Acoustic trauma that can cause tinnitus impairs impulsive control but not performance accuracy in the 5-choice serial reaction time task in rats.

Although tinnitus is an auditory disorder, it is often associated with attentional and emotional problems. Functional neuroimaging studies in humans have revealed that the hippocampus, amygdala and anterior cingulate, areas of the brain involved in emotion, attention and spatial processing, are also involved in auditory memory and tinnitus perception. However, few studies of tinnitus-evoked emotional and cognitive changes have been reported using animal models of tinnitus. In the present study, we investigated whether acoustic trauma that could cause tinnitus would affect attention and impulsivity in rats. Eight male Wistar rats were exposed to unilateral acoustic trauma (110 dB, 16 kHz for 1 h under anaesthesia) and eight rats underwent the same anaesthesia without acoustic trauma. Tinnitus was tested in noise-exposed rats using a frequency-specific shift in a discrimination function with a conditioned lick suppression paradigm. At 4 months after the noise exposure, the rats were tested in a 5-choice serial reaction time task. The behavioural procedure involved training the rats to discriminate a brief visual stimulus presented randomly in one of the five spatial locations and responding by poking its nose through the illuminated hole and collecting a food pellet from the magazine. While all of the animals performed equally well in making correct responses, the animals exposed to acoustic trauma made significantly more premature responses. The results suggest that rats exposed to acoustic trauma and some of which have chronic tinnitus are impaired in impulsive control, but not performance accuracy.

Role of vestibular input in triggering and modulating postural responses in unilateral and bilateral vestibular loss patients.

The aim of this study was to determine whether the greater medial-lateral (ML) instability observed in patients with compensated unilateral vestibular loss (UVL), tested on a seesaw platform with eyes closed, is task-dependent. UVL patients, categorized into three groups according to time since lesion (1 week, 1 month and 1 year), bilateral vestibular loss patients and age-matched healthy control subjects were tested in three dynamic postural tasks. These tasks involved different supports - a seesaw platform (Satel), a platform generating horizontal linear translations (Synapsys) and foam rubber placed on a static platform - each requiring different somatosensory cues to maintain equilibrium. Displacements of the subjects' center of pressure in both the anterior-posterior (AP) and ML directions were recorded by strain gauges within the platforms. Only tests performed with eyes closed were analyzed. Bilateral vestibular loss patients fell during foam and seesaw trials but not on the platform generating translations. We previously reported that UVL patients had greater postural oscillations on the seesaw platform in the ML compared to AP direction. In this study, we show similar ML/AP differences in patient performance on foam when standing with 'feet close together'. In contrast, these differences were not found when patients were tested on linear translation or on foam standing with feet apart. In conclusion, the postural performance of patients with vestibular loss depends on the exact task used to measure postural stability. UVL patients are less stable when subjected to movement in the ML direction because of the biomechanical constraints of the tasks and/or the availability of proprioceptive information.

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.

[Skull vibration induced nystagmus test]. / Le test vibratoire osseux vestibulaire.

