Ocular Motor Disorders Caused by Lesions in the Cerebellum

The vestibulocerebellum consists of the flocculus, ventral paraflocculus, nodulus, and uvula. ■ The flocculus receives inputs from the vestibular nucleus and nerve, nucleus prepositus hypoglossi (NPH), inferior olivary nucleus, cell groups of the paramedian tracts (PMT), nucleus reticularis tegmenti pontis (NRTP), and mesencephalic reticular formation. ■ The ventral paraflocculus receives inputs from contralateral pontine nuclei. ■ Project to ipsilateral superior and medial vestibular nuclei, and the y-group ■ Receive input from the medial and inferior vestibular nuclei, vestibular nerve, NPH, and inferior olivary nucleus ■ Project to the vestibular nuclei ■ The oculomotor vermis consists of parts of the declive, folium, tuber, and pyramis. ■ Receives inputs from the inferior olivary nucleus, vestibular nuclei, NPH, paramedian pontine reticular formation (PPRF), NRTP, and dorsolateral and dorsomedial pontine nuclei ■ Projects to the caudal fastigial nucleus ■ Stimulation of the Purkinje cells in the dorsal vermis elicits contralaterally directed saccades and smooth pursuit ■ Receives inputs from the dorsal vermis, inferior olivary nucleus, and NRTP ■ Decussates and projects via the uncinate fasciculus of the brachium conjunctivum to the contralateral PPRF, rostral interstitial nucleus of the medial longitudinal fasciculus, nucleus of the posterior commissure, omnipause neurons in nucleus raphe interpositus, the mesencephalic reticular formation, and superior colliculus ■ Neurons in the fastigial oculomotor region (FOR) fire during both ipsilateral and contralateral saccades. 1. The contralateral FOR neurons burst before the onset of saccade, and the onset of firing is not correlated with any property of the saccade. 2. Conversely, the time of onset for neurons in the ipsilateral FOR varies, with bursts occurring later for larger saccades. 3. Thus, the difference in time of onset between contralateral and ipsilateral FOR activity encodes the amplitude of saccades (i.e., the larger the difference in time of onset, the larger the saccade amplitude). Eye movement abnormalities in uncinate fasciculus lesion include hypometric ipsilesional saccades and hypermetric contralesional saccades (“contrapulsion”). Arnold-Chiari malformation is a malformation of the medullary–spinal junction with herniation of intracranial contents through the foramen magnum. The three types are illustrated in the figure below.

Ocular Motor Disorders Caused by Lesions in the Brainstem

Oculopalatal tremor usually occurs many months after an initial insult, due to neural deafferentation. It rarely resolves spontaneously. Treatment is with gabapentin, ceruletide, or anticolinergic agents. The y-group is a small group of cells that lies rostral to the inferior cerebellar peduncle. It receives inputs from the saccule (part of the otolith) and from Purkinje cells of the flocculus, and it projects to the oculomotor and trochlear nuclei via the superior cerebellar peduncle and a crossing ventral tegmental tract. 1. Discharge during upward smooth pursuit, optokinetic, and combined eye-head tracking (VOR cancellation), but not during VOR in darkness (see sections 3.14 and 5.2) 2. Together with the flocculus and ventral paraflocculus, may contribute to vertical VOR adaptation (see section 3.12) No known documented clinical correlate Collections of neurons scattered along the midline fiber tracts in the pons and medulla, including: 1. The nucleus pararaphales in the medulla, which receives vertical eye position signals from the INC, and projects to the flocculus and ventral paraflocculus 2. The nucleus incertus in the pons, which contains burst-tonic neurons that mainly discharge in relation to horizontal eye movements, and projects to the flocculus Function: may send an “efference copy” of eye movement commands to the flocculus for gaze holding or longer term adaptation No known documented clinical correlate The abducens nucleus contains: 1. Abducens motoneurons that innervate the ipsilateral lateral rectus 2. Abducens internuclear neurons, the axons of which cross the midline and ascend via the MLF to innervate the contralateral medial rectus motoneurons in the oculomotor nucleus. 3. Neurons that project to the cerebeller flocculus The abducens nucleus is the final common motor pathway for horizontal conjugate eye movements, as it receives input for horizontal saccades, VOR, and smooth pursuit. The paramedian pontine reticular formation (PPRF) contains: Excitatory burst neurons (EBN) in the dorsomedial nucleus reticularis pontis caudalis (NRPC) that ■ Project to the ipsilateral abducens nucleus to generate ipsilateral, conjugate, horizontal saccades ■ Project to inhibitory burst neurons in the nucleus paragigantocellularis dorsalis (PGD) and receive inhibitory inputs from omnipause neurons in nucleus raphe interpositus (rip)

Horizontal Smooth Pursuit Adaptation in Macaques After Muscimol Inactivation of the Dorsolateral Pontine Nucleus (DLPN)

