Yury P. Shimansky

Contributions of Different Modes of TRPV1 Activation to TRPV1 Antagonist-Induced Hyperthermia

Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (−0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.

Role of vision in aperture closure control during reach-to-grasp movements

We have previously shown that the distance from the hand to the target at which finger closure is initiated during the reach (aperture closure distance) depends on the amplitude of peak aperture, as well as hand velocity and acceleration. This dependence suggests the existence of a control law according to which a decision to initiate finger closure during the reach is made when the hand distance to target crosses a threshold that is a function of the above movement-related parameters. The present study examined whether the control law is affected by manipulating the visibility of the hand and the target. Young adults made reach-to-grasp movements to a dowel under conditions in which the target or the hand or both were either visible or not visible. Reaching for and grasping a target when the hand and/or target were not visible significantly increased transport time and widened peak aperture. Aperture closure distance was significantly lengthened and wrist peak velocity was decreased only when the target was not visible. Further analysis showed that the control law was significantly different between the visibility-related conditions. When either the hand or target was not visible, the aperture closure distance systematically increased compared to its value for the same amplitude of peak aperture, hand velocity, and acceleration under full visibility. This implies an increase in the distance-related safety margin for grasping when the hand or target is not visible. It has been also found that the same control law can be applied to all conditions, if variables describing hand and target visibility were included in the control law model, as the parameters of the task-related environmental context, in addition to the above movement-related parameters. This suggests that that the CNS utilizes those variables for controlling grasp initiation based on a general control law.

Control of aperture closure during reach-to-grasp movements in parkinson’s disease

This study examined whether the pattern of coordination between arm-reaching toward an object (hand transport) and the initiation of aperture closure for grasping is different between PD patients and healthy individuals, and whether that pattern is affected by the necessity to quickly adjust the reach-to-grasp movement in response to an unexpected shift of target location. Subjects reached for and grasped a vertical dowel, the location of which was indicated by illuminating one of the three dowels placed on a horizontal plane. In control conditions, target location was fixed during the trial. In perturbation conditions, target location was shifted instantaneously by switching the illumination to a different dowel during the reach. The hand distance from the target at which the subject initiated aperture closure (aperture closure distance) was similar for both the control and perturbation conditions within each group of subjects. However, that distance was significantly closer to the target in the PD group than in the control group. The timing of aperture closure initiation varied considerably across the trials in both groups of subjects. In contrast, aperture closure distance was relatively invariant, suggesting that aperture closure initiation was determined by spatial parameters of arm kinematics rather than temporal parameters. The linear regression analysis of aperture closure distance showed that the distance was highly predictable based on the following three parameters: the amplitude of maximum grip aperture, hand velocity, and hand acceleration. This result implies that a control law, the arguments of which include the above parameters, governs the initiation of aperture closure. Further analysis revealed that the control law was very similar between the subject groups under each condition as well as between the control and perturbation conditions for each group. Consequently, the shorter aperture closure distance observed in PD patients apparently is a result of the hypometria of their grip aperture and bradykinesia of hand transport movement, rather than a consequence of a deficit in transport-grasp coordination. It is also concluded that the perturbation of target location does not disrupt the transport-grasp coordination in either healthy individuals or PD patients.

A novel model of motor learning capable of developing an optimal movement control law online from scratch

Abstract.A computational model of a learning system (LS) is described that acquires knowledge and skill necessary for optimal control of a multisegmental limb dynamics (controlled object or CO), starting from “knowing” only the dimensionality of the object’s state space. It is based on an optimal control problem setup different from that of reinforcement learning. The LS solves the optimal control problem online while practicing the manipulation of CO. The system’s functional architecture comprises several adaptive components, each of which incorporates a number of mapping functions approximated based on artificial neural nets. Besides the internal model of the CO’s dynamics and adaptive controller that computes the control law, the LS includes a new type of internal model, the minimal cost (IMmc) of moving the controlled object between a pair of states. That internal model appears critical for the LS’s capacity to develop an optimal movement trajectory. The IMmc interacts with the adaptive controller in a cooperative manner. The controller provides an initial approximation of an optimal control action, which is further optimized in real time based on the IMmc. The IMmc in turn provides information for updating the controller. The LS’s performance was tested on the task of center-out reaching to eight randomly selected targets with a 2DOF limb model. The LS reached an optimal level of performance in a few tens of trials. It also quickly adapted to movement perturbations produced by two different types of external force field. The results suggest that the proposed design of a self-optimized control system can serve as a basis for the modeling of motor learning that includes the formation and adaptive modification of the plan of a goal-directed movement.

