Shijun Zhao

Yongfeng Zhang

Luca Messina

Christian Brandl

Editorial: Computational Defect Properties

A century of studies has demonstrated that many properties of materials are controlled predominantly by defects or faults in the crystal structures. Indeed, defects are major carriers that mediate atomic and mass transport and influence the structural stability and performance of materials. Line defects such as dislocations are central to the mechanical properties of materials and crystal growth. Dopant defects are decisive ingredients in the modern silicon-based semiconductor industry. Solid-state lasers, battery technologies, and solid oxide fuel cells all rely on the characteristics of impurities and/or defects. Therefore, the knowledge of defect properties is of vital importance for understanding materials performance and further for rational materials design. Thanks to the development of advanced experimental characterization techniques and computer simulation methodologies, the field of defects has witnessed massive development in recent years. In this hand-in-hand progress, simulations have been an indispensable tool to gain insight into the process invisible to experiment equipment. This is exactly the purpose of this Research Topic, where we focus on the latest development in computational defect properties based on state-of-the-art theoretical approaches.

The topics touched upon in this collection involve basic defect energetics, defect-induced strain, defect diffusion, the surface and size effects on defect properties, and radiation-induced segregation. It spans over a wide range of materials, including structural materials such as W and Ni-based alloys, nuclear fuels, and novel high entropy alloys. Besides, various computational techniques are introduced, ranging from electronic-level density functional theory calculations, atomic-level molecular dynamics to the continuum-level rate theory models. Notably, the combination of these methods with machine learning techniques is successfully demonstrated.

First, the work of Benjamin Beeler et al. represented a thorough evaluation of the defects in α phase of Uranium, the fundamental source of nuclear fuel, based on ab initio molecular dynamics (AIMD) at finite temperatures. The α phase with face-centered orthorhombic structure is the favorable form of U below 935 K. The calculated temperature-dependent thermophysical properties, including lattice parameters, thermal expansion, and heat capacity, exhibit a transition, with rapid changes below 400 K, followed by a moderate change. Temperaturedependent point defect formation energies and induced lattice strains were also determined to shed light on the experimentally observed irradiation-induced growth. It was found that interstitials cause significantly higher strain than vacancies, and that strain is strongly dependent on lattice directions, where the a direction expands and the b contracts. The direction of point defect-induced lattice strain is contrary to the irradiation growth behavior of α-U. These results lay the foundation for mesoscale simulations for α-U in which defect populations, defect diffusion, and defect strain behaviors come into play together.

Another work by Anus Manzoor et al. reported the application of machine learning in predicting the point defect energies in multi-principal element alloys (MPEAs), including high-entropy alloys (HEAs). In MPEAs, defect energies are highly dependent on the local atomic environments due to the chemical disorder. This work showed that machine learning built upon a database of constituent binary alloys can be used to predict vacancy migration and formation energies in face-centered cubic ternary, quaternary, and quinary alloys in the Ni-Fe-Cr-Co-Cu system. Such machine learning methodology may enable rapid assessment of defect energies in MPEAs, which is extremely helpful to understand and tune their irradiation performance.

The contribution of Bochuan Sun et al. focused on the effect of strain on the diffusion of both near-surface selfinterstitials (SIAs) and adatoms in tungsten (W), the most promising candidate material for the plasma-facing components and divertor in fusion reactors. Based on molecular dynamics, the authors investigated the average time required for an SIA in the center of a tungsten slab to a (110) surface at different strains and temperatures. The results suggested that strain significantly modifies the propensity for SIAs to reach the surface, and the fraction of them that forms dislocation loops in the bulk crystal. Adatom diffusion is also strongly affected by strain, resulting in strain-dependent surface roughness evolution.

Shenyang Hu et al. presented a microstructure-dependent rate theory model for radiation-induced segregation (RIS) in binary alloys, in which the effects of inhomogeneous thermodynamic and kinetics properties of defects were explicitly considered. Using four independent variables to describe the system, including atom A, interstitial A, interstitial B, and vacancy on [A, B] sublattice, the spatial characteristics of defect generation and diffusion were accounted for. The developed model reveals the effects of defect chemical potentials and mobilities on RIS in polycrystalline AB model alloys.

The work of Abdurrahman Ozturk et al. focused on the surface and grain size effects on the transient and steadystate behaviors of point defects in irradiated pure Ni and binary Ni-Cr based on a spatially resolved rate-theory modeling approach. In this model, the influences of dose rate, production bias, defects recombination, reactions with volumetric sinks, and diffusion to surface sinks are examined. It is found that surface and size always exert effects on defect behavior in the presence of production bias. The author showed that this is related to a surfaceinduced and size-regulated instability triggered above a critical size between 100 and 500 nm, which favors the separation of vacancies and interstitials. Such patterns induce anomalies in the dependence of defect concentrations and sink strength on grain size, leading to more severe radiation damage. In alloys, the magnitude and range of elemental enrichment/depletion at the boundaries increase with size.

Finally, Daniel Vizoso et al. reported molecular dynamics simulations on the dependence of vacancy formation energies in γ U-Zr alloys at 0 K on the first nearest neighbor configurations with varying Zr concentrations. Comparisons between random populated systems with special quasi-random structures show that there is only a slight change in statistically averaged vacancy formation energies, indicating the dominant role of local atomic environments on vacancy properties. Therefore, adequate sampling of the local configurations is the key to get a full understanding of defect properties in alloys.

We hope this Research Topic will attract readers working in the field of defects and stimulate novel research ideas.

Keywords: defect properties, computational method, computational materials sciences, nuclear materials, radiation damage


Mathilde Boussac
email: mathilde.boussac@inserm.fr.

