Evaluation of lower limb cross planar kinetic connectivity signatures post-stroke

Following stroke, aberrant three dimensional multijoint gait impairments emerge that present in kinematic asymmetries such as circumduction. A precise pattern of cross-planar coordination may underlie abnormal hemiparetic gait as several studies have underscored distinctive neural couplings between medio-lateral control and sagittal plane progression during walking. Here we investigate potential neuromechanical constraints governing abnormal multijoint coordination post-stroke. 15 chronic monohemispheric stroke patients and 10 healthy subjects were recruited. Coupled torque production patterns were assessed using a volitional isometric torque generation task where subjects matched torque targets for a primary joint in 4 directions while receiving visual feedback of the magnitude and direction of the torque. Secondary torques at other lower limb joints were recorded without subject feedback. We find that common features of cross-planar connectivity in stroke subjects include statistically significant frontal to sagittal plane kinetic coupling that overlay a common sagittal plane coupling in healthy subjects. Such coupling is independent of proximal or distal joint control and limb biomechanics. Principal component analysis of the stroke aggregate kinetic signature reveals unique abnormal frontal plane coupling features that explain a larger percentage of the total torque coupling variance. This study supports the idea that coupled cross-planar kinetic outflow between the lower limb joints uniquely emerges during pathological control of frontal plane degrees of freedom resulting in a generalized extension of the limb. It remains to be seen if a pattern of lower limb motor outflow that is centrally mediated contributes to abnormal hemiparetic gait.     

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.     

The effect of connective tissue material uncertainties on knee joint mechanics under isolated loading conditions

Although variability in connective tissue parameters is widely reported and recognized, systematic examination of the effect of such parametric uncertainties on predictions derived from a full anatomical joint model is lacking. As such, a sensitivity analysis was performed to consider the behavior of a three-dimensional, non-linear, finite element knee model with connective tissue material parameters that varied within a given interval. The model included the coupled mechanics of the tibio-femoral and patello-femoral degrees of freedom. Seven primary connective tissues modeled as non-linear continua, articular cartilages described by a linear elastic model, and menisci modeled as transverse isotropic elastic materials were included. In this study, a multi-factorial global sensitivity analysis is proposed, which can detect the contribution of influential material parameters while maintaining the potential effect of parametric interactions. To illustrate the effect of material uncertainties on model predictions, exemplar loading conditions reported in a number of isolated experimental paradigms were used. Our findings illustrated that the inclusion of material uncertainties in a coupled tibio-femoral and patello-femoral model reveals biomechanical interactions that otherwise would remain unknown. For example, our analysis revealed that the effect of anterior cruciate ligament parameter variations on the patello-femoral kinematic and kinetic response sensitivities was significantly larger, over a range of flexion angles, when compared to variations associated with material parameters of tissues intrinsic to the patello-femoral joint. We argue that the systematic sensitivity framework presented herein will help identify key material uncertainties that merit further research and provide insight on those uncertainties that may not be as relative to a given response.     

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.     

Roles of Glutamine Synthetase Inhibition in Epilepsy

Glutamine synthetase (GS, E.C. 6.3.1.2) is a ubiquitous and highly compartmentalized enzyme that is critically involved in several metabolic pathways in the brain, including the glutamine-glutamate-GABA cycle and detoxification of ammonia. GS is normally localized to the cytoplasm of most astrocytes, with elevated concentrations of the enzyme being present in perivascular endfeet and in processes close to excitatory synapses. Interestingly, an increasing number of studies have indicated that the expression, distribution, or activity of brain GS is altered in several brain disorders, including Alzheimer’s disease, schizophrenia, depression, suicidality, and mesial temporal lobe epilepsy (MTLE). Although the metabolic and functional sequelae of brain GS perturbations are not fully understood, it is likely that a deficiency in brain GS will have a significant biological impact due to the critical metabolic role of the enzyme. Furthermore, it is possible that restoration of GS in astrocytes lacking the enzyme could constitute a novel and highly specific therapy for these disorders. The goals of this review are to summarize key features of mammalian GS under normal conditions, and discuss the consequences of GS deficiency in brain disorders, specifically MTLE.