Garrett E. Alexander - US grants

The patterns of extrinsic connections of the two nuclear subdivisions of the primate neostriatum suggest that the putamen and caudate nucleus may subserve different functions, with the putamen participating principally in motor control while the caudate nucleus is involved in more complex behavioral processes. The studies proposed will examine the degree to which the neostriatum is functionally differentiated, and attempt to clarify some of the mechanisms by which this structure projects its influences to other brain regions via the output nuclei of the basal ganglia (in particular, the internal segment of the globus pallidus (GPi)). The specific aims of the project are: 1) To examine, using single cell recording and microstimulation techniques, the hypothesis that the putamen participates in the preparation for and execution of instruction-dependent motor responses. 2) To examine, using single cell recording techniques, the hypothesis that the caudate nucleus is functionally differentiated in accordance with the topographic distribution of its heterogeneous cortical inputs, and thus may have a role a) in the initial memory processes required for certain instruction-dependent motor responses, and b) in the programing (and possibly execution) of saccadic eye movements in an instruction-dependent visual tracking task. 3) To determine whether the putamen and caudate nucleus have unique and dissociated roles in the motor and more complex behavioral functions which underly instruction-dependent motor responses, by comparing the effects of fiber-sparing neurotoxic (ibotenic acid) lesions of each of these structures on task performance. 4) To determine whether normal movements, as well as those evoked by putamen microstimulation, depend upon GABA-mediated transmission through the output nuclei of the basal ganglia, by characterizing the influence of GPi injections of GABA-related drugs on both types of motor activity. These studies are designed to elucidate the roles of the putamen and caudate nucleus in normal motor and more complex behavioral processes, and should also provide insight into basic mechanisms underlying certain disorders of movement and high-level motor control in patients with diseases of the basal ganglia, including Parkinson's and Huntington's diseases.

The patterns of extrinsic connections of the two nuclear subdivisions of the primate neostriatum suggest that the putamen and caudate nucleus may subserve different functions, with the putamen participating principally in motor control while the caudate nucleus is involved in more complex behavioral processes. The studies proposed will examine the degree to which the neostriatum is functionally differentiated, and attempt to clarify some of the mechanisms by which this structure projects its influences to other brain regions via the output nuclei of the basal ganglia (in particular, the internal segment of the globus pallidus (GPi)). The specific aims of the project are: 1) To examine, using single cell recording and microstimulation techniques, the hypothesis that the putamen participates in the preparation for and execution of instruction-dependent motor responses. 2) To examine, using single cell recording techniques, the hypothesis that the audate nucleus is functionally differentiated in accordance with the topographic distribution of its heterogeneous cortical inputs, and thus may have a role a) in the spatial memory processes required for certain instruction-dependent motor responses, and b) in the programming (and possibly execution) of saccadic eye movements in an instruction-dependent visual tracking task. 3) To determine whether the putamen and caudate nucleus have unique and dissociated roles in the motor and more complex behavioral functions which underly instruction-dependent motor responses, by comparing the effects of fiber-sparing neurotoxic (ibotenic acid) lesions of each of these structures on task performance. 4) To determine whether normal movements, as well as those evoked by putamen microstimulation, depend upon GABA-mediated transmission through the output nuclei of the basal ganglia, by characterizing the influence of GPi injections of GABA-related drugs on both types of motor activity. These studies are designed to elucidate the roles of the putamen and caudate nucleus in normal motor and more complex behavioral processes, and should also provide insight into basic mechanisms underlying certain disorders of movement and high-level motor control in patients with diseases of the basal ganglia, including Parkinson's and Huntington's diseases.

The principal issues addressed in this proposal are: 1) whether motor processing within the basal ganglia-thalamocortical `motor circuit' is organized, at the neuronal level, in a predominantly serial or parallel fashion; and 2) whether there are systematic transformations, at successive stages of the circuit, in the neural representations of variables that have been implicated in different functional `levels' of motor processing. The proposed studies are designed to determine a) whether the same categories of information (i.e., the same motor variables) are proposed at different stages (cortical, striatal, pallidal, thalamic) of the `motor circuit'; b) whether there are systematic changes in the proportionate representation of a given motor variable by neurons at successive stages of the circuit; and c) whether there are systematic shifts, at successive stages of the circuit, in the regression slopes relating variable-specific changes in neuronal discharge rates to gradations in the represented variables. The Specific Aims for the project are as follows: [1] To determine whether, during the planning and execution of visually guided limb movements, multiple `levels' of motor processing are represented in parallel by neuronal activity within each of the precentral motor fields that contribute to the `motor circuit'. The activity of individual neurons in SMA, MC and APA will be recorded in monkeys performing tasks that require them to make reaching movements to position a cursor in two-dimensional space. The tasks involve both the preparation and execution `modes' of motor processing, and will also dissociate variables relevant to different `levels' of processing viz, target level variables, trajectory/kinematic variables, and dynamic/muscle-related variables. Data from the three areas will then be compared, based on results of both categorical and regression analyses. [2] To determine whether, during the planning and execution of visually guided limb movements, multiple `levels' of motor processing are represented in parallel by neuronal activity at the striatal stage of the `motor circuit'. Task-related single unit activity will be sampled from the arm region of the putamen in monkeys performing the same tasks employed in Specific Aim 1. After being subjected to the same set of analyses, the data will be compared with those obtained in Specific Aim 1. [3] To determine whether, during the planning and execution of visually guided limb movements, multiple `levels' of motor processing are represented in parallel by neuronal activity at the pallidal stage of the `motor circuit'. Task-related single unit activity will be sampled from the arm region of GPi in monkeys performing the same tasks used in Specific Aims 1 and 2. These data will be compared with those obtained in Specific Aim 2, in the same manner as the putamen and cortical data are to be compared. [4] To determine whether, during the planning and execution of visually guided limb movements, multiple `levels' of motor processing are represented in parallel by neuronal activity at the thalamic stage of the `motor circuit'. Task-related single unit activity will be sampled from the are region of VLo in monkeys performing the same tasks used in Specific Aims 1-3. These data will be subjected to the same analyses outlined above, and compared with both a) the SMA data from Specific Aim 1, and b) the GPi data from Specific Aim 3.