Pr Christophe Arbus

Helene Klinger

Alexandre Eusebio

Elodie Hainque

Jean-Christophe Christophe Corvol

Olivier Rascol

Vanessa Rousseau

Estelle Harroch

Charlotte Scotto D'apollonia

Aurélie Croiset

Fabienne Ory-Magne

Amaury De Barros

Margherita Fabbri

Dr Caroline Moreau

Anne-Sophie Rolland

Isabelle Benatru

Mathieu Anheim

Dr Ana-Raquel Marques

David Maltête

Sophie Drapier

Béchir Jarraya

Cécile Hubsch

Dominique Guehl

Mylène Meyer

Pr Tiphaine Rouaud

Bruno Giordana

Mélissa Tir

David Devos

Christine Brefel-Courbon

Sophie Rolland

Alain Duhamel

Maeva Kheng

Julien Labreuch

Dominique Deplanque

Edouard Millois

Mr Nolwen Dautrevaux

Victor Laugeais

Maxime Cail- Lier

Aymen Aouni

Pauline Guyon

Francine Niset

Valérie Santraine

Mrs Marie Pleuvret

Julie Moutarde

Laetitia Thibault

Pr Luc Defebvre

Dr Nicolas Carriere

Dr Guillaume Grolez

Dr Guil- Laume Baille

Dr Kreisler

Pr Jean-Pierre Pruvo

Dr Pr Leclerc

Dr Renaud Lopes

Dr Romain Viard

Mr Gregory Kuchcinski

Pr Julien Dumont

Kathy Dujardin

Mme M Delliaux

Dr Mrs M Brion

Pr Gus- Tavo Touzet

Pr Nicolas Reyns

Mrs Arnaud Delval

Mrs Valerie Santraine

Thavarak Ouk

Camille Potey

Celine Leclercq

Marie- Laure Welter

Lucette Lacomblez

David Grabli

Emmanuel Roze

Yulia Worbe

Cécile Delorme

Hana You

Jonas Ihle

Raquel Guimeraes-Costa

Florence Cormier-Dequaire

Andréas Aurélie Méneret

Louise-Laure Mariani

Stéphane Lehericy

Virginie Czernecki

Fanny Pineau

Frédérique Bozon

Camille Huiban

Eve Benchetrit

Carine Karachi

Soledad Navarro

Philippe Cornu

Arlette Welaratne

Carole Dongmo-Kenfack

Lise Mantisi

Nathalie Jarry

Sophie Aix

Carine Lefort

Pr Philippe Damier

Dr Pascal Derkinderen

Dr Anne-Gaelle Corbille

Mrs Elisabeth Calvier-Auffray

Mrs Laetitia Rocher

Dr Anne-Laure Deruet

Dr Raoul Sylvie

Roualdes Vincent

Mrs Le Dily

Dr Beran- Gere Debilly

Pr Franck Durif

Dr Philippe Derost

Dr Charlotte Beal

Carine Chassain

Laure Delaby

Pr Tiphaine Vidal

Jean Jacques Lemaire

Isabelle Rieu

Elodie Durand

Alexandre Pr

Pr Jean- Philippe Eusebio

Dr Tatiana Azulay

Dr Frédérique Witjas

Dr Stephan Fluchère

Pr Nadine Grimaldi

Eve Girard

Marie Benchetrit

Dr Romain Delfini

Pr Jean Carron

Dr Giorgio Regis

Camille Spatola

Mag- Naudet

Dr Marseille Hm

Dr Ansquer Solène

Dr Benatru Isabelle

Pr Colin Olivier

Pr Houeto Jl

Guillevin Remy

Mrs Fradet

Mrs Anziza Manssouri

Dr Blondeau Sophie

Dr Richard Philippe

Dr Cam Philippe

Pr Page Philippe

Bataille Benoit

Mrs Rabois

Mrs Guille

Dr Drapier Sophie

Dr Frédérique Leh

Pr Alexandre 677 Bonnet

Dr Marc Vérin

Jean-Christophe Ferré

Mr Jean Franc

Pr Claire Houvenaghel

Mrs Francoise Haege- 679 Len

Mrs Kestens

Solenn Ory

Dr Nathalie Damon-Perriere

Pr Wassilios Meiss- 682 Ner

Pr Francois Tison

Dr Stéphanie Bannier

Pr Elsa Krim

Sandrine Molinier- 684 Blossier

Morgan Ollivier

Marion Lacoste

Marie Auzou

Pr Emmanuel Bonnet

Dr Julien Cuny

Olivier Branchard

Clotilde Huet

Julie Blanchard

Rascol Pr

Dr Christine Brefel Olivier

Dr Courbon

Dr Fabienne Ory Magne

Marion Simonetta Moreau

Dr Fabrice Bonneville

Albert Lotterie

Marion Sarrail

Pr Charlotte Scotto 692 D'apollonia

Pr Franc ¸ois Patrick Chaynes

Caire

Dr David Maltete

Romain Lefaucheur

Dr Damien Fetter

Dr Nicolas Magne

Mrs Mrs San- 696 Drine Bioux

Maud Loubeyre

Mrs Evangéline

Mrs Dorothée Bliaux

Pr Stéphane Pouliquen

Mrs Linda Der- 698 Rey

Dr Frédéric Vernon

Ziegler

Ouhaid Lagha-Boukbiza

Christine Tranchant

Odile

Solveig Gebus

S Montaut

Nadine Kremer

Clélie Phillips

Jimmy Voirin

Marie Des Neiges

Dominique Santin

Dr Chaussemy

Amaury

Dr Oline Giordana

Claire Marsé

Lydiane Mondot

Robin Kardous

Bernadette Bailet

Héloise Joly

Dr Denys Fontaine

Aurélie Leplus

Amélie Faustini

Vanessa Ferrier

Personality Related to Quality-of-Life Improvement After Deep Brain Stimulation in Parkinson's Disease (PSYCHO-STIM II)

