Superior colliculus firing changes after lesion or electrical stimulation of the subthalamic nucleus in the rat

Brain Research 943 (2002) 93–100 www.elsevier.com / locate / bres

Research report

Superior colliculus firing changes after lesion or electrical stimulation of the subthalamic nucleus in the rat Karine Bressand*, Maurice Dematteis, Dong Ming Gao, Laurent Vercueil, Alim Louis Benabid, Abdelhamid Benazzouz ´ , INSERM U318, Centre Hospitalier Universitaire, 38043 Grenoble Cedex 09, France Laboratoire de Neurobiologie Preclinique Accepted 5 March 2002

Abstract Recent data have suggested a critical role for the basal ganglia in the remote control of epileptic seizures. In particular, it has been shown that inhibition of either substantia nigra pars reticulata or subthalamic nucleus as well as activation of the superior colliculus suppresses generalized seizures in several animal models. It was previously shown that high frequency stimulation of the subthalamic nucleus, thought to act as functional inhibition, stopped ongoing non-convulsive generalized seizures in rats. In order to determine whether high frequency stimulation of the subthalamic nucleus involved an activation of superior colliculus neurons, we examined the effects of subthalamic nucleus manipulation, by either high frequency stimulation or chemical lesion, on the spontaneous electrical activity of superior colliculus neurons. Acute high frequency stimulation of the subthalamic nucleus (frequency 130 Hz) induced an immediate increase of unitary activity in 70% of responding cells, mainly located within the deep layers, whereas a reduction was observed in the remaining 30%. The latter responses are dependent on the intensity and frequency of the stimulation. Unilateral excitotoxic lesion of the subthalamic nucleus induced a delayed and transient decrease of superior colliculus activity. Our data suggest that high frequency stimulation of the subthalamic nucleus suppresses generalised epileptic seizures through superior colliculus activation.  2002 Elsevier Science B.V. All rights reserved. Theme: Motor systems and sensorimotor integration Topic: Basal ganglia Keywords: Epilepsy; High frequency stimulation; Subthalamic nucleus; Superior colliculus

1. Introduction Evidence has been collected demonstrating the existence of remote control circuits exerting an inhibitory influence on certain types of epileptic seizures (for review see Depaulis et al. [18]). Recent studies have pointed to the basal ganglia as one of the main system involved in the control of epileptic seizures [21,22]. It has been shown that activation of striatal neurons by local injection of gluta-

Abbreviations: GAERS, genetic absence epilepsy rats from Strasbourg; HFS, high frequency stimulation; SC, superior colliculus; SNpr, substantia nigra pars reticulata; STN, subthalamic nucleus *Corresponding author. Centre Paul Broca, INSERM U573 2ter, rue ´ d’Alesia 75014 Paris, France. Tel.: 133-1-4078-9221; fax: 133-1-45807293. E-mail address: [email protected] (K. Bressand).

mate or NMDA agonists, dopaminergic D1 and / or D2 agonists or GABA antagonists suppresses both convulsive and nonconvulsive generalized seizures in rats [10,24,50]. In addition, injection of a GABAA antagonist to the globus pallidus or the ventral pallidum, one of the major output of the striatal complex, also results in the suppression of seizures in the GAERS (genetic absence epilepsy rat from Strasbourg) [23]. This latter effect was suggested to involve a reduction of the subthalamic nucleus (STN) activity since injection of a GABA agonist in this structure has been shown to suppress non-convulsive generalized seizures [19], generalized tonic–clonic seizures [26] and partial seizures with secondary generalization [20]. The subthalamic nucleus is the main glutamatergic input of the substantia nigra pars reticulata (SNpr) which, in turn, sends a bilateral GABAergic projection to the neurons located within the deep and intermediate layers of the

0006-8993 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0006-8993( 02 )02541-6

