Reversible and controlled peripheral vestibular loss by continuous infusion of ropivacaine (Narop) into the round window niche of rats

This paper describes a method for achieving a peripheral vestibular blockade in rats by instillation of local anaesthetics over the round window membrane through a permanently implanted cannula. Being rapidly reversible, the effect of the anaesthetic drug is easily controlled by a single continuous infusion, which can be repeated at any time. The method offers a unique opportunity to study the consequence of single or repeated transient vestibular loss without any use of general anaesthetics, which may be a severe confounding factor. Such studies might shed light on balance disorders related to permanent vestibular loss or episodic vestibular dysfunction. To evaluate the method, spontaneous horizontal eye movements were recorded during the first 4 h of continuous infusion. Unilateral infusion of ropivacaine gave rise to a high-frequency spontaneous nystagmus, reaching levels that have not been documented after a surgical labyrinthectomy under general anaesthesia. This vestibulo-oculomotor behaviour is consistent with a previous report using a single intratympanic instillation of lidocaine to achieve a short-lasting vestibular blockade. In the present study, it was demonstrated that the initial high-frequency nystagmus decreased during the first 100 min of infusion before stabilizing at the same level as recorded when the effect of general anaesthesia has worn off after a surgical ablation. When the transient vestibular blockade was repeated by a second infusion during the following day, the nystagmus frequency saturated on a significantly lower level than during the first blockade. Also, serial single infusions, with recovery between each functional vestibular loss, gave rise to a less severe nystagmus. It is suggested that this phenomenon is an expression of the behavioural concept of 'vestibular habituation', the neural substrate of which is rather unknown.     

Early compensation of vestibulo-oculomotor symptoms after unilateral vestibular loss in rats is related to GABA(B) receptor function

The horizontal vestibulo-oculomotor reflex was studied in pigmented rats during the first 5 days after a unilateral chemical or surgical vestibular deafferentation. Spontaneous eye movements in darkness and slow phase velocity gain of compensatory eye movements during horizontal sinusoidal rotation were evaluated. The most evident vestibulo-oculomotor symptom immediately after a unilateral vestibular loss was a spontaneous nystagmus, which gradually abated during the following days. Further, an asymmetry between ipsi- and contra-lesional gains was evident during sinusoidal vestibular stimulation. Single systemic doses of the GABA(B) receptor antagonist [3-[1-(S)-[[3-(cyclohexylmethyl)-hydroxyphosphinoyl]-2-(S)-hydroxypropyl]amino]ethyl]-benzoic acid (CGP 56433A), the agonist baclofen, or the GABA(A) receptor agonist (4,5,6,7-tetrahydroisoxazolo-[5,4-c]-pyridin-3-ol (THIP) were given at different intervals after unilateral vestibular deafferentation. CGP 56433A highly aggravated the vestibulo-oculomotor symptoms, observed as an increase in spontaneous nystagmus and slow phase velocity gain asymmetry. This effect was most pronounced during the first 2 days after unilateral vestibular loss, when CGP 56433A even decompensated the vestibular system to the extent that all vestibular responses were abolished. Baclofen caused no effect during the first days after unilateral vestibular loss, but in parallel with the abatement of spontaneous nystagmus, the drug equilibrated or even reversed the remaining spontaneous nystagmus with corresponding effects on the slow-phase velocity gain asymmetry. The effects of baclofen were very similar after both chemical and surgical deafferentation. THIP caused a slight depression of all vestibular responses. All single dose effects of the drugs were transient.Altogether these results reveal that endogenous stimulation of GABA(B) receptors in GABA-ergic vestibulo-oculomotor circuits are important for reducing the vestibular asymmetry during the early period after unilateral vestibular deafferentation. A possible role for GABA(B) receptors in the reciprocal inhibitory commissural pathways in the vestibular nuclei is suggested.     

Nystagmus induced by electrical stimulation of the vestibular and prepositus hypoglossi nuclei in the monkey: evidence for site of induction of velocity storage

