Glial cells and chronic pain.

Over the past few years, the control of pain exerted by glial cells has emerged as a promising target against pathological pain. Indeed, changes in glial phenotypes have been reported throughout the entire nociceptive pathway, from peripheral nerves to higher integrative brain regions, and pharmacological inhibition of such glial reactions reduces the manifestation of pain in animal models. This complex interplay between glia and neurons relies on various mechanisms depending both on glial cell types considered (astrocytes, microglia, satellite cells, or Schwann cells), the anatomical location of the regulatory process (peripheral nerve, spinal cord, or brain), and the nature of the chronic pain paradigm. Intracellularly, recent advances have pointed to the activation of specific cascades, such as mitogen-associated protein kinases (MAPKs) in the underlying processes behind glial activation. In addition, given the large number of functions accomplished by glial cells, various mechanisms might sensitize nociceptive neurons including a release of pronociceptive cytokines and neurotrophins or changes in neurotransmitter-scavenging capacity. The authors review the conceptual advances made in the recent years about the implication of central and peripheral glia in animal models of chronic pain and discuss the possibility to translate it into human therapies in the future.

A strange foot not far from CRPS I

Introduction.- Since the work of the "International Association for the Study of Pain" (IASP), complex regional pain syndrome type 1 (CRPS I) or algodystrophy includes motor disorders (tremor, dystony, myoclony) as diagnosis criterion. This can lead to confusion with some neurologic disorders which can wrongly be considered as CRPS I. The following observation illustrates this problem.Observation.- A 31-year-old man was hospitalised in a rehabilitation clinic in April 2007 with suspected CRPS I with persistent pain in the left leg. In 2005, the patient underwent ligament reconstruction at the right ankle. In May 2006, a recurrence of his ankle sprain was treated conservatively. The course of this pathology was unfavourable with an extension of the pain areas (leg and foot) as well as an appearance of abnormal motion. Toe motion in abduction was observed (especially T5) followed by a flexion cramp; an hypoesthesia in the sural nerve area, a scar allodynia and discrete vasomotor disorders. The scintigraphy was compatible with a stage 2 algodystrophy. Lower limb electromyography was normal; measurement of pseudo periodic activity of the motor unit at the foot level (abductor of the 5th toe, 4th interosseous). A "Painful legs and moving toes syndrome" was diagnosed which was treated with gabapentin and carbamazepine with a partial improvement.Discussion.- The "Painful legs and moving toes syndrome" is a rare pathology rehabilitation specialists should recognize. The origin is often peripheral nerve damage. The medullar interneuron activation (between the dorsal and ventral horn) is considered as the source of the efferent motor nerves which are responsible for the abnormal movements. This observation illustrates the need for a demanding approach before establishing the diagnosis of CRPS I and the respect of the 4th criterion of the ASP (exclusion of this syndrome when another pathology may explain pain and dysfunction).

Validation of diagnosis criteria for acquired sensory neuronopathy. a francophone multicenter study

Recently published criteria using clinical (ataxia or asymmetrical distribution at onset or full development, and sensory loss not restricted to the lower limbs) and electrophysiological items (less than two abnormal lower limb motor nerves and at least an abolished SAP or three SAP below 30% of lower limit of normal in the upper limbs) were sensitive and specific for the diagnosis of sensory neuronopathy (SNN) (Camdessanche et al., Brain, 2009). However, these criteria need to be validated on a large multicenter population. For this, a database collecting cases from fifteen Reference Centers for Neuromuscular diseases in France and Switzerland is currently developed. So far, data from 120 patients with clinically pure sensory neuropathy have been collected. Cases were classified independently from the evaluated criteria as SNN (53), non-SNN (46) or suspected SNN (21) according to the expert's diagnosis. Using the criteria, SNN was possible in 83% (44/53), 23.9% (11/46) and 71.4% (15/21) of cases, respectively. In the non-SSN group, half of the patients with a diagnosis of possible SSN had an ataxic form of inflammatory demyelinating neuropathy. In the SNN group, half of those not retained as possible SNN had CANOMAD, paraneoplasia, or B12 deficiency. In a second step, after application of the items necessary to reach the level of probable SNN (no biological or electrophysiological abnormalities excluding SNN; presence of onconeural antibody, cisplatin treatment, Sj ¨ ogren's syndrome or spinal cord MRI high signal in the posterior column), a final diagnosis of possible or probable SNN was obtained in, respectively, 90.6% (48/53), 8.8% (4/45), and 71.4% (15/21) of patients in the three groups. Among the 5 patients with a final non-SNN but initial SNN diagnosis, 3 had motor conduction abnormalities (one with CANOMAD) and among the 4 patients with a final SNN but initial non-SSN diagnosis, one had anti-Hu antibody and one was discussed as a possible ataxic CIDP. These preliminary results confirm the sensitivity and specificity of the proposed criteria for the diagnosis of SNN.

