Silatrane-Sulfonamide Hybrids as Promising Antibacterial Agents.

At the A. E. Favorsky Irkutsk Institute of Chemistry, a series of silatrane-sulfonamide hybrids 1a-d and 2a-d was synthesized. The antibacterial activity of 1a, 1b, 1d, 2a, and 2b against test strains of bacteria Yersinia pestis EV NIIEG, Yersinia enterocolitica 628/1, Listeria monocytogenes 766, and Starhylococcus aureus ATCC 6538-P (FDA 209-Р) was evaluated. The minimum inhibitory concentration for silatrane-sulfonamide hybrids was 100-200 mg/liter. Silatrane-sulfonamide hybrid 1d was the most active against all tested strains: minimum inhibitory concentration 100 mg/liter. Exposure to silatrane-sulfonamide hybrids in a doses of 100-200 mg/liter inhibited culture growth by 50-75%.

Synthesis, structure, spectral and luminescence studies of novel guanidinium aryl(oxy)(sulfanyl)(sulfonyl)acetates.

A series of promising luminescent materials, nonlinear optical crystals, and physiologically active compounds - aryl(oxy)(sulfanyl)(sulfonyl)acetates of guanidine (A) of unknown type was synthesized. Various functional groups present in (A) were identified using FTIR spectroscopy. 1H and 13C NMR spectral studies further confirm the molecular structure (A). Crystals of guanidinium 4-chlorophenyl(sulfanyl)acetate (1) and guanidinium 4-chlorophenyl(sulfonyl)acetate (2) were successfully grown. They belong to the same lowest symmetry category, but to different crystal systems: monoclinic (1) and orthorhombic (2). It has been established that intrinsic optical absorption begins at a wavelength of âˆ¼ 290 nm for crystalline compound (1) and âˆ¼ 335 nm for crystal (2). The intrinsic luminescence spectrum of crystal (1) includes two bands with maxima at 300 and 515 nm. In the intrinsic luminescence spectrum of crystal (2), only one band is observed with a maximum at 350 nm. Such luminescence in both crystals is excited in the intrinsic absorption bands, as well as by X-ray radiation. In addition, in the near ultraviolet and throughout the visible region, where optical absorption is not detected (it is very weak), low-inertia (less than 10 ns) rather intense luminescence of uncontrolled impurity-defect centers is excited. The spectral bands of optical absorption, photo- and X-ray luminescence discovered in experiments were systematized using a diagram of energy levels and quantum transitions in crystals and defect centers of the compounds under study.

A virtual reality-based system integrated with fmri to study neural mechanisms of action observation-execution: a proof of concept study.

PURPOSE: Emerging evidence shows that interactive virtual environments (VEs) may be a promising tool for studying sensorimotor processes and for rehabilitation. However, the potential of VEs to recruit action observation-execution neural networks is largely unknown. For the first time, a functional MRI-compatible virtual reality system (VR) has been developed to provide a window into studying brain-behavior interactions. This system is capable of measuring the complex span of hand-finger movements and simultaneously streaming this kinematic data to control the motion of representations of human hands in virtual reality. METHODS: In a blocked fMRI design, thirteen healthy subjects observed, with the intent to imitate (OTI), finger sequences performed by the virtual hand avatar seen in 1st person perspective and animated by pre-recorded kinematic data. Following this, subjects imitated the observed sequence while viewing the virtual hand avatar animated by their own movement in real-time. These blocks were interleaved with rest periods during which subjects viewed static virtual hand avatars and control trials in which the avatars were replaced with moving non-anthropomorphic objects. RESULTS: We show three main findings. First, both observation with intent to imitate and imitation with real-time virtual avatar feedback, were associated with activation in a distributed frontoparietal network typically recruited for observation and execution of real-world actions. Second, we noted a time-variant increase in activation in the left insular cortex for observation with intent to imitate actions performed by the virtual avatar. Third, imitation with virtual avatar feedback (relative to the control condition) was associated with a localized recruitment of the angular gyrus, precuneus, and extrastriate body area, regions which are (along with insular cortex) associated with the sense of agency. CONCLUSIONS: Our data suggest that the virtual hand avatars may have served as disembodied training tools in the observation condition and as embodied "extensions" of the subject's own body (pseudo-tools) in the imitation. These data advance our understanding of the brain-behavior interactions when performing actions in VE and have implications in the development of observation- and imitation-based VR rehabilitation paradigms.

