Effects of transient focal inactivation of the basal ganglia in parkinsonian primates

Abstract

Ablative and chronic stimulation procedures targeting the internal pallidum (GPi) and the subthalamic nucleus (STN) have led to major advancements in the treatment of Parkinson's disease and other movement disorders. Although these procedures have evolved to primarily target the posterior ventrolateral sensorimotor portion of GPi and to less selectively target STN, centrally, the ideal targets within these structures remain to be fully established. In this study, we sought to identify the optimal targeting sites in GPi and STN for reversal of parkinsonian signs through a series of reversible injections of the GABA(A) agonist muscimol in these nuclei in parkinsonian primates. Akinesia and bradykinesia were strongly ameliorated by discrete inactivation within the centromedial extent of the sensorimotor territory in GPi and the lateral portion of the sensorimotor territory in STN. This suggests that akinesia and bradykinesia might, in fact, originate from abnormalities in the same, or at least overlapping, motor circuits in the parkinsonian state. Inactivation of areas outside of the motor territories did not improve parkinsonism but induced circling and behavioral abnormalities. The segregation of basal ganglia-thalamocortical circuits appears to be therefore maintained, at least to a large extent, in the parkinsonian state. These results underscore that inactivation of discrete regions in the central territory of GPi and the lateral portion of STN are sufficient to ameliorate parkinsonian motor signs and that extension of lesions into nonmotor territories may be deleterious. Surgical outcomes might therefore be optimized by placing more discrete lesions and by restricting the extent of chronic stimulation.

Fig. 1.

Parasagittal reconstructions (lateral 5–11; according to the atlas of Winters et al., 1969) illustrating pooled proprioceptive responses of neurons to passive manipulations of the contralateral forelimb (•) and hindlimb (□), trunk (▵), and orofacial ( ) regions in the GPi in four parkinsonian monkeys (A) and the STN in three parkinsonian monkeys (B).

Fig. 2.

Parasagittal reconstructions (lateral 6–11) illustrating the sites of focal injections of muscimol in the GPi and the resultant improvements in generalized (A) and contralateral forelimb (B) akinesia in two parkinsonian monkeys. The sites producing contralateral circling and atypical behavior are also indicated (A), as are sites of injections in the GPe. Open small squares indicate sites with no motor effects, and filled squares, asterisks, and open circles indicate the levels of changes in postinjection scores from mean baseline scores for akinesia, atypical behavior, and contralateral circling, respectively. The gray shaded regions represent general (A) and specifically, forelimb (B) sensorimotor territories across four monkeys (detailed in Fig. 1A).

Fig. 3.

Parasagittal reconstructions (lateral 5–8) illustrating the sites of focal injections of muscimol in the STN and the resultant improvements in generalized (A) and contralateral forelimb (B) akinesia in two parkinsonian monkeys. The sites producing contralateral circling and atypical behavior are also indicated in Figure A.Open small squares indicate sites with no motor effects, and filled squares, asterisks, andopen circles indicate the levels of changes in postinjection scores from mean baseline scores for akinesia, atypical behavior, and contralateral circling, respectively. The gray shaded regions represent general (A) and specifically, forelimb (B) sensorimotor territories across three monkeys (detailed in Fig. 1B).