Pierre-Paul Vidal

Motoneuron survival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis

Several studies using transgenic mouse models of familial amyotrophic lateral sclerosis (ALS) have reported a life span increase in exercised animals, as long as animals are submitted to a moderate‐intensity training protocol. However, the neuroprotective potential of exercise is still questionable. To gain further insight into the cellular basis of the exercise‐induced effects in neuroprotection, we compared the efficiency of a swimming‐based training, a high‐frequency and ‐amplitude exercise that preferentially recruits the fast motor units, and of a moderate running‐based training, that preferentially triggers the slow motor units, in an ALS mouse model. Surprisingly, we found that the swimming‐induced benefits sustained the motor function and increased the ALS mouse life span by about 25 days. The magnitude of this beneficial effect is one of the highest among those induced by any therapeutic strategy in this disease. We have shown that, unlike running, swimming significantly delays spinal motoneuron death and, more specifically, the motoneurons of large soma area. Analysis of the muscular phenotype revealed a swimming‐induced relative maintenance of the fast phenotype in fast‐twitch muscles. Furthermore, the swimming programme preserved astrocyte and oligodendrocyte populations in ALS spinal cord. As a whole, these data are highly suggestive of a causal relationship not only linking motoneuron activation and protection, but also motoneuron protection and the maintenance of the motoneuron surrounding environment. Basically, exercise‐induced neuroprotective mechanisms provide an example of the molecular adaptation of activated motoneurons.

Vestibular compensation modifies the sensitivity of vestibular neurones to inhibitory amino acids.

The progressive disappearance of the postural and oculomotor syndrome triggered by unilateral labyrinthectomy (vestibular compensation) is a model of plasticity in the adult central nervous system. This recovery may involve modifications of the pharmacological profile of central vestibular neurones, in particular their sensitivity to inhibitory amino acids. We therefore compared the sensitivity of medial vestibular nucleus neurones to glycine and muscimol in slices taken either from control animals, or from guinea-pigs labyrinthectomized 3 days before. We demonstrate that the loss of excitatory inputs experienced by the ipsilesional vestibular neurones induces a decrease in their sensitivity to inhibitory amino acids. These pharmacological changes should facilitate the recovery of a normal balance between the average resting discharge of neurones in both vestibular nuclei.

Ocular and cervical VEMPs: A study of 74 patients suffering from peripheral vestibular disorders

OBJECTIVE This study compared the results of ocular and cervical vestibular evoked myogenic potentials (VEMPs) tests for healthy subjects with those for patients suffering from vestibular diseases to try to determine the clinical usefulness of combined ocular and cervical STB VEMP testing. METHODS Thirty-two healthy volunteers and 74 patients with unilateral vestibular dysfunction underwent tests for ocular and cervical VEMPs induced by AC 100 dB nHL 500 Hz STB combined with caloric and audiometric tests. RESULTS In healthy subjects, the mean P13-N23 peak-to-peak amplitude of cervical VEMPs was much larger than the mean n1-p1 peak-to-peak amplitude of ocular VEMPs. In patients, cervical and ocular VEMPs may be dissociated. The peak-to-peak amplitude of both cervical and ocular tests was abnormally in most of patients suffering from vestibular lesions. No correlations were found between VEMPs, the degree of hearing loss and/or of horizontal canalar paresis. CONCLUSIONS Ocular and cervical VEMPs provide complementary information about saccular and utricular otolithic function. SIGNIFICANCE Testing of ocular and cervical VEMPs allows the crossed vestibulo-ocular reflex and ipsilateral sacculo-collic reflex to be determined. These tests can help describe vestibular lesions and assess the effects of treatment and should therefore be used clinically.

Rocking synchronizes brain waves during a short nap

Summary Why do we cradle babies or irresistibly fall asleep in a hammock? Although such simple behaviors are common across cultures and generations, the nature of the link between rocking and sleep is poorly understood [1,2]. Here we aimed to demonstrate that swinging can modulate physiological parameters of human sleep. To this end, we chose to study sleep during an afternoon nap using polysomnography and EEG spectral analyses. We show that lying on a slowly rocking bed (0.25 Hz) facilitates the transition from waking to sleep, and increases the duration of stage N2 sleep. Rocking also induces a sustained boosting of slow oscillations and spindle activity. It is proposed that sensory stimulation associated with a swinging motion exerts a synchronizing action in the brain that reinforces endogenous sleep rhythms. These results thus provide scientific support to the traditional belief that rocking can soothe our sleep.