The smooth pursuit (SP) system can adapt its response to developmental changes, injury, and behavioral context. Previous lesion and single-unit recording studies show that the macaque cerebellum plays a role in SP initiation, maintenance, and adaptation. The aim of this study was to determine the potential role of the DLPN in SP adaptation. The DLPN receives inputs from the cortical SP system and delivers eye and visual motion information to the dorsal/ventral paraflocculus and vermis of the cerebellum. We studied SP adaptation in two juvenile rhesus monkeys ( Macaca mulatta), using double steps of target speed that step- up (10–30°/s) or step-down (25–5°/s). We used microinjection of muscimol (≤2%; 0.15 μl) to reversibly inactivate the DLPN, unilaterally. After DLPN inactivation, initial ipsilesional SP acceleration (first 100 ms) was significantly reduced by 47–74% ( P < 0.01; unpaired t-test) of control values in the single-speed step-ramp paradigm. Similarly, ipsilesional steady-state SP velocity was also reduced by 59–78% ( P < 0.01; unpaired t-test) of control values. Contralesional SP was not impaired after DLPN inactivation. Control testing showed significant adaptive changes of initial SP eye acceleration after 100 trials in either step-up or step-down paradigms. After inactivation, during ipsilesional SP, adaptation was impaired in the step-up but not in the step-down paradigm. In contrast, during contralesional tracking, adaptive capability remained in the step-down but not in the step-up paradigm. Therefore SP adaptation could depend, in part, on direction sensitive eye/visual motion information provided by DLPN neurons to cerebellum.

Context Contingent Signal Processing in the Cerebellar Flocculus and Ventral Paraflocculus During Gaze Saccades

The vestibuloocular reflex (VOR) functions to stabilize gaze when the head moves. The flocculus region (FLR) of the cerebellar cortex, which includes the flocculus and ventral paraflocculus, plays an essential role in modifying signal processing in VOR pathways so that images of interest remain stable on the retina. In squirrel monkeys, the firing rate of most FLR Pk cells is modulated during VOR eye movements evoked by passive movement of the head. In this study, the responses of 48 FLR Purkinje cells, the firing rates of which were strongly modulated during VOR evoked by passive whole body rotation or passive head-on-trunk rotation, were compared to the responses generated during compensatory VOR eye movements evoked by the active head movements of eye-head saccades. Most (42/48) of the Purkinje cells were insensitive to eye-head saccade-related VOR eye movements. A few (6/48) generated bursts of spikes during saccade-related VOR but only during on-direction eye movements. Considered as a population FLR Pk cells were <5% as responsive to the saccade-related VOR as they were to the VOR evoked by passive head movements. The observations suggest that the FLR has little influence on signal processing in VOR pathways during eye-head saccade-related VOR eye movements. We conclude that the image-stabilizing signals generated by the FLR are highly dependent on the behavioral context and are called on primarily when external forces unrelated to self-generated eye and head movements are the cause of image instability.

Computational Study on Monkey VOR Adaptation and Smooth Pursuit Based on the Parallel Control-Pathway Theory

Much controversy remains about the site of learning and memory for vestibuloocular reflex (VOR) adaptation in spite of numerous previous studies. One possible explanation for VOR adaptation is the flocculus hypothesis, which assumes that this adaptation is caused by synaptic plasticity in the cerebellar cortex. Another hypothesis is the model proposed by Lisberger that assumes that the learning that occurs in both the cerebellar cortex and the vestibular nucleus is necessary for VOR adaptation. Lisberger's model is characterized by a strong positive feedback loop carrying eye velocity information from the vestibular nucleus to the cerebellar cortex. This structure contributes to the maintenance of a smooth pursuit driving command with zero retinal slip during the steady-state phase of smooth pursuit with gain 1 or during the target blink condition. Here, we propose an alternative hypothesis that suggests that the pursuit driving command is maintained in the medial superior temporal (MST) area based on MST firing data during target blink and during ocular following blank, and as a consequence, we assume a much smaller gain for the positive feedback from the vestibular nucleus to the cerebellar cortex. This hypothesis is equivalent to assuming that there are two parallel neural pathways for controlling VOR and smooth pursuit: a main pathway of the semicircular canals to the vestibular nucleus for VOR, and a main pathway of the MST—dorsolateral pontine nuclei (DLPN)—flocculus/ventral paraflocculus to the vestibular nucleus for smooth pursuit. First, we theoretically demonstrate that this parallel control-pathway theory can reproduce the various firing patterns of horizontal gaze velocity Purkinje cells in the flocculus/ventral paraflocculus dependent on VOR in the dark, smooth pursuit, and VOR cancellation as reported in Miles et al. at least equally as well as the gaze velocity theory, which is the basic framework of Lisberger's model. Second, computer simulations based on our hypothesis can stably reproduce neural firing data as well as behavioral data obtained in smooth pursuit, VOR cancellation, and VOR adaptation, even if only plasticity in the cerebellar cortex is assumed. Furthermore, our computer simulation model can reproduce VOR adaptation automatically based on a heterosynaptic interaction model between parallel fiber inputs and climbing fiber inputs. Our results indicate that different assumptions about the site of pursuit driving command maintenance computationally lead to different conclusions about where the learning for VOR adaptation occurs. Finally, we propose behavioral and physiological experiments capable of discriminating between these two possibilities for the site of pursuit driving command maintenance and hence for the sites of learning and memory for VOR adaptation.

