Barry W. Peterson - US grants

The goal of these experiments is to determine the mechanisms that permit humans to stabilize their heads during body movements and to make smooth, accurate head movements. Sophisticated systems analysis techniques will be used to characterize two classes of mechanisms and to analyze their interactions. The class of mechanisms comprising neurally generated motor commands to the neck muscles will be studied by observing electromyographic activity of muscles that produce horizontal rotations of the head and the head torques or movements related to that activity. The second class of mechanisms comprising mechanically generated torques will be studied at the level of torque and movement measurement before and after head mechanical properties have been altered by adding mass to the head. One important question to be answered is whether short latency vestibulocollic and cervicocollic reflexes make an important contribution to head stabilization and whether their action varies with behavioral context. A second question concerns how these reflexes interact with mechanical forces and forces generated by longer latency voluntary motor commands. The ultimate answer to these and other questions will come from the preparation of a biomechanical model that describes head stabilization and head movements in terms of neural pathways and physical parameters that control head motion. The three lines of experimentation proposed in this grant are designed to converge upon the generation and thorough testing of such a model. It is expected that such a model when completed will be extremely useful both in understanding normal head movements and in diagnosing and treating the many disorders that impair head stability and motility.

Our goal is to describe the neural mechanisms responsible for stabilization and shifts of gaze in cats and primates. Gaze stabilization mechanisms will be investigated by recording reflex responses and the related activity of brainstem neurons with identified input and output connections during rotation of the whole body (vestibular stimulation) and rotation of the head with respect to the body (stimulation of neck receptors). Sinusoidal rotations and linear systems analysis techniques will be used to measure reflexly induced eye and head movements and neuronal activity as a function of stimulus frequency and to determine how neck and vestibular reflexes interact with each other and with movements induced by visual stimulation. Gaze shift (saccadic) systems will be investigated by recording muscle activity, eye movements, head movements, and discharge of identified brainstem neurons during gaze shifts produced by visual stimuli or microstimulation of the superior colliculus. The variation of sacaddic movements with initial eye position and their interaction with vestibular and neck reflexes will be investigated. Mechanisms responsible for recovery of accurate gaze control following loss of vestibular function will be investigated by examining plastic changes in neck reflex activity and in the amplitude of saccadic gaze shifts following vestibular lesions. We will also investigate adaptive changes in vestibular and neck reflexes induced by abnormal visual image motion. Collectively the proposed experiments should provide information about the structure and function of pathways involved in gaze control, which will be helpful in devising clinical procedures for diagnosing and alleviating gaze control disorders and which will contribute to the understanding of basic mechanisms that regulate motor behavior.

Funding is requested to hold a four day meeting on "Control of Head Movement". The meeting will be held from July 9-12, 1986 in Whistler, British Columbia as a sattelite to the 30th Congress of the International Union of Physiological Societies in Vancouver. The meeting will provide the first opportunity for scientists studying neck motor control to meet and share the results of their latest work. It will also result in the publication of the first comprehensive book on control of head movement, a topic of increasing interest in the areas of sensorimotor integration, neurology and rehabilitation medicine.

The goal of this study is to understand how neural circuitry in the brain generates the eye movements required to maintain gaze stability. This problem is of clinical importance since loss of gaze stability severely degrades visual acuity. Since the vestibuloocular reflex serves as a model for motor system function in general, this project will also help to increase understanding of other critical motor processes such as limb movements, postural control and locomotion. A powerful new approach involving analysis of motor function in 3 dimensions will be used to examine the properties of the vestibuloocular reflex (VOR) and optokinetic reflex and of the neural pathways that mediate them. These reflexes will be studied during rotation of an animal or of its visual surround in many planes in 3-dimensional space. Spatial and dynamic properties of the VOR will be determined by recording from the six eye muscles during such rotations. Then activity of single neurons with inputs and projections identified electrophysiologically will be recorded to determine how the brain transforms vestibular input into muscle output. When normal 3-dimensional vestibuloocular behavior has been characterized, plastic changes in the VOR that follow vestibular lesions or visuo-vestibular training will be studied at reflex and neural levels. The goal is to understand how the nervous system compensates for lesions that affect vestibuloocular function, a problem of great importance in the care and rehabilitation of patients suffering from stroke, head trauma or other neurological problems. These experiments should also bring us closer to understanding the neuronal mechanisms underlying motor learning.

