THALAMOTOMY FOR THE ALLEVIATION OF LEVODOPA-INDUCED DYSKINESIA - EXPERIMENTAL STUDIES IN THE METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE-TREATED PARKINSONIAN MONKEY

This work set out to test the hypothesis that thalamotomy in the area of the thalamus which receives the input from the medial segment of th e globus pallidus would decrease or prevent levodopa-induced dyskinesi a. Peak dose dyskinesia is a major problem in the treatment of parkins onian patients with levodopa therapy but this remains the best pharmac ological agent for treating the condition. The hypothesis was derived from previous work which has suggested that reduced pallidal inhibitio n of the thalamus results in dyskinesia [Crossman (1990) Movement Dis. 5, 100-108]. A neuroanatomical tracing study was carried out prior to the thalamotomy work, using the anterograde tracer wheatgerm-agglutin in conjugated to horseradish peroxidase. This delineated the anterior part of the ventrolateral thalamus in the primate in terms of its affe rent inputs. Wheatgerm agglutinin-horseradish peroxidase was injected into the medial segment of the globus pallidus bilaterally in three Ma caca fascicularis and traced to terminals in the ventral thalamus and other brain areas. The appropriate thalamic area involved was plotted on atlas sections in preparation for stereotactic thalamotomy. Previou s studies of neuronal input to the ventral thalamus are confusing due to the different nomenclatures used by different workers. Early worker s used cytoarchitectonic boundaries which do not correspond with funct ion. There are also differences in nomenclature between man, monkey an d other animals. The current study maps the pallidal terminal territor y within the thalamus in terms of stereotactic co-ordinates related to a published macaque atlas [Shantha et al. (1968) A Stereotaxic Atlas of the Java Monkey Brain. S. Karger, Basel] and can thus be used by ot her workers in the field. A well-established primate model of Parkinso nism was used for the thalamotomy study. Eight monkeys (Macaca fascicu laris) were rendered parkinsonian with 1-methyl-4-1,2,3,6-tetrahydropy ridine. Regular dosing with levodopa or apomorphine reliably resulted in peak-dose dyskinesia which was scored in terms of its choreic and d ystonic components. A radiofrequency electrode was used to create the ablative lesions. Chorea was always reduced and frequently abolished b y a thalamotomy located in the pallidal terminal territory. This resul t was obtained after 10 thalamotomies in a total of six animals. Four animals received bilateral lesions, with an interval between operation s and two animals underwent unilateral surgery. Lesions which were pos itioned medial to the pallidal terminal territory (n = 3) had no perma nent effect upon chorea. Lesions were also made in the thalamic areas which receive cerebellar and nigral inputs and in other areas which re ceive input from the medial segment of the globus pallidus, including the centromedian nucleus of the thalamus, the substantia nigra pars re ticulata and the pedunculopontine nucleus. None of these lesions had a significant effect upon peak-dose chorea. In contrast to the dramatic effects upon chorea, peak-dose dystonia was not affected by any of th e thalamic lesions. The data suggest that: (i) levodopa-induced chorea can be alleviated by a thalamotomy in the pallidal terminal territory of the thalamus and (ii) chorea and dystonia are mediated by differen t pathophysiological circuits.