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.

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.

Path integration following temporal lobectomy in humans.

Path integration, a component of spatial navigation, is the process used to determine position information on the basis of information about distance and direction travelled derived from self-motion cues. Following on from studies in the animal literature that seem to support the role of the hippocampal formation in path integration, this facility was investigated in humans with focal brain lesions. Thirty-three neurosurgical patients (17 left temporal lobectomy, LTL; 16 right temporal lobectomy, RTL) and 16 controls were tested on a number of blindfolded tasks designed to investigate path integration and on a number of additional control tasks (assessing mental rotation and left-right orientation). In a test of the ability to compute a homing vector, the subjects had to return to the start after being led along a route consisting of two distances and one turn. Patients with RTL only were impaired at estimating the turn required to return to the start. On a second task, route reproduction was tested by requiring the subjects to reproduce a route consisting of two distances and one turn; the RTL group only were also impaired at reproducing the turn, but this impairment did not correlate with the homing vector deficit. There were no group differences on tasks where subjects were required to reproduce a single distance or a single turn. The results indicate that path integration is impaired in RTL patients only and suggest that the right temporal lobe plays a role in idiothetic spatial memory.

Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss.

We have completed the first large-scale gene expression study of acute spinal cord injury (SCI) in rat. Oligonucleotide microarrays containing 1,200 gene-specific probes were used to quantify mRNA levels, relative to uninjured controls, in spinal cords injured using a standard contusion model. Our results revealed a marked loss of neuron-specific mRNAs at the injury site. The surviving cells showed a characteristic inflammatory response that started at the injury site and spread to the distal cord. Changes in several mRNA levels were associated with putative regenerative responses in the spinal cord. Notably, phosphodiesterase 4, nestin, glia-derived neurite promoting factor, and GAP-43 mRNAs increased significantly. Other mRNAs clustered temporally and spatially with these regeneration-associated genes. Thus we have described global patterns of gene expression following acute SCI, and we have identified targets for future study and possible therapeutic intervention.

Phase precession and phase-locking of hippocampal pyramidal cells.

We propose that the activity patterns of CA3 hippocampal pyramidal cells in freely running rats can be described as a temporal phenomenon, where the timing of bursts is modulated by the animal's running speed. With this hypothesis, we explain why pyramidal cells fire in specific spatial locations, and how place cells phase-precess with respect to the EEG theta rhythm for rats running on linear tracks. We are also able to explain why wheel cells phase-lock with respect to the theta rhythm for rats running in a wheel. Using biophysically minimal models of neurons, we show how the same network of neurons displays these activity patterns. The different rhythms are the result of inhibition being used in different ways by the system. The inhibition is produced by anatomically and physiologically diverse types of interneurons, whose role in controlling the firing patterns of hippocampal cells we analyze. Each firing pattern is characterized by a different set of functional relationships between network elements. Our analysis suggests a way to understand these functional relationships and transitions between them.

A temporal mechanism for generating the phase precession of hippocampal place cells.

The phase relationship between the activity of hippocampal place cells and the hippocampal theta rhythm systematically processes as the animal runs through the region in an environment called the place field of the cell. We present a minimal biophysical model of the phase precession of place cells in region CA3 of the hippocampus. The model describes the dynamics of two coupled point neurons--namely, a pyramidal cell and an interneuron, the latter of which is driven by a pacemaker input. Outside of the place field, the network displays a stable, background firing pattern that is locked to the theta rhythm. The pacemaker input drives the interneuron, which in turn activates the pyramidal cell. A single stimulus to the pyramidal cell from the dentate gyrus, simulating entrance into the place field, reorganizes the functional roles of the cells in the network for a number of cycles of the theta rhythm. In the reorganized network, the pyramidal cell drives the interneuron at a higher frequency than the theta frequency, thus causing a systematic precession relative to the theta input. The frequency of the pyramidal cell can vary to account for changes in the animal's running speed. The transient dynamics end after up to 360 degrees of phase precession when the pacemaker input to the interneuron occurs at a phase to return the network to the stable background firing pattern, thus signaling the end of the place field. Our model, in contrast to others, reports that phase precession is a temporally, and not spatially, controlled process. We also predict that like pyramidal cells, interneurons phase precess. Our model provides a mechanism for shutting off place cell firing after the animal has crossed the place field, and it explains the observed nearly 360 degrees of phase precession. We also describe how this model is consistent with a proposed autoassociative memory role of the CA3 region.

Interactions between hippocampus and medial septum during sharp waves and theta oscillation in the behaving rat.

The medial septal region and the hippocampus are connected reciprocally via GABAergic neurons, but the physiological role of this loop is still not well understood. In an attempt to reveal the physiological effects of the hippocamposeptal GABAergic projection, we cross-correlated hippocampal sharp wave (SPW) ripples or theta activity and extracellular units recorded in the medial septum and diagonal band of Broca (MSDB) in freely moving rats. The majority of single MSDB cells (60%) were significantly suppressed during SPWs. Most cells inhibited during SPW (80%) fired rhythmically and phase-locked to the negative peak of the CA1 pyramidal layer theta waves. Because both SPW and the negative peak of local theta waves correspond to the maximum discharge probability of CA1 pyramidal cells and interneuron classes, the findings indicate that the activity of medial septal neurons can be negatively (during SPW) or positively (during theta waves) correlated with the activity of hippocampal interneurons. We hypothesize that the functional coupling between medial septal neurons and hippocampal interneurons varies in a state-dependent manner.