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superior colliculus (SC) [11,12,25,53]. Both SNpr and SC have been described as key structures of a remote control circuit of epileptic seizures (for review see Depaulis et al. [18]) since inhibition of the SNpr GABAergic neurons results in suppression of convulsive [27,32,37,49] and non-convulsive seizures [15,16] and increase in SC activity [14]. Moreover, the direct activation of the SC neurons by either GABA antagonist or glutamate agonist leads to significant antiepileptic effects [17,28,44]. Furthermore, bilateral lesions of the SC were shown to reverse the antiepileptic effects induced by GABA agonist injection into the SNpr, whereas lesions of other nigral outputs had no significant consequences [17,29]. This suggests that the disinhibition of SC neurons, more especially those located within the deep and intermediate layers of the SC [46], is involved in the remote suppression of seizures [18]. Taken together, the above data support a crucial role of STN, SNpr and CS in the control of epileptic seizures. Recent experimental [4] and clinical [35] evidence has clearly demonstrated that parkinsonian symptoms, known to arise from a disorganisation of basal ganglia activity, are alleviated by electrical high frequency (130 Hz) stimulation (HFS) of the STN. The same effects were obtained with STN lesion in the primate [1]. Therefore, HFS is thought to act as a functional inactivation of the stimulated structure. Indeed, STN-HFS has inhibitory effects on output structures, in particular, it induces a decrease in spontaneous firing of SNpr [5]. Furthermore, STN-HFS is able to stop an ongoing generalized non-convulsive seizure in GAERS [51]. Together, this suggests that STN-HFS may have antiepileptic effects through a putative disinhibition of SC neurons secondary to a reduction of SNpr activity. In this study we thus examined the effects of HFS or excitotoxic lesion of the STN on the spontaneous activity of neurons within the deep and intermediate layers of the SC.

2. Materials and methods

2.1. Animals The experiments were carried out on adult male wistar rats (Iffa Credo, Les Oncins, France) weighing 250–350 g. The animals were housed at constant room temperature on a 12 h light–dark cycle, with food and water ad libitum. All animals experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86 / 609 / EEC).

2.2. STN electrical stimulations On the recording day, under anaesthesia (see Section 2.4), a concentric stimulating bipolar electrode (tip diameter5200 mm, NEX-100X, 30 mm, Roucaire, France)

was stereotactically inserted within the STN of 17 rats with a 128 rostro–caudal angle (2 mm caudal and 2.5 mm lateral to bregma, 8.2 mm ventral to the skull according to the atlas of Paxinos and Watson [41]). Square waves pulses were delivered by a train generator (A310 Accupulser pulse generator, WPI, Sarasota, USA) interfaced with a pulse isolator (A360, and WPI). Stimulation parameters were: frequency, 1–1000 Hz; pulse width, 60 ms; intensity, 100–1000 mA; train duration, 5 s.

2.3. STN excitotoxic lesions Anaesthetized rats (chloral hydrate, 400 mg / kg, i.p.) received kainic acid (2 mg / 0.5 ml / 2 min, Sigma, France) within the right STN through stereotactically implanted stainless steel cannula (3.8 mm caudal and 2.5 mm lateral to bregma, 8 mm ventral to the skull according to the atlas of Paxinos and Watson [41]) as previously described [42]. Animals were then individually housed and allowed to recover for at least 1 week. Functional verification of the STN unilateral lesions was performed using the test of rotational behaviour induced by apomorphine (150 mg / kg, i.m.) as previously reported [42].

2.4. Extracellular single-unit recordings Anaesthetized animals (urethane, non-lesioned rats 2.5 g / kg, lesioned rats 1.5 g / kg, i.p. to prevent high rate of death) were placed in a stereotaxic apparatus (David Kopf Instruments) and the skull overlying the SC was removed. Extracellular single-unit recordings were performed in SC (6.5 mm caudal and 5 mm lateral to bregma, 4–6 mm ventral to the skull according to the atlas of Paxinos and Watson [41]) using tungsten microelectrodes (tip diameter51 mm, impedance510 MV at 1000 Hz, FHC, Brunswick, USA). In stimulation experiments, the baseline firing rate of each SC neuron tested (n557 in 17 rats) was recorded for at least 1 min before STN electrical stimulation. Because of generated electrical artefacts, spikes were quantified just after the end of the stimulation and until the firing rate returned to the baseline level. A 1-min baseline activity was compared with a 5-s period following stimulation. Significant modifications were considered for at least 10% variation. At the end of each experiment, a 20-mA positive DC current was delivered for 20 s in order to mark the electrode tip location. In lesion experiments, the spikes discharge of each neuron was recorded for 100 s along three trajectories in the SC (n5455 neurons ipsilaterally to the lesion, n5182 cells controlaterally, in 28 rats). Four groups of rats were studied, 1 (n58 rats), 2 (n55), 4 (n56), 6 (n55) or 10 (n54) weeks after STN lesions. Firing rates of lesioned animals were compared with those of non-lesioned rats. Four rats without STN lesion or stimulating electrode implantation were studied under the same conditions as the

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experimental rats and were considered as controls since the firing rate of collicular neurons was not different (data not shown).

