Oculomotor Vermis Research Articles

Closed-Loop Optogenetic Perturbation of Macaque Oculomotor Cerebellum: Evidence for an Internal Saccade Model.

Internal models are essential for the production of accurate movements. The accuracy of saccadic eye movements is thought to be mediated by an internal model of oculomotor mechanics encoded in the cerebellum. The cerebellum may also be part of a feedback loop that predicts the displacement of the eyes and compares it to the desired displacement in real time to ensure that saccades land on target. To investigate the role of the cerebellum in these two aspects of saccade production, we delivered saccade-triggered light pulses to channelrhodopsin-2-expressing Purkinje cells in the oculomotor vermis (OMV) of two male macaque monkeys. Light pulses delivered during the acceleration phase of ipsiversive saccades slowed the deceleration phase. The long latency of these effects and their scaling with light pulse duration are consistent with an integration of neural signals at or downstream of the stimulation site. In contrast, light pulses delivered during contraversive saccades reduced saccade velocity at short latency and were followed by a compensatory reacceleration which caused gaze to land on or near the target. We conclude that the contribution of the OMV to saccade production depends on saccade direction; the ipsilateral OMV is part of a forward model that predicts eye displacement, whereas the contralateral OMV is part of an inverse model that creates the force required to move the eyes with optimal peak velocity for the intended displacement.

Neural Changes after Vision Therapy in Convergence Insufficiency: A Systematic Review.

To investigate if the use of vision therapy (VT) in convergence insufficiency (CI) has a significant neural impact and how it correlates with the clinical changes occurring with this option of treatment. A systematic review of the scientific literature was carried out in the PubMed and Scopus databases, where all the scientific literature on the neural impact of VT in CI was analyzed. A total of 17 articles were initially found and a detailed analysis was carried out. After full-text reading, only four studies met the defined inclusion criteria. The following data from them were extracted: CI cases and controls, clinical and neural parameters evaluated, the neural response to VT observed, type of study, and VT performed. The quality of the studies was assessed using the GRADE tool. Some neural changes have been reported after VT in CI with the use of functional magnetic resonance imaging (fMRI). Specifically, a modification of the functional activity of some brain areas (especially front fields, oculomotor vermis, and cerebellum) was found. However, contradictory findings in terms of the change in functional activity (increase or decrease) were found that might be associated to differences in fMRI protocols. In the GRADE analysis, serious concerns were found in the categories of risk of bias, inconsistency, indirectness, and imprecision, so the certainty of evidence for each outcome was very low. The research performed to this date does not allow confirming if there are neural changes occurring after vision therapy in patients with CI because the quality of the research performed on this issue is very low, with several methodological concerns.

Complex spikes perturb movements and reveal the sensorimotor map of Purkinje cells

Computations that are performed by the cerebellar cortex are transmitted via simple spikes of Purkinje cells (P-cells) to downstream structures, but because P-cells are many synapses away from muscles, we do not know the relationship between modulation of simple spikes and control of behavior. Here, we recorded the spiking activities of hundreds of P-cells in the oculomotor vermis of marmosets during saccadic eye movements and found that following the presentation of a visual stimulus, the olivary input to a P-cell coarsely described the direction and amplitude of the visual stimulus as well as the upcoming movement. Occasionally, the complex spike occurred just before saccade onset, suppressing the P-cell's simple spikes and disrupting its output during that saccade. Remarkably, this brief suppression of simple spikes altered the saccade's trajectory by pulling the eyes toward the part of the visual space that was preferentially encoded by the olivary input to that P-cell. Thus, there is an alignment between the sensory space encoded by the complex spikes and the behavior conveyed by the simple spikes: a reduction in simple spikes is a signal to bias the ongoing movement toward the part of the sensory space preferentially encoded by the olivary input to that P-cell.

Cerebellar complex spikes multiplex complementary behavioral information.