Summary Electrical stimulation of the vestibular nuclei (VN) and prepositus hypoglossi nuclei (PPH) of alert cynomolgus monkeys evoked nystagmus and eye deviation while they were in darkness. At some sites in VN, nystagmus and after-nystagmus were induced with characteristics suggesting that velocity storage had been excited. We analyzed these responses and compared them to the slow component of optokinetic nystagmus (OKN) and to optokinetic after-nystagmus (OKAN). We then recorded unit activity in VN and determined which types of nystagmus would be evoked from the sites of recording. Nystagmus and eye deviations were also elicited by electrical stimulation of PPH, and we characterized the responses where unit activity was recorded in PPH. Horizontal slow phase velocity of the VN storage responses was contralateral to the side of stimulation. The rising time constants and peak steady-state velocities were similar to those of OKN, and the falling time constants of the after-nystagmus and of OKAN were approximately equal. Both the induced after-nystagmus and OKAN were habituated by stimulation of the VN. When horizontal after-nystagmus was evoked with animals on their sides, it developed yaw and pitch components that tended to shift the vector of the slow phase velocity toward the spatial vertical. Similar cross-coupling occurs for horizontal OKAN or for vestibular post-rotatory nystagmus elicited in tilted positions. Thus, the storage component of nystagmus induced by VN stimulation had the same characteristics as the slow component of OKN and the VOR. Positive stimulus sites for inducing nystagmus with typical storage components were located in rostral portions of VN. They lay in caudal ventral superior vestibular nucleus (SVN), dorsal portions of central medial vestibular nucleus (MVN) caudal to the abducens nuclei and in adjacent lateral vestibular nucleus (LVN). More complex stimulus responses, but with contralateral after-nystagmus, were induced from surrounding regions of ventral MVN and LVN, rostral descending vestibular nucleus and the marginal zone between MVN and PPH. Vestibular-only (VO), vestibular plus saccade (VPS) and tonic vestibular pause (TVP) units were identified by extracellular recording. Stimulation near type I lateral and vertical canalrelated VO units elicited typical storage responses with after-nystagmus in 23 of 29 tracks (79%). Stimulus responses were more complex from the region of neurons with oculomotor-related signals, i.e., TVP or VPS cells, although after-nystagmus was also elicited from these sites. Effects of vestibular nerve and nucleus stimulation were compared. Nerve stimulation evoked nystagmus with both a rapid and slow component and after-nystagmus. There was a more prominent rapid rise in slow phase velocity, higher peak velocities, shorter latencies and a shorter falling time constant from nerve than from nucleus stimulation. This indicates more prominent activation of rapid pathways from nerve stimulation. From a comparison of nerve- and nucleus-induced nystagmus, we infer that there was predominant activation of the network responsible for velocity storage by electrical stimulation at many sites in the VN. Microstimulation at sites in PPH elicited nystagmus with ipsilateral slow phases or ipsilateral eye deviations. Slow phase eye velocity changed rapidly at the onset of nystagmus, and peak eye velocities were about 10–15°/s lower than from VN stimulation. The nystagmus had no slow component, and it was not followed by after-nystagmus. Only burst or burst-tonic neurons were recorded in PPH. Stimulation at sites of recording of these units induced either nystagmus with a rapid component or ipsilateral eye deviation. We conclude that the slow component of optokinetic and vestibular nystagmus, attributable to velocity storage is produced in the VN, not in the PPH. We postulate that VO neurons lying in caudal ventral portions of SVN, dorsal portions of MVN and adjacent LVN are part of the network that generates velocity storage.     

GABAB receptors contribute to vestibular compensation after unilateral labyrinthectomy in pigmented rats

The horizontal vestibulo-ocular reflex was studied in pigmented rats, which had been unilaterally, chemically labyrinthectomised 6-144 days previously. During this partially compensated stage after unilateral labyrinthectomy (UL), both static and dynamic deficits remain. The former was evaluated by recording of spontaneous eye movements in darkness, and the latter by estimating the slow-phase velocity (SPV) gain of compensatory eye movements during horizontal vestibular stimulation. The GABA(B) agonist baclofen caused a reversal of the remaining ipsilesional drift of the eyes in darkness into a nystagmus with a contralesional slow phase. The GABA(B) antagonist CGP 36742 caused a decompensation by exaggerating the remaining ipsilesional eye drift. Further, baclofen equilibrated or reversed the asymmetry between ipsi- and contralesional SPV gains during horizontal sinusoidal rotations at 0.2 Hz and 0.8 Hz. This was achieved by an increase in the ipsilesional gain and a decrease in the contralesional gain. The phase lead during sinusoidal rotation (0.2 Hz) was larger following rotation to the lesioned side than to the intact side in UL rats. This asymmetry was reversed by baclofen. CGP 36742 inhibited the effects of baclofen, while the antagonist per se aggravated SPV gain and phase lead asymmetries in UL rats during vestibular stimulation. Per- and post-rotatory nystagmus induced by velocity step stimulation revealed an imperfect velocity-storage function in UL animals, which was modulated by baclofen. An investigation of the baclofen effect on SPV gain asymmetry during different time intervals after chemical UL showed a completely developed effect on the 6th day. Bilateral flocculectomy did not alter the effects of baclofen on UL animals. It is concluded that physiological stimulation of GABA(B) receptors contributes to minimise the vestibulo-oculomotor asymmetry during the partially compensated period after UL. Administration of an agonist or an antagonist changes the asymmetry towards the ipsi- or contralesional side, possibly by altering the spontaneous neuronal activity in the bilateral medial vestibular nuclei. The results are compatible with a hypothesis, supported by in vitro slice experiments, that the efficacy of GABA(B) receptors is up-regulated on the ipsilesional side and down-regulated on the contralesional side.     

