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Saccades normally place the eye on target with one smooth movement. In late-onset Tay-Sachs (LOTS), intrasaccadic transient decelerations occur that may result from (1) premature omnipause neuron (OPN) re-activation due to malfunction of the latch circuit that inhibits OPNs for the duration of the saccade or (2) premature inhibitory burst neuron (IBN) activation due to fastigial nucleus (FN) dysregulation by the dorsal cerebellar vermis. Neuroanatomic analysis of a LOTS brain was performed. Purkinje cells were absent and gliosis of the granular cell layer was present in the dorsal cerebellar vermis. Deep cerebellar nuclei contained large inclusions. IBNs were present with small inclusions. The sample did not contain the complete OPN region; however, neurons in the OPN region contained massive inclusions. Pathologic findings suggest that premature OPN re-activation and/or inappropriate firing of IBNs may be responsible for interrupted saccades in LOTS. Cerebellar clinical dysfunction, lack of saccadic slowing, and significant loss of cerebellar cells suggest that the second cause is more likely.

Electrical stimulation in the monkey vestibulocerebellum has previously been shown to produce ocular nystagmus, but large stimulating current values were used. Using long duration (< or = 10-second) stimulus pulse trains and low current values (< 50 microA), we studied the nystagmus evoked by microstimulation in the uvular/nodular regions of the cerebellum. In doing this, we found quantitative differences in the nystagmus evoked from these two regions. Stimulation of the nodulus typically produced a vigorous nystagmus with a contralateral slow phase and a prolonged afternystagmus in the same direction. In contrast, stimulation of the uvula typically produced a regular ipsilateral nystagmus pattern with a very short, if any, afternystagmus in the same direction. In addition, at some stimulation sites in the uvula we observed an adaptation in the slow phase eye velocity during the time that the stimulation remained on. This effect could result in a secondary nystagmus, with a slow phase velocity direction opposite to that first evoked by the stimulation, followed by a prolonged afternystagmus in the direction of the secondary nystagmus at stimulus offset. The nystagmus evoked by these cerebellar stimulations differs from both natural nystagmus produced by large field visual motion and from the nystagmus produced by electrical stimulation of the nucleus of the optic tract. The nystagmus produced by uvular and nodular stimulation shows a shorter latency and a more rapid slow phase eye velocity buildup. The uvula stimulations also showed a much shorter afternystagmus. Also, the same nystagmus was evoked whether the animal was in a lighted or dark surround. These characteristics and recent single-unit recording studies in the uvula seem to suggest that the uvula acts not as a direct input to the velocity storage mechanism, but instead perhaps as part of an internal regulator for balance between the bilateral vestibular nuclei which are normally part of the nystagmus response. On the other hand, the nodulus, with its prolonged afternystagmus in the same direction as the evoked nystagmus, may be involved as a part of the velocity storage mechanism.

The cerebellar vermal cortex in monkey was electrically stimulated through a microelectrode with brief pulse strains synchronized to the onset of selected saccadic eye movements. The delivery of these intrasaccadic microstimuli were randomly interposed in groups of saccadic eye movements made by trained monkeys to known target locations. The trajectory of the saccades with intrasaccadic stimuli were then compared to those made to the same target without stimulation. Contralaterally directed saccades were consistently slowed from their normal trajectory (normally at 12 ms after stimulus onset) and were made hypometric. Ipsilaterally directed saccades were not affected. Vertical eye movement components were also affected at some stimulating sites. Changing the stimulus train duration from 10 to 80 ms had no effect on the change in velocity or amount of dysmetria produced in contralateral saccades. Taken together these results suggest that a different set of cerebellar elements were being stimulated by the intrasaccadic mode as contrasted to stimulation at the same site at random times. Furthermore, the short period of time during an ongoing saccade presents a unique instant in which to test the relationship of various central structures to the saccadic system. Based on current concepts of the organization of the brainstem saccadic pulse generators, these data are interpreted to suggest that: (1) the cerebellar vermis has a rather direct influence on the contralateral saccade generator, (2) this influence can act to recode (diminish) the generator's representation of the size of motor error, (3) the effect occurs at a point in the generator where motor error is spatially coded.

The cerebellar vermis (lobules V to VII) was focally stimulated (maximum current = 300 microA) through microelectrodes in alert monkeys trained to fixate on visual targets located at different positions in the eye movement field. Microstimulation of this area evoked saccades whose direction and amplitude were dependent on the spatial locus of the vermal point stimulated and on the position of the eye at the time of stimulation. Stimulation evoked saccades on most (70%) of the electrode penetrations. By alternatively stimulating and recording through the electrode as it advanced through the depth of the vermis, it was possible to map the threshold for evoking saccades along a penetration as well as to ascertain the type of tissue (white matter or Purkinje cell layer) situated at the stimulation points. On penetrations where saccades were evoked, there was generally one (90%) and sometimes two (10%) low-threshold region(s). These low-threshold regions were located in fiber tracks and not in the Purkinje or other cellular layers of the cerebellar cortex. The direction and size of the evoked saccades were dependent on position of the eye in the orbit. At a few sites, even the presence or the absence of an evoked saccade depended on the initial eye position. Postsaccadic drifts after termination of evoked saccades were also a common feature (50% of the tracks) associated with vermal microstimulation. The presence or absence as well as the direction of the postsaccadic drift were also dependent on initial eye position. These observations suggest that the vermal stimulations evoked saccades by the antidromic activation of mossy fiber afferent inputs that emanate from the brain stem saccadic burst generator. Furthermore, stimulation in this manner would actually bypass the cerebellar circuitry and produce saccades without the usual modifying influence of the cerebellum.

