Benzodiazepine sensitivity in normal human subjects.

Increasing intravenous doses of diazepam or placebo were administered to ten healthy normal volunteers, and the changes in saccadic eye velocity, self-rated sedation and anxiety, and plasma cortisol and growth hormone concentrations were measured. Diazepam administration (4.4 to 140 micrograms/kg, cumulative dose) resulted in a dose-dependent decrease in saccadic eye velocity and plasma cortisol level as well as a dose-dependent increase in self-rated sedation and plasma growth hormone level. Self-rated anxiety was unaffected in these relatively nonanxious subjects. The diazepam-induced changes in saccadic eye velocity, sedation, and growth hormone and cortisol levels were highly correlated with each other and with increasing plasma diazepam concentration. These results are consistent with a benzodiazepine receptor-mediated action of diazepam. The highly quantifiable and dose-dependent decrease in saccadic eye velocity by benzodiazepines should make this a useful measure of benzodiazepine receptor sensitivity in humans.

Two cases of downbeat nystagmus and oscillopsia associated with carbamazepine.

Downbeat nystagmus is often associated with structural lesions at the craniocervical junction, but has occasionally been reported as a manifestation of metabolic imbalance or drug intoxication. We recorded the eye movements of two patients with reversible downbeat nystagmus related to carbamazepine therapy. The nystagmus of both patients resolved after reduction of the serum carbamazepine levels. Neuroradiologic investigations including magnetic resonance imaging scans in both patients showed no evidence of intracranial abnormality. In patients with downbeat nystagmus who are taking anticonvulsant medications, consideration should be given to reduction in dose before further investigation is undertaken.

Near-evoked nystagmus in spasmus nutans.

Near-evoked nystagmus was evident in two children with spasmus nutans by clinical observation and electro-oculographic recording. In one child the nystagmus appeared to be evoked by fusional convergence and in the other by convergence-accommodation. These cases represent an atypical form of spasmus nutans in which the nystagmus is modulated by centers controlling visuomotor changes with near viewing.

Vertical optokinetic nystagmus and vestibular nystagmus in the monkey: up-down asymmetry and effects of gravity.

Vertical optokinetic nystagmus (OKN) i.e., OKN in the sagittal plane, was asymmetrical in the monkey when it was induced with animals lying on their sides in a 90 degrees roll position. In typical monkeys the slow phase velocity of downward OKN (slow phases up) increased proportionally with stimulus velocity at close to unity gain to about 60 degrees/s and saturated at about 100 degrees/s. Upward OKN (slow phases down) increased with close to unity gain only to about 40 degrees/s and saturated at about 60 degrees/s. The slow phase velocity of upward OKN was usually irregular and its frequency was lower than that of downward or horizontal OKN. Upward and downward optokinetic after-nystagmus (OKAN) were also asymmetrical. Upward OKAN was weak or absent and when present it usually saturated at 10 degrees/s. Downward OKAN was stronger, increasing with a gain of about 0.7 with regard to stimulus velocity to a saturation velocity of about 50-60 degrees/s. This was usually about 10-30 degrees/s less than the saturation velocity of horizontal OKAN. The weak or absent upward OKAN indicates that stored activity related to slow phase eye velocity contributes little to the production of upward OKN. In agreement with this, there was little or no slow rise in slow phase velocity to a steady state level during upward OKN. Instead eye velocity rose to its peak velocity at the onset of stimulation. The lack of stored velocity information is probably largely responsible for the differences in regularity, gain and frequency between upward and downward OKN. Vertical vestibular nystagmus was induced by rotating monkeys in darkness with steps of velocity about a vertical axis, while they were lying on their sides in a 90 degree roll position. The velocities of the initial upward and downward slow phases were approximately equal. Gains of the vertical VOR ranged from about 0.5 to 0.98 for stimuli up to 150 degrees/s. Despite equivalent initial gains for upward and downward nystagmus, the vertical VOR was asymmetrical in that downward nystagmus had a higher frequency and generally lasted longer than upward nystagmus. Time constants of downward nystagmus (slow phases up) were about 15 s on average and were similar to those of horizontal nystagmus. Mean time constants of upward nystagmus (slow phases down) were about 8 s. This is only slightly longer than the average time constant of afferent activity in the semicircular canal nerves induced by steps of velocity.(ABSTRACT TRUNCATED AT 400 WORDS)

The use of clonazepam in the treatment of nystagmus-induced oscillopsia.

The effect of clonazepam was studied in ten patients with nystagmus-induced oscillopsia due to downbeating or other primary position nystagmus. A 1-2-mg single-dose clonazepam test was used to determine whether long-term clonazepam therapy was indicated and to help distinguish between visual loss from underlying retinal or optic nerve disease and visual loss due to the nystagmus itself. With the single-dose clonazepam test, nystagmus was eliminated in 6 of 10 patients in the primary position of gaze and in 7 of 10 patients in downgaze. In all positions of gaze in all patients there was significant reduction in nystagmus intensity and slow phase velocity. Symptoms of oscillopsia were reduced or eliminated in all patients, and 7 of 8 patients with reduced visual acuity had clinical improvement. Guidelines are presented for the use of clonazepam in a single-dose clonazepam test and for long-term therapy.

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

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 degrees/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 degrees/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.

Quantitative analysis of the velocity characteristics of optokinetic nystagmus and optokinetic after-nystagmus.