The goal of this research is to learn how the cortical motor fields (CMFs) use exteroceptive and contextual information in the selection and planning of visually instructed limb movements. Studies of neuronal activity in cortical motor areas suggest the orderly recruitment of sensory-related, followed by associative, followed by motor-related activity during such behaviors. These and other observations suggest a model of the CMFs in which sensory-to-motor transformations (SMTs) required for visual instructed limb movements are distributed both in time, within each motor field, and in space, across the network of CMFs. Among the model's predictions are early recruitment of CMFs engaged in sensory and associative processing of visual information, and later recruitment of areas whose processing is more strictly motor. This proposal has 4 specific aims: SA1: To test the hypothesis that for spatial SMTs in which the location of a visual stimulus (IS) instructs a targeted limb movements instructed there is a common sequence of neuronal recruitment (sensory-related-greater than-greater than motor- related activity) within each participating CMF. Neuronal activity will be sampled from motor cortex (MC), the dorsaal premotor area (PMd), and pre-PMd in monkeys performing tasks that dissociate sensory, associative, and motor-related processing. Multiple regression will be used in a continuous time course analysis to determine the proportions of each cell's activity attributable to the 3 types of processing. Population analyses will assess whether recruitment follows the predicted pattern within each region. SA2: To test the hypothesis that spatial SMTs entail a cascading sequence of neuronal recruitment distributed across the network of CMFs, with early recruitment of CMFs engaged in sensory processing, followed in turn by those specialized for associative and finally motor processing. Data collected from MC, PMd, and pre-PMd in SA1 will be compared across regions, to determine whether the pattern of neuronal recruitment distributed across the network of CMFs conforms to the model's predictions. SA3: To test the hypothesis that within each participating CMF the same sequence of neuronal recruitment predicted for spatial SMTs (SA1) holds for visual SMTs that are non-spatial. Neuronal activity will be sampled from MC, the supplementary motor area (SMA), and pre-SMA in monkeys performing non- targeted limb movements instructed by the colors and shapes (not locations) of visual stimuli. Data will be analyzed in the same manner as in SA1. SA4: To test the hypothesis that non-spatial SMTs entail a pattern of neuronal recruitment distributed across the network of CMFs comparable to that predicted for spatial SMTs (SA2). Data collected from MC, SMA, and pre-SMA in SA3 will be compared across CMFs to assess whether the pattern of recruitment distributed across the network conforms to the model's predictions.

The goal of this project is to localize the neural substrates of target-directed reaching in humans. Functional brain mapping with 15-O positron emission tomography (PET) will be used to image task-related changes in regional cerebral blood flow (rCBF) in normal human volunteers, and transcranial magnetic stimulation (TMS) will be used to reversibly disrupt the functioning of selected cortical areas of subjects performing a variety of targeted reaching tasks. While the substrates of motor learning have been mapped in some detail, much less is known about the substrates of on-line error correction, long-term sensorimotor adaptation, and coordination of visual and kinesthetic control signals. There are three specific aims, corresponding to the issues: Specific Aim 1: To delineate the respective neural substrates for visual versus kinesthetic control of targeted reaching. Three experiments will address this aim, each with a separate group of subjects (10 subjects per experiment), using targeted reaching paradigms that dissociate visual and kinesthetic targeting and trajectory control. Exp. 1.1: PET study of visual versus kinesthetic targeting and guidance of reaching. Exp. 1.2: PET study of visual versus kinesthetic guidance during on-line error correction. Exp. 1.3: PET study of visual versus kinesthetic trajectory guidance during prism adaptation. Specific Aim 2: To identify the neural substrates for on-line error correction and motor error-induced sensorimotor adaptation in targeted reaching. Four experiments are planned and each will involve set of targeted reaching paradigms to dissociate on-line error correction and motor error-induced sensorimotor adaptation. Exp. 2.1: PET study of on-line error correction versus motor error-induced sensorimotor adaptation. Exp. 2.2: PET study of limb versus oculomotor components of motor error-induced sensorimotor adaptation. Exp. 2.3: PET study of conscious versus subliminal on-line error correction. Exp. 2.4: TMS study of posterior parietal contribution to on-line error correction: overt versus subliminal target displacements and visual versus kinesthetic guidance of reaching trajectory. Specific Aim 3: To identify the neural substrates for sensorimotor adaptation induced by perceptual distortions (sensory mismatch and reafference mismatch) during target-directed reaching. Four experiments are planned. Each will involve a set of targeted reaching paradigms that dissociate the three factors implicated in long-term sensorimotor adaptation: sensory mismatch, reafferance mismatch, and motor error. Exp. 3.1: PET study of active versus passive prism adaptation. Exp. 3.2: PET study of prism adaptation with and without visual motor error. Exp. 3.3: PET study of cognitive factors in prism adaptation. Exp. 3.4: TMS study of lateral prefrontal versus posterior parietal effects on prism adaptation.