Head unrestrained horizontal gaze shifts after unilateral labyrinthectomy in the rhesus monkey

Following the orienting saccade of a combined eye-head gaze shift, normal monkeys exhibit a compensatory eye counterrotation that stabilizes gaze as the head movement continues. This counterrotation, which has a gain (eye velocity/head velocity) of near unity, is a manifestation of the vestibulo-ocular reflex (VOR). Acute unilateral labyrinthectomy (UL) causes severe asymmetry in the VOR during passive head rotations that recovers incompletely over time. The purpose of this investigation was to compare the recovery of the counterrotation gain during horizontal gaze shifts with that of the passive VOR after UL. During the 1st week after UL, counterrotation gains were asymmetric, being lower for head movements towards the lesion but nearly normal for head movements towards the intact side. Whereas this asymmetry in the counterrotation gain resolved within a week after UL, asymmetries in the passive VOR persisted. During the 1st week after UL, behavioral performance was generally poor, with a high incidence of inaccurate gaze shifts and larger latencies. In addition, animals used slower head movements such that peak head amplitude during the eye saccade was significantly lower during the 1st week after UL as compared to control values. Bilateral labyrinthectomy (BL) resulted in larger but symmetric deficits in counterrotation, which, contrary to the passive VOR, exhibited significant recovery over time. It is hypothesized that recovery of counterrotation gain after UL has contributions from multiple sources, including the contralateral intact labyrinth and an efference copy of the head movement. Electronic Publication     

Human eye-head gaze shifts in a distractor task. I. Truncated gaze shifts.

This study examines two current ideas regarding the control of eye-head gaze shifts. The first idea stems from recent studies involving electrical stimulation in the primate superior colliculus that suggest that a residual feedback of gaze displacement persists for approximately 100 ms after completion of a gaze shift. In light of this hypothesis, we examined the accuracy of gaze shifts generated very soon after the end of a preceding gaze shift. Human subjects were presented with a visual or auditory target along with an accompanying stimulus of the other modality. The accompanying stimulus appeared either at the same place as the target or at the diametrically opposite position, in which case it was termed a distractor. Subjects often made an incorrect gaze shift (IGS) in the direction of the distractor, followed by a recorrect gaze shift (RGS) in the direction of the target. We found that RGSs were accurately driven to the target, even when they followed IGSs by <5 ms, regardless of the size of the IGS. The second idea is that a gaze shift cannot be cancelled in midflight. The end point of IGSs frequently fell short of the distractor. The dynamics of these movements, and of the head movement components during the IGSs in particular, suggests that these hypometric IGSs were planned for a much larger excursion but were truncated and superceded by the reversing RGSs. These results emphasize that the gaze shifting system can change the desired goal of a gaze shift in midflight and that the superceding movement is accurate regardless of the metrics or timing of the preceding movement.     

Combined eye-head gaze shifts in the primate. I. Metrics

Gaze (eye-in-space) velocity-duration and velocity-amplitude curves were prepared for head-fixed and head-free gaze shifts in the rhesus monkey with an emphasis on large amplitudes. These plots revealed the presence of two distinct gaze reorientation mechanisms, one used when the gaze shift was small (less than 20 degrees) and the other utilized for large coordinated gaze shifts when the head was free. When head-free and head-fixed saccadic gaze shifts were compared in the same animal, no differences in the metrics were found for amplitudes less than 20 degrees. However, for large gaze shifts where contribution of the head to the change in gaze angle was considerable, head-free saccades were found to exhibit lower peak gaze velocities and greater durations than those recorded with the head-fixed paradigm. In order to differentiate between the eye saccades and combined saccadic eye-head gaze shifts, the latter have been termed gaze saccades. Change in head position and change in eye position were both measured during the actual gaze shift and were plotted against the gaze-shift amplitude to determine whether the head movement contributed significantly to the change in gaze angle. The results indicate that below 20 degrees the gaze shift is accomplished almost exclusively with the eyes and the head moves very little; however, for larger saccades, the head contributes approximately 80% of the total change in gaze angle with the eyes contributing only approximately 20%. Large saccadic eye-head gaze shifts do not exhibit 'bell-shaped' velocity profiles as do smaller head-fixed saccades; instead, gaze accelerates to reach a peak velocity after approximately 30-40 ms. This velocity is then maintained for the duration of the gaze shift. Close scrutiny of the fine structure of the velocity profiles of the eye, head, and gaze channels indicates that during gaze saccades, the eye and head movement motor programs interact to maintain gaze velocity nearly constant, unaffected by changes in head velocity. Previous authors had stated that when velocity-duration plots are obtained for oblique saccades of constant amplitude, the resulting points could be fitted with a hyperbolic function. These results were confirmed for head-free gaze saccades and extended to larger amplitudes. When an oblique saccade is made, the smaller component is stretched in duration to match the duration of the larger component. However, as the gaze shift becomes large (greater than 40 degrees), the relationship becomes more complex.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of long-term testosterone exposure on ovarian function and morphology in the rhesus monkey

