Characterizing head motion in three planes during combined visual and base of support disturbances in healthy and visually sensitive subjects.

Multiplanar environmental motion could generate head instability, particularly if the visual surround moves in planes orthogonal to a physical disturbance. We combined sagittal plane surface translations with visual field disturbances in 12 healthy (29-31 years) and 3 visually sensitive (27-57 years) adults. Center of pressure (COP), peak head angles, and RMS values of head motion were calculated and a three-dimensional model of joint motion was developed to examine gross head motion in three planes. We found that subjects standing quietly in front of a visual scene translating in the sagittal plane produced significantly greater (p<0.003) head motion in yaw than when on a translating platform. However, when the platform was translated in the dark or with a visual scene rotating in roll, head motion orthogonal to the plane of platform motion significantly increased (p<0.02). Visually sensitive subjects having no history of vestibular disorder produced large, delayed compensatory head motion. Orthogonal head motions were significantly greater in visually sensitive than in healthy subjects in the dark (p<0.05) and with a stationary scene (p<0.01). We concluded that motion of the visual field could modify compensatory response kinematics of a freely moving head in planes orthogonal to the direction of a physical perturbation. These results suggest that the mechanisms controlling head orientation in space are distinct from those that control trunk orientation in space. These behaviors would have been missed if only COP data were considered. Data suggest that rehabilitation training can be enhanced by combining visual and mechanical perturbation paradigms.

Perturbation parameters associated with nonlinear responses of the head at small amplitudes.

The head-neck system has multiple degrees of freedom in both its control and response characteristics, but is often modeled as a single joint mechanical system. In this study, we have attempted to quantify the perturbation parameters that would elicit nonlinear responses in a single degree-of-freedom neuromechanical system at small amplitudes and velocities of perturbation. Twelve healthy young adults seated on a linear sled randomly received anterior-posterior sinusoidal translations with +/-15 mm and +/-25 mm peak displacements at 0.81, 1.76, and 2.25 Hz. Head angular velocity and angular position data were examined using a nonlinear phase-plane analysis. Poincare sections of the phase plane were computed and Lyapunov exponents calculated to measure divergence (chaotic behavior) or convergence (stable behavior) of system dynamics. Variability of head angular position and velocity across the entire phase plot was compared to that of the Poincare sections to quantify spatial-temporal irregularity. Multiple equilibrium points and positive Lyapunov exponents revealed chaotic behavior at 0.81 Hz at both amplitudes whereas responses at 1.76 and 2.25 Hz exhibited periodic oscillations, clustered phase points, and negative Lyapunov exponents. However, intersubject variability increased at the lowest frequency and a few subjects presented chaotic behavior at all frequencies. An inverted pendulum with position and velocity threshold nonlinearity was adopted as a simplistic model of the head and neck. Simulations with the model resulted in features similar to those observed in the experimental data. Our principal finding was that increasing the perturbation amplitude had a stabilizing effect on the behavior across frequencies. Nonlinear behaviors observed at the lowest stimulus frequency might be attributed to fluctuations in control between the multiple sensory inputs. Although this study has not conclusively pointed toward any single mechanism as responsible for the responses observed, it has revealed clear directions for further investigation. To examine if changing the sensory modalities would elicit a significant change in the nonlinear behaviors observed here, further experiments that target a patient population with some sort of sensory deficit are warranted.

Neuromuscular reflexes contribute to knee stiffness during valgus loading.

We have previously shown that abduction angular perturbations applied to the knee consistently elicit reflex responses in knee joint musculature. Although a stabilizing role for such reflexes is widely proposed, there are as of yet no studies quantifying the contribution of these reflex responses to joint stiffness. In this study, we estimate the mechanical contributions of muscle contractions elicited by mechanical excitation of periarticular tissue receptors to medial-lateral knee joint stiffness. We hypothesize that these reflex muscle contractions will significantly increase knee joint stiffness in the adduction/abduction direction and enhance the overall stability of the knee. To assess medial-lateral joint stiffness, we applied an abducting positional deflection to the fully extended knee using a servomotor and recorded the torque response using a six degree-of-freedom load-cell. EMG activity was also recorded in both relaxed and preactivated quadriceps and hamstrings muscles with surface electrodes. A simple, linear, second-order, delayed model was used to describe the knee joint dynamics in the medial/lateral direction. Our data indicate that excitation of reflexes from periarticular tissue afferents results in a significant increase of the joint's adduction-abduction stiffness. Similar to muscle stretch reflex action, which is modulated with background activation, these reflexes also show dependence on muscle activation. The potential significance of this reflex stiffness during functional tasks was also discussed. We conclude that reflex activation of knee muscles is sufficient to enhance joint stabilization in the adduction/abduction direction, where knee medial-lateral loading arises frequently during many activities.

