Intermittent atrial tachycardia promotes repolarization alternans and conduction slowing during rapid rates, and increases susceptibility to atrial fibrillation in a free-behaving sheep model.

INTRODUCTION: Paroxysmal atrial fibrillation (AF) may be triggered by intermittent atrial tachycardia, and ultimately lead to persistent AF. However, the mechanisms by which intermittent atrial tachycardia promotes sustained AF are not well understood. METHODS AND RESULTS: Eight sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms, and for the delivery of electrophysiological stimulation protocols and intermittent right atrial tachycardia. Right atrial kinetics of activation recovery interval (ARI) as a surrogate for action potential duration, of conduction time and velocity, and of repolarization alternans were analyzed at incremental pacing rates during the remodeling process induced by weeks of intermittent atrial tachycardia until the development of sustained AF. Intermittent atrial tachycardia decreased ARI and blunted its rate adaptation, facilitated atrial capture, and slowed conduction at high rates, and increased susceptibility to pacing-induced AF. In spite of blunted ARI rate adaptation, right atrial repolarization alternans was maintained during remodeling, and further increased in magnitude just before rapid pacing-induced AF. CONCLUSION: This study suggests that weeks of intermittent right atrial tachycardia result in a gradual electrical remodeling favorable for wavebreaks and reentry that may facilitate fibrillation.

Propagation velocity kinetics and repolarization alternans in a free-behaving sheep model of pacing-induced atrial fibrillation.

AIMS: Experimental models have reported conflicting results regarding the role of dispersion of repolarization in promoting atrial fibrillation (AF). Repolarization alternans, a beat-to-beat alternation in action potential duration, enhances dispersion of repolarization when propagation velocity is involved. METHODS AND RESULTS: In this work, original electrophysiological parameters were analysed to study AF susceptibility in a chronic sheep model of pacing-induced AF. Two pacemakers were implanted, each with a single right atrial lead. Right atrial depolarization and repolarization waves were documented at 2-week intervals. A significant and gradual decrease in the propagation velocity at all pacing rates and in the right atrial effective refractory period (ERP) was observed during the weeks of burst pacing before sustained AF developed when compared with baseline conditions. Right atrial repolarization alternans was observed, but because of the development of 2/1 atrioventricular block with far-field ventricular interference, its threshold could not be precisely measured. Non-sustained AF was not observed at baseline, but appeared during the electrical remodelling in association with a decrease in both ERP and propagation velocity. CONCLUSION: We report here on the feasibility of measuring ERP, atrial repolarization alternans, and propagation velocity kinetics and their potential in predicting susceptibility to AF in a free-behaving model of pacing-induced AF using the standard pacemaker technology.

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.

The expansion of 300 CTG repeats in myotonic dystrophy transgenic mice does not induce sensory or motor neuropathy.

Although many studies have been carried out to verify the involvement of the peripheral nervous system (PNS) in dystrophia myotonica (DM1) patients, the results remain controversial. The generation of DM1 transgenic mice displaying the human DM1 phenotype provides a useful tool to investigate the type and incidence of structural abnormalities in the PNS. In the present study, the morphological and morphometric analysis of semi-thin sections of sciatic and sural nerves, lumbar dorsal root ganglia (DRG) and lumbar spinal cords revealed that in DM1 transgenic mice carrying 300 CTG repeats, there is no change in the number and diameter of myelinated axons compared to wild type. Only a non-significant reduction in the percentage of thin myelinated axons was detected in electron micrographs of ultra-thin sciatic nerve sections. Analysis of the number of neurons did not reveal a loss in number of either sensory neurons in the lumbar DRG or motor neurons in the lumbar spinal cord in these DM1 mice. Furthermore, in hind limb muscle sections, stained with a neurofilament antibody and alpha-bungarotoxin, the intramuscular axon arborization appeared normal in DM1 mice and undistinguishable from that in wild-type mice. Moreover, in DM1 mice, there was no irregularity in the structure or an increase in the endplate area. Also statistical analysis did not show an increase in endplate density or in the concentration of acetylcholine receptors. Altogether, these results suggest that 300 CTG repeats are not sufficient to induce axonopathy, demyelination or neuronopathies in this transgenic mouse model.

