Changes In Axonal Excitability Research Articles

Arginine butyrate per os protects mdx mice against cardiomyopathy, kyphosis and changes in axonal excitability

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by lack of dystrophin, a sub-sarcolemmal protein, which leads to dramatic muscle deterioration. We studied in mdx mice, the effects of oral administration of arginine butyrate (AB), a compound currently used for the treatment of sickle cell anemia in children, on cardiomyopathy, vertebral column deformation and electromyographic abnormalities.Monthly follow-up by echocardiography from the 8th month to the 14th month showed that AB treatment protected the mdx mice against drastic reduction (20–23%) of ejection fraction and fractional shortening, and also against the ≈20% ventricular dilatation and 25% cardiac hypertrophy observed in saline-treated mdx mice. The phenotypic improvement was corroborated by the decrease in serum CK level and by better fatigue resistance. Moreover, AB treatment protected against the progressive spinal deformity observed in mdx mice, another similarity with DMD patients. The value of the kyphosis index in AB-treated mice reached 94% of the value in C57BL/10 mice. Finally, axonal excitability parameters such as the membrane resting potential, the threshold and amplitude of the action potential, the absolute and relative refractory periods and the supernormal and subnormal periods, recorded from caudal and plantar muscles in response to excitability tests, that were modified in saline-treated mdx mice were not significantly changed, compared with wild-type animals, in AB-treated mdx mice. All of these results suggest that AB could be a potential treatment for DMD patients.

Sensory axonal dysfunction in cervical radiculopathy

ObjectiveThe aim of this study was to evaluate changes in sensory axonal excitability in the distal nerve in patients with cervical radiculopathy.MethodsThe patients were classified by the findings of cervical...

P850: Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation)

s of Poster Presentations / Clinical Neurophysiology 125, Supplement 1 (2014) S1–S339 S269 Figure 2. The relationship between muscle strength and transcranial stimulation motor evoked potential. Conclusions: There is the positive relation between the MEP amplitude and the muscle strength. So, the fixed quantity evaluation method using the statistical technique makes TCS-MEP reliable. And TCS-MEP may enhance us to remove tumors in central nervous system and at the same time preserve motor functions. Moreover this relation between MEP and muscle strength is useful for understanding the motor control system. P850 Electrophysiological pattern in GLUT1 deficiency syndrome (A275T mutation) C. Giliberto1, V. Sofia1, R. Barone2, R. Guerrini3, M. Zappia1 1University of Catania, Department G.F. Ingrassia, Section of Neurosciences, Catania, Italy; 2University of Catania, Pediatric Neurology, Department of Pediatrics, Catania, Italy; 3University of Florence, Pediatric Neurology, Unit and Laboratories, Children’s Hospital A. Meyer, Florence, Italy Question: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is characterized by impaired glucose transport across the blood-brain barrier due to SLC2A1-gene mutation. GLUT1DS infancy onset shows epileptic encephalopathy, ataxia and microcephaly although paroxysmal exerciseinduced dyskinesia and epilepsy may also be observed. Exercise and recovery-induced modifications of GLUT4 and GLUT1 expression in human muscle have been reported.We describe clinical and electromyographyc correlates of a GLUT1DS patient with adult-onset of exercise-induced dystonia. Patients and methods: A 19 year old male with mild mental retardation presented with a two-year history of episodic stiffness in his calves and feet and painless flexion of the toes followed by leg weakness triggered by exertion and starvation and alleviated by rest and eating. His father had experienced exercise-induced leg dystonia at younger age. A heterozygous missense of mutation (c.823G>A; p.A275T) of SLC2A1 gene was found in the proband and his father.The proband underwent an electromyographyc study after voluntary contraction (5 minutes) to investigate muscle membrane excitability with the evaluation of compound muscle action potential (CMAP) amplitude. Results: The test disclosed significant decrement of CMAP amplitude up to −42% (n.v.≤−20%) after 40 minutes from exercise with respect to the pre-exercise CMAP amplitude (baseline). The same test repeated after carbohydrate-rich food intake showed a significant improvement of CMAP from baseline (−26%). Conclusions: The electrophysiological study after exercise showed a reduction of CMAP amplitude in this patient with GLUT1DS (A275T mutation). Our data suggest a possible involvement of muscle membrane excitability in GLUT1DS. P851 Tracking the spatiotemporal profile of cortical and peripheral motor axon hyperexcitability in amyotrophic lateral sclerosis E. Bakola1, P. Kokotis1, R. Carr2, M. Schmelz2, M. Rentzos1, T. Zambelis1, N. Karandreas1 1University of Athens, Medical School, Department of Neurology, Athens, Greece; 2University of Heidelberg, Mannheim Medical School, Department of Anesthesiology, Mannheim, Germany Question: Recent studies using magnetic and electrical excitability tracking tools have confirmed early hyperexcitability in ALS. This study sets out to use excitability testing to examine directly the spatiotemporal profile of cortical and peripheral hyperexcitability in ALS patients simultaneously, to associate these parameters to the clinical course of the disease and to compare them with healthy controls. Methods: Nineteen patients with first-diagnosed definite ALS (group A), four patients with advanced disease (group B) and ten control healthy volunteers (group C) were included in the study. Multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle, current-threshold relationship) and TMS investigations including measurement of resting motor threshold (RMT) and motor evoked potential (MEP) were measured. Results: In group A there were greater changes in depolarizing threshold electrotonus (TD) compared with group B (t-test p<0.03). No differences in recovery cycle, strength-duration time constant, current-threshold relationship were noted between the three groups. Regarding the cortical excitability parameters, there was a significant decrease in the slope of MEP amplitude to TMS intensity in group B with the advanced disease in comparison to controls (Mann-Whitney U test p<0.05). ANCOVA showed strong correlation between TD and slope of cortical excitability (p<0.01) after correcting for the status of the disease (groups A,B,C). Conclusions: These are preliminary results of an ongoing study trying to understand the changes in axonal and cortical excitability in first-diagnosed and advanced disease in order to provide insight into the pathophysiological basis of the disease and furthermore provide useful information for the best treatment approach in the future.