Postural research and rehabilitation in an immersive virtual environment.

We have united an immersive dynamic virtual environment with motion of a posture platform to record biomechanical and physiological responses to combined visual, vestibular, and proprioceptive inputs. A 6 degree-of-freedom force plate provides measurements of moments exerted on the base of support. Kinematic data from the head, trunk, and lower limb is collected using 3-D video motion analysis. The virtual image is projected via a stereo-capable projector mounted behind the back-projection screen. This system allows us to explore complex behaviors necessary for rehabilitation. We are currently examining how a dynamic visual field affects posture and spatial orientation, and whether visual task demands interfere with our ability to react to a loss of balance in healthy adults and in adults with labyrinthine deficit. Our data suggest that when there is a confluence of meaningful inputs, none of the inputs are suppressed in healthy adults; the postural response is modulated by all existing sensory signals in a non-additive fashion. Labyrinthine deficient adults suppress visual inputs. Individual perception of the sensory structure also appears to be a significant component of the postural response in these protocols. We will discuss the implications of these results for the design of clinical interventions for balance disorders.

Reflex muscle contractions can be elicited by valgus positional perturbations of the human knee.

Experimental evidence on the reflex responses of thigh muscles to valgus mechanical perturbations at the human knee are presented. Random step positional deflections, ranging from 5 degrees to 12 degrees at 60 degrees /s, were applied to the fully extended knees of seven healthy subjects. Subjects were instructed to maintain a constant background co-activation ( approximately 2-11% MVC) of the quadriceps and hamstring muscles prior to and during the mechanical stimulus. We found that the reflex response to sustained valgus joint deflection in the vasti muscles had longer onset latencies (range: 83-92ms) than did the stretch reflex in the same muscles (latencies: 29-31ms). This reflex EMG response consisted typically of a peak followed by sustained muscle activity throughout the step perturbation. The sustained EMG activity was dependent on the amplitude of the perturbing stimulus, but in a nonlinear manner. The long latency of the valgus response suggests that the reflex originates in nonmuscular sensory pathways, potentially from mechanoreceptors lying in periarticular tissues such as joint ligaments and capsule. Analysis of the spatial distribution of reflex responses showed an asymmetrical pattern with preferential activation of medial vs. lateral muscles of the knee. We assess whether these asymmetric reflex contractions could promote joint stability, either by inducing generalized joint stiffening, or by preferential activation of those muscles that are best suited to resist induced ligament strain.

Effects of oestradiol and the oestrogen antagonist Ici 182,780 on the delayed type hypersensitivity (DTH) index and on serum levels of IgM and IgG in ovariectomised Balb/C and MRL/Mp-Lpr/Lpr mice, a model of systemic lupus erythematosus (SLE).

The effects of oestradiol and the oestrogen receptor antagonist ICI 182,780 were investigated on the DTH index, serum IgG and IgM levels and spleen weight in female BALB/c and MRLL/MP-lpr/lpr mice. At six weeks, the mice were ovariectomised, and one week later, over a four-week period, given biweekly s.c. doses of (i) 5 microl of olive oil, or (ii) 5 microl of oil containing 3.2 microg of 17beta-oestradiol (E2), or (iii) 5 microl of oil containing (3.2 microl of E2 + ICI 182,780, at a dose of 30 mg/kg), or (iv) the same dose of ICI 182,780 alone, E2 significantly raised the DTH index in BALB/c mice; this effect was prevented if ICI 182,780 was included in the injection. The DTH index in MRL mice was unaffected by any of the treatments. All steroid treatments raised serum IgG levels in BALB/c mice, but those in sera of MRL were unaffected and were significantly higher than those measured in BALB/c mice. ICI 182,780 depressed IgM in BALB/c mice, while all steroid treatments increased IgM in MRL mice. ICI 182,780 depressed spleen weights in both strains. Oestrogen may influence B cell function through ICI 182,780-sensitive receptors, and ICI 182,780 may have agonist actions on the immune system. (200 words).

Estrogen and progesterone receptors in murine models of systemic lupus erythematosus.