Maladies auto-immunes neuromusculaires: diagnostic et prise en charge [Dysimmune neuromuscular disorders: diagnostic challenges and new ways of management].

This review describes some dysimmune neuromuscular disorders and their recent management: syndrome of peripheral nerve hyperexcitability (treatment of cramps, immunosuppressors); Guillain-Barré syndrome (new mechanisms and consensus treatment); chronic inflammatory demyelinating polyradiculoneuropathy (new indication for the use of pulse dexamethasone, new scores of activity); importance of subcutaneous immunoglobulin in multifocal motor neuropathy and of infusions of rituximab in myasthenia gravis; new entities in myositis and their treatment.

Nedd4-2 ubiquitin ligase: a contributor to experimental neuropathic pain?

Background: Neuropathic pain is associated with altered expression of voltage-gated sodium channels (VGSCs) leading to peripheral nerve hyperexcitability. Interestingly, in cell expression systems, the ubiquitin ligase Nedd4-2 regulates the cell membrane density of the most abundant peripheral and pain-related VGSC, namely Nav1.7, and decreases its sodium current. Yet nothing is known about the involvement of Nedd4-2 in nociception and chronic pain. Therefore, the goal of this study is (i) to characterize Nedd4-2 and Nav1.7 expression in an experimental model of neuropathic pain (ii) to design by viral vector-mediated gene therapy an approach to depict the implication of Nedd4-2 in chronic pain. Methods: Western Blot and immunohistochemistry experiments detecting Nav1.7 and Nedd4-2 were performed in rodent DRGs 7 days after spared nerve injury (SNI). For the viral vector-mediated gene therapy, a recombinant Adeno-Associated Virus (rAAV2/6) was generated expressing the Nedd4-2 gene. Intrathecal injection of rAAV2/6 was followed 2 weeks after by the SNI surgery. Data are expressed in mean ± SEM, n = 4 in each condition. Results: Immunofluorescence on DRGs neurons reveals a decreased number of positive Nedd4-2 cells in the SNI model (27.0 ± 1.2%) versus sham group (43.4 ± 3.5%; p <0.005), as well as an increase in positive Nav1.7 cells in SNI (50.1 ± 2.9%) versus Sham (41.6 ± 1.8%; p <0.05). The change of Nedd4-2 expression was confirmed by western-blot analysis. In addition, we show that Nedd4-2 and Nav1.7 are largely expressed in overlapping cell populations, chiefly colocalizing with markers of small nociceptive neurons. Furthermore, we report that intrathecal injection of rAAV is able to counteract the reduction of Nedd4-2 expression in SNI animals. Conclusion: Our results indicate that Nedd4-2 is mainly expressed in nociceptors and downregulated after nerve injury. Moreover, our data suggest that the reduction of Nedd4-2, after nerve injury, may modulate Nav1.7 activity and contribute to hyperexcitability in neuropathic pain. A normal level of Nedd4-2 can be restored using a viral vector and we will further assess its functional effect on pain sensitivity.

[Doublon: 10.1007/s00428-009-0853-4] Soft tissue sarcomas with complex genomic profiles.

Soft tissue sarcomas (STS) with complex genomic profiles (50% of all STS) are predominantly composed of spindle cell/pleomorphic sarcomas, including leiomyosarcoma, myxofibrosarcoma, pleomorphic liposarcoma, pleomorphic rhabdomyosarcoma, malignant peripheral nerve sheath tumor, angiosarcoma, extraskeletal osteosarcoma, and spindle cell/pleomorphic unclassified sarcoma (previously called spindle cell/pleomorphic malignant fibrous histiocytoma). These neoplasms show, characteristically, gains and losses of numerous chromosomes or chromosome regions, as well as amplifications. Many of them share recurrent aberrations (e.g., gain of 5p13-p15) that seem to play a significant role in tumor progression and/or metastatic dissemination. In this paper, we review the cytogenetic, molecular genetic, and clinicopathologic characteristics of the most common STS displaying complex genomic profiles. Features of diagnostic or prognostic relevance will be discussed when needed.