Thyroid hormone enhances transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury.

Improvement of nerve regeneration and functional recovery following nerve injury is a challenging problem in clinical research. We have already shown that following rat sciatic nerve transection, the local administration of triiodothyronine (T3) significantly increased the number and the myelination of regenerated axons. Functional recovery is a sum of the number of regenerated axons and reinnervation of denervated peripheral targets. In the present study, we investigated whether the increased number of regenerated axons by T3-treatment is linked to improved reinnervation of hind limb muscles. After transection of rat sciatic nerves, silicone or biodegradable nerve guides were implanted and filled with either T3 or phosphate buffer solution (PBS). Neuromuscular junctions (NMJs) were analyzed on gastrocnemius and plantar muscle sections stained with rhodamine alpha-bungarotoxin and neurofilament antibody. Four weeks after surgery, most end-plates (EPs) of operated limbs were still denervated and no effect of T3 on muscle reinnervation was detected at this stage of nerve repair. In contrast, after 14 weeks of nerve regeneration, T3 clearly enhanced the reinnervation of gastrocnemius and plantar EPs, demonstrated by significantly higher recovery of size and shape complexity of reinnervated EPs and also by increased acetylcholine receptor (AChRs) density on post synaptic membranes compared to PBS-treated EPs. The stimulating effect of T3 on EP reinnervation is confirmed by a higher index of compound muscle action potentials recorded in gastrocnemius muscles. In conclusion, our results provide for the first time strong evidence that T3 enhances the restoration of NMJ structure and improves synaptic transmission.

Vagus nerve stimulator treatment in adult-onset Rasmussen's encephalitis.

We describe a patient with adult-onset Rasmussen's encephalitis (RE) responsive to vagus nerve stimulation. This previously healthy woman developed RE in the right hemisphere at the age of 27. Despite antiepileptic drug polytherapy, she continued to experience subcontinuous, simple-partial left-sided motor seizures and slowly progressive cognitive impairment. Resective surgery was not considered owing to the preservation of left motor skills. She was implanted with a vagus nerve stimulator at the age of 41; after 6 months she experienced a greater than 50% reduction in seizure frequency, which persisted over 2 years together with improvement of her neurological and cognitive status.

Isolated IVth (trochlear) nerve palsy due to basilar artery dolichoectasia.

BACKGROUND: Dolichoectasia (elongation, dilatation and tortuosity) of the basilar artery can cause an isolated cranial neuropathy. The trigeminal nerve and facial nerve are most frequently affected. Dysfunction of one of the ocular motor cranial nerves due to basilar artery dolichoectasia is uncommon, and an isolated IVth (trochlear) nerve palsy has not been previously described in the literature. HISTORY AND SIGNS: Two men, ages 70 and 59 years, respectively, presented with vertical diplopia due to a IVth nerve palsy. In one patient, the onset of the IVth nerve palsy was painless and gradual and in the other patient, the onset was acute and associated with periorbital pain. Neuroimaging in both patients revealed pathological tortuosity of the basilar artery around the midbrain and displacement of the artery toward the side of the affected trochlear nerve. THERAPY AND OUTCOME: The patients were observed clinically. One patient had gradual worsening of his palsy for three and one-half years then suffered a stroke. The second patient whose IVth nerve palsy had an acute onset experienced spontaneous resolution of his palsy but later developed dysfunction of other cranial nerves. CONCLUSIONS: Basilar artery dolichoectasia should be considered in the differential diagnosis of an isolated IVth nerve palsy. The clinical course may be variable, and the prognosis is not always benign.

Stimulus-response curve of human motor nerves: multicenter assessment of various indexes.

