Pedunculopontine Nucleus Area as a Target for Deep Brain Stimulation

Abstract and Introduction

Abstract

Recently, the pedunculopontine nucleus has been highlighted as a target for deep brain stimulation for the treatment of freezing of postural instability and gait disorders in Parkinson's disease and progressive supranuclear palsy. There is great controversy, however, as to the exact location of the optimal site for stimulation. In this review, we give an overview of anatomy and connectivity of the pedunculopontine nucleus area in rats, cats, non-human primates and humans. Additionally, we report on the behavioural changes after chemical or electrical manipulation of the pedunculopontine nucleus. We discuss the relation to adjacent regions of the pedunculopontine nucleus, such as the cuneiform nucleus and the subcuneiform nucleus, which together with the pedunculopontine nucleus are the main areas of the mesencephalic locomotor region and play a major role in the initiation of gait. This information is discussed with respect to the experimental designs used for research purposes directed to a better understanding of the circuitry pathway of the pedunculopontine nucleus in association with basal ganglia pathology, and with respect to deep brain stimulation of the pedunculopontine nucleus area in humans.

Introduction

Clinical studies have shown that deep brain stimulation of the pedunculopontine nucleus is safe and partially effective in ameliorating specific symptoms of Parkinson's disease, in particular gait and posture (Pierantozzi et al., 2008; Moro et al., 2010). There are, however, also clinical data that demonstrate that the outcome of pedunculopontine nucleus deep brain stimulation can be quite variable (Ferraye et al., 2010).

Fundamental and basic principles regarding neuronal control of locomotion or gait function have been remarkably preserved during evolution. The mechanism of gait of bipedal humans, however, is fundamentally different from that of quadrupedal animals (rats or cats). The differences in the organization and the functional connections within and between the basal ganglia with respect to the pedunculopontine nucleus can be explained by the phylogenetic expansion and differentiation of the neocortex in the primate, cat and rodent brain. Likewise, there is evidence that the role of basal ganglia in locomotor behaviour is different in higher primates and non-primate mammals (Murer and Pazo, 1993; Dybdal et al., 1997; Dybdal and Gale, 2000). Anatomical data also reveal that there are functional differences between the basal ganglia of primates and non-primates, which must be considered when extrapolating between species.

Human bipedal locomotion is distinct from all other bipedal mammals, which is in accordance with modern hierarchical change in evolution. Animal studies in rodents or monkeys revealed that the evolution from quadrupedal to bipedal locomotion did not affect the principal anatomical structures, but that the connectivity among the different nuclei may differ between species (Barton and Harvey, 2000; Courtine et al., 2005; Onodera and Hicks, 2009). With respect to the pedunculopontine nucleus, the topography and morphological structure are probably similar in most mammals, but the circuitry distribution of cholinergic, glutamatergic or GABA-ergic neurons within this region and the degree of afferent and efferent fibres may vary, which could account for species-dependent outcome of behaviour in experimental settings. Other differences may be related to differences of the normal versus the parkinsonian state.

There have been several recent reviews on the pedunculopontine nucleus, concentrating on various aspects including its connectivity to the basal ganglia (Mena-Segovia et al., 2004), its function in Parkinson's disease (Pahapill and Lozano, 2000), and its integrative role according to animal studies (Winn, 2006, 2008). The present review concentrates on comparative interspecies aspects according to anatomical, physiological and behavioural studies, which indicate—that at least partially—the action of deep brain stimulation might not only be mediated through modulation of the pedunculopontine nucleus but also through modulation of the adjacent cuneiform or subcuneiform nuclei. Furthermore, the review intends to provide background information that can be used to judge the internal and external validity of experimental studies that are used as an argument to support the role of the pedunculopontine nucleus area in human locomotion.

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