OBJECTIVES: To establish during a consensus meeting the fundamental basis, the validity criteria, the main indications and results of the skull vibration induced nystagmus test (SVINT) which explores the vestibule high frequencies. MATERIAL AND METHODS: The SVINT is applied on the mastoid process (right and left sides) at 100 Hz during 10 seconds on a sitting upright subject. Total unilateral peripheral lesions (tUVL: operated vestibular shwannomas, vestibular neurectomies) and partial unilateral peripheral lesions (pUVL: preoperative neuromas, Meniere's disease, vestibular neuritis, chemical labyrinthectomies) were studied. Thirty-six patients had brainstem lesions and 173 normal subjects were used as controls. RESULTS: The SVINT is considered positive when the application of the vibrator produces a reproducible sustained nystagmus always beating in the same direction following several trials in various stimulation topographies (on the right and left mastoid). The skull vibratory nystagmus (SVN) begins and ends with the stimulation; the direction of the nystagmus has no secondary reversal. The slow phase velocity (SPV) is>2 degrees /second. In tUVL the SVINT always reveals a lesional nystagmus beating toward the safe side at all frequencies. The mean SVN SPV is 10.8 degrees /s+/-7.5 SD (N=45). The mastoid site was more efficient than the cervical or vertex sites. Mastoïd stimulation efficiency is not correlated with the side of stimulation. The SVN SPV is correlated with the total caloric efficiency on the healthy ear. In pUVL the SVINT is positive in 71 to 76% of cases; the mean SVN. SPV (6.7 degrees /s+/-4.7 SD)(N=30) is significantly lower than in tUVL (P=0.0004). SVINT is positive in 6 to 10% of the normal population, 31% of brain stem lesions and negative in total bilateral vestibular peripheral lesions. CONCLUSIONS: SVINT is an effective, rapid and non invasive test used to detect vestibular asymmetry between 20 to 150 Hz stimulation. This test used in important cohorts of patients during the ten last years has demonstrated no observable adverse effect. SVINT complements other tests which evaluate lower frequencies (caloric test: 0,003 Hz) and the medium frequencies (Head-Shaking-Test (HST): 2 Hz; the head impulse test (HIT): 6 Hz). SVINT is useful in the diagnosis of labyrinthine hydrops or detection of acoustic neuromas. It is useful when the caloric test can not be practised because of middle ear problems. SVINT has its limits: in pUVL, the nystagmus direction is not always specific of the pathologic side and can change with the stimulus frequency. This test does not precisely point out the level of the lesion on the vestibular pathway.

Modulation of inhibitory and excitatory synaptic transmission in rat inferior colliculus after unilateral cochleectomy: an in situ and immunofluorescence study.

We investigated whether inhibitory synaptic transmission mediated through glycinergic receptor, GABAA receptors, glutamic acid decarboxylase, the enzyme synthesizing GABA, and excitatory synaptic transmission through alpha-amino-3-hydroxi-5-methylisoxazole-4-propionic acid receptors and N-methyl-D-aspartate receptors are affected in the inferior colliculus by unilateral surgical cochleectomy. In situ hybridization and immunohistofluorescence studies were performed in normal and lesioned adult rats at various times following the lesion (1-150 days). Unilateral auditory deprivation decreased glycine receptor alpha1 and glutamic acid decarboxylase 67 expression in the contralateral central nucleus of the inferior colliculus. This decrease began one day after cochleectomy, and continued until day 8; thereafter expression was consistently low until day 150. The glycine receptor alpha1 subunit decrease did not occur if a second contralateral cochleectomy was performed either on day 8 or 150 after the first cochleectomy. Bilateral cochleectomy caused also a bilateral inferior colliculus diminution of glutamic acid decarboxylase 67 mRNA at post-lesion day 8 but there were no changes in glycine receptor alpha1 compared with controls. In contrast, the abundance of other alpha2-3, and beta glycine receptor, gephyrin, the anchoring protein of glycine receptor, the alpha1, beta2 and gamma2 subunits of GABAA receptors, GluR2, R3 subunits of alpha-amino-3-hydroxi-5-methylisoxazole-4-propionic acid receptors, and NR1 and NR2A transcripts of N-methyl-D-aspartate receptors was unaffected during the first week following the lesion. Thus, unilateral cochlear removal resulted in a selective and long-term decrease in the amount of the glycine receptor alpha1 subunit and of glutamic acid decarboxylase 67 in the contralateral central nucleus of the inferior colliculus. These changes most probably result from the induced asymmetry of excitatory auditory inputs into the central nucleus of the inferior colliculus and may be one of the mechanisms involved in the tinnitus frequently encountered in patients suffering from a sudden hearing loss.

Modulation of the glutamatergic receptors (AMPA and NMDA) and of glutamate vesicular transporter 2 in the rat facial nucleus after axotomy.