Purkinje cell (PC) discharge, the only output of cerebellar cortex, involves 2 types of action potentials, high-frequency simple spikes (SSs) and low-frequency complex spikes (CSs). While there is consensus that SSs convey information needed to optimize movement kinematics, the function of CSs, determined by the PC’s climbing fiber input, remains controversial. While initially thought to be specialized in reporting information on motor error for the subsequent amendment of behavior, CSs seem to contribute to other aspects of motor behavior as well. When faced with the bewildering diversity of findings and views unraveled by highly specific tasks, one may wonder if there is just one true function with all the other attributions wrong? Or is the diversity of findings a reflection of distinct pools of PCs, each processing specific streams of information conveyed by climbing fibers? With these questions in mind, we recorded CSs from the monkey oculomotor vermis deploying a repetitive saccade task that entailed sizable motor errors as well as small amplitude saccades, correcting them. We demonstrate that, in addition to carrying error-related information, CSs carry information on the metrics of both primary and small corrective saccades in a time-specific manner, with changes in CS firing probability coupled with changes in CS duration. Furthermore, we also found CS activity that seemed to predict the upcoming events. Hence PCs receive a multiplexed climbing fiber input that merges complementary streams of information on the behavior, separable by the recipient PC because they are staggered in time.

Underlying neurological mechanisms associated with symptomatic convergence insufficiency

Convergence insufficiency (CI) is the most common binocular vision problem, associated with blurred/double vision, headaches, and sore eyes that are exacerbated when doing prolonged near work, such as reading. The Convergence Insufficiency Neuro-mechanism Adult Population Study (NCT03593031) investigates the mechanistic neural differences between 50 binocularly normal controls (BNC) and 50 symptomatic CI participants by examining the fast and slow fusional disparity vergence systems. The fast fusional system is preprogrammed and is assessed with convergence peak velocity. The slow fusional system optimizes vergence effort and is assessed by measuring the phoria adaptation magnitude and rate. For the fast fusional system, significant differences are observed between the BNC and CI groups for convergence peak velocity, final position amplitude, and functional imaging activity within the secondary visual cortex, right cuneus, and oculomotor vermis. For the slow fusional system, the phoria adaptation magnitude and rate, and the medial cuneus functional activity, are significantly different between the groups. Significant correlations are observed between vergence peak velocity and right cuneus functional activity (p = 0.002) and the rate of phoria adaptation and medial cuneus functional activity (p = 0.02). These results map the brain-behavior of vergence. Future therapeutic interventions may consider implementing procedures that increase cuneus activity for this debilitating disorder.

Saccadic Hypermetria From a Selective Lesion of the Fastigial Oculomotor Region

The main cerebellar structures involved in ocular motor control comprise the flocculus and paraflocculus, nodulus and uvula, as well as the oculomotor vermis (OMV) and the fastigial oculomotor region (FOR).1 Although the flocculus and paraflocculus are critical for smooth pursuit and for gaze holding,2 the so-called “vestibulocerebellar” centers, the OMV and the FOR are exclusively involved in the control of smooth pursuit and saccades.

Stimulus-Specific Visual Working Memory Representations in Human Cerebellar Lobule VIIb/VIIIa.

fMRI research has revealed that cerebellar lobule VIIb/VIIIa exhibits load-dependent activity that increases with the number of items held in visual working memory (VWM). However, it remains unclear whether these cerebellar responses reflect processes specific to VWM or more general visual attentional mechanisms. To investigate this question, we examined whether cerebellar activity during the delay period of a VWM task is selective for stimuli held in working memory. A sample of male and female human subjects performed a VWM continuous report task in which they were retroactively cued to remember the direction of motion of moving dot stimuli. Cerebellar lobule VIIb/VIIIa delay-period activation accurately decoded the direction of the remembered stimulus, as did frontal and parietal regions of the dorsal attention network. Arguing against a motor explanation, no other cerebellar area exhibited stimulus specificity, including the oculomotor vermis, a key area associated with eye movement control. Finer-scale analysis revealed that the medial portion of lobule VIIb and to a lesser degree the lateral most portion of lobules VIIb and VIIIa, which exhibit robust resting state connectivity with frontal and parietal regions of the dorsal attention network, encoded the identity of the remembered stimulus, while intermediate portions of lobule VIIb/VIIIa did not. These findings of stimulus-specific coding of VWM within lobule VIIb/VIIIa indicate for the first time that the distributed network responsible for the encoding and maintenance of mnemonic representations extends to the cerebellum.SIGNIFICANCE STATEMENT There is considerable debate concerning where in the brain the contents of visual working memory (VWM) are stored. To date, this literature has primarily focused on the role of regions located within cerebral cortex. There is growing evidence for cerebellar involvement in higher-order cognitive functions including working memory. While the cerebellum has been previously shown to be recruited by VWM paradigms, it is unclear whether any portion of cerebellum actively encodes and maintains mnemonic representations. The present study demonstrates that cerebellar lobule VIIb/VIIIa activity patterns are selective for remembered stimuli and that this selectivity persists in the absence of perceptual input. These findings provide novel evidence for the participation of cerebellar structures in the persistent storage of visual information.

