Somatotopic organization in the internal segment of the globus pallidus in Parkinson's disease

Abstract

Ablation or deep brain stimulation in the internal segment of the globus pallidus (GPi) is an effective therapy for the treatment of Parkinson's disease (PD). Yet many patients receive only partial benefit, including varying levels of improvement across different body regions, which may relate to a differential effect of GPi surgery on the different body regions. Unfortunately, our understanding of the somatotopic organization of human GPi is based on a small number of studies with limited sample sizes, including several based upon only a single recording track or plane. To fully address the three-dimensional somatotopic organization of GPi, we examined the receptive field properties of pallidal neurons in a large cohort of patients undergoing stereotactic surgery. The response of neurons to active and passive movements of the limbs and orofacial structures was determined, using a minimum of three tracks across at least two medial-lateral planes. Neurons (3183) were evaluated from 299 patients, of which 1972 (62%) were modulated by sensorimotor manipulation. Of these, 1767 responded to a single, contralateral body region, with the remaining 205 responding to multiple and/or ipsilateral body regions. Leg-related neurons were found dorsal, medial and anterior to arm-related neurons, while arm-related neurons were dorsal and lateral to orofacial-related neurons. This study provides a more detailed map of individual body regions as well as specific joints within each region and provides a potential explanation for the differential effect of lesions or DBS of the GPi on different body parts in patients undergoing surgical treatment of movement disorders.

Introduction

As one of two primary output structures of the basal ganglia, the internal segment of the globus pallidus (GPi) serves as a critical nodal point for both the direct and indirect pathways of the basal ganglia thalamocortical circuit. It has been demonstrated to play a role in normal motor behavior (DeLong, 1971) in the development of movement disorders (Alexander et al., 1986, DeLong, 1990, Filion and Tremblay, 1991, Filion et al., 1991) and serves as a surgical target for patients with Parkinson's disease (PD) (Kumar et al., 2000, Rodriguez-Oroz et al., 2005) or dystonia (Diamond et al., 2006, Mueller et al., 2008, Pretto et al., 2008). In monkeys rendered parkinsonian with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), it has been demonstrated that changes in motor behavior are associated with increased discharge rates in GPi (Filion and Tremblay, 1991, Filion et al., 1991). More recently, altered patterns of neuronal activity in the form of increased bursting and greater synchronization (Brown et al., 2004, Brown and Williams, 2005, Gatev et al., 2006, Maurer et al., 2004, Nini et al., 1995, Raz et al., 2000, Wichmann et al., 1994b, Wichmann et al., 2002) as well as a widening of receptive fields to proprioceptive input (Filion et al., 1988, Leblois et al., 2006, Vitek et al., 1998) have been reported to occur in GPi in the parkinsonian state. And while a causal relationship between these changes and the cardinal features of PD has yet to be determined, it is clear that therapeutic benefit can be achieved for patients with PD through exogenous modulation of pallidal activity (Baron et al., 2002, Bergman et al., 1990, Burchiel et al., 1999, Nakamura et al., 2007, Rodriguez-Oroz et al., 2005, Vitek et al., 2003, Weaver et al., 2005). As currently performed, such procedures involve the targeting and, in most centers, the identification of the sensorimotor region of the GPi, followed by either radiofrequency ablation or the implantation of a deep brain stimulation (DBS) lead for chronic electrical stimulation.

Studies of the sensory and motor systems of the central nervous system have revealed a high degree of topographic organization in both humans and non-human animal models. Within the GPi, studies using the non-human primate model have revealed that movement-related neurons tend to be located posterolateraly (DeLong, 1971, DeLong et al., 1985). Within that region, a gross somatotopic organization has been demonstrated such that units related to upper limb movement tend to be located inferior, lateral and to a lesser extent caudal to more centrally located lower limb-related units, with orofacial-related units concentrated within the caudal extend of the nucleus ventral to upper limb-related units (DeLong et al., 1985). Studies performed during intra-operative mapping of human patients with either PD (Guridi et al., 1999, Sterio et al., 1994, Taha et al., 1996, Vitek et al., 1998) or dystonia (Chang et al., 2007) have largely supported the presence of a somatotopic arrangement of the GPi in humans. However, most of these studies suffer from limited sample sizes or methodological shortcomings, including acquiring data from only a single trajectory (Taha et al., 1996) or mapping each patient only along a single parasagittal plane (Sterio et al., 1994, Taha et al., 1996). We report here the somatotopic characteristics of the GPi based on the collection of over 3000 neurons from 299 patients with PD obtained during microelectrode mapping of the GPi over a period of ten years.