Revue de la littérature 2013--les neuropathies inflammatoires [2013: what's new in inflammatory neuropathies].

Several high-quality publications were published in 2013 and some major trials studies were started. In Guillain-Barré syndrome, events included the launch of IGOS and a better understanding of diagnostic limits, the effect of influenza vaccination, and better care, but uncertainty remains about analgesics. A new mouse model was also described. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), diagnostic pitfalls can be recalled. Our knowledge of underlying pathophysiological processes has improved, and the value of monitoring with function and deficit scores has been demonstrated. IVIG can sometimes be effective longer than expected, but CIDP remains sensitive to corticosteroids, particularly with the long-term beneficial effects of megadose dexamethasone. The impact of fingolimod remains to be demonstrated in an ongoing trial. Advances concerning multifocal motor neuropathy, inflammatory plexopathy, and neuropathy with anti -MAG activity are discussed but treatments already recognized as effective should not be changed. Imaging of peripheral nerve progresses.

Double seronegative myasthenia gravis with antiphospholipid syndrome: a case report.

INTRODUCTION: Myasthenia gravis is an autoimmune disease characterized by fluctuating muscle weakness. It is often associated with other autoimmune disorders, such as thyroid disease, rheumatoid arthritis, systemic lupus erythematosus, and antiphospholipid syndrome. Many aspects of autoimmune diseases are not completely understood, particularly when they occur in association, which suggests a common pathogenetic mechanism. CASE PRESENTATION: We report a case of a 42-year-old Caucasian woman with antiphospholipid syndrome, in whom myasthenia gravis developed years later. She tested negative for both antibodies against the acetylcholine receptor and against muscle-specific receptor tyrosine-kinase, but had typical decremental responses at the repetitive nerve stimulation testing, so that a generalized myasthenia gravis was diagnosed. Her thromboplastin time and activated partial thromboplastin time were high, anticardiolipin and anti-β2 glycoprotein-I antibodies were slightly elevated, as a manifestation of the antiphospholipid syndrome. She had a good clinical response when treated with a combination of pyridostigmine, prednisone and azathioprine. CONCLUSIONS: Many patients with myasthenia gravis test positive for a large variety of auto-antibodies, testifying of an immune dysregulation, and some display mild T-cell lymphopenia associated with hypergammaglobulinemia and B-cell hyper-reactivity. Both of these mechanisms could explain the occurrence of another autoimmune condition, such as antiphospholipid syndrome, but further studies are necessary to shed light on this matter.Clinicians should be aware that patients with an autoimmune diagnosis such as antiphospholipid syndrome who develop signs and neurological symptoms suggestive of myasthenia gravis are at risk and should prompt an emergent evaluation by a specialist.

Céphalées pharmacorésistantes: nouvelles approches du casse-tête [Drug-resistant headache: is it the end?].

Chronic primary headache often cause significant interference with function and quality of life despite acute and preventive medicines. New treatments are emerging for pharmacologically intractable cluster headache and migraine. Occipital nerve stimulation in chronic cluster headache and botulinum toxin in chronic migraine represent the most promising therapies.

Reproducibility of twitch mouth pressure, sniff nasal inspiratory pressure, and maximal inspiratory pressure.

Twitch mouth pressure (Pmo,tw) during magnetic phrenic nerve stimulation and sniff nasal inspiratory pressure (SNIP) were recently proposed as alternative noninvasive methods for assessing inspiratory muscle strength. This study aimed to compare their reproducibility with maximal inspiratory pressure (MIP) in normal subjects. Ten healthy subjects were studied at functional residual capacity in semirecumbent position. Cervical magnetic phrenic nerve stimulation was performed during gentle expiration against an occlusion incorporating a small leak. Constancy of stimulation was controlled by recording diaphragmatic electromyogram. Within and between-session reproducibility of pressure were studied for Pmo,tw, SNIP, and MIP. The subjects were studied during a session of 10 manoeuvres repeated after 1 day and 1 month. The mean values were 16 cmH2O for Pmo,tw, 118 cmH2O for SNIP, and 115 cmH2O for MIP. For the three tests, the within subject variation was small in relation to between-subject variation, with the intraclass correlation coefficient ranging 0.79-0.90 for Pmo,tw, 0.85-0.92 for SNIP, and 0.88-0.92 for MIP. At 1 day interval, the coefficient of repeatability (2 SD of differences) was 3.6 cmH2O for Pmo,tw, 32 cmH2O for SNIP and 28 cmH2O for MIP. At 1 month interval, the coefficient of repeatability was 5.8 cmH2O for Pmo,tw, 23 cmH2O for SNIP and 21 cmH2O for MIP. We conclude that the within session reproducibility of the new tests twitch mouth pressure and sniff nasal inspiratory pressure is sufficient to be clinically useful. For sniff nasal inspiratory pressure, the between session reproducibility established after 1 day was maintained after 1 month. For twitch mouth pressure, the between session reproducibility declined slightly after 1 month. These characteristics should be considered when using these methods to follow an individual patient over time.

