Marjorie E. Anderson - US grants

The effects exerted on movement by different portions of the globus pallidus will be examined and compared to those of the cerebello-thalamo-cortical system using electrophysiological stimulation and recording techniques in awake monkeys performing arm movements in reaction time tasks. We will test the hypothesis, pertinent to the movement disorders seen in patients with Parkinson's and Huntington's disease, that portions of the pallidum receiving input from sensorimotor regions of the cerebral cortex and the thalamic neurons to which they project are important in scaling the amplitude of muscle activity and, thus, the speed of movement, but are not important in controlling the initiation of movement. Other portions of the globus pallidus, which anatomical studies shown are connected with prefrontal, cingulate, and posterior portions of the cerebral cortex, may have more profound effects on motor programming and reaction times, as does cerebellar output from the dentate nucleus. This project will be the first in which thalamic neurons in the pallidothalamocortical and cerebellothalamocortical systems are identified and their activity is compared in the same animal doing the same motor task. In addition, we will begin and extensive anatomical and electrophysiological investigation of the pedunculopontine region, which is known to be reciprocally connected with the globus pallidus and to receive input from other motor-related areas such as the red nucleus and the precentral motor cortex.

This proposal is designed to enable 20 young investigators to participate in an international symposium, "Neural Control of Limb Movements," a satellite symposium to be held in Seattle, Washington, July 9-11, 1986, prior to the XXX International Congress of Physiological Sciences, to be held in Vancouver, B.C., Canada. The symposium is designed to facilitate interaction between scientists investigating various "motor" and "premotor" areas of the CNS involved in the control of limb movement. Although conferences are commonly organized around particular anatomical structures (cerebral cortex, cerebellum, basal ganglia, etc.), the focus of this symposium will be the interaction between different CNS structures in generating the neural discharge patterns controlling movements. Participants will also be encouraged to discuss new techniques and promising future directions for motor systems research. The symposium will be held on the campus of the University of Washington, the location of the Regional Primate Research Center at the University of Washington. This location will minimize per diem costs, making attendance less expensive (a consideration for trainees and individuals outside the U.S. who currently face unfavorable exchange rates.) Thus, the support requested will allow young investigators, including M.D.'s pursuing research in motor control, to participate in scientific sessions and small group discussions with international scientists with whom they otherwise could not interact. The modest administrative and supply support requested will reduce the registration fee and insure participation of foreign scientists.

We propose to compare the roles played by three motor-related systems in the control of temporally or spatially patterned motor sequences. The three systems are 1) pallidal-thalamo- supplementary motor cortex, 2) cerebello-thalamo-premotor cortex, and 3) cerebello-thalamo-primary motor cortex. Monkeys will be trained to make sequential arm movements under conditions in which 1) sequential spatial or temporal cues are or are not presented, 2) the spatial or temporal motor pattern is actually produced or must only be "internally rehearsed", and 3) the pattern is one that the monkey has practiced and produces using a predictive stategy vs. a random and unpredictable spatial or temporal pattern, in which the monkey responds to the spatial or temporal cue. The contribution of the three systems will be studied during perormance of these motor tasks by 1) recording from neurons in the supplementary motor or lateral premotor cortex, 2) recording from neurons in the thalamus that have been identified physiologically as receiving input from the globus pallidus or different portions of the cerebellar nuclei, and 3) interrupting individual systems, using either chemical inhibition or lesions. These experiments will allow us to test the hypothesis that the basal ganglia and cerebellar output directed to supplementary and lateral premotor areas of cortex contribute differentially to the control of sensory-guided vs. "internally programmed" or "learned" complex motor sequences.

We propose to compare the roles played by three motor-related systems in the control of temporally or spatially patterned motor sequences. The three systems are 1) pallidal-thalamo- supplementary motor cortex, 2) cerebello-thalamo-premotor cortex, and 3) cerebello-thalamo-primary motor cortex. Monkeys will be trained to make sequential arm movements under conditions in which 1) sequential spatial or temporal cues are or are not presented, 2) the spatial or temporal motor pattern is actually produced or must only be "internally rehearsed", and 3) the pattern is one that the monkey has practiced and produces using a predictive stategy vs. a random and unpredictable spatial or temporal pattern, in which the monkey responds to the spatial or temporal cue. The contribution of the three systems will be studied during perormance of these motor tasks by 1) recording from neurons in the supplementary motor or lateral premotor cortex, 2) recording from neurons in the thalamus that have been identified physiologically as receiving input from the globus pallidus or different portions of the cerebellar nuclei, and 3) interrupting individual systems, using either chemical inhibition or lesions. These experiments will allow us to test the hypothesis that the basal ganglia and cerebellar output directed to supplementary and lateral premotor areas of cortex contribute differentially to the control of sensory-guided vs. "internally programmed" or "learned" complex motor sequences.

