Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior.

The ability to selectively lesion mouse basal forebrain cholinergic neurons would permit experimental examination of interactions between cholinergic functional loss and genetic factors associated with neurodegenerative disease. We developed a selective toxin for mouse basal forebrain cholinergic neurons by conjugating saporin (SAP), a ribosome-inactivating protein, to a rat monoclonal antibody against the mouse p75 nerve growth factor (NGF) receptor (anti-murine-p75). The toxin proved effective and selective in vitro and in vivo. Intracerebroventricular injections of anti-murine-p75-SAP produced a dose-dependent loss of choline acetyltransferase (ChAT) activity in the hippocampus and neocortex without affecting glutamic acid decarboxylase (GAD) activity. Hippocampal ChAT depletions induced by the immunotoxin were consistently greater than neocortical depletions. Immunohistochemical analysis revealed a dose-dependent loss of cholinergic neurons in the medial septum (MS) but no marked loss of cholinergic neurons in the nucleus basalis magnocellularis after intracerebroventricular injection of the toxin. No loss of noncholinergic neurons in the MS was apparent, nor could we detect loss of noncholinergic cerebellar Purkinje cells, which also express p75. Behavioral analysis suggested a spatial learning deficit in anti-murine-p75-SAP-lesioned mice, based on a correlation between a loss of hippocampal ChAT activity and impairment in Morris water maze performance. Our results indicate that we have developed a specific cholinergic immunotoxin for mice. They also suggest possible functional differences in the mouse and rat cholinergic systems, which may be of particular significance in attempts to develop animal models of human diseases, such as Alzheimer's disease, which are associated with impaired cholinergic function.

Posturographic evidence of nonorganic sway patterns in normal subjects, patients, and suspected malingerers.

During the last 10 years, computerized dynamic posturography has yielded various patterns of sway on the sensory organization test and the motor control test that have been associated with a variety of organic balance disorders. Some aspects of performance during computerized dynamic posturography, however, are under conscious control. Voluntary movements not indicative of physiologic response to balance system stimulation can also affect computerized dynamic posturography results. Quantification of nonorganic or "aphysiologic" response patterns in normal subjects, patients, and suspected malingerers is crucial to justify use of computerized dynamic posturography for identification of physiologically inconsistent results. For this purpose the computerized dynamic posturography records of 122 normal subjects, 347 patients with known or suspected balance disorders, and 72 subjects instructed to feign a balance disturbance were critically evaluated by use of seven measurement criteria, which were postulated as indicating aphysiologic sway. Each criterion was scored with a standard calculation of the raw data in a random, blinded fashion. The results of this multicenter study show that three of the seven criteria are significantly different in the suspected "malingerer" group when compared with either the normal or patient group. The relative strength of each criterion in discerning organic from nonorganic sway provides the examiner with a measure of reliability during platform posture testing. This study demonstrates that computerized dynamic posturography can accurately identify and document nonorganic sway patterns during routine assessment of posture control.

Alternative approaches to the assessment of mild head injury in athletes.

OBJECTIVES: Athletic trainers and team physicians are often faced with decisions concerning the severity and timing of an athletes return to play following mild head injury (MHI). These decisions can be the most difficult ones facing clinicians because of the limited amount of quantitative information indicating injury severity. Several authors have published guidelines for return to play following MHI, however these guidelines are based on limited scientific data. The purpose of this paper was to examine the effects of MHI on two objective measures, postural stability and cognitive function, to determine their usefulness in MHI assessment. The data gathered from these two measures has the potential to establish recovery curves based on objective data. METHODS: Eleven Division I collegiate athletes who sustained a MHI and eleven matched control subjects were assessed for postural stability and cognitive function at four intervals following injury. Postural stability was assessed using the Sensory Organization Test on the NeuroCom Smart Balance Master. Cognitive functioning was measured through the use of four neuropsychological tests: Stroop Test, Trail Making Test, Digits Span and Hopkins Verbal Learning Test. Separate mixed model repeated measures ANOVAs were calculated for the composite score and three ratio (vestibular, visual and somato-sensory) scores from the Sensory Organization Test and the scores from the neuropsychological test to reveal significant differences between groups and across days postinjury. RESULTS: A significant group by day interaction for overall postural stability (composite score) revealed that MHI athletes displayed increased postural instability for the first few days following MHI (p < .05). Analysis of the ratio scores revealed a significant interaction for the visual ratio. No significant group differences were revealed for any of the neuropsychological tests (p > .05), however significant day differences were revealed (p < .05). CONCLUSIONS: The results from this study indicate that athletes demonstrate decreased stability until 3 days postinjury. It appears this deficit is related to a sensory interaction problem, whereby the injured athlete fails to use their visual system effectively. These findings suggest that measures of postural stability may provide clinicians with a useful clinical tool for determining when an athlete may safely return to competition, although these findings need to be confirmed in larger groups of athletes.

