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Triple stimulation technique (TST) has previously shown that transcranial magnetic stimulation (TMS) fails to activate a proportion of spinal motoneurons (MNs) during motor fatigue. The depression in size of the TST response, but no attenuation of the conventional motor-evoked potential, suggested increased probability of repetitive spinal MN activation during exercise, even if some MNs failed to discharge by the brain stimulus. Here we used a modified TST [quadruple stimulation (QuadS) and quintuple stimulation (QuintS)] to examine the influence of fatiguing exercise on second and third MN discharges after a single TMS in healthy subjects. This method allows an estimation of the percentage of double and triple discharging MNs. Following a sustained contraction of the abductor digiti minimi muscle at 50% maximal force maintained to exhaustion, the size of QuadS and QuintS responses increased markedly, reflecting that a greater proportion of spinal MNs was activated two or three times by the transcranial stimulus. The size of QuadS responses did not return to precontraction levels during 10-min observation time, indicating long-lasting increase in excitatory input to spinal MNs. In addition, the postexercise behavior of QuadS responses was related to the duration of the contraction, pointing to a correlation between repeated activation of MNs and the subject's ability to maintain force. In conclusion, the study confirmed that an increased fraction of spinal MNs fire more than once in response to TMS when the muscle is fatigued. Repetitive MN firing may provide an adaptive mechanism to maintain motor unit activation and task performance during sustained voluntary activity.

Motor nerve excitability studies by "threshold tracking" in amyotrophic lateral sclerosis (ALS) revealed heterogeneous abnormalities in motor axon membrane function possibly depending on disease stage. It remains unclear to which extent the excitability deviations reflect a pathogenic mechanism in ALS or are merely a consequence of axonal degeneration. We investigated motor axon excitability in presymptomatic and symptomatic SOD1(G127X) mutants, a mouse model of ALS with late clinical onset and rapid disease progression. After clinical onset, there was a rapid loss of functional motor units associated with an increase in rheobase and strength-duration time constant, an increase in refractoriness at the expense of the superexcitability, larger than normal threshold deviations during both depolarizing and hyperpolarizing threshold electrotonus with impaired accommodation and reduction of the input conductance. These abnormalities progressed rapidly over a few days and were associated with morphological evidence of ongoing axonal degeneration. Presymptomatic mice with unaltered motor performance at rotor-rod measurement also had an increase in refractoriness at the expense of the superexcitability during the recovery cycle. This was, however, associated with smaller than normal deviations during threshold electrotonus, and a steeper resting current-threshold slope indicating slight axonal depolarization in agreement with motoneuronal hyperexcitability indicated by enhanced F-waves. Our data suggest that SOD1(G127X) motor axons undergo a state of membrane depolarization; however, during rapid motoneuron loss disease-specific nerve excitability measures are confounded by excitability changes in degenerating but still conducting axons. These findings should be considered in the interpretation of disease-stage-related nerve excitability changes in ALS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: The diagnosis of amyotrophic lateral sclerosis (ALS) includes demonstration of lower motor neuron (LMN) and upper motor neuron (UMN) involvement of bulbar and spinal muscles. Electromyography (EMG) is essential to confirm LMN affection in weak muscles, and to demonstrate changes in clinically non-involved muscles. The aim of the study was to determine the relative importance of ongoing (active) denervation, fasciculations, chronic partial denervation with reinnervation at weak effort and loss of motor units at maximal voluntary contraction (MVC) in ALS., Methods: EMG was carried out in weak and non-weak muscles in 220 patients suspected of ALS using concentric needle electrodes. Denervation activity and fasciculations in 966 muscles was quantified, the mean durations and amplitudes of motor unit potentials (MUPs) were compared to controls in 745 muscles, and the amplitudes and recruitment patterns at maximal voluntary effort were measured in 939 muscles. Twenty-five percent of patients had clinical involvement of 1 region, 42% of 2 regions and 33% of 3 regions. Clinically 65% had UMN involvement. Eighty-six percent of the patients had died on follow-up., Results: Denervation activity occurred in 72% of weak muscles but in only 45% of non-weak muscles. Fasciculations occurred in 56% of weak muscles and in 65% of non-weak muscles. MUPs showed reinnervation in 87-91% of weak and non-weak muscles and in 44% of muscles neurogenic MUPs occurred in the absence of denervation activity. In patients with clinical involvement of 1 region, combined EMG criteria increased the number of affected regions in 93%, and in 40% of patients with clinical involvement of 2 regions EMG increased the number of involved regions., Conclusions: Quantitative EMG confirmed widespread LMN involvement in patients with early ALS including clinically non-involved regions. These findings suggest that the maintenance of force is due to compensatory reinnervation in early disease and that this capacity may decline at later stages of ALS., Significance: These findings support a recent consensus report (the Awaji criteria) that EMG should have equivalent weight to clinical manifestations to indicate LMN involvement. The findings strongly indicate that spontaneous activity is insufficient to show LMN involvement in non-affected muscles at early stages of disease, and that analysis of MUPs are needed to document the distribution of LMN involvement., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Acute exposure of peripheral axons to the free radical Nitric Oxide (NO) may trigger conduction block and, if prolonged, Wallerian degeneration. It was hypothesized that this neurotoxic effect of NO may be due primarily to energy restriction by inhibition of mitochondrial respiration. We compared the neurotoxic effect of NO with the effect of the mitochondrial uncoupler 2,4-dinitrophenol (DNP) on electrically active axons of mouse sciatic nerve. The right tibial nerve was stimulated at the ankle. Muscle responses were recorded from plantar muscles and ascending nerve action potentials were recorded form the exposed sciatic nerve by means of a hook electrode. The sciatic nerve was focally immersed over a length of 1 cm in either phosphate buffered saline (PBS), a solution of approximately 4 microM NO obtained from 10 mM of the NO-donor DETA NONOate, or a solution of up to 1 mM DNP. Following 3 hours of 200 Hz stimulation, the nerves were washed in PBS for 1 hour, the surgical wounds were closed and the mice were left to recover. Following repetitive stimulation in PBS, the nerve responses recovered within 1 hour and the muscle responses within 1 day. The effects of focal acute exposure to NO or DNP were similar: (i) a transient conduction failure that rapidly normalized within one hour of washout and (ii) subsequent Wallerian degeneration of some axons confirmed at morphological studies. Taken together, these data support the hypothesis that neurotoxicity may be caused by energy restriction. Since the pharmacologic effect of NO and DNP was only transient, our data suggest that even a brief period of focal energy restriction can trigger Wallerian degeneration.