DESCRIPTION (Adapted from the applicant's abstract): It has been proposed that the basal ganglia and the supplementary motor area (SMA), to which much of the output of motor areas of the basal ganglia is directed, play special roles in the control of movements that are based on internally stored information. It also has been proposed that information from SMA and the postarcuate premotor cortex (APA), which is hypothesized to play an important role in movement guided by externally derived sensory signals, send information to separate neurons in the basal ganglia. To test these hypotheses, the proposed experiments will: 1) compare the activity of individual pallidal (and SMA) neurons during kinematically similar movements made under behavioral conditions that do or do not require memory of target location or sequence, 2) determine whether different groups of pallidal neurons receive input from different motor and premotor cortical areas, and 3) determine the changes produced in motor performance (and SMA neuronal activity) on internally and externally guided tasks when normal pallidal output is disrupted. These experiments will extend our understanding of the control of normal targeted limb movements and will provide information that can be used to assess, and perhaps rehabilitate, individuals with motor disabilities due to conditions such as Parkinson's disease, Huntington's chorea, slowly growing brain tumors and vascular or traumatic brain injury.

Our current objective is to determine whether pallidal neurons discharge differently during movements that are a part of a learned spatial sequence. We have recorded the activity of more than 250 neurons in the external and internal pallidal segments of five monkeys that learned to move to multiple sequences of two or three peripheral targets under several conditions. These movements could be to targets that became visible at the time of the trigger, either in random order or in a fixed sequence, or they could be made to remembered target locations. The remembered target locations were presented under two conditions either each was precued, with a delay from precue to trigger, or the entire sequence had to be remembered (ALL8). Whereas the fixed, repeated sequence task might elicit implict learning, the remembered task requires that the animal explicitly learn the sequence. A large fraction of the pallidal cells studied show a significant difference between the mea n dischar ge rate before the GO signal (HOLD) in the random or fixed task, compared with the precued or remembered task. Another significant group of pallidal cells shows a change in perimovement discharge during the ALL8 task, compared with the random or fixed tasks. We are now completing analysis to determine whether these different types of responses occurred in cells in different locations of the globus pallidus. A manuscript on sequence learning and pallidal discharge is in preparation. FUNDING NIH grants RR00166 and NS15017.

musculoskeletal system; cognition; nervous system; rehabilitation; Primates; Mammalia;

To study the effects of pallidotomy on motor and cognitive functions and on gait rhythmic motor functions as measured by specialized tests.

Our current objectives are to determine the actions of dopamine via D1 and D2 receptors on tonic and phasic discharge of neurons in external and internal pallidal segments, and to study the effects of striatal GABA on striatal output neurons. Pharmacological agents have been applied to the striatum through implanted PAN-PVC tubing in three monkeys. In all, the technique developed by Dr. Dubach has resulted in accurate placement of the tubing along a curved longitudinal trajectory in the lateral portion of the putamen. We have applied the D1-selective antagonist SCH23390 and the D2-selective antagonist raclopide successfully while monitoring behavior and recording from pallidal neurons. In high concentrations similar to those injected by others into the cortex, both agents interrupted behavior, and SCH23390 caused drowsiness. Even at concentrations reduced by 10- to 100-fold, the animal stopped working, but only after a longer drug perfusion and with a shorter wash out time to behavioral recovery. The behavioral data showed that, even when the intervals between successful trials were very long, the reaction time and movement time for successful trials was not significantly longer than the times before or after drug application. This suggests that drug administration alters attention, more than processes directly related to motor output. FUNDING NIH grants RR00166 and NS15017. Anderson, M.E., Dubach, M., Ruffo, M., Eaton, R., and Buford, J.A. Effects on motor behavior of dopamine antagonists applied locally in the putamen of awake monkeys. Soc. Neurosci. Abstr. 24:1650, 1998.

disease /disorder model; injection /infusion; lenticular nucleus

The University of Washington will establish a Medical Rehabilitation Research Network that will facilitate high quality research in rehabilitation in the 15-state western region of the United States. This network will (1) promote new rehabilitation research by clinicians and basic scientists, (2) attract talented investigators to the field, (3) foster interactive approaches to questions central to the rehabilitation research, (4) serve as an educational resource to enhance the capabilities interested in rehabilitation research. The network will include two Scientific Resource Cores, an Information Technology Core, and an Administrative Core. It also will fund up to three pilot projects annually that utilize the services of the network's scientific resources. The Experimental Design and Biostatistics Scientific Resource core will respond to the need of many investigations to access expertise regarding the complex environmental design of studies in rehabilitation. One element of this core will be in the design and conduct of research studies in rehabilitation. Second element will be the development of an experimental design course for rehabilitation researchers. A second element will be the development of an experimental design course for rehabilitation researchers. This course, which will be modular in format, will initially be piloted on-site as an intensive short course in the University of Washington. As the course modules are refined, they will be made available as interactive Web-based learning modules. The Functional Imaging Scientific Resource core will be based at the Brain Mapping Center of the University of California in Los Angeles (UCLA). This core will provide expertise on the design, implementation, and analysis of experimental studies of the nervous system that use functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation. Core scientists at UCLA will assist new investigators to obtain experience and pilot fMRI data. The Information Technology Core will publicize the resources available from the network to rehabilitation researchers in the regions, will implement and manage an interactive Web site on which materials developed by the network can be accessed by rehabilitation researchers, and will provide linkages to information about grant funding sources. Three pilot projects that utilize the Research Resource Cores will be funded during each project period, with a maximum duration of two years each.

