Excessive checking behavior during an image comparison task in schizophrenia.

BACKGROUND: Patients with schizophrenia display significant working memory and executive deficits. In patients with obsessive-compulsive disorder (OCD), several studies suggest that working memory dysfunction may be one of the causes of compulsive checking behaviors. Hence, this study aimed at assessing whether patients with schizophrenia were impaired on an image comparison task used to measure checking behaviors, and whether the origin and profile of impairment on this task was different between schizophrenia and OCD. METHODS: Eye movement recordings were used to assess the checking behavior of 24 patients with schizophrenia and 24 control participants who had to decide whether two images were different or identical. The verbal and visuo-spatial components of participants' working memory were measured using the reading span and backward location span tests. RESULTS: Compared to controls, patients with schizophrenia had reduced working memory spans and showed excessive checking behavior when comparing the two images. However, the intensity of their checking behavior was not significantly related to their working memory deficits. CONCLUSIONS: Several recent studies demonstrated that the excessive checking behaviors displayed by patients with OCD were related to working memory dysfunction. The absence of a relationship between the excessive checking behavior of patients with schizophrenia and their working memory deficits suggests that checking behaviors do not have the same origin in the two disorders.

Forgetting what you have checked: a link between working memory impairment and checking behaviors in obsessive-compulsive disorder.

BACKGROUND: Compulsive checking behaviors are common in obsessive-compulsive disorder (OCD). Several authors have suggested that these checking rituals could be related to memory deficits. Our aim was to test whether patients with OCD show working memory impairment in relation to their checking behavior. METHODS: We evaluated the verbal and visuospatial components of patients' and controls' working memory using the reading span and backward location span tests. Checking behaviors were measured by recording participants' eye movements during an image comparison task using a non-invasive, infra-red TOBII 1750 eyetracker. Participants were seated, head-free, in a natural position in front of the eyetracker screen where the images were displayed. RESULTS: Patients with OCD made more gaze moves to compare images than controls. Both patients' working memory spans were reduced, and the patients' deficit in the comparison task was negatively related to their working memory spans. CONCLUSIONS: This work demonstrates that checking behavior in OCD is linked to a general reduction of the patients' verbal and visuospatial working memory span.

A critical review of the contribution of eye movement recordings to the neuropsychology of obsessive compulsive disorder.

OBJECTIVE: Dysfunctions of saccadic and/or smooth pursuit eye movements have been proposed as markers of obsessive compulsive disorder (OCD), but experimental results are inconsistent. The aim of this paper was to review the literature on eye movement dysfunctions in OCD to assess whether or not saccades or smooth pursuit may be used to diagnose and characterize OCD. METHOD: Literature was searched using PubMed, ISI Web of Knowledge, and PsycINFO databases for all studies reporting eye movements in adult patients suffering from OCD. RESULTS: Thirty-three articles were found. As expected, eye movements of the patients with OCD were mostly assessed with simple oculomotor paradigms involving saccadic and/or smooth pursuit control. In contrast to patients with schizophrenia, however, patients with OCD only displayed rather unspecific deficits, namely slight smooth pursuit impairments and longer response latencies on antisaccade tasks. There was no relationship between these deficits and the severity of patients' symptoms. Interestingly, eye movements of the patients with OCD were almost never recorded during more complex cognitive tasks. CONCLUSION: As in schizophrenia and autism, eye movement recordings during more complex tasks might help to better characterize the cognitive deficits associated with OCD. Such recordings may reveal specific OCD-related deficits that could be used as reliable diagnostic and/or classification tools.

Evidence against a role of gap junctions in vestibular compensation.

