Excitability properties of mouse motor axons in the mutant SOD1(G93A) model of amyotrophic lateral sclerosis

Non-invasive excitability studies of motor axons in patients with amyotrophic lateral sclerosis (ALS) have revealed a changing pattern of abnormal membrane properties with disease progression, but the heterogeneity of the changes has made it difficult to relate them to pathophysiology. The SOD1(G93A) mouse model of ALS displays more synchronous motoneuron pathology. Multiple excitability measures of caudal and sciatic nerves in mutant and wild-type mice were compared before onset of signs and during disease progression (4-19 weeks), and they were related to changes in muscle fiber histochemistry. Excitability differences indicated a modest membrane depolarization in SOD1(G93A) axons at about the time of symptom onset (8 weeks), possibly due to deficient energy supply. Previously described excitability changes in ALS patients, suggesting altered sodium and potassium conductances, were not seen in the mice. This suggests that those changes relate to features of the human disease that are not well represented in the animal model.

Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home

The Oxford Programme for Immunomodulatory Immunoglobulin Therapy has been operating since 1992 at Oxford Radcliffe Hospitals in the UK. Initially, this program was set up for patients with multifocal motor neuropathy or chronic inflammatory demyelinating poly-neuropathy to receive reduced doses of intravenous immunoglobulin (IVIG) in clinic on a regular basis (usually every 3 weeks). The program then rapidly expanded to include self-infusion at home, which monitoring showed to be safe and effective. It has been since extended to the treatment of other autoimmune diseases in which IVIG has been shown to be efficacious.

Muscle ischaemia in patients with orthostatic hypotension assessed by velocity recovery cycles

Patients with orthostatic hypotension may experience neck pain radiating to the occipital region of the skull and the shoulders while standing (so-called coat-hanger ache). This study assessed muscle membrane potential in the trapezius muscle of patients with orthostatic hypotension and healthy subjects during head-up tilt (HUT), by measuring velocity recovery cycles (VRCs) of muscle action potentials as an indicator of muscle membrane potential.

Velocity recovery cycles of human muscle action potentials: Repeatability and variability

Velocity recovery cycles (VRCs) of human muscle action potentials have been proposed as a new technique for assessing muscle membrane function in myopathies. This study was undertaken to determine the variability and repeatability of VRC measures such as supernormality, to help guide future clinical use of the method.

Nerve excitability studies characterize Kv1.1 fast potassium channel dysfunction in patients with episodic ataxia type 1

Episodic ataxia type 1 is a neuronal channelopathy caused by mutations in the KCNA1 gene encoding the fast K(+) channel subunit K(v)1.1. Episodic ataxia type 1 presents with brief episodes of cerebellar dysfunction and persistent neuromyotonia and is associated with an increased incidence of epilepsy. In myelinated peripheral nerve, K(v)1.1 is highly expressed in the juxtaparanodal axon, where potassium channels limit the depolarizing afterpotential and the effects of depolarizing currents. Axonal excitability studies were performed on patients with genetically confirmed episodic ataxia type 1 to characterize the effects of K(v)1.1 dysfunction on motor axons in vivo. The median nerve was stimulated at the wrist and compound muscle action potentials were recorded from abductor pollicis brevis. Threshold tracking techniques were used to record strength-duration time constant, threshold electrotonus, current/threshold relationship and the recovery cycle. Recordings from 20 patients from eight kindreds with different KCNA1 point mutations were compared with those from 30 normal controls. All 20 patients had a history of episodic ataxia and 19 had neuromyotonia. All patients had similar, distinctive abnormalities: superexcitability was on average 100% higher in the patients than in controls (P < 0.00001) and, in threshold electrotonus, the increase in excitability due to a depolarizing current (20% of threshold) was 31% higher (P < 0.00001). Using these two parameters, the patients with episodic ataxia type 1 and controls could be clearly separated into two non-overlapping groups. Differences between the different KCNA1 mutations were not statistically significant. Studies of nerve excitability can identify K(v)1.1 dysfunction in patients with episodic ataxia type 1. The simple 15 min test may be useful in diagnosis, since it can differentiate patients with episodic ataxia type 1 from normal controls with high sensitivity and specificity.

