MSc Cyril Atkinson-Clement
email: 8cyril.atkinson-clement@lpl-aix.fr

MSc Émilie Cavazzini

MSc Alexandre Zénon

MD, Ph.D Tatiana Witjas

MD, Ph.D Frédérique Fluchère

MD, Ph.D Jean-Philippe Azulay

MSc Christelle Baunez

MD, Ph.D Alexandre Eusebio

Effects of subthalamic nucleus stimulation and levodopa on decision-making in Parkinson's disease

Keywords: Basal ganglia, Deep brain stimulation, Dopamine, Cost-benefit, Effort

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder entailing several dopaminergic dysfunctions in its early stages, leading to rest tremor, akinesia and rigidity [START_REF] Marsden | Parkinson's disease[END_REF], but also to dysfunction in the affective and motivational processes such as depression, apathy or anhedonia (for review: [START_REF] Kaji | Apathy and anhedonia in Parkinson's disease[END_REF]). Dopamine replacement therapy and, in more advanced PD, high frequency deep brain stimulation (DBS; particularly in the subthalamic nucleus [STN]) are both very effective at reducing motor symptoms. However, it is now well admitted that these treatments also impact motivated behaviors.

In PD, levodopa can induce a hyperdopaminergic state that can affect decision-making processes.

However, the exact effects of levodopa on decision-making are still unclear. Indeed, experimental data suggest that levodopa can impair (e.g. by increasing impulsive activation of muscles [START_REF] Fluchère | Dopa therapy and action impulsivity: subthreshold error activation and suppression in Parkinson's disease[END_REF]), improve (e.g. by increasing response inhibition [START_REF] Manza | Levodopa improves response inhibition and enhances striatal activation in early-stage Parkinson's disease[END_REF]) or not influence (e.g. [START_REF] Obeso | Levodopa medication does not influence motor inhibition or conflict resolution in a conditional stop-signal task in Parkinson's disease[END_REF]) cognitive processes involved in decisionmaking as well as inhibitory processes. According to computational models of decision-making, a hyperdopaminergic state could lead to failure of the cognitive processes involved in decisionmaking [START_REF] Frank | By Carrot or by Stick: Cognitive Reinforcement Learning in Parkinsonism[END_REF]. Clinically, it seems that levodopa could induce a failure of decision-making processes (i.e. by inducing impulse control disorders), even if this effect is stronger with dopamine agonists [START_REF] Weintraub | Impulse Control Disorders in Parkinson Disease: A Cross-Sectional Study of 3090 Patients[END_REF].

STN is a key structure of basal ganglia, involved in motor control, but also in cognitive and emotional processes. STN-DBS improves the motor symptomatology of PD, but could lead to alterations of decision-making processes. The computational function of STN in decision-making has been modeled as a structure involved in slowing down decision processes, particularly in a situation of conflict, to give the system enough time to choose the best response, giving an inhibitor role to the STN (reactive [START_REF] Frank | Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism[END_REF] and proactive [START_REF] Ballanger | Stimulation of the subthalamic nucleus and impulsivity: Release your horses[END_REF] hypotheses; for review: [START_REF] Jahanshahi | A fronto-striato-subthalamic-pallidal network for goal-directed and habitual inhibition[END_REF]). In addition, we have recently shown that the STN was involved in effort-based decision-making, particularly in cost-benefit valuation processes [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF].

However, this data did not prove causality as it only provided correlative evidence. Our aim was therefore to examine the impact of levodopa consumption and STN activity manipulation on decisionmaking using the same paradigm as previously [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF] but involving a novel PD patients cohort and adding healthy participants. Establishing this is clinically relevant as there is an ongoing controversy on the effect of STN-DBS on decision-making and in particular whether or not it can cause impulsivity. Indeed, while some previous studies have reported an impairment of decision-making (through action impulsivity) after STN-DBS [START_REF] Cavanagh | Subthalamic nucleus stimulation reverses mediofrontal influence over decision threshold[END_REF][START_REF] Coulthard | Distinct roles of dopamine and subthalamic nucleus in learning and probabilistic decision making[END_REF], others have shown improvement (for choice impulsivity) [START_REF] Eusebio | Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson's disease[END_REF][START_REF] Lhommee | Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours[END_REF][START_REF] Witjas | Addiction in Parkinson's disease: Impact of subthalamic nucleus deep brain stimulation[END_REF][START_REF] Lhommée | Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial[END_REF].

Here we hypothesize the following: 1\ PD patients (without levodopa) are less motivated to perform an effort-based decision-making task, 2\ levodopa increases that motivation, and 3\ STN-DBS modifies cost-benefit valuation.

Methods

Patients

Seventeen idiopathic PD patients operated for STN-DBS and fulfilling UK Parkinson's disease Brain Bank Criteria [START_REF] Gibb | A comparison of clinical and pathological features of young-and old-onset Parkinson's disease[END_REF] for the diagnosis of idiopathic PD, were recruited in the Department of Neurology and Movement Disorders of La Timone University Hospital, after providing written informed consent. The surgical procedure of electrode implantation was as previously described [START_REF] Fluchere | Controlled general anaesthesia for subthalamic nucleus stimulation in Parkinson's disease[END_REF]. The stimulation electrodes were the Medtronic model 3389 with 4 plots, 1.27mm in diameter and 1.5mm in height, separated by insulating bands 0.5mm in height. Only 13 patients performed the entire experiment, the four others were excluded for clinical reasons (e.g., excessive motor impairment preventing task performance; difficulty in understanding instructions). Clinical characteristics of the patients and STN-DBS parameters are provided in Table 1. In a second step, 13 age and gender matched healthy controls were recruited. This project was approved by the local ethics committee and realized in compliance with the national legislation and the Declaration of Helsinki[21].

[TABLE.1]

All participants were screened, under medication and STN-DBS turned On, for depression (Beck Depression Inventory [BDI; [START_REF] Beck | Screening depressed patients in family practice. A rapid technic[END_REF]]; Montgomery-Asberg Depression Rating Scale [MADRS; [START_REF] Montgomery | A new depression scale designed to be sensitive to change[END_REF]]), anxiety (Hamilton Anxiety Rating Scale [HAM-A; [START_REF] Hamilton | The assessment of anxiety states by rating[END_REF]]), apathy (Lille Apathy Rating Scale [LARS; [START_REF] Sockeel | The Lille apathy rating scale (LARS), a new instrument for detecting and quantifying apathy: validation in Parkinson's disease[END_REF]]), impulsivity (Minnesota Impulsive Disorders Interview [MIDI; [START_REF] Christenson | Compulsive buying: descriptive characteristics and psychiatric comorbidity[END_REF]]), cognition (Mattis Dementia Rating Scale [MDRS; [START_REF] Mattis | Mental status examination for organic mental syndrome in the elderly patients[END_REF]]) and quality of life (Parkinson's Disease Questionnaire-39 [PDQ-39; [START_REF] Jenkinson | The Parkinson's Disease Questionnaire (PDQ-39): development and validation of a Parkinson's disease summary index score[END_REF]]). Motor impairment was assessed under four treatment conditions (without treatment [Off DBS/Off Dopa], with levodopa alone [Off DBS/On Dopa], with STN-DBS alone [On DBS/Off Dopa], with both [On DBS/On Dopa]) using Unified Parkinson's Disease Rating Scale part-III (UPDRS-III; [START_REF] Fahn | Members of the UPDRS Development Committee. Recent developments in Parkinson's Disease[END_REF]). Demographics and clinical data are available in Table 2.

[TABLE.2]

Task

The patients were instructed to squeeze a dynamometer with variable force (12 levels) and with promise of a variable virtual monetary reward (5c, 20c, 100c). First, a fixation cross was displayed for 500-1500ms. Then, the reward cue was displayed, indicating the reward value. The second cue indicated the level of force needed for the current trial and was represented as a vertical gauge with a horizontal bar indicating the level required, hereafter called the threshold. When the second cue appeared, the patients had to decide whether they accepted the trial. They were instructed to decide whether or not the promised reward was worth performing the required effort.

In case they accepted, they had to start pressing the dynamometer, then the level in the gauge raised with a speed proportional to the force applied to the dynamometer. The speed was computed so that filling the gauge completely required exerting a force equal to the maximal voluntary contraction force (MVC) for 7.6s. The 12 levels used were 0.5, 0.725, 0.95, 1.0, 1.45, 1.9, 2.0, 2.9, 3.8, 4.0, 5.8, 7.6s at MVC (corresponding to the integral of exerted force over time), although, as noted above, subjects were free to vary how these effort levels were achieved by trading duration for force. The MVC was measured at the beginning of each block and the force levels adapted accordingly to adjust for fatigue.

After the level indicated on the gauge reached the threshold, a fixation cross was displayed for 500-1500ms, followed by the reward feedback, accompanied by a bell sound with the sentence "You win", shown on the screen for 2000ms (Fig. 1). Any squeezing of the bulb before the effort cue onset stopped the trial.

When the patients wished to refuse the proposed trial, they had to withhold their response for 4s, then a display of the reward amount they had refused was shown superimposed with a red crossed on the screen for 2000ms. Intercue intervals were randomized so as to limit the expectation of the upcoming cue and any related preparation. Each of the 36 conditions (3 reward x 12 force) were equal and they were presented in randomized order. Due to time constraints, only the participant's dominant hand performed the grip task.

[FIGURE.1]

Procedure

After the patients were seated, they first had to perform three MVC by squeezing the pressure bulb as hard as possible for effort adjustments during the following block. They received vocal encouragements during this exercise. Patients were then trained on the task with a slowed-down version in which a break was added between each phase, allowing the experimenter to explain the meaning of each phase of the task and the responses that were expected from them. Then, each patient performed four 8min blocks of the task On and Off STN-DBS, with a total of 128min over two half-days (one half-day On levodopa, the other Off levodopa). The treatment conditions were applied in a pseudo-randomized order to decrease the influence of repetition, habituation or fatigue caused by the task. Each block included an average of 30.8±2.6 trials. The Off levodopa sessions were realized after an overnight (12hours) withdrawal of treatment [START_REF] Langston | Core assessment program for intracerebral transplantations (CAPIT)[END_REF]. The On levodopa sessions were undertaken 45-60min after the intake of a unique levodopa dose corresponding to 150% of each patient's morning dose. Efficacy of the levodopa administration in the ON-drug state was assessed using the UPDRS-III score about 45min after ingestion of levodopa. All patients felt at "best On" and improved their UPDRS-III score by 68.1%±13.3% compared with the Off-drug state (t=7.47, p<0.001). The Off/On STN-DBS sessions were undertaken at least 20min after STN-DBS switched Off/On as about 75% of the UPDRS-III score decrease occurs within this time frame following discontinuation of DBS [START_REF] Temperli | How do parkinsonian signs return after discontinuation of subthalamic DBS?[END_REF]. For example, during the first day, a patient performed one session without any treatment (4 blocks) followed by one session with active STN-DBS (4 blocks), while during the second day, he did one session with both levodopa and active STN-DBS (4 blocks) followed by one session under levodopa alone (4 blocks).