Does training with traditionally presented and virtually simulated tasks elicit differing changes in object interaction kinematics in persons with upper extremity hemiparesis?

OBJECTIVE: To contrast changes in clinical and kinematic measures of upper extremity movement in response to virtually simulated and traditionally presented rehabilitation interventions in persons with upper extremity hemiparesis due to chronic stroke. DESIGN: Non-randomized controlled trial. SETTING: Ambulatory research facility. PARTICIPANTS: Subjects were a volunteer sample of twenty one community-dwelling adults (mean age: 51 ± 12 years) with residual hemiparesis due to stroke more than 6 months before enrollment (mean: 74 ± 48 months), recruited at support groups. Partial range, against gravity shoulder movement and at least 10° of active finger extension were required for inclusion. All subjects completed the study without adverse events. INTERVENTIONS: A 2 weeks, 24-hour program of robotic/virtually simulated, arm and finger rehabilitation activities was compared to the same dose of traditionally presented arm and finger activities. RESULTS: Subjects in both groups demonstrated statistically significant improvements in the ability to interact with real-world objects as measured by the Wolf Motor Function Test (P = 0.01). The robotic/virtually simulated activity (VR) group but not the traditional, repetitive task practice (RTP) group demonstrated significant improvements in peak reaching velocity (P = 0.03) and finger extension excursion (P = 0.03). Both groups also demonstrated similar improvements in kinematic measures of reaching and grasping performance such as increased shoulder and elbow excursion along with decreased trunk excursion. CONCLUSIONS: Kinematic measurements identified differing adaptations to training that clinical measurements did not. These adaptations were targeted in the design of four of the six simulations performed by the simulated activity group. Finer grained measures may be necessary to accurately depict the relative benefits of dose matched motor interventions.

Control processes underlying elbow flexion movements may be independent of kinematic and electromyographic patterns: experimental study and modelling.

Using a non-linear dynamic model based on the lambda version of the equilibrium-point hypothesis, we investigated the shape and duration of the control patterns underlying discrete elbow movements. The model incorporates neural control variables, time-, position- and velocity-dependent intrinsic muscle and reflex properties. Two control variables (R and C) specify a positional frame of reference for activation of flexor and extensor motoneurons. The variable R (reciprocal command) specifies the referent joint angle (R) at which the transition of net flexor to extensor active torque or vice versa can be observed during changes in the actual joint angle elicited by an external force. The variable C (coactivation command) surrounds the transition angle by an angular range in which flexor and extensor muscles may be simultaneously active (if C > 0) or silent (if C < or = 0). An additional, time-dimensional control variable (mu command) influences the dependency of the threshold of the stretch reflex on movement velocity. This control variable is responsible for the reflex damping. Changes in the R command result in shifts in the equilibrium state of the system, a dynamical process leading to electromyographic modifications and movement production. Commands C and mu provide movement stability and effective energy dissipation preventing oscillations at the end of movement. A comparison of empirical and model data was carried out. A monotonic ramp-shaped pattern of the R command can account for the empirical kinematic and electromyographic patterns of the fastest elbow flexion movements made with or without additional inertia, as well as of self-paced movements. The rate of the shifts used in simulation was different for the three types of movements but independent of movement distance (20-80 degrees). This implies that, for a given type of movement, the distance is encoded by the duration of shift in the equilibrium state. The model also reproduces the kinematic and electromyographic patterns of the fastest uncorrected movements opposed in random trials by a high load (80-90% of the maximal) generated by position feedback to a torque motor. The following perturbation effects were simulated: a substantial decrease in the arm displacement (from 60-70 degrees to 5-15 degrees) and movement duration (to about 100 ms) so that these movements ended near the peak velocity of those which were not perturbed; a prolongation of the first agonist electromyographic burst as long as the load was applied; the suppression of the antagonist burst during the dynamic and static phases of movements: the reappearance of the antagonist burst in response to unloading accompanied by a short-latency suppression of agonist activity. These kinematic and electromyographic features of both perturbed and non-perturbed movements were reproduced by using the same control patterns which elicited a monotonic shift in the equilibrium state of the system ending before the peak velocity of non-perturbed movements. Our results suggest that the neural control processes underlying the fastest unopposed changes in the arm position are completed long before the end of the movement and phasic electromyographic activity. Neither the timing nor the amplitude of electromyographic bursts are planned but rather they represent the long-lasting dynamic response of central, reflex and mechanical components of the system to a monotonic, short-duration shift in the system's equilibrium state.