This study was aimed at developing a model in the rhesus monkey for the human gynecologic disorder termed the polycystic ovary syndrome (PCOS). The effects of chronic constant androgen exposure upon quantitative ovarian morphology and ovulatory function were examined. Twenty-five normally cycling females, aged 4-12 yr and weighing 3.3-8.2 kg, were enrolled in the study in random fashion. Seventeen animals were implanted subcutaneously (s.c.) with 10 or 25 mg testosterone-filled silastic tubing so as to maintain steady serum levels of testosterone averaging 80 ng/dl (low-dose group, n = 8) and 115 ng/dl (high-dose group, n = 9) for 13-16 months. Eight animals served as controls (sham implants); in these, mean serum testosterone levels averaged 24 ng/dl. No effect of androgen treatment was observed on ovulatory function as gauged by periodic luteal phase progesterone determinations and the presence of a fresh corpus luteum at laparoscopy. Menstrual cycle frequency (number of cycles over number of months of observation) was, however, slightly but significantly (P less than 0.05) reduced in the high-dose (88.9%) vs. the control (96.7%) and low-dose (95.0%) groups. Quantitative morphology, performed by light microscopy on a single ovary obtained from 16 of the 25 animals and read in a blinded fashion, revealed no differences in ovarian weight, capsular width and numbers, size, or proportion of healthy and atretic follicles among the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coupling between horizontal and vertical components of saccadic eye movements during constant amplitude and direction gaze shifts in the rhesus monkey

When the head is free to move, changes in the direction of the line of sight (gaze shifts) can be accomplished using coordinated movements of the eyes and head. During repeated gaze shifts between the same two targets, the amplitudes of the saccadic eye movements and movements of the head vary inversely as a function of the starting positions of the eyes in the orbits. In addition, as head-movement amplitudes and velocities increase, saccade velocities decline. Taken together these observations lead to a reversal in the expected correlation between saccade duration and amplitude: small-amplitude saccades associated with large head movements can have longer durations than larger-amplitude saccades associated with small head movements. The data in this report indicate that this reversal occurs during gaze shifts along the horizontal meridian and also when considering the horizontal component of oblique saccades made when the eyes begin deviated only along the horizontal meridian. Under these conditions, it is possible to determine whether the variability in the duration of the constant amplitude vertical component of oblique saccades is accounted for better by increases in horizontal saccade amplitude or increases in horizontal saccade duration. Results show that vertical saccade duration can be inversely related to horizontal saccade amplitude (or unrelated to it) but that horizontal saccade duration is an excellent predictor of vertical saccade duration. Modifications to existing hypotheses of gaze control are assessed based on these new observations and a mechanism is proposed that can account for these data.     

Head-unrestrained gaze shifts after muscimol injection in the caudal fastigial nucleus of the monkey

The effects of unilateral cFN inactivation on horizontal and vertical gaze shifts generated from a central target toward peripheral ones were tested in two head unrestrained monkeys. After muscimol injection, the eye component was hypermetric during ipsilesional gaze shifts, hypometric during contralesional ones and deviated toward the injected side during vertical gaze shifts. The ipsilesional gaze hypermetria increased with target eccentricity until approximately 24 degrees after which it diminished and became smaller than the hypermetria of the eye component. Contrary to eye saccades, the amplitude and peak velocity of which were enhanced, the amplitude and peak velocity of head movements were reduced during ipsilesional gaze shifts. These changes in head movement were not correlated with those affecting the eye saccades. Head movements were also delayed relative to the onset of eye saccades. The alterations in head movement and the faster eye saccades likely explained the reduced head contribution to the amplitude of ipsilesional gaze shifts. The contralesional gaze hypometria increased with target eccentricity and was associated with uncorrelated reductions in eye and head peak velocities. When compared with control movements of similar amplitude, contralesional eye saccades had lower peak velocity and longer duration. This slowing likely accounted for the increase in head contribution to the amplitude of contralesional gaze shifts. These data suggest different pathways for the fastigial control of eye and head components during gaze shifts. Saccade dysmetria was not compensated by appropriate changes in head contribution, raising the issue of the feedback control of movement accuracy during combined eye-head gaze shifts.     