Facial nerve axotomy is a good model for studying neuronal plasticity and regeneration in the peripheral nervous system. We investigated in the rat the effect of axotomy on the different subunits of excitatory glutamatergic AMPA (GLuR1-4), NMDA (NR1, NR2A-D) receptors, post-synaptic density 95, vesicular glutamate transporter 2, beta catenin and cadherin. mRNA levels and/or protein production were analyzed 1, 3, 8, 30 and 60 days after facial nerve axotomy by in situ hybridization and immunohistofluorescence. mRNAs coding for the GLuR2-4, NR1, NR2A, B, D subunits of glutamatergic receptors and for post-synaptic density 95, were less abundant after axotomy. The decrease began as early as 1 or 3 days after axotomy; the mRNAs levels were lowest 8 days post-lesion, and returned to normal or near normal 60 days after the lesion. The NR2C subunit mRNAs were not detected in either lesioned or intact facial nuclei. Immunohistochemistry using specific antibodies against GLuR2-3 subunits and against NR1 confirmed this down-regulation. There was also a large decrease in vesicular glutamate transporter 2 immunostaining in the axotomized facial nuclei at early stages following facial nerve section. In contrast, no decrease of NR2A subunit and of post-synaptic density 95 could be detected at any time following the lesion. beta Catenin and cadherin immunoreactivity pattern changed around the cell body of facial motoneuron by day 3 after axotomy, and then, tends to recover at day post-lesion 60 days. Therefore, our results suggest a high correlation between restoration of nerve/muscle synaptic contact, synaptic structure and function in facial nuclei. To investigate the mechanisms involved in the change of expression of these proteins following axotomy, the facial nerve was perfused with tetrodotoxin for 8 days. The blockade of action potential significantly decreased GLuR2-3, NR1and NR2A mRNAs in the ipsilateral facial nuclei. Thus, axotomy-induced changes in mRNA abundance seemed to depend partly on disruption of activity.

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.

The differential response of astrocytes within the vestibular and cochlear nuclei following unilateral labyrinthectomy or vestibular afferent activity blockade by transtympanic tetrodotoxin injection in the rat.

In this study, we investigated whether changes in the vestibular neuronal activity per se influence the pattern of astrocytes morphology, glial fibrillary acidic protein (GFAP) expression and ultimately their activation within the vestibular nuclei after unilateral transtympanic tetrodotoxin (TTX) injections and after unilateral inner ear lesion. The rationale was that, theoretically the noninvasive pharmacological functional blockade of peripheral vestibular inputs with TTX, allowed us to dissociate the signals exclusively related to the shutdown of the resting activity of the first-order vestibular neurons and from neuronal signals associated with trans-ganglionic changes in first order vestibular neurons induced by unilateral labyrinthectomy (UL). Since the cochlea was removed during the surgical procedure, we also studied the astrocytic reaction within the deafferented cochlear nuclei. No significant changes in the distribution or relative levels of GFAP mRNA expression, relative levels of GFAP protein or immunoreactivity for GFAP were found in the ipsilateral vestibular nuclei at any post-TTX injection times studied. In addition, no sign of microglia activation was observed. In contrast, a robust increase of the distribution and relative levels of GFAP mRNA expression, protein levels and immunoreactivity was observed in the deafferented vestibular and cochlear nuclei beginning at 1 day after inner ear lesion. GFAP mRNA expression and immunoreactivity in the cochlear nucleus was qualitatively stronger than in the ipsilateral vestibular nuclei. The results suggest that astrocyte activation in the vestibular nuclei is not related to drastic changes of vestibular nuclei neuronal activity per se. Early trans-ganglionic changes due to vestibular nerve dendrites lesion provoked by the mechanical destruction of vestibular receptors, most probably induced the glial reaction. Its functional role in the vestibular compensation process remains to be elucidated.

Modulation of the beta1-3 voltage-gated sodium channels in rat vestibular and facial nuclei after unilateral labyrinthectomy and facial nerve section: an in situ hybridization study.

