Basic Neuroscience
Portable microstimulator for chronic deep brain stimulation in freely moving rats

https://doi.org/10.1016/j.jneumeth.2012.05.027Get rights and content

Abstract

In the last decades, deep brain stimulation (DBS) has been widely used as a functional surgical strategy for the treatment of a variety of neurological and psychiatric disorders, including Parkinson's disease (PD), dystonia, epilepsy, depression or obsessive-compulsive disorder. While the therapeutic benefits of DBS are now recognized, experimental data on its mechanisms and impact at long term remain poor. This is mainly due to the lack of a microstimulation system adapted for chronic DBS in small laboratory animals. In this context, we have developed a microstimulator for DBS adapted to rat. This device, which has a size and weight compatible for use in freely moving rat, can be clipped to a support fixed on the animal's head. This easy “removal” property is crucial because it enables removing or even switching the microstimulator during the experiments without having to anaesthetize or to operate the animal, thus minimizing stress. The design of the microstimulator allows to set the DBS parameters easily (intensity, frequency and pulse width) and to replace the battery for long-term DBS. To validate our device, we performed continuous DBS of the subthalamic nucleus (known to improve motor deficits in clinic) in a classical rat model of PD during 5 weeks. We show that this long duration stimulation reduces significantly PD-induced akinesia without inducing animal discomfort and tissue damage. These first data demonstrated that long term DBS procedure in behaving rat is now workable.

Highlights

► We present a portable microstimulator for chronic deep brain stimulation in rat. ► The reusable removable device may be used in various model of neuropathology. ► Deep brain stimulation was performed for more than one month in freely moving rat.

Introduction

During the last decade, deep brain stimulation (DBS) has been used to treat a number of neurological and psychiatric diseases (for review Benabid, 2007, Dowling, 2008, Gubellini et al., 2009). Initially applied to chronic pain, DBS is now routinely used to treat movement disorders, predominantly Parkinson's disease (PD), essential tremor, and dystonia. Recently, numerous indications for DBS are emerging, including epilepsy, obsessive-compulsive disorder, depression, Tourette's syndrome, refractory obesity and persistent vegetative or minimally conscious state. Although the clinical application of this surgical procedure is rapidly growing up, its long term impact on the functioning of neuronal networks and action mechanisms are still not well understood. It is however recognized that the action of this functional neurosurgery is more complex than a simple activation or inhibition of the neurons in the targeted brain structure but involves activation of large networks of afferent fiber systems (Gradinaru et al., 2009). Moreover, we are far from an experimentally validated identification of the best target for each novel indication. This striking contrast between the boom of the clinical developments and the poor knowledge in research is actually due to the absence of a chronic stimulation device in small laboratory animal. Indeed, most of the publications from experimental animal models concern very short duration DBS application (from seconds to hours) in anaesthetized animals using an external stimulator, without any examination of the DBS behavioral outcomes (Gubellini et al., 2009, Spieles-Engemann et al., 2010). The very few literature studies using sub-chronic DBS in awake implanted animals do not excess a couple of days, or consists of intermittent stimulation periods, especially due to the heaviness of the procedure with freely moving animal physically connected via a cable to the external stimulator. Thus these data are poorly relevant to clinical conditions, especially if we consider that patients are stimulated chronically for months or years. At this point, it is clear that the experimental approach to DBS must be improved by a portable device for long-term continuous stimulation (Spieles-Engemann et al., 2010). To date, the only microstimulator described in the literature needs to be encapsulated and implanted in the thoracic cavity (Harnack et al., 2008). Even if this device can be considered as a great technical challenge, this procedure requires an invasive surgery and prevents direct access to the microstimulator.

In this context, we propose a new microstimulation procedure for chronic DBS in small animal of laboratory, including an adapted portable microstimulator (under French patent #09/00788) easily accessible because it is not inside the animal body but it clips on its head. We validate our stimulation procedure in the classical 6-hydroxydopamine (6-OHDA) rat model of PD. Besides the technological innovation and animal care, attention has been paid to limit cost of the materials to promote accessibility to a large scientific community working on DBS for basic as well as clinically-relevant researches.

Section snippets

Microstimulation system overview

The DBS system that allows performing long duration deep brain stimulation in rat consists of three major components: a stimulating electrode, a stimulator support and an electrical portable microstimulator that is removable (Fig. 1). These components are placed sequentially on the rat head.

In vitro validation

First, when we compare a large range of electrical parameter settings (frequency, pulse width and amplitude) with those really delivered and measured in vitro for several hours, the differences are negligible (results not shown), demonstrating that the stimulation device is reliable. Table 1 sums up the main characteristics of in vitro performances and parameters measured for the system.

Spontaneous behavior of the animal

The stimulation device fits well on the rat head (Fig. 5C) and does not modify the spontaneous activities of

Discussion

We have successfully developed a “removable” and then a “reusable” brain stimulator device adapted for small laboratory animal which allows applying stable and safe DBS with adjustable parameters for more than one month. We validated our procedure on a rat model of PD and report for the first time that continuous STN DBS in hemiparkinsonian rats for several weeks induces significant relief of akinesia, a key motor symptom of PD.

Conclusion

We have developed an original and useful procedure for chronic DBS in the rat that we have validated by showing that its application for 5 weeks in hemi-parkinsonian rats has significant anti-akinetic action. The easy use and opportunities given by our procedure, with a portable microstimulator that is compatible with bilateral stimulation, could promote preclinical studies of DBS in the context of various neurological and psychiatric disorders, as well as studies of activity-driven plasticity

Acknowledgments

This work was supported by the Centre National de la Recherche Scientifique, Aix-Marseille University, Agence Nationale pour la Recherche (contract ANR-05-NEUR-013-03.

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