The value of various indexes to characterize the stimulus-response curve of human motor nerves was assessed in 40 healthy subjects recruited from four European centers of investigation (Créteil, Lausanne, Liège, Marseille). Stimulus-response curves were established by stimulating the right median and ulnar motor nerves at the wrist, with stimulus durations of 0.05 and 0.5 ms. The following parameters were studied: the threshold intensity of stimulation to obtain 10% (I 10), 50% (I 50), and 90% (I 90) of the maximal compound muscle action potential, the ratios I 10/I 50, I 90/I 50, (I 90 - I 10)/I 10, (I 90-I 50)/I 50, and (I 50 - I 10)/I 10, and the slopes of the stimulus-response curves with or without normalization to I 50. For each parameter, within-center variability and reproducibility (in a test-retest study) were assessed and between-center comparisons were made. For most of the parameters, the results varied significantly within and between the centers. Within the centers, only the ratios I 10/I 50 and I 90/I 50 were found constant and reproducible. Between the centers, the absolute intensity thresholds (I 10, I 50, I 90) and the ratio I 90/I 50 did not show significant differences at stimulus duration of 0.5 ms, whatever the stimulated nerve. The reduced variability and good reproducibility of the ratios I 10/I 50 and I 90/I 50 open perspectives in neurophysiological practice for the use of these indexes of the stimulus-response curve, a rapid and noninvasive test.

Familial frontotemporal dementia with ubiquitin inclusion bodies and without motor neuron disease.

Frontotemporal dementia (FTD) is the second most common degenerative dementia after Alzheimer's disease and its Lewy body variant. Clinical pathology can be subdivided in three main neuropathological subtypes: frontal lobe dementia, Pick's disease and FTD with motor neuron disease (MND), all characterised by distinct histological features. Until recently the presence of ubiquitin-positive intraneuronal inclusions in the dentate gyrus, and the temporal and frontal cortex was usually associated with the MND type. Such inclusions were also observed in a few sporadic cases of FTD without or with parkinsonism (FTDP) in the absence of MND. We present here clinical, neuropathological and immunohistochemical data about a Swiss FTD family with FTDP-like features but without MND. Spongiosis and mild gliosis were observed in the grey matter. No neurofibrillary tangles, Pick bodies, Lewy bodies, senile plaques or prion-positive signals were present. However, ubiquitin-positive intracytoplasmic inclusions were detected in various structures but predominantly in the dentate gyrus. These observations support the existence of a familial form of FTDP with ubiquitin-positive intracytoplasmic inclusions (Swiss FTDP family).

Spatiotemporal neuromodulation therapies engaging muscle synergies improve motor control after spinal cord injury.

Electrical neuromodulation of lumbar segments improves motor control after spinal cord injury in animal models and humans. However, the physiological principles underlying the effect of this intervention remain poorly understood, which has limited the therapeutic approach to continuous stimulation applied to restricted spinal cord locations. Here we developed stimulation protocols that reproduce the natural dynamics of motoneuron activation during locomotion. For this, we computed the spatiotemporal activation pattern of muscle synergies during locomotion in healthy rats. Computer simulations identified optimal electrode locations to target each synergy through the recruitment of proprioceptive feedback circuits. This framework steered the design of spatially selective spinal implants and real-time control software that modulate extensor and flexor synergies with precise temporal resolution. Spatiotemporal neuromodulation therapies improved gait quality, weight-bearing capacity, endurance and skilled locomotion in several rodent models of spinal cord injury. These new concepts are directly translatable to strategies to improve motor control in humans.

