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Biomedical subjects

J R Bloedel

Publications and source records attributed to J R Bloedel.

At least 19 recordsLinked to original sources
PubMed2006

Inferior olivary inactivation abolishes conditioned eyeblinks: extinction or cerebellar malfunction?

The inferior olive (IO) is a required component of neural circuits controlling the classical conditioning of eyeblink responses. Previous reports indicated that lesioning or inactivating the IO abolishes conditioned eyeblinks (CRs), but there was disagreement regarding the timing of the CR performance deficit. As a result, it was not clear whether IO inactivation produces unlearning of CRs or a non-specific dysfunction of cerebellar circuits. Since most of these studies used methods that could block unrelated axons passing through the IO region, additional experiments are required to further elucidate IO function, using inactivating agents that act selectively on cell bodies. In the present study, the IO was inactivated using the glutamate receptor antagonist DGG and the GABA-A receptor agonist muscimol in rabbits performing well-learned CRs. Effects of inactivating the IO on CR expression and on neuronal activity in the anterior cerebellar interposed nucleus (IN) were examined. We found that either blocking excitatory glutamate inputs or activating inhibitory GABA inputs to the IO abolished CRs. This effect occurred with variable delay following drug injections. Additional experiments, in which post-injection testing was delayed to allow for drug diffusion, revealed invariably immediate suppression of CRs. This demonstrated that suppressing IO activity using DGG or muscimol does not induce unlearning of CRs. Single-unit recording during DGG injections revealed that CR suppression was paralleled by a dramatic suppression of IN neuronal activity. We concluded that inactivating the rostral parts of the IO complex abolishes CRs by producing a tonic malfunction of cerebellar eyeblink conditioning circuits.

Action Potentials↗
PubMed2005

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.

Aged↗
PubMed2004

Glutamate neurotransmission in the cerebellar interposed nuclei: involvement in classically conditioned eyeblinks and neuronal activity.

The cerebellar interposed nuclei (IN) are critical components of a neural network that controls the expression of classically conditioned eyeblinks. The IN receive 2 major inputs: the massive, gamma-aminobutyric acid (GABA)-mediated input from the Purkinje cells of the cerebellar cortex and the relatively weaker, glutamate-mediated input from collaterals of mossy and climbing fiber cerebellar afferent systems. To elucidate the role of IN glutamate neurotransmission in conditioned response (CR) expression, effects of blocking fast glutamatergic neurotransmission in the IN with gamma-d-glutamylglycine (DGG) on the expression of conditioned eyeblinks and on cerebellar nuclear neuronal activity were examined. Surprisingly, blocking fast glutamate receptors in the IN did not abolish CRs. DGG decreased CR incidence and slightly increased CR latency. In contrast, identical amounts of DGG applied to the cerebellar cortex abolished CRs. Similar to the behavioral effects, DGG had unexpectedly mild effects on IN neurons. At the population level, the baseline firing frequency of IN cells was not affected. After DGG injections, the incidence of excitatory modulation of cell activity in the interstimulus interval decreased but was not abolished. A combined block of fast glutamate and GABA(A) neurotransmission using a mixture of DGG and picrotoxin dramatically reduced CR incidence, increased the firing frequency of all cell types, and virtually abolished all modulation of neuronal activity. These results indicate that fast glutamate neurotransmission in the IN plays only an accessory role both in the expression of behavioral CRs and in the generation of associated neuronal activity in the IN.

Action Potentials↗
PubMed2003

Adaptation of reach-to-grasp movement in response to force perturbations.

This study examined how reach-to-grasp movements are modified during adaptation to external force perturbations applied on the arm during reach. Specifically, we examined whether the organization of these movements was dependent upon the condition under which the perturbation was applied. In response to an auditory signal, all subjects were asked to reach for a vertical dowel, grasp it between the index finger and thumb, and lift it a short distance off the table. The subjects were instructed to do the task as fast as possible. The perturbation was an elastic load acting on the wrist at an angle of 105 deg lateral to the reaching direction. The condition was modified by changing the predictability with which the perturbation was applied in a given trial. After recording unperturbed control trials, perturbations were applied first on successive trials (predictable perturbations) and then were applied randomly (unpredictable perturbations). In the early predictable perturbation trials, reach path length became longer and reaching duration increased. As more predictable perturbations were applied, the reach path length gradually decreased and became similar to that of control trials. Reaching duration also decreased gradually as the subjects adapted by exerting force against the perturbation. In addition, the amplitude of peak grip aperture during arm transport initially increased in response to repeated perturbations. During the course of learning, it reached its maximum and thereafter slightly decreased. However, it did not return to the normal level. The subjects also adapted to the unpredictable perturbations through changes in both arm transport and grasping components, indicating that they can compensate even when the occurrence of the perturbation cannot be predicted during the inter-trial interval. Throughout random perturbation trials, large grip aperture values were observed, suggesting that a conservative aperture level is set regardless of whether the reaching arm is perturbed or not. In addition, the results of the predictable perturbations showed that the time from movement onset to the onset of grip aperture closure changed as adaptation occurred. However, the spatial location where the onset of finger closure occurred showed minimum changes with perturbation. These data suggest that the onset of finger closure is dependent upon distance to target rather than the temporal relationship of the grasp relative to the transport phase of the movement.