Keywords: Cooperativeness, DBS-STN, novelty seeking, Parkinson's disease, quality of life validated

41 [START_REF] Benabid | Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease[END_REF][START_REF] Kleiner-Fisman | Subthalamic nucleus deep brain stimulation: Summary and meta-analysis of outcomes[END_REF][START_REF] Krack | Five-year follow-up of bilateral stimulation of the subthalamic nucleus in advanced Parkinson's disease[END_REF][START_REF] Castelli | Chronic deep brain stimulation of the subthalamic nucleus for Parkinson's disease: effects on cognition, mood, anxiety and personality traits[END_REF]. Nonetheless, some patients do not feel DBS 42 benefits despite objective motor improvement [START_REF] Albanese | Suicide after successful deep brain stimulation for movement disorders[END_REF][START_REF] Agid | Neurosurgery in Parkinson's disease: the doctor is happy, the patient less so? In Parkinson's Disease and Related Disorders[END_REF]. [START_REF] Tome | Serotonergic autoreceptor blockade in the reduction of antidepressant latency: personality variables and response to paroxetine and pindolol[END_REF] That is why it seems crucial to find some individual objective and subjective factors such as physical and psychological health, as well as personal feeling of well-being and happiness experienced [START_REF] Cella | Quality of life: Concepts and definition[END_REF][START_REF] Lucas-Carrasco | Using the Satisfaction with Life Scale in people with Parkinson's disease: A validation study in different European countries[END_REF].

Because personality is a very individual characteristic and describes how people think, behave and manage their life [START_REF] Hansenne | Le modèle biosocial de la personnalité de Cloninger[END_REF], it seems a factor of interest to predict QoL. To assess personality, several questionnaires have been developed, based on different concepts. From them, the Temperament and Character Inventory (TCI) evaluates personality through seven dimensions [START_REF] Cloninger | A psychobi-781 ological model of temperament and character[END_REF]. It is derived from the neurobiological and psychological concept of personality made by Cloninger [START_REF] Hansenne | Le modèle biosocial de la personnalité de Cloninger[END_REF]. The TCI was already used in several studies assessing PD personality [11] and was history, MDS-UPDRS part I-IV [17], part-III being performed in OFF and ON state during a standardized acute levodopa challenge, neuropsychological testing, patient and caregivers' questionnaires. Along our ancillary study, only one personality questionnaire was added to evaluation at baseline: the TCI.

Here, only patients evaluated before (V0) and after one year of DBS-STN (V1) were used in this study.

The MDS-UPDRS-III was evaluated for two conditions at V0: OFF and ON medication; and for four conditions at V1: ON stimulation ON medication (stimON-medON), ON stimulation OFF medication (stimON-medOFF), OFF stimulation ON medication (stimOFF-medON) and OFF stimulation OFF medication (stimOFF-medOFF).

The total Levodopa Equivalent Dose (LED) was calculated [18]. The Parkinson's Disease Questionnaire 39-items (PDQ-39) is a self-questionnaire evaluating specifically QoL of PD patients [19] and was assessed at V0 and V1. Its eight sub-scales can be divided into a Physical Component Score ("Mobility", "Activities of Daily Living" and "Bodily Discomfort" subscores) and a Mental Component Score ("Emotional Well-Being", "Stigma", "Social Support", "Cognition" and "Communication" sub-scores) of QoL.

The TCI was measured only at V0 in order to serve as predictive factor of QoL improvement after DBS-STN. It is a self-questionnaire of 226 binary questions used to assess patients' personality through seven dimensions [START_REF] Cloninger | A psychobi-781 ological model of temperament and character[END_REF]. It includes four temperaments (which are supposed to be genetically determined personality traits [START_REF] Hansenne | Le modèle biosocial de la personnalité de Cloninger[END_REF]): Novelty Seeking (NS), Harm Avoidance (HA), Reward Dependence (RD), and Persistence (P); and three characters (which are developmental personality traits evolving through time and life history [START_REF] Hansenne | Le modèle biosocial de la personnalité de Cloninger[END_REF]): Self-Directedness (SD), Cooperativeness (C), and Self-Transcendence (ST).

Each of these seven personality dimensions are measured by an independent score: higher is the score, higher the individual will present the personality an "improvement" (difference of PDQ-39 total score between V1 and V0 < -4.72) and a "no improvement" group (difference of PDQ-39 total score between V1 and V0 ≥ -4.72). TCI dimensions and subdimensions scores were compared in these groups (two-sample Mann-Whitney tests with FDR correction for 31 comparisons).

Differences between groups of responding patients

As supplementary exploratory analysis, we have chosen to study discrepancy between motor complications (MDS-UPDRS-IV) and QoL (PDQ-39 total) evolution. From the two PDQ-39 groups above and two similar MDS-UPDRS-IV groups (an "improvement" group based on MCID [21] (difference of MDS-UPDRS-IV score between V1 and V0 < -0.9) and a "no improvement" group (difference of MDS-UPDRS-IV score between V1 and V0 ≥ -0.9)), PD patients were divided into three final groups of responding patients: a "paradoxically unimproved" group (MDS-UPDRS "improvement" group and PDQ-39 "no improvement" group), a "realistic" group (MDS-UPDRS and PDQ-39 "improvement" groups or MDS-UPDRS and PDQ-39 "no improvement" groups) and a "paradoxically improved" group (MDS-UPDRS "no improvement" group and PDQ-39 "improvement" group). Each group were compared two by two in terms of TCI dimensions and

Impact of DBS-STN at V1 (Table 1)

One year after DBS-STN, PD patients had a significant decrease in their dopaminergic treatments (LED). HAMD, HAMA, and MoCA scores significantly decreased after DBS, while LARS scores slightly increased.