S18: Changes in neuromuscular axonal excitability in benign cramps-fasciculation syndrome

S18: Changes in neuromuscular axonal excitability in benign cramps-fasciculation syndrome

Pain assessment in animal models: do we need further studies?

In the last two decades, animal models have become important tools in understanding and treating pain, and in predicting analgesic efficacy. Although rodent models retain a dominant role in the study of pain mechanisms, large animal models may predict human biology and pharmacology in certain pain conditions more accurately. Taking into consideration the anatomical and physiological characteristics common to man and pigs (median body size, digestive apparatus, number, size, distribution and communication of vessels in dermal skin, epidermal–dermal junctions, the immunoreactivity of peptide nerve fibers, distribution of nociceptive and non-nociceptive fiber classes, and changes in axonal excitability), swines seem to provide the most suitable animal model for pain assessment. Locomotor function, clinical signs, and measurements (respiratory rate, heart rate, blood pressure, temperature, electromyography), behavior (bright/quiet, alert, responsive, depressed, unresponsive), plasma concentration of substance P and cortisol, vocalization, lameness, and axon reflex vasodilatation by laser Doppler imaging have been used to assess pain, but none of these evaluations have proved entirely satisfactory. It is necessary to identify new methods for evaluating pain in large animals (particularly pigs), because of their similarities to humans. This could lead to improved assessment of pain and improved analgesic treatment for both humans and laboratory animals.

Excitability properties of single human motor axons: are all axons identical?