Adaptation, Physiological↗
PubMed2001

Intermediate cerebellum and conditioned eyeblinks. Parallel involvement in eyeblinks and tonic eyelid closure.

The intermediate cerebellum (the intermediate cerebellar cortex and interposed nuclei) and associated brainstem circuits are essential for the acquisition and expression of classically conditioned eyeblinks in the rabbit. The purpose of the present experiment was to determine whether these circuits are also involved in adaptive eyelid closure learned in an instrumental paradigm. For that purpose, rabbits with unrestrained eyelids were trained in two tasks: (1) classical conditioning of the eyeblink; and (2) a new instrumental task in which they avoided delivery of an aversive stimulus by maintaining tonic eyelid closure. To examine the involvement of the intermediate cerebellum in these two types of learned behavior, the cerebellar interposed nuclei were injected with the GABAA agonist muscimol and with the GABAA antagonist picrotoxin. Inactivating the interposed nuclei with muscimol abolished classically conditioned eyeblinks and severely affected the rabbit's capacity to maintain tonic eyelid closure. On the other hand, reducing inhibition with picrotoxin failed to interrupt the learned responses and increased the amplitude of eyelid closure. These data indicate that the cerebellar interposed nuclei control both phasic classically conditioned eyeblinks and tonic instrumental eyelid closure. To account for this new finding, a "hybrid" hypothesis combining the cerebellar learning hypothesis and the performance hypothesis is proposed.

Animals↗
PubMed2000

The human cerebellum and associative learning: dissociation between the acquisition, retention and extinction of conditioned eyeblinks.

The present paper is part of a systematic exploration of the neural substrates of conditioned eyeblink responses in humans. Normal subjects and patients with lesions restricted to the cerebellum were examined for their ability to acquire new classically conditioned eyeblinks to an auditory conditioned stimulus and whether they were able to perform and extinguish a previously learned natural anticipatory eyeblink response - the kinesthetic threat eyeblink response (KTER). In classical conditioning to an auditory conditioned stimulus, cerebellar patients failed to acquire new conditioned responses. In contrast to this impairment, in the KTER task both cerebellar patients and control subjects exhibited a high incidence of anticipatory eyeblinks which were initiated before the forehead tap. These results indicate that the cerebellar circuits, which are critical for the acquisition of new conditioned responses, are not essential for the storage and expression of naturally acquired conditioned responses. In the extinction experiment, cerebellar patients failed to extinguish their KTERs. This finding suggests that in humans, the acquisition of new and the extinction of previously learned conditioned responses depends on a similar set of cerebellar circuits.

Animals↗
PubMed2000

Effects of accuracy constraints on reach-to-grasp movements in cerebellar patients.

Reach-to-grasp movements of patients with pathology restricted to the cerebellum were compared with those of normal controls. Two types of paradigms with different accuracy constraints were used to examine whether cerebellar impairment disrupts the stereotypic relationship between arm transport and grip aperture and whether the variability of this relationship is altered when greater accuracy is required. The movements were made to either a vertical dowel or to a cross bar of a small cross. All subjects were asked to reach for either target at a fast but comfortable speed, grasp the object between the index finger and thumb, and lift it a short distance off the table. In terms of the relationship between arm transport and grip aperture, the control subjects showed a high consistency in grip aperture and wrist velocity profiles from trial to trial for movements to both the dowel and the cross. The relationship between the maximum velocity of the wrist and the time at which grip aperture was maximal during the reach was highly consistent throughout the experiment. In contrast, the time of maximum grip aperture and maximum wrist velocity of the cerebellar patients was quite variable from trial to trial, and the relationship of these measurements also varied considerably. These abnormalities were present regardless of the accuracy requirement. In addition, the cerebellar patients required a significantly longer time to grasp and lift the objects than the control subjects. Furthermore, the patients exhibited a greater grip aperture during reach than the controls. These data indicate that the cerebellum contributes substantially to the coordination of movements required to perform reach-to-grasp movements. Specifically, the cerebellum is critical for executing this behavior with a consistent, well-timed relationship between the transport and grasp components. This contribution is apparent even when accuracy demands are minimal.