Acute and subacute polyneuropathies present diagnostic challenges since many require prompt initiation of treatment in order to limit axonal degeneration and since an exact and detailed diagnosis is a prerequisite for making the correct choice of treatment. It is for instance of utmost importance to recognize whether the underlying pathological changes are due to demyelination or to axonal degeneration and electrodiagnostic tests can thus in most cases contribute considerably to the securing of an exact diagnosis. The specific and characteristic electrophysiological findings in the different types of acute and subacute neuropathies are discussed, and the various electrophysiological pitfalls and technical problems, which are met in these patients, are mentioned.

After conduction of prolonged trains of impulses the increased Na+/K+ pump activity leads to hyperpolarization. The aim of this study was to develop a mouse model to investigate the Na+/K+ pump function in peripheral nerve by measuring the decrease in excitability during activity-dependent hyperpolarization. Acute electrophysiological investigations were carried out in seven adult mice. Nerve excitability was evaluated by tracking the change in threshold current after 5 min of 100 Hz stimulation of the tibial nerve at ankle. We developed a threshold tracking system that allowed us to follow several excitability measures simultaneously from the evoked plantar compound muscle action potential (CMAP) and sciatic compound nerve action potential (CNAP). Three minutes after repetitive supramaximal stimulation maximal CMAP and CNAP amplitudes recovered but the threshold was increased approximately 40% for motor axons approximately 34% for axons generating CNAP. The threshold recovered with a rate of 3.8%/minute that was similar for nerve and motor responses. By tracking the effect of polarizing currents we found evidence of activity dependent hyperpolarization, and our data suggest that the observed threshold change after repetitive stimulation of the mouse tibial nerve is an indicator of the Na+/K+ pump function in vivo. Evaluation of activity-dependent hyperpolarization may be an important indicator of axonal ability to cope with Na+ load.

Functional outcome after peripheral nerve regeneration is often poor, particularly involving nerve injuries far from their targets. Comparison of sensory and motor axon regeneration before target reinnervation is not possible in the clinical setting, and previous experimental studies addressing the question of differences in growth rates of different nerve fibre populations led to conflicting results. We developed an animal model to compare growth and maturation of the fastest growing sensory and motor fibres within the same mixed nerve after Wallerian degeneration. Regeneration of cat tibial nerve after crush (n = 13) and section (n = 7) was monitored for up to 140 days, using implanted cuff electrodes placed around the sciatic and tibial nerves and wire electrodes at plantar muscles. To distinguish between sensory and motor fibres, recordings were carried out from L6-S2 spinal roots using cuff electrodes. The timing of laminectomy was based on the presence of regenerating fibres along the nerve within the tibial cuff. Stimulation of unlesioned tibial nerves (n = 6) evoked the largest motor response in S1 ventral root and the largest sensory response in L7 dorsal root. Growth rates were compared by mapping the regenerating nerve fibres within the tibial nerve cuff to all ventral or dorsal roots and, regardless of the lesion type, the fastest growth was similar in sensory and motor fibres. Maturation was assessed as recovery of the maximum motor and sensory conduction velocities (CVs) within the tibial nerve cuff. Throughout the observation period the CV was approximately 14% faster in regenerated sensory fibres than in motor fibres in accordance with the difference observed in control nerves. Recovery of amplitude was only partial after section, whereas the root distribution pattern was restored. Our data suggest that the fastest growth and maturation rates that can be achieved during regeneration are similar for motor and sensory myelinated fibres.

We found persistent abnormalities in the recovery of membrane excitability in long-term regenerated motor nerve fibres in the cat as indicated in the companion paper. These abnormalities could partly be explained by membrane hyperpolarization. To further investigate this possibility, we compared the changes in excitability in control nerves and long-term regenerated cat nerves (3-5 years after tibial nerve crush) during manoeuvres known to alter axonal membrane Na(+)-K(+) pump function: polarization, cooling to 20 degrees C, reperfusion after 10 min ischaemia, and up to 60 s of repetitive stimulation at 200 Hz. The abnormalities in excitability of regenerated nerves were reduced by depolarization and cooling and increased by hyperpolarization and during postischaemia. Moreover, the time course of recovery of excitability from repetitive stimulation and ischaemia was prolonged in regenerated nerves. Our data are consistent with an increased demand for electrogenic Na(+)-K(+) pumping in regenerated nerves leading to membrane hyperpolarization. Such persistent hyperpolarization may influence the ability of the axon to compensate for changes in membrane potential following normal repetitive activity.

The purpose of our study was to assess by threshold tracking internodal and nodal membrane excitability during the maturation process after tibial nerve crush in cat. Various excitability indices (EI) were computed non-invasively by comparing the threshold of a submaximal compound motor potential at different stimulation durations (strength-duration relationship), after a conditioning nerve impulse (recovery of excitability), or during the application of a polarizing current (threshold electrotonus). Four months after the lesion, regenerated nerves showed a higher rheobase, shorter chronaxie, shorter refractory period and higher than normal threshold variations during threshold electrotonus (TE). A partial recovery was observed during the first 2 years of maturation. The recovery to depolarizing TE seemed complete but all other EI remained abnormal even after 5 years of regeneration, the most pronounced being the 157 +/- 8% (mean +/- S.E.M.) increase in threshold during hyperpolarizing TE compared with 94 +/- 4% in controls. These EI abnormalities are consistent with increased input impedance. Nevertheless, the time course of maturation and incomplete recovery of EI could only be partially explained by changes in fibre morphology. The highly abnormal response to hyperpolarizing but not to depolarizing TE suggests that voltage-dependent membrane function also remained abnormal, possibly due to membrane hyperpolarization.

Regeneration of myelinated and unmyelinated sensory nerve fibres after a crush lesion of the rat sciatic nerve was investigated by means of retrograde labelling. The advantage of this method is that the degree of regeneration is estimated on the basis of sensory somata rather than the number of axons. Axonal counts do not reflect the number of regenerated neurons because of axonal branching and because myelinated axons form unmyelinated sprouts. Two days to 10 weeks after crushing, the distal sural or peroneal nerves were cut and exposed to fluoro-dextran. Large and small dorsal root ganglion cells that had been labelled, i.e., that had regenerated axons towards or beyond the injection site, were counted in serial sections. Large and small neurons with presumably myelinated and unmyelinated axons, respectively, were classified by immunostaining for neurofilaments. The axonal growth rate was 3.7 mm/day with no obvious differences between myelinated and unmyelinated axons. This contrasted with previous claims of two to three times faster regeneration rates of unmyelinated as compared to myelinated fibres. The initial delay was 0.55 days. Fewer small neurons were labelled relative to large neurons after crush and regeneration than in controls, indicating that regeneration of small neurons was less complete than that of large ones. This contrasted with the fact that unmyelinated axons in the regenerated sural nerve after 74 days were only slightly reduced.