Properties of low-threshold motor axons in the human median nerve

This study investigated the excitability and accommodative properties of low-threshold human motor axons to test whether these motor axons have greater expression of the persistent Na(+) conductance, I(NaP). Computer-controlled threshold tracking was used to study 22 single motor units and the data were compared with compound motor potentials of various amplitudes recorded in the same experimental session. Detailed comparisons were made between the single units and compound potentials that were 40% or 5% of maximal amplitude, the former because this is the compound potential size used in most threshold tracking studies of axonal excitability, the latter because this is the compound potential most likely to be composed entirely of motor axons with low thresholds to electrical recruitment. Measurements were made of the strength-duration relationship, threshold electrotonus, current-voltage relationship, recovery cycle and latent addition. The findings did not support a difference in I(NaP). Instead they pointed to greater activity of the hyperpolarization-activated inwardly rectifying current (I(h)) as the basis for low threshold to electrical recruitment in human motor axons. Computer modelling confirmed this finding, with a doubling of the hyperpolarization-activated conductance proving the best single parameter adjustment to fit the experimental data. We suggest that the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel(s) expressed on human motor axons may be active at rest and contribute to resting membrane potential.

A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome

Although the term 'reflex sympathetic dystrophy' has been replaced by 'complex regional pain syndrome' (CRPS) type I, there remains a widespread presumption that the sympathetic nervous system is actively involved in mediating chronic neuropathic pain ["sympathetically maintained pain" (SMP)], even in the absence of detectable neuropathophysiology.

Threshold-dependent effects on peripheral nerve in vivo excitability properties in the rat

Various factors, including maturity, have been shown to influence peripheral nerve excitability measures, but little is known about differences in these properties between axons with different stimulation thresholds. Multiple nerve excitability tests were performed on the caudal motor axons of immature and mature female rats, recording from tail muscles at three target compound muscle action potential (CMAP) levels: 10%, 40% ("standard" level), and 60% of the maximum CMAP amplitude. Compared to lower target levels, axons at high target levels have the following characteristics: lower strength-duration time constant, less threshold reduction during depolarizing currents and greater threshold increase to hyperpolarizing currents, most notably to long hyperpolarizing currents in mature rats. Threshold-dependent effects on peripheral nerve excitability properties depend on the maturation stage, especially inward rectification (Ih), which becomes inversely related to threshold level. Performing nerve excitability tests at different target levels is useful in understanding the variation in membrane properties between different axons within a nerve. Because of the threshold effects on nerve excitability and the possibility of increased variability between axons and altered electric recruitment order in disease conditions, excitability parameters measured only at the "standard" target level should be interpreted with caution, especially the responses to hyperpolarizing currents.

In vivo assessment of HCN channel current (I(h)) in human motor axons

The "Trond" protocol of nerve excitability tests has been used widely to assess axonal function in peripheral nerve. In this study, the routine Trond protocol was expanded to refine assessment of cAMP-dependent, hyperpolarization-activated current (I(h)) activity. I(h) activity is generated by hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels in response to hyperpolarization. It limits activity-dependent hyperpolarization, contributes to neuronal automaticity, and is implicated in chronic pain states. Published data regarding I(h) activity in motor nerve are scant. We used additional strong, prolonged hyperpolarizing conditioning stimuli in the threshold electrotonus component of the Trond protocol to demonstrate the time-course of activation of I(h) in motor axons. Fifteen healthy volunteers were tested on four occasions during 1 week. I(h) action was revealed in the threshold electrotonus by the limiting and often reversal, after about 100 ms, of the threshold increase caused by strong hyperpolarizing currents. Statistical analysis by repeated-measures analysis of variance enabled confidence limits to be established for variation between subjects and within subjects. The results demonstrate that, of all the excitability parameters, those dependent on I(h) were the most characteristic of an individual, because variance between subjects was more than four times the variance within subjects. This study demonstrates a reliable method for in vivo assessment of I(h,) and also serves to document the normal variability in nerve excitability properties within subjects.

