High frequency stimulation of the entopeduncular nucleus sets the cortico-basal ganglia network to a new functional state in the dystonic hamster
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 dtsz-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 dtsz-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 dtsz-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 dtsz-hamsters compared to controls. By contrast, c-Fos protein expression, reflecting transcriptional activity, was down-regulated in all motor-related analyzed structures in dtsz-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 dtsz-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 dtsz-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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2022, Neurobiology of DiseaseCitation 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).
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2022, Experimental NeurologyCitation 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.
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2021, Neurobiology of DiseaseCitation 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.
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2011, Behavioural Brain ResearchCitation 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].
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These two authors have equally contributed and should be considered as first authors.