We investigated whether the production of the mRNAs for the auxiliary beta subunits of the Na channels are modulated in deafferented medial vestibular nucleus (MVN) and in axotomized facial motoneurons. No beta1-3 mRNAs modulation was detected at any time following unilateral labyrinthectomy in the deafferented and intact medial vestibular nucleus. In contrast, beta1 gene expression in the axotomized facial nucleus decreased compared to controls as soon as day post-lesion 3.

Modulation of the voltage-gated sodium- and calcium-dependent potassium channels in rat vestibular and facial nuclei after unilateral labyrinthectomy and facial nerve transsection: an in situ hybridization study.

We investigated whether the expression in the vestibular and facial nuclei of the voltage-dependent Na alpha I and Na alpha III channels and of the Ca(2+)-activated K(+)-channel subunits, small-conductance (SK) 1, SK2 and SK3, is affected by unilateral inner-ear lesion including both labyrinthectomy and transsection of the facial nerve. Specific sodium (Na alpha I, Na alpha III) and potassium (SK1, SK2, SK3) radioactive oligonucleotides were used to probe sections of rat vestibular and facial nuclei by in situ hybridization methods. The signal was detected with films or by emulsion photography. Animals were killed at various times following the lesion: 1 day, 3 days, 8 days or 30 days. In normal adult animals, mRNAs for Na alpha I, and SK1, SK2, and SK3 channels were found in several brainstem regions including the lateral, medial, superior and inferior vestibular nuclei and the facial nuclei. In contrast, there was little Na alpha III subunit mRNA anywhere in the brainstem. Following unilateral inner ear lesion in rats, the medial vestibular nuclei were probed with Na alpha I, Na alpha III, SK1, SK2 and SK3 oligonucleotide probes: autoradiography indicated no difference between the two sides, at any of the times studied. Na alpha I and SK2 mRNAs were less abundant and Na alpha III, SK1 and SK3 mRNAs were more abundant in the axotomized facial nuclei motoneurons than in controls. Removal of vestibular input did not affect the abundance of the mRNAs for the sodium- or calcium-dependent potassium channels in the deafferented vestibular nuclei. There is thus no evidence that modulation of these conductances contributes to the recovery of a normal resting discharge of the deafferented vestibular neurons and consequently to the functional recovery of the postural and oculomotor deficits observed at the acute stage. However, facial axotomy induced a long-term modulation of both Na and SK conductances mRNAs in the facial motoneurons ipsilateral to the lesion. Presumably, retrograde injury factors resulting from axotomy were able to alter durably the membrane properties and thus the excitability of the facial motoneurons.

Intratympanic gentamicin injections for Meniere disease: vestibular hair cell impairment and regeneration.

The authors treated 22 patients with intratympanic gentamicin. Vestibular function was measured using caloric and head impulse tests and vestibular evoked myogenic potentials induced by high amplitude sounds and short duration galvanic currents. Roughly one-third of the patients, after initially losing their caloric responses and displaying refixation saccades to head impulse tests, recovered within 2 years of the lesion. Vertigo did not recur in patients in whom the galvanic response was abolished.

GluR2-R4 AMPA subunit study in rat vestibular nuclei after unilateral labyrinthectomy: an in situ and immunohistochemical study.