All parts of the MDS-UPDRS scores improved significantly after DBS-STN except the part-II-ON which worsened.

Associations between MDS-UPDRS and PDQ-39 scores at V1

At V1, the MDS-UPDRS part-I and part-II stimON-medON were positively associated with PDQ-39 total and 8 sub-scores (q < 0.01). The

MDS-UPDRS part-III stimON-medON and part-

IV were positively associated with PDQ-39 total score (q < 10 -4 ), most of the Physical Component Score ("Mobility" and "Activities of Daily Living") (p < 10 -3 ) and part of the Mental Component Score ("Emotional Well-Being", "Stigma", and "Communication") (q < 0.05). The "Bodily Discomfort" was associated only with the MDS-UPDRS part-IV (q < 10 -3 ).

Associations between TCI dimensions at V0 and PDQ-39 changes at V1 (n = 303)

There were significant associations between TCI dimensions and PDQ-39 sub-scores change at V1 (Table 2). We mainly considered TCI dimensions Mann-Whitney tests: * p < 0.05; * * p ≤ 0.01; q, FDR adjusted p value; CI, confidence interval of the difference at 95% confidence level; HA4, Fatigability; C, Cooperativeness; C3, Helpfulness. having the strongest association with PDQ-39 subscores (presenting only significant FDR adjusted p value that is q ≤ 0.05) to avoid making assumption about lower associations.

The NS1 sub-dimension and some C sub-dimensions (C1 and C4) were significantly and negatively associated with the PDQ-39 "Mobility" sub-score change.

PD patients were separated into the PDQ-39 total "improvement" (n = 150) and the "no improvement"

(n = 153) groups according to the MCID [20]. Among the "no improvement" group, 63% of patients had a no clinically relevant amelioration (that is a delta PDQ-39 total score between the MCID of -4.72 and 0) and 37% were not ameliorated (that is a delta PDQ-39 total score superior to 0). Uncorrected significant differences of HA4, C and C3 scores were found between the "improvement" group and the "no improvement" group which did not maintain significance with FDR correction (Table 3). and accept others [START_REF] Morlon | Le modele psychobiologique de Cloninger pour evaluer la personnalite du patient douloureux: etude en medecine generale[END_REF][START_REF] Pelissolo | Le modèle de personnalité de Cloninger et le questionnaire TCI[END_REF]. PD patients with higher

415

Cooperativeness probably better listen to their rel-416 atives and believe them, which can help them to 417 remember their past difficulties and to realize the strong motor improvement they benefit from DBS-STN. Indeed, it is usual that PD patients forget their past difficulties after DBS and need a reminder from their relatives or caregivers to become aware of their improvements [START_REF] Thomson | He's back so i'm not alone": the impact of deep brain stimulation on personality, self, and relationships in Parkinson's disease[END_REF]. In literature, low Cooperativeness was associated with treatment-resistance in depressive patients [START_REF] Takahashi | Personality traits as risk factors for treatment-resistant depression[END_REF], and high Cooperativeness was also linked with good QoL or life satisfaction in different populations [START_REF] Demirci | The effects of temperament and character traits on perceived social support and quality of life in patients with epilepsy[END_REF][START_REF] Park | Character profiles and life satisfaction[END_REF][START_REF] Masthoff | The relationship between dimensional personality models and quality of life in psychiatric outpatients[END_REF]. Also, this hypothesis makes sense because Cooperativeness mostly impact physical QoL improvement after DBS, only part of QoL that can be assessed by patients' relatives. Therefore, relatives probably have a more objective feeling on these improvements which may contrast with patients' subjective one. Moreover, it is interesting to compare personality-QoL associations before and after DBS. Before, Self-Directedness (representing the individual maturity) was associated with better QoL [16]; whereas, after, Cooperativeness (social maturity) becomes associated with better QoL. This may reflect that, before surgery, PD patients were used to their disease and to their relatives' comments because of adaptive process through chronic disease; whereas, after DBS, PD patients are confronted to abrupt changes [START_REF] Schüpbach | Psychosocial adjustment after deep brain stimulation in Parkinson's disease[END_REF] and motor improvement are often obvious. Thus, their relatives can appreciate these improvements and inform the patients, helping them to become more aware of these changes. Hence, before surgery, in case of a slowly evolving chronic disease, PD patients may rely more on their personal Novelty Seeking is a temperament representing a tendency to respond positively and with excitation to new stimuli [START_REF] Morlon | Le modele psychobiologique de Cloninger pour evaluer la personnalite du patient douloureux: etude en medecine generale[END_REF][START_REF] Pelissolo | Le modèle de personnalité de Cloninger et le questionnaire TCI[END_REF]. It reflects good adaptability to new situations and motivation facing change. PD patients with higher Novelty Seeking may thus better adapt to the abrupt changes caused by DBS-STN and so really feel the strong motor improvement they benefit from the stimulation. In literature, higher Novelty Seeking was also associated with better global QoL and physical health in patients with schizophrenia [START_REF] Ritsner | Satisfaction with quality of life varies with temperament types of patients with schizophrenia[END_REF].