Partial Ablations of the Flocculus and Ventral Paraflocculus in Monkeys Cause Linked Deficits in Smooth Pursuit Eye Movements and Adaptive Modification of the VOR

The vestibuloocular reflex (VOR) generates compensatory eye movements to stabilize visual images on the retina during head movements. The amplitude of the reflex is calibrated continuously throughout life and undergoes adaptation, also called motor learning, when head movements are persistently associated with image motion. Although the floccular-complex of the cerebellum is necessary for VOR adaptation, it is not known whether this function is localized in its anterior or posterior portions, which comprise the ventral paraflocculus and flocculus, respectively. The present paper reports the effects of partial lesions of the floccular-complex in five macaque monkeys, made either surgically or with stereotaxic injection of 3-nitropropionic acid (3-NP). Before and after the lesions, smooth pursuit eye movements were tested during sinusoidal and step-ramp target motion. Cancellation of the VOR was tested by moving a target exactly with the monkey during sinusoidal head rotation. The control VOR was tested during sinusoidal head rotation in the dark and during 30°/s pulses of head velocity. VOR adaptation was studied by having the monkeys wear ×2 or ×0.25 optics for 4–7 days. In two monkeys, bilateral lesions removed all of the flocculus except for parts of folia 1 and 2 but did not produce any deficits in smooth pursuit, VOR adaptation, or VOR cancellation. We conclude that the flocculus alone probably is not necessary for either pursuit or VOR learning. In two monkeys, unilateral lesions including a large fraction of the ventral paraflocculus produced small deficits in horizontal and vertical smooth pursuit, and mild impairments of VOR adaptation and VOR cancellation. We conclude that the ventral paraflocculus contributes to both behaviors. In one monkey, a bilateral lesion of the flocculus and ventral paraflocculus produced severe deficits smooth pursuit and VOR cancellation, and a complete loss of VOR adaptation. Considering all five cases together, there was a strong correlation between the size of the deficits in VOR learning and pursuit. We found the strongest correlation between the behavior deficits and the size of the lesion of the ventral paraflocculus, a weaker but significant correlation for the full floccular complex, and no correlation with the size of the lesion of the flocculus. We conclude that 1) lesions of the floccular complex cause linked deficits in smooth pursuit and VOR adaptation, and 2) the relevant portions of the structure are primarily in the ventral paraflocculus, although the flocculus may participate.

Cerebellar Flocculus and Ventral Paraflocculus Purkinje Cell Activity During Predictive and Visually Driven Pursuit in Monkey

Purkinje cells in the flocculus and ventral paraflocculus were studied in tasks designed to distinguish predictive versus visually guided mechanisms of smooth pursuit. A sum-of-sines task allowed studies of complex predictive pursuit. A perturbation task examined visually driven pursuit during unpredictable right-angle changes in target direction. A gap task examined pursuit that was maintained when the target was turned off. Neural activity patterns were quantified using multi-linear models with sensitivities to the position, velocity, and acceleration of both motor output (eye motion) and visual input (retinal slip). During the sum-of-sines task, neural responses led eye motion by an average of 12 ms, a value larger than the 9-ms transmission delay between flocculus stimulation and eye motion. This suggests that flocculus/paraflocculus neurons drove pursuit along predictable sum-of-sines trajectories. In contrast, neural responses led eye motion by an average of only 2 ms during the perturbation task and by 6 ms during the gap task. These values suggest a follow-up role during tasks more heavily dependent on visual processing. Activity in all three tasks was explained primarily by sensitivities to eye position and velocity. Eye acceleration played a minor role during ongoing pursuit, although its influence on firing rate increased during the high accelerations following unexpected changes in target motion. Retinal slip had a relatively small influence on responses during pursuit. This was particularly true for the sum-of-sines and gap tasks where predictive control eliminated any consistent retinal-slip signals that might have been used to drive the eye. Surprisingly, the influence of retinal slip did not increase appreciably during unpredictable perturbations in target direction that generated large amounts of retinal slip. Thus although visual control signals are needed in varying amounts during the three pursuit tasks, they have been converted to motor control signals by the time they leave the flocculus/paraflocculus system. Individual neurons showed a remarkable constancy in eye-sensitivity direction across tasks that indicated direct links to oculomotor neurons. However, some neurons showed changes in sensitivity magnitude that suggested changes in control strategy for different tasks. Magnitude differences were largest for the perturbation task. We conclude that the flocculus/paraflocculus system plays a major role in driving predictive pursuit. It also processes visually driven control signals that originate in other brain regions after a slight delay.