motor neurons. Unilateral transection, ligation, or crushing of the sciatic nerve resulted in a loss of MO-1 binding and a concomitant rise in immunoreactivity for NGFR within axotomized motor neurons in lumbar levels of the spinal cord. These changes, detectable within 5 days following nerve injury, are reversed with reinnervation, but persist if reinnervation is prevented by chronic axotomy. Thus, regulation of the expression of NGFR and the MO-1 epitope appears to be critically dependent upon interactions between motor neurons and target muscles. These observations are also consistent with the idea that during regeneration, neurons may revert to a developmentally immature state; in motor neurons, this state is characterized by the presence of NGFRs and the absence of the MO-1 epitope. Transection of the hypoglossal nerve, a purely motor nerve, resulted in a similar loss of MO-1 binding and a selective rise in NGFR immunoreactivity in neurons within the ipsilateral hypoglossal motor nucleus. In addition immunoreactivity for ChAT was also lost in axotomized hypoglossal motor neurons. In contrast, injury to the sciatic nerve, which bears both sensory and motor axons, did not result in any detectable change in ChAT immunoreactivity in spinal motor neurons. © 1993 Wiley-Liss, Inc.     

节段性运动神经传导测定在慢性炎性脱髓鞘性多发性神经根神经病和腓骨肌萎缩症1型之间的差异

目的 探讨节段性运动神经传导测定在慢性炎性脱髓鞘性多发性神经根神经病(chronic inflammatory demyelinating polyradiculoneuropathy,CIDP)和腓骨肌萎缩症1型(Charcot-MarieTooth type1,CMT1)鉴别诊断中的价值.方法 收集16例CIDP和13例CMT1患者,进行节段性运动神经传导测定,比较两组远端运动潜伏期、运动神经传导速度,以及近端和远端比较复合肌肉动作电位波幅、面积和时限变化的差异.结果 CIDP和CMT1患者远端运动潜伏期分别为(5.6±3.4)、(9.3±2.1)ms(t=5.347,P=0.000),运动传导速度分别为(31.1±14.3)、(22.2±5.8)m/s(t=6.369,P=0.000),近端和远端比较波幅下降百分比M5o分别为29.7%和4.9%(Z=7.141,P=0.000).在CIDP患者,所有测定神经中40.3%(25/62)远端潜伏期正常,18.1%(26/144)的神经节段传导速度正常,而在CMT1中所有测定神经的远端潜伏期均延长,所有测定节段的传导速度均减慢.在CIDP患者29.2%的神经节段可见传导阻滞或异常波形离散,而在CMT1仅有3.0%的节段可见传导阻滞(x2=20.829,P=0.000).结论 当针对CIDP和CMT1进行鉴别时,如果节段性运动神经传导测定发现传导阻滞和异常波形离散、不同神经节段传导速度下降程度差别较大,可以支持 CIDP的诊断.     

Morphological differences in skeletal muscle atrophy of rats with motor nerve and/or sensory nerve injury

Skeletal muscle atrophy occurs after denervation. The present study dissected the rat left ventral root and dorsal root at L4-6 or the sciatic nerve to establish a model of simple motor nerve injury, sensory nerve injury or mixed nerve injury. Results showed that with prolonged denervation time, rats with simple motor nerve injury, sensory nerve injury or mixed nerve injury exhibited abnormal behavior, reduced wet weight of the left gastrocnemius muscle, decreased diameter and cross-sectional area and altered ultrastructure of muscle cells, as well as decreased cross-sectional area and increased gray scale of the gastrocnemius muscle motor end plate. Moreover, at the same time point, the pathological changes were most severe in mixed nerve injury, followed by simple motor nerve injury, and the changes in simple sensory nerve injury were the mildest. These findings indicate that normal skeletal muscle morphology is maintained by intact innervation. Motor nerve injury resulted in larger damage to skeletal muscle and more severe atrophy than sensory nerve injury. Thus, reconstruction of motor nerves should be considered first in the clinical treatment of skeletal muscle atrophy caused by denervation.     