Interestingly, Novelty Seeking and/or Cooperativeness are two personality dimensions potentially implicated in placebo responses [START_REF] Geers | Goal activation, expectations, and the placebo effect[END_REF][START_REF] Schweinhardt | The anatomy of the mesolimbic reward system: a link between personality and the placebo analgesic response[END_REF][START_REF] Jakšić | Does personality play a relevant role in the placebo effect?[END_REF]. Therefore, 470 these two personality dimensions may enhance the 471 part of placebo effect induced by DBS-STN [START_REF] De La Fuente-Fernández | Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson's disease[END_REF].

472

For example, the sub-dimension C3 (Helpfulness)

473

reflects solidarity and good level of team work which 474 may enhance placebo effect [START_REF] Blasini | The role of patient-practitioner relationships in placebo and nocebo phenomena[END_REF]. individuals [START_REF] Cloninger | The temperament and character inventory (TCI): a guide to its development and use[END_REF]. It is a system facilitating condi-516 tioning to reward stimuli [START_REF] Pelissolo | Le modèle de personnalité de Cloninger et le questionnaire TCI[END_REF] and therefore may 517 be associated with placebo effect. Indeed, some 518 studies have found associations between higher 519 Reward Dependence scores and better outcomes 520 after interpersonal therapy [START_REF] Joyce | Temperament, character and personality disorders as predictors of response to interpersonal psychotherapy and cognitive-behavioural therapy for depression[END_REF] or antidepressants 521 [START_REF] Tome | Serotonergic autoreceptor blockade in the reduction of antidepressant latency: personality variables and response to paroxetine and pindolol[END_REF]. Moreover, treatment adhesion was shown to be related to higher Reward Dependence temperament in a weight-loss therapy, probably thanks to better collaborative relationship with the clinicians [START_REF] De Panfilis | Personality and attrition from behavioral weight-loss treatment for obesity[END_REF]. Nonetheless, these differences between realistic, paradoxically improved or unimproved patients could not be explained by differences in cognitive or behavioral changes after DBS-STN.

This study has some limits. Being the first study on this subject, only analyses of associations between QoL outcomes and personality dimensions were done. Thus, our results are not predictive but rather Finally, only personality dimensions before DBS were evaluated (there was no re-evaluation of personality after stimulation), and it remains possible that some personality dimensions evolve after DBS. Even if temperaments are not supposed to change with time [START_REF] Hansenne | Le modèle biosocial de la personnalité de Cloninger[END_REF], personality in PD patients seems to evolve with the disease course particularly with the introduction of dopaminergic treatments [START_REF] Boussac | Personality dimensions of patients can change during the course of parkinson's disease[END_REF]. DBS could also impact personality as shown by some studies [START_REF] Lhommée | 947 Personality, dopamine, and Parkinson's disease: Insights 948 from subthalamic stimulation[END_REF][START_REF] Pham | Personality changes after deep 952 brain stimulation in Parkinson's disease[END_REF][START_REF] Fassino | Novelty-seeking in Parkinson's disease after deep 957 brain stimulation of the subthalamic nucleus: a case-control 958 study[END_REF][START_REF] Dupouy | Personnalité et maladie de Parkinson 960 idiopathique: à propos d'une revue de la littérature et de 961 deux études expérimentales[END_REF][START_REF] Abbate-Daga | Personality 964 and deep brain stimulation of the subthalamic nucleus in 965 Parkinson's disease[END_REF]. In any case, our aim was to find "predictive" factors of QoL improvement after DBS. Thus, even if personality changes after stimulation, it is not supposed to affect our results. Lastly, our three groups of responding PD patients ("paradoxically unimproved", "realistic" and "paradoxically improved")

were done according to their motor complications improvement (reflected by MDS-UPDRS part-IV) since it is the main purpose of DBS-STN action.

Nonetheless, improvements of non-motor symptoms (pain, fatigue etc.) were not accounted in these analyses, although non-motor symptoms can benefit of DBS-STN [START_REF] Kurtis | The 967 effect of deep brain stimulation on the non-motor symp-968 toms of Parkinson's disease: a critical review of the current 969 evidence[END_REF] and are best predictors of QoL in PD [START_REF] Skorvanek | Relationship between the non-motor items of the[END_REF], because we were interested in more objective

INTRODUCTION 37 Deep

 37 brain stimulation of the sub-thalamic nucleus 38 (DBS-STN) is proposed to Parkinson's disease (PD) 39 patients with motor fluctuations and generally leads 40 to a great improvement of their quality of life (QoL)

44 predictive

 44 factors of QoL improvement after DBS-45 STN in order to assure at best patients' amelioration 46 after this invasive therapy. QoL improvement is an important outcome when 48 evaluating treatment efficiency. It depends on both 49

  characteristic associated. NS corresponds to impulsive and curious temperament; HA to anxious and pessimist traits; RD to socially attached and sensitive individuals; P to hardworking and perseverant personality; and the three characters are associated to levels of maturity: SD to individual maturity, C to social maturity, and ST to spiritual maturity. Except the P, each of these seven dimensions is subdivided into sub-dimensions: NS and HA are formed by 4 sub-dimensions, RD and ST by 3, and SD and C by 5. Each of these twenty-four sub-dimensions represents a specific aspect of the global dimension, also ranging 161 in a spectrum of scores. 162 Statistical analyses and MoCA were checked (Wilcoxon Signed Rank 176 Test for Paired Samples). 177 Associations between TCI dimensions and 178 PDQ-39 scores at V0 179 Linear regression models were performed to test 180 the association between the different PDQ-39 sub-181 scores and total score at V0 and the seven TCI 182 dimensions. Models were univariate with only one 183 explanatory variable (each TCI dimensions) by mod-184 els, resulting in seven models per response variable 185 (each PDQ-39 scores) which were adjusted by age, 186 sex, disease duration and LED at V0. A False Dis-187 covery Rate (FDR) correction was applied for 31 188 comparisons with calculation of q values (corre-189 sponding to FDR adjusted p values). We have chosen 190 univariate models to study if some TCI personal-191 ity dimensions were separately associated with QoL. 192 Moreover, because studying TCI sub-dimensions as 193 well as main dimensions seemed of interest, multi-194 variate analysis seemed inappropriate since too many 195 explanatory variables would be used (that is 31 vari-196 ables -7 dimensions plus 24 sub-dimensions) which 197 can be too much in view of the parsimony rule.

