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%.

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.

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.

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.

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.

Deficits in adaptive upper limb control in response to trunk perturbations in Parkinson's disease.

The ability of patients with Parkinson's disease (PD) to compensate for unexpected perturbations remains relatively unexplored. To address this issue PD subjects were required to compensate at the arm for an unexpected mechanical perturbation of the trunk while performing a trunk-assisted reach. Twelve healthy and nine PD subjects (off medication) performed trunk-assisted reaching movements without vision or knowledge of results to a remembered target in the ipsilateral (T1) or contralateral (T2) workspace. On 60% of the trials trunk motion was unrestrained (free condition). On the remaining 40% of randomly selected trials trunk motion was arrested at movement onset (blocked condition). If subjects appropriately changed arm joint angles to compensate for the trunk arrest, there should be spatial and temporal invariance in the hand trajectories and in the endpoint errors across conditions. The control group successfully changed their arm configuration in a context-dependent manner which resulted in invariant hand trajectory profiles across the free and blocked conditions. More so, they initiated these changes rapidly after the trunk perturbation (group mean 70 ms). Some PD subjects were unable to maintain invariant hand paths and movement errors across conditions. Their hand velocity profiles were also more variable relative to those of the healthy subjects in the blocked-trunk trials but not in the free-trunk trials. Furthermore, the latency of compensatory changes in arm joint angles in movements toward T1 was longer in the PD group (group mean 153 ms). Finally, PD subjects' arm and trunk were desynchronized at movement onset, confirming our previous findings and consistent with PD patients' known problems in the sequential or parallel generation of different movement components. The findings that individual PD subjects were unsuccessful or delayed in producing context-dependent responses at the arm to unexpected perturbations of the trunk suggests that the basal ganglia are important nodes in the organization of adaptive behavior.

A virtual reality based exercise system for hand rehabilitation post-stroke: transfer to function.

We present preliminary results from a virtual reality (VR)-based system for hand rehabilitation that uses a CyberGlove and a Rutgers Master II-ND haptic glove. This system trains finger range of motion, finger flexion speed, independence of finger motion and finger strength. Eight chronic post-stroke subjects participated. In keeping with variability in both the lesion site and in initial upper extremity function, each subject showed improvement on a unique combination of movement parameters in VR training. These improvements transferred to gains on clinical tests, as well as to significant reductions in task completion times for the prehension of real objects. These results are indicative of the potential feasibility of this exercise system for rehabilitation in patients with hand dysfunction resulting from neurological impairment.

Arm-trunk coordination in the absence of proprioception.

During trunk-assisted reaching to targets placed within arm's length, the influence of trunk motion on the hand trajectory is compensated for by changes in the arm configuration. The role of proprioception in this compensation was investigated by analyzing the movements of 2 deafferented and 12 healthy subjects. Subjects reached to remembered targets (placed approximately 80 degrees ipsilateral or approximately 45 degrees contralateral to the sagittal midline) with an active forward movement of the trunk produced by hip flexion. In 40% of randomly selected trials, trunk motion was mechanically blocked. No visual feedback was provided during the experiment. The hand trajectory and velocity profiles of healthy subjects remained invariant whether or not the trunk was blocked. The invariance was achieved by changes in arm interjoint coordination that, for reaches toward the ipsilateral target, started as early as 50 ms after the perturbation. Both deafferented subjects exhibited considerable, though incomplete, compensation for the effects of the perturbation. Compensation was more successful for reaches to the ipsilateral target. Both deafferented subjects showed invariance between conditions (unobstructed or blocked trunk motion) in their hand paths to the ipsilateral target, and one did to the contralateral target. For the other deafferented subject, hand paths in the two types of trials began to deviate after about 50% into the movement, because of excessive elbow extension. In movements to the ipsilateral target, when deafferented subjects compensated successfully, the changes in arm joint angles were initiated as early as 50 ms after the trunk perturbation, similar to healthy subjects. Although the deafferented subjects showed less than ideal compensatory control, they compensated to a remarkably large extent given their complete loss of proprioception. The presence of partial compensation in the absence of vision and proprioception points to the likelihood that not only proprioception but also vestibulospinal pathways help mediate this compensation.