Test-retest of a phoria adaptation stimulus-induced functional MRI experiment.

This study was designed to identify the neural substrates activated during a phoria adaptation task using functional magnetic resonance imaging (MRI) in young adults with normal binocular vision and to test the repeatability of the fMRI measurements for this protocol. The phoria adaptation task consisted of a block protocol of 90 seconds of near visual crossed fixation followed by 90 seconds of far visual uncrossed fixation, repeated three times; the data were collected during two different experimental sessions. Results showed that the oculomotor vermis, cuneus, and primary visual cortex had the greatest functional activity within the regions of interest studied when stimulated by the phoria adaptation task. The oculomotor vermis functional activity had an intraclass correlation coefficient (ICC) of 0.3, whereas the bilateral cuneus and primary visual cortex had good ICC results of greater than 0.6. These results suggest that the sustained visual fixation task described within this study reliably activates the neural substrates of phoria adaptation. This protocol establishes a methodology that can be used in future longitudinal studies investigating therapeutic interventions that may modify phoria adaptation.

Whole-body somatotopic maps in the cerebellum revealed with 7T fMRI

The cerebellum is known to contain a double somatotopic body representation. While the anterior lobe body map has shown a robust somatotopic organization in previous fMRI studies, the representations in the posterior lobe have been more difficult to observe and are less precisely characterized. In this study, participants went through a simple motor task asking them to move either the eyes (left-right guided saccades), tongue (left-right movement), thumbs, little fingers or toes (flexion). Using high spatial resolution fMRI data acquired at ultra-high field (7T), with special care taken to obtain sufficient B1 over the entire cerebellum and a cerebellar surface reconstruction facilitating visual inspection of the results, we were able to precisely map the somatotopic representations of these five distal body parts on both subject- and group-specific cerebellar surfaces. The anterior lobe (including lobule VI) showed a consistent and robust somatotopic gradient. Although less robust, the presence of such a gradient in the posterior lobe, from Crus II to lobule VIIIb, was also observed. Additionally, the eyes were also strongly represented in Crus I and the oculomotor vermis. Overall, crosstalk between the different body part representations was negligible. Taken together, these results show that multiple representations of distal body parts are present in the cerebellum, across many lobules, and they are organized in an orderly manner.

Test-Retest Reliability of Functional Magnetic Resonance Imaging Activation for a Vergence Eye Movement Task.

Vergence eye movements are the inward and outward rotation of the eyes responsible for binocular coordination. While studies have mapped and investigated the neural substrates of vergence, it is not well understood whether vergence eye movements evoke the blood oxygen level-dependent signal reliably in separate experimental visits. The test-retest reliability of stimulus-induced vergence eye movement tasks during a functional magnetic resonance imaging (fMRI) experiment is important for future randomized clinical trials (RCTs). In this study, we established region of interest (ROI) masks for the vergence neural circuit. Twenty-seven binocularly normal young adults participated in two functional imaging sessions measured on different days on the same 3T Siemens scanner. The fMRI experiments used a block design of sustained visual fixation and rest blocks interleaved between task blocks that stimulated eight or four vergence eye movements. The test-retest reliability of task-activation was assessed using the intraclass correlation coefficient (ICC), and that of spatial extent was assessed using the Dice coefficient. Functional activation during the vergence eye movement task of eight movements compared to rest was repeatable within the primary visual cortex (ICC = 0.8), parietal eye fields (ICC = 0.6), supplementary eye field (ICC = 0.5), frontal eye fields (ICC = 0.5), and oculomotor vermis (ICC = 0.6). The results demonstrate significant test-retest reliability in the ROIs of the vergence neural substrates for functional activation magnitude and spatial extent using the stimulus protocol of a task block stimulating eight vergence eye movements compared to sustained fixation. These ROIs can be used in future longitudinal RCTs to study patient populations with vergence dysfunctions.

