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.

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.

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.

Pointing to remembered targets in 3-D space in Parkinson's disease.

A three-dimensional tracking system was used to examine whether subjects with Parkinson's disease (PD) would show characteristic performance deficits in an unconstrained pointing task. Five targets were presented in a pyramidal array in space to 11 individuals with mild to moderate PD and 8 age-matched controls. After the target was indicated, subjects closed their eyes and pointed to the remembered target locations without vision. Despite the absence of visual feedback during movement, PD subjects were as accurate overall as controls. However, PD subjects showed greater variable errors, more irregular trajectories, and a vertical endpoint bias in which their endpoints were significantly lower than controls. They also showed deficiencies in the compensatory organization of joint rotations to ensure consistency in azimuthal (horizontal) positioning of the arm endpoint. We concluded that, under appropriate task conditions, PD subjects may not show overall deficits in accuracy even when making targeting movements at normal speed without visual feedback. Nevertheless, our findings indicate that there are certain dimensions of performance which are selectively altered in Parkinson's disease even when overall performance is normal.

Pointing in 3D space to remembered targets. I. Kinesthetic versus visual target presentation.

This study investigated the influence of different modalities of target information (visual, kinesthetic) on the accuracy, kinematics, and interjoint coordination of pointing movements to remembered targets. The targets were presented by a robot arm in five locations in three-dimensional (3D) space, either as a point of light in a dark room ("visual" condition), or kinesthetically. Relative pointing accuracy in the visual compared with kinesthetic conditions was influenced by the target location: pointing errors were the largest for the visual targets most eccentric relative to the subject's head. In addition, for the two most lateral targets, the final arm positions were, on average, closer to the center than the targets in the visual condition and farther from the center than the targets in the kinesthetic conditions. This result suggests that the pattern of errors in the visual condition described elsewhere ("range effect") may derive from visual processing rather than motor planning and implementation. Two modes of kinesthetic target presentation were utilized. During "passive" kinesthetic presentation of the target, the experimenter moved the subject's relaxed arm. Alternately, in "active" kinesthetic presentation of the target, the subject actively (with minimal help from the experimenter) moved his arm. No visual feedback was allowed in either kinesthetic condition. The variability in the final fingertip position was significantly smaller in the active condition than in the passive condition. In contrast, variability in the final values of arm orientation angles did not differ significantly in the active and passive conditions. This apparent contradiction may be resolved by the fact that, for the given target location, the influence of the deviation of these angles in the given trial from their average values on the position of the fingertip tended to be mutually compensated, and this tendency was stronger in the active condition. Our analysis of the correlations among the arm orientation angles and of the relationship between the initial and final arm configurations suggests that the kinesthetic conditions enabled the implementation of a mixture of strategies for achieving accuracy. The first strategy is to use a specific memory of an adequate arm configuration (that assumed during target presentation), such that accuracy is achieved by using this memory as a template. The second strategy is to use synergistically coordinating joint angles, such that accuracy is achieved by focusing on a specific endpoint that can be reached by a range of equivalent arm positions. The latter strategy was better utilized in the active condition. In conclusion, our results indicate that human subjects can use diverse sensory information to achieve comparable final accuracy, but that the details of the strategies employed differ with the kind of information available.

The interaction of visual and proprioceptive inputs in pointing to actual and remembered targets.

Errors in pointing to actual and remembered targets presented in three-dimensional (3D) space in a dark room were studied under various conditions of visual feedback. During their movements, subjects either had no vision of their arms or of the target, vision of the target but not of their arms, vision of a light-emitting diode (LED) on their moving index fingertip but not of the target, or vision of an LED on their moving index fingertip and of the target. Errors depended critically upon feedback condition. 3D errors were largest for movements to remembered targets without visual feedback, diminished with vision of the moving fingertip, and diminished further with vision of the target and vision of the finger and the target. Moreover, the different conditions differentially influenced the radial distance, azimuth, and elevation errors, indicating that subjects control motion along all three axes relatively independently. The pattern of errors suggest that the neural systems that mediate processing of actual versus remembered targets may have different capacities for integrating visual and proprioceptive information in order to program spatially directed arm movements.