198

  Associations between MDS-UPDRS and199 PDQ-39 scores at V1 200 These associations were tested using linear regres-201 sion models adjusted by age, sex, disease duration, 202 and LED at V1. The PDQ-39 scores at V1 served 203 as response variables (the total and eight PDQ-39 204 sub-scores) and the MDS-UPDRS (part-I, part-II 205 stimON-medON, part-III stimON-medON and part-206 IV) scores at V1 as explanatory variables. Models 207 were univariate with only one explanatory variable by models, resulting in four models per response variable. An FDR correction was applied for 4 comparisons. Associations between TCI dimensions at V0 and PDQ-39 changes at V1 Percentages of changes from V0 to V1 were calculated from the PDQ-39 total and sub-scores. Linear regression models were performed. The response variables corresponded to each calculated percentages of PDQ-39 change. The explanatory variables corresponded to each TCI dimensions and sub-dimensions. As explained above, models were univariate with only one explanatory variable by models, resulting in thirty-one models per response variable, adjusted by age, sex, disease duration and LED at V0, to account for any potential center effect. The same FDR correction was applied with q values calculation for 31 comparisons. PD population was also divided into two groups according to the Minimal Clinically Important Difference (MCID) of PDQ-39 total score change [20]:

308

  and positively associated with PDQ-39 total score 309 (q = 1 × 10 -8 , R 2 = 0.16; and q = 9 × 10 -3 , R 2 = 0.07, 310 respectively) whereas SD scores were significantly 311 and negatively associated with PDQ-39 total score 312 (q = 2 × 10 -7 , R 2 = 0.14)).

Fig. 1 .

 1 Fig. 1. Differences in Reward Dependence scores between groups of responding patients.

Fig. 2 .

 2 Fig. 2. Differences in Cooperativeness scores between groups of responding patients.

  resources (individual maturity) to adapt and have a better QoL [16]; whereas, after DBS, they focus more on the external comments (social maturity) to adapt to the abrupt changes. It would thus be interesting to see the impact of Cooperativeness on QoL after longtime of DBS, when PD patients would have become used to these changes, with the PREDISTIM 5-year QoL evaluation.

475

  Moreover, our study has shown good associa-476 tions between the more objective evaluation of PD 477 symptoms (MDS-UPDRS) and the subjective eval-478 uation of PD QoL (PDQ-39). Mainly, the objective 479 motor examination, MDS-UPDRS-III, as well as the 480 motor complications assessed by the MDS-UPDRS-481 IV, were mostly associated with physical components 482 of the PDQ-39 evaluation, assuring that both scales 483 are reliable and evaluate PD patients in the same 484 way [38]. Nonetheless, some PD patients (43.6%) 485 had a feeling of evolution after DBS-STN that differs 486 from the objective motor complications examina-487 tion (MDS-UPDRS-IV). Indeed, eighteen patients 488 (6.8%) felt "paradoxically improved" after DBS: they 489 felt improvement of their QoL, whereas the MDS-490 UPDRS-IV showed no improvement of their motor 491 complications. Also, ninety-seven patients (36.7%) 492 felt "paradoxically unimproved" after DBS: they did 493 not feel any improvement of their QoL, whereas the 494 MDS-UPDRS-IV showed an improvement of their 495 motor complications. This dissociation between real-496 ity of PD symptoms improvement after DBS and PD 497 patients' feelings has already been shown in several 498 studies [5, 6] and can be explained by differences 499 between patients' expectations and reality, difficul-500 ties of psychosocial adjustment, mood and behavioral 501 changes [26, 31, 39, 40], etc. Moreover, we have 502 decided to focus our analysis on discrepancy between 503 QoL evolution and MDS-UPDRS-IV change since 504 DBS preferentially improves motor complications. 505 Here, paradoxically unimproved PD patients had 506 lower Cooperativeness scores than realistic and para-507 doxically improved ones. This result seems to be 508 congruent with our previous observation that lower 509 Cooperativeness scores before surgery lead to less 510 improvement of QoL after DBS-STN. Moreover, 511 paradoxically improved PD patients had higher 512 Reward Dependence scores than the paradoxically 513 unimproved ones. Reward Dependence temperament 514 is associated with sensitive, dependent and social 515

  suggestive. Hence, they should be used in order to prevent disappointment of PD patients after DBS-STN (not to select PD patients for DBS) acting in two ways: 1) by supporting them upstream and explaining them at best what they should expect of DBS, and 2) by preparing and encouraging their relatives to be really present with the patients after the operation to enhance their cooperation (which seems to facilitate their positive outcomes). Additionally, our models explaining less than ten percent of the variance (R 2 ) of QoL improvement after DBS-STN, we are aware that personality dimensions are not enough to guaranty PD patients' QoL improvement after stimulation and that other variable are needed to explain at best QoL outcome after surgery. However, our focus being concentrated on personality dimensions' evaluation, we did not look for other potential predictive variables as it will be the aim of the main PREDI-STIM study.

