Localization of motor and verbal fluency effects in subthalamic DBS for Parkinson's disease

Highlights

• We identify anatomic sites of maximal stimulation effect in STN DBS.

• Sites for overall motor improvement, bradykinesia, and rigidity co-localize.

• The site for maximal tremor reduction lies posterior.

• The site for maximal verbal fluency decline lies medial.

• Directionally controlled DBS may allow motor improvement without fluency decline.

Abstract

Introduction

Subthalamic nucleus deep brain stimulation (STN DBS) improves cardinal motor symptoms of Parkinson's disease (PD) but can worsen verbal fluency (VF). An optimal site of stimulation for overall motor improvement has been previously identified using an atlas-independent, fully individualized, field-modeling approach. This study examines if cardinal motor components (bradykinesia, tremor, and rigidity) share this identified optimal improvement site and if there is co-localization with a site that worsens VF.

Methods

An atlas-independent, field-modeling approach was used to identify sites of maximal STN DBS effect on overall and cardinal motor symptoms and VF in 60 patients. Anatomic coordinates were referenced to the STN midpoint. Symptom severity was assessed with the MDS-UPDRS part III and established VF scales.

Results

Sites for improved bradykinesia and rigidity co-localized with each other and the overall part III site (0.09 mm lateral, 0.93 mm posterior, 1.75 mm dorsal). The optimal site for tremor was posterior to this site (0.10 mm lateral, 1.40 mm posterior, 1.93 mm dorsal). Semantic and phonemic VF sites were indistinguishable and co-localized medial to the motor sites (0.32 mm medial, 1.18 mm posterior, 1.74 mm dorsal).

Conclusion

This study identifies statistically distinct, maximally effective stimulation sites for tremor improvement, VF worsening, and overall and other cardinal motor improvements in STN DBS. Current electrode sizes and voltage settings stimulate all of these sites simultaneously. However, future targeted lead placement and focused directional stimulation may avoid VF worsening while maintaining motor improvements in STN DBS.

Introduction

Subthalamic nucleus deep brain stimulation (STN DBS) is an effective surgical treatment for the motor symptoms of Parkinson's disease (PD) [1]. STN DBS reduces United Parkinson's Disease Rating Scale motor scores (UPDRS Part III) by 58%, with cardinal motor improvements of 57% for bradykinesia, 52% for rigidity, and 82% for tremor [2]. However, while STN DBS improves overall and component motor symptoms in PD patients, the therapy often impairs verbal fluency (VF) [[3], [4], [5]]. One explanation for these contrasting effects may be that STN DBS stimulates neighboring motor and VF neural circuits. While some prior investigations report that stimulation location impacts VF [[6], [7], [8]], other studies find no spatial relationship [9,10].

The objective of this study is to localize the sites of stimulation that maximally impact overall and cardinal motor improvements and VF decline in STN DBS for PD. Among the cardinal motor symptoms of PD, tremor improves more dramatically than bradykinesia or rigidity. For this reason, we hypothesize that the optimal stimulation site for tremor reduction will be distinct from the sites for bradykinesia and rigidity. In addition, since acute on/off-stimulation adjustment does not affect VF [11], as occurs with motor symptoms, we hypothesize that a separate site or mechanism is responsible for VF decline. Should these motor and VF sites be distinguishable, targeting and directional stimulation techniques may be considered to achieve differential clinical effects among motor and non-motor symptoms of PD.

Precise identification of optimal sites of DBS stimulation can be extremely challenging, due to anatomical variation among individual patients [12]. Traditional atlas-based localization in Talairach space relative to the mid-commissural point has greater variance than localization relative to nearby anatomic structures, such as the red nucleus [13]. To minimize variance, we measured STN DBS contact locations in an atlas-independent fashion, relative to the anatomic midpoint of each individual STN [14]. In addition, we incorporated two neurophysiological features into our model: (1) the magnitude of improvement achieved by stimulation at a given location, and (2) the amplitude of stimulation required to achieve a clinical effect. The resulting algorithm is atlas-independent and explicitly includes electrical-field modeling and clinical outcomes to calculate each site of maximal DBS effect [14].