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.

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.

Semicircular canal occlusion causes permanent VOR changes.

We measured the guinea pig horizontal vestibulo-ocular reflex (hVOR) to high acceleration impulsive head rotations following a unilateral lateral semicircular canal (LSCC) occlusion. We found a significant hVOR deficit for rotations toward the side of the occluded LSCC and this deficit did not show systematic changes over 3 months. We considered the LSCC nerve was still functional as shown by the normal appearance of the crista of the LSCC ampulla and also electrical stimulation of the LSCC. We conclude that the VOR during angular acceleration in response to high acceleration shows no adaptive plasticity following a unilateral LSCC occlusion.

Electrophysiological evidence for vestibular activation of the guinea pig hippocampus.

Vestibular information modulates hippocampal activity for spatial processing and place cell firing. However, evidence of a purely vestibular stimulus modulating hippocampal activity is confounded as most studies use stimuli containing somatosensory and visual components. In the present study, high-frequency electrical stimulation of specific vestibular sensory regions of the right labyrinth in anaesthetized guinea pigs induced an evoked field potential in the hippocampal formation bilaterally with a latency of about 40 ms following stimulation onset. Field potentials localized in the hippocampal formation occurred with stimulus current parameters that were too small to produce eye movements. This provides direct electrophysiological evidence of vestibular input to the hippocampus.

Testable predictions from realistic neural network simulations of vestibular compensation: integrating the behavioural and physiological data.

Neural network simulations have been used previously in the investigation of the horizontal vestibulo-ocular reflex (HVOR) and vestibular compensation. The simulations involved in the present research were based on known anatomy and physiology of the vestibular pathway. This enabled the straightforward comparison of the network response, both in terms of behavioural (eye movement) and physiological (neural activity) data to empirical data obtained from guinea pig. The network simulations matched the empirical data closely both in terms of the static symptoms (spontaneous nystagmus) of unilateral vestibular deafferentation (UVD) as well as in terms of the dynamic symptoms (decrease in VOR gain). The use of multiple versions of the basic network, trained to simulate individual guinea pigs, highlighted the importance of the particular connections: the vestibular ganglion to the type I medial vestibular nucleus (MVN) cells on the contralesional side. It also indicated the significance of the relative firing rate in type I MVN cells which make excitatory connections with abducens cells as contributors to the variability seen in the level of compensated response following UVD. There was an absence of any difference (both in terms of behavioural and neural response) between labyrinthectomised and neurectomised simulations. The fact that a dynamic VOR gain asymmetry remained following the elimination of the spontaneous nystagmus in the network suggested that the amelioration of both the static and dynamic symptoms of UVD may be mediated by a single network. The networks were trained on high acceleration impulse stimuli but displayed the ability to generalise to low frequency, low acceleration sinusoids and closely approximated the behavioural responses to those stimuli.

High acceleration impulsive rotations reveal severe long-term deficits of the horizontal vestibulo-ocular reflex in the guinea pig.

While there is agreement that unilateral vestibular deafferentation (UVD) invariably produces an immediate severe horizontal vestibulo-ocular reflex (HVOR) deficit, there is disagreement about whether or not this deficit recovers and, if so, whether it recovers fully or only partly. We suspected that this disagreement might mainly be due to experimental factors, such as the species studied, the means chosen to carry out the UVD, or the nature of the test stimulus used. Our aim was to sort out some of these factors. To do this, we studied the HVOR of alert guinea pigs in response to low and high acceleration sinusoidal and high acceleration impulses after UVD by either labyrinthectomy or by vestibular neurectomy. The HVOR in response to high acceleration impulsive yaw rotations was measured before, and at various times after, either unilateral labyrinthectomy or superior vestibular neurectomy. Following UVD, there was a severe impairment of the HVOR for ipsilesional rotations and a slight impairment for contralesional rotations, after either operation. This asymmetrical HVOR deficit in the guinea pig parallels the deficit observed in humans. Between the first measurement, which was made 1 week after UVD, and the last, which was made 3 months after UVD, there was no change in the HVOR. This lack of recovery was the same after labyrinthectomy as after vestibular neurectomy. The HVOR to low and high acceleration sinusoidal yaw rotations were measured after UVD, and the results were compared with those in response to impulsive rotations. For low acceleration sinusoidal rotations (250 degrees/s2), the gain was symmetrical, although reduced bilaterally. As the peak head acceleration increased, the HVOR became increasingly asymmetric. The HVOR asymmetry for sinusoidal rotations was significantly less than for impulsive rotations that had the same high peak head acceleration (2500 degrees/s2). Our results show that the HVOR deficit after UVD is the same in guinea pigs as in humans; that it is the same after vestibular neurectomy as after labyrinthectomy; that it is lasting and severe in response to high acceleration rotations; and, that it is more obvious in response to impulses than to sinusoids.