574

  assessments than MDS-UPDRS parts I and II. More-575 over, we are aware that using MCIDs to classify into 576 groups of "improvement" or "no improvement" may 577 not precisely reflect the evolution of patients after 578 DBS, mainly since at this stage of motor fluctua-579 tions a change of 0.9 points in the MDS-UPDRS 580 part-IV may not be sufficient to be clinically sig-581 nificant. Nonetheless, the choice of this MCID was 582 done accordingly with literature. Ultimately, we are 583 aware that there are other models of personality that 584 could have been explore in this study to depict a more 585 complete exploration of personality associated with 586 QoL. Nonetheless, the TCI being a long question-587 naire, we thought that using a multilayer approach 588 (through different personality investigations) would 589 have been too complex in clinical practice and too 590 tiring for the PD patients. 591 In conclusion, PD patients with higher Coopera-592 tiveness and Novelty Seeking scores at baseline seem 593 to have the best QoL outcome after one year of DBS-594 STN in the physical component of QoL. A tendency 595 of being more trustful towards relatives and more 596 motivated by changes could explained the ability 597 of these PD patients to feel a better QoL improve-598 ment following the abrupt changes after surgery. 599 Moreover, PD patients with low Cooperativeness 600 were more paradoxically unimproved after DBS, 601 whereas PD patients with high Reward Dependence 602 were more paradoxically improved after DBS. There-603 fore, systematic TCI examination could be proposed 604 as standard evaluation before DBS. Subsequently, 605 according to PD patients' scores at the Novelty 606 Seeking and Cooperativeness dimensions, specific 607 educational programs should be proposed to patients 608 with higher risk of QoL unimprovement after DBS to 609 prepare them at best for the stimulation. For this, we 610 are now looking for cut-off scores for these dimenfunded by the France Parkin-614 son charity and French Ministry of Health (PHRC 615 national 2012). This is an ancillary study to

Table 1

 1 Description of TCI dimensions and clinical characteristics at V0 and V1

			V0	V1	p	CI of the
			(mean ± SD)	(mean ± SD)		difference
		Age	60.0 ± 7.4	/	/	/
		Disease duration	10.1 ± 3.9	/	/	/
		Novelty Seeking	16.7 ± 5.0	/	/	/
		Harm Avoidance	17.4 ± 6.5	/	/	/
		Reward Dependence	15.4 ± 3.5	/	/	/
		Persistence	5.4 ± 1.7	/	/	/
		Self-Directedness	34.4 ± 6.0	/	/	/
		Cooperativeness	33.8 ± 4.7	/	/	/
		Self-Transcendence LED HAMD HAMA LARS MoCA MDS-UPDRS I MDS-UPDRS II OFF † MDS-UPDRS II ON ‡ MDS-UPDRS III OFF † MDS-UPDRS III ON ‡ MDS-UPDRS IV PDQ-39 Total PDQ-39 Mobility PDQ-39 ADL	12.3 ± 5.8 1348.6 ± 740.2 5.2 ± 4.1 5.9 ± 5.1 -27.9 ± 5.7 27.1 ± 2.2 10.9 ± 5 18.7 ± 7.6 6.5 ± 5.9 43 ± 16.2 12.5 ± 7.8 8.8 ± 3.3 31.3 ± 11.4 36.7 ± 20.4 37.7 ± 18.1	/ 689.6 ± 480.3 4.6 ± 4.1 4.7 ± 4.2 -25.2 ± 8.3 25.9 ± 2.8 9.3 ± 5.2 15.1 ± 8.5 8.1 ± 5.8 21.8 ± 12.9 10.8 ± 7.9 4.1 ± 3.7 26.8 ± 13.5 32.6 ± 22.7 29.2 ± 20	/ 9 × 10 -33 * * 4 × 10 -02 * 2 × 10 -03 * * 1 × 10 -06 * * 1 × 10 -11 * * 5 × 10 -06 * * 9 × 10 -12 * * 8 × 10 -05 * * 3 × 10 -46 * * 3 × 10 -02 * 3 × 10 -33 * * 3 × 10 -11 * * 2 × 10 -03 * * 5 × 10 -13 * *	/ 535.7; 674.0 0.0; 1.5 0.5; 2.0 -3.0; -1.0 1.0; 1.5 1.0; 2.5 3.5; 5.5 -2.5; -1.0 19.0; 22.5 0.0; 2.5 4.5; 5.5 3.4; 6.0 1.3; 6.3 8.3; 12.5
		PDQ-39 Emotional Well-being PDQ-39 Stigma PDQ-39 Social support PDQ-39 Cognition PDQ-39 Communication PDQ-39 Bodily discomfort	32 ± 17.7 33.2 ± 22.3 11.7 ± 15.9 28.3 ± 17.1 24.9 ± 17.9 46.3 ± 21.1	31.1 ± 19.2 23.1 ± 20.3 14 ± 18 24 ± 17.2 28.1 ± 21 32.5 ± 21.4	0.30 5 × 10 -15 * * 1 × 10 -02 * 6 × 10 -05 * * 3 × 10 -03 * * 9 × 10 -19 * *	-0.00004; 4.2 9.4; 15.6 -8.3; 0.0 3.1; 6.3 -8.3; 0.0 12.5; 20.8
	Mann-Whitney tests: 265
	266	tical significance of 0.05 was used. As explained
	267	above, FDR corrections were applied and interpre-
	268	tations were made carefully according to strength of
		the results.