Purkinje cell activity in the primate flocculus during optokinetic stimulation,smooth pursuit eye movements and VOR-suppression

Summary Purkinje cell (PC), activity in the flocculus of trained monkeys was recorded during: 1) Vestibular stimulation in darkness. 2) Suppression of the vestibulo-ocular reflex (VOR-supp) by fixation of a small light spot stationary with respect to the monkey. 3) Visual-vestibular conflict (i.e. the visual surround moves together with the monkey during vestibular stimulation), which leads to attenuation or suppression of vestibular nystagmus. 4) Smooth pursuit eye movements. 5) Optokinetic nystagmus (OKN). 6) Suppression of nystagmus during optokinetic stimulation (OKN-supp) by fixation of a small light spot; whereby stimulus velocity corresponds then to image slip velocity.Results were obtained from PCs, which were activated with VOR-supp during rotation to the ipsilateral side. The same PCs were also modulated during smooth pursuit and visual-vestibular conflict. No tonic modulation during constant velocity OKN occurred with slow-phase nystagmus velocities below 40–60 deg/s. Tonic responses were only seen at higher nystagmus velocities. Transient activity changes appeared at the beginning and end of optokinetic stimulation. PCs were not modulated by image slip velocity during OKN-supp.The results show that in primates the same population of floccular PCs is involved in different mechanisms of visual-vestibular interaction and that smooth pursuit and certain components of OKN slow-phase velocity share the same neural pathway. It is argued that the activity of these neurons can neither be related strictly to gaze, eye or image slip velocity; instead, their activity pattern can be best interpreted by assuming a modulation, which is complementary to that of central vestibular neurons of the vestibular nuclei, in the control of slow eye movements.Supported by Swiss National Foundation for Scientific Research 3.343-2.78, and Deutsche Forschungsgemeinschaft, SFB 200, A2     

Velocity storage in the vestibulo-ocular reflex arc (VOR)

Summary Vestibular and optokinetic nystagmus (OKN) of monkeys were induced by platform and visual surround rotation. Vision prolonged per-rotatory nystagmus and cancelled or reduced post-rotatory nystagmus recorded in darkness. Presumably, activity stored during OKN summed with activity arising in the semicircular canals. The limit of summation was about 120 °/s, the level of saturation of optokinetic after-nystagmus (OKAN). OKN and vestibular nystagmus, induced in the same or in opposite directions diminished or enhanced post-rotatory nystagmus up to 120 °/s. We postulate that a common storage mechanism is used for producing vestibular nystagmus, OKN, and OKAN. Evidence for this is the similar time course of vestibular nystagmus and OKAN and their summation. In addition, stored activity is lost in a similar way by viewing a stationary surround during either OKAN or vestibular nystagmus (fixation suppression).These responses were modelled using direct pathways and a non-ideal integrator coupled to the visual and peripheral vestibular systems. The direct pathways are responsible for rapid changes in eye velocity while the integrator stores activity and mediates slower changes. The integrator stabilizes eye velocity during whole field rotation and extends the time over which the vestibulo-ocular reflex can compensate for head movement.     

Characteristics of eye velocity storage during periods of suppression and reversal of eye velocity in monkeys

Summary An eye velocity storage mechanism has been postulated in the vestibulo-optokinetic system to account for the prolongation of vestibular nystagmus (VN) and the occurrence of optokinetic afternystagmus (OKAN). Presentation of a subject-stationary full-field surround during VN and OKAN (= full-field fixation) rapidly reduces activity related to eye velocity of the storage mechanism. If the subject-stationary full-field surround is presented for short periods during VN or OKAN, nystagmus resumes when the animal is again in darkness, but at a lesser velocity than would be predicted from a control response. This reduction in peak eye velocity after fixation reflects a decrease in activity of the storage mechanism due to full-field fixation. This decrease in activity occurs with a shorter time constant compared to that in control trials, it has been called dumping. We demonstrate that a subject-stationary small target light presented during VN or OKAN (= target fixation) also reduces activity of the storage mechanism with a time constant slightly greater than that for full-field fixation, but still considerably smaller than that in control trials. In 3 monkeys the time constant of discharge was reduced during the post-rotatory period from 20 s in control trials to 4.6 s by fixation of a single target light and to 2.9 s by fixation of a full-field. The time constant of discharge was reduced during OKAN from 13.2 s in control trials to 3.8 s by target fixation and to 2.6 s by full-field fixation. We report a second experimental paradigm with which the dynamics of visual-vestibular interaction involving the eye velocity storage mechanism is analysed by means of transient step responses. In this paradigm eye velocity due to activation of the storage mechanism (OKAN) is forced to reverse by a short exposure to a full-field moving in the opposite direction of the slow phases of nystagmus. Short periods of eye velocity reversal did not reduce activity of the storage mechanism more rapidly than fixation, i.e. suppression of eye velocity alone. Fixation of a full-field or of a single target light during vestibular or optokinetic stimulation reduces peak nystagmus velocity after stimulation when monkeys are in darkness. Suppression of OKN by target fixation during full-field stimulation reduces the initial eye velocity of OKAN to 15–20% compared to the OKAN velocity when OKN is allowed to occur. Fixation during vestibular or optokinetic stimulation obviously inhibits full activation of the eye velocity storage mechanism. The results are discussed in relation to current models of visual-vestibular interaction.Supported by Swiss National Foundation for Scientific Research (no. 3.593-0.84)     

Stabilization of gaze during circular locomotion in darkness. II. Contribution of velocity storage to compensatory eye and head nystagmus in the running monkey.