Microneurography in rats: a minimally invasive method to record single C-fiber action potentials from peripheral nerves in vivo

Microneurography is a method suitable for recording intraneural single or multiunit action potentials in conscious subjects. Microneurography has rarely been applied to animal experiments, where more invasive methods, like the teased fiber recording technique, are widely used. We have tested the feasibility of microneurographic recordings from the peripheral nerves of rats. Tungsten microelectrodes were inserted into the sciatic nerve at mid-thigh level. Single or multiunit action potentials evoked by regular electrical stimulation were recorded, digitized and displayed as a raster plot of latencies. The method allows unambiguous recording and recognition of single C-fiber action potentials from an in vivo preparation, with minimal disruption of the nerve being recorded. Multiple C-fibers can be recorded simultaneously for several hours, and if the animal is allowed to recover, repeated recording sessions can be obtained from the same nerve at the same level over a period of weeks or months. Also, single C units can be functionally identified by their changes in latency to natural stimuli, and insensitive units can be recognized as 'silent' nociceptors or sympathetic efferents by their distinctive profiles of activity-dependent slowing during repetitive electrical stimulation, or by the effect on spontaneous efferent activity of a proximal anesthetic block. Moreover, information about the biophysical properties of C axons can be obtained from their latency recovery cycles. Finally, we show that this preparation is potentially suitable for the study of C-fiber behavior in models of neuropathies and nerve lesions, both under resting conditions and in response to drug administration.

Unmyelinated afferents in human skin and their responsiveness to low temperature

In humans, there are different types of cutaneous cold-sensitive afferents responsible for cold sensation and cold pain. Innocuous cold is primarily mediated by a population of slow A delta afferents, based on psychophysical and neurophysiological studies. Noxious cold (usually below 15 degrees C) is mediated, at least in part, by polymodal nociceptors. There is also a population of unmyelinated afferents responsive to innocuous low temperature, some of which also respond to heat, whose sensory function has not been completely defined. A paradoxical hot/burning evoked by cooling is unmasked by A-fibre block, and similar sensations are evoked by applying simultaneous cool and warm stimuli to adjacent skin areas. These unmyelinated fibres activated by innocuous cooling (and heating) may contribute to this hot/burning sensation, along with other thermoregulatory functions.

Eros and Transgression in an Age of Immanence: Georges Bataille’s (Religious) Critique of Kinsey

This paper explores the religious implications of eroticism in Western culture since the Sexual Revolution, a period at once applauded for its open and immanent view of sexuality and denounced for its shamelessness and promiscuity. After discussing the work and effects of Alfred C. Kinsey, the father of the Sexual Revolution, I focus on a critical appraisal of Kinsey written by French theorist Georges Bataille (“Kinsey, the Underworld and Work,” in L’Erotisme, 1957). Bataille situates contemporary Western sexuality within a larger historical movement towards the “desacralization” of all aspects of human life: sex, under the scientific gaze of the Kinsey team, became simply another “object” to be analyzed and classified, and “good” sex defined solely in terms of frequency and explosiveness of orgasm. For many, including Hugh Hefner, this approach to sex occasioned a refreshing awakening from the long dark night of Victorian sexual repression. However, as Bataille’s protégé Foucault has shown, the scientific approach to sexuality often masks a desire to control and delimit sexual behaviour, not “liberate” it. Moreover, Bataille makes the point that the desacralization of sexuality denudes sex of a vital component—eroticism—which is necessary for real pleasure and ecstasy. Beyond the “moral” critiques one often hears leveled against Kinsey and his work, Bataille provides a “religious” critique, one that stands, perhaps surprisingly, on the “near side” of sexuality.

Muscle velocity recovery cycles: effects of repetitive stimulation on two muscles

We sought to characterize the excitability properties of tibialis anterior (TA) and brachioradialis (BR) muscles at rest and during electrically induced muscle activation in normal subjects.

Temperature dependency of human muscle velocity recovery cycles

Velocity recovery cycles (VRCs) of human muscle action potentials have been proposed as a new technique for studying muscle membrane function. This study was undertaken to determine the temperature dependency of VRC parameters.