High frequency stimulation of the entopeduncular nucleus sets the cortico-basal ganglia network to a new functional state in the dystonic hamster

doi:10.1016/j.nbd.2009.05.022

Neurobiology of Disease

Volume 35, Issue 3, September 2009, Pages 399-405

https://doi.org/10.1016/j.nbd.2009.05.022 Get rights and content

Abstract

High frequency stimulation (HFS) of the internal pallidum is effective for the treatment of dystonia. Only few studies have investigated the effects of stimulation on the activity of the cortex-basal ganglia network. We here assess within this network the effect of entopeduncular nucleus (EP) HFS on the expression of c-Fos and cytochrome oxidase subunit I (COI) in the dt^sz-hamster, a well-characterized model of paroxysmal dystonia. In dt^sz-hamsters, we identified abnormal activity in motor cortex, basal ganglia and thalamus. These structures have already been linked to the pathophysiology of human dystonia. EP-HFS (i) increased striatal c-Fos expression in controls and dystonic hamsters and (ii) reduced thalamic c-Fos expression in dt^sz-hamsters. EP-HFS had no effect on COI expression. The present results suggest that EP-HFS induces a new network activity state which may improve information processing and finally reduces the severity of dystonic attacks in dt^sz-hamsters.

Introduction

Dystonia defines a clinical syndrome comprising involuntary muscle contractions leading to abnormal movements and postures, which are often triggered by voluntary movements, speaking or sensory input (Fahn, 1988). Although the exact pathophysiology remains unclear, modified firing activity has been observed in the basal ganglia output nuclei and the thalamus of dystonic patients. Changes in cortical excitability and a loss of inhibition of brainstem and spinal reflexes have also been related to dystonia (cf. reviews Berardelli et al., 1998, Breakefield et al., 2008, Vitek, 2002). Impaired metabolic activity has also been found in different cortical and subcortical areas suggesting widespread abnormal brain activity in dystonia (Ceballos-Baumann et al., 1995, Eidelberg et al., 1995). To what extent this complex neuronal activity pattern represents the disease itself or is a secondary phenomenon remain to be unraveled.

High frequency stimulation of the internal pallidum (GPi-HFS) is an established therapy to alleviate symptoms of segmental and generalized dystonia refractory to conservative treatment (Coubes et al., 2000, Kupsch et al., 2006, Vidailhet et al., 2005). Hitherto, only few clinical studies have assessed the mechanisms of GPi-HFS underlying clinical improvement in dystonic patients. GPi-HFS decreases the perfusion at rest in the cerebellum, the anterior cingulated cortex, the left lentiform nucleus, the left thalamus, the pons and the midbrain (Yianni et al., 2005). Moreover, decreased regional cerebral blood flow of the left superior frontal gyrus, the right temporal cortex, the left putamen and the left thalamus has been observed during HFS of the left GPi while performing a simple joystick movement (Detante et al., 2004). GPi-HFS does also reverse increased excitability of brainstem and spinal reflexes (Tisch et al., 2006a,b). Finally, GPi-HFS reduces the amplitude of motor evoked potentials after paired associative stimulation suggesting that it may decrease abnormal LTP-like synaptic plasticity in the motor cortex of dystonic patients (Tisch et al., 2007).

The dt^sz-hamster is a well-characterized model of non-kinesiogenic paroxysmal dystonia. Animals display age-dependent long-lasting attacks of generalized dystonia in response to mild stress (Loscher et al., 1989, Richter and Loscher, 1998, 2002). In concordance with human data, bilateral HFS of the entopeduncular nucleus (EP, corresponds to human GPi) reduces the severity of dystonic symptoms in these animals (Harnack et al., 2004).

We here assessed for the first time mechanisms of HFS in an animal model of dystonia. The main goal was to determine the impact of HFS on the activity of the cortex-basal ganglia network in dystonic hamsters by using c-Fos protein immunohistochemistry and cytochrome oxidase subunit I (COI) histochemistry. C-Fos protein is the product of the immediate early gene c-fos, the latter reflecting transcriptional activity (Martin and Magistretti, 1998, Sheng and Greenberg, 1990). COI is localized within the mitochondria and is assumed to be a marker of neuronal energy demand (Wong-Riley, 1989).