Melanocortins and lesion-induced plasticity in the CNS: a review.

This review summarises and critically evaluates the literature pertaining to the actions of short fragments of the adrenocorticotropic hormone (ACTH) ("melanocortins') on lesion-induced plasticity in the central nervous system (CNS). The majority of the evidence suggests that melanocortins are more effective in enhancing recovery from lesions of subcortical structures than cortical structures, although there is substantial variability in findings depending upon the specific ACTH fragment used and the way in which it is administered. Five specific melanocortin (MC) receptors have been identified, however, the evidence to date suggests that short ACTH fragments may not enhance lesion-induced plasticity in the CNS via these MC receptor subtypes. It is possible that another, as yet unidentified, MC receptor subtype is involved, or else that some short ACTH fragments act allosterically on another receptor type (e.g., the N-methyl-D-asparate (NMDA) receptor).

Response of guinea pig vestibular nucleus neurons to clicks.

Responses of single neurons in the vestibular nuclei to clicks were studied by extracellular recording in anaesthetised guinea pigs. Eighty-four neurons in the ipsilateral vestibular nuclei were activated with an average latency of 1.75 +/- 0.30 ms, which is about 0.9 ms longer than the mean latency of activation of click-sensitive vestibular afferents to intense clicks. The threshold of clicks for evoking the response of these neurons was around 70 dB above the auditory brainstem response threshold. Earlier studies have indicated that click-sensitive vestibular afferents are tilt-sensitive and likely to originate from saccular receptors, and in the present study nine of the click-sensitive vestibular nucleus neurons were tilt-sensitive, suggesting that these central neurons receive monosynaptic input from the corresponding saccular afferents. Recording sites were marked by means of iontophoretic injection of FCF green dye; they were located in the lateral portion of the descending vestibular nucleus and the caudal and ventral regions of the lateral vestibular nucleus.

The opioid receptor antagonist, naloxone, enhances ocular motor compensation in guinea pig following peripheral vestibular deafferentation.

The opioid receptor antagonist, naloxone, has been demonstrated to enhance recovery from spinal cord injury and fluid percussion brain injury. The present study investigated, for the first time, the effects of naloxone on behavioral recovery following unilateral peripheral vestibular deafferentation (unilateral labyrinthectomy, UL) in guinea pig. An ip injection of 5 mg/kg naloxone 30 min pre-UL and 5 h post-UL was found to significantly reduce the frequency of spontaneous nystagmus relative to the vehicle control group (P < 0.005). However, a lower dose (2.5 mg/kg) had no effect. At either dose, the effects on the postural symptoms, yaw head tilt and roll head tilt, were small by comparison and in most cases nonsignificant. These results suggest that naloxone can reduce the ocular motor effects of UL in a dose-dependent fashion.

Evidence that short ACTH fragments enhance vestibular compensation via direct action on the ipsilateral vestibular nucleus.

The aim of the present study was to determine whether administration of the synthetic ACTH-(4-9) analogue, Org 2766, directly into the ipsilateral vestibular nucleus complex (VNC), would enhance vestibular compensation following unilateral labyrinthectomy (UL). Either artificial cerebrospinal fluid (ACSF; n = 4) or Org 2766 (0.67 nmol kg-1 every 4 h for 52 h; n = 4), was administered directly into the VNC via a stainless steel cannula connected to an osmotic minipump implanted s.c. Three symptoms of UL, spontaneous ocular nystagmus (SN), roll head tilt (RHT) and yaw head tilt (YHT), were measured at 10, 20, 25, 30, 40, 45 and 50 h post-UL. Org 2766 produced a significant decrease in the frequency of SN and accelerated its compensation. Org 2766 had no significant effect on either the compensation of RHT or YHT. This result suggests that vestibular compensation is enhanced by short ACTH fragments as a result of direct action on the ipsilateral VNC itself.

Early diazepam treatment following unilateral labyrinthectomy does not impair vestibular compensation of spontaneous nystagmus in guinea pig.