[Steady state-kinetic model of the regulation by autoadrenoreceptors of noradrenaline secretion]. / Statsionarno-kineticheskaia model' reguliatsii autoadrenoretseptorami sekretsii noradrenalina.

The process of noradrenaline secretion regulation by autoreceptors is described in the terms of the stationary-kinetic reaction. Constants of this reaction are determined using the authors' own data. Analysis of the model has permitted explaining some data from literature which were used to refute the principle of noradrenaline secretion self-regulation by autoreceptors.

[A model of control of the movement of the multiarticular extremity]. / Model' upravleniia dvizheniiami mnogosustavnoi konechnosti.

A model for coordinated execution of multijoint goal-directed limb movements is suggested from the following principles. (1) Central control signals for a single limb joint are individually formed, proceeding from its ability to bring the limb nearer to the target and leaving control signals directed simultaneously to other joint out of account. The joints thereby behave as a set of Tsetlin's abstract automata [11], each functioning independently and guided by a common, collective effect. (2) Neither levels of muscle activation, nor force and kinematic variables are directly specified by the command signals. They only modify the system's parameters that affect equilibrium joint positions, and thus make the limb to move to the goal. A concrete model based on the above principles is described and its behavior is compared with actual goal-directed movements in man and spinal frogs. Various control strategies for multiarticular movements in living organisms are discussed.

[Analysis of the regulation of noradrenaline secretion by autoadrenoreceptors and stimulation frequency]. / Analiz reguliatsii sekretsii noradrenalina autoadrenoretseptorami i chastotoi stimuliatsii.

A mathematical model is presented which quantitatively describes the value of secreted mediator to each subsequent impulse in the series of presynaptic impulses. The model is constructed with the account taken of the role of presynaptic adrenoreceptors regulating noradrenaline secretion. An analysis of the model shows that the observed decrease and further stabilization of presynaptic responses in the series of presynaptic impulses observed in neurophysiological experiments can be connected with the work of alpha- and beta-autoadrenoreceptors. The increase of impulsation frequency affects the sensitivity of these receptors, which brings about an increase of concentration of secreted to each subsequent impulse mediator in the synaptic slit in the series of presynaptic impulses and stabilization of secretion at a higher level.

[Biomechanical characteristics of the wiping reflex cycle]. / Biomekhanicheskie osobennosti tsikla potiratel'nogo refleksa.

Multijoint goal-directed hindlimb movements in response to chemical stimulation delivered to different skin sites on the medial back surface (wiping reflex-WR) were filmed and analysed in spinal or intact frogs Rana temporaria. Each WR cycle was divisible into five phases (flexion, lifting, aiming, wiping and extension) usually separated from each other by postural interruptions. One or several of the phases might spontaneously be reduced or deleted at all (e. g. the extension phase), although the WR was still effective. Such a reduction was, as a rule, observed in intact frogs while spinal ones usually exhibited the maximum phase sequence. It is suggested that the central spinal generator of the WR is formed of separate functional blocks each of which specifies a certain interjoint coordination and brings the joints to the central-conditioned equilibrium positions.

[Analysis of late components of evoked potentials arising in the paramedian lobule of the cerebellum in response to stimulation of nerves and the cerebral cortex]. / Analiz pozdnikh komponentov vyzvannykh potentsialov, voznikaiushchikh v paramediannoi dol'ke mozzhechka pri razdrazhenii kory bol'shikh polusharii i nervov.

The field potentials in response to stimulation of the cerebral sensorimotor cortex and of the limb nerves were recorded in the granular layer of the cerebellar paramedian lobule in nonanesthetized cats. The field potentials contained long-latency components, i.e. slow negative waves generated by granule cells. The long-latency component to nerve stimulation was recorded both inside and outside the projection area of the given limb, while the cerebral stimulation with a low intensity (1.8-2.5 thresholds) evoked this component in the given projection area only. The long latency component to cerebral stimulation followed higher rates and was less sensitive to the action of the barbital anaesthesia than the component following the nerve stimulation. Simultaneous cerebral and nerve stimulation evoked the long latency component equal to the sum of the separate components. It is suggested that slow conduction spinal and cerebral inputs form separate mossy fibres - granule cell pathways.