Novel anesthetics and other treatment strategies for refractory status epilepticus

Refractory status epilepticus (RSE)-that is, seizures resistant to at least two antiepileptic drugs (AEDs)-is generally managed with barbiturates, propofol, or midazolam, despite a low level of evidence (Rossetti, 2007). When this approach fails, the need for alternative pharmacologic and nonpharmacologic strategies emerges. These have been investigated even less systematically than the aforementioned compounds, and are often used, sometimes in succession, in cases of extreme refractoriness (Robakis & Hirsch, 2006). Several possibilities are reviewed here. In view of the marked heterogeneity of reported information, etiologies, ages, and comedications, it is extremely difficult to evaluate a given method, not to say to compare different strategies among them. Pharmacologic Approaches Isoflurane and desflurane may complete the armamentarium of anesthetics,' and should be employed in a ''close'' environment, in order to prevent intoxication of treating personnel. c-Aminobutyric acid (GABA)A receptor potentiation represents the putative mechanism of action. In an earlier report, isoflurane was used for up to 55 h in nine patients, controlling seizures in all; mortality was, however, 67% (Kofke et al., 1989). More recently, the use of these inhalational anesthetics was described in seven subjects with RSE, for up to 26 days, with an endtidal concentration of 1.2-5%. All patients required vasopressors, and paralytic ileus occurred in three; outcome was fatal in three patients (43%) (Mirsattari et al., 2004). Ketamine, known as an emergency anesthetic because of its favorable hemodynamic profile, is an N-methyl-daspartate (NMDA) antagonist; the interest for its use in RSE derives from animal works showing loss of GABAA efficacy and maintained NMDA sensitivity in prolonged status epilepticus (Mazarati & Wasterlain, 1999). However, to avoid possible neurotoxicity, it appears safer to combine ketamine with GABAergic compounds (Jevtovic-Todorovic et al., 2001; Ubogu et al., 2003), also because of a likely synergistic effect (Martin & Kapur, 2008). There are few reported cases in humans, describing progressive dosages up to 7.5 mg/kg/h for several days (Sheth & Gidal, 1998; Quigg et al., 2002; Pruss & Holtkamp, 2008), with moderate outcomes. Paraldehyde acts through a yet-unidentified mechanism, and appears to be relatively safe in terms of cardiovascular tolerability (Ramsay, 1989; Thulasimani & Ramaswamy, 2002), but because of the risk of crystal formation and its reactivity with plastic, it should be used only as fresh prepared solution in glass devices (Beyenburg et al., 2000). There are virtually no recent reports regarding its use in adults RSE, whereas rectal paraldehyde in children with status epilepticus resistant to benzodiazepines seems less efficacious than intravenous phenytoin (Chin et al., 2008). Etomidate is another anesthetic agent for which the exact mechanism of action is also unknown, which is also relatively favorable regarding cardiovascular side effects, and may be used for rapid sedation. Its use in RSE was reported in eight subjects (Yeoman et al., 1989). After a bolus of 0.3 mg/kg, a drip of up to 7.2 mg/kg/h for up to 12 days was administered, with hypotension occurring in five patients; two patients died. A reversible inhibition of cortisol synthesis represents an important concern, limiting its widespread use and implying a careful hormonal substitution during treatment (Beyenburg et al., 2000). Several nonsedating approaches have been reported. The use of lidocaine in RSE, a class Ib antiarrhythmic agent modulating sodium channels, was reviewed in 1997 (Walker & Slovis, 1997). Initial boluses up to 5 mg/kg and perfusions of up to 6 mg/kg/h have been mentioned; somewhat surprisingly, at times lidocaine seemed to be successful in controlling seizures in patients who were refractory to phenytoin. The aforementioned dosages should not be overshot, in order to keep lidocaine levels under 5 mg/L and avoid seizure induction (Hamano et al., 2006). A recent pediatric retrospective survey on 57 RSE episodes (37 patients) described a response in 36%, and no major adverse events; mortality was not given (Hamano et al., 2006 Verapamil, a calcium-channel blocker, also inhibits P-glycoprotein, a multidrug transporter that may diminish AED availability in the brain (Potschka et al., 2002). Few case reports on its use in humans are available; this medication nevertheless appears relatively safe (under cardiac monitoring) up to dosages of 360 mg/day (Iannetti et al., 2005). Magnesium, a widely used agent for seizures elicited by eclampsia, has also been anecdotally