Edward L. Keller - US grants

We are continuing a research program in the physiology, psychophysics and biophysical analysis of normal and abnormal visual and oculomotor processes. productive collaboration between basic scientists and clinical investigators will be emphasized. The program will comprise work in the following major subdivision: 1) Human ocular motility - quantatitive study of the mechanisms underlying the control and mechanics of normal and abnormal eye movements applied to the calculation of strabismus surgery. 2) Clinical alteration of extraocular muscle function - an alternative to strabismus surgery. 3) Human eyelid movements and forces - evaluated for their feasibility in diagnosis and guidance of ptosis surgery. 4) Three-dimensional aspects of vision and oculomotility - a project to assess translational and rotational movements in an accurate quantitative fashion. 5) A temporal aspect of binocular vision -testing temporal resolution and contour orientation threshold at the fovea. 6) Etiology and diagnosis of retinal and cortical diseases - electrophysiological studies of local cortical properties and binocular interactions in amblyopia, and psychophysical studies in glaucoma. 7) Studies of the oculomoter system of alert primates - single neuron studies of plastic adaptation of the visual-vestibular system. 8) Experimental studies of adenoviral ocular infections - developing immunoenzyme diagnostic tests for adenovirus keratoconjunctivitis. 9) Tactile mobility aid evaluation - studying the feasibility of a system providing the blind with greater spatial resolution and localization capability.

A conference is planned to examine recent results in the broad field of adaptation as applied to visual and oculomotor systems. This conference is the fourth in a series dating back to 1970 which have attempted to provide a focal point for the interchange of information and ideas between basic research scientists in ocular motility, neurophysiology and anatomy, and clinical scientists in the fields of strabismus, amblyopia, and neuro-ophthalmology. As was the case in previous meetings, the organization of the conference is designed to provide an equal participation of these two groups of investigators in order to insure a maximum interdisciplinary cross fertilization. The focus of the meeting is on the adaptive control of vision and eye movements and its clinical implications. Sessions are planned on the following topics: 1) peripheral adaptation at the neuromuscular level in ocular motility disorders; 2) adaptation in primary visual pathways; 3) ocular alignment, retinal correspondence, fusion, and binocularity; 4) oscillopsia and congenital nystagmus; 5) higher visuomotor centers; 6) visual adaptation of oculomotor systems; 7) adaptation to vestibular lesions; and 8) neuronal mechanisms of adaptation. Several speakers will be invited to cover each of these topics from basic science or clinical perspectives. Other pertinent presentations will be selected from abstracts submitted in response to the meeting announcement. The meeting results in the form of papers will be edited and will be published as a separate conference publication.

Our objective is to decipher the organization of the primate oculomotor system at the neuronal level. The basic information provided by this research project in the alert monkey will lead to a deeper understanding of the operation of this system in both normal and diseased states in man. Detailed knowledge of this system will also improve the utility of the extensive battery of diagnostic neuroophthalmological tests that have been developed in recent years. The focus of the present project is on the role of the cerebellum and its most important visual input pathways, those from the pontine nuclei, in the control of ocular motility. Specific aims include: 1) To ascertain the role of several small groups of neurons in the dorsal and lateral portion of the pontine nuclei, including nucleus reticularis tegmenti pontis, the mediodorsal, lateral and the dorsolateral pontine nuclei. This is accomplished by the placement of focal chemical lesions (using lidocaine and ibotenic acid) in each of these regions in monkeys previously trained and tested on a wide variety of visual and oculomotor paradigms. Post lesion tests are designed to uncover deficits in the pursuit, optokinetic or saccadic subsystems or in visuovestibular processing. Additional paradigms test for changes in adaptive capability in the pursuit, saccadic, or vestibular systems. 2) To provide a comprehensive picture of the neuronal processing of visual, vestibular, and oculomotor signals within two regions of cerebellar cortex which receive extensive input from the visual portions of pons, but have not previously been studied in the monkey. To accomplish this goal single-neuron recordings will be made in the uvula and the paraflocculus in alert animals. The same paradigms used in Specific aim (1) will be used to characterize the visual and oculomotor properties of both input and cortical neurons in these two cerebellar regions.