Statistical analyses

All statistical analyses were conducted with R [START_REF] Core | R: A language and environment for statistical computing[END_REF] and SAS software [START_REF]9.3 Help and Documentation[END_REF]. Clinical and demographic comparisons consisted of non-parametric statistics (Kruskal-Wallis). For other variables, we ran Generalized Linear Mixed Models (GLMM). The model included systematically treatment condition (Off DBS/Off Dopa; Off DBS/On Dopa; On DBS/Off Dopa; On DBS/On Dopa; HC), reward cue value (5c; 20c; 100c), effort cue value (from 1 to 12) and all their interactions. Participants were included as random effects, taking into account the between-subject variations of intercepts and all fixed effect slopes. Moreover, the association between each patient and his matched healthy control were included in our analyses. Three variables were analyzed: the acceptance rate which corresponds to the percentage of accepted trials (logit), the decision time (Gaussian) and the time to complete each item (log; equivalent to the exerted force). The acceptance rate corresponds to the successful trials and tried but failed trials divided by the total number of trials. Lastly, we performed Sidak's adjustment for multiple comparisons between HC and all PD treatments conditions (to identifying how PD states are different from a "normal" behavior) and between Off DBS/Off Dopa condition and the three other treatments conditions (to identifying how treatments modify patient's behavior).

Results

Demographic and clinical results

We compared PD and HC as for demographic and clinical data. We found no significant difference in age, validating the matching of our groups. Regarding clinical data, we found differences between PD patients and HC for several assessments, corresponding to lower scores for PD patients in the BDI (χ 2 =9.8, p=0.001), MDRS (χ 2 =5.5, p=0.018) and semantic fluency (χ 2 =7.8, p=0.004). Moreover, we found an improvement of the UPDRS part-II (χ 2 =11, p<0.001) and of the Schwab and England scale (χ 2 =12.2, p<0.001) under the treatment condition compared with the without treatment condition.

Acceptance rate

As expected, the acceptance rate increased with the reward value (F(2,24)=28.55, p<0.0001) and decreased with the effort required (F(1,12)=63.66, p<0.0001). In addition, the treatment condition had a significant effect on the acceptance rate (F(4,48)=3.59, p=0.0063) and we observed a significant interaction between treatment condition and reward value (F(8,96)=3.25, p=0.0011) and magnitude of effort (F(4, 48)=2.61, p=0.0334; Fig. 2.A). In a second step, contrast analyses between each treatment condition revealed that patients Off DBS/Off Dopa exhibited decreased acceptance rate (p=0.0127) linked both to effort (p=0.0088) and to reward (p=0.0419). Patients Off DBS/On Dopa also exhibited decreased acceptance rate (p=0.0404) but linked only to effort (p=0.0336). Similarly, patients Off DBS/Off Dopa less often agreed to execute the task than patients under STN-DBS, whether with (p=0.0049) or without levodopa (p=0.0226).

Decision time

The results of the GLMM on decision time revealed a significant main effect of reward value (F(2,24)=6.04, p=0.0024), effort magnitude (F(1,12)=27.05, p<0.0001) and treatment condition (F(4,48)=2.48, p=0.0419, Fig. 2.B) but no significant interaction (all p>0.05). Contrasts between treatment conditions revealed only one significant difference, namely an increase in decision time for the patients Off DBS/On Dopa when compared with the HC group (p=0.0374).

Time to complete

The time taken to complete a trial corresponded to the reciprocal of the average force exerted on the dynamometer. The longer the time, the lower the exerted force. As expected, the GLMM analysis revealed an effect of the effort (F(1,12)=397.75, p<0.0001), but also a significant effect of the treatment condition (F(4,48)=2.51, p=0.0397) and an interaction between effort magnitude and treatment condition (F(4,48)=2.72, p=0.028). Contrast analyses revealed a significant increase in the time to complete each trial for patients under the Off DBS/Off Dopa condition comparatively to HC (p=0.0185), patients under the On DBS/On Dopa (p=0.007) and On DBS/Off Dopa conditions (p=0.0318). For the interaction between treatment condition and effort level, we observed significant differences between the HC group (intercept=7.53; slope=0.146) and patients under the Off DBS/Off Dopa (intercept=7.805; slope=0.113; p=0.01) and Off DBS/On Dopa conditions (intercept=7.703; slope=0.104; p=0.008; Fig. 2.C).

[FIGURE.2]

Discussion

The present study is, to the best of our knowledge, the first to explore the effects of both levodopa and STN-DBS on effort and reward-based decision-making in PD patients. Our data revealed three major findings. First, PD patients Off treatment exhibited a decrease in the acceptance rate and force applied when compared with controls. Second, we observed no difference between HC and patients under STN-DBS. Third, interestingly no significant effect of levodopa was found on acceptance rate alone or combined with STN-DBS.

Consistent with our first hypothesis, the first outcome of the present study is that patients without treatment exhibited a decrease in their acceptance rate and their exerted force compared with HC.

These results represent a significant contribution to our previous study using the same task, but without comparison with HC [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF]. These results are partly in line with the report of decreased acceptance rate for low rewards mentioned in a previous study assessing effort-based decision-making in PD patients without treatment comparatively to HC [START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF]. However, we observed here a decrease in acceptance rate related to rewards and efforts and a decrease in exerted force, which can be interpreted as a general decrease in motivation induced by PD. This reinforces the hypothesis that striatal dysfunction induces a decrease in the motivation to exert an action to obtain a reward. This may indicate that PD modifies the cost-benefit valuation, by decreasing the value of a reward and increasing the cost of an effort. In fact, a part of the scientific literature suggests that the mesolimbic system could be involved in reward valuation (e.g. inducing an aberrant focus on reward-driven activities [START_REF] Stark | Nigrostriatal and Mesolimbic D2/3 Receptor Expression in Parkinson's Disease Patients with Compulsive Reward-Driven Behaviors[END_REF] and contributing deciding to engage in an effortful task for a reward [START_REF] Salamone | The pharmacology of effort-related choice behavior: Dopamine, depression, and individual differences[END_REF]), while the mesocortical system could be involved in effort processing (e.g. contributing to decide how difficult is an action in a specific context [START_REF] Rudebeck | Separate neural pathways process different decision costs[END_REF] and implying in effort learning signal [START_REF] Hauser | Separate mesocortical and mesolimbic pathways encode effort and reward learning signals[END_REF]), both impaired in PD [START_REF] Phillips | Calculating utility: preclinical evidence for cost-benefit analysis by mesolimbic dopamine[END_REF].

Consequently, it is reasonable to propose that the impairment of these two non-motor networks could contribute to the decreased vigor in movements executed by PD patients without treatment.

Then, we tested the hypothesis whether levodopa could improve these impairments of decisionmaking. We observed a normalization (in comparison to HC) of the exerted force, most likely due to motor improvement under levodopa. Surprisingly, no difference was observed between Off and On levodopa conditions on the acceptance rate, invalidating our second hypothesis. On the one hand, some evidence from both human and animal studies suggests that dopamine is involved in decisionmaking processes, and especially on the exertion of an effort to obtain a reward [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF][START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF][START_REF] Beierholm | Dopamine Modulates Reward-Related Vigor[END_REF][START_REF] Treadway | Dopaminergic mechanisms of individual differences in human effort-based decision-making[END_REF]. In this context, the effects of levodopa can be interpreted as a correction of the motivational deficit induced by striatal dysfunction [START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF]. On the other hand, some studies suggest that dopamine only has a partial influence on decision-making, and more precisely that dopamine would have an effect on reward sensitivity but not on other parameters involved in effort-based decision-making processes [START_REF] Bouc | Computational Dissection of Dopamine Motor and Motivational Functions in Humans[END_REF][START_REF] Zénon | Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost[END_REF]. This may support the fact that, in our task, dopamine had a limited effect on effort cost representation, but was involved in the modulation of how much effort a given reward is worth [START_REF] Zénon | Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost[END_REF]. In fact, levodopa partially corrected the deficit by only restoring the acceptance rate based on reward representations (but not on representations of effort) while restoring the motor capacity to produce a normal level effort. Taken together, these results may suggest that levodopa is involved in reward valuation [START_REF] Hauser | Separate mesocortical and mesolimbic pathways encode effort and reward learning signals[END_REF] and restores the capacity to produce an effort to normal levels but patients remain reluctant to exert highlevel efforts. This suggests that levodopa remained insufficient for cost-benefit computation in the present task, indicating that the motivation deficits observed in PD patients cannot be explained only by a lack of dopamine. However, it is still possible that the absence of levodopa effects could be artefactual. More precisely, we can hypothesize that the levodopa dose (150% of each patient's morning dose), as well as the short duration between the levodopa consumption and the participation to our task, were not sufficient to provide full dopaminergic restoration.