2.5. Histology Upon completion of experiments, anaesthetised animals were killed by decapitation, brains were then removed, frozen and cut. Coronal sections (25 mm) were stained with cresyl violet in order to identify recording tracks and / or stimulation sites and to confirm the lesion of the STN previously assessed by a rotational test as described in Section 2.3. Only rats showing total or subtotal destruction of STN or stimulating electrode tracks within the STN and recording electrode tracks within the SC were considered for analysis.

2.6. Statistics Results are expressed as means6standard error of the mean (S.E.M.). The Student t-test for independent samples was used to compare the firing rates of SC neurons between normal and lesioned rats, between STN-HFSincreased cells and STN-HFS-decreased cells and between cells located within the deep and intermediate layers of the SC. Firing rates of SC cells were compared before and after stimulation with a Student t-test for paired values. Responses for increasing intensities and frequencies of stimulations were analysed using the Mann–Whitney U test. Difference between values was considered as statistically significant if P,0.05.

3. Results

3.1. Effects of high frequency electrical stimulations of the subthalamic nucleus on the firing rate of the intermediate and deep layers neurons of the superior colliculus In a first attempt, we aimed to determine whether STNHFS could modify the activity of SC neurons. The firing rate of SC neurons located within the deep and intermediate layers was thus measured after STN-HFS (Fig. 1A) applied with parameters known to inhibit SNpr cells (frequency: 130 Hz, intensity: 500 mA, pulse width: 60 ms, train duration: 5 s) as previously described [5]. Different responses were observed in the 57 collicular neurons recorded after a 5-s STN-HFS. An increase in firing rate occurred in 27 out of 57 neurons (47.4%), whereas 12 out of 57 (21%) showed a decrease. The remaining 18 neurons (31.6%) did not show any modification. Global analysis of all recorded cells (excited1inhibited1unresponding cells, n557 neurons), revealed that STN-HFS significantly increased the firing rate of collicular neurons by 21%

Fig. 1. High frequency stimulation of the subthalamic nucleus (STNHFS) (frequency: 130 Hz, intensity: 500 mA, pulse width: 60 ms, pulse duration: 5 s) and recording of the extracellular single unit activity of neurons in the deep and intermediate layers of the superior colliculus. (A) Photomicrograph of a rat cresyl violet stained coronal section. The arrow indicates the location of the tip of the stimulating electrode in the subthalamic nucleus. (B) Firing rate was transiently increased by STNHFS (vertical bars) for 70% of the responding neurons. (C) Firing rate was transiently decreased by STN-HFS (vertical bars) for 30% of the recorded neurons.

(12.561.2 vs. 15.161.7 spikes / s after STN-HFS, P, 0.05). Among the responding cells, 70% (27 / 39) were excited while the activity of the remaining 30% (12 / 39) was reduced. The firing rate of the former, being excited by STN-HFS, was found to be increased by 92% (10.260.9 vs. 19.662.9 spikes / s after STN-HFS, P,0.01). The response was immediate, reproducible for the same neuron and transient, the firing returning to baseline within 19.461.3 s (Fig. 1B). The 12 reduced cells exhibited a basal firing rate of 18.564 spikes / s which was significantly higher (P,0.01) than the mean basal activity of the 27 excited neurons. Following HFS, this spontaneous firing was decreased by 42% (10.863.6 spikes / s, P,0.01) in an immediate and transient manner, with an effect lasting 14.863 s (Fig. 1C).

