Short-term stimulations of the entopeduncular nucleus induce cerebellar changes of c-Fos expression in an animal model of paroxysmal dystonia.

Deep brain stimulation (DBS) of the globus pallidus internus (entopeduncular nucleus, EPN, in rodents) is important for the treatment of drug-refractory dystonia. The pathophysiology of this movement disorder and the mechanisms of DBS are largely unknown. Insights into the mechanisms of DBS in animal models of dystonia can be helpful for optimization of DBS and add-on therapeutics. We recently found that short-term EPN-DBS with 130 Hz (50 µA, 60 µs) for 3 h improved dystonia in dtsz hamsters and reduced spontaneous excitatory cortico-striatal activity in brain slices of this model, indicating fast effects on synaptic plasticity. Therefore, in the present study, we examined if these effects are related to changes of c-Fos, a marker of neuronal activity, in brains derived from dtsz hamsters after these short-term DBS or sham stimulations. After DBS vs. sham, c-Fos intensity was increased around the electrode, but the number of c-Fos+ cells was not altered within the whole EPN and projection areas (habenula, thalamus). DBS did not induce changes in striatal and cortical c-Fos+ cells as GABAergic (GAD67+ and parvalbumin-reactive) neurons in motor cortex and striatum. Unexpectedly, c-Fos+ cells were decreased in deep cerebellar nuclei (DCN) after DBS, suggesting that cerebellar changes may be involved in antidystonic effects already during short-term DBS. However, the present results do not exclude functional changes within the basal ganglia-thalamo-cortical network, which will be further investigated by long-term EPN stimulations. The present study indicates that the cerebellum deserves attention in ongoing examinations on the mechanisms of DBS in dystonia.

Deep brain stimulation in animal models of dystonia.

During the last decades deep brain stimulation (DBS) has become an important treatment option for a variety of neurological disorders such as drug-intractable dystonia. Yet, the mechanisms of action of DBS are still largely unknown. Dystonia is a heterogenous movement disorder characterized by involuntary muscle contractions causing abnormal movements, postures, or both. The underlying pathophysiological processes remain unclear, but a dysfunction of the basal ganglia circuit is critically involved as supported by the effectiveness of DBS of the globus pallidus internus (GPi) in various types of dystonia. However, the degree of clinical improvement differs among the types of dystonia, as well as from patient to patient, and the delayed response to GPi-DBS in dystonia patients hampers the adjustment and optimization of stimulation parameters. Preclinical studies in suitable animal models can contribute decisively to detect the underlying mechanisms of DBS and biomarkers, to identify new possible stimulation targets and to optimize stimulation patterns. In this review, we give an overview of previous research on DBS in animal models of dystonia. With regard to the aims of research we discuss the opportunities and limitations concerning different available animal models of dystonia and technical challenges.

The software defined implantable modular platform (STELLA) for preclinical deep brain stimulation research in rodents.

Context.Long-term deep brain stimulation (DBS) studies in rodents are of crucial importance for research progress in this field. However, most stimulation devices require jackets or large head-mounted systems which severely affect mobility and general welfare influencing animals' behavior.Objective.To develop a preclinical neurostimulation implant system for long-term DBS research in small animal models.Approach.We propose a low-cost dual-channel DBS implant called software defined implantable platform (STELLA) with a printed circuit board size of Ø13 × 3.3 mm, weight of 0.6 g and current consumption of 7.6µA/3.1 V combined with an epoxy resin-based encapsulation method.Main results.STELLA delivers charge-balanced and configurable current pulses with widely used commercial electrodes. Whilein vitrostudies demonstrate at least 12 weeks of error-free stimulation using a CR1225 battery, our calculations predict a battery lifetime of up to 3 years using a CR2032. Exemplary application for DBS of the subthalamic nucleus in adult rats demonstrates that fully-implanted STELLA neurostimulators are very well-tolerated over 42 days without relevant stress after the early postoperative phase resulting in normal animal behavior. Encapsulation, external control and monitoring of function proved to be feasible. Stimulation with standard parameters elicited c-Fos expression by subthalamic neurons demonstrating biologically active function of STELLA.Significance.We developed a fully implantable, scalable and reliable DBS device that meets the urgent need for reverse translational research on DBS in freely moving rodent disease models including sensitive behavioral experiments. We thus add an important technology for animal research according to 'The Principle of Humane Experimental Technique'-replacement, reduction and refinement (3R). All hardware, software and additional materials are available under an open source license.