1. Yaw eye in head (Eh) and head on body velocities (Hb) were measured in two monkeys that ran around the perimeter of a circular platform in darkness. The platform was stationary or could be counterrotated to reduce body velocity in space (Bs) while increasing gait velocity on the platform (Bp). The animals were also rotated while seated in a primate chair at eccentric locations to provide linear and angular accelerations similar to those experienced while running. 2. Both animals had head and eye nystagmus while running in darkness during which slow phase gaze velocity on the body (Gb) partially compensated for body velocity in space (Bs). The eyes, driven by the vestibuloocular reflex (VOR), supplied high-frequency characteristics, bringing Gb up to compensatory levels at the beginning and end of the slow phases. The head provided substantial gaze compensation during the slow phases, probably through the vestibulocollic reflex (VCR). Synchronous eye and head quick phases moved gaze in the direction of running. Head movements occurred consistently only when animals were running. This indicates that active body and limb motion may be essential for inducing the head-eye gaze synergy. 3. Gaze compensation was good when running in both directions in one animal and in one direction in the other animal. The animals had long VOR time constants in these directions. The VOR time constant was short to one side in one animal, and it had poor gaze compensation in this direction. Postlocomotory nystagmus was weaker after running in directions with a long VOR time constant than when the animals were passively rotated in darkness. We infer that velocity storage in the vestibular system had been activated to produce continuous Eh and Hb during running and to counteract postrotatory afterresponses. 4. Continuous compensatory gaze nystagmus was not produced by passive eccentric rotation with the head stabilized or free. This indicates that an aspect of active locomotion, most likely somatosensory feedback, was responsible for activating velocity storage. 5. Nystagmus was compared when an animal ran in darkness and in light. the beat frequency of eye and head nystagmus was lower, and the quick phases were larger in darkness. The duration of head and eye quick phases covaried. Eye quick phases were larger when animals ran in darkness than when they were passively rotated. The maximum velocity and duration of eye quick phases were the same in both conditions. 6. The platform was counterrotated under one monkey in darkness while it ran in the direction of its long vestibular time constant.(ABSTRACT TRUNCATED AT 400 WORDS)     

Nystagmus induced by stimulation of the nucleus of the optic tract in the monkey

Summary 1. The nucleus of the optic tract (NOT) was electrically stimulated in alert rhesus monkeys. In darkness stimulation evoked horizontal nystagmus with ipsilateral slow phases, followed by after-nystagmus in the same direction. The rising time course of the slow phase velocity was similar to the slow rise in optokinetic nystagmus (OKN) and to the charge time of optokinetic after-nystagmus (OKAN). The maximum velocity of the steady state nystagmus was approximately the same as that of OKAN, and the falling time course of the after-nystagmus paralled OKAN. 2. Increases in frequency and duration of stimulation caused the rising and falling time constants of the nystagmus and after-nystagmus to become shorter. Changes in the falling time constant of the after-nystagmus were similar to changes in the time constant of OKAN produced by increases in the velocity or duration of optokinetic stimulation. 3. Stimulus-induced nystagmus was combined with OKN, OKAN and per- and post-rotatory nystagmus. The slow component of OKN as well as OKAN could be prolonged or blocked by stimulation, leaving the rapid component of OKN unaffected. Activity induced by electrical stimulation could also sum with activity arising in the semicircular canals to reduce or abolish post-rotatory nystagmus. 4. Positive stimulus sites for inducing nystagmus were located in the posterolateral pretectum. This included portions of NOT that lie in and around the brachium of the superior colliculus and adjacent regions of the dorsal terminal nucleus (DTN). 5. The data indicate that NOT stimulation had elicited the component of OKN which is responsible for the slow rise in slow phase velocity and for OKAN. The functional implication is that NOT, and possibly DTN, are major sources of visual information related to retinal slip in the animal's yaw plane for semicircular canal-related neurons in the vestibular nuclei. Analyzed in terms of a model of OKN and OKAN (Cohen et al. 1977; Waespe et al. 1983), the indirect pathway, which excites the velocity storage mechanism in the vestibular system to produce the slow component of OKN and OKAN, lies in NOT in the monkey, as it probably also does in cat, rat and rabbit. Pathways carrying activity for the rapid rise in slow phase velocity during OKN or for ocular pursuit appear to lie outside NOT.Supported by NIH grants EY02296, EY04148, EY01867 and PSC-CUNY FRAP award 6-63231     

Role of irregular otolith afferents in the steady-state nystagmus during off-vertical axis rotation.