Cell behaviour as a dynamic attractor in the intracellular signalling system.

We present a model of the cell signalling network based on the generic properties of interactions between protein kinases (PKs) and protein phosphatases (PPs) inside cells. The model is designed to examine the global properties and intrinsic dynamics of the phosphorylation system. A genetic algorithm (GA) is used to evolve populations of "cells". The GA selects cells and ranks them based on an analysis of the dynamics of the proteins within the networks from a series of different random starting conditions. The fittest cells are taken to be those which can generate a variety of different "behaviours" from a series of different initial conditions. During the GA, intracellular protein interactions evolve via mutation and an analogue of domain shuffling between protein types that is thought to occur during biological evolution. The dynamics of the simulated networks are presented and we discuss the hypothesis that changes in the behaviour of a cell may be interpretable as a switch between attractor basins in the intracellular signalling network.

The rhythmicity of cells of the medial septum/diagonal band of Broca in the awake freely moving rat: relationships with behaviour and hippocampal theta.

Chronic extracellular recordings were obtained from cells of the medial septum and diagonal band of Broca in rats performing a simple behavioural task. The cells were found to display a variety of bursting patterns phase-locked to hippocampal theta rhythm to a greater or lesser degree. Among phase-locked cells, no systematic distribution in preferential phase could be found, and these cells were shown to maintain their preferential phase for extended periods. Cells were classified into those which showed signs of a broadening of the repolarization phase of their action potential ('inflected': putative cholinergic) and those without ('non-inflected': putative GABAergic). Non-inflected cells tended to fire rhythmic bursts while inflected cells mostly fired in an irregular fashion, although still significantly phase-locked to hippocampal theta. In neither population did the phase-locked cells show any coherent distribution of their preferential phase. Sixty-five per cent of the rhythmically bursting cells showed a significant correlation between the interburst frequency and the animal's running speed. Five cells displayed rhythmic activity only when the rat ran in a specific direction. These results have implications for models of septohippocampal function and the effects of variable septal rhythmicity on the production of hippocampal theta rhythm.

A dynamical model of the distributed interaction of intracellular signals.

The behaviour of cells is coordinated by a large array of different types of intracellular protein kinases, protein phosphatases and second messenger molecules. Current experimental evidence suggests that these kinases, phosphatases and other messengers form a vast complicated interconnected signalling network inside the cell. A generic model of this signalling network is presented which is specifically designed to examine the global properties that can be expected from a model based on the available knowledge of these molecular interactions. Different protein types are represented as nodes in a network that interact via a connection matrix. During interactions, idealised kinases and phosphatases activate and deactivate other protein types by altering the level of phosphorylation of their regulatory sites. The occupancy of regulatory sites on protein kinases and phosphatases in turn determines their activity. Monte Carlo simulations are carried out on ensembles of networks. Steady states and periodic behaviour are observed in these networks. We discuss the potential of this type of model for understanding cell behaviour.

Memory for places: a navigational model in support of Marr's theory of hippocampal function.

In this report we describe a model that applies Marr's theory of hippocampal function to the problem of map-based navigation. Like many others we attribute a spatial memory function to the hippocampus, but we suggest that the additional functional components required for map-based navigation are located elsewhere in the brain. One of the key functional components in this model is an egocentric map of space, located in the neocortex, that is continuously updated using ideothetic (self-motion) information. The hippocampus stores snapshots of this egocentric map. The modeled activity pattern of head direction cells is used to set the best egocentric map rotation to match the snapshots stored in the hippocampus, resulting in place cells with a nondirectional firing pattern. We describe an evaluation of this model using a mobile robot and demonstrate that with this model the robot can recognize an environment and find a hidden goal. This model is discussed in the context of prior experiments that were designed to discover the map-based spatial processing of animals. We also predict the results of further experiments.

Phase relationship between hippocampal place units and the EEG theta rhythm.

Many complex spike cells in the hippocampus of the freely moving rat have as their primary correlate the animal's location in an environment (place cells). In contrast, the hippocampal electroencephalograph theta pattern of rhythmical waves (7-12 Hz) is better correlated with a class of movements that change the rat's location in an environment. During movement through the place field, the complex spike cells often fire in a bursting pattern with an interburst frequency in the same range as the concurrent electroencephalograph theta. The present study examined the phase of the theta wave at which the place cells fired. It was found that firing consistently began at a particular phase as the rat entered the field but then shifted in a systematic way during traversal of the field, moving progressively forward on each theta cycle. This precession of the phase ranged from 100 degrees to 355 degrees in different cells. The effect appeared to be due to the fact that individual cells had a higher interburst rate than the theta frequency. The phase was highly correlated with spatial location and less well correlated with temporal aspects of behavior, such as the time after place field entry. These results have implications for several aspects of hippocampal function. First, by using the phase relationship as well as the firing rate, place cells can improve the accuracy of place coding. Second, the characteristics of the phase shift constrain the models that define the construction of place fields. Third, the results restrict the temporal and spatial circumstances under which synapses in the hippocampus could be modified.