The compound sensory nerve action potential (SNAP) is the result of phase summation and cancellation of single fiber potentials (SFAPs) with amplitudes that depend on fiber diameter, and the amplitude and shape of the SNAP is determined by the distribution of fiber diameters. Conduction velocities at different conduction distances are determined by summation of SFAPs of varying fiber diameters, and differ in this respect, also, from the compound muscle action potential (CMAP) for which conduction velocities are determined by the very fastest fibers in the nerve. The effect and extent of temporal dispersion over increasing conduction distance is greater for the SNAP than CMAP, and demonstration of conduction block is therefore difficult. In addition, the effect of temporal dispersion on amplitude and shape is strongly dependent on the number of conducting fibers and their distribution, and, with fiber loss or increased conduction velocity variability changes of the SNAP may be smaller than expected from normal nerve. The biophysical characteristics of sensory and motor fibers differ, and this may to some extent determine divergent pathophysiological changes in sensory and motor fibers in different polyneuropathies. In this review, different factors that characterize sensory fibers and set the SNAP apart from the CMAP are discussed to emphasize the supplementary and complementary information that can be obtained from sensory conduction studies. Sensory conduction studies require particular effort and attention to theory and practical detail that may be time consuming.

Purpose of Review: The review concentrates on the use of clinical neurophysiology in peripheral nerve disorders covered in the present issue. It is pertinent to distinguish different types of involvement of fibers in diabetic neuropathy, including the involvement of small and large fibers, to outline the diagnostic criteria of inflammatory neuropathies, and to describe the spectrum of peripheral nerve pathophysiology in inherited neuropathies. Painful neuropathies represent a particular challenge to clinical neurophysiology since it is mainly small fibers, which are difficult to study, that are affected., Recent Findings: Electrodiagnostic studies have relevance in distinguishing neuropathies with different etiologies in diabetes mellitus, and different strategies and methods are necessary to study patients with autonomic and small-fiber involvement. The involvement of motor or sensory fibers, or both, and primary axonal or demyelinative pathology are important questions relating to immune-mediated neuropathies studied in the context of the specificity of antibodies against various neuronal and Schwann-cell structures. In hereditary neuropathy, electrophysiological studies are also used to distinguish axonal neuropathies from demyelinating neuropathies, though overlap and 'intermediate' patterns have become well recognized. In pain syndromes, conventional electrophysiological studies may give normal results if large fibers are not involved, and the use of autonomic measures in these situations has particular relevance., Summary: The usefulness of electrodiagnostic measures depends on the clinical, diagnostic, or pathophysiological question involved, and the strategy employed should reflect the advantages and limitations of these methods. If adequate consideration is paid to these properties, then such studies have a central role in the diagnosis and adequate treatment of patients with neuromuscular disorders.

Purpose of Review: The physiological properties of nerve and muscle are influenced by pathological changes and the aim of this review is to discuss recent contributions of electrophysiological studies to the understanding and diagnosis of selected peripheral nerve disorders. The relationships between pathology and physiology emphasize the close interdependence between electrophysiological studies, clinical deficits and other laboratory information. Attention should be paid to the strengths and limitations of electrophysiological methods, considering their impact on diagnosis and treatment of patients., Recent Findings: Several studies have shown particular pathophysiological profiles associated with different antibody subtypes in autoimmune peripheral neuropathies and this association further supports the suggestion of pathological specificity in both acute and chronic neuropathy. The sensitivity and specificity of physiological profiles therefore become increasingly important since some of these neuropathies are accessible to treatment. On the other hand, the pathophysiological and clinical profiles may be heterogeneous in patients with some disorders. This could be related to a more indistinct division between different types of pathology with increased understanding of pathogenetic mechanisms. Moreover, new insights into disturbed axonal function have stimulated attempts to develop methods to explore normal and diseased human nerve function., Summary: The exploration of axonal membrane and ion-channel function has become accessible using studies of excitability and are of potential value where conventional studies only provide nonspecific evidence of the number of fibers and the integrity of myelin. These studies will presumably become increasingly important in the years ahead considering the lack of understanding of the functional disturbances in axonal neuropathies.

Regeneration in the peripheral nervous system is often incomplete though it is uncertain which factors, such as the type and extent of the injury or the method or timing of repair, determine the degree of functional recovery. Serial electrophysiological techniques were used to follow recovery from median nerve lesions (n = 46) in nonhuman primates over 3 to 4 years, a time span comparable with such lesions in humans. Nerve gap distances of 5, 20, or 50mm were repaired with nerve grafts or collagen-based nerve guide tubes, and three electrophysiological outcome measures were followed: (1) compound muscle action potentials in the abductor pollicis brevis muscle, (2) the number and size of motor units in reinnervated muscle, and (3) compound sensory action potentials from digital nerve. A statistical model was used to assess the influence of three variables (repair type, nerve gap distance, and time to earliest muscle reinnervation) on the final recovery of the outcome measures. Nerve gap distance and the repair type, individually and concertedly, strongly influenced the time to earliest muscle reinnervation, and only time to reinnervation was significant when all three variables were included as outcome predictors. Thus, nerve gap distance and repair type exert their influence through time to muscle reinnervation. These findings emphasize that factors that control early axonal outgrowth influence the final level of recovery attained years later. They also highlight that a time window exists within which axons must grow through the distal nerve stump in order for recovery after nerve lesions to be optimal. Future work should focus on interventions that may accelerate the growth of axons from the lesion site into the distal nerve stump.

The extent to which the long-term recovery of nerve fibers differs according to the cause of Wallerian degeneration is not clear, although outgrowth of axons is better after lesions with continuity of basal lamina of the Schwann cell tubes (nerve crush) compared with lesions with interruption of basal lamina (nerve section). Post-reinnervation maturation of myelinated nerve fibers of the cat tibial nerve was followed in chronic electrophysiologic studies after crushing, sectioning, and section+freeze lesions, and compared with morphometric analysis of the same nerves. The amplitudes of the compound nerve action potentials (CNAPs) recovered to a much lesser extent after sectioning than after crushing the nerve. This difference could be related to a smaller number of large fibers, a greater degree of sprouting after sectioning than after crushing, or less synchronization of conduction in regenerated fibers. In comparison, the compound muscle action potentials (CMAPs) recovered to a greater extent than the CNAP after sectioning and section+freeze, though not to the same degree or as fast as after crushing. The difference between the recovery of the CNAP and the CMAP could be due to better regeneration of motor fibers, to differences in the size of motor units or to a better summation of motor unit action potentials. The maximal conduction velocities (CV) in mixed nerve and in motor fibers increased faster after crushing than after sectioning and section+freeze to 60%-70% of control values. The diameters of the largest myelinated fibers increased in all lesions to about 80% of controls. The relation between fiber diameter and CV was influenced by remodeling of myelin during maturation. Hence, long-term functional recovery is influenced by the nature of the nerve lesion, and a smaller proportion of fibers recovered functionally after nerve section than after crush.