Estrogens are believed to play a role in the etiology of both human and murine systemic lupus erythematosus (lupus; SLE), presumably through the agency of their cellular receptor proteins. There is now considerable interest in the molecular mechanism of action of estrogens in immune tissues, particularly with regard to autoimmune disorders, which are generally more prevalent in women. In this laboratory, an attempt is being made to characterize estrogen receptors in murine models of SLE and to try and relate this to estrogen receptor function in vivo. The initial aim was to compare binding properties of estrogen receptors in brain, reproductive and immune tissues of BALB/c and MRL/MP-lpr/lpr mice. The latter strain spontaneously develops an autoimmune disease resembling human systemic lupus erythematosus (lupus; SLE). It is hypothesized that estradiol, through its receptors, mediates the progression of murine SLE, and that in autoimmune disease, the estrogen receptor is functionally and/or structurally changed. Initial studies suggest that there are differences in estrogen receptors between BALB/c mice, which do not get autoimmune disease, and two strains that do, MRL/MP-lpr/lpr and NZB/W mice. In MRL mice, these differences may be reflected in impaired priming of the progesterone receptor.

Computation of a stabilizing set of feedback matrices of a large-scale nonlinear musculoskeletal dynamic model.

The purpose of this study is to present a general mathematical framework to compute a set of feedback matrices which stabilize an unstable nonlinear anthropomorphic musculoskeletal dynamic model. This method is activity specific and involves four fundamental stages. First, from muscle activation data (input) and motion degrees-of-freedom (output) a dynamic experimental model is obtained using system identification schemes. Second, a nonlinear musculoskeletal dynamic model which contains the same number of muscles and degrees-of-freedom and best represents the activity being considered is proposed. Third, the nonlinear musculoskeletal model (anthropomorphic model) is replaced by a family of linear systems, parameterized by the same set of input/output data (nominal points) used in the identification of the experimental model. Finally, a set of stabilizing output feedback matrices, parameterized again by the same set of nominal points, is computed such that when combined with the anthropomorphic model, the combined system resembles the structural form of the experimental model. The method is illustrated in regard to the human squat activity.

Impaired estrogen priming of progesterone receptors in uterus of MRL/MP-lpr/lpr mice, a model of systemic lupus erythematosus (SLE).

Estrogens exacerbate the autoimmune disease SLE and progesterone is immunoprotective. Estrogens increase synthesis of progesterone receptors (PR) and it is hypothesized that this physiological balance may be impaired in SLE. To test this, cytosolic PR were measured in hypothalamus, thymus and uterus from 6-week-old female ovariectomized BALB/c and MRL/MP-lpr/lpr mice 48 h after s.c. injection of estradiol benzoate (3.2 microg/0.1 ml; OB) in peanut oil or 0.1 ml peanut oil alone. PR were measured using [(3)H]ORG 2058, which does not bind to corticosteroid-binding globulin (CBG), and bound and free ligand were separated using minicolumns of Sephadex LH20 at 0 degrees C. PR were measured in cytosols from hypothalamus and uterus of oil-treated BALB/c mice, but were undetectable in thymus, whereas receptors were measurable in all three tissues of MRL mice. There was a significantly greater priming effect of OB on PR in uterus of BALB/c mice, but not in hypothalamus, and PR became detectable in thymus cytosols from BALB/c mice. Also, the apparent affinity of the binding reaction between [(3)H]ORG 2058 and PR was significantly higher than those measured in other tissues in hypothalamic cytosols of both strains. These results suggest that there is an impairment of estrogen priming of progesterone receptors in uterus and perhaps thymus of MRL mice.

Strain differences in binding properties of estrogen receptors in immature and adult BALB/c and MRL/MP-lpr/lpr mice, a model of systemic lupus erythematosus.

The aim was to compare binding properties of estrogen receptors in brain, reproductive and immune tissues of immature and adult female BALB/c mice, and in the same tissues of MRL/MP-lpr/lpr mice. The latter strain spontaneously develops an autoimmune disease resembling human systemic lupus erythematosus (lupus; SLE). It is hypothesized that estradiol, through its receptors, mediates the progression of murine SLE. High-speed cytosols were prepared from hypothalamus, spleen, thymus and uterus of both strains, and incubated with the synthetic estrogen (3)H-moxestrol (NEN). Scatchard plots were derived from binding isotherms obtained after in vitro incubation. In addition, cervical lymph nodes from MRL mice could be used, but were too small in BALB/c mice. There was a significant increase in the affinity of the binding reaction i.e. a decrease in the apparent molar dissociation constant (Kd), in immune tissues and uterus with maturation in MRL but not BALB/c mice, whose tissues had, overall, a lower affinity for (3)H-moxestrol. Receptor concentrations were significantly higher in spleen and cervical lymph nodes of adult compared with immature MRL mice, but the opposite pattern was observed in BALB/c mouse spleen on maturation. These properties of estrogen receptors in MRL mice may underlie estrogen-mediated exacerbation of murine SLE.

