David S. Zee - US grants

The objective of the proposed research is to apply knowledge gained from basic research to the understanding of human ocular motor disorders. Our effort will emphasize 1) quantitative measurements of ocular motor function in both human beings and monkeys, and 2) control systems analysis to intrepret our data. Our first major interest is in the role of the cerebellum in eye movement control. We will investigate in-depth carefully selected groups of patients with abnormalities of ocular fixation related to cerebellar dysfunction as well as trained monkeys with experimental lesions in the cerebellum. We will measure the function of the vestibular, pursuit, optokinetic, and saccadic systems and with the aid of computer simulations compare the effects of simulated lesions to the ocular motor behavior of our patients and experimental animals. Our investigations should 1) provide new information about the neural control and anatomic substrate for both normal and pathologic eye movements, 2) enhance topical neuro-ophthalmologic diagnosis through more precise clinico-pathological correlations, and 3) ultimately enable us to use the knowledge gained to apply optical, pharmacological and neurosurgical techniques to the treatment of the disabling visual disturbances that frequently plague patients with ocular motor disorders and cerebellar disease.

The objective of the proposed research is to learn more about the mechanisms underlying both normal eye movement control and human ocular motor disorders. The research strategy is to make quantitative measurements of ocular motor function in both human beings and monkeys and to use control systems analysis to interpret the findings. Our major interest is in the mechanisms that maintain ocular motor accuracy with particular emphasis on problems peculiar to binocularity, eye muscle proprioception and the cerebellum. We will emphasize the study of adaptive mechanisms that improve binocular functions -- specifically the capability to make disconjugate, orbital-position dependent adjustments that compensate for asymmetrical muscle weakness. We will then use the models of unilateral ocular muscle palsy, prolonged monocular patching and spectacle correction for anisometropia to elicit and to characterize disconjugate ocular motor adaptation. Using techniques to open the vergence disparity feedback loop, we will also study vergence adaptation -- specifically using the initiation of vergence as a measure of vergence dynamics. To define the neurophysiological substrate of these adaptive mechanisms we will study the effects of interruption of ocular muscle proprioceptors and of lesions in the cerebellar flocculus -- the potential anatomical substrate(s) for disconjugate adaptation. Our results will provide new information about (1) disconjugate and vergence adaptive control and how they relate to disorders of ocular alignment such as paralytic and nonparalytic strabismus, (2) the function of ocular muscle proprioceptors, long a glaring unknown in ocular motor physiology and (3) the role of the cerebellum in ocular motor learning and plasticity specifically related to disorders of binocularity.

The objective of the proposed research is to learn more about the mechanisms underlying both normal eye movement control and human ocular motor disorders. The research strategy is to make quantitative measurements of ocular motor function in both human beings and monkeys and to use control systems analysis to interpret the findings. Our major interest is in the mechanisms that maintain ocular motor accuracy with particular emphasis on problems peculiar to binocularity, eye muscle proprioception and the cerebellum. We will emphasize the study of adaptive mechanisms that improve binocular functions -- specifically the capability to make disconjugate, orbital-position dependent adjustments that compensate for asymmetrical muscle weakness. We will then use the models of unilateral ocular muscle palsy, prolonged monocular patching and spectacle correction for anisometropia to elicit and to characterize disconjugate ocular motor adaptation. Using techniques to open the vergence disparity feedback loop, we will also study vergence adaptation -- specifically using the initiation of vergence as a measure of vergence dynamics. To define the neurophysiological substrate of these adaptive mechanisms we will study the effects of interruption of ocular muscle proprioceptors and of lesions in the cerebellar flocculus -- the potential anatomical substrate(s) for disconjugate adaptation. Our results will provide new information about (1) disconjugate and vergence adaptive control and how they relate to disorders of ocular alignment such as paralytic and nonparalytic strabismus, (2) the function of ocular muscle proprioceptors, long a glaring unknown in ocular motor physiology and (3) the role of the cerebellum in ocular motor learning and plasticity specifically related to disorders of binocularity.

