Fay B. Horak - US grants

Automatic postural adjustments responsible for human balance will be studied in young and old normal adults, in patients with disorders of posture control, and in elderly people with undiagnosed falling problems. The goal of these studies are 1) to define, quantitatively, the normal repertoire of postural movement strategies in standing humans for different speeds and amplitudes, 2) to determine the effects of peripheral sensory versus central cerebellar disorders on selection and parameterization of postural strategies and approach, and 3) to determine whether falling in the elderly can be related to specific peripheral or central nervous system degeneration. Subjects will stand on a movable platform system. Postural adjustments to a variety of different movement perturbations will be described by analyzing the EMG activity of selected leg and lower trunk muscles and by recording surface forces and motions of the ankle, knee, hip and neck angles. Experiments are designed to test the hypothesis that the CNS preprograms a discrete set of automatic postural strategies, each which is normally triggered within bounded stimulus conditions and that these boundaries can change with neural pathology causing postural instability in the elderly. We predict that peripheral sensory system loss will primarily affect the stimulus boundaries from which intact postural responses are selected whereas central (cerebellar) damage will affect both the internal structure of the postural response and the ability to use prior experience to 'fine tune' the response. Initially, select groups of young and old patients with well-defined peripheral vestibular deficits, peripheral neuropathy and cerebellar deficits will be studied. Results will be used to determine if specific components of postural dyscontrol could be used to identify specific peripheral and central nervous system degenerations in elderly people with well-documented stability problems.

Automatic postural adjustments responsible for human balance will be studied in normal adults and in patients with disorders of posture control. The goal of these studies is to define, quantitatively, the normal repertoire of postural movement strategies in standing humans for different speeds and directions, to address the question of relative contribution of various types of sensory feedback versus central programming in determination of postural strategy selection and then to apply this approach to differentiating between the postural ataxia associated with specific types of peripheral and central CNS-disordered patients. The long term aim is to improve assessment and treatment of patients with postural instability. Subjects will stand on a movable platform system. Postural adjustments to a variety of different movement perturbations will be described by analyzing the EMG activity of selected leg and lower trunk muscles and by recording surface forces and motions of the ankle, knee, hip and neck angles. Experiments are designed to test the hypothesis that the CNS preprograms a discrete set of automatic postural strategies, each of which is normally triggered within bounded stimulus conditions and that these boundaries can change with neural pathology causing postural instability. Select groups of patients with peripheral vestibular deficits, peripheral neuropathy and cerebellar deficits will be studied. The ability of patients to select postural strategies appropriate to conditions as well as the intactness of their postural synergy patterns will be determined.

The long-term goal of this study is to better understand how vestibular and somatosensory information are integrated to control human postural stability. The specific aims of this proposal are: 1) to determine how bilateral loss of vestibular function affects postural responses to surface and vibratory perturbations; 2) to determine whether somatosensory disruption affects postural responses to head and vestibular perturbations; 3) and to characterize how vestibular and somatosensory inputs interact in the control of postural stability. Although vestibular and somatosensory loss are known to cause severe postural instability, the relationships between these sensory systems in normal and disordered postural control are not well understood. Understanding how these sensory systems interact together is important because multisensory deficits involving both the vestibular and somatosensory systems are the most common etiology for "nonspecific" balance problems in the elderly, affecting the majority of people over 70 years old. Compensating for vestibular or somatosensory loss depends upon complex interactions of remaining senses in the central nervous system, yet there are few studies focused on these sensory interactions in humans. We hypothesize that: 1) the loss of peripheral vestibular function in patients with vestibular disorders results in an increased gain of postural responses elicited by somatosensory inputs; 2) that disruption of somatosensory function in patients with diabetic peripheral neuropathy or in healthy subjects standing on altered surfaces results in increased gain of postural responses elicited by vestibular inputs; and 3) that combinations of vestibular and somatosensory perturbations to posture interact in complex ways in healthy subjects. Somatosensory perturbations to stability will be induced mechanically with a moveable platform and directly by muscle vibration. Vestibular perturbations will be induced mechanically with an air-jet head perturber and directly with galvanic stimulation to the mastoid processes. Postural responses of the legs, trunk, and head will be quantified by muscle activation patterns, surface reactive forces under each foot, and kinematics of body motion. The influence of vision will be eliminated by blindfolding all subjects. These studies will provide insight into the interactive mechanisms underlying effective compensation for vestibular and somatosensory deficits. A better understanding of vestibular-somatosensory interactions will allow us to better identify abnormal sensory interactions in patients with balance problems and to develop effective approaches to facilitate sensory compensation.