Under natural motor control, repetitive firing of motoneurons is transmitted by their motor axons to muscle fibers in the “one to one” fashion that allows the analysis of human motoneuron firing via recordings of motor unit (MU) action potentials (see Kernell, 2006; Heckman and Enoka, 2012). However, when axons are diseased or damaged, local increasing axonal excitability may result in disturbing this basic principle and creating an additional focus of excitation in an axon itself, leading to different symptoms, including MU spontaneous discharges. In order to gain an insight into possible pathophysiological mechanisms underlying changes in axonal excitability, many studies were addressed exploring axonal excitability properties in healthy humans and their fundamental characteristics have been obtained (reviewed by Bostock et al., 1998; Burke et al., 2001; Nodera and Kaji, 2006). In particular, axonal activation has been found to be followed by certain excitability recovery cycle as tested commonly after a supramaximal conditioning stimulus (e.g., Kiernan et al., 1996; Bostock et al., 1998; Murray and Jankelowitz, 2011) or after the cessation of maximal voluntary muscle contractions (Vagg et al., 1998; Kuwabara et al., 2001; Rossi et al., 2012). Traditionally, axon excitability properties were explored for whole motoneuronal pool, using a compound muscle action potential (CMAP), without analysing the behavior of single MUs. However, such approach gives no information on the excitability properties of motor axons belonging to different types of MUs. A few reports, beginning with the seminal studies of Bergmans (1970, 1973), addressed the excitability properties of single motor axons, as a rule, low-threshold to electrical stimulation and thus belonging to large MUs, high-threshold to voluntary muscle contraction (Borg, 1980; Bostock and Baker, 1988; Shefner et al., 1996; Hales et al., 2004; Bostock et al., 2005). At the same time there are no data on the excitability properties of axons belonging to small, slow MUs during their natural activation, while these MUs are essential part of motoneuronal pools as they are primarily activated during both voluntary movements and the maintenance of posture, as well as at reflex activation. The question arises of whether or not the excitability properties of these axons are similar to that of MUs with high-threshold to voluntary muscle contraction. Our findings reported below give some possibility to start the discussion of this question.

Sustained Maximal Voluntary Contraction Produces Independent Changes in Human Motor Axons and the Muscle They Innervate

The repetitive discharges required to produce a sustained muscle contraction results in activity-dependent hyperpolarization of the motor axons and a reduction in the force-generating capacity of the muscle. We investigated the relationship between these changes in the adductor pollicis muscle and the motor axons of its ulnar nerve supply, and the reproducibility of these changes. Ten subjects performed a 1-min maximal voluntary contraction. Activity-dependent changes in axonal excitability were measured using threshold tracking with electrical stimulation at the wrist; changes in the muscle were assessed as evoked and voluntary electromyography (EMG) and isometric force. Separate components of axonal excitability and muscle properties were tested at 5 min intervals after the sustained contraction in 5 separate sessions. The current threshold required to produce the target muscle action potential increased immediately after the contraction by 14.8% (p<0.05), reflecting decreased axonal excitability secondary to hyperpolarization. This was not correlated with the decline in amplitude of muscle force or evoked EMG. A late reversal in threshold current after the initial recovery from hyperpolarization peaked at −5.9% at ∼35 min (p<0.05). This pattern was mirrored by other indices of axonal excitability revealing a previously unreported depolarization of motor axons in the late recovery period. Measures of axonal excitability were relatively stable at rest but less so after sustained activity. The coefficient of variation (CoV) for threshold current increase was higher after activity (CoV 0.54, p<0.05) whereas changes in voluntary (CoV 0.12) and evoked twitch (CoV 0.15) force were relatively stable. These results demonstrate that activity-dependent changes in motor axon excitability are unlikely to contribute to concomitant changes in the muscle after sustained activity in healthy people. The variability in axonal excitability after sustained activity suggests that care is needed when using these measures if the integrity of either the muscle or nerve may be compromised.

Pathophysiology of HNPP explored using axonal excitability

ObjectiveHereditary liability to pressure palsies (HNPP) is an autosomal dominant disorder of myelination resulting in susceptibility to pressure palsies from compression or stretching of peripheral nerves.Patients and methodsThis study examined...

Activity‐dependent depression of the recurrent discharge of human motoneurones after maximal voluntary contractions