Subclinical femoral neuropathy after anterior cruciate ligament reconstruction

Background and aim of the study: Patients with anterior cruciate ligament (ACL) reconstruction and femoral catheter analgesia may develop quadriceps amyotrophy. We aimed to determine whether this amyotrophy might be related to a femoral neuropathy. Material and method: After Ethical Committee approval and patients' written informed consent, 17 patients ASA I and II scheduled to undergo ACL reconstruction were recruited. An electromyography (EMG) was performed before the operation in order to exclude a femoral neuropathy. A femoral nerve catheter was inserted before the surgery with the aid of a nerve stimulator, and 20 ml of 0.5% ropivacaine was injected. The operation was done under spinal or general anaesthesia. Postoperative analgesia was provided with 0.2% ropivacaine for 72 hours, in association with oxycodone, paracetamol and ibuprofen. A second EMG was performed 4 weeks after the ACL repair. A femoral neuropathy was defined as a reduction of the surface of the motor response of more than 20%, compared to the first EMG. A third EMG was performed at 6 months if a neuropathy was present. Results: Mean age of this group of patients was 27 years old (range 18-38 y.). Among the 17 patients, 4 developed a transient femoral neuropathy (incidence of 24%) without clinical complain. Conclusion: In this study, the incidence of subclinical femoral neuropathy after ACL reconstruction is high. This lesion may be caused by the femoral catheter (mechanical damage, toxicity of local anaesthesia) or by the Tourniquet. Further studies are needed to investigate the incidence of subclinical neuropathy, according to the type of analgesia (epidural analgesia, PCA) and surgery.

Relationship of physical activity with motor skills, aerobic fitness and body fat in preschool children: a cross-sectional and longitudinal study (Ballabeina).

Adiposity, low aerobic fitness and low levels of activity are all associated with clustered cardiovascular disease risk in children and their high prevalence represents a major public health concern. The aim of this study is to investigate the relationship of objectively measured physical activity (PA) with motor skills (agility and balance), aerobic fitness and %body fat in young children. This study is a cross-sectional and longitudinal analyses using mixed linear models. Longitudinal data were adjusted for baseline outcome parameters. In all, 217 healthy preschool children (age 4-6 years, 48% boys) participated in this study. PA (accelerometers), agility (obstacle course), dynamic balance (balance beam), aerobic fitness (20-m shuttle run) and %body fat (bioelectric impedance) at baseline and 9 months later. PA was positively associated with both motor skills and aerobic fitness at baseline as well as with their longitudinal changes. Specifically, only vigorous, but not total or moderate PA, was related to changes in aerobic fitness. Higher PA was associated with less %body fat at baseline, but not with its change. Conversely, baseline motor skills, aerobic fitness or %body fat were not related to changes in PA. In young children, baseline PA was associated with improvements in motor skills and in aerobic fitness, an important determinant of cardiovascular risk.

Cells with neuronal characteristics differentiate and persist for one year in rat optic nerve explants cultures.

Evidence concerning the presence or absence of common neuronglia lineages in the postnatal mammalian central nervous system is still a matter of speculation. We address this problem using optic nerve explants, which show an extremely long survival in culture. Morphological, immunocytochemical and immunochemical methods were applied. The results obtained from in vitro tissue were compared with optic nerves (ONs) and whole-brain samples from animals of different ages. Newborn rat ONs represented the starting material of our tissue culture; they are composed of unmyelinated axons, astrocytes and progenitor cells but devoid of neuronal cell bodies. At this age, Western blots of ONs were positively stained by neurofilament and synapsin I specific antibodies. These bands increased in intensity during postnatal in situ development. In explant cultures, the glia cells reach a stage of functional differentiation and they maintain, together with undifferentiated cells, a complex histotypic organization. After 6 days in vitro, neurofilaments and synapsin I could not be detected on immunoblots, indicating that 1) axonal degeneration was completed, and 2) neuronal somata were absent at the time. Surprisingly, after about 4-5 weeks in culture, a new cell type appeared, which showed characteristics typical of neurons. After 406 days in vitro, neurofilaments and synapsin I were unequivocally detectable on Western blots. Furthermore, both immunocytochemical staining and light and electron microscopic examinations corroborated the presence of this earlier-observed cell type. These in vitro results clearly show the high developmental plasticity of ON progenitor cells, even late in development. The existence of a common neuron-glia precursor, which never gives rise to neurons in situ, is suggested.

Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of myotonic dystrophy.

Acute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders and, if so, to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography, we assessed the breathing function in control mice and DMSXL mice generated after large expansions of the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. Histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice, characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible breakdown in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Because EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures might underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.