1992 — 2001 |
Crutcher, Michael D |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cortical Mechanisms of Motor Processing
The broad, long-term objectives of our research are to elucidate the nature of motor processing in the CNS 1) by demonstrating neural correlates of different levels of motor processing, and 2) by comparing different areas to clarify the different roles of these areas in motor control. The current proposal is based upon the results of our recent single cell recording study of rhesus monkeys performing visually-guided, delayed, tracking tasks. The activity of a significant number of cells in the supplementary motor area (SMA), motor cortex (MC) and putamen was related to the target or goal of the movement independent of the direction of limb movement and independent of the pattern of muscle activity. Our hypothesis is that this target-dependent activity is a neural representation of very high level motor processes involved in "capturing" the target or goal of the movement. The goals of the present project are 1) to thoroughly characterize the nature of this high-level, target-dependent activity using a variety of paradigms, and 2) to examine the arcuate premotor area (APA) and rostral and caudal cingulate motor areas (CMAr and CMAc) in addition to the SMA and MC in order to compare and contrast these five precentral motor areas. Comparisons will be made with respect to the frequency of occurrence and timing of each type of cell activity observed. The activity of individual neurons in the SMA, APA, CMAr, CMAc and MC will be recorded in monkeys performing a variety of tasks that require them to make visually guided limb movements. These tasks are specifically designed to determine whether the activity of each cell is of the target-dependent variety, to rule out several alternative explanations for such activity, and to extend these findings to other tasks that also require the animal to capture the same visual target in quite different ways. The specific aims are 1: To ascertain for each cell whether the activity of that cell is directional and, if so, whether that activity is related to the location of the target/goal of the movement (target-dependent activity) or to the direction of limb movement (limb-dependent activity). These paradigms will also attempt to rule out the possibility that any target-dependent activity that is observed is related to the preparation for, or execution of, saccadic eye movements. 2: To determine for each cell with target-dependent activity whether that activity is a neural correlate of spatial memory. 3: To determine for each cell with target-dependent activity whether that activity is a neural correlate of selective attention. 4: To determine whether target-dependent activity can be observed in tasks that require the animal to capture the same visual targets by using entirely different limb movements. Two different approaches will be used: 1) the animal will 'capture" the target by making relatively unconstrained reaching movements in 3-dimensional space to a touchscreen mounted on the video monitor, and 2) the animal will perform the standard tracking task using the hand ipsilateral to the recorded neuron.
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1998 |
Crutcher, Michael D |
P50Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These grants differ from program project grants in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes. |
Models of Parkinsons Disease--Therapeutic Implications
The proposed studies of this Center grant are focused on basic issues concerning the pathophysiology of Parkinson's disease (PD) and their therapeutic implications. These studies are, in part, concerned with animal models of PD and key aspects of the current basal ganglia- thalamocortical circuit models of parkinsonism. Project 1 is focused on the development of a more appropriate model of PD, in particular, one that exhibits the progressive nature of PD. The proposed model employs chronic systemic inhibition of complex I by rotenone in rodents with possible extension to primates. The conceptual connective framework for projects 2-5 is the exploration and testing of the current circuit model in both animal models and patients with PD. The studies in Project 2 explore in patients with PD the effects of deep brain stimulation (DBS) of the internal pallidum (GPi) and subthalamic nucleus (TN) on behavior and brain activation of 0-15 PET. These studies will help clarify functional correlates of the amelioration of specific parkinsonian symptoms by DBS of GPi and STN. Project 3 explores, in the primate metabolism in the thalamocortical circuit using a combination of single cell recording and FDG PET. Microdialysis combined with DBS of the STN will help to clarify the mode of action of DBS. This project will also examine the potential neuroprotective effects of STN inactivation. Project 4 explores key controversial issues regarding the pathophysiology of PD using microdialysis in primates. Metabotrophic glutamate receptors are abundant in STN and GPi and specific subtypes may be promising therapeutic targets. Project 5 will test the hypothesis that specific subtypes of metabotrophic glutamate receptors may play a therapeutically relevant role in PD. The Center will also provide state-of-the-art, multi-disciplinary training of fellows in research into parkinsonism and related conditions with an emphasis on translational.
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