Natela M Shanidze, PhD - US grants

DESCRIPTION (provided by applicant): Eye and head movements must be coordinated to redirect the line of sight ("gaze direction") and to reduce image motion across the retina as the head moves through space. Because these goals are inherently in conflict, the required pattern of coordination is complex. In previous research, eye movements were often used to study vestibular responses (vestibulo-ocular reflex or VOR);experiments were performed in head-restrained subjects undergoing passive rotational stimuli. However, this approach is unable to assess the interplay that naturally occurs between movements of the eye, head, and body and thus is limited in its ability to illuminate the role of the vestibular system in eye-head coordination. In this study, the head is unrestrained and we compare responses to passive whole body rotations (PWBR) and self-generated (active) head movements. PWBR allows for the study of eye and head movements that synergistically contribute to gaze stability. In contrast, during self-generated head movements, compensatory head movements would oppose the animal's intention to redirect the line of sight. Thus, the role of the vestibular system during active head movements must be distinguished from its role during compensatory movements associated with PWBR. The goal of this research is to understand the contribution of the vestibular system during the differing patterns of eye-head coordination provoked by PWBR or self-generated head movements. This goal will be achieved in two specific aims: (1) determine the role of descending vestibular inputs to cervical motoneurons during PWBR and (2) determine the role of descending vestibular inputs to cervical motoneurons during self-generated head movements versus the PWBR condition. Weak galvanic vestibular stimulation (GVS) will be used as an experimental intervention to manipulate the vestibular outflow since this method has been shown to selectively suppress or enhance the vestibular signal from irregular afferents that may preferentially contribute to the vestibulospinal signal. These aims will test the hypothesis that descending vestibular inputs play a significant role in producing the compensatory head movement response during PWBR but may be suppressed during active head movements. Cervical motoneuron activity will be assessed independently of head movement by measuring EMG activity from selected neck muscles involved in the compensatory or active head turns. PUBLIC HEALTH RELEVANCE: Diagnostic tests of inner ear balance mechanisms rely heavily on measurement of eye movements. However, balance is naturally the result of a coordinated interaction of eye, head and body movements;thus consideration of only one of these components may lead to an incomplete understanding of the cause of an inner ear medical problem. This research will be instrumental in the development of novel approaches to clinical tests of inner ear dysfunction as well as its improved treatments.

? DESCRIPTION (provided by applicant): Age-related macular degeneration is the most common cause of vision loss in the central portion of the retina, making central field loss a major problem in the world today. Eye movements essential for everyday tasks are largely reliant on the central retina in humans. As a result, patients with central field loss have poor visual acuity and impaired eye movements, which causes difficulty with reading and facial recognition. Many studies have systematically examined fixation stability in individuals with central field loss and few of these have even looked at saccadic eye movements responsible for target acquisition. To date, however, no study has systematically measured smooth pursuit in these individuals, despite its importance for tracking moving targets. The smooth pursuit system is particularly affected because the patient's central scotoma occludes the target of interest and because the patients' perception of this event may be altered as they are typically unaware of the size, location and even presence of their scotoma. To that end, we propose to study the perception and pursuit of motion in patients with central field loss, as well as in healthy subjects with artificial scotomas that can be precisely controlled for size and location. Because the properties of the patients' binocular vision are further complicated by the discrepant sizes and locations of the scotomas in the two eyes, we propose to conduct the smooth pursuit experiments during both binocular and monocular pursuit.