Mechanisms of pallidal deep brain stimulation: Alteration of cortico-striatal synaptic communication in a dystonia animal model.

Pallidal deep brain stimulation (DBS) is an important option for patients with severe dystonias, which are thought to arise from a disturbance in striatal control of the globus pallidus internus (GPi). The mechanisms of GPi-DBS are far from understood. Although a disturbance of striatal function is thought to play a key role in dystonia, the effects of DBS on cortico-striatal function are unknown. We hypothesised that DBS, via axonal backfiring, or indirectly via thalamic and cortical coupling, alters striatal function. We tested this hypothesis in the dtsz hamster, an animal model of inherited generalised, paroxysmal dystonia. Hamsters (dystonic and non-dystonic controls) were bilaterally implanted with stimulation electrodes in the GPi. DBS (130 Hz), and sham DBS, were performed in unanaesthetised animals for 3 h. Synaptic cortico-striatal field potentials, as well as miniature excitatory postsynaptic currents (mEPSC) and firing properties of medium spiny striatal neurones were recorded in brain slice preparations obtained immediately after EPN-DBS. The main findings were as follows: a. DBS increased cortico-striatal evoked responses in healthy, but not in dystonic tissue. b. Commensurate with this, DBS increased inhibitory control of these evoked responses in dystonic, and decreased inhibitory control in healthy tissue. c. Further, DBS reduced mEPSC frequency strongly in dystonic, and less prominently in healthy tissue, showing that also a modulation of presynaptic mechanisms is likely involved. d. Cellular properties of medium-spiny neurones remained unchanged. We conclude that DBS leads to dampening of cortico-striatal communication, and restores intrastriatal inhibitory tone.

Deep brain stimulation by optimized stimulators in a phenotypic model of dystonia: Effects of different frequencies.

Deep brain stimulation (DBS) of the globus pallidus internus (GPi, entopeduncular nucleus, EPN, in rodents) has become important for the treatment of generalized dystonia, a severe and often intractable movement disorder. It is unclear if lower frequencies of GPi-DBS or stimulations of the subthalamic nucleus (STN) are of advantage. In the present study, the main objective was to examined the effects of bilateral EPN-DBS at different frequencies (130 Hz, 40 Hz, 15 Hz) on the severity of dystonia in the dtsz mutant hamster. In addition, STN stimulations were done at a frequency, proven to be effective by the present EPN-DBS in dystonic hamsters. In order to obtain precise bilateral electrical stimuli with magnitude of 50 µA, a pulse width of 60 µs and defined frequencies, it was necessary to develop a new optimized stimulator prior to the experiments. Since the individual highest severity of dystonic episodes is known to be reached within three hours after induction in dtsz hamsters, the duration of DBS was 180 min. During DBS with 130 Hz the severity of dystonia was significantly lower within the third hour than without DBS in the same animals (p < 0.05). DBS with 40 Hz tended to exert antidystonic effects after three hours, while 15 Hz stimulations of the EPN and 130 Hz stimulations of the STN failed to show any effects on the severity. DBS of the EPN at 130 Hz was most effective against generalized dystonia in the dtsz mutant. The response to EPN-DBS confirms that the dtsz mutant is suitable to further investigate the effects of long-term DBS on severity of dystonia and neuronal network activities, important to give insights into the mechanisms of DBS.