Organizing sensory information for postural control in altered sensory environments.

Healthy human subjects can maintain adequate balance despite distorted somatosensory or visual feedback or vestibular feedback distorted by a peripheral vestibular disorder. Although it is not precisely known how this sensorimotor integration task is achieved, the nervous system coordinates information from multiple sensory systems to produce motor commands differently in different sensory environments. These different ways of coordinating sensory information and motor commands can be thought of as "sensorimotor states". The way the nervous system distributes the monitoring of postural sway among states is analysed in this paper as a logical structure of transitions between states. The form of the transition structure is specified and distinguished from a finite state machine. The hypothesis that the nervous system could use a transition structure to maintain balance is tested by developing transition structures which are consistent with a set of experimental observations of postural control in healthy subjects and three groups of patients with peripheral vestibular disease.

What is the minimal vestibular function required for compensation?

Living with an uncompensated, abnormal vestibular system requires oppressive modification of life style and often prevents return to work and activities of daily living. Patients with vestibular abnormalities were studied to determine the minimal residual vestibular function required to achieve compensation. Three groups of patients with (a) complete unilateral loss of vestibular function with normal horizontal canal-vestibulo-ocular (HCVOR) function in the opposite ear, (b) complete unilateral loss with abnormal HCVOR function in the opposite ear, and (c) bilateral reduction of vestibular function from aminoglycoside toxicity underwent vestibuloocular (VOR), optokinetic (OKN), visual-VOR (VVOR), and computerized dynamic posturography (CDP) tests before and after therapeutic procedures. Results suggest that a minimal VOR response amplitude must be present for compensation of VVOR function to occur. The roles of VOR and OKN phase shifts in vestibular compensation are more complicated and require further study. Compensation of vestibulospinal function does not necessarily accompany VOR or VVOR compensation. Ascending and descending vestibular compensatory mechanisms may involve different spatial sensory inputs. Results of these studies have important implications for the diagnosis and treatment of patients with vestibular disorders, including selection and monitoring of patients for therapeutic regimens such as vestibular nerve section and streptomycin therapy.

Gender differences in the balance of healthy elderly as demonstrated by dynamic posturography.

BACKGROUND: Prior studies indicate that older women fall more often than men although there is no evidence of gender-based balance differences. Using a force platform, we measured the effects of restricted sensory input and support surface movement to detect gender differences in balance. METHODS: Healthy, elderly community dwellers (N = 234, mean age = 76 +/- 5 years, 52% female) were administered the following perturbations on the balance platform: The platform and/or visual surround were fixed or tilted proportionally to the subject's sway with the eyes open or closed, forward or backward horizontal translations, and toes-up and toes-down rotations. RESULTS: Gender-based balance differences were not present during quiet standing, or when the support surface or visual input were manipulated separately. Women swayed and lost their balance more than men when the surface was sway-referenced while vision was compromised, but by the third trial their sway control was comparable to the men. Women also initially lost their balance more frequently than men during toes-up and -down rotations, and compared to men continued to lose their balance more often during repeated toes-up rotations. Finally, women developed less angular momentum than men in response to forward platform rotations. DISCUSSION: Elderly women show impairments of balance when simultaneously deprived of visual and somatosensory inputs or during a backwards destabilization. Since there is little evidence for a CNS source for such gender differences, biomechanical origins (e.g., dorsiflexion strength and range of motion) are a more likely cause. Limited postural control of women under conditions stressing balance may explain their greater frequency of falling.