On-line compensation for perturbations of a reaching movement is cerebellar dependent: support for the task dependency hypothesis

Although the cerebellum has been shown to be critical for the acquisition and retention of adaptive modifications in certain reflex behaviors, this structure’s role in the learning of motor skills required to execute complex voluntary goal-directed movements still is unclear. This study explores this issue by analyzing the effects of inactivating the interposed and dentate cerebellar nuclei on the adaptation required to compensate for an external elastic load applied during a reaching movement. We show that cats with these nuclei inactivated can adapt to predictable perturbations of the forelimb during a goal-directed reach by including a compensatory component in the motor plan prior to movement initiation. In contrast, when comparable compensatory modifications must be triggered on-line because the perturbations are applied in randomized trials (i.e., unpredictably), such adaptive responses cannot be executed or reacquired after the interposed and dentate nuclei are inactivated. These findings provide the first demonstration of the condition-dependent nature of the cerebellum’s contribution to the learning of a specific volitional task.

Quantitative model of transport-aperture coordination during reach-to-grasp movements

It has been found in our previous studies that the initiation of aperture closure during reach-to-grasp movements occurs when the hand distance to target crosses a threshold that is a function of peak aperture amplitude, hand velocity, and hand acceleration. Thus, a stable relationship between those four movement parameters is observed at the moment of aperture closure initiation. Based on the concept of optimal control of movements (Naslin 1969) and its application for reach-to-grasp movement regulation (Hoff and Arbib 1993), it was hypothesized that the mathematical equation expressing that relationship can be generalized to describe coordination between hand transport and finger aperture during the entire reach-to-grasp movement by adding aperture velocity and acceleration to the above four movement parameters. The present study examines whether this hypothesis is supported by the data obtained in experiments in which young adults performed reach-to-grasp movements in eight combinations of two reach-amplitude conditions and four movement-speed conditions. It was found that linear approximation of the mathematical model described the relationship among the six movement parameters for the entire aperture-closure phase with very high precision for each condition, thus supporting the hypothesis for that phase. Testing whether one mathematical model could approximate the data across all the experimental conditions revealed that it was possible to achieve the same high level of data-fitting precision only by including in the model two additional, condition-encoding parameters and using a nonlinear, artificial neural network-based approximator with two hidden layers comprising three and two neurons, respectively. This result indicates that transport-aperture coordination, as a specific relationship between the parameters of hand transport and finger aperture, significantly depends on the condition-encoding variables. The data from the aperture-opening phase also fit a linear model, whose coefficients were substantially different from those identified for the aperture-closure phase. This result supports the above hypothesis for the aperture-opening phase, and consequently, for the entire reach-to-grasp movement. However, the fitting precision was considerably lower than that for the aperture-closure phase, indicating significant trial-to-trial variability of transport-aperture coordination during the aperture-opening phase. Implications for understanding the neural mechanisms employed by the CNS for controlling reach-to-grasp movements and utilization of the mathematical model of transport-aperture coordination for data analysis are discussed.

Control of aperture closure initiation during reach-to-grasp movements under manipulations of visual feedback and trunk involvement in Parkinson’s disease

The present project was aimed at investigating how two distinct and important difficulties (coordination difficulty and pronounced dependency on visual feedback) in Parkinson’s disease (PD) affect each other for the coordination between hand transport toward an object and the initiation of finger closure during reach-to-grasp movement. Subjects with PD and age-matched healthy subjects made reach-to-grasp movements to a dowel under conditions in which the target object and/or the hand were either visible or not visible. The involvement of the trunk in task performance was manipulated by positioning the target object within or beyond the participant’s outstretched arm to evaluate the effects of increasing the complexity of intersegmental coordination under different conditions related to the availability of visual feedback in subjects with PD. General kinematic characteristics of the reach-to-grasp movements of the subjects with PD were altered substantially by the removal of target object visibility. Compared with the controls, the subjects with PD considerably lengthened transport time, especially during the aperture closure period, and decreased peak velocity of wrist and trunk movement without target object visibility. Most of these differences were accentuated when the trunk was involved. In contrast, these kinematic parameters did not change depending on the visibility of the hand for both groups. The transport-aperture coordination was assessed in terms of the control law according to which the initiation of aperture closure during the reach occurred when the hand distance-to-target crossed a hand-target distance threshold for grasp initiation that is a function of peak aperture, hand velocity and acceleration, trunk velocity and acceleration, and trunk-target distance at the time of aperture closure initiation. When the hand or the target object was not visible, both groups increased the hand-target distance threshold for grasp initiation compared to its value under full visibility, implying an increase in the hand-target distance-related safety margin for grasping. The increase in the safety margin due to the absence of target object vision or the absence of hand vision was accentuated in the subjects with PD compared to that in the controls. The pronounced increase in the safety margin due to absence of target object vision for the subjects with PD was further accentuated when the trunk was involved compared to when it was not involved. The results imply that individuals with PD have significant limitations regarding neural computations required for efficient utilization of internal representations of target object location and hand motion as well as proprioceptive information about the hand to compensate for the lack of visual information during the performance of complex multisegment movements.

Two-phase strategy of neural control for planar reaching movements: I. XY coordination variability and its relation to end-point variability.