Vestibular compensation following unilateral labyrinthectomy is associated with modifications of the membrane and firing properties of central vestibular neurons. To determine whether gap junctions could be involved in this process, immunofluorescent detection of neuronal connexin 36 and astrocytic connexin 43 was performed in the medial vestibular nucleus (MVN) of rats. In non-lesioned animals, strong staining was observed with anti-connexin 43 antibodies, while moderate staining was obtained with the anti-connexin 36 antibody. However, the expression of either type of connexin was not modified following unilateral labyrinthectomy. These morphological observations were complemented by pharmacological tests performed during extracellular recordings of MVN neurons in guinea pig brainstem slices. In non-lesioned animals, the gap junction blocker carbenoxolone reversibly decreased or suppressed the spontaneous discharge of about 60% of MVN neurons. This reduction was often associated with a long-duration disruption of the regularity of spike discharge. Both effects were mimicked by several other gap junction blockers, but not by glycyrrhizic acid, an analog of carbenoxolone that does not block gap junctions but reproduces its non-specific effects, nor by the selective inhibitor of astrocytic connexin-based networks endothelin-1. Similar effects of carbenoxolone were obtained on the spontaneous activity of ipsilesional MVN neurons recorded in brainstem slices taken from labyrinthectomized animals. Altogether, these results suggest that neuronal gap junctions are involved in shaping the spontaneous activity of MVN neurons. However, unilateral labyrinthectomy does not affect the expression of gap junctions in vestibular nuclei nor their implication in the regulation of neuronal activity.

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.

Psychophysiological correlates of the inter-individual variability of head movement control in seated humans.

We recently conducted experiments where 24 seated participants were subjected (with eyes closed) to small amplitude, high-jerk impulses of linear acceleration. Responses were distributed as a continuum between two extremes. The "stiff" participants showed little movement of the head relative to the trunk, whereas the "floppy" participants showed a large head rotation in the direction opposite the sled movement. We hypothesized that the stiff behavior resulted from the spontaneous use of an imagined visual frame of reference and undertook this larger-scale study to test that idea. The distribution along the "stiff-floppy" continuum was compared with the scores on psychophysiological tests measuring vividness of imagery, visual field-dependence and motion sickness susceptibility. Multivariate regression analysis revealed that the "stiffness" of individuals was loosely, but significantly related to the vividness of their imagery. However, "stiffness" was not linked to visual field-dependence or motion sickness susceptibility. Even if it explains only 20% of the variance of the data, the increase of "stiffness" with vividness of imagery fits our hypothesis. With eyes closed, stiff people may use imagined external visual cues to stabilize their head and trunk. Floppy people, who are poorer imagers, may rely more on "egocentric", proprioceptive and vestibular inputs.

Intrinsic membrane properties of vertebrate vestibular neurons: function, development and plasticity.

Central vestibular neurons play an important role in the processing of body motion-related multisensory signals and their transformation into motor commands for gaze and posture control. Over recent years, medial vestibular nucleus (MVN) neurons and to a lesser extent other vestibular neurons have been extensively studied in vivo and in vitro, in a range of species. These studies have begun to reveal how their intrinsic electrophysiological properties may relate to their response patterns, discharge dynamics and computational capabilities. In vitro studies indicate that MVN neurons are of two major subtypes (A and B), which differ in their spike shape and after-hyperpolarizations. This reflects differences in particular K(+) conductances present in the two subtypes, which also affect their response dynamics with type A cells having relatively low-frequency dynamics (resembling "tonic" MVN cells in vivo) and type B cells having relatively high-frequency dynamics (resembling "kinetic" cells in vivo). The presence of more than one functional subtype of vestibular neuron seems to be a ubiquitous feature since vestibular neurons in the chick and frog also subdivide into populations with different, analogous electrophysiological properties. The ratio of type A to type B neurons appears to be plastic, and may be determined by the signal processing requirements of the vestibular system, which are species-variant. The membrane properties and discharge pattern of type A and type B MVN neurons develop largely post-natally, through the expression of the underlying ion channel conductances. The membrane properties of MVN neurons show rapid and long-lasting plastic changes after deafferentation (unilateral labyrinthectomy), which may serve to maintain their level of activity and excitability after the loss of afferent inputs.

Postural control in patients with unilateral vestibular lesions is more impaired in the roll than in the pitch plane: a static and dynamic posturography study.