Lastly, similar acceptance rates, decision time and exerted force between PD patients under DBS (with and without levodopa) and HC were found. This is in agreement with our third hypothesis, addressing that STN-DBS induces a modification of cost-benefit valuation in PD. Two main interpretations could contribute to explain this outcome. First, we can suggest that STN-DBS induces a deregulation of costbenefit valuation processes in contexts involving a significant cognitive cost, such as a cognitive conflict [START_REF] Frank | Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism[END_REF][START_REF] Zavala | Midline Frontal Cortex Low-Frequency Activity Drives Subthalamic Nucleus Oscillations during Conflict[END_REF] or under speed pressure [START_REF] Pote | Subthalamic nucleus deep brain stimulation induces impulsive action when patients with Parkinson's disease act under speed pressure[END_REF]. A recent study found no effect of STN-DBS in the absence of conflict, time pressure or anticipation [START_REF] Leimbach | Deep Brain Stimulation of the Subthalamic Nucleus Does Not Affect the Decrease of Decision Threshold during the Choice Process When There Is No Conflict, Time Pressure, or Reward[END_REF]. These findings could explain the results variability of the scientific literature according to experimental tasks [START_REF] Graef | Differential Influence of Levodopa on Reward-Based Learning in Parkinson's Disease[END_REF][START_REF] Huang | Different effects of dopaminergic medication on perceptual decision-making in Parkinson's disease as a function of task difficulty and speed-accuracy instructions[END_REF], probably related to different mechanisms and explaining the ongoing controversy about the role of STN-DBS on impulsivity. To some extent, impulsivity should be fragmented: iImpulsivity of action, often measured with precocious responding, is increased after STN-DBS [START_REF] Fluchère | Subthalamic nucleus stimulation, dopaminergic treatment and impulsivity in Parkinson's disease[END_REF]; while impulsivity of choice, assessed using delay-discounting tasks [START_REF] Winstanley | Lesions to the subthalamic nucleus decrease impulsive choice but impair autoshaping in rats: the importance of the basal ganglia in Pavlovian conditioning and impulse control[END_REF], risky and ambiguous choices [START_REF] Brandt | Betting on DBS: Effects of subthalamic nucleus deep brain stimulation on risk taking and decision making in patients with Parkinson's disease[END_REF], or even gambling tasks [START_REF] Adams | Deep-Brain Stimulation of the Subthalamic Nucleus Selectively Decreases Risky Choice in Risk-Preferring Rats[END_REF] can be reduced after STN-DBS. Even though our experimental task can lead to cognitive conflicts [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF], we suggest that the degree of conflict is not sufficient to observe a deregulation of cost-benefit valuation, and that our task is more related to choice impulsivity rather than action impulsivity. Secondly, we can interpret our results as a normalization of decision-making processes under STN-DBS, as previously observed for extreme decision-making disorders like inhibition impairment (for a review: [START_REF] Jahanshahi | Parkinson's Disease, the Subthalamic Nucleus, Inhibition, and Impulsivity[END_REF]), dopamine dysregulation syndrome [START_REF] Eusebio | Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson's disease[END_REF] or more generally for hyperdopaminergic behaviors and neuropsychiatric disorders [START_REF] Lhommee | Subthalamic stimulation in Parkinson's disease: restoring the balance of motivated behaviours[END_REF][START_REF] Lhommée | Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial[END_REF]. An additional argument could be also the fact that STN-DBS is known to improve PD patients with impulsive-compulsive behaviors [START_REF] Eusebio | Subthalamic nucleus stimulation and compulsive use of dopaminergic medication in Parkinson's disease[END_REF][START_REF] Lhommée | Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial[END_REF][START_REF] Rossi | Measures of impulsivity in Parkinson's disease decrease after DBS in the setting of stable dopamine therapy[END_REF][START_REF] Gee | The Influence of Bilateral Subthalamic Nucleus Deep Brain Stimulation on Impulsivity and Prepulse Inhibition in Parkinson's Disease Patients[END_REF]. Regarding potential neural mechanisms, we hypothesize that STN-DBS normalizes the integration of reward value signals from the orbitofrontal cortex [START_REF] Padoa-Schioppa | The orbitofrontal cortex and the computation of subjective value: consolidated concepts and new perspectives: OFC and subjective value[END_REF] and effort inputs from the anterior cingulate, insula and supplementary motor area [START_REF] Croxson | Effort-Based Cost-Benefit Valuation and the Human Brain[END_REF][START_REF] Zénon | Disrupting the Supplementary Motor Area Makes Physical Effort Appear Less Effortful[END_REF].

This would lead to a normalization of cost-benefit valuation [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF] and control of the attribution of a motor effort required for a response [START_REF] Tan | Subthalamic Nucleus Local Field Potential Activity Helps Encode Motor Effort Rather Than Force in Parkinsonism[END_REF]. Nevertheless, STN-DBS is frequently associated with a reduction of levodopa consumption, making it more difficult to conclude about the direct effect of functional neurosurgery. However, one recent study reported a decrease in impulsive behavior in PD patients after STN-DBS or Globus Pallidus internus DBS without any reduction in medication consumption, concluding that the improvement of motivated behaviors is due to the effect of DBS alone or combined with levodopa, but not to the sole reduction in medication consumption [START_REF] Rossi | Measures of impulsivity in Parkinson's disease decrease after DBS in the setting of stable dopamine therapy[END_REF].

With a similar experimental paradigm used previously [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF][START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF] and results somewhat different, our study also questions the possibility of long-term neuroplastic reorganization mechanisms following STN-DBS [START_REF] Van Hartevelt | Neural Plasticity in Human Brain Connectivity: The Effects of Long Term Deep Brain Stimulation of the Subthalamic Nucleus in Parkinson's Disease[END_REF]. This would explain why the effect of levodopa in decision-making is different before and after STN-DBS. Actually, some studies observed a reduced psychostimulant effect of levodopa under STN-DBS, resulting from striatum desensitization due to the reduction of dopaminergic consumption [START_REF] Castrioto | Psychostimulant effect of levodopa: reversing sensitisation is possible[END_REF]. In addition, DBS leads to a decrease in beta band power after 6 and 12 months, independently of electrical stimulation parameters, and this decrease correlates with motor UPDRS improvement [START_REF] Trager | Subthalamic beta oscillations are attenuated after withdrawal of chronic high frequency neurostimulation in Parkinson's disease[END_REF]. These results underlie that long-term STN-DBS induces plasticity in the sensorimotor pathway. Therefore, because of such plasticity, our results may be different from those previously obtained, which considered PD patients without DBS [START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF] or with a short delay after surgery [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF].

Limitations

We acknowledge that several limitations in our study have to be addressed. The use of fictive monetary rewards may be considered a limitation although it has been successfully used in previous similar experiments [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF][START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF][START_REF] Bouc | Computational Dissection of Dopamine Motor and Motivational Functions in Humans[END_REF][START_REF] Rossi | Impulsivity in Parkinson's disease is associated with altered subthalamic but not globus pallidus internus activity[END_REF]. Neuroimaging studies revealed that real and fictive rewards recruit overlapping neural networks [START_REF] Bickel | Congruence of BOLD Response across Intertemporal Choice Conditions: Fictive and Real Money Gains and Losses[END_REF], suggesting that our results could be reasonably extrapolated to a situation involving a real reward. Also, even if a previous study using a comparable task showed that levodopa on motor improvement was not involved in decision-making [START_REF] Chong | Dopamine enhances willingness to exert effort for reward in Parkinson's disease[END_REF], several other studies observed that STN-DBS could induce an improvement of maximal voluntary contraction [START_REF] Vaillancourt | Effects of deep brain stimulation and medication on strength, bradykinesia, and electromyographic patterns of the ankle joint in Parkinson's disease[END_REF], could improve the regulation of force levels [START_REF] Chen | Stimulation of the subthalamic region at 20Hz slows the development of grip force in Parkinson's disease[END_REF] and that STN local field potentials of the STN are modulated in patients who generated different levels of isometric force [START_REF] Florin | Modulation of local field potential power of the subthalamic nucleus during isometric force generation in patients with Parkinson's disease[END_REF]. Thus, it is possible to suggest that our findings may be partly attributable to motor improvement due to levodopa and/or STN-DBS.

Moreover, the relatively small number of participants for the amount of conditions studied as well as the large inter-and intra-variability of the measures constitutes a limitation of this study, although several comparable studies were performed with a similar number of participants [START_REF] Zénon | The human subthalamic nucleus encodes the subjective value of reward and the cost of effort during decision-making[END_REF][START_REF] Leimbach | Deep Brain Stimulation of the Subthalamic Nucleus Does Not Affect the Decrease of Decision Threshold during the Choice Process When There Is No Conflict, Time Pressure, or Reward[END_REF][START_REF] Huang | Different effects of dopaminergic medication on perceptual decision-making in Parkinson's disease as a function of task difficulty and speed-accuracy instructions[END_REF][START_REF] Fischer | Subthalamic nucleus beta and gamma activity is modulated depending on the level of imagined grip force[END_REF]. To partly overcome this situation, we chose to use GLMM, allowing stringent statistical analysis and reinforcing the robustness of our significant results. However, this approach may have lead us to miss some differences between groups. For example, as shown in Fig. 2.B, levodopa significantly increases decision time. Whether this reflects a specific effect of levodopa or rather an uncorrected effect of the disease itself could not be established here. Also, we reported significant differences between PD patients and HC for cognitive (MDRS and semantic fluency) and mood (BDI) assessments. We cannot exclude that these differences could contribute to our results. However, the patients' scores did not reach the threshold of cognitive impairments and depression. Lastly, the delay of 20min after STN-DBS was switched on/off could be insufficient, in so far as some STN-DBS non-motor effects may appear/disappear after a period of several minutes, hours or even days. As STN-DBS effects evolve quickly and resolve slowly, we cannot exclude that the Off STN-DBS condition does not perfectly correspond to an Off state.

Conclusion

Our findings show that PD alters effort-based decision-making processes, and that levodopa did not fully restore these processes. Only high frequency STN-DBS, with or without levodopa, seemed to normalize cost-benefit valuation in our task. We hypothesize that STN-DBS could help restoring the integration of input from cortical territories in relation to reward and effort valuation. Furthermore, our study suggests that some aspects of decision-making disorders like impulsive behaviors may be improved by STN-DBS, contributing to the controversy around DBS-induced impulsivity.

Tables and figures captions

Table

1 .

 1 Clinical data and STN-DBS parameters of the Parkinson's disease patients. Contacts: locations of STN-DBS current delivery on the 4 possible contacts along the electrode (generator case positive, electrode contact negative); Hz: STN-DBS frequency in hertz; F: female; LED: levodopa equivalent dose during the experiment; M: male; µs: STN-DBS pulse width in microseconds; SD: standard deviation; STN-DBS: high frequency subthalamic nucleus deep brain stimulation; V: STN-DBS voltage in volts.

Table 2 .

 2 Demographics and clinical data of the Parkinson's disease patients and healthy controls. -: not available; BDI: Beck Depression Inventory; HAM-A: Hamilton Anxiety Rating Scale; LARS: Lille Apathy Rating Scale; MADRS: Montgomery-Asberg Depression Rating Scale; MDRS: Mattis Dementia Rating Scale; MIDI: Minnesota Impulsive Disorders Interview; PDQ-39: Parkinson's Disease Questionnaire -39; UPDRS: Unified Parkinson's Disease Rating Scale (I: Non-motor aspects of experiences of daily living; II: Motor aspects of experiences of daily living; III: Motor evaluation; IV: Motor complications); p-value: non-parametric Kruskal-Wallis Test.