1. During constant velocity off-vertical axis rotations (OVAR) in the dark a compensatory ocular nystagmus is present throughout rotation despite the lack of a maintained signal from the semicircular canals. Lesion experiments and canal plugging have attributed the steady-state ocular nystagmus during OVAR to inputs from the otolith organs and have demonstrated that it depends on an intact velocity storage mechanism. 2. To test whether irregularly discharging otolith afferents play a crucial role in the generation of the steady-state eye nystagmus during OVAR, we have used anodal (inhibitory) currents bilaterally to selectively and reversibly block irregular vestibular afferent discharge. During delivery of DC anodal currents (100 microA) bilaterally to both ears, the slow phase eye velocity of the steady-state nystagmus during OVAR was reduced or completely abolished. The disruption of the steady-state nystagmus was transient and lasted only during the period of galvanic stimulation. 3. To distinguish a possible effect of ablation of the background discharge rates of irregular vestibular afferents on the velocity storage mechanism from specific contributions of the dynamic responses from irregular otolith afferents to the circuit responsible for the generation of the steady-state nystagmus, bilateral DC anodal galvanic stimulation was applied during optokinetic nystagmus (OKN) and optokinetic afternystagmus (OKAN). No change in OKN and OKAN was observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of the flocculus and paraflocculus in optokinetic nystagmus and visual-vestibular interactions: Effects of lesions

Optokinetic nystagmus (OKN), optokinetic after-nystagmus (OKAN), vestibular nystagmus and visual-vestibular interactions were studied in monkeys after surgical ablation of the flocculus and paraflocculus. After bilateral flocculectomy the initial rapid rise in slow phase eye velocity of horizontal and vertical OKN was severely attenuated, and maximum velocities fell to the preoperative saturation level of OKAN. There is generally little or no upward OKAN in the normal monkey, and upward OKN was lost after bilateral lesions. Unilateral flocculectomy affected the rapid rise in horizontal velocity to both sides. Consistent with the absence of a rapid response to steps of surround velocity, animals were unable to follow acceleration of the visual field with eye accelerations faster than about 3-5 degrees/s2. The slow rise in OKN slow phase velocity to a steady state level was prolonged after operation. However, rates of rise were approximately equal for the same initial retinal slips before and after operation. The similarity in the time course of OKN when adjusted for initial retinal slip, and in the gain, saturation level and time course of OKAN before and after flocculectomy indicates that the lesions had not significantly altered the coupling of the visual system to the velocity storage integrator or its associated time constant. When animals were rotated in a subject-stationary visual surround after flocculectomy, they could not suppress the initial jump in eye velocity at the onset of the step. Despite this, they could readily suppress the subsequent nystagmus. The time constant of decline in the conflict situations was almost as short as in the normal monkey and was in the range of the peripheral vestibular time constant. This suggests that although the animals were unable to suppress rapid changes in eye velocity due to activation of direct vestibulo-oculomotor pathways, they had retained their ability to discharge activity from the velocity storage mechanism. Consistent with this, animals had no difficulty in suppressing OKAN after flocculectomy. Visual-vestibular interactions utilizing the velocity storage mechanism were normal after flocculectomy, as was nystagmus induced by rotation about a vertical axis or about axes tilted from the vertical. Also unaffected were the discharge of nystagmus caused by tilting the head out of the plane of the response and visual suppression of nystagmus induced by off-vertical axis rotation. The flocculus does not appear to play an important role in mediating these responses. The data before and after flocculectomy were simulated by a model which is homeomorphic to that presented previously.(ABSTRACT TRUNCATED AT 400 WORDS)     

Vestibular nerve activity in the alert monkey during vestibular and optokinetic nystagmus

Summary Activity of vestibular nerve fibers and eye movements were recorded in the alert monkey during natural stimulation. The animal was rotated about a vertical axis in the dark with velocity trapezoids (vestibular), or a striped cylinder was rotated around the stationary monkey (optokinetic), or these stimuli were combined.After velocity steps in the dark, neuronal activity declined with a dominant time constant of 5–6 s. The time constant of nystagmus recorded simultaneously was always longer, on average 23 s. Vestibular nerve activity was not influenced by optokinetic patterns or additional visual stimuli during combined visualvestibular stimulation. Thus, in contrast to vestibular nuclei neurons, vestibular nerve activity in the alert monkey is only determined by head acceleration and cannot be related to the nystagmus response or visual stimuli.Supported by a grant from the Swiss National Foundation for Scientific Research 3.343-2.78     

The slow inhibitory postsynaptic potential in rat hippocampal CA1 neurones is blocked by intracellular injection of QX-314

Intracellular recordings were made from CA1 pyramidal neurones in the rat hippocampus slice preparation. The recording electrodes contained potassium acetate (4 M) with or without the quaternary lidocaine derivative, QX-314 (50 mM). Both fast (f) and slow (s) inhibitory postsynaptic potentials (IPSP) were evoked by low-frequency orthodromic stimulation. The s-IPSP was rapidly reduced by QX-314 injection. It decreased along a similar time course to the dV/dt of the action potential (AP). The f-IPSP and excitatory postsynaptic potential were not significantly reduced in size at a time when the s-IPSP was virtually abolished by QX-314. It is concluded that conductance through the K⁺ channels which are coupled to GABA_B receptors is readily blocked by QX-314, while the Cl⁻ channels which are coupled to GABA_A receptors and the cation channels coupled to the glutamate receptors are relatively resistant to the local anaesthetic.     