The spinal frog takes into account the scheme of its body during the wiping reflex.

The hindlimb of the spinal frog produces a wiping reflex evoked by electrically or chemically stimulating distal skin of the forelimb. The reflex was released in frogs supported on a flat surface or suspended. It was found to have two stages. During the first, the frog fixed the hindlimb in an intermediate posture irrespective of forelimb position. In the second, the movement depended on forelimb position, which determined the final posture of the hindlimb. In this final posure, all joints except the hip joint were fully extended; the hip angle was correlated with forelimb position and varied on repeated wipings. When the stimulus was applied to the skin of the back, the pattern of final postures was the same, but the intermediate postures differed. The organization of the wiping reflex is discussed in light of the hypothesis that movement is evoked according to changes in the equilibrium (postural state) of the system.

Activity of motoneurons during fictitious scratch reflex in the cat.

(1) Intracellular recording of motoneurons of different hindlimb muscles: tibialis anterior (TA), gastrocnemius and soleus (GS), vastus crureus (Vast), posterior biceps and semitendinosus (PBSt), was carried out during the fictitious scratch reflex in decerebrate cats. (2) During the postural stage of the reflex, a depolarizaiton (3.8 mV on average) was observed in TA motoneurons accompanied by tonic discharge. No change of the membrane potential (MP) and no discharge were observed during this stage in GS, Vast and PBSt motoneurons. (3) In the rhythmical stage of the reflex, the MP of TA motoneurons changed only slightly during the 'long' (L) phase of the scratch cycle and remained at approximately the same level as during the postural stage. In this phase, motoneurons discharged at frequencies of 20-100 pps. In the 'short' (S) phase of the scratch cycle a strong repolarization occurred, the MP reached the same level as observed during resting conditons (MP0), and the discharge discontinued. (4) GS motoneurons were gradually depolarized during the second half of the L-phase. The depolarization reached its maximum (5.5 mV on average in relation to the MP0) on average in relation to the MP0) in the S-phase, and several action potentials were generated with intervals of 5-10 msec. Then, at the beginning of the L-phase, the motoneurons were repolarized and the MP reached the level of the MP0. The behavior of Vast motoneurons was essentially similar to that of GS motoneurons. (5) The PBSt motoneurons usually had two peaks of depolarization per cycle--in the S-phase and at the beginning of the L-phase. The maximal depolarization was 3.5 mV (on average). The motoneurons generated action potentials at one or both peaks of depolarization. (6) The possible organization of the central influences upon motoneurons of different muscles during scratching is discussed.

[Possibility of using an analgesic (fentanyl) for electrophysiologic studies of the cerebellar cortex]. / O vozmozhnosti ispol'zovaniia anal'getika (fentanila) pri élektrofiziologicheskikh issledovaniiakh kory mozzhechka.

The effect of the central analgetic, fentanyl, on evoked potentials and Purkinje cells discharges in the cerbellar cortex to stimulation either the cerebral cortex or somatic nerves were studied in nonanaesthetized cats. It was found that the analgetic dose fentanyl (10-30 microgram/kg) did not affect the evoked potentials. The fentanyl dose of 30 microgram/kg suppressed the resting discharges and responses of Purkinje cells while the dose of 10 microgram/kg facilitated them. However these effects were substantially weaker as compared with those of nembutal. Therefore fentanyl can be used for analgesia during electrophysiological study of the cerebellar cortex in nonanaesthetized cats.

Generation of scratching. I. Activity of spinal interneurons during scratching.