Figure 1 .

 1 Figure 1. Experimental design of the study.

Figure 2 .

 2 Figure 2. Acceptance rate (least square mean) per treatment (A1), effort required (A2) and reward

Acknowledgements

We are thankful to Patrick Rossi, Laura Mundler, Pr. Jean-Marie Régis and Dr. Romain Carron for their implication during the realization of this study. The authors would like to thank Ms. Mignard for her helpful revision of the English of the article.

Financial disclosure & competing

This study was sponsored by Assistance Publique -Hôpitaux de Marseille and funded by the Agence Nationale de la Recherche (France, ANR-09-MNPS-028-01). C. Atkinson-Clement received a PhD grant funded by the PACA Regional Council and Orthomalin. The authors have no financial involvement with any organization or entity with a financial interest or conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.


domain: info shs

text:
Anaïs Koptient
email: anais.koptient.etu@univ-lille.fr

Natalia Grabar
email: natalia.grabar@univ-lille.fr

Peter Bath

Päivi Jokela

Laura Sbaffi

Fine-grained text simplification in French: steps towards a better grammaticality

Keywords: Automatic Text Simplification, Evaluation, Grammaticality, Medical Texts, Natural Language Processing

The question of easy access to medical and health information by patients has attracted attention of the society and researchers. It has indeed been observed that poor understanding of medical and health information by patients may be harmful for their healthcare process. We assume that simplification and adaptation of technical documents may provide a solution to this situation. While the dedicated guidelines to the simplification summarize different kinds of criteria to consider, actually, it is still difficult to respect all these criteria. Usually, automatic systems for text simplification only address some lexical or syntactic transformations. Besides, little work is done on simplification and adaptation of documents from specialized areas, such as medical and health texts. We propose to combine lexical and syntactic simplification within a rule-based system, and to make the simplification process more fine-grained through additional processing. More particularly, we consider transformation of passive sentences into active sentences, and we control the grammatical concordance within sentences. We work with technical medical documents in French. The results are mainly evaluated according to the three measures specifically dedicated to the simplification: semantics, simplicity and grammaticality.

Introduction

As in any specialized area, the medical area is using specific and technical notions and terms. They are usually not understandable by patients, who have not specific education in medicine. Yet, during the healthcare process, patients are confronted with technical medical documents and information. Usually, patients have some difficulties in understanding such documents. Consider for instance these few examples: information on drug intake [START_REF] Vander Stichele | Promises for a measurement breakthrough[END_REF][START_REF] Patel | Errors in interpreting quantities as procedures : The case of pharmaceutical labels[END_REF], such as understanding of steps necessary to drug preparation and intake; clinical documents [START_REF] Zeng-Treiler | Text characteristics of clinical reports and their implications for the readability of personal health records[END_REF] which contain important information for patients and their healthcare process; clinical brochures and informed consents [START_REF] Williams | Inadequate functional health literacy among patients at two public hospitals[END_REF] created specifically for patients; more globally, information which can be found on health websites also created for patients [START_REF] Rudd | In : Annual Review of Adult Learning and Literacy[END_REF][START_REF] Berland | Health information on the Internet. Accessibility, quality, and readability in English ans Spanish[END_REF][START_REF] Mcgray | Promoting Health Literacy[END_REF][START_REF]Barriers and Drivers of Health Information Technology Use for the Elderly, Chronically Ill, and Underserved. Agency for healthcare research and quality[END_REF][START_REF] Kingsley | The readability of pediatric patient education materials on the World Wide Web[END_REF][START_REF] Brigo | Clearly written, easily comprehended ? The readability of websites providing information on epilepsy[END_REF]. For all these reasons, poor and difficult understanding between patients and medical doctors may be complicated and harmful for the healthcare process [START_REF] Jucks | Choice of words in doctor-patient communication : an analysis of healthrelated internet sites[END_REF][START_REF] Tran | Internet et soins : un tiers invisible dans la relation médecin/patient ?[END_REF]. Hence, the issue related to the easy access to information by patients has gained an important place and attracted attention of researchers and society. Recently, simplification guidelines have been proposed [START_REF] Ruel | Guide de rédaction pour une information accessible[END_REF][START_REF]Guide de style de l'OCDE Troisième édition : Troisième édition[END_REF][START_REF] Unapei | L'information pour tous[END_REF] thanks to the activity of different associations and initiatives. Such guidelines allow us to understand what should be modified when simplifying a text in order to make it more understandable from the point of view of common readers. Hence, simplification can be done at several levels: lexical, semantic, syntactic, pragmatic, and stylistic. As for the automatic text simplification, three types of methods can be exploited: methods based on distributional probabilities with, for instance, word embeddings [START_REF] Glavas | Simplifying Lexical Simplification : Do We Need Simplified Corpora ?[END_REF][START_REF] Kim | SimpleScience : Lexical Simplification of Scientific Terminology[END_REF], methods based on automatic translation [START_REF] Zhao | Leveraging Multiple MT Engines for Paraphrase Generation[END_REF][START_REF] Wubben | Sentence Simplification by Monolingual Machine Translation[END_REF][START_REF] Sennrich | Improving Neural Machine Translation Models with Monolingual Data[END_REF][START_REF] Nisioi | Exploring Neural Text Simplification Models[END_REF], and methods based on rules [START_REF] Carroll | Simplifying Text for Language-Impaired Readers[END_REF][START_REF] Bautista | Feasibility analysis for semi-automatic conversion of text to improve readability[END_REF][START_REF] Belder | Lexical Simplification[END_REF]. Most of those works have been done on English texts. Besides, very few works addressed the simplification of medical texts in French [START_REF] Cardon | Approche lexicale de la simplification automatique de textes médicaux[END_REF]. According to the existing guidelines for the creation of simple or simplified texts [START_REF] Ruel | Guide de rédaction pour une information accessible[END_REF][START_REF]Guide de style de l'OCDE Troisième édition : Troisième édition[END_REF][START_REF] Unapei | L'information pour tous[END_REF], several linguistic phenomena should be taken into account. Among the desiderata, we can find for instance: using short words that are frequent and non-ambiguous, avoiding abbreviations, limiting the variability of the vocabulary used, making sentences that are syntactically simple, avoiding sentences that are in the passive or negative voice, using personal style, explaining difficult concepts, using pictures. Yet nowadays, automatic text simplification is more about lexical phenomena, is especially addressing the use of short and frequent words when replacing difficult words [START_REF] Glavas | Simplifying Lexical Simplification : Do We Need Simplified Corpora ?[END_REF][START_REF] Belder | Lexical Simplification[END_REF][START_REF] Specia | SemEval-2012 Task 1 : English Lexical Simplification[END_REF]. Syntactic phenomena linked to sentence simplicity [START_REF] Chandrasekar | Motivations and methods for text simplification[END_REF][START_REF] Brouwers | Simplification syntaxique de phrases pour le français[END_REF] and the use of the active voice [START_REF] Carroll | Simplifying Text for Language-Impaired Readers[END_REF][START_REF] Chandrasekar | Motivations and methods for text simplification[END_REF] are also taken into account, but less frequently. The purpose of our work is to provide automatic simplification of medical texts in French in order to help human users to understand better such texts, and thus to help them to also understand better their pathology or treatments. We use an existing corpus built with documents from different genres (drug leaflets found on the government website, abstracts from systematic reviews and online encyclopedia articles) for fitting our system and testing it. We use a rule-based method. Thesemethods have shown good precision but low recall [START_REF] Belder | Lexical Simplification[END_REF]. We are especially interested by the capacity of this kind of methods to target and to treat simplification phenomena more precisely. Concerning the recall, we think that it might be improved if the lexical resources used have a better coverage and quality. We first present the method proposed (Section 2). It is rule-based and addresses lexical and syntactic simplification. We then present and discuss the results obtained (Section 3). Finally, we conclude and indicate some issues for future works (Section 4).

Methods

The texts used are first syntactically tagged and parsed by Cordial [START_REF] Laurent | L'analyseur syntaxique Cordial dans Passage[END_REF], because the system uses the syntactic information of the text in order to do the simplification. Then, the simplification is done at lexical and syntactic levels.

Lexical simplification

The detection of difficult words and lexical simplification are done with a dedicated lexicon issued from previous work. Currently, this lexicon contains over 6,000 entries. Each entry is within this format: technical word => simpler equivalent (like for instance, abcès (abscess) => accumulation de pus (collection of pus), tachycardie (tachycardia) => accélération du coeur (heart speeding), erythème (erythema) => rougeur (redness), ACO (OAC) => anticoagulant oral (oral anticoagulant), acétonémie (acetonemia) => taux d'acétone dans le sang (level ofacetone in blood), hémarthrose (hematrosis) => saignements musculo-articulaires (musculo-articular bleedings)). The entries are the technical terms, which are related to non-specialised and easier to understand equivalents, definitions and explanations, or, in case of abbreviations, to their developed forms. This lexicon is also syntactically tagged by Cordial, which provides the morpho-syntactic characteristics for the words of each entry: abcès/NCMIN (abscess/masculine common noun with the same form in singular and plural), concentration localisée de pus/NCFS VPARPFS PREP NCMIN (localized aggregation of pus/singular feminine common noun, past participle singular feminine, preposition, common masculine noun singular or plural) is a noun phrase which syntactic head is a singular feminine noun (concentration). A given entry can have several possible simplifications. For instance, the word hypoxie (hypoxia) has several equivalents: faible oxygénation (low oxygenation), faible teneur en oxygène (low oxygen level), manque d'oxygène dans le sang (deficit in blood oxygen), manque d'oxygène dans les organes (deficit of oxygen in organs), taux d'oxygène bas dans le sang (low oxygen level in blood). For each syntactic phrase delimited by Cordial, we search if it exists in the lexical resource and, if this is the case, the phrase is considered as difficult to understand and is treated during the simplification. If the term is an abbreviation, then its developed form is added between brackets:

• simplified sentence: L'OMS (Organisation mondiale de la santé) recommande un calendrier de vaccination antitétanique durant l'enfance de 5 doses. (WHO (World Health Organization) advises a five-injection calendar for the tetanus vaccine during childhood). In other cases, the simple equivalent is substituted:

• source sentence: Elle peut conduire très rarement à une syncope (It may rarely cause a syncope)

• simplified sentence: Elle peut conduire très rarement à un évanouissement ou sensation d'évanouissement (It may rarely cause a fainting or a faint feeling). When several equivalents are available, the shorter one (which is also considered as the simpler) is chosen, for now. We can also add that in sentences that already contain explanation for a given technical term, this term is therefore not replaced. This is a case of non-simplification context, like in this example, which already explains the meaning of CARE:

• source sentence: L'étude Cholesterol and Recurrent Events (CARE), est un essai randomisé, en double aveugle, contrôlé contre placebo (The study Cholesterol and Recurrent Events (CARE), is a randomized trial, double blinded, controlled against the placebo). Lexical substitutions do not always provide satisfying results, especially concerning the sentence grammaticality. Indeed, if a technical term and its simpler equivalent do not share the same part-ofspeech category or have different gender (acétonémie (acetonemia) which is feminine => taux d'acétone dans le sang (level of blood acetone) which is masculine) or number (hémathrose (hematrosis) which is singular => saignements musculo-articulaires (musculo-articular bleedings) which is plural), then it is necessary to make other modifications within the sentence in order to respect its grammaticality. Thus, when the gender or the number differ within source and simplified phrases, we must concord adjectives, past participles and determiners accordingly:

• source sentence: les essais de génotoxicité se sont révélés négatifs (genotoxicity trials(plural masculine) appear to be negative(plural masculine)) • simplified sentence: les études de génotoxicité se sont révélées négatives (the studies(plural feminine) on genotoxicity appear to be negative(plural feminine))). When the number is different, we also change the conjugation of verbs:

• source sentence: le traitement doit être arrêté progressivement (the treatment must(third person of the singular) be stopped progressively) • simplified sentence: vous devez arrêter le traitement progressivement (you must(second person of the plural) stop the treatment progressively)). When necessary, the style of the sentence becomes more personal, as in the example above. Besides, we can also take into account both regular and irregular forms of adjectives and verbs. Here is one example with irregular adjective form:

• source sentence: Les effets hypotenseurs sont additifs (hypotensive effects(plural masculine) are additive))

• simplified sentence: Les diminutions de la pression artérielle sont additives (the decrease of arterial pressure(plural feminine) is additive).

Syntactic simplification

When the sentences are syntactically complex and contain more than one clause, it is possible, on the one hand, to divide them in order to create simpler sentences, and, on the second hand, to delete information which can be considered as secondary. Here, we are interested in sentence segmentation. Thus, when a sentence includes two clauses, it becomes a candidate for sentence division. Currently, we are using two types of markers to do the division. These markers are related to types of clauses and to discursive markers: Another kind of syntactic modifications is related to the transformation of sentences with passive voice into sentences with active voice. The transformation rules passive to active are also based on syntactic analysis by Cordial. Hence, if the sentence is in passive voice, our system extracts: (1) the verbal phrase in passive voice, and (2) its subject and object. The verb is then transformed into the active verb form, while the syntactic positions of the object and subject are inverted. In some cases, the verb must also be modified in order to become concorded with the new subject. The following example illustrates this situation:



• source sentence: Une prudence particulière devra être observée par les conducteurs d'automobiles et les utilisateurs de machines (A particular attention should be paid by car drivers and vehicle users)

• simplified sentence: Les conducteurs d'automobiles et les utilisateurs de machines devront observer une prudence particulière (Car drivers and vehicle users should be particularly attentive).

Evaluation

In order to evaluate the simplification results, we consider three metrics [START_REF] Wubben | Sentence Simplification by Monolingual Machine Translation[END_REF][START_REF] Biran | Putting it Simply : a Context-Aware Approach to Lexical Simplification[END_REF] specifically dedicated to this task. They are usually evaluated by human users:

 Simplicity.
The simplicity judgment has to define whether the simplification makes indeed the sentences easier to understand. In order to measure it, we provide both the technical and the simplified sentences to human evaluators. In each pair of sentences, the sentence order is random. The evaluators are then instructed to indicate which sentence is the simpler one. If the simpler sentence is detected correctly, then we consider that the simplification is real and provides the expected result (simpler sentences);  Fluency. The fluency judgment has to decide whether the simplified sentence is correct grammatically. In other words: is the simplified sentence fluent and understandable? Indeed, in medical texts, the lexical (word substitution) and syntactic (sentence segmentation, transformation from passive voice to active voice) simplification can disrupt the sentence grammaticality. In order to measure the grammaticality of simplification, the evaluators are instructed to indicate the fluency and understandability of the simplified sentence with a Likert scale going from 1 (not grammatical sentence) to 5 (perfectly grammatical sentence);  Adequacy. The adequacy judgment has to define whether the simplified sentence has the same meaning as the technical sentence. In other words: is the simplified sentence semantically close to the technical source sentence? The evaluators are then instructed to indicate the semantic similarity between the two sentences with a Likert scale going from 1 (sentences with independent semantics) to 5 (semantically identical sentences). The evaluation has been done on ten documents from the CLEAR corpus [START_REF] Grabar | CLEAR -Simple Corpus for Medical French[END_REF]: seven drug leaflets, two systematic review abstracts and one encyclopedia article. These documents have been randomly selected among all the documents that contain the fine-grained simplification cases treated by our method. The ten evaluated documents contain 3,674 sentences and 53,247 word occurrences. These documents have not been used for the development and fitting of the system. One hundred sentences, all containing at least one type of transformation aimed, have been manually evaluated by two evaluators. These evaluators had to provide their judgment on these three measures. The evaluators have no medical training and represent common knowledge of medical notions. As for the evaluation of the intermediate steps of our method (lexical substitution, development of abbreviations, gender, number, verbal and determiner agreement, passive to active transformation), we also compute the precision of the results. Besides, we compute the Spearman correlation [START_REF] Spearman | The proof and measurement of association between two things[END_REF] for fluency and adequacy.

Results of the Simplification

In Table 1, we indicate the total number of transformations that have been done within the ten test documents (column Total number of transformations). In the next column, we indicate the number of transformations contained in the hundred sentences that have been manually evaluated (column Number of evaluated transformations). The column Number of correct transformations indicates the number of transformations that have been considered as correct by the evaluators. Finally, the last column Precision indicates the precision obtained at these steps.

Table 1 Transformations done during the simplification and their evaluation. The adjustment of grammatical concordance shows 0.62 of the overall precision. We can distinguish three types of concords within sentences, which we present, explain and exemplify in what follows:

Transformation types

Total number of transformations

Number of evaluated transformations

Number of correct transformations Precision

Concordance



Cases, in which it is necessary to concord words on gender and number, have low frequency (14 occurrences only) and low precision (0.43) as well. In the following example, we can see that the noun phrase, upon which the verb must be concorded, has a nested structure, which may cause the failure for the automatic system: o simplified sentence: Cependant une surveillance devra être effectuée chez ces patients car certains symptômes(plural masculine) de la baisse du taux de sucre dans le sang peuvent être masquées(plural feminine). (Yet, the surveillance must be done in such patients because some symptoms due to the decrease of sugar level in blood can be hidden.)

In this example, the system fails to compute the correct noun with which the concordance must be done: it decides on putting the past participle masqué (hidden) in plural feminine, while the correct form would be plural masculine related to certains symptômes (some symptoms).



We count 138 cases in which it is necessary to concord the verbal forms with the new subjects. Among the 49 transformations that have been evaluated, 32 are correct, which gives 0.65 precision. In the following example, the negation occurring in the sentence introduces specific syntactic structure and causes the failure of the correct transformation: o simplified sentence: La sertraline n'a provoquer(infinitive verb) l'apparition ni la stimulation ni l'anxiété associées à la d-amphétamine, ni la sédation et l'altération psychomotrice associées à l'alprazolam. (Sertraline did not cause occurrence, or stimulation, or anxiety associated to d-amphetamine neither did it cause sedation or psychomotor alteration associated with alprazolam.) Here, the main verb is in the infinitive form provoquer (cause) instead of the past participle form provoqué (caused).



We count 575 cases in which it is necessary to concord the determiner. Among the 28 transformations that have been evaluated, 22 are correct, which gives 0.79 precision. In the following example, it is necessary to contract the preposition with the determiner that follows, which the system fails to do: o simplified sentence: Dans les cas extrêmes de résistance de les(preposition+determiner) battements cardiaques très lents au traitement, un stimulateur cardiaque pourra être mis en place. (In cases of extreme resistance to treatment of slow heartbeats, cardiac pacemaker may be inserted.) In this example, the de les sequence must be contracted in des. Concerning the two other syntactic transformations:

• The ten documents analyzed contain 103 sentences in the passive voice which have been transformed into sentences with active voice. The 31 sentences that have been evaluated show 0.74 precision. Globally, this type of transformation is performed correctly. Among the errors observed, we can show this example:

• source sentence: Les bêta-bloquants doivent être administrés avec prudence (The beta blockers must be administrated with caution.)

• simplified sentence: Les bêta-bloquants vous devez administrer avec prudence (The beta blockers you should administrate with caution). The error is due to the syntactic structure chosen to make the sentence style personal when addressing the patient. Hence, the style of the sentence could not be respected.

• The evaluation of the 11 segmented sentences shows 0.64 precision. These segmentations are triggered in the following cases: four relative propositions and three coordinated propositions that have been correctly divided, while two discursive markers (aussi [also]), and two subordinate propositions both introduced by comme (as) have been segmented incorrectly. Due to its inherent semantic complexity, we assume that this last case (subordination introduced by comme (as)) should be excluded from the sentence segmentation triggers. As for the lexical substitution, we count 1,153 cases of substitutions and 159 cases of abbreviation developments. First of all, the quality of such transformations depends on the quality of the exploited resource. Their quality is also evaluated according to the three metrics specific to simplification:



Simplicity: among the 100 evaluated sentences, 30 have been judged as badly simplified, which corresponds to 0.70 precision. The errors in the detection of simplified sentences may be due to the fact that simplified sentences become longer (contain more words): lexical substitutions of technical terms by their paraphrases and development of abbreviation make the sentences longer. Hence, in the following example, the source sentence contains 19 words while its simplified version contains 34 words: o source sentence: Cependant une surveillance devra être effectuée chez ces patients car certains symptômes de l'hypoglycémie peuvent être masqués (tachycardie, palpitations). (Yet, the surveillance must be done on such patients because some hypoglycemia symptoms may be hidden (tachycardia, palpitations).) o simplified sentence: Cependant une surveillance devra être effectuée chez ces patients car certains symptômes de la baisse du taux de sucre dans le sang peuvent être masquées (accélération des battements du coeur, battements du coeur gênants). (Yet, the surveillance must be done on such patients because some symptoms related to the decrease of blood sugar level may be hidden (increase of the heart rate, t palpitations).) Since several terms (hypoglycemia, tachycardia, palpitation) are replaced by the equivalent paraphrases, the sentence becomes indeed much longer and, for this reason, it may also become more complicated to parse and to understand.