Adult↗
PubMed2000

Movement accuracy constraints in Parkinson's disease patients.

This study examined the hypothesis that the kinematics of movements performed by PD (Parkinson's disease) patients are differentially affected depending on whether or not the aiming movement has an accuracy constraint. The aiming movements required elbow extension in the horizontal plane on a digitizer. There were two movement conditions: (1) one having a spatial accuracy requirement in which the subjects moved to the defined target and stopped on it; and (2) one requiring the subjects to move toward the defined target without stopping precisely on it. Subjects were instructed to make their movements as fast and as accurate as possible in response to the auditory imperative signal. PD patients modified the movement speed and kinematics depending on the two accuracy conditions. However, when the accuracy constraint was imposed, movement slowness observed in the patients was much more pronounced. The most revealing result was localized to the deceleration phase, particularly as the target was approached. The patients also were found to make a higher number of acceleration zero crossings from negative to positive to reach the target, indicating that the movements were more irregular. For the patients, the first acceleration zero crossing from negative to positive occurred much earlier in the movement than that for the controls. In addition, when movement accuracy was constrained, the number of zero crossings was accentuated. These data show that when PD patients make aiming movements to a target, their deceleration phase becomes longer and more variable.

Aged↗
PubMed1999

The kinesthetic threat eyeblink: a new type of anticipatory eyeblink response.

The present paper is part of a systematic exploration of naturally acquired conditioned eyeblink responses in human subjects. Normal human subjects were examined for the presence of anticipatory eyeblinks in a new paradigm. They were instructed to move their hand quickly toward their face and tap their forehead. In this situation, subjects generated anticipatory eyeblinks which were initiated before the forehead tap. Additional experiments revealed that visual stimuli and internal movement-planning cues are not required for the initiation of this response. The kinesthetic information from the passively moving arm, however, was sufficient to trigger this kinesthetic threat eyeblink response (KTER). The KTER extinguished when the forehead tap did not reinforce it. These data indicate that the KTER is a unique type of naturally acquired conditioned response system which is maintained by aversive reinforcing events.

Acoustic Stimulation↗
PubMed1999

Inactivation of interposed nuclei in the cat: classically conditioned withdrawal reflexes, voluntary limb movements and the action primitive hypothesis.

The cerebellar interposed nuclei are considered critical components of circuits controlling the classical conditioning of eyeblink responses in several mammalian species. The main purpose of the present experiments was to examine whether the interposed nuclei are also involved in the control of classically conditioned withdrawal responses in other skeletomuscular effector systems. To achieve this objective, a unique learning paradigm was developed to examine classically conditioned withdrawal responses in three effector systems (the eyelid, forelimb and hindlimb) in individual cats. Trained animals were injected with muscimol in the cerebellar interposed nuclei, and the effects on the three conditioned responses (CRs) were examined. Although the effects of muscimol were less dramatic than previously reported in the rabbit eyeblink preparation, the inactivation of the cerebellar nuclei affected the performance of CRs in all three effector systems. In additional experiments, animals were injected with muscimol at the sites affecting classically conditioned withdrawal responses to determine the effects of these injections on reaching and locomotion behaviors. These tests demonstrated that the same regions of the cerebellar interposed nuclei which control withdrawal reflexes are also involved in the control of limb flexion and precision placement of the paw during both locomotion and reaching tasks. The obtained data indicate that the interposed nuclei are involved in the control of ipsilateral action primitives and that inactivating the interposed nuclei affects several modes of action of these functional units.

Animals↗
PubMed1998

Microinjections of anisomycin into the intermediate cerebellum during learning affect the acquisition of classically conditioned responses in the rabbit.

The purpose of this study was to examine the effects of protein synthesis inhibition in the intermediate cerebellum on the acquisition and expression of classically conditioned nictitating membrane responses in the rabbit. Animals were conditioned for three days in a standard delay paradigm. Before each training session, either a solution of anisomycin (a protein synthesis inhibitor) or vehicle was bilaterally injected into the interposed cerebellar nuclear. Following these three training sessions, rabbits were tested to determine whether the previous training under the influence of anisomycin or vehicle resulted in the acquisition of conditioned responses. In this test, animals that were injected previously with the protein synthesis inhibitor exhibited significantly less retention of conditioned responses than rabbits injected with vehicle. Additional experiments demonstrated that anisomycin does not block the expression of conditioned responses during conditioning or in well-trained animals. Microinjections of muscimol at the same sites of the previous drug infusions suppressed the expression of conditioned responses, indicating that the protein synthesis inhibitor was applied to the eyeblink-related parts of cerebellar circuits. The obtained data are the first to demonstrate that a manipulation of cerebellar circuits, which does not affect the performance of learned behavior, can affect the process of learning. These results suggest that the synthesis of new proteins in the intermediate cerebellum participates in the formation of plastic changes responsible for eyeblink conditioning.