Functional recovery after nerve lesions in the peripheral nervous system requires the accurate regeneration of axons to their original target end organs. This paper examines axonal regeneration of the primate median nerve lesioned at the wrist over nerve gap distances of up to 50 mm. Nerve gaps were bridged by either a sural nerve graft or a biodegradable collagen nerve guide tube, and recovery was followed for up to 1100 d. Nondestructive physiological methods were used to serially examine the number of regenerated motor units, and binomial statistics were used to compare the observed number of regenerated motor units with that expected if axonal regeneration of motor neurons were random. We found up to twice the number of motor units expected by random regeneration in direct suture and sural cable graft groups but not in nerve guide repairs of 20 or 50 mm. In all repaired nerves, aberrant motor axon collaterals were detected in digital sensory nerve territory. The results support the contention that the aberrant fibers represent collaterals of an alpha-motor axon, which also innervates muscle. Although the aberrant motor axon collaterals remained in digital sensory nerve territory for long periods, they remained relatively immature compared with their sibling collateral projecting to muscle, or sensory axons within the digital nerve. The number of such aberrant motor axon collaterals decreased over time in some repair groups, suggesting a selective pruning of the inappropriate collateral under certain conditions.

This review describes some of the factors that may lead to erroneous interpretations of electromyographic and nerve conduction studies. Such errors may be due either to technical or to biological factors, and it is imperative that the consequent limitations of the methods be considered in a diagnostic setting. Electrodiagnostic findings should always be interpreted in the clinical context, and since they are rarely specific for a particular disorder or pathology, it is necessary to satisfy several criteria to make a specific diagnosis. The aim of electromyographic examination is to ascertain whether weakness is due to a neurogenic lesion or to myopathy. It is, however, not sufficient to show the presence of denervation activity since this may occur in either condition. Therefore the motor unit potentials from both weak and nonaffected muscles should be examined quantitatively. Nerve conduction studies are carried out to ascertain whether motor or sensory myelinated fibers are lost, and whether the primary pathology is due to demyelination or axonal loss or to both. The nerve conduction velocity is of primary importance in this distinction. However, loss of large myelinated fibers leads to slowing of conduction; in some instances the conduction velocity may be normal if only a few large fibers are spared. In addition collateral sprouting in chronic conditions may lead to apparent sparing of motor fibers. Hence an erroneous diagnosis may be made of a sensory neuropathy if additional electromyography or other tests are not carried out. Conduction studies investigate only large myelinated fibers, and therefore in some instances there is discordance between the morphology and physiology. Acquired demyelinating neuropathies are sometimes associated with focal slowing of conduction or with conduction block. The demonstration of conduction block is important, but several requirements must be fulfilled in terms of technique, clinical context, and temporal development in order to avoid errors.

Cisplatin is a valuable antineoplastic drug which as a dose-limiting side-effect causes sensory neuropathy, and which therefore is often combined with less neurotoxic carboplatin. It has not been possible to reproduce cisplatin neuropathy in experimental animals, and the neurotoxic mechanism in man is disputed. We investigated post-mortem material from 12 patients and 15 control subjects. Half of the fibres with diameters of > or = 9 microns, or more than 15% of all fibres (P < 0.02), had disappeared in the sural nerves of patients. Signs of axonal regeneration were lacking. The dorsal root ganglia D12 and L2 of some but not of all patients contained necrotic neurons and nodules of Nageotte. The mean volume of the somata was reduced by 18% (P < 0.03). A relation between cumulated doses, treatment free interval and changes in nerve or ganglia was not found. The platinum content was high in all tissues except in the spinal cord when the patient had died shortly after treatment, and it decreased with increasing interval, least so in liver, sensory ganglia and sural nerves. The results support the hypothesis that cisplatin neuropathy is a neuroneopathy rather than a dying-back axonopathy.

The accurate diagnosis of peripheral neuropathy is important with respect to the therapeutic possibilities and limitations, which are especially relevant in immune-mediated polyneuropathies. These polyneuropathies may be axonal or demyelinating and have an acute or chronic course, and they may be difficult to distinguish from non-treatable neuropathies on clinical grounds. Efforts have been made to establish clinical, neurophysiological, morphological, biochemical, immunological and molecular biological criteria to attain specific diagnosis. This has shown heterogeneity not only within the treatable neuropathies, which may have implications for the treatment. It has also been shown that hereditary or diabetic polyneuropathy may have features which respond to immunosuppressive treatment. Molecular biology studies have revealed markers for the diagnosis of hereditary neuropathy, and have in some instances also delineated the gene product.

Peripheral nerve regeneration is considered to be influenced by structural, cellular and humoral factors in the distal nerve stump. Axonal elongation was, however, not affected by the presence of a 20 mm acellular nerve segment (ANS) distal to a crush lesion in a cat tibial nerve which was shielded from the environment by a silicone cuff [K. Fugleholm, H. Schmalbruch, C. Krarup, Early peripheral nerve regeneration after crushing, sectioning, and freeze studied by implanted electrodes in the cat, J. Neurosci., 14 (1994) 2659-2673]. In the present study axons were challenged to regenerate through crush lesions combined with 30-, 40-, 50-, 60- and 70-mm ANSs. For 30- and 40-mm ANSs, the nerves were shielded by impermeable silicone cuffs containing electrodes for electrophysiological evaluation of axonal elongation. All nerves were examined histologically by light microscopy 9 weeks after the lesion. The elongation through the shielded 30-mm ANS was slower than through a shielded nerve segment with viable cells. In the isolated 40-mm ANS, incomplete Wallerian degeneration and lack of blood vessels were observed, and axonal elongation was severely impaired. Regeneration across 40-70 mm non-shielded ANSs was intact and there was no relation between the number of regenerated fibers and the length of the ANS. There was no reduction in the number of blood vessels in the non-isolated ANSs. The results suggest that regeneration through an isolated acellular nerve segment exceeding 30 mm depends on cellular and humoral support from the near-nerve environment. Thus, the near-nerve environment is crucial for regeneration through long ANSs, and the importance of humoral, cellular and vascular support is discussed., (Copyright 1998 Elsevier Science B.V.)