神经型布氏杆菌病周围神经损害的临床与电生理研究

目的研究神经型布氏杆菌病周围神经损害的临床特征,探讨电生理对其的诊断价值。方法对32例神经型布氏杆菌病周围神经损害患者(病例组)和32名性别及年龄与病例组匹配的正常对照组进行神经电生理检查,并对所得检查结果进行统计学分析。结果病例组与对照组在运动末梢潜伏期(distal motor latency,DML)、复合肌肉动作电位(compound motor active potentials,CMAP)波幅、运动神经传导速度(motor nerve conduction velocity,MCV)、感觉神经动作电位潜伏期(sensory nerve action potential latency,SL)、感觉神经动作电位(sensory nerve action potential,SNAP)波幅及感觉神经传导速度(sensory nerve conduction velocity,SCV)方面的比较,差异均有统计学意义(P0.05)。电生理检查提示上下肢周围神经损害,感觉神经及运动神经均受累,其中感觉神经占55.47%,运动神经占16.80%,上肢以正中神经(64条)最多见,下肢以腓肠神经(16条)最多见。四肢运动神经256条中43条传导速度减慢,占16.80%,四肢感觉神经256条中142条传导速度减慢,占55.47%,SCV较MCV改变明显,上肢病变重于下肢。结论神经电生理检查为神经型布氏杆菌病周围神经损害的临床诊断提供了客观依据。     

Effects of motor versus sensory nerve grafts on peripheral nerve regeneration

Autologous nerve grafting is the current standard of care for nerve injuries resulting in a nerve gap. This treatment requires the use of sensory grafts to reconstruct motor defects, but the consequences of mismatches between graft and native nerve are unknown. Motor pathways have been shown to preferentially support motoneuron regeneration. Functional outcome of motor nerve reconstruction depends on the magnitude, rate, and precision of end organ reinnervation. This study examined the role of pathway type on regeneration across a mixed nerve defect. Thirty-six Lewis rats underwent tibial nerve transection and received isogeneic motor, sensory or mixed nerve grafts. Histomorphometry of the regenerating nerves at 3 weeks demonstrated robust nerve regeneration through both motor and mixed nerve grafts. In contrast, poor nerve regeneration was seen through sensory nerve grafts, with significantly decreased nerve fiber count, percent nerve, and nerve density when compared with mixed and motor groups (P < 0.05). These data suggest that use of motor or mixed nerve grafts, rather than sensory nerve grafts, will optimize regeneration across mixed nerve defects.     

Correlations between nonverbal intelligence and nerve conduction velocities in right-handed male and female subjects

A neurological theory of intelligence suggesting a direct correlation between nerve conduction velocity and psychometric intelligence was tested. Cattell's Culture Fair Intelligence Test was used to asses the nonverbal intelligence (IQ) of subjects. The motor median nerve conduction velocity from right hand of males was positively correlated with IQ. In subjects with no familial sinistrality (FS-), the motor ulnar-nerve conduction velocity from the right and left hands of males negatively correlated with IQ; there were inverse correlations between IQ and nerve conduction velocity (motor median nerve from right, sensory median nerve from right and left) in females. In subjects with familial sinistrality (FS+), IQ directly correlated with nerve conduction velocity from motor median (right and left), sensory median (right), and motor ulnar (right) nerves, but only in males. The speed hypothesis and neurological theory of intelligence were not supported by these results, which, in contrast, emphasized the importance of sex and familial sinistrality in any theory of intelligence.     

Maximal and minimal motor nerve conduction velocities determined by a collision method: correlation with axonal conduction velocity of type-identified motor units

Maximal and minimal motor nerve conduction velocities of the medial gastrocnemius (MG) muscle nerve were measured by a new collision method in 20 rats of 8–9 weeks of age; the rate of tension increase produced by the muscle was also recorded. Single motor unit analysis in the other 20 rats obtained axonal conduction velocity and contractile properties of type-identified MG motor units. Comparison of the data from these experiments revealed that the maximal and minimal motor nerve conduction velocities obtained by this collision method were most likely to be the axonal conduction velocity of fast-twitch and slow-twitch motor units, respectively. Therefore, these motor nerve conduction velocities in man may also be used as functional parameters of human fast-twitch and slow-twitch motor units, respectively.     

Trophic reactions of crayfish muscle fibers and neuromuscular synapses after denervation,tenotomy, and immobilization

Severed motor nerve terminals remain morphologically intact and functionally competent for several months following transection of the motor nerve to the claw opener muscle of crayfish (Procambarus clarki). However, severed motor axons are not entirely normal in that excitatory synapses produce junctional potentials that are somewhat smaller than control values. Tenotomy or immobilization often produce little change in synaptic potentials for at least 180 days. Opener muscle fibers with severed motor axons or immobilized muscle fibers show little ultrastructural change for at least 100 days, provided the nerve terminals remain intact. However, after tenotomy, muscle fibers atrophy within 20 to 30 days. This atrophy is more rapid and more severe if nerve terminals on that muscle fiber have degenerated. These atrophic changes in muscle fine structure include disorganization of myofibrils and disruption or loss of the sarcomere Z bands. In summary, our data show that drastic changes in crayfish muscle structure can proceed after tentomy without concomitant changes in function of the motor nerve terminals; and conversely, although transecting the motor nerve has some effect on motor nerve terminals, decentralization has little effect on muscle fiber structure as long as nerve terminals remain intact. These data are in agreement with the hypothesis that crustacean muscle fibers are trophically dependent on the presence of functional nerve terminals and on passive fiber tension (or resting length).     