Responses to pure visual stimuli and visual-vestibular interactions similar to those reported in other vertebrates were found in single vestibular nucleus neurons in cat. Contrary to prevailing hypotheses, the cerebellum is not an essential part of the pathway mediating these visual responses.

Head velocity-related modulations in Purkinje cell activity were observed in lobules VI and VII of the cerebellar vermis. The sensitivities and phase shifts with respect to head velocity of Purkinje cells were comparable with vestibular responses observed in the fastigial nuclei. The results support the hypothesis of a vermal target velocity correlate and necessitate the inclusion of vermal lobules VI and VII among the cerebellar regions involved with vestibular information processing.

1. The observation of smooth-pursuit eye and retinal image velocity signals in lobules VI and VII of the vermis has given rise to the hypothesis that a neural correlate of a target velocity signal exists in this region of the cerebellum (29). However, activity signaling head velocity is also required to regenerate a target velocity signal. Vermal Purkinje cell activity was, therefore, recorded during the performance of paradigms designed to dissociate head movement-related responses. 2. The activity of 107 Purkinje cells was found to be related to horizontal head velocity. Of these, 52% increased their discharge rate for ipsilaterally directed passive head movement (type I), and 48% were excited by contralateral head movements (type II). 3. In five Purkinje cells in which sufficient data were obtained, cell discharge rate increased monotonically with head velocity over the range of 5-40 deg/s. The sensitivity to head velocity at 0.4 Hz +/- 25 deg/s averaged approximately 0.5 spikes.s-1/deg.s-1 in a larger sample of cells (n = 39). The sensitivities to head velocity, at this same frequency and velocity, of type I and type II Purkinje cells were comparable at 0.44 and 0.51 spikes.s-1/deg.s-1, respectively. 4. The Purkinje cell responses led head velocity by an average of 12 degrees at 0.4 Hz +/- 25 deg/s of passive head rotation. The phase shifts associated with type I and II responses were similar with phase leads of 13 and 9 degrees with respect to head velocity, respectively. 5. A linear interaction of smooth-pursuit eye and head velocity signals was observed during the performance of a variety of antiphase and inphase eye and head movement paradigms. The results support the conclusion that some Purkinje cells in lobules VI and VII of the cerebellar vermis encode a gaze velocity signal. Contributions of the head velocity signal to the regeneration of target velocity are considered in a companion paper (32).

1. Purkinje cell activity was recorded from lobules VI and VII of the cerebellar vermis during the performance of visuooculomotor tasks designed to dissociate the signals related to head, smooth-pursuit eye, and retinal image movements. Task-related modulations in the simple spike discharge rates of 157 cells were observed in three alert monkeys. 2. Of 65 Purkinje cells that were completely tested for all three signals, all exhibited smooth-pursuit eye movement-related activity. An additional vestibular or visual response was observed in 17 and 11% of the cells, respectively. Eye, head, and retinal image velocity signals were all recorded in the same unit in 52% of the Purkinje cells. The responses of 5% of the fully tested cells were associated with changes in the direction of eye, head, and retinal image movement. 3. The observed sensorioculomotor responses were direction selective in 98% of the Purkinje cells. For the Purkinje cells that were fully tested, 60% of the cells exhibited peak discharge rates for ipsilateral and 40% for contralateral eye velocity. Of these Purkinje cells, 45% exhibited eye, head, and retinal image velocity signals with equivalent direction preferences. 4. Of 42 Purkinje cells tested, 88% demonstrated some kinds of interactive responses during combined eye and sensory stimulation. The interaction of eye and head velocity signals has been discussed in a companion paper (38). The modulation in discharge rate observed during tracking in the presence of a random dot background pattern could be predicted from the dissociated responses to smooth pursuit in the dark and to movements of the background pattern during suppression of eye movements. 5. The sensitivity to smooth-pursuit eye velocity averaged 1.4 times the sensitivity to head velocity. In 80% of the Purkinje cells, however, the sensitivity to eye velocity exceeded the sensitivity to head velocity by an average of only 10%. The sensitivity to smooth-pursuit eye velocity averaged 1.6 times the sensitivity to retinal image velocity. 6. An increase in Purkinje cell discharge rate was observed during the open-loop period of the initiation of smooth-pursuit eye movements. This open-loop response was consistent with the presence of a visual signal during ocular pursuit, since these cells were also shown to be responsive to a dissociated retinal image velocity signal. Furthermore, the magnitude of the open-loop response indicated an enhancement of the sensitivity to retinal image velocity when visual information became behaviorally significant.(ABSTRACT TRUNCATED AT 400 WORDS)