The overall aim of this proposal is to examine the role of the ventrolateral (VL) thalamus in the development of parkinsonian motor signs and drug-induced dyskinesia. It has recently been demonstrated in the monkeys MPTP model of Parkinson's disease (PD) that neuronal activity is increased in the subthalamic nucleus (STN) and globus pallidus, pars interna (GPi) and that inactivation or lesioning of either STN or GPi reverses all the major motor signs of PD. Based on these finding it has been postulated that parkinsonian motor signs occur as a result of excessive (inhibitory) output from the GPi which acts to inhibit the motor thalamus ventralis lateralis, pars oralis (VLo). Conversely, it has been demonstrated that neuronal activity in GPi is decreased in L- Dopa-induced dyskinesia in the MPTP monkey model of PD, and it has long been known that lesions in the STN, which results in decreased inhibitory output from GPi, produce a hyperkinetic state. Thus, a model of hypo/hyperkinetic movement disorders has developed in which the motor thalamus, the primary target of efferents from the basal ganglia, plays an integral role in the development of parkinsonian motor signs and drug- induced dyskinesias. Although the evidence in support of this model is compelling at the level of STN and GPi, at present there is no evidence at the thalamic level in primates to support or refute its predictions. A role for the thalamus in mediating these disorders is supported by results in humans undergoing stereotactic surgery for PD, since lesions in VL are reported to alleviate rigidity, tremor and drug-induced dyskinesia. These observations, however, are not consistent with the hypothesis that decreased activity of thalamic neurons results in parkinsonism, since lesions in the thalamus would further reduce thalamic activity and should exacerbate parkinsonian signs. An alternative explanation is that excessive inhibition not only decreases but alters neuronal activity in the thalamus and its is this altered activity which leads to the development of disordered movement. Results from human thalamotomies, while supportive of this hypothesis, are controversial, since histologic verification of the lesions site is seldom possible. As a result, it is unclear where the lesions are actually placed, where the optimal lesion site is, if the most effective site varies for different parkinsonian signs as reported by many surgeons, or if thalamic lesions are effective in alleviating akinesia, as sign which has been reported to remain the same worsen or improve following thalamotomy. This study is designed to test the current working model of hypo- and hyperkinetic movement disorders at the level of the thalamus using the technique of single cell recording to examine the changes in neuronal activity of the motor thalamus in animal models of PD and drug-induced dyskinesia both before and after fibersparing (FS) lesion in the GPi. This study will also test the model by studying the effects of reversible and permanent FS lesions of different thalamic sub-nuclei to examine the differential role of these subnuclei in the mediation of parkinsonian motor signs and drug-induced dyskinesias. These studies will provide important information regarding the role of the thalamus in the pathophysiology of PD and dyskinesia, refine the current model of hypo and hyperkinetic movement disorders, as well as improve our understanding of the role for thalamotomy in the surgical treatment of these disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29NS030719-05
Application #
2703007
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Oliver, Eugene J
Project Start
1994-05-01
Project End
1999-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Neurology
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Hashimoto, Takao; Elder, Christopher M; Okun, Michael S et al. (2003) Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci 23:1916-23