Horizontal vestibuloocular reflex evoked by high-acceleration rotations in the squirrel monkey. II. Responses after canal plugging.

The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in four squirrel monkeys after unilateral plugging of the three semicircular canals. During the period (1-4 days) that animals were kept in darkness after plugging, the gain during steps of acceleration (3, 000 degrees /s(2), peak velocity = 150 degrees /s) was 0.61 +/- 0.14 (mean +/- SD) for contralesional rotations and 0.33 +/- 0.03 for ipsilesional rotations. Within 18-24 h after animals were returned to light, the VOR gain for contralesional rotations increased to 0. 88 +/- 0.05, whereas there was only a slight increase in the gain for ipsilesional rotations to 0.37 +/- 0.07. A symmetrical increase in the gain measured at the plateau of head velocity was noted after animals were returned to light. The latency of the VOR was 8.2 +/- 0. 4 ms for ipsilesional and 7.1 +/- 0.3 ms for contralesional rotations. The VOR evoked by sinusoidal rotations of 0.5-15 Hz, +/-20 degrees /s had no significant half-cycle asymmetries. The recovery of gain for these responses after plugging was greater at lower than at higher frequencies. Responses to rotations at higher velocities for frequencies >/=4 Hz showed an increase in contralesional half-cycle gain, whereas ipsilesional half-cycle gain was unchanged. A residual response that appeared to be canal and not otolith mediated was noted after plugging of all six semicircular canals. This response increased with frequency to reach a gain of 0.23 +/- 0.03 at 15 Hz, resembling that predicted based on a reduction of the dominant time constant of the canal to 32 ms after plugging. A model incorporating linear and nonlinear pathways was used to simulate the data. The coefficients of this model were determined from data in animals with intact vestibular function. Selective increases in the gain for the linear and nonlinear pathways predicted the changes in recovery observed after canal plugging. An increase in gain of the linear pathway accounted for the recovery in VOR gain for both responses at the velocity plateau of the steps of acceleration and for the sinusoidal rotations at lower peak velocities. The increase in gain for contralesional responses to steps of acceleration and sinusoidal rotations at higher frequencies and velocities was due to an increase in the gain of the nonlinear pathway. This pathway was driven into inhibitory cutoff at low velocities and therefore made no contribution for rotations toward the ipsilesional side.     

Effects of satiety on self-stimulation of the orbitofrontal cortex in the rhesus monkey.

Self-stimulation of the orbitofrontal cortex of the rhesus monkey was found to be attenuated after the monkeys were fed to satiety. Self-stimulation at some other sites (e.g. the nucleus accumbens septi, the region of the substantia nigra, and the caudate nucleus) was relatively unaffected in the same test sessions by the satiety. In recordings from single neurons in the monkey orbitofrontal cortex, neurons of the type found in the lateral hypothalamus with sustained responses associated with the sight of preferred foods were not found. However, some orbitofrontal neurons did respond to the removal of food or other desired objects. These experiments show that self-stimulation of the monkey orbitofrontal cortex in modulated by hunger, and show that some orbitofrontal neurons have complex responses which could be related to the control of feeding.     

Saccade dysmetria in head-unrestrained gaze shifts after muscimol inactivation of the caudal fastigial nucleus in the monkey

Lesions in the caudal fastigial nucleus (cFN) severely impair the accuracy of visually guided saccades in the head-restrained monkey. Is the saccade dysmetria a central perturbation in issuing commands for orienting gaze (eye in space) or is it a more peripheral impairment in generating oculomotor commands? This question was investigated in two head-unrestrained monkeys by analyzing the effect of inactivating one cFN on horizontal gaze shifts generated from a straight ahead fixation light-emitting diode (LED) toward a 40 degrees eccentric target LED. After muscimol injections, when viewing the fixation LED, the starting position of the head was changed (ipsilesional and upward deviations). Ipsilesional gaze shifts were associated with a 24% increase in the eye saccade amplitude and a 58% reduction in the amplitude of the head contribution. Contralesional gaze shifts were associated with a decrease in the amplitude of both eye and head components (40 and 37% reduction, respectively). No correlation between the changes in the eye amplitude and in head contribution was observed. The amplitude of the complete head movement was decreased for ipsilesional movements (57% reduction) and unaffected for contralesional movements. For both ipsilesional and contralesional gaze shifts, the changes in eye saccade amplitude were strongly correlated with the changes in gaze amplitude and largely accounted for the gaze dysmetria. These results indicate a major role of cFN in the generation of appropriate saccadic oculomotor commands during head-unrestrained gaze shifts.     