The postural instability of patients with vestibular loss (11 with bilateral and 101 with unilateral vestibular loss) at different times following the lesion was investigated by means of posturography and compared to healthy subjects. In addition, subjects submitted to galvanic vestibular stimulation were also studied to compare their postural performances with those of patients with complete unilateral vestibular lesion. The platform consisted of a static computerized force platform, on which a seesaw platform could be placed to test the subjects in dynamic conditions. The displacement of the center of foot pressure was measured under different conditions: subjects standing on the fixed platform, eyes open and eyes closed and subjects standing on the seesaw platform, eyes open and eyes closed. In the last condition, balance was tested in the subject's pitch plane by allowing the platform to rotate forwards and backwards only and in the patient's roll plane by allowing the platform to rotate to the left and to the right. The results showed that in static conditions, only bilateral vestibular loss patients had abnormal values compared to controls. In contrast, in dynamic eyes-closed conditions, both bilateral and unilateral patients could be differentiated from controls. Bilateral patients were unable to stand up without falling in both pitch and roll planes. Unilateral patients fell in the first week following the lesion and exhibited increased postural oscillations in both planes from the 2-week up to the 1-year postlesion stage. In addition and more importantly, they fell more often or had higher sway in the roll than in the pitch plane. Therefore, this study suggests that dynamic posturography on a seesaw platform could be a valuable tool for clinical diagnosis and quantitative analysis of imbalance in patients suffering from a unilateral vestibular loss up to 1 year after the lesion.

Second-order vestibular neurons form separate populations with different membrane and discharge properties.

Membrane and discharge properties were determined in second-order vestibular neurons (2 degrees VN) in the isolated brain of grass frogs. 2 degrees VN were identified by monosynaptic excitatory postsynaptic potentials after separate electrical stimulation of the utricular nerve, the lagenar nerve, or individual semicircular canal nerves. 2 degrees VN were classified as vestibulo-ocular or -spinal neurons by the presence of antidromic spikes evoked by electrical stimulation of the spinal cord or the oculomotor nuclei. Differences in passive membrane properties, spike shape, and discharge pattern in response to current steps and ramp-like currents allowed a differentiation of frog 2 degrees VN into two separate, nonoverlapping types of vestibular neurons. A larger subgroup of 2 degrees VN (78%) was characterized by brief, high-frequency bursts of up to five spikes and the absence of a subsequent continuous discharge in response to positive current steps. In contrast, the smaller subgroup of 2 degrees VN (22%) exhibited a continuous discharge with moderate adaptation in response to positive current steps. The differences in the evoked spike discharge pattern were paralleled by differences in passive membrane properties and spike shapes. Despite these differences in membrane properties, both types, i.e., phasic and tonic 2 degrees VN, occupied similar anatomical locations and displayed similar afferent and efferent connectivities. Differences in response dynamics of the two types of 2 degrees VN match those of their pre- and postsynaptic neurons. The existence of distinct populations of 2 degrees VN that differ in response dynamics but not in the spatial organization of their afferent inputs and efferent connectivity to motor targets suggests that frog 2 degrees VN form one part of parallel vestibulomotor pathways.

Resonance of spike discharge modulation in neurons of the guinea pig medial vestibular nucleus.

The modulation of action potential discharge rates is an important aspect of neuronal information processing. In these experiments, we have attempted to determine how effectively spike discharge modulation reflects changes in the membrane potential in central vestibular neurons. We have measured how their spike discharge rate was modulated by various current inputs to obtain neuronal transfer functions. Differences in the modulation of spiking rates were observed between neurons with a single, prominent after hyperpolarization (AHP, type A neurons) and cells with more complex AHPs (type B neurons). The spike discharge modulation amplitudes increased with the frequency of the current stimulus, which was quantitatively described by a neuronal model that showed a resonance peak >10 Hz. Modeling of the resonance peak required two putative potassium conductances whose properties had to be markedly dependent on the level of the membrane potential. At low frequencies (< or =0.4 Hz), the gain or magnitude functions of type A and B discharge rates were similar relative to the current input. However, resting input resistances obtained from the ratio of the membrane potential and current were lower in type B compared with type A cells, presumably due to a higher level of active potassium conductances at rest. The lower input resistance of type B neurons was compensated by a twofold greater sensitivity of their firing rate to changes in membrane potential, which suggests that synaptic inputs on their dendritic processes would be more efficacious. This increased sensitivity is also reflected in a greater ability of type B neurons to synchronize with low-amplitude sinusoidal current inputs, and in addition, their responses to steep slope ramp stimulation are enhanced over the more linear behavior of type A neurons. This behavior suggests that the type B MVNn are moderately tuned active filters that promote high-frequency responses and that type A neurons are like low-pass filters that are well suited for the resting tonic activity of the vestibular system. However, the more sensitive and phasic type B neurons contribute to both low- and high-frequency control as well as signal detection and would amplify the contribution of both irregular and regular primary afferents at high frequencies.