The interaction of visual and proprioceptive inputs in pointing to actual and remembered targets in Parkinson's disease.

We previously reported that Parkinson's disease patients could point with their eyes closed as accurately as normal subjects to targets in three-dimensional space that were initially presented with full vision. We have now further restricted visual information in order to more closely examine the individual and combined influences of visual information, proprioceptive feedback, and spatial working memory on the accuracy of Parkinson's disease patients. All trials were performed in the dark. A robot arm presented a target illuminated by a light-emitting diode at one of five randomly selected points composing a pyramidal array. Subjects attempted to "touch" the target location with their right finger in one smooth movement in three conditions: dark, no illumination of arm or target during movement; movement was to the remembered target location after the robot arm retracted; finger, a light-emitting diode on the pointing fingertip was visible during the movement but the target was extinguished; again, movement was to the remembered target location; and target, the target light-emitting diode remained in place and visible throughout the trial but there was no vision of the arm. In the finger condition, there is no need to use visual-proprioceptive integration, since the continuously visualized fingertip position can be compared to the remembered location of the visual target. In the target condition, the subject must integrate the current visible target with arm proprioception, while in the dark condition, the subject must integrate current proprioception from the arm with the remembered visual target. Parkinson's disease patients were significantly less accurate than controls in both the dark and target conditions, but as accurate as controls in the finger condition. Parkinson's disease patients, therefore, were selectively impaired in those conditions (target and dark) which required integration of visual and proprioceptive information in order to achieve accurate movements. In contrast, the patients' normal accuracy in the finger condition indicates that they had no substantial deficits in their relevant spatial working memory. Final arm configurations were significantly different in the two subject groups in all three conditions, even in the finger condition where mean movement endpoints were not significantly different. Variability of the movement endpoints was uniformly increased in Parkinson's disease patients across all three conditions. The current study supports an important role for the basal ganglia in the integration of proprioceptive signals with concurrent or remembered visual information that is needed to guide movements. This role can explain much of the patients' dependence on visual information for accuracy in targeted movements. It also underlines what may be an essential contribution of the basal ganglia to movement, the integration of afferent information that is initially processed through multiple, discrete modality-specific pathways, but which must be combined into a unified and continuously updated spatial model for effective, accurate movement.

Azimuth errors in pointing to remembered targets under extreme head rotations.

Errors in pointing to remembered target locations in 3-D space were studied when subjects were free to move their heads, and when they rotated their heads to the extreme right or left. Relative to pointing when the head was free to move, head rotations to the right shifted the final position of the responding arm to the left, whereas head rotations to the left shifted the final position of arm to the right. Horizontal rotation of the head had no systematic influence on elevation and radial distance errors. The influence of head rotations on pointing errors may be mediated by small shifts in the internal representation of external space, shifting the presentation of space in the opposite direction of the head rotation.

A novel quantitative method for 3D measurement of Parkinsonian tremor.