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When analyzed according to the anatomical location of the responding cells, our results showed that the mean spontaneous firing rate was significantly different in the deep layers (10.4361.13 spikes / s) as compared to the intermediate layers (16.6362.83 spikes / s, P,0.05) i.e. 62.7% lower within the former (Fig. 2). Responses to STN-HFS were also different. Indeed, the firing rate was significantly increased within the deep layers (16.5362.69, n522 neurons, P,0.05) whereas it was not significantly modified within the intermediate layers (16.9362.53 spikes / s, n517 neurons) (Fig. 2). Concerning the remaining 18 unresponding cells, the basal firing rate (12.0161.6 spikes / s) was not different either from the excited cells or from the reduced cells. Neither was the spontaneous firing rate different whether the cells located within the deep layers (12.1461.27, n59) or within the intermediate layers (11.8862.97, n59). Moreover, in order to test if the effect could be maintained we applied a long-lasting HFS (5–30 min). Such a stimulation has no after-effect on the activity of collicular neurons. Our results finally showed that STN-HFS induced two type of effects on SC neurons we recorded, with a majority being excited. This activation was mainly sustained by the neurons located within the deep layers of the SC.

STN-HFS on collicular neurons were then investigated to establish the intensity threshold and to determine whether the observed effect was high frequency specific. Ranges of intensities (100–800 mA) and frequencies (10–200 Hz) were tested on 22 responding SC neurons (14 being excited and 8 being reduced). For a frequency kept constant at 130 Hz, the amplitude of SC activity variations was significantly increased, as compared to the lowest intensity, at intensities higher than 400 mA in neurons excited by the STN-HFS (n56). The response was stabilized between 500 and 800 mA (Fig. 3A). A nonsignificant decrease of the amplitude of SC activity variations was observed for neurons inhibited by STN-HFS (n53) (Fig. 3A). For a 500-mA current intensity, the amplitude of the response significantly increased from 10–20 Hz up to 50 Hz, after which there was no further significant difference between responses until 200 Hz in neurons excited by the

3.2. Influence of the intensity and frequency of the subthalamic nucleus stimulation on the responses of collicular neurons The effects of different intensities and frequencies of

Fig. 2. Activity of collicular neurons within the deep and intermediate layers before and after high frequency stimulation of the subthalamic nucleus (STN-HFS) (frequency: 130 Hz, intensity: 500 mA, pulse width: 60 ms, pulse duration: 5 s); n, number of neurons; *, P,0.05 after vs. before STN-HFS with a t-test for paired values; §, P,0.05 intermediate vs. deep layers with a t-test for unpaired values.

Fig. 3. Activity of excited and reduced collicular neurons after stimulation of the subthalamic nucleus according to the intensity (A) and frequency (B) of the stimulation (pulse width: 60 ms, pulse duration: 5 s); n, number of neurons; *, P,0.05 vs. 100 mA (A) or 10 Hz (B) with a Mann–Whitney U test.

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STN-HFS (n58) (Fig. 3B). A significant decrease of the amplitude of SC activity variations was observed for neurons inhibited by STN-HFS (n55) (Fig. 3B). This experiment showed that the activity of neurons both excited and reduced by STN-HFS depended on the intensity and frequency of the stimulation.

3.3. Effects of excitotoxic lesions of the subthalamic nucleus on the firing rate of the intermediate and deep layers neurons of the superior colliculus The STN-HFS, considered as a functional inactivation, was supposed to be equivalent to a lesion. We thus examined whether a chemical lesion of the STN would modify the activity of SC neurons. In this experiment, the firing rate of SC neurons located within the deep and

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intermediate layers was examined at different times after a unilateral STN lesion. Ipsilaterally to the lesion (Fig. 4A), SC neuronal firing rate decreased by 46.1 and 41.7%, 2 and 4 weeks after the lesion, respectively. At 6 and 10 weeks after the lesion, the firing had returned to the baseline level (Fig. 4B). On the controlateral side, a similar decrease of the SC activity was observed 2 and 4 weeks postlesion and then returned to the baseline level (Fig. 4B). Therefore, the unilateral STN excitotoxic lesion resulted in a bilateral delayed and transient decrease in the activity of the collicular neurons located in the intermediate and deep layers.