A quantitative model of optimal transport–aperture coordination (TAC) during reach-to-grasp movements has been developed in our previous studies. The utilization of that model for data analysis allowed, for the first time, to examine the phase dependence of the precision demand specified by the CNS for neurocomputational information processing during an ongoing movement. It was shown that the CNS utilizes a two-phase strategy for movement control. That strategy consists of reducing the precision demand for neural computations during the initial phase, which decreases the cost of information processing at the expense of lower extent of control optimality. To successfully grasp the target object, the CNS increases precision demand during the final phase, resulting in higher extent of control optimality. In the present study, we generalized the model of optimal TAC to a model of optimal coordination between X and Y components of point-to-point planar movements (XYC). We investigated whether the CNS uses the two-phase control strategy for controlling those movements, and how the strategy parameters depend on the prescribed movement speed, movement amplitude and the size of the target area. The results indeed revealed a substantial similarity between the CNS’s regulation of TAC and XYC. First, the variability of XYC within individual trials was minimal, meaning that execution noise during the movement was insignificant. Second, the inter-trial variability of XYC was considerable during the majority of the movement time, meaning that the precision demand for information processing was lowered, which is characteristic for the initial phase. That variability significantly decreased, indicating higher extent of control optimality, during the shorter final movement phase. The final phase was the longest (shortest) under the most (least) challenging combination of speed and accuracy requirements, fully consistent with the concept of the two-phase control strategy. This paper further discussed the relationship between motor variability and XYC variability.

Cold-induced thermogenesis and inflammation-associated cold-seeking behavior are represented by different dorsomedial hypothalamic sites: a three-dimensional functional topography study in conscious rats

In the past, we showed that large electrolytic lesions of the dorsomedial hypothalamus (DMH) promoted hypothermia in cold-exposed restrained rats, but attenuated hypothermia in rats challenged with a high dose of bacterial lipopolysaccharide (LPS) in a thermogradient apparatus. The goal of this study was to identify the thermoeffector mechanisms and DMH representation of the two phenomena and thus to understand how the same lesion could produce two opposite effects on body temperature. We found that the permissive effect of large electrolytic DMH lesions on cold-induced hypothermia was due to suppressed thermogenesis. DMH-lesioned rats also could not develop fever autonomically: they did not increase thermogenesis in response to a low, pyrogenic dose of LPS (10 μg/kg, i.v.). In contrast, changes in thermogenesis were uninvolved in the attenuation of the hypothermic response to a high, shock-inducing dose of LPS (5000 μg/kg, i.v.); this attenuation was due to a blockade of cold-seeking behavior. To compile DMH maps for the autonomic cold defense and for the cold-seeking response to LPS, we studied rats with small thermal lesions in different parts of the DMH. Cold thermogenesis had the highest representation in the dorsal hypothalamic area. Cold seeking was represented by a site at the ventral border of the dorsomedial nucleus. Because LPS causes both fever and hypothermia, we originally thought that the DMH contained a single thermoregulatory site that worked as a fever–hypothermia switch. Instead, we have found two separate sites: one that drives thermogenesis and the other, previously unknown, that drives inflammation-associated cold seeking. SIGNIFICANCE STATEMENT Cold-seeking behavior is a life-saving response that occurs in severe systemic inflammation. We studied this behavior in rats with lesions in the dorsomedial hypothalamus (DMH) challenged with a shock-inducing dose of bacterial endotoxin. We built functional maps of the DMH and found the strongest representation of cold-seeking behavior at the ventral border of the dorsomedial nucleus. We also built maps for cold-induced thermogenesis in unanesthetized rats and found the dorsal hypothalamic area to be its main representation site. Our work identifies the neural substrate of cold-seeking behavior in systemic inflammation and expands the functional topography of the DMH, a structure that modulates autonomic, endocrine, and behavioral responses and is a potential therapeutic target in anxiety and panic disorders.

Two-phase strategy of controlling motor coordination determined by task performance optimality

A quantitative model of optimal coordination between hand transport and grip aperture has been derived in our previous studies of reach-to-grasp movements without utilizing explicit knowledge of the optimality criterion or motor plant dynamics. The model’s utility for experimental data analysis has been demonstrated. Here we show how to generalize this model for a broad class of reaching-type, goal-directed movements. The model allows for measuring the variability of motor coordination and studying its dependence on movement phase. The experimentally found characteristics of that dependence imply that execution noise is low and does not affect motor coordination significantly. From those characteristics it is inferred that the cost of neural computations required for information acquisition and processing is included in the criterion of task performance optimality as a function of precision demand for state estimation and decision making. The precision demand is an additional optimized control variable that regulates the amount of neurocomputational resources activated dynamically. It is shown that an optimal control strategy in this case comprises two different phases. During the initial phase, the cost of neural computations is significantly reduced at the expense of reducing the demand for their precision, which results in speed-accuracy tradeoff violation and significant inter-trial variability of motor coordination. During the final phase, neural computations and thus motor coordination are considerably more precise to reduce the cost of errors in making a contact with the target object. The generality of the optimal coordination model and the two-phase control strategy is illustrated on several diverse examples.