ABSTRACT Age-related macular degeneration is the most common cause of vision loss in the central visual field, making central field loss (CFL) a major problem in the world today. Two-thirds of patients with CFL complain of vestibular problems, such as dizziness and instability, leading to a high incidence of potentially fatal accidents and falls. The problem is exacerbated by the patient population's advanced age, due to the documented decline in vestibular function in senescence. Vestibular deficits in CFL patients are likely due to miscalibrated or non-optimal stabilizing eye movements - many essential oculomotor behaviors are highly reliant on retinal input. Individuals with compromised vestibular responses have difficulties with visual field stability, navigation, and self- and external motion perception. These limitations are particularly true for CFL patients, whose visual acuity is already compromised and for whom the vestibular system becomes the predominant source of motion information. Furthermore, vestibular deficits likely affect patients' use of head movements to compensate for oculomotor limitations due to eccentric viewing and a patchy visual field. Despite the day-to-day importance of visual and vestibular interaction, these behaviors have not been comprehensively studied in CFL. This proposal seeks to address this gap. The first aim examines the contribution of head movements to smooth pursuit in CFL patients. This aim extends previous work quantifying smooth pursuit deficits in CFL to a more natural, head-unrestrained condition to determine if head movements are helpful or detrimental in CFL. Understanding the contribution of head movements can guide future rehabilitation strategies and clinical testing in this population. The second aim examines the effect of CFL on the angular vestibuloocular reflex (VOR). The reflex has little foveal dependence and is thus likely to be unaffected in CFL. However, foveal vision is known to contribute to both the calibration of this reflex and to its suppression when the head movement follows target motion. A deficit in any aspect of angular VOR will have consequences on the visual instability and vestibular discomfort of the affected individuals. Understanding these problems would inform necessary treatments in this population. The final aim examines the effects of CFL on translational VOR, a behavior that is completely fovea-dependent and is essential when body movement is present. Determining the degree of its impairment and exact influences of CFL is key to understanding vestibular dysfunction due to this visual deficit. VOR responses will be studied during passive and volitional, active motion. Previous research suggests fundamental differences in the processing of these two types of behavior, which indicates that they might be affected differently by central vision loss. If present, this dichotomy could have implications on how patients are advised and trained to interact with their environment while maintaining an active and productive lifestyle. Active behaviors (including head-free smooth pursuit) will be examined during the mentored portion of this project, while passive vestibular studies make up the bulk of the independent research.

Abstract Loss of stability and falls is a major risk factor for injury and death in older adults. Previously overlooked, lifetime noise exposure has been shown to cause damage to the vestibular periphery; although, animal models and human studies that can provide a mechanistic basis connecting noise-induced vestibular dysfunction and age-related fall risk are limited. The vestibular system plays a critical role in detection of head movements and orientation with respect to gravity and is essential for normal vision and postural control. Due to their anatomical proximity to the cochlea, the otolith organs are exposed to sound pressure and are at risk for noise overstimulation, which may contribute to vestibular dysfunction. However, damage may not be limited to the otolith organs. Recent studies have linked noise overstimulation to decreased vestibular nerve activity and loss of a specialized class of irregularly firing vestibular afferents which exhibit enhanced sensitivity to acceleration. It is likely that these afferents play an important role initiating postural compensation for abrupt changes in head or body position due to their physiological characteristics and their projection to secondary vestibular neurons that project to the spinal cord. Therefore, the effects of noise may accelerate disability associated with natural aging. The goal of this proposal is to characterize vestibular loss associated with natural aging and how it is compounded by cumulative noise exposures throughout one?s life. Thus, we will systematically investigate the effects of noise exposure across the lifespan on otolith and canal structure and function (Aim 1), specifically address the extent of irregular afferent damage and its functional consequences (Aim 2), and asses changes in posture, mobility and balance with noise exposure (Aim 3). Changes in sensory cell synapses will be correlated with vestibular reflex impairment and fall risk associated with postural instability and loss of balance. To improve our understanding of how these changes occur over the lifetime, we will assess anatomical and functional changes in early-, middle-, and late-adulthood. Further, functional experiments will be done in parallel in rats and human participants for maximal translation of our results to the clinic. Individually, both animal and rodent studies have proven invaluable to our understanding of the effects of noise exposure on vestibular function. However, both have limitations that can be best addressed with a set of complimentary studies in the two systems. This proposal describes a comprehensive, multidisciplinary approach that strives to evaluate the underlying mechanisms in increased falls and fall risk due to a history of noise exposure in older adults. The susceptibility of these individuals to potentially fatal falls underscores the need for a systematic approach, that can eventually result in improved training and rehabilitation methods to be used with this population.