Fluency: the average index of fluency if between 4.52 and 4.71, according to the evaluators. It is a relatively high value, which shows that globally the fluency is kept. We think that the fine-grained treatment of sentences (grammatical concordance and anaphora resolution) permits to preserve the fluency during the simplification. The Spearman correlation index is 0,2419.

 Adequacy: the average index of adequacy is between 4.52 and 4.83, according to the evaluators. This is also a high value, which shows that the evaluators consider that semantics is preserved during the simplification. We think that this index is mainly dependent on the quality of the resource used for lexical substitutions. Besides, the fact that the evaluators do not have medical training may bias this evaluation measure, as the evaluators present the potential to incorrectly judge the semantics of the evaluated sentences. The Spearman correlation index is 0,4409. These three evaluation measures are not used systematically in the existing works. We can only compare our results with those obtained in one previous work [START_REF] Wubben | Sentence Simplification by Monolingual Machine Translation[END_REF] done with texts in English. Globally, our system shows better scores for adequacy and fluency, which are between 3 and 4 in the cited work. Our simplicity scores are comparable with those from this previous work. As the correlation index between the annotators is quite low, we plan to involve more annotators in the process.

If our method attempts to satisfy different desiderata from the existing simplification guidelines, it also shows that some aspects have to be improved yet. The evaluation proposed mainly indicates that the issues related to the syntactic transformation (sentence division, concordance, transformation from passive voice to active voice) are performed quite well but need still some additional improvements. Another perspective is related to the improvement of adequacy. For instance, abbreviations can be ambiguous and have several possible developments, like AFS, which means Agence Française du Sang (French Blood Agency) but also American Fertility Society. In our resource, 171 abbreviations are affected by ambiguity. We are currently working on context-based disambiguation of abbreviations with supervised methods.

Conclusions

In this paper, we described and evaluated a rule-based method dedicated to the simplification of technical documents from medical domain in French. In its functionalities, the method is inspired by previous research works in simplification, but also by the desiderata expressed in the existing simplification guidelines. Thus, we take into account different lexical and syntactic criteria. This leads to the simplification process performed at two levels and addressing several fine-grained issues (grammatical concordance, transformation passive→active, sentence segmentation, non-simplification contexts). An evaluation done on 100 sentences with specific simplification metrics shows that fluency and adequacy are well respected while the simplicity must be improved. This last issue is mainly related to the cases when lexical substitutions lead to the increase of the sentence size, due to the fact that simpler lexical equivalents are usually longer lexical units (paraphrases, definitions, abbreviation developments). We have several perspectives, such as taking into account other linguistics criteria and aspects and the improvement of simplicity.

  We consider two types of clauses, detected further to the syntactic analysis of Cordial: subordinate clauses and coordinate clauses. For instance, in the following example, the sentence is segmented on the coordination clause and provides two sentences: On the basis of relative markers (qui (who), ce qui (which), celui (the one), celle-là (that one)), we also take into account relative clauses. Indeed, we observed that Cordial cannot detect relative clauses exhaustively. Here is an example of segmentation of sentences with relative clause into two sentences with the recovery of the antecedent of qui (which):osource sentence: Le tramadol peut provoquer chez les nouveau-nés des modifications de la fréquence respiratoire, qui sont généralement sans conséquences cliniques préjudiciables (Tramadol can cause in newborn babies modifications of breathing frequency, which do not have harmful clinical consequences) o simplified sentence: Le tramadol peut provoquer chez les nouveau-nés des modifications de la fréquence respiratoire (Tramadol can cause in newborn babies modifications breathing frequency.). Elles sont généralement sans conséquences cliniques préjudiciables (These have no harmful clinical consequences).  On the basis of discursive markers (cependant (however), aussi (also)...), we take into account other types of syntactically complex sentences, such as in: o source sentence: La ranitidine est éliminée par voie rénale, aussi les taux plasmatiques du médicament augmentent chez les patients présentant une insuffisance rénale (Ranitidine is eliminated by the kidney, also the plasma levels of the medication increase in patients suffering from renal insufficiency). o simplified sentence: La ranitidine est éliminée par voie rénale (Ranitidine is eliminated by kidney). De cette manière, les taux plasmatiques du médicament augmentent chez les patients présentant une insuffisance rénale (In this way, the plasma levels of the medication increase in patients suffering from renal insufficiency).

	o source sentence: L'administration concomitante du chlorhydrate de tamsulosine avec
	la paroxétine a entrainé une augmentation de la Cmax et de l'ASC du chlorhydrate de
	tamsulosine d'unfacteur 1,3 et 1,6 respectivement, mais ces augmentations ne sont
	pas considérées comme étant cliniquement significatives (Concomitant administration
	of tamsulosin hydrochloride with paroxetine leads to the increase of Cmax and
	tamsulosin hydrochloride ASC of respectively 1.3 and 1.6, but this increase is not
	considered to be clinically significative)

o simplified sentence: L'administration concomitante du chlorhydrate de tamsulosine avec la paroxétine a entrainé une augmentation de la Cmax et de l'ASC du chlorhydrate de tamsulosine d'unfacteur 1,3 et 1,6 respectivement (Concomitant administration of tamsulosin hydrochloride with paroxetine leads to the increase of Cmax and tamsulosin hydrochloride ASC of respectively 1.3 and 1.6.). Ces augmentations ne sont pas considérées comme étant cliniquement significatives (This increase is not considered to be clinically significative). 

Proceedings of the 18 th International Symposium on Health Information Management Research

Editors: Peter Bath, Päivi Jokela, Laura Sbaffi

Acknowledgements

This work was funded by the French National Agency for Research (ANR) as part of the CLEAR project (Communication, Literacy, Education, Accessibility, Readability), ANR-17-CE19-0016-01. The authors would like to thank the reviewers for their questions and comments that helped in improving the article.


Alexey N Bilyachenko

Victor N Khrustalev

Yan V Zubavichus

Lidia S Shul'pina

Alena N Kulakova

Xavier Bantreil

Frédéric Lamaty

Mikhail M Levitsky

Evgeniy I Gutsul

Elena V Shubina

Fredeŕic Lamaty

Elena S Shubina

Georgiy B Shul'pin

Heptanuclear Fe 5 Cu 2 -Phenylgermsesquioxane containing 2,2'-Bipyridine: Synthesis, Structure, and Catalytic Activity in Oxidation of C-H Compounds

come

■ INTRODUCTION

The design of metal-based 3D (polycyclic, cagelike) compounds has been the focus of numerous research teams worldwide due to their structural multiplicity and varied potential applications. 1 Among cage metalla complexes, a significant amount of attention has been given to metal-lasilsesquioxanesmetalla derivatives of silicon sesquioxane (RSiO 1,5 ) cage compounds. The major features of these compounds are (i) high flexibility of silsesquioxane ligands, permitting a great number of structures and (ii) a universality of these ligands, readily complexing to a wide range of metal ions. 2 In turn, cagelike metallasesquioxanes based on germanium instead of silicon (metallagermsesquioxanes) are quite rare. A hydrothermal synthetic approach to "hybrid" metallagermsesquioxanes, including metal ions in the composition of both metallagermoxane units M-O-Ge and carboxylic acid salt fragments -COOM, was first reported by Yang and co-workers in 2009. [START_REF] He | Lanthanide Germanate Cluster Organic Frameworks Constructed from {Ln 8 Ge 12 } or {Ln 11 Ge 12 } Cage Cluster Building Blocks[END_REF] Lately, this synthetic procedure has been elaborated in several additional works. 4 An alternative method of synthesis, which allowed isolation of the first example of cage compounds, constructed solely from metallagermoxane units M-O-Ge, has been suggested by some of us in recent work. [START_REF] Bilyachenko | Cage-like Fe,Na-Germsesquioxanes: Structure, Magnetism, and Catalytic Activity[END_REF] This approach, employing the selfassembling reaction of PhGe(OMe) 3 with Na + and Fe 3+ cations, leads to the formation of the unusual three-pointedstar geometry [(Ph 5 Ge 5 O 10 ) 3 Fe 6 (OH) 3 (O)Na 2 ]•2EtOH•H 2 O (1) with an Fe 6 O 19 "Lindqvist ion" central unit, surrounded by three germoxanolate [PhGeO 1.5 ] 5 ligands (Figure 1, left). This particular architecture allows the observation of magnetic interactions of Fe ions as well as high catalytic activity. Here we present the progress of metallagermsesquioxane chemistry the opportunity to synthesize cage germsesquioxane, incorporating different types of transition-metal ions. Along with their fundamental interest, such multimetallic compounds are known to be extremely effective in catalysis. 6 Among these, mixed Fe/ Cu complexes were proved to be active in a wide range of relevant processes, e.g. in Fischer-Tropsch synthesis, 7 the water-gas shift reaction, 8 semihydrogenation of alkynes, 9 CO 2 reduction, 10 C-H borylation, 11 small-molecule activation, [START_REF] Jayarathne | Small molecule activation chemistry of Cu-Fe heterobimetallic complexes toward CS 2 and N 2 O[END_REF] and carbon-carbon and carbon-heteroatom coupling reactions. [START_REF] Panda | Cu/Fe-Catalyzed Carbon-Carbon and Carbon-Heteroatom Cross-Coupling Reactions[END_REF] Keeping in mind the prominent metallic character of germanium itself, one could expect a high catalytic activity of Cu/Fe/Ge complexes. In accord with this, we were interested in the synthesis of mixed Fe/Cu germsesquioxanes and the application of such products in catalysis. Here we present the first example of the Fe(III)/Cu(II) phenylgermsesquioxane 2 (Figure 1, right) and the study of this compound catalytic activity.