Conflicting visual-vestibular stimulation and vestibular nucleus activity in alert monkeys

Summary In alert Rhesus monkeys (Macaca mulatta) neuronal activity of vestibular nuclei was recorded during pure vestibular and conflicting visual-vestibular stimulation. Pure vestibular stimulation consisted of rotating the monkey about the vertical axis in complete darkness. During conflicting visual-vestibular stimulation the monkeys were rotated in the light within a vertically striped cylinder mechanically coupled to the turntable. The conflict is that although the monkey is accelerated, there is no relative movement between visual surrounding and the animal. In the conflict situation thresholds of neuronal modulation and of nystagmus were raised compared with those during pure vestibular stimulation. Nystagmus slow-phase velocity could always be dissociated from the neuronal activity, the nystagmus often being totally suppressed whereas the neuronal activity was only attenuated. This suggests a further information processing between vestibular and oculomotor nuclei in the generation of nystagmus.Supported in part by Swiss National Foundation for Scientific Research 3.672-0.77, and Emil Barell-Foundation of Hoffmann-La Roche, Basel, Switzerland     

Lidocaine-induced unilateral internuclear ophthalmoplegia: effects on convergence and conjugate eye movements

1. To characterize the vergence signal carried by the medial longitudinal fasciculus (MLF), it was subjected to reversible blockade by small injections of 10% lidocaine hydrochloride. The effects of these blockades on both conjugate and vergence eye movements were studied. 2. With this procedure, experimentally induced internuclear ophthalmoplegia (INO) and its effects on conjugate eye movements could be studied acutely, without possible contamination from long-term oculomotor adaptation. In the eye contralateral to the MLF blockade, saccadic and horizontal smooth-pursuit eye movements were normal. Horizontal abducting nystagmus, often seen in patients with INO, was not observed in this eye. 3. As previously reported for INO, profound oculomotor deficits were seen in the eye ipsilateral to the MLF blockade. During maximal blockade, adducting saccades and horizontal smooth-pursuit movements in this eye did not cross the midline. Adducting saccades were reduced in amplitude and peak velocity and showed significantly increased durations. Abducting saccades, which were slightly hypometric, displayed a marked postsaccadic centripetal drift. 4. The eye ipsilateral to the blockade displayed a pronounced, upward, slow drift, whereas the eye contralateral to the blockade showed virtually no drift. Furthermore, although vertical saccades to visual targets remained essentially conjugate, the size of the resetting quick phases in each eye was related to the amplitude of the slow phase movement in that eye. Thus the eye on the affected side displayed large quick phases, whereas the eye on the unaffected side showed only slight movements. On occasion, unilateral downbeating nystagmus was seen. This strongly suggests that the vertical saccade generators for the two eyes can act independently. 5. The effect of MLF blockade on the vergence gain of the eye on the affected side was investigated. As a measure of open-loop vergence gain, the relationship of accommodative convergence to accommodation (AC/A) was measured before, during, and after reversible lidocaine block of the MLF. After taking conjugate deficits into account, the net vergence signal to the eye ipsilateral to the injection was found to increase significantly during the reversible blockade. 6. The most parsimonious explanation for this increased vergence signal is suggested by the accompanying single-unit study. This study showed that abducens internuclear neurons, whose axons course in the MLF, provide medial rectus motoneurons with an appropriate horizontal conjugate eye position signal but an inappropriate vergence signal. Ordinarily, this incorrect vergence signal is overcome by another, more potent, v     

Effects of kainic acid lesions of the nucleus reticularis tegmenti pontis on fast and slow phases of vestibulo-ocular and optokinetic reflexes in the pigmented rat

