Review articleDeep brain stimulation of the subthalamic nucleus in Parkinson’s disease: From history to the interaction with the monoaminergic systems
Introduction
Parkinson’s disease is the second most common neurodegenerative disorder, affecting 1–3% of the population older than 50 years and more than 5 million people worldwide. This neurological disorder is characterized by the manifestation of motor symptoms, including bradykinesia, rigidity, resting tremor, and gait disturbance with postural instability, which are mainly attributed to the degeneration of dopamine neurons in the pars compacta of substantia nigra (SNc) (Ehringer and Hornykiewicz, 1960). Furthermore, despite the focus on motor deficits, PD is also characterized by the manifestation of non-motor symptoms, including anxiety and depression, which can be present in more than 40% of PD patients (for review, Chaudhuri and Schapira, 2009, Delaville et al., 2011).
The restoration of dopaminergic transmission by levodopa (l-Dopa) has been used successfully to improve the cardinal motor symptoms for several years (Cotzias, 1968, Yahr et al., 1969). However, after 4–6 years of l-Dopa treatment, patients develop major motor fluctuations, loss of therapeutical efficacy and various complications such as dyskinesia, which represents a major drawback (for review, Bastide et al., 2015). At this stage, deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been proposed as an excellent alternative (Benazzouz et al., 1993). The introduction of ventralis intermedius nucleus (VIM) DBS for tremor by the Grenoble’s group went largely unnoticed at first, but with the expansion of applications and targets, especially the VIM procedure became obsolete. The introduction of VIM DBS for tremor was based on clinical research and empirical surgery, in the absence of animal models for tremor and pre-clinical and basic research (Benabid et al., 1991). This surgical procedure has been shown to improve parkinsonian rest tremor without any efficacy on akinesia, rigidity, gait disturbance and postural instability. The choice of STN for parkinsonian motor symptoms was driven mainly by progress in the understanding of basal ganglia physiology and pathophysiology (Albin et al., 1989). The efficacy of STN DBS has been shown in monkeys rendered hemiparkinsonian by the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Benazzouz et al., 1993, Benazzouz et al., 1996), which allowed its successful transfer to patients with advanced PD (Pollak et al., 1993, Limousin et al., 1995a). STN-HFS is now admitted as the neurosurgical therapy of choice for PD patients suffering from severe advanced stage of the disease with motor fluctuations and major side effects of dopaminomimetic treatments. It induces the improvement of all the cardinal motor symptoms of PD, but several reports have described behavioral abnormalities after surgery (Krack et al., 2003, Krack et al., 2001, Herzog et al., 2003, Saint-Cyr et al., 2000). The interpretation of these longitudinal studies that examined patients before and after implantation of STN electrodes for DBS is complex.
So far, studies designed to examine the impact of PD therapies on emotional processing have reported controversial results, in particular on emotion-specific impairments and on the differential effects of DBS and l-Dopa therapies.
Section snippets
DBS history
Functional surgery started in the early 1950s by ablative procedures in order to avoid the side effects of the frontal lobotomy commonly used in the treatment of psychiatric illness (Spiegel and Spiegel-Adolf, 1952). Prior to ablation, electrical stimulation was used during surgery for the exploration of the brain target. Delgado (1952) developed a new method of “radio communication with the brain” using chronically implanted electrodes connected to a subcutaneous receiver implanted in the
STN DBS induces improvement of motor symptoms
Since 1993, DBS of the STN has been successfully transferred to human patients and has been shown to alleviate all the major motor symptoms of PD while allowing a dramatic reduction in daily l-Dopa requirements, which is at the origin of the alleviation of dyskinesias (Limousin et al., 1995c). This study was the first to show that bilateral STN DBS (130 Hz frequency, 0.06 ms pulse width and 2-4 V) considerably reduced akinesia and rigidity and improved the quality of life in the three first
Effects of STN DBS on axial symptoms
Axial symptoms, including gait disability and postural instability are common and highly debilitating in patients with advanced PD. Around 10–15 years after diagnosis of the disease, freezing of gait and postural instability dominate the motor disabilities and hamper the ability of patients to generate effective forward-stepping movements (Nieuwboer and Giladi, 2013). These axial symptoms, which are resistant to dopamine agents, are at the origin of recurrent falls, reduced mobility and loss of
Effects of STN DBS on secondary parkinsonism
All these clinical studies have demonstrated that STN DBS is efficient in idiopathic PD patients and that dopaminergic drug responses can be considered predictors for motor responsiveness to STN DBS. Indeed, patients with multiple system atrophy (MSA) are not good candidates for STN surgery, as they didn’t show beneficial response to either l-Dopa, apomorphine or STN DBS (Pinter et al., 1999, Krack et al., 2000, Talmant et al., 2006). Nevertheles, another study presented the case of a woman
STN DBS and neuroprotection of dopaminergic neurons
Similar to the medical management of PD, STN DBS was developed as a symptomatic treatment. Although the cause of PD is still unknown, a growing body of evidence supports the interaction of environmental factors and genetic vulnerability at the origin of abnormal protein folding and subsequent abnormal proteasomal processing, resulting in the accumulation of toxic protein products precipitating a degenerative process and finally dopamine cell death (Calne, 2000, Mouradian, 2002). Another
Effects of STN DBS on non-motor symptoms
It is now admitted that nonmotor symptoms have a greater impact on quality of life of PD patients than the motor symptoms and a therapy modality can only be considered holistic and truly effective if it addresses the specific problems posed by both the motor and non-motor symptoms of the disease.
Few years after the transfer of STN DBS to parkinsonian patients and the demonstration of its spectacular beneficial effects on motor symptoms, several studies have examined the effects of the
Interaction of STN DBS with the monoaminergic systems
Despite the focus on the progressive degeneration of DA neurons, PD is a multi-system disorder also characterized by the additional degeneration of norepinephrine neurons of the locus coeruleus (Bertrand et al., 1997, Fornai et al., 2007, Delaville et al., 2011) and/or serotonin cells of the dorsal raphe nucleus (Kish, 2003), affecting at least 40% of PD patients in general. Accordingly, the loss of these two monoaminergic systems have also been suggested as other landmarks of PD.
Among the
Acknowledgments
This work has been supported by grants from the Centre National de la Recherche Scientifique (CNRS), the Université de Bordeaux and the Fondation de France.
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