In vivo validation of a new portable stimulator for chronic deep brain stimulation in freely moving rats

Highlights

• We successfully developed a new portable stimulator for freely moving rats.

• The device is characterized by the large range of stimulation parameters.

• The device delivers biphasic current-control and charge balancing to maximize tissue safety.

• Bilateral stimulation improved severe motor deficits in the 6-OHDA rat model of Parkinson’s disease.

• The device can be used to test deep brain stimulation in different animal models of human brain diseases.

Abstract

Background

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is considered as a gold standard therapy for the alleviation of motor symptoms in Parkinson’s disease (PD). This success paved the way to its application for other neurological and psychiatric disorders. In this context, we aimed to develop a rodent-specific stimulator with characteristics similar to those used in patients.

New method

We designed a stimulator that can be connected to an electrode container with options for bilateral or unilateral stimulation selection and offers a wide range of frequencies, pulse widths and intensities, constant current, biphasic current-control and charge balancing. Dedicated software was developed to program these parameters and the device was tested on a bilateral 6-hydroxydopamine (6-OHDA) rat model of PD.

Results

The equipment was well tolerated by the animals with a good general welfare. STN stimulation (130 Hz frequency, 0.06 ms pulse width, 150 μA average intensity) improved the motor deficits induced by 6-OHDA as it significantly increased the number of movements compared to the values obtained in the same animals without STN stimulation. Furthermore, it restored motor coordination by significantly increasing the time spent on the rotarod bar.

Conclusion

We successfully developed and validated a new portable and programmable stimulator for freely moving rats that delivers a large range of stimulation parameters using bilateral biphasic current-control and charge balancing to maximize tissue safety. This device can be used to test deep brain stimulation in different animal models of human brain diseases.

Introduction

High frequency stimulation (HFS) of deep brain structures, named deep brain stimulation (DBS), is now a recognized therapeutic approach used for the treatment of a wide range of neurological and psychiatric disorders (Krack et al., 2010). Parkinson's disease (PD) is the first neurological condition to benefit from DBS when dopaminergic treatments are no longer tolerated by patients (Lang and Lozano, 1998). Animal studies have been developed in rodents and non-human primates to better understand the pathophysiology of PD and to develop new therapeutic approaches. Indeed, HFS of the subthalamic nucleus (STN) alleviated the cardinal motor symptoms induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a non-human primate model of the disease (Benazzouz et al., 1993). Then, STN-HFS was transferred and successfully applied to parkinsonian patients with advanced severe motor symptoms (Limousin et al., 1995). The electrodes are implanted chronically and connected to an implantable stimulator delivering continuous HFS to improve the symptoms.

STN-HFS is now considered as an alternative treatment of choice proposed to parkinsonian patients when they develop motor fluctuations and dyskinetic involuntary abnormal movements in response to medication (Limousin et al., 1995, 1998; Krack et al., 2003). However, although the beneficial effects of STN-HFS are well established, the underlying mechanisms are still under debate (Benazzouz and Hallett, 2000; Tai et al., 2003; Meissner et al., 2005; Salin et al., 2002; Faggiani and Benazzouz, 2017; Schor and Nelson, 2019). Understanding the functional mechanisms should lead to the improvement of DBS therapy and devices, as well as characterizing and minimizing the potential related side effects. While several side effects are linked to surgery, others, such as mood and cognitive changes, dysarthria, verbal fluency decrease, exacerbation of gait disorders, and weight gain have also been reported and may be related to the spread of current to the surrounding areas of the STN (Temel et al., 2005; Krack et al., 2010). In this regard, there is a need for further investigations in animal models of PD. Moreover, the success of DBS in PD, and its reversibility in contrast to ablation of brain structures, paved the way to its application in other neurological and psychiatric disorders.

The present study aimed to develop a new DBS dedicated stimulator adapted for chronic experiments on rodents and that mimics the conditions of DBS human therapy. In addition to this objective, the device was developed to be highly configurable and tunable to allow for various investigations. Dedicated software was also developed to program the stimulation parameters and the device was tested on a bilateral 6-hydroxydopamine (6-OHDA) rat model of PD.