1. In decerebrate, curarized cats, stimulation of the cervical spinal cord evoked fictitious scratching (9), i.e., periodical activity of the hindlimb motoneurons with a discharge pattern typical of actual scratching (cycle duration about 250 ms, flexor phase about 200 ms, extensor phase about 50 ms). During fictitious scratching, extra-cellular records were obtained from 182 spinal neurons located in different regions of the gray matter cross section (except for the motor nuclei), from segments L4 and L5. 2. The firing rate of 73% of neurons was rhythmically modulated in relation with the scratch cycle. Most of the modulated neurons fired in bursts and were silent between bursts. They were located mainly in Rexed's (22) layer VII. 3. Burst onsets ("switchings on" of the neurons) were distributed rather evenly throughout the scratch cycle except for a small maximum at the very beginning of the cycle (the cycle was assumed to start with the termination of the extensor phase). Burst terminations ("switchings off") in the overwhelming majority of the neurons were distributed over the last-third part of the cycle. As a result, those neurons which began to fire earlier in the cycle usually had longer bursts, compared to the neurons which began to fire later. Besides, since there were very few switchings off in the first half of the cycle, the number of simultaneously active neurons increased during the first half of the cycle, reached the maximum somewhat later than the middle of the cycle, and considerably decreased by the end of the cycle. 4. With more intensive scratching, the firing rate in the bursts considerably increased in all neurons tested, while the duration of the scratch cycle changed only slightly. 5. A correlation between the burst position in the cycle and the behavior during the latent period of scratching (when stimulation of the cervical spinal cord had already been started but rhythmical oscillations had not yet appeared) was found in many neurons. Most of the neurons which began to fire at the beginning of the scratch cycle and had long bursts were tonically activated during the latent period. On the contrary, most of the neurons which fired in short bursts at the end of the cycle were either inhibited or not affected during this period. 6. A correlation betwen the burst position in the cycle and the frequency pattern was found in many neurons. In most of the neurons which began to fire in the first half of the cycle (except for the very beginning), the discharge rate increased in the course of the burst. In the remaining neurons, the discharge rate changed only slightly during the burst. 7. Hypotheses concerning organization of the spinal mechanism of scratching are discussed.

Generation of scratching. II. Nonregular regimes of generation.

1. The activity of muscle nerves and that of spinal interneurons from the L4 and L5 segments was recorded during fictitious scratching (5), which was evoked in decerebrate curarized cats by stimulation of the cervical spinal cord. In some experiments, rhythmical generation was disturbed by stimulation of the fifth lumbar dorsal root (DL5). 2. Excluding the very beginning of scratching, rhythmical generation was usually rather regular: fluctuations of the cycle duration were less than +/-5%. But changes in the stimulation strength, in the stimulating electrode position, and in the hindlimb position led to changes of the generation regime. In different regimes, the mean value of the cycle duration could differ by 20-30%. No correlation was found between mean durations of flexor and extensor phases for different regimes. 3. Rhythmical generation was possible only if the hindlimb was put to "scratch posture," i.e., deflected forward. Generation immediately stopped when the limb was deflected backward, and immediately started when it was returned to scratch posture. 4. In some experiments, stimulation of the cervical spinal cord first resulted in generation of slow oscillations with the temporal pattern typical of stepping (cycle duration about 500 ms, flexor and extensor phases being almost equal to each other). Then, during 5-20 cycles, gradual transition to a normal scratch cycle (about 250 ms) occurred mainly due to considerable shortening (5-10 times) of the extensor phase. In some experiments, considerable spontaneous variations of the flexor phase were observed, while the extensor phase was constant. 5. A single stimulus applied to DL5 considerably affected the cycle duration. Repetitive DL5 stimulation,with a rhythm close to that of scratching, resulted in synchronization of the spinal generator by the stimuli. 6. Spinal interneurons recorded during transition from slow oscillations to a normal scratch cycle only slightly changed phases of their activity in relation to the activity of motoneurons. 7. A hypothesis is advanced that generation of different kinds of limb movements is produced by one and the same central spinal mechanism which can operate in different regimes. The role of sensory input for operation of this mechanism is discussed.

[Variations in the membrane potentials of motor neurons during the generation of scratching]. / O kolebaniiakh membrannogo potentsiala motoneironov pri generatsii chesaniia.

The activity of motoneurons of the ankle flexor and extensor muscles was recorded intracellularly during fictitious scratching in decerebrate curarized cats. Before the beginning of rhythmical oscillation a large depolarization and tonic discharge were observed in flexor motoneurons, while the membrane potential of extensor ones did not change. When the rhythmical generation began, a short periodic hyperpolarization and corresponding pause in the discharge lasting for the extensor phase of the cycle appeared in flexor motoneurons. In extensor motoneurons a periodic depolarization increasing in the course of the flexor phase was observed; a maximal depolarization occurred in the extensor phase in which a short burst of spikes was generated.