Deep brain stimulation changes basal ganglia output nuclei firing pattern in the dystonic hamster

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Abstract

Dystonia is a heterogeneous syndrome of movement disorders characterized by involuntary muscle contractions leading to abnormal movements and postures. While medical treatment is often ineffective, deep brain stimulation (DBS) of the internal pallidum improves dystonia. Here, we studied the impact of DBS in the entopeduncular nucleus (EP), the rodent equivalent of the human globus pallidus internus, on basal ganglia output in the dtsz-hamster, a well-characterized model of dystonia by extracellular recordings. Previous work has shown that EP-DBS improves dystonic symptoms in dtsz-hamsters. We report that EP-DBS changes firing pattern in the EP, most neurons switching to a less regular firing pattern during DBS. In contrast, EP-DBS did not change the average firing rate of EP neurons. EP neurons display multiphasic responses to each stimulation impulse, likely underlying the disruption of their firing rhythm. Finally, neurons in the substantia nigra pars reticulata display similar responses to EP-DBS, supporting the idea that EP-DBS affects basal ganglia output activity through the activation of common afferent fibers.

Introduction

Dystonia is a heterogeneous syndrome of movement disorders characterized by involuntary muscle contractions leading to abnormal twisting movements and postures (Fahn, 1988). A modification of neuronal activity in the basal ganglia (BG), the thalamus, the cerebellum and different cortical areas, and a loss of inhibition of brainstem and spinal reflexes have been related to dystonia (Berardelli et al., 1998, Vitek, 2002). As predicted by the Albin and Delong model of BG pathophysiology (Albin et al., 1989), pallidal neurons of dystonic patients display a reduced mean spontaneous firing rate in comparison to parkinsonian patients and healthy monkeys (Hutchison et al., 2003, Starr et al., 2005, Tang et al., 2007, Vitek et al., 1999). In addition, pallidal local field potentials are excessively synchronized (Chen et al., 2006, Sharott et al., 2008, Silberstein et al., 2003).

Medical treatment of dystonia is often ineffective (Bressman, 2000). By contrast, deep brain stimulation (DBS) of the globus pallidus internus (GPi) improves dystonia (Coubes et al., 2000, Kupsch et al., 2006, Vidailhet et al., 2005). The mechanisms underlying the therapeutic effects of DBS in other movement disorders such as Parkinson's disease are likely the result of a complex action of the electrical stimulus on neurons and fibers in the vicinity of the stimulating electrode (Gradinaru et al., 2009, Hammond et al., 2008). Following stimulation, the activation of efferent and afferent axons can give rise to sustained neurotransmitter release (Windels et al., 2000, Windels et al., 2005) modifying local, up- and downstream neuronal activity. Hitherto, only few studies have investigated the mechanisms of action of DBS in dystonica. While previous studies have pointed to changes in the mean activity of single GPi neurons (Pralong et al., 2007) and in downstream thalamic activity (Montgomery, 2006) during GPi-DBS in dystonic patients, more complex changes in BG output remain to be determined.

The dtsz-hamster is a well-characterized model of non-kinesiogenic paroxysmal dystonia (Löscher et al., 1989, Richter and Löscher, 1998, Richter and Löscher, 2002). In agreement with the Albin and Delong model (Albin et al., 1989) and similar to differences between dystonic patients and parkinsonian patients or healthy monkeys (Starr et al., 2005, Vitek et al., 1999), firing rates in the entopeduncular nucleus (EP), the rodent equivalent of the GPi, are reduced in dystonic dtsz-hamsters (Bennay et al., 2001, Gernert et al., 2000, Gernert et al., 2002). Similar to human dystonia, the severity of dystonic symptoms is decreased during EP-DBS in dtsz-hamsters (Harnack et al., 2004). Moreover, EP-DBS in this model modifies transcriptional activity in striatum and thalamus (Reese et al., 2009), while GPi-DBS modulates cerebral blood flow in the same regions in dystonic patients (Detante et al., 2004).

The dtsz-hamster seems therefore to be a suitable model to further study DBS effects and mechanisms of action in dystonia. Here, we report for the first time changes in neuronal activity induced during DBS in dystonic animals. Using extracellular single-unit recordings, we characterize the impact of EP-DBS on the activity of EP and substantia nigra pars reticulata (SNr) neurons in dtsz-hamsters.

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 (n = 10) and control hamsters (n = 12) were obtained by breeding pairs from an inbred line by selective breeding as described before (Löscher et al., 1989). Male and female dtsz-hamsters show age-dependently dystonic symptoms that can be triggered by external stressing stimuli (Löscher et al., 1989). Dystonic

EP-DBS changes individual, but not average firing rate of EP neurons

Mean baseline firing rate of EP neurons was significantly lower in dtsz-hamsters than in controls (P < 0.05, Figs. 1A and B). DBS did neither change the average firing rate in dystonic hamsters (χ2 = 0.9, df = 2, P > 0.5, Fig. 1A) nor in controls (χ2 = 2.0, df = 2, P > 0.05, Fig. 1B). Saturation of the amplifier during the stimulation impulse occluded spiking activity during 1.3 ± 0.2 ms on average (mean ± SD, range 0.9 to 1.9 ms). The adjusted mean firing rate of EP neurons during DBS excluding the saturation

Discussion

In the present study, we show that EP-DBS disrupts the firing pattern of BG output neurons in dystonic hamsters. This disruption is accompanied by a reduction of both the asymmetry index of ISI distributions and single-unit oscillatory behavior at 4–30 Hz. Possibly underlying the changes in firing pattern, each stimulus pulse modifies EP neuron firing probability, inducing an initial excitation followed by an inhibition and a late excitation. Finally, we show that EP-DBS induces, except for the

Conclusion

Our study provides the first recordings of BG neuronal activity during DBS in a well-characterized animal model of dystonia. We provide evidence that EP-DBS modulates the activity of BG output neurons and give insights about the underlying mechanisms. The main finding is a switch to a less regular firing pattern for most EP neurons in dystonic hamsters. Moreover, EP neurons display a multiphasic response to each stimulation impulse during DBS, continuously interfering with their firing pattern

Acknowledgments

We are thankful to Jérôme Baufreton for critical reading of an earlier version of the manuscript. This study was supported by the Centre National de la Recherche Scientifique, Université Victor Ségalen Bordeaux 2, Région Aquitaine and IFR de Neurosciences (INSERM N°8; CNRS N°13), as well as the Deutsche Forschungsgemeinschaft (RI845/1-3).

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    Both authors contributed equally to this work and should therefore be considered as first authors.

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