OBJECTIVE: To demonstrate the usefulness of a three dimensional (3D) motion analysis system for the quantitative measurement of tremor in patients with Parkinson's disease (PD). METHODS: Six PD patients with hand tremors were studied using a system that employed 3D electromagnetic position sensors to measure the actual, cumulative displacement of the tremoring finger. Patients were studied in different hand positions and activating conditions before and 30, 60, 90 and 120 min after intake of Pramipexole, a dopamine agonist known to reduce tremor. Tremor amplitude and frequency, before and after drug intake, were compared using Mann-Whitney U test and Wilcoxon rank test, respectively. RESULTS: The motion analysis system allowed discrimination of tremor related events from movement artifact and allowed the calculation of real world movement of the finger tremor despite altered hand positions and orientation. Average 3D tremor frequency ranged from 3.71 to 4.34 Hz. Median tremor amplitude (total distance traveled per 5 s interval) decreased with drug from 4.9 to 1.6 cm for resting tremor, 4.5 to 3.7 cm for postural tremor, 3.4 to 3.3 cm for precision tremor, 10.2 to 3.3 cm for tapping activation and 108.6 to 5.7 cm for counting activation. CONCLUSIONS: Our method of 3D analysis provides a robust, single quantitative measure of tremor amplitude that is intuitive and likely to reflect the functional impact of tremor. This methodology should be useful in comparing tremor across patients and in measuring the efficacy of therapeutic interventions.

Influence of movement speed on accuracy of pointing to memorized targets in 3D space.

Subjects performed three-dimensional (3D) pointing movements as accurately as possible with their eyes closed under four different speed conditions: 'slow', 'normal', 'fast' and 'maximal' (peak velocities of 0.62, 1.61, 2.51 and 4.68 m/s, respectively). Movement speed did not significantly affect the magnitude of constant pointing errors, nor that of variable errors, except for movements in the 'maximal' condition when peak velocity values larger than 4.5 m/s were reached. The findings are consistent with the hypothesis that final arm position may be specified regardless of movement dynamics.

Virtual reality-enhanced stroke rehabilitation.

A personal computer (PC)-based desktop virtual reality (VR) system was developed for rehabilitating hand function in stroke patients. The system uses two input devices, a CyberGlove and a Rutgers Master II-ND (RMII) force feedback glove, allowing user interaction with a virtual environment. This consists of four rehabilitation routines, each designed to exercise one specific parameter of hand movement: range, speed, fractionation or strength. The use of performance-based target levels is designed to increase patient motivation and individualize exercise difficulty to a patient's current state. Pilot clinical trials have been performed using the above system combined with noncomputer tasks, such as pegboard insertion or tracing of two-dimensional (2-D) patterns. Three chronic stroke patients used this rehabilitation protocol daily for two weeks. Objective measurements showed that each patient showed improvement on most of the hand parameters over the course of the training. Subjective evaluation by the patients was also positive. This technical report focuses on this newly developed technology for VR rehabilitation.

Virtual reality-based post-stroke hand rehabilitation.

A VR-based system using a CyberGlove and a Rutgers Master II-ND haptic glove was used to rehabilitate four post-stroke patients in the chronic phase. Each patient had to perform a variety of VR exercises to reduce impairments in their finger range of motion, speed, fractionation and strength. Patients exercised for about two hours per day, five days a week for three weeks. Results showed that three of the patients had gains in thumb range (50-140%) and finger speed (10-15%) over the three weeks trial. All four patients had significant improvement in finger fractionation (40-118%). Gains in finger strength were modest, due in part to an unexpected hardware malfunction. Two of the patients were measured against one-month post intervention and showed good retention. Evaluation using the Jebsen Test of Hand Function showed a reduction of 23-28% in time completion for two of the patients (the ones with the higher degrees of impairment). A prehension task was performed 9-40% faster for three of the patients after the intervention illustrating transfer of their improvement to a functional task.

[A model of central regulation of movement parameters]. / Model' tsentral'noi reguliatsii parametrov dvigatel'nykh traektorii.

The central processes responsible for a gradation of muscle torques or joint angles are suggested on the basis of the mass-spring hypothesis. Two fundamental commands (reciprocal and co- activative ) involved in the control over antagonist muscles are defined in terms of shifts of the so-called invariant characteristics (muscle torque vs joint angle). Each of the commands is graded by a neuronal ensemble arranged in line. Excitation propagates along the line at a centrally established rate. As the wave front moves, the output ensemble neurons are tonically recruited, and they discretely contribute to the respective command according to the superposition principle. The terminal position of the wave front of the reciprocal command is responsible for the final angular limb position, whereas the wave velocity--for the movement speed. The coactivation command just enhances muscle stiffness for a time of the movement. The theory presented is sufficiently well-defined to yield a variety of specific and testable predictions. After insignificant modifications the theory may be referred to the generation of the eye and head movements, both slow and fast ones.