A dynamic posturography study of balance in healthy elderly.

Using dynamic posturography, we studied the balance of 234 community-dwelling elderly subjects (mean age, 76 +/- 5 years) as well as 34 young controls (mean age, 34 +/- 12 years). Almost all measures of balance were worse in elderly subjects compared with young controls. The decrements in older persons indicate a diminished capacity to process conflicting sensory input as well as a possible narrowing of the limit of stability (or, alternatively, an increase in sway). We propose that this occurs most likely as a result of biomechanical or central processing changes as opposed to diminished sensory or vestibular input. Furthermore, with difficult tasks sequentially presented, the performance of the older subjects improved, suggesting that balance, at least in the short term, adapts to stressful conditions. In these elderly subjects screened for age-related diseases affecting balance, only small decrements of balance occurred between the ages of 70 and 85 years. This nominal decrease over a 15-year span suggests that clinically significant balance impairment is the result of age-related disease rather than an inevitable consequence of aging and is therefore potentially treatable.

Postural inflexibility in parkinsonian subjects.

In order to identify the types of postural deficits seen in parkinsonian patients with postural instability, we compared the performance of parkinsonian subjects with young and old control subjects in 3 aspects of postural control: (1) the use of sensory information for postural orientation, (2) the coordination of postural movement patterns in response to surface displacements, and (3) the flexible modification of postural response patterns to changes in support conditions. Parkinsonian subjects had very small sway, even under altered sensory conditions. Postural response latencies to displacements were also normal. Postural instability was associated with abnormal patterns of postural responses including excessive antagonist activity and inflexibility in adapting to changing support conditions. Some parkinsonian subjects appeared to have difficulty sequencing motor programs for postural correction. The parkinsonian subjects appeared stiffer since the rate-of-change of sway in response to displacements was reduced. Levodopa improved postural coordination but not the flexible adaptation to changing support conditions.

Dynamic posturography in the diagnosis and management of dizziness and balance disorders.

This article reviews the basic concepts underlying the balance system, describes the information provided by dynamic posturography, and explains how the technique complements and expands on the information provided by traditional tests of vestibular function.

Postural strategies associated with somatosensory and vestibular loss.

This study examines the roles of somatosensory and vestibular information in the coordination of postural responses. The role of somatosensory information was examined by comparing postural responses of healthy control subjects prior to and following somatosensory loss due to hypoxic anesthesia of the feet and ankles. The role of vestibular information was evaluated by comparing the postural responses of control subjects and patients with bilateral vestibular loss. Postural responses were quantified by measuring 1) spatial and temporal characteristics of leg and trunk EMG activation; 2) ankle, knee, and hip joint kinematics, and 3) surface forces in response to anterior and posterior surface translations under different visual and surface conditions. Results showed that neither vestibular nor somatosensory loss resulted in delayed or disorganized postural responses. However, both types of sensory deficits altered the type of postural response selected under a given set of conditions. Somatosensory loss resulted in an increased hip strategy for postural correction, similar to the movement strategy used by control subjects while standing across a shortened surface. Vestibular loss resulted in a normal ankle strategy but lack of a hip strategy, even when required for the task of maintaining equilibrium on a shortened surface. Neither somatosensory nor vestibular loss resulted in difficulty in utilizing remaining sensory information for orientation during quiet stance. These results support the hypothesis that cutaneous and joint somatosensory information from the feet and ankles may play an important role in assuring that the form of postural movements are appropriate for the current biomechanical constraints of the surface and/or foot. The results also suggest that vestibular information is necessary in controlling equilibrium in a task requiring use of the hip strategy. Thus, both somatosensory and vestibular sensory information play important roles in the selection of postural movement strategies appropriate for their environmental contexts.

Effects of unilateral loss of vestibular function on the vestibulo-ocular reflex and postural control.