■ EXPERIMENTAL SECTION Materials. Phenyltrimethoxygermane (ABCR) and other chemicals (Sigma-Aldrich) were used without further purification. Methanol was distilled prior to use following a trivial procedure.

The Fe,Na-phenylgermsesquioxane [(Ph 5 Ge 5 O 10 ) 3 Fe 6 (OH) 3 (O)-Na 2 ]•2EtOH•H 2 O (1) was synthesized as described in ref 5.

Synthesis of Complex 2. Method A. To a methanol/toluene (50 mL/15 mL, placed in a round-bottom flask) solution were added compound 1 (0.300 g, 0.09 mmol) and, after total dissolution of 1, copper(II) chloride (0.012 g, 0.09 mmol). The mixture was rigorously stirred for 3 h. Then 2,2′-bipyridine (0.014 g, 0.09 mmol) was added at once to the solution and the resulting mixture was stirred overnight. Filtration of the mixture from the insoluble part gave a clear solution, suitable for crystallization. Slow evaporation of the solvents over 2 weeks gave a crystalline material. Several crystals were used for the single-crystal X-ray diffraction analysis (see below for details). Anal. Calcd for {[Fe 5 O 17 (OH)]Cu 2 (bipy) 2 (PhGeO) 12 (PhGe) 2 O}: Ge, 30.70; Fe, 8.43; Cu, 3.84; N, 1.69. Found (for vacuum-dried sample): Ge, 30.53; Fe, 8.32; Cu, 3.76; N, 1.60. Yield: 0.013 g (9%).

Method B. PhGe(OMe) 3 (2.00 g, 8.2 mmol) was dissolved in 50 mL of methanol. Then 0.44 g (11.1 mmol) of NaOH was added, and the resulting mixture was heated to reflux for 2 h. Afterward the solution was cooled to room temperature, and 0.48 g (3.00 mmol) of FeCl 3 and 0.16 g (1.17 mmol) of CuCl 2 were added at once. The solution was stirred for 3 h, and then 0.18 g (1.17 mol) of bipy was added at once to the solution and the resulting mixture was stirred overnight. Filtration of the mixture from the insoluble part gave a clear solution, suitable for crystallization. Slow evaporation of solvents over 2 weeks gave a crystalline material. Several crystals were used for the single-crystal X-ray diffraction analysis (cell parameters were found to be equal to those of the product of method A). Anal. Calcd for {[Fe 5 O 17 (OH)]Cu 2 (bipy) 2 (PhGeO) 12 (PhGe) 2 O}: Ge, 30.70; Fe, 8.43; Cu, 3.84; N, 1.69. Found (for vacuum-dried sample): Ge, 30.59; Fe, 8.34; Cu, 3.79; N, 1.61. Yield: 0.40 g (21%).

Elemental analysis was carried out with an XRF VRA-30 spectrometer.

IR spectra were recorded on Shimadzu IR Prestige21 FTIR spectrometer in KBr pellets.

UV-vis absorption spectra were recorded on a Varian Cary 50 spectrophotometer in cells with 5 and 10 mm optical path lengths.

X-ray Study. X-ray diffraction data were collected on the "Belok" beamline (λ = 0.96990 Å) of the National Research Center "Kurchatov Institute" (Moscow, Russian Federation) using a Rayonix SX165 CCD detector. A total of 720 images were collected using an oscillation range of 1.0°and φ scan mode and corrected for absorption using the Scala program. [START_REF] Evans | Scaling and assessment of data quality[END_REF] The data were indexed, integrated, and scaled using the utility iMOSFLM in the CCP4 program. [START_REF] Battye | iMOSFLM: a new graphical interface for diffractionimage processing with[END_REF] For details, see Table S1 in the Supporting Information. The structure was determined by direct methods and refined by full-matrix least-squares techniques on F 2 with anisotropic displacement parameters for non-hydrogen atoms. Six of the twelve phenyl substituents were found to be disordered over two sites with occupancies of 0.50:0.50 or 075:0.25. The crystal of 2 contains very large solvent-accessible voids; however, all attempts to model and refine positions of the solvate molecules were unsuccessful. Therefore, their contribution to the total scattering pattern was removed by use of the utility SQUEEZE in PLATON06. [START_REF] Spek | A Multipurpose Crystallographic Tool[END_REF] The hydrogen atom of the OH group was localized in the difference Fourier map and included in the refinement within the riding model with fixed isotropic displacement parameters (U iso (H) = 1.5U eq (O)). The other hydrogen atoms were placed in calculated positions and refined within riding model with fixed isotropic displacement parameters (U iso (H) = 1.2U eq (C)). All calculations were carried out using the SHELXTL program. [START_REF] Sheldrick | Crystal structure refinement with SHELXL[END_REF] Oxidation of Alkanes and Alcohols. The reactions of alcohols and hydrocarbons were carried out in air in thermostated Pyrex cylindrical vessels with vigorous stirring and using MeCN as solvent. Typically, catalyst 2 and the cocatalyst (acid) were introduced into the reaction mixture in the form of stock solutions in acetonitrile. The substrate (alcohol or hydrocarbon) was then added, and the reaction started when hydrogen peroxide or TBHP was introduced in one portion. (Caution! The combination of air or molecular oxygen and H 2 O 2 with organic compounds at elevated temperatures may be explosive.) In order to determine concentrations of all cyclohexane oxidation products the samples of reaction solutions after addition of nitromethane as a standard compound were in some cases analyzed twice (before and after their treatment with PPh 3 ) by GC (LKhM-80-6 instrument, columns 2 m with 5% Carbowax 1500 on 0.25-0.315 mm Inerton AW-HMDS; carrier gas argon) to measure concentrations of cyclohexanol and cyclohexanone. This method (an excess of solid triphenylphosphine was added to the samples 10-15 min before the GC analysis) was proposed by Shul'pin earlier. 18 Attribution of peaks was made by comparison with chromatograms of authentic samples. Blank experiments with cyclohexane showed that in the absence of catalyst 2 no products were formed.

General Procedure for Amidation. In a sealed tube were added successively amine hydrochloride (0.5 mmol), CaCO 3 (50.1 mg, 0.5 mmol), anhydrous CH 3 CN (1 mL), 2 (0.9 mg, 0.29 μmol), benzylic alcohol (104 μL, 1.0 mmol), and TBHP (5.5 M in nonane, 225 μL, 1.25 mmol). The mixture was stirred at 80 °C for 2 h, and TBHP (5.5 M in nonane, 225 μL, 1.25 mmol) was again added to the mixture. After 22 h at 80 °C, the mixture was cooled to room temperature and 1 N HCl and AcOEt were added. The mixture was extracted twice with AcOEt, and the combined organic phases were washed with a saturated solution of NaHCO 3 and brine and concentrated under reduced pressure. To remove the excess of benzylic alcohol, 80 mL of H 2 O was added to the organic phase and evaporated under reduced pressure. The crude product was then solubilized in AcOEt, dried over MgSO 4 , and concentrated under vacuum. The crude product was purified by silica gel chromatography using gradients of cyclohexane/ AcOEt to yield the pure compounds.

■ RESULTS AND DISCUSSION

The transmetalation reaction of [(Ph 5 Ge 5 O 10 ) 3 Fe 6 (OH) 3 (O)-Na 2 ]•2EtOH•H 2 O (1) with CuCl 2 was performed so to substitute sodium ions of 1 by copper atoms with the expected formation of the first example of a cage metallagermsesquioxane containing ions of two different transition metals. The crystallization of the product was found to be a difficult task, most likely due to its good solubility and/or the time required for the process of cage assembly. A change in crystallization systems gave no result, while the use of additional N ligation (from 2,2′-bipyridine) allows isolation in a yield of 9% the crystalline product 2heptanuclear Fe 5 Cu 2 -phenylgermsesquioxane with 2,2′-bipyridines coordinating copper centers (Scheme 1, method A).

Compound 2 (Figure 2, top), despite inheriting at first sight the structural features of initial complex 1, presents deep changes in molecular organization. Indeed, the central core of Lindqvist ion type (Fe 6 O 19 ) in 1 (Figure 2, bottom left) underwent a FeO elimination, forming an Fe 5 -based cage of Fe 5 O 18 composition, with consequent back-filling of the vacant position by the (PhGe) 2 O group. Such specific "degradation and replacement" allowed two copper(II) ions to occupy left and right bottom coordination sites at this core with simultaneous formation of the earlier unknown mixed oxa cluster of composition Cu 2 Fe 5 Ge 2 O 19 (Figure 2, bottom right).

Quite logically, the shift in metal content/location causes changes in composition/structure of germsesquioxane ligands. In comparison to 1, containing three ligand of the same type, a cisoid pentameric cycle (PhGeO 1.5 ) 5 (Figure 3, left), the newly synthesized product 2 includes two different germsesquioxane fragments. Namely, these are (i) the digermoxane bridge Ph 2 Ge 2 O 5 , linking copper(II) ions, and (ii) dodecameric [PhGeO 2 ] 12 cycle, embracing iron(III) centers (Figure 3, right). This is the first observation of such germsesquioxane ligands for all earlier described types of metallagermsesquioxanes. [START_REF] He | Lanthanide Germanate Cluster Organic Frameworks Constructed from {Ln 8 Ge 12 } or {Ln 11 Ge 12 } Cage Cluster Building Blocks[END_REF][4][START_REF] Bilyachenko | Cage-like Fe,Na-Germsesquioxanes: Structure, Magnetism, and Catalytic Activity[END_REF] Our further investigations showed that the yield of this fascinating compound 2 could be increased using a selfassembling reaction (Scheme 1, method B). This synthetic regime allows consideration of the desired atomic ratio for the reaction (Ge 14 :Cu 2 :Fe 5 :N 4 ). These precise loadings of reactants favor the formation of target compound 2 (in case of method A the reactant atomic ratio is limited by a certain composition of compound 1). Finally, this method leads to the isolation of product 2 in higher yield (21%). For both synthetic routes (methods A and B) an exclusive interaction of bipyridine ligands with copper centers occurs while iron centers prefer to arrange in an Fe 5 Ge 2 O 19 core, indicating its high stability.

We have found that complex 2 is an excellent catalyst in alkane oxidation with hydrogen peroxide at low temperature (40-50 °C). An example of cyclohexane oxidation is shown in Figure 4. The yield of products is negligible if HNO 3 is not added to the reaction solution. The acid possibly breaks some bonds between germanium atoms and ions of copper and/or iron. This opens the approach of catalytically active species to the substrate.