Direct and indirect effects of muscimol on medial vestibular nucleus neurones in guinea-pig brainstem slices.

Inhibitory amino acids are considered as major transmitters in the vestibular system. Using intracellular recordings in slices, we applied gamma-aminobutyric acid (GABA) and muscimol (a specific agonist of the GABAA receptor) to the two main types of medial vestibular nucleus neurones (A and B MVNn). In either a high Mg2+/low Ca2+ solution, or a solution containing tetrodotoxin, all MVNn were hyperpolarized by GABA and muscimol. This indicates that both types of MVNn are endowed with postsynaptic, hyperpolarising GABAA receptors. In a normal medium, about half of A and B MVNn were, in contrast, depolarised by GABA and muscimol, whereas the remaining cells were hyperpolarised. These results could be due to a modulation by GABA and muscimol of a tonic GABA release in the slice. Such a release was, indeed, suggested by results showing the depolarising effect of either tetrodotoxin (TTX) or bicuculline, when applied alone. The cells that were depolarised by GABA or muscimol in control conditions were always hyperpolarised in the presence of TTX. Our data therefore suggest that GABA acting at GABAA receptors in the medial vestibular nucleus can play a role either through a postsynaptic hyperpolarising action or indirectly by inhibiting a tonic GABA release, probably resulting from the spontaneous activity of local inhibitory interneurones. A GABAergic regulation of these interneurones could be important in processes of vestibular habituation and/or adaptation.

Developmental regulation of the membrane properties of central vestibular neurons by sensory vestibular information in the mouse.

The effect of the lack of vestibular input on the membrane properties of central vestibular neurons was studied by using a strain of transgenic, vestibular‐deficient mutant KCNE1−/− mice where the hair cells of the inner ear degenerate just after birth. Despite the absence of sensory vestibular input, their central vestibular pathways are intact. Juvenile and adult homozygous mutant have a normal resting posture, but show a constant head bobbing behaviour and display the shaker/waltzer phenotype characterized by rapid bilateral circling during locomotion. In juvenile mice, the KCNE1 mutation was associated with a strong decrease in the expression of the calcium‐binding proteins calbindin, calretinin and parvalbumin within the medial vestibular nucleus (MVN) and important modifications of the membrane properties of MVN neurons. In adult mice, however, there was almost no difference between the membrane properties of MVN neurons of homozygous and control or heterozygous mutant mice, which have normal inner ear hair cells and show no behavioural symptoms. The expression levels of calbindin and calretinin were lower in adult homozygous mutant animals, but the amount of calcium‐binding proteins expressed in the MVN was much greater than in juvenile mice. These data demonstrate that suppression of sensory vestibular inputs during a ‘sensitive period’ around birth can generate the circling/waltzing behaviour, but that this behaviour is not due to persistent abnormalities of the membrane properties of central vestibular neurons. Altogether, maturation of the membrane properties of central vestibular neurons is delayed, but not impaired by the absence of sensory vestibular information.

Intrinsic membrane properties of central vestibular neurons in rodents

Numerous studies in rodents have shown that the functional efficacy of several neurotransmitter receptors and the intrinsic membrane excitability of central vestibular neurons, as well as the organization of synaptic connections within and between vestibular nuclei can be modified during postnatal development, after a lesion of peripheral vestibular organs or in vestibular-deficient mutant animals. This review mainly focuses on the intrinsic membrane properties of neurons of the medial vestibular nuclei of rodents, their postnatal maturation, and changes following experimental or congenital alterations in vestibular inputs. It also presents the concomitant modifications in the distribution of these neurons into different neuron types, which has been based on their membrane properties in relation to their anatomical, biochemical, or functional properties. The main points discussed in this review are that (1) the intrinsic membrane properties can be used to distinguish between two dominant types of neurons, (2) the system remains plastic throughout the whole life of the animal, and finally, (3) the intracellular calcium concentration has a major effect on the intrinsic membrane properties of central vestibular neurons.

