From single extracellular unit recording in experimental and human Parkinsonism to the development of a functional concept of the role played by the basal ganglia in motor control

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects the whole basal ganglia (BG). Various techniques have been used to study BG physiology and pathophysiology. Among these, extracellular single unit recording remains of particular importance. An impressive number of studies of BG electrophysiological activity have been carried out, both in non-human and in human primates, but the data collected show many omissions and disparities. BG activity has been well defined in the physiological situation, but remains far from clear in the Parkinsonian and virtually unexplored in the dopamine (DA)-replacement situation. This paper provides a brief synopsis of (i) recording techniques and (ii) BG electrophysiological activity in normal, Parkinsonian, and dopamine-replacement situations. We have restricted the data used to those obtained in BG structures of human and non-human primates. Only single unit recordings have been reported and four electrophysiological characteristics retained: mean firing frequency, firing pattern, periodic oscillation, and response to both passive and active movement. We have attempted to summarize (i) the commonly accepted characteristics of each BG structure in the three situations, (ii) discrepancies that exist, and (iii) missing elements. Then, the main successive theories aimed to explain the role played by BG in motor control are presented and discussed in the light of the most recently obtained results using the latest technological advances.

Introduction

Parkinson’s disease (PD) is a progressive neurodegenerative disorder observed in 1% of the population over 65, mean age at which the disease is first diagnosed (Hoehn and Yahr, 1967). It was first characterized by Parkinson (1817) and consists in a syndrome including tremor, rigidity, postural abnormalities, and akinesia, the difficulty or failure to execute a willed movement (Patrick and Levy, 1922, Agid, 1991).

The main pathological characteristic of PD is the death of pigmented neurons of the substantia nigra pars compacta (SNc, Hassler, 1938). The loss of these nigrostriatal neurons, since identified as dopamine (DA) providers for the main input structure of the basal ganglia (BG), the striatum (Ehringer and Hornykiewicz, 1960, Hornykiewicz, 1966), modifies the homeostatic equilibrium of extracellular DA levels within the striatum (Zigmond et al., 1990, Zoli and Fuxe, 1996). This, in turn, gradually upsets the activity of the whole BG network (DeLong, 1990), the group of nuclei involved in extrapyramidal motor control, and leads eventually to declared Parkinsonism.

The structural organization of the extrapyramidal motor circuit links the cortex, the basal ganglia, and the thalamus (Parent and Hazrati, 1995a, Fig. 1) and constitutes one of the five parallel pathways that have been identified as processing information between the cortex and the basal ganglia (Alexander et al., 1986). Inputs from pre/postcentral motor areas are processed by the putamen that then transmits motor information to both the globus pallidus pars internalis (GPi) and the substantia nigra pars reticulata (SNr), the output nuclei of the basal ganglia. These structures in turn project mainly to the ventrolateral thalamus and secondarily to the brainstem. The basal ganglia also comprise the external part of the globus pallidus pars externalis (GPe) and the subthalamic nucleus (STN).

Various techniques have been used to study BG physiology and pathophysiology. Among these, extracellular single unit recording remains of particular importance. In spite of the huge development of more sophisticated and fashionable techniques such as functional anatomy or functional imaging, single unit recording is the only technique that allows the measurement of neuronal activity during the execution of movement with the same degree of temporal and spatial precision (respectively milliseconds and hundreds of micrometers) and that accurately reflects neuronal encoding without any distortion. But it has drawbacks, in that it requires large samples of neurons and shows a bias towards recording large units more readily than small and fast firing rates more than slow. It remains, nonetheless, a first class tool for the understanding of the physiology and the pathophysiology of the central nervous system.

Most research has understandably been done on experimental models of PD, but the recent renewal of interest in the surgical treatment of PD (Obeso et al., 1997b, Quinn and Bhatia, 1998, Gross et al., 1999) has allowed an access to human data on BG activity, since most surgical teams use microelectrode recording to determine the exact location of the target (e.g. Hutchinson et al., 1994, Taha et al., 1996b, Stefani et al., 1997). This per-operatory technique was first developed by Albe-Fessard and her colleagues in the early 1960s, principally to map the thalamus before thalamotomy (Albe-Fessard et al., 1963, Albe-Fessard et al., 1966, Albe-Fessard et al., 1967), and is now used mainly for precise identification of the Vim of the thalamus and the different components of the pallidal complex, the GPi, GPe and STN (for review, see Gross et al., 1999). These human recording data can be compared with the results obtained in subhuman primates rendered Parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. For the purpose of this article, MPTP-treated monkeys are referred to as Parkinsonian monkeys. We are naturally, however, aware that the mechanisms underlying dopaminergic denervation and the pattern of cellular death are not those of the human disease (Pifl et al., 1991, Damier et al., 1999).

An impressive number of studies of BG activity have been carried out, both in non-human and in human primates but the data collected show many omissions and disparities. BG activity has been well defined in the physiological situation but remains far from clear in the Parkinsonian and virtually unexplored in the DA-replacement situation. This paper provides a brief synopsis of (i) recording techniques and (ii) BG electrophysiological activity in normal, Parkinsonian, and dopamine-replacement situations. We have restricted the data used to those obtained in BG structures of human and non-human primates. Only single unit recordings have been reported and four electrophysiological characteristics retained: mean firing frequency, firing pattern, periodic oscillation, and response to both passive and active movement. We have attempted to summarize (i) the commonly accepted characteristics of each BG structure in the three situations, (ii) discrepancies that exist, and (iii) missing elements. The prospects and possibilities offered by electrophysiology in this field of research, in particular, multi-channel recording, are discussed in the conclusion.