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.

Role of External Pallidal Segment in Primate Parkinsonism: Comparison of the Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism and Lesions of the External Pallidal Segment

“…Striatal dopamine loss is postulated to result in increased striatal inhibition of GPe, which in turn results in disinhibition of STN and increased basal ganglia output from GPi. This concept is supported by the fact that STN inactivation results in a substantial reduction of the severity of parkinsonian motor signs in monkeys (Bergman et al, 1990;Guridi et al, 1993;Baron et al, 2002) and human patients (Sellal et al, 1992;Gill and Heywood, 1997;Alvarez et al, 2001).…”

Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

“…2), again raising a paradoxical result. Indeed a decrease in STN neuronal activity should parallel an increased motor activity (Baron et al, 2002;Mehta and Chesselet, 2005). The known hypotensive action of prazosin could be ruled out, because it occurs at doses 10-fold higher than that used here (Sommermeyer et al, 1995).…”

“…The STN has been shown to play a key role in PD pathophysiology by the disorganization of its neuronal activity (Bergman et al, 1994;Hassani et al, 1996;Ni et al, 2001c). Because lesion (Bergman et al, 1990), high frequency stimulation (Benazzouz et al, 1993), and pharmacological inhibition (Baron et al, 2002) of the STN improved parkinsonian motor abnormalities in MPTP-treated monkey and in PD patients (for review, see Gross et al, 1999), we hypothesized that a part of the antiparkinsonian effects of ␣2-AR antagonists could be mediated by a direct action on STN neurons.…”

Deep Brain Stimulation of the Globus Pallidus Internus in the Parkinsonian Primate: Local Entrainment and Suppression of Low-Frequency Oscillations

“…Therefore the present results may not provide an accurate representation of pallidal efferent signaling during GPiDBS. Nevertheless, because GPi somata form a critical bottleneck for the pathologic neuronal activity associated with parkinsonism (Baron et al 2002;Lonser et al 1999), stimulation-induced reductions in abnormal somatic firing are likely to reflect true network-wide suppressions of those abnormalities. The effects of stimulation on nearby somata and fiber tracts are influenced by electrode geometry and stimulation parameters (Miocinovic et al 2006).…”