In the present investigation, we address the question of whether the expression of GluR2-R4 subunits mRNAs and GluR2 and GluR4 subunits protein of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-selective glutamate receptors are modulated in the vestibular nuclei following unilateral labyrinthectomy. Specific GluR2-R4 radioactive oligonucleotides were used to probe sections of rat vestibular nuclei according to in situ hybridization methods. The signal was detected by means of film or emulsion photography. GluR2 and GluR4 subunit expression were also measured in control and operated rats by use of specific monoclonal GluR2 and GluR4 antibodies. Animals were killed at different stages following the lesion: 1, 3 or 8 days for the in situ hybridization study and 4 and 8 days for the immunohistochemical study. In normal animals, several brainstem regions including the lateral, medial, superior and inferior vestibular nuclei expressed all the GluR2, GluR3 and GluR4 subunit mRNAs. Moreover, numerous vestibular nuclei neurons are endowed with AMPA receptors containing the GluR2 and the GluR4 subunits. In unilaterally labyrinthectomized rats, no asymmetry could be detected on autoradiographs between the two medial vestibular nuclei probed with the GluR2 and the GluR4 oligonucleotide probes regardless of the delay following the lesion. However, compared to control, a bilateral decrease (-22%) in GluR3 gene expression was observed in the medial vestibular nuclei 3 days after the lesion followed by a return to normal at day 8 post-lesion. No significant asymmetrical changes in the density of GluR2- and GluR4-immunopositive cells could be detected between the intact and deafferented sides in any part of the vestibular nuclear complex and at any times (day 4 or day 8) following the lesion. Our data show that the removal of glutamatergic vestibular input induced an absence of modulation of GluR2 and GluR4 gene and subunits expression. This demonstrates that GluR2 and GluR4 expression do not play a role in the recovery of the resting discharge of the deafferented medial vestibular nuclei neurons and consequently in the functional restoration of the static postural and oculomotor deficits. The functional role of the slight and bilateral GluR3 mRNA decrease in the vestibular nuclei remains to be elucidated.

Cochlear electrical stimulation: influence of age of implantation on Fos immunocytochemical reactions in inferior colliculi and dorsal cochlear nuclei of the rat.

The influence of age at the time of implantation of a stimulating electrode unilaterally in the inner ear on central auditory pathways was investigated in rats deafened shortly after birth. Immunoreactivity for Fos served as a functional marker of neuronal activity. Electrodes were implanted in the left cochlea of rats aged 3 weeks or 4 months. Stimulation lasted 45 minutes, then rats were sacrificed and tissues processed for immunocytochemistry. The younger animals showed significantly more neurons with Fos immunoreactivity bilaterally in the dorsal cochlear nuclei (DCN) and inferior colliculi (IC) than the older rats or control animals with normal hearing receiving the same stimulation. Activity was more prominent in the left DCN and right IC. The results show that electrical stimulation of the inner ear is more effective in younger animals in eliciting gene expression associated with development of a functional network in the auditory pathways. This suggests that deaf children should be provided with cochlear implants as early as possible.

Calcium-dependent interleukin-8 gene expression in T84 human colonic epithelial cells.

OBJECTIVE AND DESIGN: IL-8 is a chemokine that activates and recruits neutrophils and plays a major role in intestinal inflammation. Signal transduction pathways mediated by protein kinases are central in regulating IL-8 gene expression, however, little is known about the role of Ca2+ in this event. In this study, we characterize the effect of intracellular Ca2+ on interleukin-8 gene expression in T84 human colonic epithelial cells. MATERIALS AND METHODS: Cells were stimulated with Ca2+ ionophore, A23187 or thapsigargin, a Ca2+-ATPase inhibitor. Semi-quantitative RT-PCR was used to examine IL-8 mRNA and ELISA for protein quantification. Reporter gene techniques were used to determine transcription rate. RESULTS: A23187 and thapsigargin caused a dose- and time-dependent accumulation of IL-8 mRNA and protein production which was dependent on the release of Ca2+ from intracellular stores. FK506, a specific inhibitor of calcineurin, inhibited A23187- and thapsigargin-induced IL-8 mRNA expression in a dose dependent manner. Reporter gene studies and actinomycin D chase experiments showed that A23187 and thapsigargin enhanced IL-8 gene transcription and stabilized IL-8 mRNA transcripts, respectively. CONCLUSION: Intracellular Ca2+ plays an important role in regulating IL-8 transcriptionally and posttranscriptionally through calcium/calmodulin-dependent calcineurin.

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.