reported in RSE (Fisher et al., 1988; Robakis & Hirsch, 2006), but with scarce results even at serum levels of 14 mm. The rationale may be found in the physiologic blockage of NMDA channels by magnesium ions (Hope & Blumenfeld, 2005). Ketogenic diet has been prescribed for decades, mostly in children, to control refractory seizures. Its use in RSE as ''ultima ratio'' has been occasionally described: three of six children (Francois et al., 2003) and one adult (Bodenant et al., 2008) were responders. This approach displays its effect subacutely over several days to a few weeks. Because ''malignant RSE'' seems at times to be the consequence of immunologic processes (Holtkamp et al., 2005), a course of immunomodulatory treatment is often advocated in this setting, even in the absence of definite autoimmune etiologies (Robakis & Hirsch, 2006); steroids, adrenocorticotropic hormone (ACTH), plasma exchanges, or intravenous immunoglobulins may be used alone or in sequential combination. Nonpharmacologic Approaches These strategies are described somewhat less frequently than pharmacologic approaches. Acute implantation of vagus nerve stimulation (VNS) has been reported in RSE (Winston et al., 2001; Patwardhan et al., 2005; De Herdt et al., 2009). Stimulation was usually initiated in the operation room, and intensity progressively adapted over a few days up to 1.25 mA (with various regimens regarding the other parameters), allowing a subacute seizure control; one transitory episode of bradycardia/asystole has been described (De Herdt et al., 2009). Of course, pending identification of a definite seizure focus, resective surgery may also be considered in selected cases (Lhatoo & Alexopoulos, 2007). Low-frequency (0.5 Hz) transcranial magnetic stimulation (TMS) at 90% of the resting motor threshold has been reported to be successful for about 2 months in a patient with epilepsia partialis continua, but with a weaning effect afterward, implying the need for a repetitive use (Misawa et al., 2005). More recently, TMS was applied in a combination of a short ''priming'' high frequency (up to 100 Hz) and longer runs of low-frequency stimulations (1 Hz) at 90-100% of the motor threshold in seven other patients with simple-partial status, with mixed results (Rotenberg et al., 2009). Paradoxically at first glance, electroconvulsive treatment may be found in cases of extremely resistant RSE. A recent case report illustrates its use in an adult patient with convulsive status, with three sessions (three convulsions each) carried out over 3 days, resulting in a moderate recovery; the mechanism is believed to be related to modification of the synaptic release of neurotransmitters (Cline & Roos, 2007). Therapeutic hypothermia, which is increasingly used in postanoxic patients (Oddo et al., 2008), has been the object of a recent case series in RSE (Corry et al., 2008). Reduction of energy demand, excitatory neurotransmission, and neuroprotective effects may account for the putative mechanism of action. Four adult patients in RSE were cooled to 31_-34_C with an endovascular system for up to 90 h, and then passively rewarmed over 2-50 h. Seizures were controlled in two patients, one of whom died; also one of the other two patients in whom seizures continued subsequently deceased. Possible side effects are related to acid-base and electrolyte disturbances, and coagulation dysfunction including thrombosis, infectious risks, cardiac arrhythmia, and paralytic ileus (Corry et al., 2008; Cereda et al., 2009). Finally, anecdotic evidence suggests that cerebrospinal fluid (CSF)-air exchange may induce some transitory benefit in RSE (Kohrmann et al., 2006); although this approach was already in use in the middle of the twentieth century, the mechanism is unknown. Acknowledgment A wide spectrum of pharmacologic (sedating and nonsedating) and nonpharmacologic (surgical, or involving electrical stimulation) regimens might be applied to attempt RSE control. Their use should be considered only after refractoriness to AED or anesthetics displaying a higher level of evidence. Although it seems unlikely that these uncommon and scarcely studied strategies will influence the RSE outcome in a decisive way, some may be interesting in particular settings. However, because the main prognostic determinant in status epilepticus appears to be related to the underlying etiology rather than to the treatment approach (Rossetti et al., 2005, 2008), the safety issue should always represent a paramount concern for the prescribing physician. Conclusion The author confirms that he has read the Journal's position on issues involved in ethical publication and affirms that this paper is consistent with those guidelines.

