New Targets for Deep Brain Stimulation Treatment of Parkinson's Disease

Anna Castrioto; Elena Moro

Disclosures

Expert Rev Neurother. 2013;13(12):1319-1328. 

In This Article

Abstract and Introduction

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi) has been shown to be an effective treatment for patients with Parkinson's disease. Strong clinical evidence supports the improvement of motor and non-motor complications and quality of life, with some data suggesting that GPi DBS might be less effective than STN DBS. However, neither STN nor GPi stimulation provides a satisfactory control of non-dopaminergic symptoms, such as gait and balance impairment and cognitive decline, which are frequent and disabling symptoms in advanced Parkinson's disease patients. Therefore, several efforts have been made to discover alternative and new targets to overcome these current DBS limitations. Among these new targets, the stimulation of the pedunculopontine nucleus has initially appeared encouraging. However, findings from different double-blind trials have mitigated the enthusiasm. A multi-target strategy aimed at improving symptoms with different pathogenetic mechanisms might be a promising approach in the next years.

Introduction

The treatment of Parkinson's disease (PD) has been revolutionized by the introduction of deep brain stimulation (DBS) surgery, a procedure which allows delivering continuous current to brain targets. The first systematic application of DBS in PD dates back to 1987, when Benabid et al. targeted the thalamic ventral intermediate nucleus (Vim) for the treatment of tremor.[1] Since then, DBS has become an established treatment in PD and other movement disorders, and other brain structures, besides Vim, have been studied, that is, the subthalamic nucleus (STN) and the globus pallidus pars interna (GPi). It became evident that the stimulation of Vim allowed only the control of tremor, whereas subthalamic and pallidal stimulation also improved rigidity and bradykinesia. STN DBS has been shown to be superior to the best medical treatment in the control of motor fluctuations and dyskinesia, and in the improvement of quality of life.[2,3] Its effects have been shown to persist over many years.[4] Hence, the STN has become the most widely used DBS target.

Although STN stimulation represents a breakthrough in the treatment of PD, it does not satisfactorily improve the symptoms that do not respond to dopaminergic treatment, such as axial signs (postural instability, freezing of gait, posture abnormalities, dysarthria) and cognitive decline. These symptoms are the main source of disability for patients with advanced PD, the main burden for their caregivers and the main challenge to deal with for physicians. The pathogenesis of these symptoms appears to be complex and linked to the involvement of non-dopaminergic structures. Therefore, DBS of different new brain targets is under investigation.

In this review, we will focus on new experimental brain targets for PD, and specifically the pedunculopontine nucleus (PPN), the caudal zona incerta (cZi), the thalamic centromedian-parafascicular (CM-Pf)complex, the substantia nigra pars reticulate (SNr), and we will also discuss different therapeutic strategies, such as multi-target stimulation.

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