[A wave nature of the central regulation of the trajectory of the articular angle in man]. / O volnovoi prirode tsentral'nogo protsessa formirovaniia traektorii izmeneniia sustavnogo ugla u cheloveka.

It is supposed that muscles of a single joint are controlled by a wave propagation of excitation along a central line-ordered neuronal ensemble. The number of steady active output ensemble neurons increases with wave-front displacement and the neurons discretely contribute to the motor command that is defined in terms of shifts of the so-called invariant muscle force-length characteristics. The terminal position of the wave front is responsible for the final angular limb position, whereas the wave velocity responsible for the peak movement speed. To verify the wave model, human time-angle trajectories of rapid arm movements to different positions in the horizontal plane were analysed. The trajectories fall into groups having the following properties: 1) The initial profiles of the trajectories that belong to one group are identical; 2) the duration of the coincidence of any two grouped trajectories increases with their extent; 3) summation of two or more grouped trajectories with a certain time delay between them again gives a trajectory which belongs to the same group. The data obtained are in good agreement with the wave model.

Mechanisms of neural reorganization in chronic stroke subjects after virtual reality training.

This study investigates patterns of brain reorganization in chronic stroke subjects after two weeks of robot-assisted arm and hand training in virtual reality (VR). Four subjects were studied with event-related fMRI while doing simple paretic hand finger movements before (double baseline) and after training. Bilateral hand movements were recorded and used to provide real-time feedback to subjects during scanning to eliminate performance confounds on fMRI results. The kinematic parameters of each movement were also used in the general linear model with the BOLD signal to investigate training-induced changes in neuromotor coupling. Univariate analysis showed an increase in BOLD signal in the ipsilesional hemisphere in two subjects and a decrease in activity in the other two subjects. Seed voxel based functional connectivity analysis revealed an increase in connectivity between ipsilesional motor cortex and bilateral sensorimotor cortex during finger movements in all four subjects. Hemispheric laterality index values showed a tendency to decrease reflecting a reduction in the over-dominance of the contralesional hemisphere. The study is novel in terms of 1) tracking finger movement during a motor task in the scanner, 2) monitoring motor performance during the experiment and 3) giving online visual feedback of subjects' movement. This pilot study introduces a novel approach to study neural plasticity by combining measures of regional intensity, interregional interactions (using functional connectivity analysis and hemispheric laterality index), and modulation in the strength of neuromotor coupling.

Innovative approaches to the rehabilitation of upper extremity hemiparesis using virtual environments.

AIM: Upper-extremity interventions for hemiparesis are a challenging aspect of stroke rehabilitation. Purpose of this paper is to report the feasibility of using virtual environments (VEs) in combination with robotics to assist recovery of hand-arm function and to present preliminary data demonstrating the potential of using sensory manipulations in VE to drive activation in targeted neural regions. METHODS: We trained 8 subjects for 8 three hour sessions using a library of complex VE's integrated with robots, comparing training arm and hand separately to training arm and hand together. Instrumented gloves and hand exoskeleton were used for hand tracking and haptic effects. Haptic Master robotic arm was used for arm tracking and generating three-dimensional haptic VEs. To investigate the use of manipulations in VE to drive neural activations, we created a "virtual mirror" that subjects used while performing a unimanual task. Cortical activation was measured with functional MRI (fMRI) and transcranial magnetic stimulation. RESULTS: Both groups showed improvement in kinematics and measures of real-world function. The group trained using their arm and hand together showed greater improvement. In a stroke subject, fMRI data suggested virtual mirror feedback could activate the sensorimotor cortex contralateral to the reflected hand (ipsilateral to the moving hand) thus recruiting the lesioned hemisphere. CONCLUSION: Gaming simulations interfaced with robotic devices provide a training medium that can modify movement patterns. In addition to showing that our VE therapies can optimize behavioral performance, we show preliminary evidence to support the potential of using specific sensory manipulations to selectively recruit targeted neural circuits.