Compensation from the loss of function of one labyrinth is an important clinical problem, and an excellent example of sensorimotor adaptation and learning. Patients who undergo acute unilateral vestibular deafferentation (UVD), as a surgical intervention for acoustic neuroma or Meniere's disease, suffer from a variety of vestibular, oculomotor, and postural disorders. Initially, they have a vigorous spontaneous nystagmus due to the sudden imbalance of vestibular tone, which largely resolves itself after a few weeks. Associated with this static imbalance is a dynamic disturbance: the gain (eye velocity / head velocity) of the vestibular- ocular reflex (VOR), in response to head rotations, is significantly decreased, and is lower for rotations toward the lesioned side. This leads to problems of postural stability, disorientation, dizziness, and blurred vision during head motion. The gain of the VOR gradually increases and becomes more symmetric. However, tests of VOR gain with rapid, high- acceleration steps of head rotation show a decreased and asymmetric gain even up to a year after nerve section. We propose a series of studies designed to enhance our knowledge of the process of compensation to UVD. These studies will help us better to understand vestibular adaptation in normals, and will aid us in the development of appropriate exercises for the most rapid and effective rehabilitation of patients after UVD. This project has four major aims. First, to study adaptation to asymmetric vestibular stimuli in normal humans. Second, to measure the ability of patients to adapt to these same stimuli, and determine if adaptive capability in this situation enhances their ability to compensate for UVD. Third, to design visual-vestibular stimuli that provide the most rapid and complete increases in the gain of the VOR in normals, as a preliminary to applying these same stimuli to exercises for UVD patients. Fourth, to promote recovery of vestibular function -- even if the gain of the VOR can not be enhanced -- by a program of rapid combined eye and head movements to visual targets. This task reproduces those circumstances that UVD patients find troubling during recovery; its study in the clinic and laboratory can help us to determine those strategies that patients employ in order to augment an insufficient VOR, so that we can specifically target these strategies in programs of physical therapy.

DESCRIPTION (provided by applicant): The overall goal of this research is to understand the effects of large static magnetic fields, such as those encountered in an MRI machine, on brain function in general and the vestibular system in particular. This proposal follows anecdotal reports of subjects feeling dizzy near and in high strength MRI scanners and builds on an astounding discovery: All normal subjects develop a horizontal spontaneous nystagmus (drift of the eyes) when simply placed in the static field inside a 7 Tesla MRI machine, without any images being taken. This magnetic field-induced nystagmus likely reflects a vestibular imbalance induced by the effect of the magnetic field on the inner ear labyrinths. Previous research on MRI induced vertigo relied largely on subjective reports of dizziness and perception of movement. Using eye movements we have an objective, easily quantified way to investigate the effects of magnetic fields on brain function. Here we propose to investigate this phenomenon to understand its basic mechanism and relationship to labyrinthine function, and to derive the implications 1) for the diagnosis and potentially treatment of patients with brain diseases and especially those of the inner ear, 2) for neuroscientists who must interpret the changes in brain activity associated with different behavioral tasks during functional imaging studies, and.3) for the safety of human patients who undergo MRI scanning and for the health care workers who are exposed to magnetic fields. We first plan to discover whether induction of electric currents, flow of fluids within the semicircular canals, or the diamagnetic properties of labyrinthine structures, is the likely cause of the magnetic field induced nystagmus. Our strategy is to record eye movements using an infrared video system (to look for nystagmus in the dark so that subjects cannot fixate and suppress any induced nystagmus) and simultaneously the strength of the magnetic field as subjects are moved into and out of the bore at different speeds, in magnetic fields of different strength, for different durations in the MRI bore, and with the head in different orientations in the bore. To decipher the role of labyrinthine structures in this phenomenon we will see the pattern of MRI induced nystagmus in patients with different types of labyrinthine loss (e.g., unilateral vs. bilateral, partial vs. complete). We will use vestibular function tests performed away from the magnet including caloric and head rotational responses to assess the function of the semicircular canals, and ocular and cervical vestibular evoked myogenic potentials (VEMPs) to assess the otolith organs. These experiments address fundamental questions about the influence of magnetic fields on brain function. There will be important and potentially unsettling ramifications of the results of these experiments for many key areas of functional imaging research including cognition, motor control and perception. Finally, there are potentially important applications to medical diagnosis and treatment of vestibular disorders. PUBLIC HEALTH RELEVANCE: The research proposed here is directly aimed at understanding the mechanisms by which high strength magnetic fields affect human beings and the vestibular system in particular. Our goal is to develop new techniques for diagnosis and treatment of vestibular disorders. Our results also bear on a wide variety of functional imaging studies of human movement, perception and cognition.