Normal maximal and minimal motor nerve conduction velocities in adults determined by a collision method

Using a new collision method, we measured motor nerve conduction velocities of the ulnar nerve in the forearm and the action potential amplitude of the abductor digiti minimi muscle on 60 adults, ages 20 to 82 years and apparently free from diseases of the peripheral nervous system. Both maximal and minimal motor nerve conduction velocities were linear functions of age; 64.42-0.05 age and 60.45-0.12 age, respectively. The percentage of the minimal to the maximal motor nerve conduction velocities was expressed as 94.45-0.13 age. The maximum amplitude of evoked muscle action potentials was also correlated with age. This novel method may be useful in detecting pathology of motor nerve fibers which results in a decrease in submaximal conduction velocities.     

Influence of terminal nerve branch size on motor neuron regeneration accuracy

A necessary prerequisite for recovery of motor function following a peripheral nerve injury is the correct choice by regenerating motor neurons to reinnervate the original distal nerve branch to denervated muscle. The present studies use the mouse femoral nerve as a model system to examine factors that influence such motor neuron regeneration accuracy. We examined motor reinnervation accuracy over time in this model under two conditions: 1) when the two terminal nerve branches to either skin (cutaneous) or muscle (quadriceps) were roughly comparable in size, and 2) when the cutaneous branch was larger than the muscle branch. When the terminal nerve branches were similar in size, motor neurons initially projected equally into both branches, but over time favored the terminal muscle branch. When the cutaneous terminal nerve branch was enlarged (via transgenic technology), motor neuron projections significantly favored this inappropriate pathway during early time points of regeneration. These results suggest that regenerating motor neuron projections are not determined by inherent molecular differences between distal terminal nerve branches themselves. Rather, we propose a two-step process that shapes motor neuron reinnervation accuracy. Initial outgrowth choices made by motor axons at the transection site are proportional to the relative amount of target nerve associated with distal nerve axons that previously projected to each of the terminal nerve pathways. Secondly, the likelihood of an axon collateral from a motor neuron remaining in either terminal nerve branch is based upon the relative trophic support provided to the parent motor neuron by the competing terminal pathways and/or end-organs.     

The effects of pyronin on sprouting and regeneration of mouse motor nerves

Administration to mice of a 0.1% solution of pyronin G in their drinking water caused an acceleration both of axonal sprouting from nodes of Ranvier in partly denervated gluteus maximus muscles, and of motor nerve regeneration following a crush to the soleus nerve. Sprouting from soleus motor nerve terminals in response to botulinum toxin-induced paralysis was, however, unaffected. Removal of degenerating axons following nerve section was also accelerated by pyronin treatment. Pyronin is therefore likely to act upon the process of Wallerian degeneration, rather than upon intact motor nerves directly.     

Matching of motor-sensory modality in the rodent femoral nerve model shows no enhanced effect on peripheral nerve regeneration

The treatment of peripheral nerve injuries with nerve gaps largely consists of autologous nerve grafting utilizing sensory nerve donors. Underlying this clinical practice is the assumption that sensory autografts provide a suitable substrate for motoneuron regeneration, thereby facilitating motor endplate reinnervation and functional recovery.This study examined the role of nerve graft modality on axonal regeneration, comparing motor nerve regeneration through motor, sensory, and mixed nerve isografts in the Lewis rat. A total of 100 rats underwent grafting of the motor or sensory branch of the femoral nerve with histomorphometric analysis performed after 5, 6, or 7 weeks. Analysis demonstrated similar nerve regeneration in motor, sensory, and mixed nerve grafts at all three time points. These data indicate that matching of motor-sensory modality in the rat femoral nerve does not confer improved axonal regeneration through nerve isografts.     