Proper stabilization of the head is essential for humans to carry out many of the essential activities of daily living. Throughout most of the activities in which we engage the head is held in a stereotyped position with respect to gravity. This helps to maintain the orientation of the head's special sensory receptors in space and regulates the attitude of the head on the trunk as part of overall postural control. Vestibulocollic reflexes (VCRs), which utilize information from sensors of the vestibular labyrinth to generate neck muscle activity to stabilize the head are a critical part of the head stabilization system. They interact with cervicocollic reflexes (CCRs), voluntary and reaction time movements and head-neck biomechanics in controlling head position. To resolve controversies regarding the importance of each of these four mechanisms, our primary goal involves characterizing the 4 mechanisms and determining how they contribute to head stabilization. A second goal is to determine the dynamic and kinematic properties of voluntary head tracking movements. If successful, the proposed resolution of head stabilization and tracking into their component mechanisms will have broad application to many areas of motor control that await similar analysis. To achieve these goals we will pursue three series of experiments in both human and monkey subjects: Exp. 1 will examine the dynamic properties of the open loop VCR and CCR to determine their transfer functions and will characterize the inertial and viscoelastic properties of human and monkey head-neck mechanical plant. Exp. 2 will perform a similar analysis of the closed loop VCR, where the head is free to move in response to body rotation. Exp. 3 will analyze the dynamic and kinematic properties of voluntary head tracking using electromyographic and fluoroscopic recording to obtain data to test our detailed biomechanical models of the head-neck system. Experimental results will be interpreted using two models. The first is a dynamic model which starts with well tested vestibuloocular reflex models and adds biomechanical properties and multiple rotation axes that characterize the head movement system. It will incorporate elements corresponding to known physiology of labyrinthine receptors and reflex pathways and will attempt to show how position, velocity and acceleration information, embedded in firing patterns of regular and irregular peripheral afferents, drives neck muscles to maintain stability of the head in space. The second is a detailed biomechanical model of the human head-neck system that quantifies the actions of all joints, muscles and passive mechanics and allows prediction of appropriate patterns of muscle activity to stabilize the head in the face of angular and linear perturbations.

This program grant continues our study of neural mechanisms controlling motor performance and homeostasis. Control of movements nad homeostatic functions represents the major set of actions of the central nervous system (CNS). Understanding the CNS mechanisms that underlie these fundamental control systems is of great importance as a basic question in neurobiology and also for the understanding and eventual treatment of many diseases. In recent years neuroscientists have made rapid progress in elucidating the molecular and cellular mechanisms that underlie nervous system functioning. New neuroanatomical techniques have also revealed many of the connections that subserve CNS functions and have provided information about the neural transmitters that they employ. The biggest gap in our understanding of integrative actions of the CNS is the relationship of these pathways and mechanisms to function in a behavioral context. To help fill this gap, we are proposing 8 projects whose goal is to determine how the CNS integrates single neuron activity to generate actual behavior. Peterson proposes to study the control of head movement by vestibulospinal and reticulospinal systems. McCrimmon will investigate the electrophysiology and neuropharmacology of pathways that regulate respiration. McKenna will study brainstem control of sexual reflexes. Rymer will investigate the role of spinal circuits in generating movement synergies. Baker will study the role o the vestibulocerebellum in plastic, adaptive changes in the vestibuloocular reflex. Slate will study the biophysics and pharmacology of plasticity in the cerebellar cortex. Hockberger will study the pacemaker properties of cerebellar Purkinje cells. Houk will study neural substrates of motor programs in the cerebello-rubrospinal system. These eight projects center around four overlapping themes: 1) Brainstem control of patterned motor outputs, 2) organization of motor patterns, 3) cerebellar circuits for sensorimotor control and 4) mechanisms of motor learning. Collectively these four themes represent a concerted attack on some of the most challenging problems of integrative neuroscience. Core support is requested for computer, instrumentation, histology and administration in order to provide the projects with state-of-the-art facilities and support as required to accomplish the scientific aims of this proposal. The unique value of this Program Project lies in the extensive interaction between members of the Program Project group and in the way in which the eight projects and four core facilities serve as magnet to focus their extensive research activities into a concerted effort to confront neural systems problems in novel and effective ways.

