Subdyskinetic apomorphine responses in globus pallidus and subthalamus of parkinsonian patients: lack of clear evidence for the ‘indirect pathway’

Abstract

Objectives: Previous studies suggested that the hypo-activity of the external pallidus (GPe) might drive the hyper-activity of subthalamic neurons, which underlies the cardinal symptoms of Parkinson's disease. We have challenged this view, based on the so-called ‘indirect pathway’, by recording apomorphine effects from both structures of parkinsonian patients, at rest and during passive movements.Methods: We performed single-unit recordings from external pallidus (GPe), internal pallidus (GPi) and subthalamic nucleus (STN) during the stereotactic neurosurgery aimed to implant deep brain stimulating electrodes in GPi or STN. First, we verified the firing frequency of each structure in off-state conditions. Then, therapeutic, subdyskinetic concentrations of the dopaminergic agonist apomorphine was delivered to assess each nucleus response.Results: The firing rate of STN averaged about 40Hz; a large proportion (75%) of STN units exhibited marked responsiveness to passive movements. Apomorphine reduced the firing discharge of parkinsonian STN in all cells, although electrophysiological recovery was usually incomplete. Movement-related activity was also dramatically reduced. In contrast, apomorphine failed to modify the firing frequency of GPe, despite the amelioration of hypo-kinetic symptoms and the simultaneous inhibition of GPi firing discharge.Conclusions: We demonstrate that part of the models on basal ganglia circuitry needs to be revised. The re-balancing of STN hyper-activity, when patients benefit from dopaminergic therapy, is not due to an increased input from GPe, but, instead, due to changes in STN intrinsic firing properties and/or modulation of glutamatergic inputs.