Despite maximal voluntary effort, the output of human motoneurone pools diminishes during fatigue. To assess motoneurone behaviour, we measured recurrent discharges evoked antidromically by supramaximal nerve stimulation after isometric maximal voluntary contractions (MVCs).They were measured as F-waves in the electromyographic activity (EMG). Supramaximal stimuli to the common peroneal and ulnar nerves evoked F-waves at rest before and after MVCs in tibialis anterior (TA) and abductor digit minimi (ADM), respectively. F-waves were depressed immediately after a sustained MVC. For TA, the size and time course of depression of the F-wave area (26 ± 13%; mean ± SD; P =0.007) and persistence (∼20%) were similar after a 10-s or 1-min MVC. For ADM, the decline in F-wave area (39.8 ± 19.6%; P <0.01) was similar after the two contractions but the decline in persistence (probability of occurrence) of the F-wave differed (14.6 ± 10.5% and 32.5 ± 17.1% after 10-s and 1-min MVCs respectively). Comparison of a very long (2-min) with a very short (2-s)MVC in ADM showed that the depression of F-wave area, as well as persistence, was greater after the longer contraction. This suggests, at least for ADM, that the depression is related to the duration of voluntary activity and that the decrease in F-waves could contribute to central fatigue. To examine whether changes in motor axon excitability caused the depression, we measured compound muscle action potentials (M-waves) to submaximal stimulation of the ulnar nerve after a 2-s and 2-min MVC. Submaximal M-waves were not depressed after a 2-s MVC. They were depressed by a 2-min MVC, but the time course of depression of the F- and M-waves differed. Thus, depression of F-waves does not simply reflect reduced excitability of peripheral motor axons.Hence, we propose that activity-dependent changes at the soma or the initial segment depress the recurrent discharge of human motoneurones and that this may contribute to central fatigue.

Progressive axonal dysfunction and clinical impairment in amyotrophic lateral sclerosis

ObjectiveTo elucidate longitudinal changes in axonal function in amyotrophic lateral sclerosis (ALS) patients, and to relate such changes with motor unit loss and functional impairment. Methods37 ALS patients (age, 53.7±1.7years; 22 males) were studied using axonal excitability techniques at baseline and 12weeks follow-up. ResultsLongitudinal measurements across excitability parameters suggested increasing K+ channel dysfunction, with further increases in depolarising threshold electrotonus (90–100ms, baseline, 46.8±1.0%; follow-up, 48.7±0.8%; P=0.02) and superexcitability (baseline, −24.0±1.2%; 12weeks, −26.0±1.2%; P=0.04). Patients with preserved compound muscle action potential (CMAP) amplitude at follow-up developed more severe changes in axonal excitability than those in whom CMAP decreased from baseline, suggesting that the most pronounced disease effects were on motor axons immediately prior to axonal loss in ALS patients. Fine motor decline was associated with more severe changes in axonal excitability, suggesting that functional impairment was related to axonal dysfunction. ConclusionsLongitudinal changes in axonal excitability in ALS patients suggest increasing K+ channel dysfunction in motor axons. SignificanceAxonal excitability studies enable investigation of longitudinal changes in axonal ion channel dysfunction, and thereby the processes that potentially contribute to axonal degeneration in ALS.

Clarifying distal axonal properties of the median nerve

Although length-dependent axonal excitability changes have been reported in the median nerve, the mechanisms underlying these changes remain to be further clarified. Axonal excitability studies were performed on median nerve at the palm and wrist in 20 healthy controls, with responses recorded over the abductor pollicis brevis. The strength-duration time constant was significantly shorter (palm: 0.35 ± 0.01 ms; wrist: 0.48 ± 0.03 ms; P < 0.001), whereas rheobase was significantly increased (palm: 2.90 ± 1.12 mA; wrist: 2.09 ± 1.11 mA; P < 0.05) at the palm. In addition, there was a significant increase in depolarizing threshold electrotonus at 90-100 ms (P < 0.001) and a reduction in S2 accommodation (P < 0.001) and late subexcitability (P < 0.001) at the palm. The changes in excitability were independent of factors influencing median nerve cross-sectional area. The present study reveals significant length dependent changes in median nerve excitability which may reflect differences in intrinsic membrane properties.

Do the motor manifestations of parkinson disease alter motor axon excitability?

Axonal excitability is altered in common medical conditions such as stroke, multiple sclerosis, and spinal cord injury. Given the motor neuron changes in the presence of rigidity and tremor in Parkinson disease, we examine whether there are also changes in motor axon excitability. Axonal excitability studies were performed in 15 Parkinson subjects and 12 age-matched control subjects. There was no significant difference in excitability indices between Parkinson subjects and control subjects. It is unlikely that the lack of change in the excitability indices reflects a balance between the effects of bradykinesia ("underactivity") and the effects of rigidity and tremor ("overactivity") on the motoneuron and its axon. It is more likely that plastic changes in motoneuron properties do not occur symmetrically with decreases and increases in activity, being more profound when activity levels are interrupted and less obvious when they are enhanced.

