Cerebral blood flow responses to dorsal and ventral STN DBS correlate with gait and balance responses in Parkinson's disease

Abstract

Objectives

The effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on gait and balance vary and the underlying mechanisms remain unclear. DBS location may alter motor benefit due to anatomical heterogeneity in STN. The purposes of this study were to (1) compare the effects of DBS of dorsal (D-STN) versus ventral (V-STN) regions on gait, balance and regional cerebral blood flow (rCBF) and (2) examine the relationships between changes in rCBF and changes in gait and balance induced by D-STN or V-STN DBS.

Methods

We used a validated atlas registration to locate and stimulate through electrode contacts in D-STN and V-STN regions of 37 people with Parkinson's disease. In a within-subjects, double-blind and counterbalanced design controlled for DBS settings, we measured PET rCBF responses in a priori regions of interest and quantified gait and balance during DBS Off, unilateral D-STN DBS and unilateral V-STN DBS.

Results

DBS of either site increased stride length without producing significant group-level changes in gait velocity, cadence or balance. Both sites increased rCBF in subcortical regions and produced variable changes in cortical and cerebellar regions. DBS-induced changes in gait velocity are related to premotor cortex rCBF changes during V-STN DBS (r = − 0.40, p = 0.03) and to rCBF changes in the cerebellum anterior lobe during D-STN DBS (r = − 0.43, p = 0.02).

Conclusions

DBS-induced changes in gait corresponded to rCBF responses in selected cortical and cerebellar regions. These relationships differed during D-STN versus V-STN DBS, suggesting DBS acts through distinct neuronal pathways dependent on DBS location.

Introduction

Reductions in gait velocity and stride length characterize the postural instability and gait disturbances common in idiopathic Parkinson's disease (PD) (Ferrandez and Blin, 1991). Deep brain stimulation of the subthalamic nucleus (STN DBS) improves gait and balance in some individuals with PD (Faist et al., 2001, Nilsson et al., 2009) yet its mechanisms of action remain unclear. Understanding the mechanisms underlying response variability may provide insights into the neural control of gait and balance and the functional anatomy of the STN.

One key factor contributing to response variability may be stimulation of different anatomic sites in the STN region. Investigations of STN circuitry in non-human primates reveal distinct regions with potentially disparate functions. The dorsolateral STN region connects to sensorimotor areas of the basal ganglia and to motor cortical areas while the ventral STN region connects to higher order cortical regions subserving cognitive functions (Parent and Hazrati, 1995); in vivo magnetic resonance imaging techniques may confirm this in humans (Lambert et al., 2012). Electrode contact location along the typical dorsolateral to ventromedial surgical implantation trajectory through the STN region may therefore influence the clinical effects of DBS. In support of this hypothesis, unilateral stimulation of the ventral STN region (V-STN DBS) impaired response inhibition performance in individuals with PD more than stimulation of the dorsal STN region (D-STN DBS) (Hershey et al., 2010). On the other hand, the influence of contact location on gait and balance remains unclear: D-STN stimulation (Johnsen et al., 2010) or V-STN stimulation (Hilliard et al., 2011) may be optimal, or either location may be equally effective for improving gait and balance (McNeely et al., 2011).

Neuroimaging can identify pathways activated by DBS (Ballanger et al., 2009, Hershey et al., 2003, Perlmutter et al., 2002) and the responses in these pathways subsequently correlated with behavioral responses (Campbell et al., 2008, Karimi et al., 2008). Stimulation of different STN regions could activate distinct downstream cortical and cerebellar areas dependent upon different anatomic connections. Therefore, comparing regional cerebral blood flow (rCBF) responses during D-STN versus V-STN DBS and evaluating any relationships between rCBF and motor responses may provide further insights into the functional anatomy of the STN. These comparisons may help to determine which circuits subserve motor functions and to explain the variability of motor responses to STN DBS.

Thus the purposes of this study were to compare the effects of D-STN versus V-STN DBS on gait, balance and rCBF and then determine the relationships between motor performance and rCBF responses. To achieve these goals, we employed a validated process to locate (Videen et al., 2008) and selectively stimulate through electrode contacts in the D-STN and V-STN regions. In our within-subjects, double-blind and counterbalanced design controlled for stimulation variables (voltage, pulse width, frequency) we measured rCBF responses (PET imaging with ¹⁵O-labeled water), gait (GAITRite Systems), and balance (Mini-BESTest) during each of three stimulation conditions: DBS Off, unilateral D-STN DBS, and unilateral V-STN DBS.