4. Discussion The results of the present study shows that acute STNHFS in the rat induces contrasting responses of SC neurons. Mainly STN-HFS induces a transient increase in the activity of a neuronal subpopulation of the superior colliculus, mostly located within the deep layers. In a not inconsiderable minority STN-HFS induces a decrease of activity. Another experiment shows that lesion of the STN results in a general decrease of the collicular neurons activity.

4.1. Disinhibition of collicular neurons by STN-HFS

Fig. 4. Excitotoxic lesion of the subthalamic nucleus with kainic acid and recording of the extracellular single unit activity of neurons in the deep and intermediate layers of the superior colliculus. (A) Photomicrograph of a cresyl violet stained coronal section of a rat showing the lesioned side (asterisks). (B) Evolution of SC neuronal firing rate 1, 2, 4, 6 and 10 weeks after kainic acid injection into the subthalamic nucleus; n, number of neurons; **, P,0.01 when compared to control rats with a t-test for unpaired values.

The mechanisms of action of the HFS are not yet fully understood. Some experimental studies support the hypothesis that HFS results in local inhibition of brain structures. In particular, HFS in the STN has been shown to significantly decrease the frequency of extracellularly recorded STN neurons in rats [6]. Moreover, STN-HFS, in vitro, produced a full blockade of spontaneous activities of STN neurons through blockade of voltage-gated currents [9]. On the other hand, some neurochemical findings argue against this hypothesis. Windels et al. [54] showed that STN-HFS (130 Hz) induced an increase of extracellular glutamate in globus pallidus and SNpr as well as a rapid increase of extracellular GABA in the SNpr. These results favour the involvement of STN target structures in the action of STN-HFS rather than an inactivation of STN neurons. In this study, it is interesting that modifications of SC activity after STN stimulation were significant at 50 Hz, a not so-called high frequency. This is in agreement with previous reports showing anti-parkinsonian effect with 35 or 50 Hz STN stimulation [35]. Thus there is not really a high frequency specific effect. Rather than the frequency, the discharge mode of the cells must be important for the effectiveness of the stimulation [8]. Moreover long-lasting stimulations were ineffective which contrasts with their effects on movements disorders [35]. This discrepancy suggests different mechanisms to control epileptic seizures and motor functions [21].

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Whatever the mechanism, it has been shown that STNHFS transiently inhibits neurons of SNpr, its main output structure [5,6]. Moreover, inhibition of SNpr by local application of GABA agonists or activation of its main inhibitory inputs results in disinhibition of SC neurons [13]. In this study, using the parameters of stimulation previously described to strongly inhibit SNpr [5,6] (frequency: 130 Hz and intensity: 500 mA) a disinhibition of collicular neurons was observed. It is thus tempting to hypothesise that the excitation of collicular cells observed after HFS results from an inhibition of GABAergic nigrocollicular neurons. Otherwise, STN-HFS has also been shown to decrease the activity of the entopeduncular nucleus [5], another output of the basal ganglia which send inhibitory projections to the deep layers of the SC [47]. STN-HFS could then lead to disinhibition of SC deep layers neurons also through the entopeduncular nucleus. This may also be mediated by the effect that STN-HFS could exert on the zona incerta, surrounding the STN, since inhibitory projection from this area to the deep layers of the SC has been described [33]. However this possibility can be reasonably ruled out given that Vercueil et al. [51] reported that HFS within zona incerta has no effect on epileptic seizures. It also remains possible that tecto-subthalamic fibers [48] may be antidromically activated by the stimulation and participate to the effect via local circuitry within the SC. Altogether, the dominant consequence of STN-HFS was an activation of collicular neurons mainly within the deep layers.

4.2. Inhibition of collicular neurons by STN-HFS Increase of collicular neurons activity was not, however, the single effect observed during STN-HFS. Indeed, among the responding cells, 30% were reduced by the stimulation. Such heterogeneous results have previously been observed after chemical manipulations of either SNpr [11,39,52] or cerebellum [40]. Moreover, it was already described that SC neurons were functionally divided into subpopulations with regards to their afferences. Some SC neurons receive GABAergic inputs from the SNpr whereas others were under glutamatergic influence from the peduncle and the optic tract [11]. One subgroup is under both excitatory and inhibitory influences from cerebellum and SNpr respectively [52]. This suggests that the inhibitory effects of STN-HFS on SC neurons observed in our study may correspond to an anatomo–functional heterogeneity. Our results favour this hypothesis since we observed that the two subsets of SC neurons had different basal firing rates. Neurons reduced by STN-HFS exhibited a higher spontaneous activity than excited neurons. However, excited and inhibited SC neurons responded in a same manner when different frequencies and intensities of STN stimulations were used. Additionally, we observed that STN-HFS-excited cells