Analysis of Variance↗
PubMed1998

Current concepts of climbing fiber function.

This review examines several of the current postulates regarding the function of one of the most intriguing afferent systems in the brain, the climbing fiber system. The fact that these afferents are activated under a variety of conditions has contributed substantially to the diversity of postulates that have been proposed. In part because of the unique anatomical relationship between individual climbing fibers and the dendritic tree of Purkinje cells, these afferents have been proposed as a key input in establishing long-term plastic changes in the cerebellar cortex. This concept is contrasted with other postulates proposing that the heterosynaptic action of this system produces a short-lasting enhancement rather than a long-term depression of Purkinje cell responsiveness. Although a generally accepted view regarding climbing fiber function does not exist, this review emphasizes the extensive functional insights that have been reported and supports the notion that progress toward a complete understanding of these afferents will require an integration of their morphological characteristics with the fundamental physiological properties of their responses assessed in a variety of contexts and conditions.

Animals↗
PubMed1998

Reach-to-grasp movements during obstacle avoidance.

The transport and grip components are two controlled components of a prehensile movement. These components are coordinated so that objects of varying size and shape resting in diverse locations can be grasped easily. It has been suggested that the timing between these two components is a specified parameter, although the origin of such timing is unknown. The present study examines the interdependency of the reach and grasp components when the transport component is modified by placing an obstacle of varying height (9 cm and 11 cm) in the hand path between the starting position and the target object location. Subjects were asked to reach over a Plexiglas barrier and grasp a 2-cm dowel. To reach the object, the subject had to elevate the hand. At issue in this experiment is whether changes in hand path trajectory caused by obstacle avoidance produce corresponding changes in the kinematics of grip aperture. The findings showed that reaching in the presence of an obstacle resulted in the prolongation of most transport component time parameters except peak acceleration and a few amplitude parameters. Changes in the transport component also produced systematic prolongation in all time parameters of grip kinematics, including grip closure time. Temporal prolongation was also reflected in a significant decrease in grip opening and closing velocity; only relative time-to-peak closing velocity was maintained. Closure distance and maximum grip aperture were smaller for the obstacle conditions. Together with the observed smaller variability for the distance to peak aperture, these findings suggest that spatial localization of the hand aperture is an important prehensile movement control feature. Parameterization processes for the grip component are closely linked to those of the transport component, and their organization appears to be interdependent.

Adult↗
PubMed1998

Ataxia reflected in the simulated movements of patients with cerebellar lesions.

Previous studies demonstrated that the time required to simulate mentally a complex movement is highly correlated with the time required to execute the same task. The purpose of this experiment was to examine whether this relationship exists when execution times are prolonged as a consequence of the motor abnormalities exhibited by patients with substantial cerebellar pathology. The paradigm required subjects to alternate between moving a hand-held stylus horizontally on a digitizing tablet through a four-segment template and imagining the same movement through the same template. These two modes of performance were compared based on the times required to complete the two types of trials. Performance using both upper extremities was assessed using templates with two different levels of difficulty. Difficulty was varied by interposing gates that narrowed the path through the template. Using a MANOVA, measurements of actual and simulated movement times were compared between the group of cerebellar patients and a group of age- and sex-matched controls. The results showed that: (1) both movement times and mental-simulation times were greater for cerebellar patients than for control subjects under all experimental conditions, (2) both the movement times and the mental-simulation times of the patients were greater on the more-affected side than on the less-affected side, and (3) on the more-affected side, there was no significant difference between the patients' simulation and movement times for either the more difficult or less difficult condition. Thus, the consequence of cerebellar dysfunction on the time required to execute a volitional movement is reflected in the time needed to simulate the same behavior.

Adult↗
PubMed1998

Adaptive changes in responses to repeated locomotor perturbations in cerebellar patients.