* p < 0.05; * * p ≤ 0.01; CI, confidence interval of the difference in means at 95% confidence level; V0, baseline; V1, one year after DBS-STN; † MDS-UPDRS medOFF (V0) vs. stimON-medOFF (V1); ‡ MDS-UPDRS medON (V0) vs. stimON-medON (V1); ADL, Activities of Daily Living. cognitive and behavioral (HAMD, HAMA, LARS, 258 and MoCA) changes after DBS-STN (two-sample 259 Mann-Whitney tests). FDR adjusted p values (q val-260 ues) were calculated for 7 comparisons for the TCI 261 dimensions analysis and for 4 comparisons for the 262 cognitive and behavioral changes analysis. 263 All analyses were conducted on R Studio Software 264 Version 1.1.456 and a threshold of bilateral statis-269 RESULTS 270 Three hundred and three PD patients were 271 enrolled in this study (204 men (67.3%) and 99 272 women (32.7%)) (Table 1). Statistical testing did 273 not show relevant significant differences across cen-274 ters: only age and disease duration shown significant 275 differences between centers in the Kruskal-Wallis testing (p = 0.003 and p = 0.03, respectively) which no more reached significance during the post-hoc analysis; LED at V0, percentage of PDQ-39 changes at V1 and TCI dimensions were not different between centers (p > 0.05). In any case, age, disease duration, sex and LED were used as adjustment variables in the linear regression models to control for any potential center effect.

Table 2

 2 Significant associations between TCI dimensions at V0 and percentages of PDQ-39 change at V1 (n = 303)

		Percentage of PDQ-39 evolution	TCI	coefficients	P	q	R 2	C I
			dimensions
		% PDQ-39 Total	NS	-1.02	0.04 *	0.46	0.07	-2.01; -0.03
			HA4	-2.41	0.03 *	0.46	0.07	-4.62; -0.21
			C3	-4.48	0.03 *	0.46	0.07	-8.47; -0.49
		% PDQ-39 Mobility	NS1	-9.42	0.0006 * *	0.02 *	0.05	-14.75; -4.08
			NS4	-7.34	0.047 *	0.29	0.02	-14.55; -0.13
			C	-3.11	0.01 * *	0.12	0.03	-5.60; -0.62
			C1	-13.17	0.004 * *	0.04 *	0.04	-22.15; -4.19
			C4	-9.30	0.004 * *	0.04 *	0.04	-15.65; -2.96
		% PDQ-39 ADL	C3	-10.24	0.047 *	0.978	0.02	-20.30; -0.18
		% PDQ-39 Emotional Well-Being	HA	-2.30	0.02 *	0.37	0.04	-4.29; -0.32
			HA4	-7.54	0.01 * *	0.35	0.05	-13.34; -1.74
			P	8.18	0.04 *	0.40	0.04	0.46; 14.89
		% PDQ-39 Stigma	RD	-2.39	0.03 *	0.40	0.01	-4.53; -0.24
			RD3	-5.84	0.04 *	0.40	0.01	-11.41; -0.28
			ST3	4.20	0.03 *	0.40	0.01	0.40; 8.01
		% PDQ-39 Social Support	ST	1.80	0.02 *	0.31	0.02	0.29; 3.31
			ST3	5.30	0.02 *	0.31	0.02	0.92; 9.68
		% PDQ-39 Cognition	NS	-2.56	0.009 * *	0.262	0.03	-4.45; -0.66
			SD	1.63	0.04 *	0.26	0.02	0.07; 3.19
			SD1	6.84	0.02 *	0.26	0.02	0.98; 12.70
			C1	7.72	0.04 *	0.26	0.02	0.30; 15.13
			C2	6.56	0.04 *	0.26	0.02	0.27; 12.85
		% PDQ-39 Communication	HA4	-5.55	0.04 *	0.70	0.00	-10.95; -0.15
		% PDQ-39 Bodily Discomfort	NS	-1.90	0.01 * *	0.34	0.02	-3.37; -0.43
			NS1	-3.78	0.03 *	0.34	0.02	-7.20; -0.35
			C3	-6.50	0.03 *	0.34	0.02	-12.45; -0.56
	Adjusted linear regression models: 299
	300	munication" sub-scores significantly worsened after
	301	surgery.
	302	Associations between TCI dimensions and
	303	PDQ-39 scores at V0
	304	TCI dimensions were mainly associated with
	305	the Mental Component Score of the PDQ-39 at
	306	V0. Indeed, the linear regression models between
		TCI dimensions and PDQ-39 sub-scores at V0

* p < 0.05; * * p ≤ 0.01; q, FDR adjusted q value; significant p value in bold; CI, confidence interval at 95% confidence level; NS, Novelty Seeking; HA4, Fatigability; C3, Helpfulness; NS1, Exploratory excitability; NS4, Disorderliness; C, Cooperativeness; C1, Social acceptance; C4, Compassion; HA, Harm Avoidance; P, Persistence; RD, Reward Dependence; RD3, Dependence; ST3, Spiritual acceptance; ST, Self-Transcendence; SD, Self-Directedness; SD1, Responsibility; C2, Empathy.

Total PDQ-39 scores significantly improved after 294 one year of DBS-STN as well as the "Mobility", 295 "Activities of Daily Living", "Stigma", "Cogni-296 tion", and "Bodily Discomfort" sub-scores, whereas 297 the "Emotional Well-Being" sub-score did not sig-298 nificantly change. The "Social Support" and "Com-307 showed that HA and ST scores were significantly

Table 3

 3 Differences of TCI dimensions scores between PDQ-39 total improvement groups at V1 (n = 303)

	Mean ± SD

Rating Scale (HAMD), Hamilton Anxiety Rating

support from the French clinical research network NS-Park/F-Crin and the Fédération de

Scale (HAMA), Lille Apathy Rating Scale (LARS), tively) (Fig. 2).

ACCEPTED MANUSCRIPT -CLEAN COPY

CONFLICT OF INTEREST

The authors have no conflict of interest to report.