Deep brain stimulation in neurological diseases and experimental models: From molecule to complex behavior
Introduction
Deep brain stimulation (DBS) is now widely utilized as a functional surgical strategy for the treatment of a variety of neurological and psychiatric disorders. DBS at high frequency, also called high-frequency stimulation (HFS), has been shown to mimic the effects of lesioning the targeted structure and has thus widely replaced the ablative procedures. For example, the tremor characterizing Parkinson's disease (PD) as well as essential tremor is reduced by delivering DBS at high frequency to the ventral intermediate nucleus of the thalamus (VIM). A great improvement of the cardinal PD motor symptoms is achieved by HFS of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi), two structures of the basal ganglia (BG). DBS is also applied for the treatment of pain, dystonia, Tourette syndrome, refractory epilepsy, depression, obsessive–compulsive disorder (OCD), obesity and minimal conscious states.
Electrical stimulation assisted by stereotaxy was developed in the late 1940s in order to help identify and map deep brain structures (Spiegel et al., 1947). Since the 1950s, DBS has been utilized for intrasurgical localization prior to therapeutic lesion of several brain structures, in particular for pallidotomy and thalamotomy (Spiegel and Wycis, 1952), and anecdotally reported as a therapy for untreatable pain syndromes (Bittar et al., 2005, Tasker and Vilela, 1995). Although nowadays DBS is mainly used to alleviate neurological motor disorders, it was only in the 1960s that DBS of the ventrolateral thalamus was first reported to alleviate tremor (Hassler et al., 1960, Ohye et al., 1964). However, during this decade DBS was still utilized for targeting a brain region prior to its lesion: in some cases, DBS was delivered with chronically implanted electrodes over a period that could reach several days, in order to best define the target to be lesioned. In the 1970–1980s, the therapeutic use of chronic DBS of the cerebellum emerged for treating movement disorders or epilepsy (Brice and McLellan, 1980, Cooper, 1973, Cooper et al., 1973, Cooper et al., 1976), and thalamic DBS was used for alleviating pain (Hosobuchi et al., 1973). In particular, Benabid et al. (1987) reported that stimulating the VIM at high frequency could ameliorate PD tremor during the targeting procedure for surgical lesioning of this structure. Such observation led to the application of chronic VIM HFS for the treatment of PD, essential tremor and extra-pyramidal dyskinesias, which was the first example of DBS at high frequency delivered by chronically implanted electrodes connected to a pacemaker-like portable stimulator (Benabid et al., 1989, Benabid et al., 1991). Since then, this surgical technique, applied to several brain structures, has become widespread for the treatment of a variety of brain disorders. However, despite its undoubtedly therapeutic efficacy, there are still several controversies about its action mechanisms and the long-term impact on neuronal circuits. A considerable amount of data has thus been produced experimentally in order to address this issue. Here we will provide a wide review of the data obtained from experimental models of DBS at molecular, cellular, physiological and behavioral levels, which contributed to a better understanding of the mechanisms and the consequences of this treatment. We will also refer to the accumulating functional investigations performed in patients with DBS neurosurgery. A comprehensive list of stimulation parameters, electrode features, experimental models, and DBS targets described in the scientific reports reviewed here is provided in Table 1.
Section snippets
Basic principles of DBS
At the beginning of the 20th century, Georges Weiss was the first to investigate quantitatively the basic principles of electrostimulation (Weiss, 1901). In his pioneering 1901 paper “Sur la possibilité de rendre comparables entre eux les appareils servant à l’excitation électrique” (On the possibility of rendering mutually comparable the devices used for electrical excitation), Weiss tried to find an answer to the following questions, some of which are still open today: “Coming to nerves and
Deep brain stimulation and Parkinson's disease
PD is a debilitating neurodegenerative movement disorder with a long course and a high prevalence (1–2 over 1000 individuals in the European Union) that increases with demographic ageing. It is widely accepted that the progressive loss of DAergic SNc neurons leads to the manifestation of the main symptoms of PD (muscle rigidity, tremor and bradykinesia/akinesia) due to a disturbance of the dynamic balance between excitatory and inhibitory neurotransmitters in the BG. SNc neurons innervate
Dystonia
Dystonia is characterized by involuntary muscle contractions causing twisting and repetitive movements and abnormal postures (Fahn, 1988). It affects few (focal dystonia) to most (generalized dystonia) of the muscle groups of the body with variable severity. Etiological classification includes two wide categories: primary (or idiopathic) and secondary (or symptomatic). Primary dystonias, especially generalized, are often hereditary and respond poorly to medical treatment. Their pathophysiology
Deep brain stimulation and psychiatric disorders
Tourette syndrome, OCD, and treatment-resistant depression (TRD) are the three major disorders currently under investigation with DBS in psychosurgery (Larson, 2008). For these psychiatric disorders, as for movement disorders, there was sometimes a background of responsiveness to lesioning procedures that provided the rationale for their treatment by functional surgery and the basis for some target selection. The identification of new candidate targets, although limited by the lack of
Deep brain stimulation and epilepsy
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures, affecting 0.5–1% of mankind. An epileptic seizure is caused by an excessive and/or hypersynchronous electrical neuronal activity, which can affect a specific brain area or structure (focal seizure), or can be largely distributed (generalized seizures). Usually seizures are self-limiting and can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other
Acknowledgments
This work has been supported by grants from the Centre National de la Recherche Scientifique (CNRS) and the Université de la Méditerranée, the European Community (contract QLK6-1999-02173, 5th PCRDT, attributed to LK), the Agence Nationale pour la Recherche (ANR-05-NEUR-021, ANR-05-NEUR-013 and ANR-JC05-48262 attributed, respectively, to PG, PS and CB), the Action Concertée Incitative (ACI) program of the French Research Ministry (ACI Grant 04 2 91, project NIC0057 attributed to LK), the
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