Novel pathogenic pathways in diabetic neuropathy.

Diabetic peripheral neuropathy (DPN) is a common complication affecting more than one third of diabetes mellitus (DM) patients. Although all cellular components participating in peripheral nerve function are exposed to and affected by the metabolic consequences of DM, nodal regions, areas of intense interactions between Schwann cells and axons, may be particularly sensitive to DM-induced alterations. Nodes are enriched in insulin receptors, glucose transporters, Na(+) and K(+) channels, and mitochondria, all implicated in the development and progression of DPN. Latest results particularly reinforce the idea that changes in ion-channel function and energy metabolism, both of which depend on axon-glia crosstalk, are among the important contributors to DPN. These insights provide a basis for new therapeutic approaches aimed at delaying or reversing DPN.

Rituximab treatment in non-malignant inflammatory sensory polyganglionopathy

Non-malignant inflammatory sensory polyganglionopathy (NISP) is the most common form of acquired ganglionopathies, a rare and distinct subgroup of peripheral nerve diseases characterized by a primary degeneration of sensory neurons in dorsal root ganglia. There is a rational for the use of immune modifying agents (IMA) in NISP since an underlying auto-immune process is demonstrated or suspected. However, commonly used IMA such as corticosteroids, azathioprine, methotrexate or IVIG do not prevent disease's progression in the majority of patients. The use of newer IMA, especially those directed against B-cells, may be a therapeutic alternative. An interesting candidate is rituximab, a mouse-human chimeric anti CD20 antibody that specifically eliminates B-cells and B-cells precursors.Objectives: This is a prospective open label pilot study to determine the efficacy of rituximab treatment in NISP patients, who did not respond to commonly used IMA.Methods: Five patients (40% male) with a mean age of 55 years (range 49-67), diagnosed with NISP after extensive work-up, were treated (schema used for one cure: 2 9 1gr within 15 days interval). Neurological scores (NIS, ISSS, ODSS) and B cell counts were assessed at baseline and during clinical follow-up at 2 and 6 monthsto assess treatment efficacy.Results: The treatment was generally well tolerated. Minor adverse events reported were transient arterial hypotension during the infusions in two patients and intermittent mild leucopenia in one patient. Clinical evolution during the follow-up period was characterized by a stability of the functional scores in four patients (80%) and the continuation of disability progression of one patient (20%). CD4 cells disappeared in all patients after the second infusion, an effect that lasted until the follow up at 6 months.Conclusion: The preliminary results of this pilot study indicate that rituximab is generally well tolerated and prevents progression of disability during the 6-month observation period in NISP patients. Inclusion of additional patients and extending of the follow-up period are intended to further investigate the efficacy of rituximab in NISP.

Comparison of the power spectral changes of the voluntary surface electromyogram and M wave during intermittent maximal voluntary contractions.

INTRODUCTION: To compare the power spectral changes of the voluntary surface electromyogram (sEMG) and of the compound action potential (M wave) in the vastus medialis and vastus lateralis muscles during fatiguing contractions. METHODS: Interference sEMG and force were recorded during 48 intermittent 3-s isometric maximal voluntary contractions (MVC) from 13 young, healthy subjects. M waves and twitches were evoked using supramaximal femoral nerve stimulation between the successive MVCs. Mean frequency (F mean), and median frequency were calculated from the sEMG and M waves. Muscle fiber conduction velocity (MFCV) was computed by cross-correlation. RESULTS: The power spectral shift to lower frequencies was significantly greater for the voluntary sEMG than for the M waves (P < 0.05). Over the fatiguing protocol, the overall average decrease in MFCV (~25 %) was comparable to that of sEMG F mean (~22 %), but significantly greater than that of M-wave F mean (~9 %) (P < 0.001). The mean decline in MFCV was highly correlated with the mean decreases in both sEMG and M-wave F mean. CONCLUSIONS: The present findings indicated that, as fatigue progressed, central mechanisms could enhance the relative weight of the low-frequency components of the voluntary sEMG power spectrum, and/or the end-of-fiber (non-propagating) components could reduce the sensitivity of the M-wave spectrum to changes in conduction velocity.