Novel Targets and Techniques in Deep Brain Stimulation for Movement Disorders

Introduction

The surgical treatment of movement disorders has evolved considerably over the past 20 years with the increasing application of deep brain stimulation (DBS), principally for the treatment of Parkinson disease (PD), essential tremor, and dystonia. The sites most commonly targeted for DBS in the treatment of movement disorders have been the subthalamic nucleus (STN), the internal segment of the globus pallidus (GPi), and the motor thalamus—mainly the ventral intermediate nucleus (VIM) in Hassler’s nomenclature. A growing body of evidence supports DBS targeting of the GPi or STN for treatment of PD with disabling motor fluctuations or dyskinesias, despite optimal medical management ^, ; the VIM for medication-refractory tremor ; and the GPi and STN for generalized dystonia. ^, The US Food and Drug Administration approved DBS of the STN or GPi for the treatment of PD, unilateral thalamic stimulation for the treatment of essential tremor, and under a Humanitarian Device Exemption, unilateral or bilateral stimulation of the GPi or STN for the treatment of dystonia.

The growing literature of STN, GPi, and VIM DBS expands upon limitations, including lack of clinical benefit and stimulation adverse effects, prompting the “off label” application of DBS to other targets. Examples of limitations in targeting conventional structures are provided. DBS of the STN for PD improves motor performance by approximately 50%, and activities of daily living by approximately 30%. Unfortunately, these remarkable benefits of STN DBS wane over time, reflecting the progressive nature of PD. Consequently, adjunct pharmacological adjustments are necessary. Adverse effects of STN DBS can also occur, and in some situations, may be challenging to treat. Dyskinesias are common in STN DBS and are often managed by reducing dopaminergic medications. However, reduction in medication dose can result in worsened parkinsonism, especially on the side contralateral to dyskinesias. In rare situations, neuropsychiatric manifestations of mania, apathy, and depression also may be induced by STN DBS. With bilateral VIM DBS, dysarthria and ataxia are the most common stimulation-induced side effects and are challenging to treat. Bilateral VIM DBS has an incidence of 56% worsened dysarthria and a 30% to 50% impairment of balance. ^, STN and GPi stimulation have shown inconsistent benefit with respect to some axial symptoms of PD, especially those that manifest later in the course of the disease. Particularly problematic are freezing of gait that persists despite medication, postural instability, and falls. In a long-term follow-up study of patients treated with STN DBS, an initial benefit in postural instability was lost after 1 year, and instability progressed significantly by 5 years. A survey of 55 patients who had undergone STN DBS at two centers in the Netherlands revealed that 42% described a delayed worsening of gait, despite continued improvement in global outcome scores. Although some measures of gait have been shown to improve with DBS, in a trial of 255 patients randomized to best medical therapy versus GPi or STN DBS, there were significantly more events of falls and gait disturbance in the DBS group than for the best medical therapy group. Because of the disabling nature of freezing and postural instability and the inconsistent effects of current therapies, novel treatments are actively pursued.

In this chapter, we explore new frontiers in electrical neuromodulation for the treatment of movement disorders and the development of adaptive DBS in relation to an increasingly sophisticated understanding of the physiology of the motor system. We then discuss novel targets including the posterior subthalamic area/caudal zona incerta (PSA/cZI), the rostral zona incerta (rZI), and prelemniscal radiation for the treatment of parkinsonian tremor, rigidity, and bradykinesia, as well as for nonparkinsonian tremor; the pedunculopontine nucleus (PPN) and the substantia nigra pars reticulata (SNr) for the treatment of some of the axial symptoms of PD; and stimulation of the thalamic centromedian—parafascicular (CM/PF) complex for the treatment of parkinsonism.