Summary The nucleus reticularis tegmenti pontis (NRTP) and adjacent pontine reticular formation were lesioned chemically using the neurotoxic agent kainic acid, and the effects of these lesions on horizontal ocular optokinetic and vestibular nystagmus were examined. Eye position was measured in the alert, NRTP-lesioned animals with the electromagnetic search coil technique. Optokinetic and vestibular stimuli consisted of steps of rotations or sinusoidal oscillations of a fullfield visual pattern surrounding the animal or of the animal in total darkness, respectively. In a first group of animals, small unilateral NRTP lesions were produced by placing a single kainic acid injection in the area of the left NRTP. In one third of the animals, ipsilateral quick phases of optokinetic and vestibular nystagmus were abolished. In the remaining animals, quick phases were deficient to various degrees or not affected at all. There were no changes in the characteristics of optokinetic step responses to ipsilateral pattern rotations which activate predominantly optokinetic pathways on the side of the brainstem lesion. In animals with ipsiversive quick phase deficits, contralateral pattern rotations elicited tonic eye deviations. In a second group of animals, large uni- or bilateral lesions were produced by injecting kainic acid into three separate rostral, middle and caudal levels of the right NRTP. These animals had uni- or bilateral quick phase deficits during optokinetic and vestibular nystagmus. Optokinetic nystagmus in response to velocity steps of pattern rotation towards the lesion side was strongly reduced in gain even in those animals that had no apparent deficits in the fast contraversive reset phases. In four out of six animals, responses to sinusoidal optokinetic pattern oscillations were reduced in gain and showed increased phase lags compared to controls. Vestibulo-ocular responses to velocity steps of head rotations were of normal gain but reduced in duration (measured from onset of stimulation to reversal of nystagmus). Sinusoidal vestibulo-ocular responses evoked by head oscillations exhibited reduced gain values and strongly increased phase leads in the frequency range below 0.5 Hz. The vestibular time constant was found to be around 4.5 s in animals with NRTP lesions compared to about 7.5 s in control animals. The present results show that large kainic acid lesions of the NRTP (and adjacent area) do not abolish optokinetic eye movements in the rat, in contrast to what has been reported after electrolytic lesions. The data suggest, however, that there is a failure of slow build-up of OKN slow phase velocity as well as a shortening of the vestibular time constant which correlates with the kainic acid lesions extending into rostromedial and caudal parts of the NRTP. The implications of these findings with respect to an involvement of these structures in velocity storage are discussed.Abbreviations CN cochlear nucleus - DpSC decussation, peduncle, superior, cerebellar - ip interpeduncular nucleus - MLF medial longitudinal fasciculus - NOT nucleus of optic tract - NRTPc nucleus reticularis tegmenti pontis, central subdivision - NRTPp nucleus reticularis tegmenti pontis, pericentral subdivision - p pontine nuclei - ph praepositus hypoglossi nucleus - pMC peduncle, middle cerebellar - pSC peduncle, superior cerebellar - Pyr pyramidal tract - Rcs raphe central superior - Rm raphe magnus - rpc reticular nucleus, pontine, caudal - rpo reticular nucleus, pontine, oral - TB trapezoid body - tM trapezoid nucleus, medial - tGd tegmental nucleus of von Gudden, dorsal - tGv tegmental nucleus of von Gudden, ventral - 5 trigeminal tract or trigeminal nerve - 5m mesencephalic trigeminal nucleus - 5mt motor trigeminal nucleus - 6n abducens nucleus - 7 facial nerve Prof. W. Precht died on March 12, 1985     

Eye movements induced by off-vertical axis rotation (OVAR) at small angles of tilt

Summary Off-vertical rotation (OVAR) in darkness induced continuous horizontal nystagmus in humans at small tilts of the rotation axis (5 to 30 degrees). The horizontal slow eye velocity had two components: a mean velocity in the direction opposite to head rotation and a sinusoidal modulation around the mean. Mean velocity generally did not exceed 10 deg/s, and was less than or equal to the maximum velocity of optokinetic after-nystagmus (OKAN). Both the mean and modulation components of horizontal nystagmus increased with tilt angle and rotational velocity. Vertical slow eye velocity was also modulated sinusoidally, generally around zero. The amplitude of the vertical modulation increased with tilt angle, but not with rotational velocity. In addition to modulations in eye velocity, there were also modulations in horizontal and vertical eye positions. These would partially compensate for head position changes in the yaw and pitch planes during each cycle of OVAR. Modulations in vertical eye position were regular, increased with increases in tilt angle and were separated from eye velocity by 90 deg. These results are compatible with the interpretation that, during OVAR, mean slow velocity of horizontal nystagmus is produced by the velocity storage mechanism in the vestibular system. In addition, they indicate that the otolith organs induce compensatory eye position changes with regard to gravity for tilts in the pitch, yaw and probably also the roll planes. Such compensatory changes could be utilized to study the function of the otolith organs. A functional interpretation of these results is that nystagmus attempts to stabilize the image on the retina of one point of the surrounding world. Mean horizontal velocity would then be opposite to the estimate of head rotational velocity provided by the output of the velocity storage mechanism, as charged by an otolithic input during OVAR. In spite of the lack of actual translation, an estimate of head translational velocity could, in this condition, be constructed from the otolithic signal. The modulation in horizontal eye position would then be compensatory for the perceived head translation. Modulation of vertical eye velocity would compensate for actual changes in head orientation with respect to gravity.     

Inhibitory responses of rat basolateral amygdaloid neurons recorded in vitro

The purpose of the present study was to characterize the ionic and pharmacological basis of the actions of synaptically released and exogenously applied GABA in basolateral amygdaloid pyramidal cells in vitro. Stimulation of forebrain afferents to pyramidal neurons in the basolateral amygdala evoked an excitatory postsynaptic potential followed by early and late inhibitory postsynaptic potentials. The early inhibitory postsynaptic potential had a reversal potential near −70 mV, was sensitive to changes in the chloride gradient across the membrane and was blocked by the GABA_A antagonists picrotoxin and bicuculline methiodide but not by the GABA_B antagonists phaclofen or 2-hydroxysaclofen. In contrast, the late inhibitory postsynaptic potential had a reversal potential of approximately −95 mV and was markedly reduced or abolished by GABA_B antagonists.