Combined eye-head gaze shifts in the primate. III. Contributions to the accuracy of gaze saccades

1. The behavior of the combined eye-head gaze saccade mechanism was investigated in the rhesus monkey under both normal circumstances and in the presence of perturbations delivered to the head by a torque motor. Animals were trained to follow a target light that stepped at regular intervals through an angle of 68 degrees (+/- 34 degrees with respect to the midsagittal plane). Thus all primary saccades were center crossing. On randomly occurring trials the torque motor was pulsed so as to perturb the trajectory of the head, thus allowing us to assess both the functional state of the vestibuloocular reflex (VOR) and the effects of such perturbations on gaze saccade accuracy (gaze is defined as the sum of eye-in-head plus head-in-space, and a gaze saccade as a combined eye-head saccadic gaze shift). 2. Gaze shifts can be divided into two discrete sections: the portion during which the gaze angle is changing (the saccadic portion), and the portion during which the gaze is stationary but the head continues to move (the terminal head-movement portion). For the system to accurately acquire eccentric targets, at least two criteria must be met: 1) the saccadic portion must be accurate, and 2) the compensatory eye movement that occurs during the terminal head-movement portion must be equal and opposite to the head movement, thereby maintaining gaze stability. Perturbations delivered during the terminal head-movement portion of the gaze shift indicated that VOR was functioning normally, and thus we concluded that the compensatory eye movements that accompany head movements were vestibular in origin. 3. As reported previously, during the saccadic portion of large-amplitude gaze saccades, the VOR ceases to function. In spite of this observation, the accuracy of the gaze saccade is not affected by perturbations delivered to the head. Gaze accuracy is maintained both by changing the duration of the saccadic portion and by altering the head trajectory. 4. Because rhesus monkeys often make very rapid head movements (1,200 degrees/s), we wished to discover the velocity range over which the monkey VOR might be expected to operate. Accordingly, in a second series of experiments, VOR function was assessed during passive whole-body rotations with the head fixed. By the use of spring-assisted manual rotations, peak velocities up to 850 degrees/s were achieved. When VOR gain was measured during such rotations, it was found to be equal to 0.9 up to the maximum velocities used.(ABSTRACT TRUNCATED AT 400 WORDS)     

Contribution of the frontal eye field to gaze shifts in the head-unrestrained monkey: effects of microstimulation

The role of the primate frontal eye field (FEF) has been inferred primarily from experiments investigating saccadic eye movements with the head restrained. Three recent reports investigating head-unrestrained gaze shifts disagree on whether head movements are evoked with FEF stimulation and thus whether the FEF participates in gaze movement commands. We therefore examined the eye, head, and overall gaze movement evoked by low-intensity microstimulation of the low-threshold region of the FEF in two head-unrestrained monkeys. Microstimulation applied at 200 or 350 Hz for 200 ms evoked large gaze shifts with substantial head movement components from most sites in the dorsomedial FEF, but evoked small, predominantly eye-only gaze shifts from ventrolateral sites. The size and direction of gaze and eye movements were strongly affected by the eye position before stimulation. Head movements exhibited little position dependency, but at some sites and initial eye positions, head-only movements were evoked. Stimulus-evoked gaze shifts and their eye and head components resembled those elicited naturally by visual targets. With stimulus train durations >200 ms, the evoked gaze shifts were more likely to be accomplished with a substantial head movement, which often continued for the entire stimulus duration. The amplitude, duration and peak velocity of the evoked head movement were more strongly correlated with stimulus duration than were those of the gaze or eye movements. We conclude that the dorsomedial FEF generates a gaze command signal that can produce eye, head, or combined eye-head movement depending on the initial orbital position of the eye.     