Glissades Are Altered by Lesions to the Oculomotor Vermis but Not by Saccadic Adaptation.

Saccadic eye movements enable fast and precise scanning of the visual field, which is partially controlled by the posterior cerebellar vermis. Textbook saccades have a straight trajectory and a unimodal velocity profile, and hence have well-defined epochs of start and end. However, in practice only a fraction of saccades matches this description. One way in which a saccade can deviate from its trajectory is the presence of an overshoot or undershoot at the end of a saccadic eye movement just before fixation. This additional movement, known as a glissade, is regarded as a motor command error and was characterized decades ago but was almost never studied. Using rhesus macaques, we investigated the properties of glissades and changes to glissade kinematics following cerebellar lesions. Additionally, in monkeys with an intact cerebellum, we investigated whether the glissade amplitude can be modulated using multiple adaptation paradigms. Our results show that saccade kinematics are altered by the presence of a glissade, and that glissades do not appear to have any adaptive function as they do not bring the eye closer to the target. Quantification of these results establishes a detailed description of glissades. Further, we show that lesions to the posterior cerebellum have a deleterious effect on both saccade and glissade properties, which recovers over time. Finally, the saccadic adaptation experiments reveal that glissades cannot be modulated by this training paradigm. Together our work offers a functional study of glissades and provides new insight into the cerebellar involvement in this type of motor error.

Role of the Vermal Cerebellum in Visually Guided Eye Movements and Visual Motion Perception.

The cerebellar cortex is a crystal-like structure consisting of an almost endless repetition of a canonical microcircuit that applies the same computational principle to different inputs. The output of this transformation is broadcasted to extracerebellar structures by way of the deep cerebellar nuclei. Visually guided eye movements are accommodated by different parts of the cerebellum. This review primarily discusses the role of the oculomotor part of the vermal cerebellum [the oculomotor vermis (OMV)] in the control of visually guided saccades and smooth-pursuit eye movements. Both types of eye movements require the mapping of retinal information onto motor vectors, a transformation that is optimized by the OMV, considering information on past performance. Unlike the role of the OMV in the guidance of eye movements, the contribution of the adjoining vermal cortex to visual motion perception is nonmotor and involves a cerebellar influence on information processing in the cerebral cortex.

Clinical and Functional Imaging Changes Induced from Vision Therapy in Patients with Convergence Insufficiency.

Office-Based Vergence/Accommodative Therapy (OBVAT) is an effective treatment for convergence insufficiency (CI) and remediates symptoms in about 75% of patients. Hence, the study of CI patients can serve as a systems-level model to understand the neural mechanisms evoked from rehabilitation. Symptomatic young adult CI patients (N=25) participated in 12 hours of OBVAT and were compared to 25 binocularly normal controls (BNC) using unpaired t-tests. CI patients have significantly lower near point of convergence and positive fusional vergence and were more symptomatic compared to BNC (p<; 0.0001). Using paired t-tests, significant differences (p<; 0.0001) were observed between CI patients' baseline and post-OBVAT measurements where the near point of convergence decreased, positive fusional vergence increased, and the results from the Convergence Insufficiency Symptom Survey (CISS) decreased. Using paired t-tests, the mean beta weights of the functional activity significantly increased for the frontal eye fields (p<; 0.01) and the oculomotor vermis (p<; 0.05) for CI patients post-OBVAT compared to baseline measurements. These data demonstrate that OBVAT increases functional activity within the brain and improves clinical function and visual symptoms in CI patients.