Explaining pathological changes in axonal excitability through dynamical analysis of conductance-based models

Neurons rely on action potentials, or spikes, to relay information. Pathological changes in spike generation likely contribute to certain enigmatic features of neurological disease, like paroxysmal attacks of pain and muscle spasm. Paroxysmal symptoms are characterized by abrupt onset and short duration, and are associated with abnormal spiking although the exact pathophysiology remains unclear. To help decipher the biophysical basis for ‘paroxysmal’ spiking, we replicated afterdischarge (i.e. continued spiking after a brief stimulus) in a minimal conductance-based axon model. We then applied nonlinear dynamical analysis to explain the dynamical basis for initiation and termination of afterdischarge. A perturbation could abruptly switch the system between two (quasi-)stable attractor states: rest and repetitive spiking. This bistability was a consequence of slow positive feedback mediated by persistent inward current. Initiation of afterdischarge was explained by activation of the persistent inward current forcing the system to cross a saddle point that separates the basins of attraction associated with each attractor. Termination of afterdischarge was explained by the attractor associated with repetitive spiking being destroyed. This occurred when ultra-slow negative feedback, such as intracellular sodium accumulation, caused the saddle point and stable limit cycle to collide; in that regard, the active attractor is not truly stable when the slowest dynamics are taken into account. The model also explains other features of paroxysmal symptoms, including temporal summation and refractoriness.

Nerve compression, membrane excitability, and symptoms of carpal tunnel syndrome

In this study we investigated the changes in axonal excitability and the generation of neurological symptoms in response to focal nerve compression (FNC) of the median nerve in carpal tunnel syndrome (CTS). Sensory excitability recordings were undertaken in 11 CTS patients with FNC being applied at the wrist using a custom-designed electrode. During FNC, refractoriness increased significantly (62.4 ± 3.4%; P < 0.001), associated with a rapid reduction in superexcitability (16.9 ± 2.8%; P < 0.001) and sensory nerve action potential amplitude (SNAP) (32.4 ± 3.9%; P < 0.001), consistent with axonal depolarization. Associated with these changes, paresthesiae steadily increased throughout FNC, as did numbness. Reductions in SNAP amplitude and superexcitability developed more rapidly for CTS patients during FNC compared with controls, and these changes were associated with more marked symptoms. Axonal responses to compression are impaired in CTS. This may suggest a greater reliance on axonal membrane Na(+) /K(+) -ATPase function.

Changes in axonal excitability of primary sensory afferents with general anaesthesia in humans

BackgroundIntraoperative monitoring of neuronal function is important in a variety of surgeries. The type of general anaesthetic used can affect the interpretation and quality of such recordings. Although the principal effects of general anaesthetics are synaptically mediated, the extent to which they affect excitability of the peripheral afferent nervous system is unclear. MethodsForty subjects were randomized in a stratified manner into two groups, anaesthetized with either propofol or sevoflurane. The threshold tracking technique (QTRAC®) was used to measure nerve excitability parameters of the sensory action potential of the median nerve before and after induction of general anaesthesia. ResultsSeveral parameters of peripheral sensory afferent nerve excitability changed after induction of general anaesthesia, which were similar for both propofol and sevoflurane. The maximum amplitude of the sensory nerve action potential decreased in both groups (propofol: 25.3%; sevoflurane: 29.5%; both P<0.01). The relative refractory period [mean (sd)] also decreased similarly in both groups [propofol: −0.6 (0.7) ms; sevoflurane: −0.3 (0.5) ms; both P<0.01]. Skin temperature at the stimulation site increased significantly in both groups [propofol: +1.2 (1.0)°C; sevoflurane: +1.7 (1.4)°C; both P<0.01]. ConclusionsSmall changes in excitability of primary sensory afferents after the induction of anaesthesia with propofol or sevoflurane were detected. These effects, which were non-specific and are possibly explained by changes observed in temperature, demonstrate possible anaesthetic effects on intraoperative neuromonitoring.

