Albert F. Fuchs - US grants

In order to fixate a visual target or in scanning a field of interest, the eyes make one or more rapid eye movements, called saccades. Many of the neural populations that act together to produce these saccadic eye movements are located in restricted regions of the brainstem reticular formation. We propose to study these populations of premotor oculomotor neurons anatomically by proceeding in a stepwise manner, starting with the neurons in the motor nuclei that project into the extraocular muscles. In particular we will determine the populations of neurons that send axons into the motor nuclei, then study the anatomy of one group that produces a burst of spikes, called inhibitory burst neurons (IBNs), and a group of neurons that pause before a saccade, called omnipause neurons (OPNs). The IBNs drive motoneurons directly and OPNs appear to trigger the saccade. By using both anterograde and retrograde antomical tracers we will study the connections of these neuron populations. By this means, it will be possible to begin to demonstrate the pathways in the brain that are used to move the eyes saccadically. The inability to make rapid, accurate saccades results in numerous visual perceptual problems, especially if it occurs early in life, so an understanding of the processes controlling the genesis of will assist in understanding and perhaps correcting these types of visual problems. In addition, because onulomotor populations with differing influences on eye movements are distributed through a major portion of the brainstem, a knowledge of their location and role will be of clinical diagnostic importance. An examination of eye movements and their abnormalities will provide localizing signs for many neurological lesions.

The objective of the proposed research is to continue our studies of mesencephalic, pontine and medullary brainstem structures that are part of or modulate pathways to ocular motoneurons. Three different projects will be undertaken, each of which will employ alert behaving monkeys. Eye position will be accurately measured by an electromagnetic technique and the animal will be trained to track a small moving light spot while subjected to whole body oscillations and full-field movements of the visual world. In the first project, the behavior of the saccadic system will be studied by recording the activity of single cells that are thought to drive the brainstem circuitry involved in saccade generation. In the second project, various neurons believed to particiate in the vestibulo-ocular reflect that stbilizes the visual word on the retina during head rotations will be studied; experiments have been designed to test whether such neurons respond to visual and vestibular inputs and whether they project to ocular motoneurons. In the third project, the discharge patterns of neurons in the pretectum and the nuclei of the accessory optic tract will be recorded to determine their possible role in smooth pursuit eye movements and the optokinetic eye movements generated by full-field movement of the visual surroundings. Studies such as ours that demonstrate the pathways and neural structures involved in different types of eye movements have made it possible to devise clinical tests to diagnose the site of lesions or strokes that cause specific eye movement disorders in human patients.

The staging area for commands that drive motoneurons, which move the eyes, resides in the pontine and medullary reticular formations of the brainstem. When the head is prevented from turning, rapid eye movements, called saccades, shift the direction of gaze with the help of brainstem neurons that discharge a burst of action potentials. These burst neurons are held in check by inhibition from neurons that usually fire steadily but cease firing or pause with all saccades. During the past year we investigated whether, when the head is free to turn and a gaze shift is composed of an eye and a head movement, the pause of these omnipause neurons (OPNs) is still best correlated with eye movement or instead controls head duration or the duration of the overall gaze shift, i.e., eye position + head position. We found that pause duration was poorly correlated with head duration. Moreover, by correlating pause duration with movement duration, we could not ascertain whether pause duration was better correlated with eye or overall gaze duration. However, when we aligned the end of the pause with the end of the saccade, the pause was almost always better aligned with the end of the eye movement than the end of the gaze movement. Therefore, we conclude that the OPNs, which lie in the pons, are involved with the eye component of a gaze shift and not with the overall gaze shift nor the head movement component. In contrast, the firing patterns of various of the aforementioned burst neurons may be better correlated with either the eye movement, the gaze movement, or the overall gaze shift. Pause and burst neurons with these characteristics fit nicely into our model for a separate control of eye and head movements during a gaze shift.

nervous system; Primates; Mammalia;