DESCRIPTION (provided by applicant): Although high-frequency deep brain stimulation (HF-DBS) in the globus pallidus or subthalamic nucleus has become a common technique used to treat drug-resistant symptoms of Parkinson's disease, the mechanisms by which HF-DBS exerts its effects are unknown. In the proposed studies, the ability of chronic administration of the insecticide rotenone, to produce an animal model of Parkinson's disease will first be tested in monkeys. Using PET imaging now available in the University of Washington Regional Primate Research Center, changes in dopamine innervation after administration of rotenone will be measured using a marker of the monoamine vescicular transporter that is present in dopaminergic nerve terminals. These changes will then be correlated, over time, with changes in behavior and with electrophysiological changes in the rate and pattern of discharge of neurons in basal ganglia-receiving areas of the thalamus. This model will then be used to couple the electrophysiological effects of HF-DBS, which can be recorded from basal ganglia-receiving neurons of the thalamus, to the stimulation-induced changes in regional metabolism in the cortex and thalamus. PET imaging with the metabolic marker, [8-F] flurodeoxyglucose (FDG), will be used to measure metabolism. This technique has generally shown a relative hypermetabolism in the globus pallidus and thalamus of humans with Parkinson's disease and a relative hypometabolism in areas of the frontal cortex. Changes reported to be induced by HF-DBS have been mixed however. The combination of electrophysiology and metabolic imaging will allow us to address some of the discrepancies from the human literature. Special attention will be paid to the development of abnormal patterns of bursting behavior in the thalamus of monkeys treated with rotenone, as well as the effect of HF-DBS on burst behavior. This will test the hypothesis that some of the symptomatology of Parkinson's disease, and its relief using HF-DBS, is a consequence of abnormal patterns of activity in basal ganglia-thalamic-cortical circuits.

[unreadable] DESCRIPTION (provided by applicant): The Western Medical Rehabilitation Research Network (RehabNet-West) will organize and conduct a conference on planning and conducting rehabilitation multi-site clinical trials. This conference will target mid-level researchers and will use examples from multi-site clinical trials conducted by rehabilitation researchers, and by researchers in different fields, as case studies to illustrate problems and solutions in the planning, design, conduct, and analysis of multi-site clinical trials. The conference will be held 22-24 October 2004 in Denver, Colorado. [unreadable] [unreadable]

neurophysiology; thalamocortical tract; thalamus; clinical research;

The University of Washington will establish a Medical Rehabilitation Research Network that will facilitate high quality research in rehabilitation in the 15-state western region of the United States. This network will (1) promote new rehabilitation research by clinicians and basic scientists, (2) attract talented investigators to the field, (3) foster interactive approaches to questions central to the rehabilitation research, (4) serve as an educational resource to enhance the capabilities interested in rehabilitation research. The network will include two Scientific Resource Cores, an Information Technology Core, and an Administrative Core. It also will fund up to three pilot projects annually that utilize the services of the network's scientific resources. The Experimental Design and Biostatistics Scientific Resource core will respond to the need of many investigations to access expertise regarding the complex environmental design of studies in rehabilitation. One element of this core will be in the design and conduct of research studies in rehabilitation. Second element will be the development of an experimental design course for rehabilitation researchers. A second element will be the development of an experimental design course for rehabilitation researchers. This course, which will be modular in format, will initially be piloted on-site as an intensive short course in the University of Washington. As the course modules are refined, they will be made available as interactive Web-based learning modules. The Functional Imaging Scientific Resource core will be based at the Brain Mapping Center of the University of California in Los Angeles (UCLA). This core will provide expertise on the design, implementation, and analysis of experimental studies of the nervous system that use functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation. Core scientists at UCLA will assist new investigators to obtain experience and pilot fMRI data. The Information Technology Core will publicize the resources available from the network to rehabilitation researchers in the regions, will implement and manage an interactive Web site on which materials developed by the network can be accessed by rehabilitation researchers, and will provide linkages to information about grant funding sources. Three pilot projects that utilize the Research Resource Cores will be funded during each project period, with a maximum duration of two years each.