Adaptation of motor function after spinal cord injury: novel insights into spinal shock

The mechanisms underlying spinal shock have not been clearly defined. At present, clinical assessment remains the mainstay to describe progression through spinal shock following traumatic spinal cord injury. However, nerve excitability studies in combination with conventional nerve conduction and clinical assessments have the potential to investigate spinal shock at the level of the peripheral axon. Therefore, peripheral motor axon excitability was prospectively and systematically evaluated in more than 400 studies of 11 patients admitted to hospital after traumatic spinal cord injury, with cord lesions above T9 (nine cervical, two thoracic). Recordings commenced within 15 days of admission from the median nerve to abductor pollicis brevis in the upper limb and the common peroneal nerve to tibialis anterior in both lower limbs, and were continued until patient discharge from hospital. Excitability was assessed using threshold tracking techniques and recordings were compared with data from healthy controls. In addition, concurrent clinical measures of strength, serum electrolytes and nerve conduction were collected. High threshold stimulus-response relationships were apparent from the early phase of spinal shock that coincided with depolarization-like features that reached a peak on Day 16.9 (± 2.7 standard error) for the common peroneal nerve and Day 11.8 (± 2.0 standard error) for the median nerve. Overall, changes in the common peroneal nerve were of greater magnitude than for the median nerve. For both nerves, the most significant changes were in threshold electrotonus, which was 'fanned in', and during the recovery cycle superexcitability was reduced (P < 0.001). However, refractoriness was increased only for the common peroneal nerve (P < 0.05). Changes in the spinal injured cohort could not be explained on the basis of an isolated common peroneal nerve palsy. By the time patients with spinal injury were discharged from hospital between Days 68 and 215, excitability for upper and lower limbs had returned towards normative values, but not for all parameters. Electrolyte levels and results for nerve conduction studies remained within normal limits throughout the period of admission. Contrary to prevailing opinion, these data demonstrate that significant changes in peripheral motor axonal excitability occur early during spinal shock, with subsequent further deterioration in axonal function, before recovery ensues.

Electrically induced quantitative sudomotor axon reflex test in human volunteers

Chemically-induced quantitative sudomotor axon reflex test (QSART) and quantitative sensory testing (QST) are established clinical tools to assess thin fiber function in humans. We investigated stimulus-response functions to transcutaneous electrical stimuli of different current intensity (3.75 to 10 mA) and pulse frequency (5 to 100 Hz) comparing sweat output (ml/h/m 2) and pain intensity (numeric rating scale [NRS], 0–10). Efferent sudomotor and afferent nociceptive responses were recorded after a 30 s electrical stimulation period of distal (hand and foot) and proximal (forearm and thorax) body sites with 3 repetitive measures per body site. Sweat responses increased intensity dependently and peaked (~ 100 ml/h/m 2) at highest currents (10 mA) that had been administered. Similarly, pain ratings increased with an escalating current intensity. At a constant stimulus intensity of 7.5 mA, sudomotor activity was highest (~ 75 ml/h/m 2) at a stimulus frequency of 20 Hz without further increase at 50 or 100 Hz. In contrast, pain ratings increased frequency dependently and reached NRS 7 at 100 Hz. Sudomotor activity, but not pain ratings, was significantly different between the body sites (p < 0.05, ANOVA) with maximum sweat responses obtained at the ventral forearm. Varying response patterns for higher stimulation frequencies between sweating (peak maximum at 20 Hz) and pain (maximum at 100 Hz) might indicate differential axonal properties of sympathetic efferent and nociceptive afferent fibers. Electrically induced QSART could be a useful explorative and clinical method to indirectly study characteristics of frequency-dependent axonal excitability changes of sudomotor fibers.