Section snippets

Animals

All experiments were carried out in accordance with the European Community Council Directive of 24 November 1986 (86/09/EEC) for the care of laboratory animals. Sex- and age matched dystonic and control hamsters were obtained by breeding pairs from an inbred line by selective breeding as described before (Loscher et al., 1989). Animals were housed in small groups under controlled environmental conditions: 12/12 h light–dark-cycle (light on at 5:00 A.M.), temperature 23 °C. Food and water were

c-Fos protein immunohistochemistry

In M1, c-Fos protein expression was lower in dt^sz-hamsters in comparison to controls (Figs. 1A and 2A, B). An overall estimation showed significant differences between disease states (F_(1,23) = 40.6, p < 0.001), while the effect of HFS (F_(1,23) = 0.4, p > 0.5) and the interaction between both factors (F_(1,23) = 0.1, p > 0.5) was not different between groups. A post hoc analysis revealed significant lower c-Fos protein expression of both, the unstimulated and stimulated sides in dystonic hamsters compared

Discussion

We assessed the effect of unilateral EP-HFS on brain network activity in the dt^sz-hamster and healthy controls. When looking at the unstimulated hemisphere, COI, a global marker of oxidative metabolism, was up-regulated in striatum, GP and motor thalamus of dt^sz-hamsters compared to controls. By contrast, c-Fos protein expression, reflecting transcriptional activity, was down-regulated in all motor-related analyzed structures in dt^sz-hamsters, while in a non-motor-related cortex, i.e. the

Conclusion

We identified a network with abnormal brain activity which includes M1 cortex, striatum, GP, STN, SNr and motor thalamus in dt^sz-hamsters. These brain structures have already been suggested to play a role in the pathophysiology of human dystonia. EP-HFS (i) increased striatal c-Fos expression in controls and dystonic hamsters and (ii) reduced thalamic c-Fos expression in dt^sz-hamsters. These results suggest that EP-HFS induces a new network activity state which improves information processing

Acknowledgments

We would like to thank Laura Cardoit for excellent technical assistance. This study was supported by the Centre National de la Recherche Scientifique, Université Victor Ségalen Bordeaux 2, Région Aquitaine and IFR de Neurosciences (INSERM No. 8; CNRS No. 13), as well as the Deutsche Forschungsgemeinschaft (RI845/1-3).