To get an insight into the nature of oxidizing species, we measured the selectivity of C(1), C(2), C(3), and C(4) parameters in oxidations of linear (n-heptane) and branched cyclic saturated (methylcyclohexane) hydrocarbons with H 2 O 2 . The regioselectivity parameters (relative normalized reactivities of hydrogen atoms at carbon atoms C(1), C(2), C(3), and C(4) of the n-heptane chain) determined for the oxidation of nheptane are summarized in Table 1. The values of these parameters are close to these determined by us previously for the oxidations by the systems which operate with the formation of hydroxyl radicals. [START_REF] Shul'pin | ≪Oxidations by the reagent ″O 2 -H 2 O 2 -vanadium derivative-pyrazine-2-carboxylic acid″ Part 12. Main features, kinetics and mechanism of alkane hydro-peroxidation≫[END_REF] The bond-selectivity parameter (1°:2°:3°; the relative normalized reactivities of hydrogen atoms at the primary, secondary, and tertiary carbons) in the 2 andFigure 5) is close to the corresponding values found for the systems oxidizing alkanes with hydroxyl radicals (see, for example, ref 19). The oxygenation of methylcyclohexane (MCH) with H 2 O 2 proceeds mainly at the tertiary carbon atom with formation of 1-methylcyclohexanol after reduction with PPh 3 (product P5). The GC profile of the products obtained in the oxidation catalyzed by 2 is similar to the profiles reported previously for some other systems which oxidize with the participation of hydroxyl radicals. All these data testify that an oxidizing species generated by the system exhibits a low selectivity typical for hydroxyl radicals.

Complex 2 catalyzes efficient oxidation of alcohols with t-BuOOH. Thus, 1-phenylethanol is transformed into acetophe-none in a yield of about 100% after 5 h at 50 °C in the presence of 0.05 M HNO 3 . Cyclohexanol was oxidized to cyclohexanone in 60% yield after 2 h at 50 °C. Hydrogen peroxide oxidizes cyclohexanol and 2-heptanol in 40 and 43% yields, respectively, at 50 °C in the presence of HNO 3 .

Seeing the good results of complex 2 in the oxidation of alkanes and alcohols, we decided to evaluate it in the oxidative amidation of alcohols (Scheme 2). This reaction was already reported with copper, [START_REF] Bantreil | Copper-Catalyzed Direct Synthesis of Benzamides from Alcohols and Amines[END_REF] iron, 21 and zinc salts, [START_REF] Wu | The First ZnII-Catalyzed Oxidative Amidation of Benzyl Alcohols with Amines under Solvent-Free Conditions[END_REF] and we demonstrated that copper and iron silsesquioxanes as well as iron germanoxane complexes could be used efficiently with catalyst loadings down to 100 ppm of copper and 500 ppm of iron. [START_REF] Bilyachenko | Cage-like Fe,Na-Germsesquioxanes: Structure, Magnetism, and Catalytic Activity[END_REF]23 Since complex 2 features both copper and iron centers, it seemed reasonable to estimate its catalytic activity in the oxidative amidation. Several amines, used as ammonium salts, were reacted with benzylic alcohol in the presence of catalytic quantities of 2. Calcium carbonate, with a high purity of 99.995% to avoid any metallic contamination, and TBHP, which acts as a terminal oxidant, were also added to the reaction mixture. After a quick optimization, it was found that a catalyst loading of 0.4 mol % of complex 2 was found to be the lower limit to obtain reasonable results in terms of yield and efficiency. The difference in activity in comparison to copper and iron silsesquioxanes might result from the germsesquioxane network in catalyst 2. Using 2 as catalyst, secondary amide 3 was isolated in an excellent yield of 93%. The use of cyclohexylamine and n-butylamine resulted in pure amides 4 and 5 in 84-85% yields. The use of secondary amines was also found to be efficient, and amides 6 and 7 could be isolated in 82% and 71% yields, respectively. Moreover, turnover number (TON) and turnover frequency (TOF) values up to 232 and 9.7 h -1 could be obtained, respectively, proving the good efficiency of germsesquioxane compound 2.

■ CONCLUSIONS

A new representative of the rare family of metallagermsesquioxanes has been proved to be available through both self-assembly (from PhGe[OMe] 3 ) and transmetalation (of sodium-containing Fe-germsesquioxane) approaches, assisted by the use of 2,2′-bipyridine. These reaction procedures allowed us to isolate the first example of Fe(III)/Cu(II)-phenylgermsesquioxane. Its specific cagelike architecture involves an unusual derivative of a Lindqvist ion (Fe 5 O 18 ), which is capable of incorporating copper ions, giving in sum a mixed-metal oxa cluster of composition Cu 2 Fe 5 Ge 2 O 19 . This metalla-based fragment is stabilized by O ligation from two types of germanium-based fragments (cyclic Ph 12 Ge 12 O 24 and acyclic Ph 2 Ge 2 O 5 ) as well as by N ligation from 2,2′-bipyridines. The presence of three types of metallic centers in 2 (Cu, Fe, Ge) and its good solubility allowed us to observe high catalytic activity in the homogeneous oxidation of alkanes and alcohols as well as in the formation of amides from alcohols. At the moment, it is not possible to conclude if metallagermsesquioxanes are more active precatalysts in comparison to their sister compounds metallasilsesquioxanes due to the presence of metalloid germanium centers. Despite many examples of Cu- 23a,24 or Fe-based 23b,c cage silsesquioxanes, tested in catalysis, the pure (Cu/Fe-based) analogue of compound 2 is still unknown in the chemistry of silsesquioxanes. According to the available information, it could be said that the catalytic activities of metallasilsesquioxanes and metallagermsesquioxanes are comparable. Synthesis of other mixed-metal germsesquioxanes and investigation of their catalytic properties are still intriguing tasks, and corresponding experiments by our team are in progress.

■ ASSOCIATED CONTENT * S Supporting Information

The Supporting Information is available free of charge on the ACS Publications Web site at DOI: The following files are available free of charge: X-ray crystallographic information (CIF) The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/ acs.inorgchem.7b02881.

Crystallographic data, general information for the amidation reactions, and NMR, IR and UV spectra (PDF)

Notes

The authors declare no competing financial interest.

■ ACKNOWLEDGMENTS

This work has been supported by the RUDN University Program "5-100", the Russian Foundation for Basic Research (Grant Nos. 16-03-00609, 16-03-00254, 16-53-150008, 16-29-05180), the French Embassy in Moscow, and the University of Montpellier, CNRS (Programme de Recherche Conjoint). Synchrotron single-crystal diffraction measurements were performed at the unique scientific facility Kurchatov Synchrotron Radiation Source supported by the Ministry of Education and Science of the Russian Federation (project code RFMEFI61917X0007).

■ REFERENCES

Figure 1 .

 1 Figure 1. Simplified view of (left) Fe,Na-phenylgermsesquioxane 1 5 and (right) Fe,Cu-phenylgermsesquioxane 2 (bipy ligands are omitted for clarity). Color code: Ge, gray; O, red; Fe, lilac; Cu, green.

Scheme 1 .

 1 Scheme 1. Synthetic Pathways to Heptanuclear Fe 5 Cu 2 -Phenylgermsesquioxane with 2,2′-Bipyridines 2

Figure 2 .

 2 Figure 2. (top) Molecular structure of 2. (bottom) Simplified view of central metal oxo cores in compounds 1 (left) and 2 (right).

Figure 3 .

 3 Figure 3. Simplified view of germanium-based ligands of compounds 1 (left) and 2 (right). Color code: Ge, gray; O, red.

Figure 4 .

 4 Figure 4. (A) Accumulation of cyclohexanol and cyclohexanone in the oxidation of cyclohexane (0.46 M) with hydrogen peroxide (2 M; 50%) catalyzed by complex 2 (5 × 10 -4 M) in the presence of HNO 3 (0.05 M) in acetonitrile at 40 °C before reduction with PPh 3 . (B) As in (A) after reduction with PPh 3 . The yield of the product was 28%; TON = 260.

a

  Accumulation of isomers of heptanol (isomeric heptanones are formed in low concentrations after reduction of the reaction mixtures with PPh 3 ) in the oxidation of n-heptane (0.5 M) with hydrogen peroxide (2 M; 50%) catalyzed by complex 2 (5 × 10 -4 M) and nitric acid (0.05 M) in acetonitrile at 50 °C.

Figure 5 .

 5 Figure 5. Products of the methylcyclohexane oxidation with H 2 O 2 catalyzed by complex 2. Scheme 2. Oxidative Amidation at Low Catalyst Loading a

Table 1 .

 1 Oxidation of n-Heptane Catalyzed by Complex 2 a

Table 2

 2

	. Oxidation of Methylcyclohexane with H 2 O 2 (50% Aqueous) Catalyzed by Complex 2 (5 × 10 -4 M) in the Presence of HNO 3 (0.05 M) in MeCN at 40 °Ca
	entry	time (min)	P1	P2	P3	P4	P5	P6	P7	P8	P9	P10	P11	P12	yield (%)
	1	20	0.0	4	4	2	20	11	20	14	7	20	9	4	32
	2	60	0.0	9	9	4	20	8	16	12	6	19	9	4	35
	3	120	0.4	7	5	2	22	7	14	11	5	16	8	3	24
	4	120 b	1	1 2	1 2	5	9	1	4	4	2	9	5	1	1 8
	5	180	0.0	7	5	2	18	6	11	9	4	13	6	2	23

a Concentrations of isomeric ketones and alcohols are given in mM. b Concentrations were measured before reduction with PPh 3 .

  Accession CodesCCDC 1572284 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_ request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

	■ AUTHOR INFORMATION Corresponding Authors
	ORCID
	Alexey N. Bilyachenko: 0000-0003-3136-3675
	Victor N. Khrustalev: 0000-0001-8806-2975
	Xavier Bantreil: 0000-0002-2676-6851
	Elena S. Shubina: 0000-0001-8057-3703

*E-mail for A.B.N.: bilyachenko@ineos.ac.ru. *E-mail for F.L.: frederic.lamaty@umontpellier.fr. *E-mail for G.B.S.: shulpin@chph.ras.ru.

DOI: 10.1021/acs.inorgchem.7b02881 Inorg. Chem. 2018, 57, 528-534