The motor nuclei and primary projections of the IXth,Xth, XIth,and XIIth cranial nerves in the monitor lizard,Varanus exanthematicus

The motor nuclei and sensory connections of the IXth, Xth, XIth, and XIIth cranial nerves of the reptile Varanus exanthematicus were studied with the methods of anterograde degeneration and anterograde and retrograde axonal transport. The motor nuclei of nerve IX are located ventrally in the rhombencephalon and are constituted medially by the large-celled glossopharyngeal part of the nucleus ambiguus and laterally by the small-celled nucleus salivatorius inferior. The motor nuclei of nerve X consist of the dorsomedially located dorsal motor nucleus of the vagus and the laterally located vagal part of the nucleus ambiguus. The rostral portion of the latter cell group contains smaller cells than its caudal portion and is rostrally continuous with the nucleus salivatorius inferior of nerve IX. The efferent axons of nerves IX and X arising from the ventrolateral medulla first course dorsomedially, form genua beneath the IVth ventricle, and then exit the brainstem. All primary afferent fibers of nerve IX and the majority of those of nerve X enter the solitary tract. Terminations of vagal fibers were observed in the postvagal portion of the nucleus of the solitary tract, the dorsal motor nucleus of the vagus, and the nucleus of the commissura infima. A small contingent of vagal fibers courses caudally just dorsolateral to the descending trigeminal tract. A separate spinal component of nerve XI could not be found. The bulbar component of this nerve forms part of nerve X and takes its main origin from a detached caudal element of the nucleus ambiguus. The motor nuclear complex of nerve XII consists of a large dorsal nucleus and a small ventral nucleus that extend from the medulla oblongata into the first segment of the cervical spinal cord.     

Ro5-4864 promotes neonatal motor neuron survival and nerve regeneration in adult rats

The translocator protein (18 kDa; TSPO), formerly known as the peripheral benzodiazepine receptor, is an outer mitochondrial membrane protein that associates with the mitochondrial permeability transition pore to regulate both steroidogenesis and apoptosis. TSPO expression is induced in adult dorsal root ganglion (DRG) sensory neurons after peripheral nerve injury and a TSPO receptor ligand, Ro5-4864, enhances DRG neurite growth in vitro and axonal regeneration in vivo . We have now found that TSPO is induced in neonatal motor neurons after peripheral nerve injury and have evaluated its involvement in neonatal and adult sensory and motor neuron survival, and in adult motor neuron regeneration. The TSPO ligand Ro5-4864 rescued cultured neonatal DRG neurons from nerve growth factor withdrawal-induced apoptosis and protected neonatal spinal cord motor neurons from death due to sciatic nerve axotomy. However, Ro5-4864 had only a small neuroprotective effect on adult facial motor neurons after axotomy, did not delay onset or prolong survival in SOD1 mutant mice, and failed to protect adult DRG neurons from sciatic nerve injury-induced death. In contrast, Ro5-4864 substantially enhanced adult facial motor neuron nerve regeneration and restoration of function after facial nerve axotomy. These data indicate a selective sensitivity of neonatal sensory and motor neurons to survival in response to Ro5-4864, which highlights that survival in injured immature neurons cannot necessarily predict success in adults. Furthermore, although Ro5-4864 is only a very weak promoter of survival in adult neurons, it significantly enhances regeneration and functional recovery in adults.     

A model of the differing change in motor and sensory action potentials over distance

Clinically recorded motor and sensory nerve responses show different degrees of change in response size over distance along a nerve. We describe a computer model to investigate possible causes of this phenomenon. Effects of the range of conduction velocity in a nerve and the size of the constituent action potentials forming the recorded response are evaluated. We conclude that the broader duration of the motor unit potential is the predominant factor in accounting for motor nerve responses showing less change over distance than sensory responses. The contributions of temporal dispersion and phase cancellation are also discussed.     

Specific and nonspecific regeneration of motor axons after sciatic nerve injury and repair in the rat

The pattern of motor axon regeneration following unilateral sciatic nerve lesions (freezing or transection) was studied in adult rats. Transected nerves were repaired with epineurial or fascicular sutures. Four months after the lesion, the motor neuron cell body localization in the spinal cord of plantar or common peroneal nerve axons were examined bilaterally with retrograde transport of horseradish peroxidase. Motor neuron cell body localization was similar bilaterally after freezing, indicating that regenerating axons had reached their original peripheral innervation territory. However, after nerve transection, irrespective of whether epineurial or fascicular sutures were used, motor neuron cell body distribution on the operated side was abnormal with numerous labeled cell bodies located outside the area of the normal motor neuron pool. This finding indicates that after nerve transection the normal pattern of motor axon innervation is not restored even after fascicular nerve repair.