behavioral /social science research tag; computer program /software; form /pattern perception; vestibuloocular reflex

computer program /software; biomedical facility; computer data analysis;

This Center is designed to define the contributions of the vestibular system to the control of balance, posture and locomotion through an integrated series of ground-based studies, three examining the vestibular-neck (vestibulocollic) reflex and three the vestibulospinal control of standing posture. One theme of the Center is to exploit the synergy between these two set of studies to produce the first complete whole body model of posture. Any model that is to lead to an adequate understanding of the postural system must incorporate and interrelate mechanisms that stabilize the head in space, the trunk with respect to the head and body center of mass with respect to gravity. Heretofore no investigator or group has had the broad array of skills and insights to attempt such a model or to undertake the interactive experiments needed to obtain the data upon which it must be based. This Center will provide the skills and resources to accomplish this important task which the field has been awaiting for a long time. The second theme of the Center is to focus upon the vestibular otolith organs and the sensory motor responses that occur when they are stimulated by gravitational forces or linear motions. Projects 1, 2 and 6 will bring on line new devices designed specifically to study otolith systems. Modelers involved in Projects 1, 2, 4 and 5 will simulate and model for the first time the role of neural pathways originating in otolith organs in stabilization of the head and body and in locomotion. Recordings proposed in Project 2 will yield the first 3-dimensional analysis of otolith signals at the level of vestibulospinal neurons. Collectively these activities will greatly increase our knowledge of otolith systems, which are of special importance for understanding how the neuro-vestibular system senses and adapts to the alteration in gravity that occurs when a space craft enters orbit and returns to earth with attendant problems of disorientation and dysequilibrium. A third theme of the Center is its extensive use of computational modeling. Projects 1 and 4 share the use of an elegant new biomechanical model that allows one to construct accurate models of musculo-skeletal systems, whose kinetic properties can then be simulated under a wide variety of conditions. Projects 1 and 5 employ non-linear systems models to simulate how central nervous system control of head or body position interacts with body biomechanics. Project 2 uses new neural network modeling approaches to analyze the function of circuits that incorporate the known connectivity of vestibulocollic pathways. Our goal is for these modeling efforts to coalesce into a multi-level model that both simulates postural stabilizing responses observed by us and others and suggests further experiments that will more effectively illumine the functions of the vestibulospinal system. The Center will also have a training component designed to give pre- and postdoctoral trainees unique opportunities to work with outstanding vestibular physiologists and modelers and to participate in work on several Center projects, thus contributing to the cross-fertilization taking place within the Center.

DESCRIPTION (Author's abstract): We propose to continue our behavioral and single unit studies of the vestibuloocular reflex (VOR) focusing on processes that alter its gain and symmetry with changes in target distance and eccentricity. While these processes can produce very large changes almost instantaneously in the angular and linear VORs (AVOR and LVOR), very little is known about their dynamic properties or neuronal substrates. This is especially true for the LVOR, which has only begun to be investigated with state-of-the-art techniques. We will therefore give high priority to examining both low frequency tilt-related and high frequency translational LVORs. Four series of experiments are planned. The first will use intra-axonal recording to study the signals carried by specific groups of feline and primate vestibuloocular relay neurons (VORNs) after which these neurons will be stained to reveal their terminations and somato-dendritic morphology. Other experiments in this series will use extracellular recordings in alert animals to specify the VOR-related signals carried by VORNs whose projections and inputs are identified electrophysiologically. The second series will quantify the 3 dimensional spatial and dynamic properties of tilt and translational LVORs and of processes that adjust the AVOR and LVORs to changes fixation distance or direction in behaving primates while the third will quantify the behavior of identified VORNs during the same behaviors. A fourth series of experiments, carried out by Dr. R. McCrea at University of Chicago, will record activity of single neurons in the nucleus prepositius hypoglossi (a site that plays a major role in integrating VOR eye velocity signals to generate an eye position command) during fixation of near, eccentric visual targets to determine how this nucleus generates the asymmetrical eye position commands required when animals fixate such targets. Extensive use will be made of mathematical models of VOR circuits to predict VOR and neural behavior and interpret experimental results. Because the modulatory processes they will study are essential to maintain the accurate fixation needed to maintain good visual acuity, these studies will have important implications for diagnosing and treating patients with vestibular and cerebellar dysfunction. These studies will also contribute to a broader, multilevel analysis of vestibular signal processing by quantifying the signal transformations that take place in the VOR and relating them to specific classes of vestibular and prepositus hypoglossi neurons, which other projects will then study in vitro to determine whether the same classes of neuron have the requisite biophysical properties to carry out such transformations.