When the head is moved passively from side to side, compensatory eye movements known as the vestibulo-ocular reflex (VOR) are elicited to rotate the eyes an amount equal to but opposite the head rotation so that the eyes keep looking straight ahead. The presence of this reflex poses a problem when one moves both the eyes and head to acquire a target lying far to the left or right. If both the eyes and head turn leftward to direct gaze to a target, the VOR would defeat this objective by causing the eyes to rotate to the right. In this project, we did two experiments to see how the brain deals with the counterproductive VOR. First, we applied brief perturbations to the head in the middle of a gaze shift to ascertain whether the VOR indeed was turned on during an active gaze shift. If the perturbation of the head movement was in the direction of the gaze shift, there was a reduction of ongoing eye movements as would be predicted if the VOR were on. These experiments, i n contrast to other reports in the literature, indicate that the VOR is not disabled, even at the onset of large amplitude gaze shifts. In the second experiment, we disabled the receptors that sense head movement. Consistent with the data obtained with brief perturbations to the head, gaze initially overshot the target because the VOR was absent and there were no compensatory eye movements. In time, however, compensatory eye movements returned in all three monkeys tested. After performing a series of behavioral tests, we concluded that the compensatory eye movements were generated by enhanced activation of neck receptors and an enhanced signal from the gaze command centers. FUNDING NIH grants RR00166 and EY00745. Freedman, E. G., Ling, L. and Fuchs, A. F. Perturbing the head re-assessing the gain of reflex interactions during orienting eye-head movements. Soc. Neurosci. Abstr. 24 1412, 1998.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Rapid eye movements called saccades remain accurate throughout life despite changes in the brain and the eye muscles brought about by growth, injury and aging. This year we published several observations that implicate the cerebellum in this motor adaptation or learning. First, the cerebellum receives a signal that reports by how much and in what direction saccades, which shift the direction of gaze, are in error. Second, when we stimulate electrically the pathway that delivers this error information to the cerebellum, we are able to cause gradual changes in both the amplitude and direction of saccades, which mimic those produced when there is a real saccade dysmetria. Third, when there is such an error, it causes a concomitant change in the activity of Purkinje cells, which provide the output of the cerebellum. In many P-cells, the changes in activity were appropriate to produce the changes in saccade amplitude that would cause a reduction of the saccade error. Finally, we have made pharmacological injections into this saccadic cerebellum and the preliminary findings suggest that different cerebellar cells are involved in increasing and decreasing saccade amplitude. We feel these results converge on the proposal that the learning of other precision behaviors, e.g., finger pointing, probably also involve similar cerebellar mechanisms.

DESCRIPTION (provided by applicant): In this application, we seek support for a basic research symposium designed to stimulate a thorough discussion of areas of controversy within the field of vestibular physiology and related movement control. The format of this 2 and 1/2 day meeting will elicit summary and position statements from established investigators within the field, followed by a vigorous discussion of these issues by all meeting participants. We will provide established scientists with an opportunity to openly discuss such issues with their colleagues, and encourage younger scientists to identify exciting areas of inquiry within vestibular and motor physiology to help shape their own career interests. We will bring together scientists interested in psychophysics, systems level neuroscience, and cellular and molecular mechanisms to facilitate discussions that incorporate a broad perspective. One objective of the meeting is to produce a series of target articles and commentary which will serve as position papers to guide researchers outside of the field to the timely topics of modern vestibular physiology. These articles will be published in the Journal of Vestibular Research. This symposium is a satellite to the Barany Society Meeting, and will complement the main meeting by providing a venue for basic scientific discussions that will then be related to clinical issues in the main meeting.

This application seeks support for a basic research symposium designed to stimulate a thorough discussion of areas of controversy in the field of vestibular physiology and related movement control. Over the course of 2 and 1/2 days, there will be six workshops concerning active research areas. We will bring together scientists interested in psychophysics, systems level neuroscience, and cellular and molecular mechanisms to facilitate discussions that incorporate a broad perspective. This format will provide basic information to the field at large, help resolve issues by direct confrontation of scientists with disparate views and inform younger investigators about the important issues in the field that they are entering. Indeed, the principal objective of this grant is to generate funds so that junior investigators and women and minority participants who are making exciting contributions to the field but who have limited travel funds may attend the meeting. An airing of the issues raised in this symposium will ultimately guide the clinical application of our knowledge in persons with balance and orientation problems, as well as a variety of motion-induced visual disorders.

DESCRIPTION (provided by applicant): Adaptation of the amplitude of saccadic eye movements is necessary so that saccadic accuracy can be maintained throughout life despite the changes caused by development, injury and aging. The long-term objective of this grant is to study the mechanism and site(s) of saccadic amplitude adaptation in non-human primates. We will address this issue in several ways. First, we will estimate the level of the saccadic system at which adaptation takes place by determining whether behavioral adaptation of reactive (more simple) saccades transfers to higher-order (more "cognitive") saccades. Amplitude adaptation will be produced by requiring monkeys to track a stepping target that is jumped forward or backward during a targeting saccade, so that the adaptation mechanism is deceived into thinking that the saccade is in error. Over approximately 1000 such deceptions, monkeys gradually reduce this error by adjusting saccade amplitude. If adaptation of a reactive saccade does not transfer to a higher-order saccade, they must have different sites for saccadic plasticity. Second, we will record from the oculomotor cerebellar vermis during behavioral adaptation and assess the associated changes in simple spike and climbing fiber activity in Purkinje cells. We expect changes in neuronal firing that will indicate how the saccadic error delivered by the climbing fibers shapes the simple spike firing of Purkinje cells. Third, during behavioral adaptation we also will examine the change in activity of cells in the caudal fastigial nucleus (CFN), which receives direct inhibition from the vermal Purkinje cells and, in turn, projects directly to the premotor brain stem generator of saccadic eye movements. We expect that changes in firing of CFN cells will be appropriate to effect downstream structures to alter saccade amplitude. Because of the remarkable similarities of simian and human saccadic behavior, the results of these experiments should have considerable relevance in the diagnosis, treatment and rehabilitation of human patients with chronic saccadic disorders.