Modification of the pacemaker activity of vestibular neurons in brainstem slices during vestibular compensation in the guinea pig.

In the guinea pig, unilateral labyrinthectomy causes an immediate and severe depression of the spontaneous activity of the ipsilateral central vestibular neurons, which subsequently recovers completely within one week. A possible underlying mechanism could be an increase in the endogenous activity of the neurons deprived of their labyrinthine input. Here, we addressed this hypothesis. The endogenous activity of the neurons was assessed by their spontaneous activity recorded extracellularly in brainstem slices in the presence of a cocktail of neurotransmitter blockers (CNQX, D-APV, bicuculline and strychnine) which freed them from their main synaptic influences. The left medial vestibular nucleus (MVN) was explored in a very systematic way and strict methodological precautions were taken in order to validate comparisons between the numbers of spontaneously active neurons recorded in the MVN of distinct slices. In the presence of neurotransmitter antagonists, the mean number of spontaneously active neurons detected in a single MVN increased dramatically from 9.5 in slices from control guinea pigs to 26.3 in slices from animals labyrinthectomized on the left side one week beforehand. The mean firing rate of the recorded neurons also increased from 7.5 +/- 5.6 spikes/s in slices from control animals to 12.3 +/- 7.6 spikes/s in slices from guinea pigs labyrinthectomized one week beforehand. These results show that deprivation of the vestibular neurons of their labyrinthine input caused a change in the deprived neurons themselves. They suggest that an increase in pacemaker activity might be a factor responsible for the restoration of spontaneous activity in the vestibular neurons after labyrinthectomy.

Variability in the control of head movements in seated humans: a link with whiplash injuries?

The aim of this study was to determine how context and on-line sensory information are combined to control posture in seated subjects submitted to high-jerk, passive linear accelerations. Subjects were seated with eyes closed on a servo-controlled linear sled. They were asked to relax and received brief accelerations either sideways or in the fore-aft direction. The stimuli had an abrupt onset, comparable to the jerk experienced during a minor car collision. Rotation and translation of the head and body were measured using an Optotrak system. In some of the subjects, surface electromyographic (EMG) responses of selected neck and/or back muscles were recorded simultaneously. For each subject, responses were highly stereotyped from the first trial, and showed little sign of habituation or sensitisation. Comparable results were obtained with sideways and fore-aft accelerations. During each impulse, the head lagged behind the trunk for several tens of milliseconds. The subjects' head movement responses were distributed as a continuum in between two extreme categories. The 'stiff' subjects showed little rotation or translation of the head relative to the trunk for the whole duration of the impulse. In contrast, the 'floppy' subjects showed a large roll or pitch of the head relative to the trunk in the direction opposite to the sled movement. This response appeared as an exaggerated 'inertial' response to the impulse. Surface EMG recordings showed that most of the stiff subjects were not contracting their superficial neck or back muscles. We think they relied on bilateral contractions of their deep, axial musculature to keep the head-neck ensemble in line with the trunk during the movement. About half of the floppy subjects displayed reflex activation of the neck muscles on the side opposite to the direction of acceleration, which occurred before or during the head movement and tended to exaggerate it. The other floppy subjects seemed to rely on only the passive biomechanical properties of their head-neck ensemble to compensate for the perturbation. In our study, proprioception was the sole source of sensory information as long as the head did not move. We therefore presume that the EMG responses and head movements we observed were mainly triggered by the activation of stretch receptors in the hips, trunk and/or neck. The visualisation of an imaginary reference in space during sideways impulses significantly reduced the head roll exhibited by floppy subjects. This suggests that the adoption by the central nervous system of an extrinsic, 'allocentric' frame of reference instead of an intrinsic, 'egocentric' one may be instrumental for the selection of the stiff strategy. The response of floppy subjects appeared to be maladaptive and likely to increase the risk of whiplash injury during motor vehicle accidents. Evolution of postural control may not have taken into account the implications of passive, high-acceleration perturbations affecting seated subjects.