We transferred a reporter gene to Schwann cells to test whether they might serve as an endoneurial delivery system for therapeutic proteins. A replication-defective adenoviral vector carrying the gene for beta-galactosidase (lacZ) was injected into the distal segment of intact or crushed sciatic nerves of adult rats, and the expression of lacZ was histochemically assessed. Less than 1% of the Schwann cells became reactive in intact nerves, but up to 18% of the proliferating Schwann cells of injured nerves expressed lacZ. Gene expression decayed with time but might persist for up to 2 months. It was enhanced by immunosuppression: daily cyclosporin A injections reduced both proliferation of Schwann cells and lymphocytic infiltration of the nerve, whereas tolerance induced by a single intrathymic injection of the vector 4 days after birth abolished the inflammatory response but not the proliferation of Schwann cells. The vector itself did not impede axonal regeneration. The results indicate that adenoviral gene transfer to Schwann cells in injured nerves is possible and suggest that induced production of neurotrophic factor may represent a therapeutic supplement to surgical nerve repair.

Neuropathy in animals is either genetically determined or is provoked by chemical compounds or physical injury. Diabetes in mice and rats may be spontaneous or induced, but a true copy of diabetic neuropathy in man is not yet available. Painful neuropathy occurs after nerve constriction or neuroma formation. A mouse mutant with delayed Wallerian degeneration demonstrates the pivotal role of this process for the regeneration of injured axons. Surprisingly, the neurotoxic effect of cisplatin which is severe in cancer patients has not yet unambiguously been reproduced in animals. Genetically determined diseases in mutants or transgenic animals may affect the myelination of peripheral axons. 'Trembler mice' are deficient in myelin and possibly correspond to CMT IA in man. The relation of sensory neuronopathies in mice, rats and dogs to human diseases is not yet clear. Motor neuronopathies in experimental animals have attracted much interest, because the recent discovery of motoneuronotrophic factors has raised high hopes. Most of the mutants described have not been appropriately studied, and the mouse mutant 'motoneurone disease' (mnd) eventually was found to have Batten's disease. None of the few more thoroughly studied models is probably a copy of human disease, although they may none the less help to test new therapies.

Pathophysiological changes in sensory fibres in chronic acquired demyelinating neuropathy (CADP) are poorly understood, and it is not known to what extent sensory loss may be due to axonal loss or to conduction block. Motor and sensory nerve condition were studied in 18 patients with CADP to delineate abnormalities in the compound sensory action potential (CSAP) recorded proximally along the limb. To distinguish small CSAPs from noise, near-nerve needle electrodes and electronic averaging were used. In all, 58 motor and 78 sensory nerves in the upper and lower limbs were studied, and in 29 nerves, motor and sensory conduction was compared over the same proximal and distal segments of the upper limbs. The proximal/distal amplitude ratio (P/D ratio) of the compound muscle action potential (CMAP) was reduced in 76% of the nerves compared with only 21% of the CSAPs. The amplitudes of CMAPs evoked and of CSAPs recorded distally were reduced to the same extent. The prolongation of the distal motor latency (DML) was linearly related to the reduction in amplitude of the CMAP whereas reduction of the distal sensory conduction velocity (SCVd) mainly occurred if the amplitude of the CSAP was reduced more than 70%. The proximal motor nerve conduction velocity (MCVp) was reduced by 40-50%, twice as much as the reduction in distal MCV (MCVd) (calculated from the reciprocal DML), and related to the reduction in the P/D ratio of the CMAP. The proximal SCV (SCVp) decreased approximately 20%, similar to the reduction in SCVd and out of proportion to the marked reduction of the MCVp. The results suggest different pathophysiological changes in sensory and motor fibres in CADP. Thus, nerve fibre loss could account for most of the abnormal parameters in sensory conduction, whereas demyelination was the dominating cause of motor nerve dysfunction.

In 18 cases of monoclonal gammopathy of undetermined significance, MGUS (monoclonal gammopathy of undetermined significance), admitted for diagnosed or suspected peripheral neuropathy, 11 patients showed other co-existing autoimmune manifestations. Two had POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-component, and skin symptoms), the others mainly endocrinopathy and polyclonal pseudolymphoma. There were 13 cases of sensorimotor neuropathy, two cases of neuritis, while neuropathy could not be confirmed in three cases. Compared with a retrospective review of autoimmunity in a randomly selected CLL (chronic lymphocytic leukemia) cohort of 115 patients, 13 out of 42 patients with clinical and/or laboratory features of autoimmunity showed co-expression of autoimmune signs, the dominating traits being Coombs positive AIHA (auto-immune hemolytic anemia), platelet autoantibodies, endocrinopathy mainly associated with the thyroid gland, serological and/or rheumatological symptoms, but only one case of sensorimotor neuropathy. Viewed from a current model of acquired autoimmunity it is perhaps not surprising that such autoimmunity is seen predominantly in patients with monoclonal gammopathy. Thus, a high concentration of cross-reacting polyreactive autoantibodies related to the M-component might be present in these patients. Furthermore, quantitative defects of the immunoglobulins including the hypogammaglobulinemia associated with M-components can presumably give rise to a defect of the anti-idiotypic network's regulation of natural autoantibodies and autoimmune manifestations in vivo. Such autoimmune manifestations, which are easily overlooked in CLL may call for additional treatment with immunosuppression and/or intravenous, polyclonal IgG.

Nerve regeneration was followed in 15 median and 1 ulnar nerve of eight Macaca fascicularis monkeys by serial electrophysiological assessments over a period of three and a half years. Nerve gaps of 5 mm at the wrist were bridged by collagen-based nerve guides, nerve autografts, or direct suture repairs. Thenar muscle reinnervation occurred between 50 and 70 d for all groups, indicating axonal elongation rates of approximately 1 mm/d. The recovery rates of the compound muscle action potential (CMAP) and the compound sensory action potential (CSAP) amplitudes were significantly slower after direct suture repair compared to the other two procedures, although the final levels of recovery were all comparable. Similar results were achieved in one median and one ulnar nerve following nerve guide repair of a 15 mm nerve gap. The functional reinnervation of Pacinian corpuscles was detected in all cases following either nerve graft or nerve guide repair, with similar amplitudes and latencies of the tactile evoked CSAP for both types of repair. Histological analysis demonstrated a significant increase in the number of myelinated axons in the median nerve distal to the nerve lesions following both nerve graft and nerve guide repairs compared to proximal and normal controls, with significant reductions of fiber diameter and corresponding increases in g-ratio. The return of a bimodal frequency distribution of myelinated axon fiber diameter was confirmed by three-dimensional surface plots which illustrate the frequency distribution of the relationship between fiber diameter and g-ratio. These combined results demonstrate that nerve regeneration after repair of a 5 mm nerve gap with a collagen nerve guide in the nonhuman primate is similar to that after graft repair, and the final level of physiological recovery for both repair procedures is comparable to direct suture repair of the median nerve.