Diazepam and other benzodiazepines are sometimes used to alleviate vertigo and dizziness following labyrinthine surgery in humans. While the results of some previous studies have suggested that the administration of diazepam and other CNS depressant drugs following unilateral labyrinthectomy (UL) may impair the vestibular compensation process, the available evidence is unclear. The objective of the present experiment was to examine the effects of multiple injections of a high dose of diazepam (that is, 10 mg/kg i.p.) 30 min before and following UL (10 h or 10 and 20 h) on the static symptom, spontaneous ocular nystagmus (SN), in guinea pigs. Although diazepam-treated animals exhibited consistently lower average SN frequency compared to vehicle controls. neither SN frequency nor its rate of compensation were significantly different between the 2 groups. The time to complete SN compensation was also similar for the 2 groups, as estimated from the x intercepts derived from a linear regression analysis. These results suggest that even high doses of diazepam before and following UL do not result in an impairment of compensation of SN in guinea pig.

An in vitro investigation of the effects of the ACTH/MSH(4-9) analogue, Org 2766, on guinea pig medial vestibular nucleus neurons.

Vestibular compensation is a process of CNS plasticity that is correlated to a return of resting activity in medial vestibular nucleus (MVN) neurons ipsilateral to a peripheral vestibular deafferentation. Systemic administration of melanocortin peptides accelerates the compensation process; the ACTH/MSH(4-9) analogue, Org 2766, accelerates this process at smaller doses than ACTH/MSH(4-10). The present study investigated the effect of Org 2766 on MVN neurons in vitro using extracellular single-cell recording. Org 2766 was less potent at the neuronal level than ACTH/MSH(4-10). When Org 2766 and ACTH/MSH (4-10) were tested consecutively on the same neuron, the response was often different. Org 2766 and ACTH/MSH (4-10) may have a different mode and/or site of action.

A dose-response analysis of the beneficial effects of the ACTH-(4-9) analogue, Org 2766, on behavioural recovery following unilateral labyrinthectomy in guinea-pig.

1. After removal of the peripheral vestibular receptors in one inner ear (unilateral labyrinthectomy, UL), oculo-motor and postural symptoms occur but disappear over time in a process of recovery known as vestibular compensation. 2. ACTH-(4-10), a fragment of the adrenocorticotrophic hormone (ACTH) molecule, which is devoid of corticotrophic activity, has been shown to enhance vestibular compensation. The present study investigated the effect of the ACTH-(4-9) analogue, Org 2766, on vestibular compensation in guinea-pig. Org 2766 is reported to be more potent behaviourally than ACTH-(4-10). 3. After UL, Org 2766 was delivered via an osmotic minipump implanted s.c. to 30 animals randomly assigned to one of five conditions: 1, 5, 10, 20 or 40 nmol kg-1 Org 2766, every 4 h for 52 h post-UL. Although infusion was continuous, in the present study the doses are expressed as nmol per 4 h in order to compare the results to a previous study in which animals received a discrete dose of ACTH-(4-10) at the end of each 4 h period. All animals were compared to saline controls (n = 6). 4. Three symptoms of UL, spontaneous ocular nystagmus, roll head tilt and yaw head tilt, were measured every 4 h for 52 h, beginning at 10 h post-UL. 5. Rates of infusion of 1, 5 and 10 nmol kg-1 accelerated spontaneous nystagmus compensation; 20 nmol kg-1 produced a significant decrease in the frequency of spontaneous nystagmus, as well as accelerating its compensation; 40 nmol kg-1 had no significant effect on spontaneous nystagmus compensation. 6. In comparison to the effects of Org 2766 on spontaneous nystagmus compensation, Org 2766 had little effect on the compensation of the postural symptoms, yaw head tilt and roll head tilt. Only 5 and 40 nmol kg-1 produced a significant change in postural compensation, and this was a reduction in the rate of roll head tilt compensation.7. At the optimal infusion rate of 20 nmol kg-1 every 4 h, Org 2766 produced a similar effect on spontaneous nystagmus compensation to that of ACTH-(4-10). However, Org 2766 was effective in accelerating spontaneous nystagmus compensation at much smaller doses per 4 h period than ACTH-(4-10). Org 2766 did not have the same effect on. postural compensation as it had on the compensation of spontaneous nystagmus.

Injections of calmidazolium chloride into the ipsilateral medial vestibular nucleus or fourth ventricle reduce spontaneous ocular nystagmus following unilateral labyrinthectomy in guinea pigs.