In vitro effects of acetyl-DL-leucine (tanganil) on central vestibular neurons and vestibulo-ocular networks of the guinea-pig.

For 40 years, the amino acid acetyl-DL-leucine (or isoleucine/Tanganil) has been used in clinical practice to reduce the imbalance and autonomic signs associated with acute vertigo crises. In animal models, acetyl-DL-leucine was shown to accelerate vestibular compensation following unilateral labyrinthectomy, while having only minor effects on normal vestibular function. However, the underlying mechanisms are unknown. In this study, the effect of acetyl-DL-leucine on the activity of central vestibular neurons of the medial vestibular nucleus (MVN) and/or the overall activity of vestibular-related networks was electrophysiologically measured in brainstem slices and in the isolated, in vitro whole brain (IWB) of guinea-pig. Only moderate effects were obtained in normal animals, where both excitatory and inhibitory actions of acetyl-DL-leucine were obtained. However, intracellular recordings from MVN neurons revealed that the nature of the response depended on the resting membrane potential. The neurons excited by acetyl-DL-leucine were significantly hyperpolarized compared to nonsensitive cells, whereas the neurons inhibited by this compound tended to display higher than normal membrane potentials. In accordance with these data, acetyl-DL-leucine reduced the prominent asymmetry characterizing the vestibular-related networks of IWBs taken from previously labyrinthectomized animals, by decreasing the activity of the abnormally depolarized neurons on the hyperactive side. Altogether, our results suggest that acetyl-DL-leucine might act mainly on abnormally hyperpolarized and/or depolarized MVN neurons, by bringing back their membrane potential towards a mean value of -65 to -60 mV. Since in animal models, acute vestibular disorders are associated with asymmetrical spontaneous activities of MVN neurons, this study suggests how acetyl-DL-leucine may reduce acute, vestibular-related imbalances in humans.

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.

Post-lesional plasticity in the central nervous system of the guinea-pig: a "top-down" adaptation process?

Vestibular compensation for the postural and oculomotor deficits following unilateral labyrinthectomy is a model of functional plasticity in the brain of adult vertebrates. The mechanisms involved in this recovery are still controversial. The post-lesional lack of vestibular input might be compensated by changes in the efficacy of the remaining sensory inputs involved in gaze and posture stabilization. However, the compensation process could also rapidly become independent of these external cues, and thus be detectable in vitro in preparations obtained from lesioned animals. In agreement with this hypothesis, we have shown recently that prominent traces of the compensation process appeared three days after the lesion on in vitro isolated brains taken from labyrinthectomized guinea-pigs, where the connectivity of the central vestibular-related networks is preserved. We report here that, one week after the lesion, a slight increase in the intrinsic, spontaneous activity of the deafferented, central vestibular neurons was found in brainstem slices. This increase became stronger in slices taken after one month of compensation, and was associated at this stage with a significant decrease in the intrinsic activity of the vestibular neurons on the contralesional side. Vestibular compensation could thus follow a "top-down" strategy: it would first rely on the external cues given by the intact sensory systems, then on an internal reorganization of the vestibular-related networks, and finally on changes in the intrinsic properties of the vestibular neurons themselves. Similar strategies may be used by the mammalian brain to compensate for other types of deafferentations or environmental changes.

Plastic changes underlying vestibular compensation in the guinea-pig persist in isolated, in vitro whole brain preparations.

