Network modulation by the subthalamic nucleus in the treatment of Parkinson's disease

Abstract

Deep brain stimulation of the subthalamic nucleus (STN DBS) has become an accepted tool for the treatment of Parkinson's disease (PD). Although the precise mechanism of action of this intervention is unknown, its effectiveness has been attributed to the modulation of pathological network activity. We examined this notion using positron emission tomography (PET) to quantify stimulation-induced changes in the expression of a PD-related covariance pattern (PDRP) of regional metabolism. These metabolic changes were also compared with those observed in a similar cohort of patients undergoing STN lesioning.

We found that PDRP activity declined significantly (P < 0.02) with STN stimulation. The degree of network modulation with DBS did not differ from that measured following lesioning (P = 0.58). Statistical parametric mapping (SPM) revealed that metabolic reductions in the internal globus pallidus (GPi) and caudal midbrain were common to both STN interventions (P < 0.01), although declines in GPi were more pronounced with lesion. By contrast, elevations in posterior parietal metabolism were common to the two procedures, albeit more pronounced with stimulation.

These findings indicate that suppression of abnormal network activity is a feature of both STN stimulation and lesioning. Nonetheless, these two interventions may differ metabolically at a regional level.

Introduction

The subthalamic nucleus (STN) plays a critical role in the modulation of cortico-striato-pallido-thalamocortical (CSPTC) motor pathways (Wichmann and DeLong, 1996, Hamani et al., 2004). The motor symptoms of Parkinson's disease (PD) are associated with increased STN activity, which results in excessive inhibitory outflow from the basal ganglia to the thalamus and brainstem (Vitek and Giroux, 2000). A variety of stereotaxic surgical approaches have been introduced to modulate STN neural activity and restore normal functioning to motor CSPTC circuitry (Lozano and Mahant, 2004).

Positron emission tomography (PET) can provide useful information concerning the functional status of CSPTC pathways in PD (Eidelberg et al., 2000). In particular, network analyses of regional PET data have consistently revealed the presence of a reproducible abnormal spatial covariance pattern associated with parkinsonism (Eidelberg et al., 1994, Moeller et al., 1999, Lozza et al., 2004, Asanuma et al., 2005a). This PD-related pattern (PDRP) is characterized by pallido-thalamic and pontine hypermetabolism associated with relative metabolic decrements in premotor, prefrontal, and posterior parietal cortical regions (Carbon and Eidelberg, 2002, Asanuma et al., 2005a). We have attributed this abnormal metabolic topography to overactivity of internal pallidal (GPi) afferents from STN and consequent increases in inhibitory pallidal outflow to the ventral thalamus and pons (Eidelberg et al., 1994, Eidelberg et al., 1997). To test this hypothesis, we quantified PDRP expression in patients with advanced disease undergoing stereotaxic subthalamotomy (Su et al., 2001). Indeed, STN lesioning was found to produce a marked and sustained reduction in network activity in human subjects (Trošt et al., 2003).

The activity of STN and its projection pathways can also be modulated by deep brain stimulation (DBS) (Vitek and Giroux, 2000, Benabid, 2003, Lozano and Mahant, 2004). The precise mechanism by which STN DBS achieves therapeutic benefit is not known. Several experimental studies have pointed to local inhibition as the predominant effect of this intervention in PD (Filali et al., 2004, Lozano and Mahant, 2004). Despite the controversy surrounding the local effects of stimulation (McIntyre et al., 2004a, McIntyre et al., 2004b), the modulation of pathological network activity is likely to be the basis for clinical benefit in STN DBS as well as in other basal ganglia interventions for PD, including lesioning of critical nodes of the CSPTC motor loop (Eidelberg et al., 1996, Fukuda et al., 2001, Su et al., 2001, Carbon and Eidelberg, 2002, Eckert and Eidelberg, 2005).

In the current study, we examined the notion that STN lesioning and stimulation were mechanistically similar at a system level. We used PET to compare the metabolic effects of the two stereotaxic interventions in patients with advanced PD who were offered one or the other treatment. Specifically, network analysis was employed to determine whether PDRP suppression is a feature of STN stimulation as well as lesioning, and whether the degree of network modulation differed with these treatment approaches.