This study examined the responses of cerebellar patients and a group of age- and sex-matched control subjects to repeated changes in treadmill speed in order to test whether cerebellar patients can adapt their gait to this type of perturbation and, if so, whether their responses are comparable to those of controls. While the subject walked on the treadmill, a perturbation consisting of a sudden slowing of the treadmill followed by a sudden increase back to the original speed was applied repeatedly at a specific time during the step cycle. Both the control subjects and cerebellar patients were able to compensate for the perturbations by minimizing their postural sway and changing step length. However, the nature of the compensatory changes in step length differed between these subject groups. Control subjects compensated for the perturbation by consistently using the same leg to initiate the response to the perturbation and by adapting a pattern of stepping such that the EMG characterizing the response occurred in a manner that was entrained to the timing of the normal locomotor cycle. In contrast, the patients, although undergoing modifications in step length, employed a much less consistent motor pattern from trial to trial than that of the normal subjects. An inconsistent pattern among their responses was apparent in both the analysis of stepping and in the EMG activity of the gastrocnemius and anterior tibial muscles. These results suggest that, although the cerebellar patients can adapt their behavior in response to locomotor perturbations, they do not establish a motor pattern comparable to that employed by normal subjects.

Adaptation, Physiological↗
PubMed1998

Effects of cerebellar nuclear inactivation on the learning of a complex forelimb movement in cats.

The purpose of this study was to determine the effects of inactivating concurrently the cerebellar interposed and dentate nuclei on the capacity of cats to acquire and retain a complex, goal-directed forelimb movement. To assess the effects on acquisition, cats were required to learn to move a vertical manipulandum bar through a two-segment template with a shape approximating an inverted "L" after the injection of muscimol (saline for the control group) in the interposed and dentate cerebellar nuclei. During training periods, they were exposed progressively to more difficult templates, which were created by decreasing the angle between the two segments of the template. After determining the most difficult template the injected animals could learn within the specified time and performance constraints, the retraining phase of the experiment was initiated in which the cats were required to execute the same sequence of templates in the absence of any injection. This stage of the experiment assessed retention and determined the extent of any relearning required to execute the task at criterion levels. Next, the animals were overtrained without any injection on the most difficult template they could perform. Finally, to determine the effects of nuclear inactivation on retention after extensive retraining, their capacity to perform the same template was determined after muscimol injection in the interposed and dentate nuclei. The findings show that during the inactivation of the dentate and interposed nuclei the animals could learn to execute the more difficult templates. However, when required to execute the most difficult template learned under muscimol on the day after injections were discontinued, the cats had to "relearn" (reacquire) the movement. Finally, when the cerebellar nuclei were inactivated after the animals learned the task in the absence of any injections during the retraining phase, retention was not blocked. The data indicate that the intermediate and lateral cerebellum are not required either for learning this type of complex voluntary movement or for retaining the capacity to perform the task once it is learned. Nevertheless, when the cerebellum becomes available for executing a task learned in the absence of this structure, reacquisition of the behavior usually is necessary. It is hypothesized that the relearning observed after acquisition during muscimol inactivation reflects the tendency of the system to incorporate the cerebellum into the interactions responsible for the learning and performance of a motor sequence that is optimal for executing the task.

Animals↗
PubMed1997

Conditioned and unconditioned forelimb reflex systems in the cat: involvement of the intermediate cerebellum.

Temporary inactivation of the cerebellar interposed nuclei was used to assess the role of the intermediate cerebellum in the performance of forelimb cutaneo-muscular reflexes in the cat. The following types of reflexive responses were evaluated: the classically conditioned and unconditioned forelimb withdrawal responses and the forelimb tactile placing, hopping and magnet responses. The experiments tested the hypothesis that the intermediate cerebellum is involved in the performance of all the above forelimb reflexes. The forelimb withdrawal reflex was classically conditioned in a newly developed paradigm in which animals were first operantly conditioned to stand on four elevated platforms. Trained animals were microinjected with a gamma-aminobutyric acid (GABA) agonist, muscimol, in the interposed nuclei, and the effects of inactivation of the intermediate cerebellar output on the forelimb reflexes were examined. The main findings of these experiments are that unilateral muscimol inactivation of the interposed nuclei in the cat abolished the expression of the classically conditioned limb flexion reflex, suppressed the performance of the unconditioned withdrawal reflex and, in parallel, down-regulated the tactile placing, hopping and magnet postural responses in the ipsilateral forelimb. These observations are inconsistent with concepts indicating exclusive involvement of the intermediate cerebellum in the classically conditioned reflexes elicited by aversive stimuli. On the contrary, they support the hypothesis of a more global involvement of this structure in learned and unlearned defensive flexion reflexes and in automatic postural response systems.

Animals↗