Reflex torque response to movement of the spastic elbow: theoretical analyses and implications for quantification of spasticity.

A parametric model of the human reflex torque response to a large-amplitude, constant angular velocity elbow extension was developed in order to help quantify spasticity in hemiparetic stroke patients, and to better understand its pathophysiology. The model accounted for the routinely observed leveling of torque (i.e., a plateau) at a mean angular increment of 51 degrees +/- 10 degrees s.d. (n = 98) after the initial rise. This torque "plateau" was observed in all eight subjects, and in 98 of 125 trials across 25 experimental sessions. The occurrence of this plateau cannot be explained by decreases in elbow flexor moment arms during elbow extension. Rather, the plateau is attributable to a consistent leveling in muscle activation as confirmed both qualitatively from recordings of rectified, smoothed electromyograph (EMG) activity, and quantitatively using an EMG coefficient model. A parametric model was developed in which the pattern of muscle activation in the stretch reflex response of elbow flexors was described as a cumulative normal distribution with respect to joint angle. Two activation functions, one related to biceps and the other to brachioradialis/brachialis, were incorporated into the model in order to account for observations of a bimodal angular stiffness profile. The resulting model yielded biologically plausible parameters of the stretch reflex response which may prove useful for quantifying spasticity. In addition, the model parameters had clear pathophysiological analogs, which may help us understand the nature of the stretch reflex response in spastic muscles.

The effect of OM-89 (Subreum) on the murine model of systemic lupus erythematosus MRL-lpr/lpr.

OM-89 (Subreum), an E. coli extract, is used clinically in the treatment of rheumatoid arthritis. In this study, the authors examined the effect of OM-89 on some aspects of SLE in the murine model MRL-lpr/lpr. Animals were given OM-89 orally at a dose of 400 mg/kg weight (40 mg active substance) 5 d a week from six weeks old. It was found that mice receiving the drug reached the point of 55% (6/11) survival at the age of 33 weeks compared with 27 weeks for the control group (54%; 7/13). There was a significant increase in the delay before developing alopecia in the treated group (P < 0.01). The increase in proteinuria in the control group was significantly higher than in the treated group (P < 0.03). In a second set of experiments sacrificing the animals at week 22, a significant decrease in anti-dsDNA auto-antibodies was also found in the treated group (P < 0.05), histopathologically a less severe tubular destruction in the kidney was observed in the treated group. It can be concluded that the oral treatment of OM-89 can significantly reduce the severity of SLE in this strain of mice. It can be postulated that the administration of the bacterial extract could modulate the immune response, modifying the Th1 and Th2 balance and inducing oral tolerance.

Effects of an aromatase inhibitor on thymus and kidney and on oestrogen receptors in female MRL/MP-lpr/lpr mice.

The effects of an aromatase inhibitor, 4-hydroxyandrostenedione (4-OHA), which blocks oestrogen formation, have been studied in female MRL/MP-lpr/lpr mice which are a model of SLE. At 11.5 weeks, mice were implanted subcutaneously either with empty Silastic implants or with implants containing 25 mg 4-OHA. At 15 weeks, they were sacrificed by decapitation and liver, thymus, kidneys and uterus taken for wet weight, histology and measurement of cytosolic and nuclear oestrogen receptors. Thymus weights were significantly lower in 4-OHA-treated mice although uterus weights were similar in both groups. Also, whereas thymuses from control-treated mice were packed with plasma cells with abundant cytoplasm, those from 4-OHA-treated mice contained T cells with large nuclei. Relative oestrogen receptor abundances were: uterus > liver > thymus, although cytosolic receptors could not be detected in thymus cytosols of MRL mice unless they were treated with the aromatase inhibitor. In kidney, there was histological evidence that inflammation was limited to mesangium in 4-OHA-treated mice. These results support the hypothesis that oestrogens may be involved in the aetiology of murine SLE and provide data suggesting that substances which block oestrogen production in vivo may be useful to treat certain forms of SLE.