This project examines the cellular basis of signal transformations that occur in vestibular reflexes. Studies of the vestibuloocular reflex have revealed short and long-term multiplicative changes in reflex gain. Functional considerations suggest similar changes should occur in the vestibulocollic reflex. The principal aim of this project is to understand and quantitate the fundamental cellular mechanisms involved in such reflex modulations using an in vitro mouse brain slice preparation. We will study the electrophysiological and pharmacological properties of vestibular afferent input to medial vestibular nucleus (MVN) neurons in these slices. focusing on the kinetic behavior of the ionotrophic glutamate receptors (NMDA and AMPA) which underlie the synaptic currents elicited by repetitive (physiologic) activation of vestibular afferents. These studies will employ both whole-cell recordings of the synaptic currents, and excised patch recordings of single and macroscopic glutamate receptor-mediated currents. We will then study the modulation of this glutamatergic afferent input to vestibular nucleus neurons by cerebellar projections, examining the cellular mechanisms by which GABAergic cerebellar afferents sculpt the response of vestibular reflex interneurons to vestibular afferent inputs. Neuroanatomical labeling techniques will be used to reveal the projections of neurons that are studied so that we can relate our data to afferent activation and cerebellar modulation of speciflt- vestibuloocular and vestibulospinal reflexes. Data obtained from experimental portions of this study will then be used to generate models of vestibular signal processing in the MVN. which will provide key. insights into the neuronal substrates of signal transformations in these vestibular reflexes. Understanding of these reflexes is important since they are essential to maintain the clear vision and stable posture required to carry out many activities of daily living.

DESCRIPTION: Program: This application requests continued support for an established program to train neuroscientists. The program emphasizes the areas of auditory and vestibular dysfunction and the molecular and genetic aspects of sensory and communication disorders. The program proposes research training for three pre- doctoral and four post-doctoral, two M.D. and two Ph.D. trainees, per year for five years. No major changes are proposed in the existing program which consists of prescribed coursework including training in the responsible conduct of science, attendance at seminars and conferences and hands-on laboratory research under the direction of one or more highly qualified preceptors. The program has a long history of producing well-trained independent investigators.

DESCRIPTION (provided by applicant): The head-neck motor system occupies a unique place in the motor control hierarchy. Depending upon behavioral context, it plays an important role in three quite distinct motor functions: head stabilization, saccadic and smooth tracking head movements and voluntary, non-visually guided head movements. We will focus on two strong descending projections to neck motoneurons: vestibulospinal and reticulospinal neurons. To begin filling major gaps in our knowledge about properties of these head control circuits, we propose experiments directed at the following three aims. 1. Characterize and compare patterns of neck muscle activity that monkeys use to execute vestibular stabilizing head movements, slow tracking head movements and rapid saccadic head movements in three dimensions. We will look for evidence that multiple muscle patterns are used in executing a movement. 2. Explore the role of single antidromically identified vestibulospinal and reticulospinal neurons in generating the head movements studied in Aim 1. Neurons will be classified according to the types of eye- and head-movement related signals they carry. We will examine how these neurons implement the brain's ability to cancel out vestibular head movement signals that arise from self-generated head movements. We will also look for evidence that multiple central controllers drive voluntary head movements. 3. Inject neuroanatomical tracers into the cervical spinal cord, brainstem reticular formation or regions of cerebral cortex projecting to vestibular nuclei and reticular formation to visualize pathways involved in neck motor control in primates. Impaired control of head movement is a debilitating symptom of many neurological disorders including stroke, cerebral palsy, Parkinson's disease and vestibular neuropathy. By increasing our understanding of how the CNS controls the head, this project should open the way to better treatment of these disorders.