Topographic Maps of Visual Space in the Human Cerebellum

The purported role of the cerebellum has shifted from one that is exclusively sensorimotor related to one that encompasses a wide range of cognitive and associative functions [1-5]. Within sensorimotor areas of the cerebellum, functional organization is characterized by ipsilateral representations of the body [6]. Yet, in the remaining cerebellar cognitive and associative networks, functional organization remains less well understood. Regions of cerebral cortex [7-9] and subcortex [10] important for visual perception and cognition are organized topographically: neural organization mirrors the retina. Recently, it was shown that known retinotopic areas in cerebral cortex are functionally connected to nodes in the cerebellum [2,11,12]. In fact, this revealed signals with visuospatial selectivity in the cerebellum [13]. Here, we analyzed the highly powered Human Connectome Project (HCP) retinotopy dataset [14] to create a comprehensive and detailed overview of visuospatial organization in the cerebellum. This revealed 5 ipsilateral topographic maps in 3 cerebellar clusters (oculomotor vermis [OMV]-lobule VIIb-lobule VIIIb), of which we quantified visual field coverage and topography. These quantifications dovetail with the known roles of these areas in eye movements (OMV) [5, 15], attention (OMV-VIIb) [5, 13], working memory (VIIb) [13], andthe integration of visuomotor information with respect to effector movements (VIIIb) [5]. To aid future research on visual perception in the cerebellum, we provide an online atlas of the visuospatial maps in Montreal Neurological Institute (MNI) space. Our findings demonstrate that the cerebellum is abundant with visuospatial information and, moreover, that it is organized according to known retinotopic properties.

How cerebellar motor learning keeps saccades accurate.

The neuronal substrate underlying the learning of a sophisticated task has been difficult to study. However, the advent of a behavioral paradigm that deceives the saccadic system into thinking it is making an error has allowed the mechanisms of the adaptation that corrects this error to be revealed in a primate. The neural elements that fashion the command signal for the generation of accurate saccades involve subcortical structures in the brain stem and cerebellum. In this review we show that sites in both those structures also are involved with the gradual adaptation of saccade size, a form of motor learning. Pharmacological manipulation of the oculomotor vermis (lobules VIc and VII) impairs mechanisms that either increase or decrease saccade size during adaptation. The net saccade-related simple spike (SS) activity of its Purkinje cells is correlated with the changes in saccade characteristics that occur during adaptation. These changes in SS activity are driven by an error signal delivered over climbing fibers, which create complex spikes whose probability of occurrence reflects the motor error between the actual and desired saccade size. These climbing fibers originate in the part of the inferior olive that receives projections from the superior colliculus (SC). Disabling the SC prevents adaptation and stimulation of the SC just after a normal saccade produces a surrogate error signal that drives adaptation without an actual visual error. Therefore, the SC provides not only the initial command that generates a saccade, as shown by others, but also the error signal that ensures that saccades remain accurate.

Modeling the Encoding of Saccade Kinematic Metrics in the Purkinje Cell Layer of the Cerebellar Vermis.

Recent electrophysiological observations related to saccadic eye movements in rhesus monkeys, suggest a prediction of the sensory consequences of movement in the Purkinje cell layer of the cerebellar oculomotor vermis (OMV). A definite encoding of real-time motion of the eye has been observed in simple-spike responses of the combined burst-pause Purkinje cell populations, organized based upon their complex-spike directional tuning. However, the underlying control mechanisms that could lead to such action encoding are still unclear. We propose a saccade control model, with emphasis on the structure of the OMV and its interaction with the extra-cerebellar components. In the simulated bilateral organization of the OMV, each caudal fastigial nucleus is arranged to receive incoming projections from combined burst-pause Purkinje cell populations. The OMV, through the caudal fastigial nuclei, interacts with the brainstem to provide adaptive saccade gain corrections that minimize the visual error in reaching a given target location. The simulation results corroborate the experimental Purkinje cell population activity patterns and their relation with saccade kinematic metrics. The Purkinje layer activity that emerges from the proposed organization, precisely predicted the speed of the eye at different target eccentricities. Simulated granular layer activity suggests no separate dynamics with respect to shaping the bilateral Purkine layer activity. We further examine the validity of the simulated OMV in maintaining the accuracy of saccadic eye movements in the presence of signal dependent variabilities, that can occur in extra-cerebellar pathways.