The effects of three injections (0.5-4.5 h post-operation) of 1-[bis-(p-chlorophenyl)methyl]-3-[2,4-dichloro-beta-(2,4- dichlorobenzyloxy)phenethyl]-imidazolium chloride (calmidazolium chloride, R24571), into the ipsilateral medial vestibular nucleus or fourth ventricle, on vestibular compensation for unilateral labyrinthectomy was studied in guinea pigs. R24571, a calmodulin antagonist and inhibitor of several Ca(2+)-dependent enzymes, caused a significant reduction in the average frequency of spontaneous ocular nystagmus (spontaneous nystagmus) during the first 53 h following unilateral labyrinthectomy (n = 5), compared with vehicle-injected animals (n = 5). Although a statistical analysis was not performed on the yaw head tilt and roll head tilt data because of the large variability between animals over the 53-h period of compensation, most R24571-treated animals had less yaw head tilt (4/4 animals) and roll head tilt (4/5 animals) at 9-11 h post-labyrinthectomy than the average values for the vehicle groups at that time. The decrease in the frequency of spontaneous nystagmus following R24571 treatment was not associated with general ataxia or sedation. These results are consistent with recent biochemical studies in suggesting that intracellular pathways associated with Ca2+ may be involved in the neuronal mechanisms of vestibular compensation following unilateral labyrinthectomy.

Effects of flunarizine on ocular motor and postural compensation following peripheral vestibular deafferentation in the guinea pig.

The aim of the present study was to determine if the calcium channel antagonist flunarizine would affect the time course of vestibular compensation for unilateral labyrinthectomy (UL) in guinea pigs. Animals received either a single IP injection of flunarizine 1 h pre-UL or a series of IP injections every 6 h for 24 h post-UL, starting at 6 h post-UL. Flunarizine was dissolved in 50-100% DMSO or suspended in 10% Tween-80 and administered at a dose of 10 mg/kg in the pre-UL condition and 10 or 20 mg/kg in the post-UL condition. All injections were 1 ml/kg in volume. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured using video analysis. When dissolved in DMSO and administered 1 h pre-UL, 10 mg/kg flunarizine had a small but significant effect on the rate of RHT compensation; otherwise, flunarizine had no significant effects on SN, YHT, or RHT when dissolved in DMSO. When suspended in Tween-80, 10 mg/kg flunarizine pre-UL resulted in a significant decrease in SN frequency and YHT relative to the control group, although the magnitude of the differences was small. When 20 mg/kg was given post-UL, both SN and YHT showed a small but significant change in the rate of compensation. No significant differences in RHT were observed. These results demonstrate that IP administration of flunarizine at a dose of 10-20 mg/kg IP has little effect on vestibular compensation compared to the effects obtained with low IM doses (0.8 mg/kg) of verapamil given 1 h pre-UL.

Comparison of the effects of ACTH-(4-10) on medial vestibular nucleus neurons in brainstem slices from labyrinthine-intact and compensated guinea pigs.

The effects of adrenocorticotrophic hormone fragment 4-10 (ACTH-(4-10)) on single medial vestibular nucleus (MVN) neurons, in brainstem slices from guinea pigs which had undergone vestibular compensation for a previous ipsilateral surgical unilateral labyrinthectomy, were compared with those on MVN neurons in slices from labyrinthine-intact guinea pigs observed in a previous study. Although the average resting discharge of MVN neurons in slices from compensated animals was significantly higher than that for MVN neurons from labyrinthine-intact animals, the responses of the two groups of MVN neurons to ACTH-(4-10) were very similar. These results suggest that ACTH-(4-10) treatment is unlikely to accelerate behavioral recovery following unilateral labyrinthectomy (vestibular compensation) by acting on a receptor within the MVN for which sensitivity to ACTH-(4-10) changes during the compensation process.

Comparison of the effects of adrenocorticotropic hormone fragment 4-10 (ACTH(4-10)) and [D-Phe7]ACTH(4-10) on the compensation of spontaneous nystagmus in guinea pig.

Following unilateral labyrinthectomy (UL), spontaneous nystagmus (SN) was measured in guinea pigs which received i.m. injections of 100 or 400 µg/kg ACTH(4-10) or 800 µg/kg [D-Phe7]ACTH(4-10), every 4 h for 48 h post-UL. The results were compared to those from a previous study, conducted under identical conditions, in which guinea pigs received similar injections of 200 µg/kg ACTH(4-10) or 0.1 ml/kg saline. ACTH(4-10) significantly accelerated the rate of compensation of SN at 100, 200, and 400 µg/kg doses, although the average effects were larger for the 200 µg/kg condition. [D-Phe7]ACTH(4-10) significantly increased the frequency of SN following UL compared to saline-treated animals; however, it also accelerated the rate of SN compensation. These results indicate that the acceleration of SN compensation in guinea pig by ACTH(4-10) follows an inverted U-shaped dose-response curve and that [D-Phe7]ACTH(4-10) increases the frequency of SN.