P7-23 Multiple measures of axonal excitability in a mouse model of Kennedy disease

Objective: To examine motor nerve properties in a mouse model of spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease (KD) (i) to characterize excitability changes during disease progression and (ii) to determine how well the model reproduces the axonal excitability changes observed in SBMA patients. Methods.SBMA and Wild Type (WT) littermate male mice were recorded, under isoflurane anesthesia, between 3 and 20 months by stimulating the tibial branch of the sciatic motor nerve and recording compound muscle action potentials (CMAPs) from plantar muscles. As in patient studies, the multiple excitability program recorded stimulus-response, strengthduration and current-threshold relationships, threshold electrotonus and recovery-cycle. Since SBMA is a slowly progressive motor neuron pathology, data were divided in two groups (1) under 12 months when the mice are preor early symptomatic, and (2) over 12 months. Mutant and WT mice were compared. Results: In younger SBMA mice, no significant changes in excitability properties were observed compared to WT. In contrast, by 12 months, SBMA mice exhibited greater changes in response to depolarizing (p < 0.01) and hyperpolarizing (p < 0.001) currents, providing a fanning out appearance on the threshold electrotonus waveforms. Older SBMA mice also displayed smaller current/threshold gradients on the current-threshold relationship (p < 0.001). Some of these abnormalities were similar to those reported in patients with SBMA, but the change in current-threshold relationship was in the opposite direction. Furthermore, an increase in strength-duration time-constant, which was related to fasciculation frequency in the patients, was not significant in the SBMA mice. Conclusion: Although the SBMA mouse reproduces the motoneuron degeneration characteristic of SBMA and some of the axonal membrane changes, it is not a good model to explore the development of axonal hyperexcitability. Acknowledgments: This project was supported by MNDA. The authors gratefully acknowledge Mr Jim Dick for his assistance throughout this project.

Changes in human sensory axonal excitability induced by focal nerve compression

The aim of the present study was to establish the changes in nerve excitability and symptom generation associated with the application of focal nerve compression (FNC). FNC was applied at the wrist by means of a custom-designed electrode in 10 healthy subjects, and was maintained for 24 min. Symptoms of paraesthesiae and signs of numbness were recorded every 30 s. Despite apparently minimal changes in axonal threshold, FNC was associated with prolongation in latency by 14.5 +/- 2.1% (P < 0.001) and reduction in compound sensory action potential (CSAP) amplitude by 34.3 +/- 5.1% (P < 0.001), with two subjects developing conduction block. The reduction in CSAP was associated with abolition of superexcitability, and an increase in refractoriness of 295.2 +/- 55.5% (P < 0.005) and strength-duration time constant (SDTC) by 48.1 +/- 10.3% (P < 0.005), all consistent with axonal depolarization. With release of FNC, threshold rapidly increased above pre-compression levels (P < 0.01), consistent with the development of axonal hyperpolarization. Associated with these changes in axonal excitability, paraesthesiae and numbness steadily increased throughout FNC and reached a peak at the termination of FNC, followed by a gradual recovery on release of FNC. When compared to previous studies that utilised the effects of more generalised limb ischaemia, the changes in axonal excitability recorded during FNC were qualitatively and quantitatively alike, suggesting that similar biophysical mechanisms contributed to the changes observed with both manoeuvres.

Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy

Intravenous immunoglobulin (IVIg) infusions may provide clinical benefits in multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP). The short delay in the clinical response to IVIg therapy is not consistent with a process of remyelination or axonal regeneration. We assessed whether or not the efficacy of IVIg infusions in MMN and CIDP could reflect changes in axonal membrane properties and nerve excitability. Ulnar motor nerve excitability was studied before and after three to five consecutive days of IVIg infusions (0.4 g/kg/day) in 10 patients with MMN, 10 patients with CIDP, and 10 neurological controls (CTRLs). Excitability recovery cycle, stimulus–response and strength–duration properties were investigated. The recovery cycle parameters (absolute and relative refractory period durations, refractoriness and supernormality) were similar in all groups and did not change after IVIg infusions. At baseline, patients with CIDP, but not with MMN, showed a reduced strength–duration time constant (chronaxie) and increased rheobase when compared to CTRLs. After IVIg infusions, strength–duration time constant remained stable in CTRLs, but decreased in patients with MMN or CIDP. Rheobase increased in the three groups after treatment. The decreased strength–duration time constant after IVIg infusions in patients with MMN or CIDP could reflect a reduction of persistent Na + current, able to limit intraaxonal Na + accumulation and then to produce neuroprotective effects. However, this could also reflect compensatory mechanisms that did not directly underlie the therapeutic effect. Whatever the underlying process, this result revealed that IVIgs were able to produce early nerve excitability changes.