A neuronal process for adaptive control of primate saccadic system.

In 1980, Dr. Optican established the existence of an adaptive plasticity of saccades and its dependence on the cerebellum with Dr. Robinson. The advantage of saccades is that the neuronal mechanisms underlying their generation have been well established. This knowledge allows us to identify the neuronal elements that participate in saccade adaptation. Briefly, the superior colliculus (SC) produces a saccade command signal, which reaches motoneurons in the abducens nucleus via the brainstem burst generator. The SC saccade command also is sent to the oculomotor vermis (OMV), a saccade-related area of the cerebellar cortex, and finally converges on the same motoneurons via the caudal fastigial nucleus (cFN) and inhibitory burst neurons (IBN). During adaptation, the saccade-related burst of SC neurons does not change; however, the activity of the cerebellum and its downstream targets do. We demonstrate that the SC is the source of the error signal to the OMV, and the error signal increases the probability of complex spike occurrence and decreases simple spike activity in the OMV. This decrease, in turn, is delivered through the cFN and IBN neurons to decrease motoneuron activity and hence saccade amplitude.

Early Trajectory Prediction in Elite Athletes

Cerebellar plasticity is a critical mechanism for optimal feedback control. While Purkinje cell activity of the oculomotor vermis predicts eye movement speed and direction, more lateral areas of the cerebellum may play a role in more complex tasks, including decision-making. It is still under question how this motor-cognitive functional dichotomy between medial and lateral areas of the cerebellum plays a role in optimal feedback control. Here we show that elite athletes subjected to a trajectory prediction, go/no-go task manifest superior subsecond trajectory prediction accompanied by optimal eye movements and changes in cognitive load dynamics. Moreover, while interacting with the cerebral cortex, both the medial and lateral cerebellar networks are prominently activated during the fast feedback stage of the task, regardless of whether or not a motor response was required for the correct response. Our results show that cortico-cerebellar interactions are widespread during dynamic feedback and that experience can result in superior task-specific decision skills.

Encoding of error and learning to correct that error by the Purkinje cells of the cerebellum.

SummaryThe primary output cells of the cerebellar cortex, Purkinje cells (P-cells), make kinematic predictions about ongoing movements via high-frequency simple spikes (SS), but receive sensory error information about that movement via low-frequency complex spikes (CS). How is the vector space of sensory errors encoded by this low-frequency signal? Here, we measured P-cell activity in the oculomotor vermis during saccades, then followed the chain of events from experience of visual error, generation of CS, modulation of SS, and ultimately change in motor-output. We found that while error direction affected probability of CS, error magnitude altered its temporal distribution. Production of CS changed the SS on the next trial, but regardless of the actual visual error, this change biased the movement only along a vector that was parallel to the P-cell’s preferred error. From these results, we inferred the anatomy of a sensory-to-motor adaptive controller that transformed visual error vectors into motor-corrections.

Short-term adaptation of saccades does not affect smooth pursuit eye movement initiation.

Scrutiny of the visual environment requires saccades that shift gaze to objects of interest. In case the object should be moving, smooth pursuit eye movements (SPEM) try to keep the image of the object within the confines of the fovea in order to ensure sufficient time for its analysis. Both saccades and SPEM can be adaptively changed by the experience of insufficiencies, compromising the precision of saccades or the minimization of object image slip in the case of SPEM. As both forms of adaptation rely on the cerebellar oculomotor vermis (OMV), most probably deploying a shared neuronal machinery, one might expect that the adaptation of one type of eye movement should affect the kinematics of the other. In order to test this expectation, we subjected two monkeys to a standard saccadic adaption paradigm with SPEM test trials at the end and, alternatively, the same two monkeys plus a third one to a random saccadic adaptation paradigm with interleaved trials of SPEM. In contrast to our expectation, we observed at best marginal transfer which, moreover, had little consistency across experiments and subjects. The lack of consistent transfer of saccadic adaptation decisively constrains models of the implementation of oculomotor learning in the OMV, suggesting an extensive separation of saccade- and SPEM-related synapses on P-cell dendritic trees.