The relationship between control, kinematic and electromyographic variables in fast single-joint movements in humans.

Two versions of the hypothesis that discrete movements are produced by shifts in the system's equilibrium point are considered. The first suggests that shifts are monotonic and end near the peak velocity of movement, and the second presumes that they are nonmonotonic ("N-shaped") and proceed until the end of movement. The first version, in contrast to the second, predicts that movement time may be significantly reduced by opposing loads without changes in the control pattern. The purpose of the present study was to test the two hypotheses about the duration and shape of the shift in the equilibrium point based on their respective predictions concerning the effects of perturbations on kinematic and EMG patterns in fast elbow flexor movements. Subjects performed unopposed flexions of about 55-70 degrees (control trials) and, in random test trials, movements were opposed by spring-like loads generated by a torque motor. Subjects had no visual feedback and were instructed not to correct arm deflections in case of perturbations. After the end of the movement, the load was removed leading to a secondary movement to the same final position as that in control trials (equifinality). When the load was varied, the static arm positions before unloading and associated joint torques (ranging from 0 to 80-90% of maximum voluntary contraction) had a monotonic relationship. Test movements opposed by a high load (80-90% of maximal voluntary contraction) ended near the peak velocity of control movements. Phasic and tonic electromyographic patterns were load-dependent. In movements opposed by high loads, the first agonist burst was significantly prolonged and displayed a high level of tonic activity for as long as the load was maintained. In the same load conditions, the antagonist burst was suppressed during the dynamic and static phases of movement. The findings of suppression of the antagonist burst does not support the hypothesis of an N-shaped control signal. Equally, the substantial reduction in movement time by the introduction of an opposing load cannot be reconciled in this model. Instead, our data indicate that the shifts in the equilibrium point underlying fast flexor movements are of short duration, ending near the peak velocity of unopposed movement. This suggests that kinematic and electromyographic patterns represent a long-lasting oscillatory response of the system to the short-duration monotonic control pattern, external forces and proprioceptive feedback.

Central modifications of reflex parameters may underlie the fastest arm movements.

Descending and reflex pathways usually converge on common interneurons and motoneurons. This implies that active movements may result from changes in reflex parameters produced by control signals conveyed by descending systems. Specifically, according to the lambda-model, a fast change in limb position is produced by a rapid change in the threshold of the stretch reflex. Consequently, external perturbations may be ineffective in eliciting additional reflex modifications of electromyographic (EMG) patterns unless the perturbations are relatively strong. In this way, the model accounts for the relatively weak effects of perturbations on the initial agonist EMG burst (Ag1) usually observed in fast movements. On the other hand, the same model permits robust reflex modifications of the timing and shape of the Ag1 in response to strong perturbations even in the fastest movements. To test the model, we verified the suggestion that the onset time of the Ag1, even in the fastest movements, depends on proprioceptive feedback in a manner consistent with a stretch reflex. In control trials, subjects (n = 6) made fast unopposed elbow flexion movements of approximately 60 degrees (peak velocity 500-700 degrees/s) in response to an auditory signal. In random test trials, a brief (50 ms) torque of 8-15 Nm either assisting or opposing the movement was applied 50 ms after this signal. Subjects had no visual feedback and were instructed not to correct arm deflections in case of perturbations. In all subjects, the onset time of the Ag1 depended on the direction of perturbation: it was 25-60 ms less in opposing compared with assisting load conditions. Assisting torques caused, at a short latency of 37 ms, an additional antagonist EMG burst preceding the Ag1. The direction-dependent effects of the perturbation persisted when cutaneous feedback was suppressed. It was concluded that the direction-dependent changes in the onset time and duration of the Ag1 as well as the antagonist activation preceding the Ag1 resulted from stretch reflex activity elicited by the perturbations rather than from a change in the control strategy or cutaneous reflexes. The results support the hypothesis on the hierarchical scheme of sensorimotor integration in which EMG patterns and movement emerge from the modification of the thresholds and other parameters of proprioceptive reflexes by control systems.