The compound sensory action potential evoked by electrical stimulation provides a measure of the number and physiological properties of myelinated fibers in the nerve but does not allow evaluation of the most distal part of the sensory nerve. This study compares the compound sensory action potential, evoked by electrical and tactile stimuli, and recorded through needle electrodes placed close to the median and sural nerves of 22 normal males aged 16-51 years. The tactile probe, with a slight preindentation, delivered an indentation of the skin of 200 microns at a rate of 400 microns/ms at the tip of digit III and the dorsolateral side of the foot. The responses were recorded from the median nerve at wrist and elbow and from the sural nerve at the lateral malleolus and midcalf. The amplitudes of the responses averaged 0.5 microV and 0.7 microV in the sural and the median nerves (P < 0.02), respectively, which was only 5-10% of the amplitude evoked by electrical stimulation. The mean maximal conduction velocity determined by tactile stimulation was 54 m/s in the sural nerve compared with 65 m/s in the median nerve and similar to that calculated after electrical stimulation. In the median nerve the sensory conduction velocity was 8% faster than the motor conduction velocity. These findings indicated that only a fraction of the fibers in the nerve were activated by the probe and that the response was conducted along large myelinated sensory fibers. The latency of the tactile response was longer than that of the electrically evoked response due to the receptor delay and conduction along thin distal fiber portions. The delay at the mechanoreceptors was about 1 ms in the sural and 0.65 ms in the median nerve (P < 0.01).

Cisplatin is a widely used anti-neoplastic agent with dose-dependent sensory neuropathy as a major side-effect. The mechanism for the neuropathy is poorly understood; it may be caused by a lesion of the dorsal root ganglion cells or by a distal axonopathy. This distinction is important since regeneration in a neuronopathy is impossible, whereas recovery may occur if the axon is affected only distally. The most distal part of the sensory nerve fibre is, however, not accessible for conventional electrophysiological examination. To ascertain whether the distal receptor-associated part of the fibre is involved, we have used a method previously untested in patients with neuropathy. In 26 males treated with cisplatin for testicular cancer 3-6.5 years previously, and in 22 normal males, the compound sensory action potentials evoked by a tactile probe were recorded through needle electrodes placed close to the sural and median nerves. The responses were compared with action potentials evoked by electrical stimulation of the same nerves. Biopsies from the distal sural nerve at the dorsolateral aspect of the foot were obtained in three patients and in four subjects not treated with cisplatin. Sixteen patients had received a conventional dose (307-435 mg/m2) of cisplatin and 10 patients had received a high dose (553-1197 mg/m2). Two-thirds of the conventional dose patients and all the high dose patients had mild to severe sensory loss and reduced or absent tendon reflexes. The amplitude of the electrically evoked sensory action potential decreased with increasing dose of cisplatin and was correlated with the reduction of vibration sense. Tactile responses, probably originating mainly from Pacinian corpuscles, were, with the exception of two high dose patients, recorded from all sural and median nerves. The two high dose patients without a tactile response had a severely reduced or no electrically evoked response at the sural nerve. The sural nerve biopsies from high dose patients showed loss of large fibres; Pacinian corpuscles were obtained in two of these patients and contained normal axons. Our findings do not suggest that cisplatin causes a primarily distal lesion with sparing of more proximal parts of the peripheral nerve. We interpret the results as being consistent with a neuronopathy affecting primarily large sensory neurons. Brainstem and somatosensory evoked potentials and H-reflexes suggested that the spinal cord and brainstem were affected as well.

To study slowly conducted components of the orthodromic compound sensory action potential (CSAP), the response evoked at the lateral malleolus in the sural nerve was recorded through near-nerve needles at two to four sites along the nerve at midcalf. When 500 to 2000 responses were averaged at high gain, components with latencies of 30 to 80 ms were often recorded. In contrast to the main component and late components with latencies of less than 15 to 20 ms, the latencies of these extremely late components diminished the closer to the spinal cord that they were recorded. This suggested that the components were conducted antidromically from proximal to distal. This assumption was supported by abolishing the components by local anesthesia of the nerve proximal to the recording electrodes. These antidromic potentials therefore appear to be due to recurrent discharges in the sural nerve. Recurrent discharges were recorded from 65% of 60 subjects (18 normal subjects and 42 patients with peripheral or central nervous system disorders). The latencies of the recurrent discharges allowed conduction to and back from the spinal cord. Although the origin of these potentials remains unknown, we suggest that they are due to dorsal root reflexes within the spinal cord. In this case, the responses may be a direct expression of primary afferent depolarization (PAD) seen in presynaptic inhibition, and may be of value in further studies on the physiology and pathophysiology of presynaptic inhibition of cutaneous fibers in man.

Conduction along the sural nerve was studied in 64 normal subjects using near-nerve electrodes. Conduction velocities over the same nerve segments were calculated: (1) from the latency recorded from a site of stimulation to a site of recording (1R-method); and (2) from the difference in latency between 2 recording sites, the site of stimulation being situated elsewhere along the nerve (2R-method). Consistently faster velocities were seen with the 2R-method and could best be explained by a fixed delay of about 0.15 ms at the stimulus site (latency of activation, utilization time). This delay was markedly prolonged when a ramp rather than a rectangular stimulus was applied, though fast fibers were excited with both types of stimuli. The delay is thought to be dependent on the relationship between the density of current at the stimulus site and the threshold of responding fibers.