were preferentially located within deep layers of SC. Heterogeneous responses were also obtained by NiemyJunkola and Westby [39] when they studied the effects of pharmacological nigral inhibition on SC neurons activity. Contrasted and spatially segregated effects observed in the SC after manipulations of its inputs are in accordance with an architecture promoting a competitive treatment of informations inside SC: one action is selected and simultaneously the opposite one is inhibited. Finally, paradoxical effects of STN-HFS or other SC input structures manipulations could be mediated by local inhibitory circuits inside the SC. Such inhibitory circuits have been described in the cat [3], the macaque [36] and the furet [38]. However, this hypothesis requires further investigations in the rat.

4.3. Delayed inhibition of collicular neurons by unilateral STN lesion STN lesions lead to a general and bilateral decrease of SC neurons activity 2 and 4 weeks after the lesion. At first sight, there is a mismatch between HFS and lesions of STN which is in contradiction with the effects of longlasting HFS in Parkinsonian patients [35] and with the general agreement that HFS mimics the effects of lesions. Even with a long-lasting stimulation we do not have any after-effect as Vercueil et al. had no effect on seizures in GAERS [51]. This suggests that control of epileptic seizures required only phasic modulation of the control system, conversely to the control of motor functions [35]. The time-course of the effect is also surprising as excitotoxic effects of kainic acid are supposed to be fast, with a neuronal cell death occurring within 2 h of injection [45]. The time-course of the SC activity reduction we observed after STN lesion suggests compensatory mechanisms occurring at the SNpr level. Upregulation of NMDA receptors in this structure has been demonstrated 2 weeks after STN lesion [43], leading to enhancement of the sensibility of SNpr neurons to the remaining excitatory influence [30,34]. The fact that this decrease of SC activity disappeared 6 weeks after the lesion, also suggests a possible reorganisation of neuronal circuits in order to compensate the STN cell loss. Although STN is not known to have controlateral projections, bilateral changes in SC activity were observed following unilateral lesions of the STN. These results are in agreement with the bilateral influence of SNpr to SC described previously [31]. Finally, we may have observed the result of compensatory mechanisms and not the first effect of the lesion.

4.4. Functional consequences The modification of SC neurons activity following STNHFS described in the present study provides some functional hypothesis for its therapeutic effects. Such stimulation is now widely used in parkinsonian patients to

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alleviate tremors and other motor symptoms [35]. Moreover, it has been shown that injection of a GABA agonist in the SNpr or microstimulation of the SC reduced blink amplitude in rats with a 6-hydroxydopamine lesion of the substantia nigra [2]. The results described in this study suggest that STN-HFS could also reduce reflex blinks hyperexcitability, a cardinal sign of Parkinson’s disease. Disinhibition of SC neurons by STN-HFS is in agreement with the antiepileptic effects of such stimulations observed on rats with spontaneous forms of nonconvulsive generalised seizures [51]. In this model, bilateral lesion of STN reduces mean duration of seizures. In this model as well as in models of convulsive seizures, activation of SC neurons by either inhibition of SNpr neurons or stimulation of collicular cells lead to significant anti-epileptic effects (for review, see Depaulis et al. [18]). The mechanisms underlying this antiepileptic effect remain to be determined. Our data suggest a preferential involvement of neurons of the deep layers of the SC in the control of seizures. This result has to be confirmed in the GAERS. In conclusion, our study provides evidence for a heterogeneous influence of STN-HFS on SC neurons which mainly leads to a disinhibition of the collicular neurons preferentially located within the deep layers of the superior colliculus.

Acknowledgements ˆ This work was supported by Region Rhones-Alpes, ´ Institut National de la Sante´ Et de la Recherche Medicale ´ and Fondation pour la Recherche Medicale. The authors wish to thank Dr. David Blum and Dr. Antoine Depaulis for their critical reading of the manuscript.

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