Vallabh E. Das - US grants

DESCRIPTION (provided by applicant): Binocular alignment must be maintained in the horizontal, vertical and torsional planes to ensure binocular sensory fusion. Normal development ensures binocular alignment during fixation and binocular coordination during eye movements. Unfortunately, abnormal visual experience during development usually leads to ocular misalignment (strabismus). In fact, various studies have reported the incidence of strabismus to be about 2-5% of the infant population. Data from strabismic humans and from strabismic monkeys in our laboratory have shown that ocular misalignment is accompanied by a lack of conjugate eye movements. Though strabismus is most often associated with a horizontal misalignment, often a combined horizontal, vertical and torsional misalignment is observed. Along with the static horizontal, vertical and torsional misalignment, there appears to be substantial dynamic cross-talk between the principal eye movement planes. In the clinical literature these apparent cross-axis interactions are usually described as 'A' and 'V' patterns of strabismus. Unfortunately, there is a lack of understanding of the neural or mechanical bases for these cross-axis movements, the putative relationship or lack thereof to the neural control of horizontal, vertical or torsional eye movements and the relationship to the etiology of the strabismus. Competing hypotheses include static malpositioning of extraocular muscle pulleys, sideslip of extraocular muscles and muscle pulleys, torsional control of eye movements gone awry leading to apparent muscle dysfunction and finally simply unexplained overaction/underaction of individual extraocular muscles. The goal of our studies is to clarify static and dynamic properties of cross-axis movements and examine its source in animals with a sensory induced strabismus. Our approach will include structural imaging of extraocular muscle to determine role of muscle pulleys; behavioral experiments to examine control of torsion and Listing's laws; neurophysiological experiments to examine the role of motor and pre-motor structures in the brain and biomechanical modeling of extraocular musculature to simulate experimental data. Completion of our studies will be of benefit to the understanding and treatment of certain types of strabismus.

eye movements; eye coordination disorder; binocular vision; Primates; animal colony;

neurophysiology; eye coordination disorder; Macaca; animal colony;

Description (provided by applicant): Developmental strabismus of sensory origin is a significant public health problem since it affects 2-5% of the infant population. Previously we showed that rearing infant monkeys under conditions of alternate monocular occlusion (AMO) reproduced a sensory strabismus syndrome with large horizontal misalignment, A/V patterns, and Dissociated Vertical Deviation (DVD). An important finding in the previous cycle was that neural factors were responsible for generating cross-axis eye movements that lead to appearance of A/V patterns and DVD. Several lines of evidence including clinical and monkey lesion studies suggest that circuits involving the midline cerebellum are important in binocular control of eye movements including alignment of the eyes. Therefore, in the current cycle, we focus on identifying the actual source for cross-axis movements by performing single cell recording and inactivation studies in the Fastigial Nucleus (FN) and the adjacent Posterior Interposed Nucleus (PIN) of the cerebellum. The experiments are organized into three specific aims. Specific aim 1 involves neuronal recording in the FN and PIN. The general approach here is to identify neuronal subtypes in each structure and examine neuronal responses for correlation to strabismus angle or cross-axis movements. One of the hypotheses that we are testing is whether neural activity related to the horizontal misalignment is maintained in cells different from those that encode cross-axis movements. In specific aim 2, we will perform unilateral and bilateral inactivation of the left and right FN and PIN using the GABAA agonist muscimol. The overall goal of these experiments is to determine relative functional contribution of the two target structures in defining properties of strabismus. Several hypotheses that will clarify roles of FN and PIN on one or both sides of the brain and relative contribution towards producing eye misalignment and cross-axis movement role will be tested. Aim 3 proposes recording from excitatory burst neurons in the paramedian pontine reticular formation to determine whether the pulse signal that drives cross-axis movements is encoded monocularly or binocularly. The strategy here is to use the framework developed via studies of binocular coordination in normal monkeys to address ocularity of drive signals for cross-axis movements. A second theme within all the aims is to compare the AMO model and a more traditionally used model for sensory strabismus, the prism-rearing model. The main goal in performing comparative studies is to validate the AMO model. The AMO and prism-rearing models differ in the type of binocular visual experience during development though they both produce similar behavioral outcomes such as A/V patterns and DVD. Therefore a second outcome is that these comparisons will clarify effect of type of binocular visual experience during development on patterns of activity within oculomotor circuits. Completion of our studies will be of benefit to the understanding and treatment of certain types of strabismus. PUBLIC HEALTH RELEVANCE Ocular misalignment (strabismus) is a developmental disorder that affects a significant number of children born in the United States and around the world. A better understanding of neural mechanisms that are affected in the different forms of strabismus will help develop rationally based therapy. This particular project will combine various physiological methods and behavior in an animal model to understand the specific problem of A/V-pattern strabismus.

DESCRIPTION (provided by applicant): Although surgical correction is often the preferred treatment method for strabismus, there can be problems with the outcome. By some accounts, 20-40% of strabismus correction surgeries fail in one way or another and therefore re-operation is required. We suggest that a reason strabismus surgery sometimes fails is that there are adaptive processes that follow the treatment that may work to negate the effects of surgery and revert the eyes to a previous state of misalignment. These adaptive processes might be localized to muscle itself (muscle remodeling) or might involve neural processes (central nervous system remodeling). The goal of this project is to develop a better understanding of the neural adaptive changes that follow strabismus correction surgery which in turn may provide additional insight into reasons for failure or success following treatment. Studies from our laboratory have shown that specially rearing infant monkeys under conditions that disrupted binocular vision reproduced a sensory strabismus syndrome with large horizontal misalignment, A/V patterns, Dissociated Horizontal Deviation (DHD) and Dissociated Vertical Deviation (DVD). Our strategy for this project is first to characterize the neural drive to horizontal extraocular muscles (medial and lateral recti) of the strabismic monkeys by recording from motoneurons in the oculomotor and abducens nuclei. Thereafter, we will treat the strabismus in these animals using similar resection or recession surgery techniques to those used in human patients. Following treatment, we will record neural responses from the same motor nuclei. Comparison of the pre- and post-surgery population neural drive to horizontal extraocular muscles will provide data on how the brain adapts to a muscle strengthening or weakening procedure. In the final aim, we will record from cells in the supraoculomotor area to examine whether the neural adaptation that follows surgical treatments has its origin in vergence circuits. Completion of our studies will be of benefit to the understanding and treatment of developmental forms of strabismus.

The Research Computer Programing Core Module will provide software design and development services to support and advance innovative vision research. The module will provide project management of custom research software and will develop or supervise development of software when the scope or sophistication of the project goes beyond what an individual investigator's lab can undertake. The principal developer works closely with investigators to clarify and document the software requirements, taking into consideration their unique needs regarding the user interface and data management, as well as technical requirements of the application. The module also will provide consultation and assistance regarding algorithms and debugging, data management, and communication with vendors on technical issues for Core investigators, their collaborators, newly hired investigators, research staff and graduate students who develop their own software. The Core Module will be supervised by Vallabh Das, PhD, Benedict Pitts Professor of Optometry and Vision Science, with a joint appointment with Biomedical Engineering. Dr. Das is an NEI-funded investigator (13 yrs) who has extensive expertise in software development for neurophysiological investigations of the oculomotor system.