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.

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.

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.

Hand trajectory invariance in reaching movements involving the trunk.

Movements of different body segments may be combined in different ways to achieve the same motor goal. How this is accomplished by the nervous system was investigated by having subjects make fast pointing movements with the arm in combination with a forward bending of the trunk that was unexpectedly blocked in some trials. Subjects moved their hand above the surface of a table without vision from an initial position near the midline of the chest to remembered targets placed within the reach of the arm in either the ipsi- or contralateral workspace. In experiment 1, subjects were instructed to make fast arm movements to the target without corrections whether or not the trunk was arrested. Only minor changes were found in the hand trajectory and velocity profile in response to the trunk arrest, and these changes were seen only late in the movement. In contrast, the patterns of the interjoint coordination substantially changed in response to the trunk arrest, suggesting the presence of compensatory arm-trunk coordination minimizing the deflections from the hand trajectory regardless of whether the trunk is recruited or mechanically blocked. Changes in the arm interjoint coordination in response to the trunk arrest could be detected kinematically at a minimal latency of 50 ms. This finding suggests a rapid reflex compensatory mechanism driven by vestibular and/or proprioceptive afferent signals. In experiment 2, subjects were required, as soon as they perceived the trunk arrest, to change the hand motion to the same direction as that of the trunk. Under this instruction, subjects were able to initiate corrections only after the hand approached or reached the final position. Thus, centrally mediated compensatory corrections triggered in response to the trunk arrest were likely to occur too late to maintain the observed invariant hand trajectory in experiment 1. In experiment 3, subjects produced similar pointing movements, but to a target that moved together with the trunk. In these body-oriented pointing movements, the hand trajectories from trials in which the trunk was moving or arrested were substantially different. The same trajectories represented in a relative frame of reference moving with the trunk were virtually identical. We conclude that hand trajectory invariance can be produced in an external spatial (experiment 1) or an internal trunk-centered (experiment 3) frame of reference. The invariance in the external frame of reference is accomplished by active compensatory changes in the arm joint angles nullifying the influence of the trunk motion on the hand trajectory. We suggest that to make a transition to the internal frame of reference, control systems suppress this compensation. One of the hypotheses opened to further experimental testing is that the integration of additional (trunk) degrees of freedom into movement is based on afferent (proprioceptive, vestibular) signals stemming from the trunk motion and transmitted to the arm muscles.

Procedural motor learning in Parkinson's disease.

We have been investigating motor control and learning in parkinsonian subjects. In the current study, we sought to explore the existence of deficits in procedural motor learning, which is a form of implicit motor learning where skill improves over repetitive blocks of trials. We sought to determine, in particular, whether any such deficit is accentuated during specific types or phases of learning. We would expect that those specific learning tasks would require the greatest participation of the basal ganglia. Numerous studies have found that Parkinson's disease (PD) patients may show deficits in learning. Combined with information about basal ganglia neuronal connections and activity, this led some investigators to suggest that one of the key functions of the basal ganglia is to facilitate learning. To investigate these learning deficits, we used a robotic device to generate conservative force fields that disturbed the subjects' arm movements, thereby generating a "virtual mechanical environment" that subjects learned to manipulate. Movements were successively grouped into blocks comprising five different conditions: motor performance, early learning, late learning, negative transfer, and aftereffect motor performance. Our results with eight right-handed PD subjects and nine age-matched controls showed a relative decrease in the rate of learning for the PD patients in all blocks, but greater differences emerged between groups during novelty phases of learning. In particular, the difference in performance during the negative transfer condition reached statistical significance, suggesting that the basal ganglia might be a key center for "switching" motor patterns. Our results support the hypothesis that deficiencies in procedural motor learning are characteristic of PD. They add to existing evidence which has suggested a key role for the basal ganglia when new sensorimotor mappings are required by novel task environments. Better understanding of these deficits should facilitate the rehabilitation of PD patients.