Long-term recovery from surgically induced unilateral loss of vestibular function was studied in 14 patients. Seven patients underwent surgical extirpation or section of the vestibular nerve, and seven patients underwent labyrinthectomy without vestibular nerve section. The vestibulo-ocular reflex (VOR) and postural control were evaluated preoperatively and monitored for up to 4 years postoperatively with use of pseudorandom rotation (combined sinusoidal frequencies from 0.009 to 1.5 Hz) and moving platform posturography. Immediately following surgery all patients showed minimal reductions in the VOR gain constant, but marked reduction in the time constant, and marked increase in slow eye velocity bias. Bias returned to normal values within about 10 days, but time constants never returned to normal values. Results of standard Romberg tests in these patients were normal throughout the preoperative and postoperative periods. However, all patients showed marked postural control abnormalities in tests of the ability to maintain balance in unusual sensory environments in the immediate postoperative period. Seventy-five percent of the patients eventually recovered normal postural control. Postural control returned to near baseline performance with a time course similar to that of the VOR bias. However, postural control also continued to improve after the recovery of VOR bias was complete.

Influence of central set on human postural responses.

1. The effect of central set on automatic postural responses was studied in humans exposed to horizontal support-surface perturbations causing forward sway. Central set was varied by providing subjects with prior experience of postural stimulus velocities or amplitudes under 1) serial and random conditions, 2) expected and unexpected conditions, and 3) practiced and unpracticed conditions. In particular, the influence of central-set conditions was examined on the pattern and magnitude of six leg and trunk electromyograph (EMG) activations and associated ankle torque responses to postural perturbations with identical stimulus parameters. 2. The scaling of initial agonist integrated EMG (IEMG) and torque responses to postural perturbation amplitude disappeared when perturbation amplitudes were randomized. This finding suggests that the initial magnitude of postural responses were centrally set to anticipated postural perturbation amplitudes based on sequential experience with the stimulus. 3. Expectation of postural stimulus amplitude had a significant effect on initial torque responses; subjects overresponded when a larger perturbation was expected and underresponded when a smaller perturbation was expected. Expectation of postural stimulus velocity had a smaller effect on initial torque responses, and subjects consistently overresponded when the velocity of the perturbation was unexpected. This difference in amplitude and velocity expectation may be because of the capacity to encode stimulus velocity, but not amplitude information, into the earliest postural responses of the current trial. The relative strength of amplitude and velocity central-set effects varied widely with individual subjects. 4. Central-set conditions did not affect initial EMG response latencies (100 +/- 20 ms, mean +/- SD) or the relative onset of proximal and distal agonists and antagonists. Unexpected or unpracticed stimulus amplitudes, however, were associated with significant late activation of ankle antagonist, tibialis. Thus errors in initial response magnitude because of central-set effects appear to be partially corrected by reciprocal antagonist activity. Agonist IEMG, however, did not always reflect significant changes in torque responses with central-set conditions. 5. Expectation of postural stimulus amplitude and velocity had two different types of effects on the magnitudes of postural responses: 1) a directionally specific, central-set effect consisting of either increased or decreased responses, depending on expectation of stimulus amplitude; and 2) a nonspecific enhanced response to novel stimulus velocities with a gradual reduction when a velocity was presented repeatedly. Two different neural mechanisms are proposed for these two adaptive effects. 6. Reduction of postural response magnitude and antagonist activity during practice may be partially explained by adaptive mechanisms based on expectation because of prior experience with stimulus velocity and amp

Organization of posture controls: an analysis of sensory and mechanical constraints.

We analyse two components of posture control in standing human subjects: (1) the mechanical properties which constrain the body's ability to execute stabilizing postural movements and (2) the mechanical and neural properties which constrain the ability of the vestibular system to sense changes in body orientation. Rules are then proposed to describe the central organization of posture controls within the sensory and mechanical constraints. The organizational rules and knowledge of constraints are combined to predict the effects of selective semicircular canal and utricular otolith lesions on postural stability and the patterns of body and head movements used to maintain balance. Our analysis leads to the prediction that semicircular canal and otolith deficits destabilize patients at different frequencies, and force them to use different patterns of body and head movements. These predictions are compared to posture controls observed in patients with different types of vestibular deficits. The additional steps required to prove or disprove the theory are discussed.