The knowledge of the segmental innervation of the skin and muscles of the lower limb in man is inadequate. For this reason, sensory and motor segmental innervation of the lower extremities was examined by electrophysiological methods in 27 normal subjects, one patient with possible L5 radiculopathy and one with possible lumbosacral plexus affection. Needle electrodes were placed at root levels from L3 to S2 using bony landmarks. The electrode was then placed close to the spinal nerve as indicated by a low (less than or equal to 1 mA) threshold necessary to stimulate motor fibres. The position was controlled by X-ray in 10 subjects. Sensory innervation was determined by recording the sensory action potential evoked by stimulating the saphenous nerve at the medial epicondyle (mainly L3 and L4) and at the medial malleolus (mainly L4 and in some L3), the medial plantar nerve at the first plantar interstice (mainly S1, some L5 and S2), the deep peroneal nerve at the first dorsal interstice (mainly L5, some S1), the sural nerve at the dorsolateral aspect of the foot (mainly S1, some L5 and S2) and at the lateral malleolus (mainly S1, some L5 and S2), and the superficial peroneal nerve at the superior extensor retinaculum (mainly L5, S1). The motor innervation was determined by stimulating the spinal nerves supramaximally and recording the evoked responses from the medial and lateral vastus (mainly L3, L4), the anterior tibial (mainly L5), the peroneus longus (L5, S1), the extensor digitorum brevis (mainly S1), the gastrocnemius (mainly S1), the abductor hallucis (mainly S2) and the biceps femoris (mainly L5, S1). Sensory and motor conduction velocity measurements along the leg and across the lumbosacral plexus indicated that there was no difference in a disto-proximal direction, except for a 10% reduction along the most distal part of the sural nerve which, however, might be explained by utilization time. There was therefore no evidence of gradual tapering of nerve fibres in a distal direction. The proximal motor conduction velocity to the most distally placed muscle (abductor hallucis) was about 20% lower than to the proximally placed muscles (gastrocnemius and biceps femoris) suggesting a general difference in fibre calibre.

The sural nerve was studied orthodromically using the near-nerve technique in 273 normal subjects (155 females, 118 males) aged 5 to 90 years. The sensory action potential (SAP), evoked at the dorsum of the foot, was recorded at the lateral malleolus and midcalf, and at the midcalf when evoked at the lateral malleolus. In addition, the SAP was recorded at intermediate distal sites and at proximal sites at the popliteal fossa, the gluteal fold, and the S-1 root. The amplitude of the SAP recorded at midcalf was 32% higher in females than in males. This was probably due to volume-conduction properties, as differences between genders were less noticeable at more distal recording sites. The amplitude decreased steeply and exponentially with age. Conduction distance had a strong influence on the amplitude of the SAP, which decreased with increasing distance following a power relationship with an exponent of 1.4 to 1.7. This decrease was due to temporal dispersion with decreased summation and increased phase cancellation. The conduction velocity was slightly lower along the very distal course of the nerve than along more proximal segments.

This paper describes the repair of peripheral nerves with a tubular conduit fabricated from collagen. The tubular collagen matrix was made semipermeable to permit nutrient exchange and accessibility of neurotrophic factors to the axonal growth zone during regeneration. In-vitro studies showed that the semipermeable collagen conduit allowed rapid diffusion of molecules the size of bovine serum albumin and was adequately cross-linked for controlled resorption in vivo. Studies on primates suggest that collagen conduits worked as effectively as nerve autografts in terms of physiological recovery of motor and sensory responses. The results of in-vitro and in-vivo studies of the collagen conduit represent a significant step towards our specific aim of developing suitable off-the-shelf prostheses for clinical repair of damaged peripheral nerves.

Although multiple sclerosis primarily affects myelin within the central nervous system, both pathologic and physiological studies suggest that mild deficits in peripheral nervous system myelin may be common. To evaluate this question further, we performed near nerve studies on sural nerves of 14 patients with multiple sclerosis. Peak-to-peak amplitude and maximum conduction velocity were normal in 9 of 14 patients, while minimum conduction velocity, or the velocity of the slowest-conducting component of the sensory action potential, was abnormally reduced in 9 patients. In addition, the supernormal period was evaluated for patients and compared with a control sample; multiple sclerosis patients showed a significant reduction in the amplitude of supernormality. Both the reduction in minimum conduction velocity and the alteration in the supernormal period are consistent with a mild defect in peripheral myelin.

Sensory function in patients with amyotrophic lateral sclerosis (ALS) is thought to be normal; however, there is convincing morphologic evidence that sensory systems are affected in addition to motor systems. In this study, compound sensory action potentials were recorded with near nerve electrodes from 18 patients with ALS. Up to 1024 responses were averaged at high gain to determine minimum conduction velocity; that is, the conduction velocity of the slowest conducting component of the sensory action potential. Nine of 18 patients had abnormally reduced minimum conduction velocity, even when peak-to-peak amplitude and maximum conduction velocity (calculated from the latency to the initial positive peak) were normal. Only 3 of 18 patients showed abnormalities in peak-to-peak amplitude. Thus, subtle abnormalities in the sensory action potential can be detected in many patients with ALS.

During recent years chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) has been characterized on the basis of clinical and laboratory findings. Immune modifying treatment with glucocorticoids, plasma exchange and infusion of immune globulins has had a therapeutic effect in controlled studies. Decisive for increased therapeutic efforts against CIDP in Denmark is intensified electrophysiological search in patients with polyneuropathy with examination of several nerve segments for evidence of demyelination including conduction block, potential dispersion and reduction of conduction velocity by more than 40%.

A group of 6 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) was treated with prednisone, azathioprine, plasma exchange and/or intravenous immunoglobulin. Three of the six patients improved during treatment with prednisone and two patients with severe CIDP both showed a remarkable therapeutic response to treatment with intravenous immunoglobulin.

The main component of the compound sensory action potential reflects the activity of large myelinated sensory fibers with diameters of greater than 9 micron(s). By recording the averaged potential using a needle electrode placed close to the nerve, small late components can be measured. The latency of these late components can be used to calculate minimum conduction velocity (CV); in normal subjects, average minimum CV is 15 m/s, corresponding to conduction in fibers of about 4 micron(s) in diameter. Minimum CV was measured in median, ulnar, and sural nerves of 187 patients with mild to severe neuropathic symptoms. A reduction in minimum CV was a sensitive measure of peripheral nerve dysfunction, often showing abnormalities when measures derived from the main component were normal. Patients with isolated abnormalities in minimum CV tended to have neuropathic symptoms but no signs of neuropathy. In addition, reduced minimum conduction velocity has implications for the pathology of different types of neuropathy. Slowing conducting potentials may originate from regenerating fibers, which may be of particular relevance in patients with neuropathic pain.