DESCRIPTION (Adapted from the Applicant's Abstract): The long-term goal of the proposal is to elucidate how somatosensory and vestibular input interact to provide the sensory information which determines postural control. Using Mergner's model of this interaction as the hypothetical construct the proposed studies manipulate vestibular input with anodal, galvanic vestibular stimulation or use patients with vestibular lesions to vary this sensation. In the presence of altered surface somatosensory input the investigators propose that they will demonstrate postural control deficits in these subjects. These defects will be demonstrated by quantified muscle activation patterns (surface EMG), surface reactive forces under each foot (torque, CoP movement), and kinematics of body movement (e.g., CoM movement). For the first series of experiments, the investigators hypothesize that alterations in somatosensory input by surface movement and sway referencing of the surface will reveal vestibulospinal asymmetries and deficits in subjects with vestibular loss. In experiment 1, they will determine if patients with unilateral vestibular loss show postural asymmetries when standing on a slowly tilting or translating platform. In experiment 2, they seek to determine if binaural, anodal galvanic vestibular stimulation produces a temporary, acute loss of vestibular input required for postural control. In the second series of experiments the somatosensory input is limited by selecting subjects with sensory neuropathy to determine if patients compensate for somatosensory loss by altering vestibular sensitivity for posture. They hypothesize that loss of somatosensation will result in an increased sensitivity to vestibular disruption of postural control. In the 3rd experiment they will "total" body somatosensory loss in a patient with a severe loss of large sensory fibers affects responses to galvanic stimulation and surface perturbation. The 4th experiment will characterize how subjects with somatosensory loss in the lower legs caused by diabetic neuropathy respond to galvanic vestibular stimulation during surface perturbations and on a sway referenced surface. The third series of experiments determines the extent to which haptic sensory information can compensate for vestibular loss in supporting postural control. The investigators propose that very light contact of one index finger stabilizes posture by improving control of the trunk when subjects stand on unstable surfaces and that subjects with bilateral loss of vestibular function will show more improvement than normal subjects. Experiment 5 will determine how light touch improves postural stability in narrow stance, on an unstable surface and during surface perturbations. The investigators propose that the studies will lead to a better understanding of the interactive mechanisms underlying compensation for vestibular and somatosensory deficits and which will facilitate development of new approaches to postural rehabilitation in patients with sensory deficits.