Pressure application of GABA to the surface of the slice typically elicited a triphasic response in basolateral amygdaloid pyramidal neurons consisting of a short-latency hyperpolarization that preceded or was superimposed on a membrane depolarization followed by a longer latency hyperpolarization. Each of the responses was associated with an increase in membrane conductance. Determinations of the reversal potential, ionic dependency and sensitivity to pharmacological blockade of each component of the GABA-induced response revealed that the initial hyperpolarizing (E_rev approximately −70 mV) and depolarizing (E_rev approximately −55 mV) responses were mediated by a GABA_A-mediated increase in chloride conductance, whereas the late hyperpolarizing response (E_rev approximately −82 mV) to GABA arose from a GABA_B-mediated increase in potassium conductance. Experiments in which GABA was applied at various locations on the cell suggested that the short-latency hyperpolarization resulted from activation of somatic GABA receptors, whereas the depolarizing and late hyperpolarizing responses were generated primarily in the dendrites. In contrast to the complex membrane response profile elicited by GABA, pressure ejection of the GABA_B agonist baclofen produced only membrane hyperpolarizations.

Taken together, these results suggest that inhibitory responses that are recorded in basolateral amygdaloid pyramidal cells are mediated by activation of both GABA_A and GABA_B receptors. Consistent with findings elsewhere in the CNS, the early inhibitory postsynaptic potential and initial hyperpolarization and depolarizing response to local GABA application appear to involve a GABA_A-mediated increase in chloride conductance, whereas the late inhibitory postsynaptic potential and the late hyperpolarizing response to GABA arise from a GABA_B-mediated increase in potassium conductance.     

GABA(A) receptor facilitation of neurokinin release from primary afferent terminals in the rat spinal cord

Our goal was to test the following hypotheses: 1) GABA_A receptors facilitate neurokinin release from primary afferent terminals; 2) they do this by suppressing an inhibitory effect of GABA_B receptors; 3) the activation of these two receptors is controlled by the firing frequency of primary afferents. We evoked neurokinin release by stimulating the dorsal root attached to spinal cord slices, and measured it using neurokinin 1 receptor (NK1R) internalization. Internalization evoked by root stimulation at 1 Hz (but not at 100 Hz) was increased by the GABA_A receptor agonists muscimol (effective concentration of drug for 50% of the increase [EC₅₀] 3 μM) and isoguvacine (EC₅₀ 4.5 μM). Internalization evoked by root stimulation at 100 Hz was inhibited by the GABA_A receptor antagonists bicuculline (effective concentration of drug for 50% of the inhibition [IC₅₀] 2 μM) and picrotoxin (IC₅₀ 243 nM). Internalization evoked by incubating the root with capsaicin (to selectively recruit nociceptive fibers) was increased by isoguvacine and abolished by picrotoxin. Therefore, GABA_A receptors facilitate neurokinin release. Isoguvacine-facilitated neurokinin release was inhibited by picrotoxin, low Cl⁻, low Ca²⁺, Ca²⁺ channel blockers and N-methyl-d-aspartate receptor antagonists. Bumetanide, an inhibitor of the Na⁺-K⁺-2Cl⁻ cotransporter, inhibited isoguvacine-facilitated neurokinin release, but this could be attributed to a direct inhibition of GABA_A receptors. The GABA_B agonist baclofen inhibited NK1R internalization evoked by 100 Hz root stimulation (IC₅₀ 1.5 μM), whereas the GABA_B receptor antagonist (2S)-3-[[(1S)-1-(3,4-dichlorophenyl)ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid (CGP-55845) increased NK1R internalization evoked by 1 Hz root stimulation (EC₅₀ 21 nM). Importantly, baclofen inhibited isoguvacine-facilitated neurokinin release, and CGP-55845 reversed the inhibition of neurokinin release by bicuculline. In conclusion, 1) GABA_B receptors located presynaptically in primary afferent terminals inhibit neurokinin release; 2) GABA_A receptors located in GABAergic interneurons facilitate neurokinin release by suppressing GABA release onto these GABA_B receptors; 3) high frequency firing of C-fibers stimulates neurokinin release by activating GABA_A receptors and inhibiting GABA_B receptors, whereas low frequency firing inhibits neurokinin release by the converse mechanisms.     

Asymmetries of vertical vestibular nystagmus in the cat

Summary In the cat, the asymmetry of vertical nystagmus in response to a rotation around the Yaxis has been characterized by measuring the beat frequency and gain of vestibulo-ocular reflexes in each direction (upward and downward). Sinusoidal variations of head velocity or velocity steps have been applied under three visual conditions (a) in darkness (pure vestibular stimulation); (b) in the light (mixed vestibular and optokinetic stimulation); (c) with a mirror placed in front of the animal; since the mirror image moved with the head, the animal was provided with a stable visual cue (stabilized vision). In all three conditions, beat frequency and gain were greater for downward than for upward nystagmus (the direction refers to that of the quick phase). In darkness, the characteristics of postrotatory nystagmus suggested a greater time constant for downward than for upward vestibulo-ocular reflexes. In the light, both stimuli acted synergistically. In stabilized vision, upward vestibular nystagmus was preferentially suppressed, suggesting an algebraic summation of the effects arising from both kinds of stimuli.This project was supported by CNRS ATP internationale and Greco 17; J. López-Barneo (Sevilla, Spain) received an ETP training grant