DESCRIPTION (Investigator's Abstract): The long-term goal of this research program is to produce quantitative neurophysiological data in monkey and comprehensive models based on this data that can constitute the basis for a deeper understanding of oculomotor disorders in man. The focus of the neurophysiological investigations during the forthcoming project period will be the organization of dynamic control in the saccadic eye movement system. Specific aims include: (1) Testing of the hypothesis that the superior colliculus provides the dynamic motor error signal that controls saccadic trajectory. This hypothesis will be tested by examining collucular discharge during saccades with highly varied velocity profiles produced by intrasaccadic electrical stimulation of the frontal eye fields or the brainstem omnipauser region or by high speed moving visual targets. (2) Exploration of the hypothesis that the collucular projection circuit composed of nucleus reticularis tegmenti pontis/fastigial nucleus provides an additional corrective control signal to that output by the colliculus. Neurons in these two structures will be recorded during saccades with different initial positions and for saccades made to moving visual stimuli--both examples of the type of saccade which requires an additional dynamic correction to that provided by the colliculus. (3) Investigation of a possible site of the neuronal mechanisms underlying saccadic adaptative gain control by making chemical lesions in the nucleus reticularis and in the fastigial nucleus. Two new development sin oculomotor research form the unifying principle around which all the experiments are planned: (1) The claim that dynamic control of saccadic trajectory is carried out by neurons in the colliculus and not the brain stem as previously supposed. (2) The suggestion that the colliculus may output a control signal to the brainstem premotor circuits which only specifies the metrics of the desired change in gaze. This signal must be refined by subsequent neural circuits to provide the necessary corrections to actually control individual ocular muscles under a variety of conditions. Examples of these varied conditions include saccades from different initial orbital positions, saccades to moving targets, and saccades made after adaptation to alterations in orbital mechanics.

DESCRIPTION (Investigator's Abstract): The long-term goal of this research program is to produce quantitative neurophysiological data in monkey and comprehensive models based on this data that can constitute the basis for a deeper understanding of oculomotor disorders in man. The focus of the neurophysiological investigations during the forthcoming project period will be the organization of dynamic control in the saccadic eye movement system. Specific aims include: (1) Testing of the hypothesis that the superior colliculus provides the dynamic motor error signal that controls saccadic trajectory. This hypothesis will be tested by examining collucular discharge during saccades with highly varied velocity profiles produced by intrasaccadic electrical stimulation of the frontal eye fields or the brainstem omnipauser region or by high speed moving visual targets. (2) Exploration of the hypothesis that the collucular projection circuit composed of nucleus reticularis tegmenti pontis/fastigial nucleus provides an additional corrective control signal to that output by the colliculus. Neurons in these two structures will be recorded during saccades with different initial positions and for saccades made to moving visual stimuli--both examples of the type of saccade which requires an additional dynamic correction to that provided by the colliculus. (3) Investigation of a possible site of the neuronal mechanisms underlying saccadic adaptative gain control by making chemical lesions in the nucleus reticularis and in the fastigial nucleus. Two new development sin oculomotor research form the unifying principle around which all the experiments are planned: (1) The claim that dynamic control of saccadic trajectory is carried out by neurons in the colliculus and not the brain stem as previously supposed. (2) The suggestion that the colliculus may output a control signal to the brainstem premotor circuits which only specifies the metrics of the desired change in gaze. This signal must be refined by subsequent neural circuits to provide the necessary corrections to actually control individual ocular muscles under a variety of conditions. Examples of these varied conditions include saccades from different initial orbital positions, saccades to moving targets, and saccades made after adaptation to alterations in orbital mechanics.

Unlike simple reactive saccades, directing the eyes to a target most appropriate in a given situation requires substantial cognitive processing. Sensory cues present in the environment need to be evaluated in terms of symbolic meanings associated with them. These then have to be translated so that the saccade goal is chosen among alternatives available at the moment. Identifying neural underpinnings of these complex processes is essential for advancing our knowledge of how the brain makes choices and how cognitive information is utilized in oculomotor behavior. Equally important, this knowledge will provide a better understanding such abnormal behaviors as oculomotor apraxia in which reflexive visually-guided saccades are preserved while saccades prompted by verbal commands are impaired and frontal lobe dysfunction in which the inability to make choice decisions is an important feature. Both the latter disorders are of public health concern. In this project, we will collect neural data while saccades are generated as a choice response based on the pre-trained associations between color and spatial location: Animals will attend to visual stimuliof different colors delivered at the fovea and respond with an eye movement to a unique location associated with each color. Experiments are designed to achieve the following specific aims: 1) To characterize neural signals in the superior colliculus (SC) and the cortical frontal eye fields (FEF) related to saccadic choice responses by recording from single neurons. Whether these signals are indeed necessary for saccadic choice responses will be determined by making reversible chemical lesions in the two structures. More specifically, by selectively inactivating the foveal portion of the FEF, we will test the hypothesis that the FEF is the place where sensory cue information given at the fovea is translated into the activation of neurons representing a target in the periphery. 2) To identify the source of cue-driven signalsobserved in the caudal SC. Given the fact that the FEF has abundant connections to this region, we will test the hypothesis that the FEF is the source of cognitive signals recorded in the SC. Reversible lesions will be made in FEF as a SC neuron with cue-driven signals is being recorded. Changes in the activation of the SC during choice response would support this hypothesis. 3) To examine the temporal relationship between the activities in pairs of FEF cells that code for the target location and others that code for non-target locations, while a choice decision is being made. This data will help to differentiate between two currentmodels that attempt to explain the neural mechanisms underlying choice response.