DESCRIPTION: (adapted from Investigator's abstract) The long-term goal of this project is to understand the adaptive mechanisms underlying control of postural orientation and equilibrium in stance and gait in order to ameliorate balance and gait disorders. Loss of sensory information in patients with neurological deficits and in the elderly result in problems with gait and balance, and the investigators hypothesize that by manipulating somatosensory information from the support surface they can reveal how somatosensory and vestibular information interact in balance and gait and gain insight into compensation for sensory loss. Specific Aim I: How do bilateral vestibular loss patients use somatosensory information for postural orientation and equilibrium during gait? Recent studies have shown that stepping-in-place on a circular treadmill ("podokinetic stimulation") produces adaptations in locomotor trajectories in normal subjects. The investigators will use adaptation to podokinetic stimulation to reveal how subjects with bilateral vestibular loss use somatosensory information to control navigation trajectories and equilibrium during locomotion. They hypothesize that loss of vestibular information increases reliance on the somatosensory/motor system for spatial orientation and equilibrium. Specific Aim II: Can repeated exposures to podokinetic stimulation result in changes in postural orientation for gait in normal subjects and patients with unilateral vestibular loss? The Investigators hypothesize that repeated exposure to podokinetic stimulation results in enhanced and long-term retention of adaptation in normal subjects, and that podokinetic stimulation can be used to develop rehabilitation approaches for the curved locomotor trajectories and dysequilibrium observed in patients with unilateral vestibular loss. Specific Aim III: What is the effect of adapting to stance on inclined surfaces on postural orientation in healthy subjects and subjects with vestibular loss? The investigators will characterize the long-term effects of adaptation to stance on inclined surfaces in vestibular loss and control patients to reveal the contribution of the somatosensory-motor system to postural orientation. They hypothesize that patients with loss of vestibular (especially otolith) function will demonstrate larger changes in both postural orientation and perceived tilt than normal controls and that active motor control is necessary for adaptation to inclined surfaces. A better understanding of how the somatosensory/motor system, together with the vestibular system, contributes to locomotion and stance posture will allow them to better identify and rehabilitate deficits in balance and gait.

DESCRIPTION (Adapted from the Applicant's Abstract): Balance, gait, speech, and swallowing deficits are major causes of disability in patients with Parkinson's disease (PD). In many patients, these "axial symptoms" are resistant to levodopa therapy. A potential advantage of deep brain stimulation (DBS) of globus pallidus internal (GPi) and the subthalamic nucleus (STN) could be improvement of these axial motor symptoms. Our long-term goal is to determine the effects off DBS on axial motor control in order to understand the role of the basal ganglia in centrally (voluntarily) and peripherally (automatically) initiated axial movements. We hypothesize that there are multiple motor outputs from the basal ganglia with differing sensitivity to dopamine and DBS. The goal of this project is to distinguish functionally different basal ganglia control mechanisms for the axial motor system by their unique patterns of response to DBS and levodopa when used separately and when used in combination. We hypothesize that DBS will he more effective than levodopa and that STN stimulation will be more effective than GPi stimulation for axial parkinsonian symptoms. This project will take advantage of a unique opportunity to rigorously quantify the effects of chronic DBS in radiologically-identified human basal ganglia in a randomized, double-blind study. These studies will quantify forces and movements in two types of postural and oromotor tasks: peripherally triggered, automatic responses to external cues and centrally-initiated voluntary movements. The specific aims are: (1) To determine how DBS affects centrally-initiated and peripherally-triggered postural control. (2) To determine how DBS affects centrally-initiated and peripherally-triggered oromotor control. (3) To investigate the interactions of DBS and levodopa treatment on postural and oromotor control. (4) To determine effects of the site (GPi versus STN) of DBS on postural and oromotor control. These experiments will quantify the efficacy of DBS and levodopa both separately and when combined for balance and oromotor deficits in patients with PD. Quantifying two types of postural and oromotor control in the same subjects will also substantially increase our understanding of the role of the basal ganglia in axial motor control.