Influence of stimulus parameters on human postural responses.

1. The role of sensory information in shaping muscle activation patterns to postural perturbations in humans was investigated by varying velocity, amplitude, or duration of the perturbing stimulus. Ten normal subjects were exposed to 120 backward translations of the support surface under conditions of varying velocities (10-35 cm/s, constant amplitude), varying amplitudes (1.2-12 cm, constant velocity), or varying durations (40-800 ms). The effects of perturbation parameters on movement kinematics and EMG latencies, patterns, and integrated areas in six trunk and leg muscles were examined. Integrated EMG activity was normalized across subjects and the early (first 75 ms), middle (second 75 ms), and late (last 350 ms) components were analyzed separately. 2. Ankle, knee, and hip angle trajectories and surface reactive forces suggest that a relatively consistent movement strategy was scaled to the perturbation velocities and amplitudes applied. 3. Short-duration perturbations (75 ms) evoked a single burst of muscle activity (75-100 ms duration) in gastrocnemius, hamstrings, paraspinal, and rectus abdominis muscles at latencies too long to be explained by simple stretch reflexes. EMG latencies, patterns, and integrated areas were independent of the velocity and amplitude of the short-duration perturbations, suggesting a minimal time to incorporate peripheral velocity information into the triggered response. 4. For translations lasting longer than 75 ms, the integrated areas of the early agonist EMG bursts were positively correlated with stimulus velocity. The integrated area of later, more tonic EMG components were best correlated with stimulus amplitude. These relationships were found in both distal (stretched) muscles and in proximal muscles. Absolute latencies (94-145 ms), intersegmental latencies (18-29 ms), and burst durations (75-100 ms) were not influenced by the velocity or amplitude of the stimulus. 5. These results suggest that the spatial and temporal organization of automatic postural responses may be organized independently of response intensity. Within a particular spatial-temporal pattern, the amount of muscle activation appears to be adjusted by sensory information, which specifies velocity and amplitude of the perturbation.

Human automatic postural responses: responses to horizontal perturbations of stance in multiple directions.

The effect of the direction of unexpected horizontal perturbations of stance on the organization of automatic postural responses was studied in human subjects. We recorded EMG activity from eight proximal and distal muscles acting on joints of the legs and hip known to be involved in postural corrections, while subjects stood on an hydraulic platform. Postural responses to horizontal motion of the platform in 16 different directions were recorded. The amplitude of the EMG responses of each muscle studied varied continuously as perturbation direction was changed. The directions for which an individual muscle showed measurable EMG activity were termed the muscle's "angular range of activation". There were several differences in the response characteristics of the proximo-axial muscles as opposed to the distal ones. Angular ranges of activity of the distal muscles were unipolar and encompassed a range of less than 180 degrees. These muscles responded with relatively constant onset latencies when they were active. Proximo-axial muscles, acting on the upper leg and hip showed larger angular ranges of activation with bimodal amplitude distributions and/or onset latency shifts as perturbation direction changed. While there were indications of constant temporal relationships between muscles involved in responses to perturbations around the sagittal plane, the onset latency relationships for other directions and the response amplitude relationships for all directions varied continuously as perturbation direction was changed. Responses were discrete in that for any particular perturbation direction there appeared to be a single unique response. Thus, while the present results do not refute the hypothesis that automatic postural responses may be composed of mixtures of a few elemental synergies, they suggest that composition of postural responses is a complex process that includes perturbation direction as a continuous variable.

Quantitative diagnostic test for perilymph fistulas.

Clinically, the definitive diagnosis of perilymph fistulas can only be made by tympanotomy. Results of various fistula tests based upon the vestibulo-ocular reflex have not correlated well with findings during tympanotomy. A new fistula test has been developed based upon vestibulo-spinal responses. By systematic removal of both visual and support-surface orientation references from the subject--leaving only vestibular control of postural reflexes--patients with perilymph fistulas demonstrated an increased (sometimes phase-locked) postural sway in response to sinusoidal changes in external auditory canal pressures. Results from 100 consecutively operated ears (64 patients)--77 of whom underwent preoperative and postoperative moving-platform fistula tests--indicate that the test sensitivity is 97 percent for this highly selective patient population. Absolute specificity could not be determined because, on patients without clinical indications for surgery, tympanotomy is contraindicated.

