High frequency stimulation of the internal Globus Pallidus (GPi) simultaneously improves parkinsonian symptoms and reduces the firing frequency of GPi neurons in the MPTP-treated monkey Thomas Boraud, Erwan Bezard, Bernard Bioulac, Christian Gross* Laboratoire de Neurophysiologie, CNRS UMR 5543, Universite ´ de Bordeaux II, 146 rue Le ´o Saignat, 33076 Bordeaux Cedex, France Received 17 May 1996; revised version received 25 July 1996; accepted 25 July 1996 Abstract The firing pattern of the neurons of the internal Globus Pallidus (GPi) is greatly disturbed in Parkinson’s disease. Surgical lesion or high frequency stimulation (HFS) of the GPi reduces parkinsonian rigidity and akinesia. We evaluated in this study the effects of HFS of the GPi on the firing pattern of its neurons. Extracellular recordings were carried out under three types of experimental conditions in rhesus monkeys, normal state, after MPTP treatment and during HFS of the GPi. After intracarotidian MPTP injection, the firing rate of GPi cells increased significantly. During HFS, MPTP-induced parkinsonian motor symptoms clearly improved correlatively with a significant decrease in the firing rate of GPi cells in the stimulated area. HFS restored a firing frequency similar to that in normal animals and, unexpectedly, did not completely block neuronal activity. Keywords: MPTP-treated monkeys; GPi high frequency stimulation; Extracellular unit recordings of GPi; Improvement of motor symptoms; Regularization of the firing frequency of GPi neurons Parkinsonian motor symptoms are associated with neu- ronal overactivity of the major output structure of the basal ganglia, the internal part of the Globus Pallidus (GPi) [1,7,10,12,16]. Surgical lesion of the GPi (mainly posteroventral palli- dotomy) improves two of these symptoms, akinesia and rigidity [9,14,15]. Since it has been observed that chronic high frequency stimulation (HFS) of the thalamic ventralis intermedius (Vim) has the same suppressive effect on par- kinsonian tremor as thalamotomy [2], we have used HFS of the GPi as a reversible alternative to lesion. Our clinical rate of success has been similar to that obtained with pal- lidotomy [11]. Postmortem examination of one patient, who died sev- eral months after successful implantation of a chronic HFS electrode in the Vim, revealed no histological modifica- tions around the tip of the electrode [6]. This would con- firm the inocuity of the procedure for the stimulated nucleus and prove the clinical interest of HFS in certain extrapyramidal diseases. Previous electrophysiological studies in rats [4,5] and MPTP-treated monkeys [3] have demonstrated a clearcut inhibitory effect of HFS upon the glutamatergic subthala- mopallidal pathway. The hypotheses so far advanced to explain the mechanisms underlying this inhibitory effect remain, however, subject to controversy: stimulation of inhibitory GABAergic inputs, or inactivation of neurons by transient and abrupt depolarization of their mem- branes? We are, thus, confronted with the question whether HFS induces complete inhibition of GPi cells, as would a rever- sible pallidotomy, or only decreases the firing rate of these cells. In the second case, the clinical state induced by HFS treatment would more closely resemble the normal phy- siological state. The present work was designed to inves- tigate the effects of HFS of the GPi upon the firing pattern of GPi neurons in order to test these different hypotheses. GPi neuronal activity was recorded under three types of experimental conditions in two rhesus monkeys (Macaca Neuroscience Letters 215 (1996) 17–20 0304-3940/96/$12.00  1996 Elsevier Science Ireland Ltd. All rights reserved PII S0304-3940(96)12943-8 * Corresponding author. Tel.: +33 57571551; fax: +33 56901421; e- mail: bdneuro@umr5543.u-bordeaux.fr