The long-term goal of this project is to understand the adaptive mechanisms underlying control of spatial orientation in stance and gait in order to ameliorate balance and gait disorders. Altered surface conditions often result in falls and instability in patients with neurological or vestibular deficits and the elderly. We aim to better understand how the nervous system adapts postural alignment and locomotor trajectory to inclined and moving surfaces. Work in our current grant cycle has shown that adaptation to altered support surfaces during stance and locomotion results in long-lasting kinesthetic after-effects. The proposed studies will examine the central and sensory recalibration mechanisms for adaptation of postural alignment and locomotor trajectories and the role of the cerebellum in this adaptation. We hypothesize that these postural and locomotor after-effects of exposure to altered surfaces reflect a slowly changing, central representation of kinesthetic trunk-to-surface spatial orientation. Our specific aims are: Specific Aim I: To identify similarities among mechanisms responsible for adapting postural alignment and locomotor trajectory. We hypothesize that the CMSuses a common mechanism to adapt postural and locomotor orientation on changing surfaces such that each individual's ability to adapt posture for changes in surface inclination will be correlated with their ability to adapt locomotion for changes in surface conditions. We also hypothesize that both postural and locomotor after-effects of adaptation can be increased with repeated exposure to surface inclinations or rotations. Specific Aim II: To determine the roles of the cerebellum and vestibular systems in adapting stance postural alignment to changes in surface inclination. We hypothesize that the cerebellum is critical for adapting postural orientation to altered surface inclinations and the vestibular system provides an important reference for upright posture when the surface is inclined. Specific Aim III: To clarify the mechanisms underlying coordination and adaptive modulation of curvature in the locomotor trajectory. We hypothesize that turning during locomotion is controlled by regulating the ratio of angular to linear central programs for leg-trunk condition. These studies provide a new conceptual framework to understanding how the nervous system adapts spatial orientation so that novel clinical rehabilitation strategies can be developed to improve control of balance and gait.

DESCRIPTION (provided by applicant): Freezing of gait (FoG) is a common problem in people with Parkinson's disease and causes loss of mobility, falls and decreased quality of life. FoG is mysterious, the clinical phenomenon not fully characterized, the pathophysiology unknown and empirical treatment largely ineffective. The goal of this workshop on FoG is to increase understanding of FoG and to stimulate interest and research on the phenomenon. The ultimate goal is better treatment for patients with FoG. Clinicians interested in FoG and basic scientists interested in motor control, balance and locomotion will gather to examine the clinical phenomenology of FoG, explore basic physiological mechanisms of balance and locomotion that might relate to FoG and to explore the many hypotheses as to the pathogenesis of FoG. Because the workshop will be small with limited attendance, the major outcome of the meeting will be one or more reviews of the topic that will be the first review(s) on this topic and will be a "state of the clinical and basic science" relevant to FoG.

DESCRIPTION (provided by applicant): (30 lines for public) This application addresses the broad Challenge Area (07): Enhancing Clinical Trials and specific Challenge Topic, 07-NS-101: Developing technology to increase efficiency and decrease cost of clinical trials. The long- term objective of this project is to use new technologies to sensitively measure, automatically analyze and efficiently manage clinical trial data for Parkinson's disease (PD) and other neurological disorders. This project will focus on developing objective measures of balance and gait because mobility disability and falls are so critical for quality of life in PD. Clinical movement disorders experts will team up with a local start-up business to develop, produce, and test a novel clinical balance and gait assessment tool, the instrumented Timed Up and Go Test (iTUG) for patients with Parkinson's disease. Balance and gait will be measured with wireless sensors worn on the wrists, ankles and trunk while patients stand up from a chair, walk, turn and return to sit on the chair. Accelerations and angular velocities from the sensors will be automatically transmitted, stored, analyzed, and displayed as Mobility Scores on a remote, centralized computer, along with other patient information important for clinical trials. Specifically, this proposal will 1) create a commercially-available, clinical trial system that includes completely wireless sensor technology, a custom-made, user-friendly, computer interface and efficient data management server;2) develop a mobility score from many potential balance and gait measures and 3) compare the sensitivity of the iTUG compared to traditional clinical tests of balance to changes in PD due to antiparkinson medication. By providing a more sensitive, accurate, and comprehensive method to quickly test and analyze balance and gait, clinical trials to improve mobility in patients with Parkinson's disease and other neurological disorders will be significantly more effective and efficient. This will permit clinical trials in Parkinson's disease to be completed with fewer subjects, shorter duration, and less cost. The current project will accelerate the development of new therapies for Parkinson's disease. This project will use new technology to develop objective instruments and centralized monitoring of balance and gait for Parkinson's disease and other neurological disorders. These new tools will permit clinical trials aimed at reducing mobility disability to be completed with fewer subjects, shorter duration, and less cost.