Abnormal vestibular control of gaze and posture in a strain of a waltzing rat.

The waltzing behavior is usually attributed to vestibular dysfunction. However, the vestibular control of gaze and posture has not yet been measured quantitatively in any waltzing mutant. Therefore, this study was aimed at investigating the relationship between inner-ear morphology, the circling behavior, and the vestibular control of gaze and posture in a new strain of waltzing rats. Light- and electron-microscopy studies of these mutants did not reveal any structural abnormalities of the vestibular neural epithelia. In addition, the expression of Calretinin and 200-kD phosphorylated and non-phosphorylated neurofilaments was also found to be normal in the vestibular neural epithelia and ganglion cells. In contrast, the mutants showed severe dysfunctions of the vestibular control of gaze and posture. The skeletal geometry of the alert unrestrained animals was studied using cineradiography. At rest, waltzing rats held their heads tilted down: the horizontal semicircular-canal's plane was near the earth-horizontal's plane, instead of being tilted up as in Long Evans control rats. In addition, their cervical column was pitched more forward (33.6 degrees) than in the control group (6.9 degrees). The circling behavior was observed frequently, and the rats had episodes of circling in both directions. The episodes of circling amounted to an average of 17 turns, and the average angular velocity of the circling was 645 degrees/s. Unilateral labyrinthectomy induced the same postural and oculomotor syndromes in the waltzing and control groups. This indicates that the mutant vestibular nerve had a significant resting discharge before the lesion. Eye movements were recorded using acutely implanted search coils. Although waltzing rats were able to perform normal spontaneous eye movements, they showed a complete deficit of the horizontal vestibulo-ocular reflex (HVOR) and an impairment of the maculo-ocular reflex (MOR) during constant velocity, off-vertical axis rotation (OVAR). These results show, for the first time, that deficient transduction and/or processing of the horizontal-canal- and macular-related information can be causally related to the circling behavior and abnormal posture, respectively.

Vestibular projections in the human cortex.

There is considerable evidence from studies on cats and monkeys that several cortical areas such as area 2v at the tip of the intraparietal sulcus, area 3av in the sulcus centralis, the parietoinsular vestibular cortex adjacent to the posterior insula (PIVC) and area 7 in the inferior parietal lobule are involved in the processing of vestibular information. Microelectrode recordings from these areas have shown that: (1) most of these cortical neurons are connected trisynaptically to the labyrinthine endorgans and (2) they receive converging vestibular, visual and somatosensory inputs. These data suggest that a multimodal cortical system is involved in postural and gaze control. In humans, recent positron emission tomography (PET) scans and functional magnetic resonance imaging (fMRI) studies have largely confirmed these data. However, because of the limited temporal resolution of these two methods, the minimum time of arrival of labyrinthine inputs from the vestibular hair cells to these cortical areas has not yet been determined. In this study, we used the evoked potential method to attempt to answer this question. Due to its excellent temporal resolution, this method is ideal for the investigation of the tri- or polysynaptic nature of the vestibulocortical pathways. Eleven volunteer patients, who underwent a vestibular neurectomy due to intractable Meniere's disease (MD) or acoustic neurinoma resection, were included in this experiment. Patients were anesthetized and the vestibular nerve was electrically stimulated. The evoked potentials were recorded by 30 subcutaneous active electrodes located on the scalp. The brain electrical source imaging (BESA) program (version 2.0, 1995) was used to calculate dipole sources. The latency period for the activation of five distinct cortical zones, including the prefrontal and/or the frontal lobe, the ipsilateral temporoparietal cortex, the anterior portion of the supplementary motor area (SMA) and the contralateral parietal cortex, was 6 ms. The short latency period recorded for each of these areas indicates that several trisynaptic pathways, passing through the vestibular nuclei and the thalamic neurons, link the primary vestibular afferents to the cortex. We suggest that all these areas, including the prefrontal area, process egomotion information and may be involved in planning motor synergies to counteract loss of equilibrium.