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Short-term stimulations of the entopeduncular nucleus induce cerebellar changes of c-Fos expression in an animal model of paroxysmal dystonia
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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 dt^sz 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 dt^sz 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
2022, Neurobiology of Disease
Citation Excerpt :
Although c-Fos protein expression can be induced by many external stimuli (Barros et al., 2015; Herdegen and Leah, 1998; Perrin-Terrin et al., 2016), this immediate early gene is commonly used as marker for cell activation after electrical stimulation (Fleischer et al., 2020; Pflüger et al., 2020). In line with electrophysiological data which suggested that EPN neurons are rather excited during EPN-DBS in dystonic hamsters (Reese et al., 2009), which would lead to enhanced inhibition of the thalamus, c-Fos was decreased in the thalamus of the stimulated site in dtsz hamsters but not in controls (Reese et al., 2009). In both, dtsz hamsters and controls, EPN-DBS increased the number of c-Fos reactive neurons in the striatum, substantiating the hypothesis that DBS has loop effects via thalamo-cortico-striatal connections (DeLong and Wichmann, 2010; Reese et al., 2009).
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.
Experimental deep brain stimulation in rodent models of movement disorders
2022, Experimental Neurology
Citation Excerpt :
This work confirms the responsiveness of EP DBS in this dystonia model and is in keeping with the beneficial, symptomatic effect of GPi DBS in dystonia patients (Grabli et al., 2009; Kupsch et al., 2006; Vidailhet et al., 2005). A further approach in the dtsz hamster model was to assess the effect of DBS on the cortico-basal ganglia network activity (Reese et al., 2009). An abnormal neuronal brain network with decreased c-Fos expression, as marker for neuronal transcriptional activity, was detected in the motor cortex, striatum, GP, STN, SNr and motor thalamus comparing the unstimulated hemisphere in dtsz hamster with wt controls.
Deep brain stimulation (DBS) is the preferred treatment for therapy-resistant movement disorders such as dystonia and Parkinson's disease (PD), mostly in advanced disease stages. Although DBS is already in clinical use for ~30 years and has improved patients' quality of life dramatically, there is still limited understanding of the underlying mechanisms of action. Rodent models of PD and dystonia are essential tools to elucidate the mode of action of DBS on behavioral and multiscale neurobiological levels. Advances have been made in identifying DBS effects on the central motor network, neuroprotection and neuroinflammation in DBS studies of PD rodent models. The phenotypic dt^sz mutant hamster and the transgenic DYT-TOR1A (ΔETorA) rat proved as valuable models of dystonia for preclinical DBS research. In addition, continuous refinements of rodent DBS technologies are ongoing and have contributed to improvement of experimental quality. We here review the currently existing literature on experimental DBS in PD and dystonia models regarding the choice of models, experimental design, neurobiological readouts, as well as methodological implications. Moreover, we provide an overview of the technical stage of existing DBS devices for use in rodent studies.
Mechanisms of pallidal deep brain stimulation: Alteration of cortico-striatal synaptic communication in a dystonia animal model
2021, Neurobiology of Disease
Citation Excerpt :
More importantly, animal studies so far were mainly conducted on healthy controls. In studies using animal models of dystonia, in turn, DBS-stimulation was delivered only under deep anaesthesia with urethane (Leblois et al., 2010; Reese et al., 2009), that is known to distort cortico-striatal connectivity (Paasonen et al., 2018). Data investigating the mechanisms of DBS in dystonia models in awake and behaving animals are completely lacking.
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 dt^sz 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
2021, Neurobiology of Disease
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 dt^sz 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 dt^sz 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 dt^sz mutant. The response to EPN-DBS confirms that the dt^sz 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.
Activity modulation of the globus pallidus and the nucleus entopeduncularis affects compulsive checking in rats
2011, Behavioural Brain Research
Citation Excerpt :
The finding that pharmacological inactivation and HFS of the EP had no effect on locomotion in saline-treated controls and in QNP-sensitized rats add to the ongoing controversy regarding the involvement of the EP in locomotion. On the one hand, HFS of the GPi/EP decreased hyperlocomotive aspects of dystonia in humans [9] and in the dt (sz) hamster model of dystonia [60,61]. In addition, ablative lesion of the EP impaired motor initiation and increased mean reaction time in rats [58].
Deep brain stimulation at high frequencies (HFS) is currently studied in the treatment of therapy-refractory obsessive–compulsive disorder (OCD). The diversity of targeted brain areas and the discrepancy in demonstrating beneficial effects, highlight the need for better mapping of brain regions in which HFS may yield anti-compulsive effects. This goal may be achieved by investigating the effects of HFS in appropriate animal models of OCD. The present study tested the effect of bilateral HFS or pharmacological inactivation (as induced by intracerebral administration of the GABA-agonist muscimol) of both the Globus pallidus (GP; rodent equivalent to human GP externus) and the Nucleus entopeduncularis (EP; rodent equivalent to human GP internus) on checking behaviour in the quinpirole rat model of OCD. We demonstrate that HFS of the GP does not and HFS of the EP only partially reduces OCD-like behaviour in rats. In contrast, pharmacological inactivation of both GP and EP significantly reduces OCD-like behaviour in the model. These data contrast previously derived data on the effectiveness of HFS of the subthalamic nucleus, nucleus accumbens, GP and EP in the same and other rat models of OCD. We conclude that (i) although GP and EP play an important role in the pathophysiology of OCD, these areas may not represent first choice target structures for HFS, (ii) the effectiveness of HFS may depend on different subtypes of OCD, represented in different animal models, and (iii) differential net mechanisms may subserve the effectiveness of HFS and pharmacological inactivation.

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¹: These two authors have equally contributed and should be considered as first authors.

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High frequency stimulation of the entopeduncular nucleus sets the cortico-basal ganglia network to a new functional state in the dystonic hamster

Abstract

Introduction

Section snippets

Animals

c-Fos protein immunohistochemistry

Discussion

Conclusion

Acknowledgments

Trends Neurosci.

Lancet

Trends Neurosci.

Neurosci. Lett.

Brain Res.

Neurobiol. Dis.

Eur. J. Pharmacol.

Neurobiol. Dis.

Prog. Neurobiol.

Neurosci. Lett.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuron

Exp. Neurol.

Neuroimage

Neuroimage

Trends Neurosci.

J. Clin. Neurosci.

Decreased striatal D2 receptor binding in non-manifesting carriers of the DYT1 dystonia mutation

Neurology

The pathophysiology of primary dystonia

Brain

Organization of the thalamostriatal projections in the rat, with special emphasis on the ventral striatum

J. Comp. Neurol.

Synaptic organisation of the basal ganglia

J. Anat.

The pathophysiological basis of dystonias

Nat. Rev. Neurosci.

Microstructural white matter changes in carriers of the DYT1 gene mutation

Ann. Neurol.

Overactive prefrontal and underactive motor cortical areas in idiopathic dystonia

Ann. Neurol.