Vestibular compensation for the postural and oculomotor deficits induced by unilateral labyrinthectomy is a model of post-lesional plasticity in the central nervous system. Just after the removal of one labyrinth, the deafferented, ipsilateral vestibular nucleus neurons are almost silent, and the discharge of the contralateral vestibular nucleus neurons is increased. The associated static disorders disappear in a few days, as normal activity is restored in both vestibular nuclei. In this study, we searched for traces of vestibular compensation in isolated whole brains taken from adult guinea-pigs. The electrophysiological responses evoked in control brains were compared to those evoked in brains taken from animals that had previously been labyrinthectomized. Guinea-pigs compensated for an initial labyrinthectomy within three days. In vivo, subsequent deafferentation of vestibular nucleus neurons on the intact side triggered "Bechterew's phenomenon": a new postural and oculomotor syndrome appeared, similar to the one induced by the first lesion, but directed to the newly deafferented side. These disturbances would be caused by the new imbalance between the discharges of neurons in the two vestibular nuclei triggered by the second deafferentation. Experiments were designed to search for a similar imbalance in vitro in brains taken from labyrinthectomized animals, where the intact vestibular nerve is cut during the dissection. Isolated whole brains were obtained from young guinea-pigs at various times (one to seven days) following an initial labyrinthectomy. An imbalance between the resting activities of medial vestibular nucleus neurons on both sides of the brainstem was revealed in brains taken more than three days after the lesion: their discharge was higher on the compensated, initially lesioned side than on the newly deafferented side. In some cases, an oscillatory pattern of discharge, reminiscent of the spontaneous nystagmus associated in vivo with Bechterew's syndrome, appeared in both abducens nerves. These data demonstrate that most of the changes underlying vestibular compensation persist, and can thus be investigated in the isolated whole brain preparation. Brains removed only one day after the lesion displayed normal commissural responses and symmetric spinal inputs to vestibular nucleus neurons. However, an unusually large proportion of the neurons recorded on both sides of the preparation had very irregular spontaneous discharge rates. These data suggest that the first stages of vestibular compensation might be associated with transient changes in the membrane properties of vestibular nucleus neurons. Brains taken from compensated animals displayed a significant, bilateral decrease of the inhibitory commissural responses evoked in the medial vestibular nucleus by single-shock stimulation of the contralateral vestibular nerve. The sensitivity of abducens motoneurons on the initially lesioned, compensated side to synaptic activation from the contralesional vestibular nucleus neurons was also decreased. Both changes may explain the long-term, bilateral decrease of vestibular-related reflexes observed following unilateral labyrinthectomy. Spinal inputs to vestibular nucleus neurons became progressively asymmetric: their efficacy was increased on the lesioned side and decreased on the intact one. This last modification may support a functional substitution of the deficient, vestibular-related synergies involved in gaze and posture stabilization by neck-related reflexes.

Vestibular compensation revisited.

Vestibular compensation for the static and dynamic disorders induced by unilateral labyrinthectomy is a good model of plasticity in the central nervous system. After the lesion, the static deficits generally disappear in a few days, whereas recuperation of the dynamic, vestibular-related synergies is much slower and merely partial. The goal of this article is to reexamine some aspects of vestibular compensation in light of several recent findings. In the first part, we show that in vertebrates the organization of the neural networks underlying vestibular reflexes is deeply linked with the skeletal geometry of the animals. Accordingly, we propose that the neuronal mechanisms underlying vestibular compensation might be plane specific. We then deal with several issues related to the exact timing of vestibular compensation in various species. In the second part, we give several examples showing that vestibular compensation can now be studied at the molecular and cellular levels. For instance, we summarize some of our recent data, which indicate that glial cells could be strongly involved in the compensation process.

Central vestibular networks in the guinea-pig: functional characterization in the isolated whole brain in vitro.

