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Saccades are rapid shifts of gaze that normally place the line of sight on a desired target with a single smooth movement. A number of disease states have been shown to result in saccadic movements that are fragmented, but still end near target position after a multi-step sequence of saccades. Among these disorders are Parkinson's disease and late-onset Tay-Sachs disease (LOTS). We have recently shown that normal human subjects and monkeys also make some two-step saccadic responses in cognitively difficult, choice response tasks. In monkeys we have been able to record neuronal responses as the animals performed a visually guided, choice saccade task. We compared the activity of neurons in the superior colliculus (SC) and the cortical frontal eye field (FEF) during the majority of trials that were accomplished with single-step saccades with those completed with two-step saccades. Several differences in discharge pattern aligned on the first saccade were uncovered. Neurons in the rostral and caudal SC were not modulated at the time of the first saccade, but a class of FEF neurons showed a burst of activity before the first saccade. If these neurons are among those known to project to the saccade generator in the brainstem, they could trigger the onset of a saccade before the remaining machinery in the saccade generator had sufficient activity to sustain the saccade. Overall the results suggest that a delicate balance of triggering and sustaining inputs are required to produce normal single-step saccades. These neural results may also help to clarify the pathology present when fragmented saccades occur in various disease states.

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.

In late-onset Tay-Sachs disease (LOTS), saccades are interrupted by one or more transient decelerations. Some saccades reaccelerate and continue on before eye velocity reaches zero, even in darkness. Intervals between successive decelerations are not regularly spaced. Peak decelerations of horizontal and vertical components of oblique saccades in LOTS is more synchronous than those in control subjects. We hypothesize that these decelerations are caused by dysregulation of the fastigial nuclei (FN) of the cerebellum, which fire brain stem inhibitory burst neurons (IBNs).