The timing of arm-trunk coordination is deficient and vision-dependent in Parkinson's patients during reaching movements.

The role of the basal ganglia in the coordination of different body segments and utilization of motor synergies was investigated by analyzing reaching movements to remembered three-dimensional (3D) targets in patients with Parkinson's disease (PD). Arm movements were produced alone or in combination with a forward bending of the trunk, with or without visual feedback. Movements in PD patients were more temporally segmented, as evidenced by irregular changes in tangential velocity profiles. In addition, the relative timing in the onsets and offsets of fingertip and trunk motions were substantially different in PD patients than in control subjects. While the control subjects synchronized both onsets and offsets, the PD patients had large mean intervals between the onsets and offsets of the fingertip and trunk motions. Moreover, PD patients showed substantially larger trial-to-trial variability in these intervals. The degree of synchronization in PD patients gradually increased during the movement under the influence of visual feedback. The mean and variability of the intersegmental intervals decreased as the fingertip approached the target. This improvement in timing occurred even though the separate variability in the timing of arm and trunk motions was not reduced by vision. In combined movements, even without vision, the PD patients were able to achieve normal accuracy, suggesting they were able to use the same movement synergies as normals to control the multiple degrees of freedom involved in the movements and to compensate for the added trunk movement. However, they were unable to recruit these synergies in the stereotyped manner characteristic of healthy subjects. These results suggest that the basal ganglia are involved in the temporal coordination of movement of different body segments and that related timing abnormalities may be partly compensated by vision. Abnormal intersegmental timing may be a highly sensitive indicator of a deficient ability to assemble complex movements in patients with basal-ganglia dysfunction. This abnormality may be apparent even when the overall movement goal of reaching a target is preserved and normal movement synergies appear to be largely intact.

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.

Pointing in 3D space to remembered targets. II. Effects of movement speed toward kinesthetically defined targets.

The accuracy of visually guided pointing movements decreases with speed. We have shown that for movements to a visually defined remembered target, the variability of the final arm endpoint position does not depend on movement speed. We put forward a hypothesis that this observation can be explained by suggesting that movements directed at remembered targets are produced without ongoing corrections. In the present study, this hypothesis was tested for pointing movements in 3D space to kinesthetically defined remembered targets. Passive versus active acquisition of kinesthetic information was contrasted. Pointing errors, movement kinematics, and joint-angle coordination were analyzed. The movements were performed at a slow speed (average peak tangential velocity of about 1.2 m/s) and at a fast speed (2.7 m/s). No visual feedback was allowed during the target presentation or the movement. Variability in the final position of the arm endpoint did not increase with speed in either the active or the passive condition. Variability in the final values of the arm-orientation angles determining the position of the forearm and of the upper arm in space was also speed invariant. This invariance occurred despite the fact that angular velocities increased by a factor of two for all the angles involved. The speed-invariant variability supports the hypothesis that there is an absence of ongoing corrections for movements to remembered targets: in the case of a slower movement, where there is more time for movement correction, the final arm endpoint variability did not decrease. In contrast to variability in the final endpoint position, the variability in the peak tangential acceleration increased significantly with movement speed. This may imply that the nervous system adopts one of two strategies: either the final endpoint position is not encoded in terms of muscle torques or there is a special on-line mechanism that adjusts movement deceleration according to the muscle-torque variability at the initial stage of the movement. The final endpoint position was on average farther from the shoulder than the target. Constant radial-distance errors were speed dependent in both the active and the passive conditions. In the fast speed conditions, the radial distance overshoots of the targets increased. This increase in radial-distance overshoot with movement speed can be explained by the hypothesis that the final arm position is not predetermined in these experimental conditions, but is defined during the movement by a feedforward or feedback mechanism with an internal delay.