1. Velocity characteristics of optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN) induced by constant velocity full field rotation were studied in rhesus monkeys. A technique is described for estimating the dominant time constant of slow phase velocity curves and of monotonically changing data. Time constants obtained by this technique were used in formulating a model of the mechanism responsible for producing OKN and OKAN.2. Slow phase velocity of optokinetic nystagmus in response to steps in stimulus velocity was shown to be composed of two components, a rapid rise, followed by a slower rise to a steady-state value. Peak values of OKN slow phase velocity increased linearly with increases in stimulus velocity to 180 degrees /sec. Maximum slow phase eye velocities in the monkey are 2-3 times as great as in humans.3. At the onset of OKAN, slow phase velocity falls by about 10-20%, followed by a slower decline to zero. Peak OKAN slow phase velocities were linearly related to optokinetic stimulus velocities up to 90-120 degrees /sec. Above 120 degrees /sec OKAN slow phase velocity saturated although OKN slow phase velocity continued to increase.4. The charge and discharge characteristics of OKAN were studied. The OKAN mechanism charged in 5-10 sec and discharged over 20-60 sec in darkness. The time constants of decay in OKAN slow phase velocity decreased as stimulus velocities increased. They also decreased on repeated testing. In several monkeys there was a consistent difference in the rate of decay of OKAN slow phase velocity to the right and left.5. Extended visual fixation discharged the activity responsible for producing OKAN. Short fixation times caused only a partial discharge of the OKAN mechanism. Following brief periods of fixation, OKAN resumed but with depressed slow phase velocities.6. A model based on a state realisation of a peak detector was formulated which approximately reproduces the salient characteristics of OKN and OKAN. This model predicts the three dominant characteristics of OKAN: (1) charge over 5-7 sec, (2) slow discharge in darkness, and (3) rapid discharge with visual fixation. With the addition of direct fast forward pathways, it also correctly predicts the rapid and slow rise in OKN. We postulate that OKAN is produced by a central integrator which is also active during OKN. Presumably this integrator acts to maximize velocities during OKN and to smooth and stabilize ocular following during movement of the visual surround.

Effects of lesions of the nucleus of the optic tract on optokinetic nystagmus and after-nystagmus in the monkey.

1. The nucleus of the optic tract (NOT) and the dorsal terminal nucleus (DTN) of the accessory optic system were lesioned electrolytically or with kainic acid in rhesus monkeys. When lesions involved NOT and DTN, peak velocities of optokinetic nystagmus (OKN) with slow phases toward the side of the lesion were reduced, and optokinetic after-nystagmus (OKAN) was reduced or abolished. The jump in slow phase eye velocity at the onset of OKN was smaller in most animals, but was not lost. Initially, there was spontaneous nystagmus with contralateral slow phases. OKN and OKAN with contralateral slow phases were unaffected. 2. Damage to adjacent regions had no effect on OKN or OKAN with two exceptions: 1. A vascular lesion in the MRF, medial to NOT and adjacent to the central gray matter, caused a transient loss of the initial jump in OKN. The slow rise in slow phase velocity was prolonged, but the gain of OKAN was unaffected. There was no effect after a kainic acid lesion in this region in another animal. 2. Lesions of the fiber tract in the pulvinar that inputs to the brachium of the superior colliculus caused a transient reduction in the buildup and peak velocity of OKN and OKAN. 3. In terms of a previous model (Cohen et al. 1977; Waespe et al. 1983), the findings suggest that the indirect pathway that activates the velocity storage integrator in the vestibular system to produce the slow rise in ipsilateral OKN and OKAN, lies in NOT and DTN. Activity for the rapid rise in OKN, carried in the direct pathway, is probably transmitted to the pontine nuclei and flocculus via an anatomically separate fiber pathway that lies in the MRF. A fiber tract in the pulvinar that inputs to the brachium of the superior colliculus appears to carry activity related to retinal slip from the visual cortex to NOT and DTN.

Horizontal saccades induced by stimulation of the central mesencephalic reticular formation.

The central mesencephalic reticular formation (cMRF) was electrically stimulated in the alert monkey. Saccadic eye movements were induced to the contralateral side in the horizontal plane at latencies of 18-35 ms. Smooth or slow eye deviations were not produced by cMRF stimulation. If the stimulus was given during slow phases of nystagmus, rapid eye movements were elicited, and the velocity of the slow phases was not affected. The function of cMRF neurons and/or of pathways that lie within it appear primarily related to generation of rapid eye movements in the horizontal plane. The amplitude of induced saccadic eye movements depended solely on the region of cMRF that was activated. When the stimulation frequency was lower, the latency was longer, but the size and characteristics of the induced movement were the same. The product of latency and stimulus frequency was approximately constant, suggesting that saccades had been triggered after a fixed number of pulses had been given. Stimulation of cMRF at frequencies that were too low to elicit rapid eye movements had a tonic effect on saccade generation. When the animal was having optokinetic nystagmus (OKN), stimulation modulated beat frequency according to the direction of the nystagmus: contralateral quick phases were facilitated and ipsilateral quick phases were suppressed. The frequencies of stimulation necessary to suppress ipsilateral quick phases increased as slow phase eye velocity increased. This demonstrates that both cMRF activity and slow phase velocity affect quick phase triggering. When the cMRF on both sides were simultaneously stimulated, the eyes were fixed in place, and no further rapid movements occurred until the stimulus had ended. Thus, activity in pathways and/or cells in cMRF is not only able to trigger saccades, but can also change the excitability of saccade generating mechanisms and promote fixation by suppressing eye movements. Two types of rapid eye movements were elicited from cMRF. From dorsal portions of cMRF saccades were induced whose size was relatively constant and not dependent on the initial position of the eyes in the orbit. The size of saccades increased from small to large as the stimulating electrode was advanced through cMRF from dorsal to ventral. This suggests that the tecto-bulbo-spinal efferents coursing through cMRF and/or cMRF neurons related to this input, are organized in a topographic fashion, with cells and fibers related to eye movements of increasing size being layered one beneath another.(ABSTRACT TRUNCATED AT 400 WORDS)