Physiology of the Motor System

STN DBS has become the mainstay frontline therapy for advanced PD, beginning with the original study by Limousin et al. (1995) demonstrating efficacy. ^{, ,} Although STN DBS for PD confers equivalent motor outcomes compared to GPi DBS, only STN DBS permits significant reduction in dopaminergic medication. Histological, hodological, and physiological evidence have localized the motor territory to the dorsolateral aspect of the rostrocaudal third of STN. ^, This evidence has informed traditional stereotactic targeting, which also relies on a combination of neuronal firing rate pattern detection and the identification of excitatory neurons responsive to active and passive kinesthetic motor output. Over the last 10 years, several US and European centers have begun to replace intraoperative testing in awake patients in favor of intraoperative image guidance with patients under general anesthesia, reinforcing a tacit, yet unvalidated, consensus among experts for the optimal therapeutic stimulation target within STN. However, a recent (2017) survey polling PD specialists on the optimal STN stimulation target, using the Shaltenbrand and Wahren atlas, indicated that despite modest convergence upon the dorsolateral STN and subthalamic area, heterogeneity in expert opinion on the optimal therapeutic target persists, and more investigation focused on refinement is required. It is conceivable that following the many thousands of successful STN implantations across different surgical centers that an objective, optimal stimulation target would have been identified, particularly given that STN can be delineated on magnetic resonance images. However, despite extensive collective experience and advances in imaging, many centers still rely on intraoperative motor testing and macrostimulation to validate STN stereotactic targeting. Recent imaging, computational, and hardware advances have led to a renewed interest and vigor in defining the optimal STN target or anatomic “sweet spot.”

Aberrant hypersynchronous oscillatory patterns have been observed in the basal ganglia of PD subjects and PD animal models at all levels of electrophysiological analysis—from single neuron to local field potentials ^, —and hypothesized as a pathophysiological hallmark. Only recently, have research groups started to use these oscillatory patterns to objectively identify the stimulation target within STN. In one of the largest studies, Zaidel et al., examined the correlation between STN spectral features and outcome of STN DBS surgery in 128 patients across 314 recording trajectories. This study found that the dorsolateral and ventromedial regions of STN could be differentiated based on an increased magnitude in the beta-oscillatory activity (higher beta in dorsal STN); importantly, implant tracks that coincided with longer dorsolateral areas were associated with better outcomes. Furthermore, there was a significant likelihood of overlap between the independently selected active contact with the dorsolateral oscillatory area. This work has directly informed the development of prospective intraoperative strategies using local field potential spectral analyses to objectively identify the optimal stimulation target within STN, which may, in the future, be incorporated into commercial recording devices. ^, In addition to beta oscillations, both high-frequency oscillations (HFO; 150 to 400 Hz) and beta-HFO phase-amplitude coupling are under investigation as another optimal STN stimulation target biomarker.

In conjunction with the use of LFP electrophysiological biomarkers to identify the optimal stimulation target in STN, there is growing interest in using structural connectivity to predict circuit modulation and outcome, via DBS, based on diffusion tensor imaging tractography. This approach uses the DBS macro-contact as a seed to perform probabilistic or deterministic tractography to identify which areas or pathways are being activated by unique contact and stimulation parameter configurations. ^, Tractographic projection profiles also differentiate between ventral and dorsal STN, with predominantly pre-motor projection tracts from the dorsal STN. Finally, Horn et al., combined LFP and tractography with the objective of identifying the optimal therapeutic physiomarker within STN, in anatomical space. Again, using the DBS contacts as seeds for whole brain tractography, they observed that peak beta activity was identified in more dorsal and posterior DBS contacts, which coincided with inputs from primary motor cortex, whereas contacts associated with peak alpha activity predominantly overlapped with inputs from premotor rand prefrontal areas.

Evident in these studies is the notion that we have not yet alighted upon the ideal STN stimulation target, which gives rise to the question of whether such a target exists. There remains the possibility that everyone with PD is a unique sample requiring a unique target. Regardless, the use of electrophysiological and neuroanatomical biomarkers to refine the STN stimulation target will improve outcomes for all patients.