Experimental thyroiditis in the rhesus monkey. I. Cytotoxic, mixed-agglutinating and complement-fixing antibodies

Rhesus monkeys inoculated repeatedly with a crude extract of pooled rhesus thyroids plus complete Freund adjuvant produced autoantibodies cytotoxic for monkey and human thyroid cells in vitro. No cytotoxicity was observed with normal rhesus kidney or adrenal cells taken as controls from the same animals. The specific cytotoxic reaction was absorbed by thyroid microsomes, but not by other tissue fractions. Monkey (as well as human) thyroiditis sera failed to fix complement with thyroglobulin although both fixed complement with crude thyroid suspensions. The cytotoxic antibody was heat stable (56°C for 30 min) and required complement for damage to tissue cells. Fractionation by sucrose gradient ultracentrifugation demonstrated that the cytotoxic antibody had a sedimentation rate of about 7S and was stable to sulphydryl agents, whereas the complement-fixing antibody sedimented more rapidly and was largely inactivated by mercaptoethanol treatment. Thus in this case, cytotoxic antibody is not identical with the over-all complement-fixing activity of an antiserum. The presence of organ specific antigen on the surface of cultured rhesus thyroid cells was detected by the mixed agglutination antiglobulin reaction using monkey antisera. The curves of antibody production detected by mixed agglutination and cytotoxicity tend to correspond although the former test was 10–100 times more sensitive.     

Effects of aging on visual recognition memory in the rhesus monkey

As part of an effort to develop a primate model of human age-related memory dysfunction, performance by six rhesus monkeys 26 to 27 years of age was compared to that of six young adult monkeys (four to five years of age) on a trial unique delayed nonmatching to sample (DNMS) task. This task assesses the monkey's ability to identify a novel from a familiar stimulus over a delay and resembles closely clinical tests that are used to assess memory function in geriatric patients. The task was presented in three stages: acquisition, delays and lists. As a group, aged monkeys were impaired relative to the young adult group on all three conditions. However, within the aged group, individual cases of efficient performance were observed. Error analyses of item positions of the lists condition revealed the absence of enhanced performance for items presented at the end of a list by aged animals, suggesting an abnormal sensitivity to proactive interference. The finding of a recognition impairment with age is in parallel with studies of normal human aging and lends support to the notion that the rhesus monkey is a suitable animal model of human aging.     

Central versus peripheral origin of vestibuloocular reflex recovery following semicircular canal plugging in rhesus monkeys

We have previously shown that there is a slowly progressing, frequency-specific recovery of the gain and phase of the horizontal vestibuloocular reflex (VOR) in rhesus monkeys following plugging of the lateral semicircular canals. The adapted VOR response exhibited both dynamic and spatial characteristics that were distinctly different from responses in intact animals. To discriminate between adaptation or recovery of central versus peripheral origin, we have tested the recovered vestibuloocular responses in three rhesus monkeys in which either one or both coplanar pairs of vertical semicircular canals had been plugged previously by occluding the remaining semicircular canals in a second plugging operation. We measured the spatial tuning of the VOR in two or three different mutually orthogonal planes in response to sinusoidal oscillations (1.1 Hz, +/-5 degrees, +/-35 degrees /s) over a period of 2-3 and 12-14 mo after each operation. Apart from a significant recovery of the torsional/vertical VOR following the first operation we found that these recovered responses were preserved following the second operation, whereas the responses from the newly operated semicircular canals disappeared acutely as expected. In the follow-up period of up to 3 mo after the second operation, responses from the last operated canals showed recovery in two of three animals, whereas the previously recovered responses persisted. The results suggest that VOR recovery following plugging may depend on a regained residual sensitivity of the plugged semicircular canals to angular head acceleration.     

Spatial memory following shifts of gaze. I. Saccades to memorized world-fixed and gaze-fixed targets

During a shift of gaze, an object can move along with gaze or stay fixed in the world. To examine the effect of an object's reference frame on spatial working memory, we trained monkeys to memorize locations of visual stimuli as either fixed in the world or fixed to gaze. Each trial consisted of an initial reference frame instruction, followed by a peripheral visual flash, a memory-period gaze shift, and finally a memory-guided saccade to the location consistent with the instructed reference frame. The memory-period gaze shift was either rapid (a saccade) or slow (smooth pursuit or whole body rotation). This design allowed a comparison of memory-guided saccade performance under various conditions. Our data indicate that after a rotation or smooth-pursuit eye movement, saccades to memorized world-fixed targets are more variable than saccades to memorized gaze-fixed targets. In contrast, memory-guided saccades to world- and gaze-fixed targets are equally variable following a visually guided saccade. Across all conditions, accuracy, latency, and main sequence characteristics of memory-guided saccades are not influenced by the target's reference frame. Memory-guided saccades are, however, more accurate after fast compared with slow gaze shifts. These results are most consistent with an eye-centered representational system for storing the spatial locations of memorized objects but suggest that the visual system may engage different mechanisms to update the stored signal depending on how gaze is shifted.