The isolated, in vitro whole brain of guinea-pig was used to assess some of the main physiological and pharmacological properties of the vestibulo-ocular pathways in this species. Extracellular and intracellular recordings were obtained from the vestibular, abducens and oculomotor nuclei, as well as from the abducens and oculomotor nerves, while inputs from the vestibular afferents, the visual pathways and the spinal cord were activated. The three main types of medial vestibular nucleus neurons (A, B and B+LTS), previously described on slices, were also identified in the isolated brain. They had similar membrane properties in both preparations. Eighty-five per cent of cells recorded in the vestibular nucleus responded with monosynaptic, excitatory postsynaptic potentials (latency 1.05-1.9 ms) to stimulation of the ipsilateral vestibular nerve, and were thus identified as second-order vestibular neurons. In addition, stimulation of the contralateral vestibular afferents revealed in most cases a disynaptic or trisynaptic, commissural inhibition. Second-order vestibular neurons displayed in the isolated brain a high degree of variability of their spontaneous activity, as in alert guinea-pigs. Type A neurons always exhibited a regular firing, while type B and B+LTS cells could have very irregular patterns of spontaneous discharge. Thus, type A and type B neurons might correspond, respectively, to the tonic and phasic vestibular neurons described in vivo. The regularity of spontaneous discharge was positively correlated with the amplitude of spike after hyperpolarization, and there was a trend for irregular neurons to be excited from ipsilateral vestibular afferents at shorter latencies than regular units. Synaptic activation could trigger subthreshold plateau potentials and low-threshold spikes in some of the second-order vestibular neurons. As a second step, the pharmacology of the synaptic transmission between primary vestibular afferents and second-order neurons was assessed using specific antagonists of the glutamatergic receptors. Both the synaptic field potentials and excitatory postsynaptic potentials elicited in the medial vestibular nucleus by single shock stimulation of the ipsilateral vestibular nerve were largely or, sometimes, totally blocked by 6-cyano-7-nitroquinoxaline-2,3-dione, indicating a dominating role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated glutamatergic transmission. The remaining component of the responses was completely or partially suppressed by DL-2-amino-5-phosphonovaleric acid in 35% of the cases, suggesting a concomitant, moderate involvement of N-methyl-D-asparate receptors. In addition, a synaptic response resistant to both antagonists, but sensitive to a zero Ca2+/high Mg(2+)-containing solution, was often observed. Finally, recordings from abducens and oculomotor complexes confirmed the existence in the guinea-pig of strong bilateral, disynaptic excitatory and inhibitory inputs from vestibular afferents to motoneurons of extraocular muscles, which contribute to generation of the vestibulo-ocular reflex. The functional integrity of vestibular-related pathways in the isolated brain was additionally checked by stimulation of the spinal cord and optic tract. Stimulation of the spinal cord evoked, in addition to antidromic responses in the vestibular nucleus, short-latency synaptic responses in both the vestibular nucleus and abducens motoneurons, suggesting possible recruitment of spinal afferents. Activation of visual pathways at the level of the optic chiasm often induced long latency responses in the various structures under study. These results demonstrate that the in vitro isolated brain can be readily used for detailed, functional studies of the neuronal networks underlying gaze and posture control.

The vestibular system as a model of sensorimotor transformations. A combined in vivo and in vitro approach to study the cellular mechanisms of gaze and posture stabilization in mammals.

To understand the cellular mechanisms underlying behaviours in mammals, the respective contributions of the individual properties characterizing each neuron, as opposed to the properties emerging from the organization of these neurons in functional networks, have to be evaluated. This requires the use, in the same species, of various in vivo and in vitro experimental preparations. The present review is meant to illustrate how such a combined in vivo in vitro approach can be used to investigate the vestibular-related neuronal networks involved in gaze and posture stabilization, together with their plasticity, in the adult guinea-pig. Following first a general introduction on the vestibular system, the second section describes various in vivo experiments aimed at characterizing gaze and posture stabilization in that species. The third and fourth parts of the review deal with the combined in vivo-in vitro investigations undertaken to unravel the physiological and pharmacological properties of vestibulo-ocular and vestibulo-spinal networks, together with their functional implications. In particular, we have tried to use the central vestibular neurons as examples to illustrate how the preparation of isolated whole brain can be used to bridge the gap between the results obtained through in vitro, intracellular recordings on slices and those collected in vivo, in the behaving animal.