When a peripheral nerve is severed and left untreated, the most likely result is the formation of an endbulb neuroma; this tangled mass of disorganized nerve fibers blocks functional recovery following nerve injury. Although there are several different approaches for promoting nerve repair, which have been greatly refined over recent years, the clinical results of peripheral nerve repair remain very disappointing. In this paper we compare the results of a collagen nerve guide conduit to the more standard clinical procedure of nerve autografting to promote repair of transected peripheral nerves in rats and nonhuman primates. In rats, we tested recovery from sciatic nerve transection and repair by 1) direct microsurgical suture, 2) 4 mm autograft, or 3) entubulation repair with collagen-based nerve guide conduits. Evoked muscle action potentials (MAP) were recorded from the gastrocnemius muscle at 4 and 12 weeks following sciatic nerve transection. At 4 weeks the repair group of direct suture demonstrated a significantly greater MAP, compared to the other surgical repair groups. However, at 12 weeks all four surgical repair groups displayed similar levels of recovery of the motor response. In six adult male Macaca fascicularis monkeys the median nerve was transected 2 cm above the wrist and repaired by either a 4 mm nerve autograft or a collagen-based nerve guide conduit leaving a 4 mm gap between nerve ends. Serial studies of motor and sensory fibers were performed by recording the evoked MAP from the abductor pollicis brevis muscle (APB) and the sensory action potential (SAP) evoked by stimulation of digital nerves (digit II), respectively, up to 760 days following surgery. Evoked muscle responses returned to normal baseline levels in all cases. Statistical analysis of the motor responses, as judged by the slope of the recovery curves, indicated a significantly more rapid rate of recovery for the nerve guide repair group. The final level of recovery of the MAP amplitudes was not significantly different between the groups. In contrast, the SAP amplitude only recovered to the low normal range and there were no statistically significant differences between the two groups in terms of sensory recovery rates. The rodent and primate studies suggest that in terms of recovery of physiological responses from target muscle and sensory nerves, entubulation repair of peripheral nerves with a collagen-based nerve guide conduit over a short nerve gap (4 mm) is as effective as a standard nerve autograft.(ABSTRACT TRUNCATED AT 400 WORDS)

A 22-year-old male was studied 3 1/2-4 1/2 years after a traumatic section-avulsion amputation of the left upper extremity at the level of the distal humerus. The arm was reattached after a cold ischemia time of 4-5 hours and good vascularization was obtained. The ulnar nerve was repaired early with an end-to-end juncture while the median and radial nerves were repaired after seven months delay using a combination of vascularized radial nerve and nonvascularized sural nerve grafts. Some intrinsic hand muscle function had recovered. Pin-prick and touch sensation was present in all digits, although localization of touch stimulation was poor. Evoked motor responses had recovered by 25-50% of control amplitude in ulnar-innervated and by 10-25% in median-innervated muscles. Amplitudes of sensory responses from digit V had recovered by 25% and from digits I and III by 1-5%. Fast-adapting touch receptors had become reinnervated. There was electrophysiological evidence of aberrant sensory regeneration and of abnormal connections between sensory and motor fibers. Digital blood flow measurements suggested the presence of vascular obstruction in vessels of the replanted upper extremity. However, the digital vasoconstriction during cold exposure indicated regeneration of sympathetic nerve fibers.

Four infants presented with hydroureteronephrosis and incomplete emptying of the bladder secondary to detrusor-sphincter dyssynergia. None of the patients had other signs suggestive of neurological dysfunction. It is presumed but not proved that these infants manifested a urodynamic reaction in response to a perinatal insult involving the brainstem area. Long-term followup has demonstrated a persistent but nonprogressive neurourological disturbance.

1. Potentiation of the isometric twitch tension was compared during and after the staircase and after tetanic stimuli in the fast-twitch extensor digitorum longus muscle of adult Lewis rats at 37-38 degrees C.2. With up to 250 stimuli the potentiation rose with an increase in both the frequency and number of stimuli in the staircase (2-5/sec) and the tetanus (100-167/sec). After a tetanus of 375 stimuli (125/sec) the potentiation was smaller. The potentiation 2 sec after a tetanus of 250 stimuli (167/sec) was + 132 +/- 5% (n = 21, s.e. of mean) which was greater (P < 0.001) than at the 250th stimulus at 5/sec, +92+/-3% (n = 21, s.e. of mean).3. After the staircase the decay of potentiation was initially slow and later more rapid. This was taken to indicate both the recovery of a process that diminished twitch tension and the decay of a process causing potentiation. After 250 stimuli (5/sec) the rate of decay of the processes causing diminution and potentiation had time constants of 34.5 +/- 3.8 sec (n = 18, s.e. of mean) and 102.2 +/- 6.6 sec (n = 20, s.e. of mean) respectively. Compared with the potentiation, the process causing diminution became relatively more pronounced the greater the frequency of stimuli.4. The decay of post-tetanic potentiation showed an initial rapid and a later slower phase of decay. After a tetanus of 250 stimuli (167/sec) the rates of decay had time constants of 5.7 +/- 0.8 sec (n = 16, s.e. of mean) and 113.5 +/- 8.7 sec (n = 19, s.e. of mean) respectively.5. Compared with the unpotentiated response the time course of the twitch was shortened initially in the staircase and when the post-tetanic potentiation was low. The contraction time was then increasingly prolonged the greater the potentiation and the greater the number of stimuli in the staircase and in the tetanus. The half-relaxation time was the more prolonged the greater the number of stimuli.6. Potentiation can be described in terms of a two-compartment model of processes which show saturation. Both compartments were activated in a tetanus whereas only the compartment with a slow rate of decay was activated in the staircase. It is speculated that the two compartments are related to the excitation-contraction coupling. The process that caused diminution of twitch tension during the staircase may be due to fatigue. It is suggested that the energy consumption in 250 twitches is about 10 times greater than in a tetanus of 250 stimuli which may explain the presence of fatigue after the staircase whereas it was absent after the tetanus.

The bulbocavernosus reflex (BCR) is a sacral segmental reflex which is suppressed throughout most of micturition. The BCR was evaluated by recording the associated EMG activity using a concentric needle electrode placed in the external urethral sphincter. The influence of the central nervous system (CNS) on the BCR was studied in 29 neurologically normal individuals and in 33 patients with upper motor neuron (UMN) lesions and voiding dysfunction. Ninety percent (26/29) of the neurologically normal patients did not have a BCR during most of micturition. By comparison, all the patients with an UMN lesion had a positive BCR beginning early during voiding. The finding of suprasegmental modulation of the BCR during voiding demonstrated by external urethral sphincter EMG was a more sensitive although slightly less specific sign of UMN bladder dysfunction than detrusor sphincter dyssynergia; uninhibited bladder contractions were neither sensitive nor specific for UMN lesions.

Conventional nerve conduction studies assess only a small proportion of the fiber population in peripheral nerve. Nerve conduction velocity is a measure of the very fast conducting fibers and varies with temperature and age. The amplitude of the compound nerve action potential is determined by fibers 9-14 microns in diameter and is dependent on the number of active fibers. The amplitude of the normal sural nerve action potential varies by a factor of 3-4 due to the large variation in the number of large myelinated fibers (1700-3300 per nerve, 7-14 microns). Nerve conduction studies performed under adequate conditions are of value in ascertaining whether there is involvement of peripheral nerve. Due to the large variation in normal nerve these studies are, however, not well suited as screening procedures in individuals exposed to toxic substances.