The major aim of this study is to better define the contribution of the basal ganglia """"""""motor"""""""" circuits to the development of hypokinetic and hyperkinetic movement disorders. The basal ganglia nuclei appear to influence motor control through multiple reentrant cortico-subcortical pathways. Lesioning and reversible inactivation studies in parkinsonian monkeys have demonstrated that the """"""""motor"""""""", and not the """"""""associative"""""""", circuits directly influence parkinsonian motor signs. Based upon the demonstration of site specific inactivation effects in the """"""""motor"""""""" territory of the internal portion of the globus pallidus (GPi), we hypothesize that the recently identified anatomically segregated cortico- subcortical """"""""motor"""""""" subcircuits differentially influence specific parkinsonian motor signs. We have recently shown that electrolytic lesioning of the sensorimotor territory of GPi is an effective means for ameliorating all parkinsonian signs, as well as drug-induced dyskinesias, in patients with idiopathic Parkinson's disease (PD). After surgery, however, patients continue to require comparable medication dosages for adequate control of their symptoms. Experimental lesions placed in the subthalamic nucleus (STN) of parkinsonian monkeys have similarly been shown to cause dramatic improvement of parkinsonian signs, with mainly transient lesion-induced dyskinesias. Because STN projects not only to GPi, but also to such structures as the substantia nigra (SN), lesioning of STN could potentially provide better amelioration of parkinsonian symptoms, while reducing patients' dependencies on dopamine therapy. The proposed studies will address these issues related to the specific pathways influencing normal and abnormal motor control. Specifically, we will 1) determine whether the primary motor cortex (MC) and supplementary motor area (SMA) subcircuits contribute differentially to the production Of parkinsonian motor signs, in the PD animal model, 2) investigate whether in the parkinsonian state, these subcircuits converge at the level of single neurons in the basal ganglia, 3) assess the contribution of SN pars reticulata to the expression of parkinsonian motor signs, 4) examine the role of STN pathways in the development of parkinsonian symptoms and drug- related dyskinesias and compare the results of GPi and STN lesions in parkinsonian animals, and 5) determine the patterns of basal ganglia neural activity associated with drug-induced dyskinesias.
| Baron, Mark S; Wichmann, Thomas; Ma, Demin et al. (2002) Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J Neurosci 22:592-9 |