Vestibular compensation: the neuro-otologist’s best friend

Why vestibular compensation (VC) after an acute unilateral vestibular loss is the neuro-otologist’s best friend is the question at the heart of this paper. The different plasticity mechanisms underlying VC are first reviewed, and the authors present thereafter the dual concept of vestibulo-centric versus distributed learning processes to explain the compensation of deficits resulting from the static versus dynamic vestibular imbalance. The main challenges for the plastic events occurring in the vestibular nuclei (VN) during a post-lesion critical period are neural protection, structural reorganization and rebalance of VN activity on both sides. Data from animal models show that modulation of the ipsilesional VN activity by the contralateral drive substitutes for the normal push–pull mechanism. On the other hand, sensory and behavioural substitutions are the main mechanisms implicated in the recovery of the dynamic functions. These newly elaborated sensorimotor reorganizations are vicarious idiosyncratic strategies implicating the VN and multisensory brain regions. Imaging studies in unilateral vestibular loss patients show the implication of a large neuronal network (VN, commissural pathways, vestibulo-cerebellum, thalamus, temporoparietal cortex, hippocampus, somatosensory and visual cortical areas). Changes in gray matter volume in these multisensory brain regions are structural changes supporting the sensory substitution mechanisms of VC. Finally, the authors summarize the two ways to improve VC in humans (neuropharmacology and vestibular rehabilitation therapy), and they conclude that VC would follow a “top-down” strategy in patients with acute vestibular lesions. Future challenges to understand VC are proposed.

The role of cervical and ocular vestibular evoked myogenic potentials in the assessment of patients with vestibular schwannomas.

Objectives To investigate the clinical utility of VEMPs in patients suffering from unilateral vestibular schwannoma (VS) and to determine the optimal stimulation parameter (air conducted sound, bone conducted vibration) for evaluating the function of the vestibular nerve. Methods Data were obtained in 63 patients with non-operated VS, and 20 patients operated on VS. Vestibular function was assessed by caloric, cervical and ocular VEMP testing. 37/63 patients with conclusive ACS ocular VEMPs responses were studied separately. Results In the 63 non-operated VS patients, cVEMPs were abnormal in 65.1% of patients in response to AC STB and in 49.2% of patients to AC clicks. In the 37/63 patients with positive responses from the unaffected side, oVEMPs were abnormal in 75.7% of patients with ACS, in 67.6% with AFz and in 56.8% with mastoid BCV stimulation. In 16% of the patients, VEMPs were the only abnormal test (normal caloric and normal hearing). Among the 26 patients who did not show oVEMP responses on either side with ACS, oVEMPs responses could be obtained with AFz (50%) and with mastoid stimulation (89%). Conclusions The VEMP test demonstrated significant clinical value as it yielded the only abnormal test results in some patients suffering from a unilateral vestibular schwannoma. For oVEMPs, we suggest that ACS stimulation should be the initial test. In patients who responded to ACS and who had normal responses, BCV was not required. In patients with abnormal responses on the affected side using ACS, BCV at AFz should be used to confirm abnormal function of the superior vestibular nerve. In patients who exhibited no responses on either side to ACS, BCV was the only approach allowing assessment of the function of the superior vestibular nerve. We favor using AFz stimulation first because it is easier to perform in clinical practice than mastoid stimulation.

Stimulation by cochlear implant in unilaterally deaf rats reverses the decrease of inhibitory transmission in the inferior colliculus

In the last decade, numerous studies have investigated synaptic transmission changes in various auditory nuclei after unilateral cochlear injury. However, few data are available concerning the potential effect of electrical stimulation of the deafferented auditory nerve on the inhibitory neurotransmission in these nuclei. We report here for the first time the effect of chronic electrical stimulation of the deafferented auditory nerve on α1 subunit of the glycinergic receptor (GlyRα1) and glutamic acid decarboxylase (GAD)67 expression in the central nucleus of inferior colliculus (CIC). Adult rats were unilaterally cochleectomized by intracochlear neomycin sulphate injection. Fifteen days later, the ipsilateral auditory nerve was chronically stimulated either 4, 8 or 22 h daily, for 5 days using intracochlear bipolar electrodes. GlyRα1 and GAD67 mRNA and protein were quantified in the CIC using in situ hybridization and immunohistofluorescence methods. Our data showed that as after surgical ablation, GlyRα1 and GAD67 expression were strongly decreased in the contralateral CIC after unilateral chemical cochleectomy. Most importantly, these postlesional down‐modulations were significantly reversed by chronic electrical stimulation of the deafferented auditory nerve. This recovery, however, did not persist for more than 5 days after the cessation of the deafferented auditory nerve electrical stimulation. Thus, downregulations of GlyRα1 and GAD67 may be involved both in the increased excitability observed in the CIC after unilateral deafness and consequently in the tinnitus frequently observed in unilateral adult deaf patients. Electrical stimulation of the deafferented auditory nerve in patients may be a potential new approach for treating tinnitus with unilateral hearing loss.