PROJECT 3 (HORAK): ABSTRACT Balance/gait disorders associated with genetic inheritance in PD Cognitive deficits and balance/gait (B&G) disorders are both progressive but heterogeneous among people with Parkinson's disease (PD), and may be due in part to genetic factors. The inaugural PANUC award demonstrated that APOE ?4 or GBA variants increases the risk for different types of cognitive impairment in PD. Project 3 will test the hypothesis that the pattern of B&G abnormalities, in part an expression of various types of cognitive impairment, differ in PD subjects with APOE ?4, GBA variants, or neither. B&G will be characterized in all Clinical Core participants using novel, inertial-sensors worn on the feet, belt, and wrist. A quick Instrumented Stand and Walk protocol that involves standing quietly for 30 seconds, followed by step- initiation, a 2-minute walk, and several 180 degree turns quantifies various domains of mobility disability, such as postural sway area, gait pace, and gait rhythm. The B&G protocol will also be repeated during simultaneous performance of a quantitative cognitive task to determine the effects of divided attention on B&G. We will test our hypotheses with three specific aims: 1) Cross-sectional: Determine patterns of B&G dysfunction in PD with APOE ?4, GBA variants, or neither, and relate B&G to cognitive impairments in these genetically-defined subsets of PD; 2) Physiological: Relate central cholinergic tone, measured with SAI, to impairments of B&G and attention in in genetically-defined subsets of PD; and 3) Longitudinal: Determine the longitudinal decline of B&G, attention, and cholinergic tone in genetically-defined subsets of PD. This work is significant because it will expand our knowledge of genetic risk for severity and decline in mobility as they relate to cognitive impairments in PD, and lay the foundation for potential cholinergic mechanisms linking cognitive with B&G dysfunction. Insights from this project, integrated within the PANUC, will provide new biomarkers for cognitive and mobility decline for better prognosis and interventions for patients with PD.

Project Summary/Abstract Our long-term goal is to develop effective physical rehabilitation approaches to improve mobility and prevent falls in people with Parkinson?s disease (PD). To reach this goal, the purpose of our proposal is to identify objective measures of turning, gait and mobility activity during daily life that best reflect fall risk and to explore the use of daily life monitoring of mobility as outcome measures for rehabilitation to improve turning quality. Quantification of turning ability with new technology involving body-worn, inertial sensors could provide powerful, new outcomes for clinical trials and clinical practice focused on mobility disability. We hypothesize that objective measures of turning will best discriminate fallers versus nonfallers, predict falls in people with PD without a fall history, and turning can be improved with rehabilitation in PD. Two cross-sectional studies will determine the usefulness of innovative, objective measures of turning, gait, and activity over 7 days of daily living with body-worn inertial sensors for use in rehabilitation. Aim I is a retrospective, observational, study comparing turning, gait, and activity with body-worn sensors in people with PD with and without a history of falls in the previous 12 months. Aim II is a prospective study, only in the nonfallers, investigating the best set of measures of mobility during daily life to predict the first falls in the 12 months after 7 days of daily life monitoring. Aim III is an exploratory, randomized, exercise intervention study to plan a future clinical trial for improving turning in daily life. Specifically, the fallers collected in Aim I will be randomized into a novel, 6-week, Turning Boot Camp group or an Active Control Strengthening) group. This study is designed to advance healthcare of people with PD by improving their mobility function and the quality of their lives by developing more effective rehabilitation for mobility disability. Balance and gait disorders affect most people with chronic disease or neurological disease, resulting in inability to control a critical balance task ? quickly change walking direction (turning). This proposal will improve our understanding of the contribution of turning impairments during community living to falls and parkinsonian impairments and explore whether rehabilitation can improve quality of turning for functional mobility in daily life. Based on these studies, clinicians will be able to use body-worn sensors to quickly and accurately assess quality of turning and implement a novel Turning Boot Camp program focused on improving mobility disability.