Central programming of postural movements: adaptation to altered support-surface configurations.

We studied the extent to which automatic postural actions in standing human subjects are organized by a limited repertoire of central motor programs. Subjects stood on support surfaces of various lengths, which forced them to adopt different postural movement strategies to compensate for the same external perturbations. We assessed whether a continuum or a limited set of muscle activation patterns was used to produce different movement patterns and the extent to which movement patterns were influenced by prior experience. Exposing subjects standing on a normal support surface to brief forward and backward horizontal surface perturbations elicited relatively stereotyped patterns of leg and trunk muscle activation with 73- to 110-ms latencies. Activity began in the ankle joint muscles and then radiated in sequence to thigh and then trunk muscles on the same dorsal or ventral aspect of the body. This activation pattern exerted compensatory torques about the ankle joints, which restored equilibrium by moving the body center of mass forward or backward. This pattern has been termed the ankle strategy because it restores equilibrium by moving the body primarily around the ankle joints. To successfully maintain balance while standing on a support surface short in relation to foot length, subjects activated leg and trunk muscles at similar latencies but organized the activity differently. The trunk and thigh muscles antagonistic to those used in the ankle strategy were activated in the opposite proximal-to-distal sequence, whereas the ankle muscles were generally unresponsive. This activation pattern produced a compensatory horizontal shear force against the support surface but little, if any, ankle torque. This pattern has been termed the hip strategy, because the resulting motion is focused primarily about the hip joints. Exposing subjects to horizontal surface perturbations while standing on support surfaces intermediate in length between the shortest and longest elicited more complex postural movements and associated muscle activation patterns that resembled ankle and hip strategies combined in different temporal relations. These complex postural movements were executed with combinations of torque and horizontal shear forces and motions of ankle and hip joints. During the first 5-20 practice trials immediately following changes from one support surface length to another, response latencies were unchanged. The activation patterns, however, were complex and resembled the patterns observed during well-practiced stance on surfaces of intermediate lengths.(ABSTRACT TRUNCATED AT 400 WORDS)

Phase-dependent organization of postural adjustments associated with arm movements while walking.

This study examines the interactions between anteroposterior postural responses and the control of walking in human subjects. In the experimental paradigm, subjects walked upon a treadmill, gripping a rigid handle with one hand. Postural responses at different phases of stepping were elicited by rapid arm pulls or pushes against the handle. During arm movements, EMG's recorded the activity of representative arm, ankle, and thigh segment muscles. Strain gauges in the handle measured the force of the arm movement. A Selspot II system measured kinematics of the stepping movements. The duration of support and swing phases were marked by heel and toe switches in the soles of the subjects' shoes. In the first experiment, subjects were instructed to pull on the handle at their own pace. In these trials all subjects preferred to initiate pulls near heel strikes. Next, when instructed to pull as rapidly as possible in response to tone stimuli, reaction times were similar for all phases of the step cycle. Leg muscle responses associated with arm pulls and pushes, referred to as "postural activations," were directionally specific and preceded arm muscle activity. The temporal order and spatial distribution of postural activations in the muscles of the support leg were similar when arm pull movements occurred while the subject was standing in place and after heel strike while walking. Activations began in the ankle and radiated proximally to the thigh and then the arm. Activations of swing leg muscles were also directionally specific and involved flexion and forward or backward thrust of the limb. When arm movements were initiated during transitions from support by one leg to the other, patterns of postural activations were altered. Alterations usually occurred 10-20 ms before hell strikes and involved changes in the timing and sometimes the spatial structure of postural activations. Postural activation patterns are similar during in-place standing and during the support phase of locomotion. Walking and posture control appear to be separately organized but interrelated activities. Our results also suggest that the stepping generators, not peripheral feedback time locked to heel strikes, modulate postural activation patterns.