Aziz Ferchiou

Andrei Szöke

Audrey Laguerre

Alexandre Méary

Marion Leboyer

M.D Franck Schürhoff
email: franck.schurhoff@inserm.fr

Exploring the relationships between tobacco smoking and schizophrenia in first-degree relatives

Keywords: nicotine, smoking, schizotypy, schizophrenia, genetic, relatives

come

Exploring the relationships between tobacco smoking

and schizophrenia in first-degree relatives.

Introduction

Individuals with schizophrenia tend to be heavy smokers. Despite the smoking cessation programs and anti-smoking campaigns implemented in many countries, up to 90% of schizophrenic subjects smoke cigarettes and are nicotine dependent [START_REF] De Leon | A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviours[END_REF]. One of the hypotheses most frequently put forward to explain the relationship between smoking and schizophrenia is that patients may use smoking as a form of self-medication to decrease the symptoms of schizophrenia or the side effects of treatment.

Convincing data have been obtained indicating that nicotine may improve sensory gating abnormalities [START_REF] Adler | Normalization of auditory physiology by cigarette smoking in schizophrenic patients[END_REF], smooth pursuit eye movements [START_REF] Olincy | Differntial effects of cigarette smoking on performance of a smooth pursuit and a saccadic eye movement task in schizophrenia[END_REF] and cognitive deficits in schizophrenic subjects [START_REF] Ochoa | Cognitive deficits in schizophrenia: Focus on neuronal nicotinic acetylcholine receptors and smoking[END_REF]. Tobacco smoking has also been shown to reduce the side-effects of antipsychotic medication by improving dopamine release in the nigrostriatum or inducing metabolic enzymes that decrease the levels of antipsychotic drugs in the blood [START_REF] Aguilar | Nicotine dependence and symptoms in schizophrenia: Naturalistic study of complex interactions[END_REF]. Several studies have shown that the level of nicotine dependence is correlated with either positive [START_REF] Ziedonis | Nicotine dependence and schizophrenia[END_REF][START_REF] De Leon | Does smoking reduce akathisia? Testing a narrow version of the self-medication hypothesis[END_REF] or negative [START_REF] Patkar | Relationship between tobacco smoking and positive and negative symptoms in schizophrenia[END_REF] symptoms. These findings led to the suggestion that schizophrenic subjects self-medicate with nicotine, mostly to alleviate positive and negative symptoms [START_REF] Lavin | What is the clinical importance of cigarette smoking in schizophrenia?[END_REF], but also to relieve symptoms of depression and anxiety [START_REF] Glynn | Why patients smoke[END_REF][START_REF] Taiminen | Smoking and cognitive deficits in schizophrenia: a pilot study[END_REF][START_REF] Herran | Determinants of smoking behaviour in outpatients with schizophrenia[END_REF]. However, studies systematically examining the relationship between tobacco use and particular symptom dimensions or antipsychotic side-effects in schizophrenia patients have yielded inconsistent findings, despite these promising neurobiological rationales. Some studies have higher levels of positive and/or negative symptoms in schizophrenic patients that smoke than in those that do not [START_REF] Ziedonis | Nicotine dependence and schizophrenia[END_REF][START_REF] Fukui | Smoking habits of chronic schizophrenics[END_REF][START_REF] Beratis | Factors affecting smoking in schizophrenia[END_REF][START_REF] Patkar | Relationship between tobacco smoking and positive and negative symptoms in schizophrenia[END_REF], whereas others have found no relationship between smoking and schizophrenia symptoms [START_REF] Dalack | Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia[END_REF][START_REF] Addington | Smoking cessation treatment for patients with schizophrenia[END_REF][START_REF] Herran | Determinants of smoking behaviour in outpatients with schizophrenia[END_REF][START_REF] Aguilar | Nicotine dependence and symptoms in schizophrenia: Naturalistic study of complex interactions[END_REF][START_REF] Fatemi | A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia[END_REF], and still others (Arias et al., 1997;[START_REF] Beratis | Factors affecting smoking in schizophrenia[END_REF] have reported negative symptoms to be inversely correlated with nicotine dependence.

There may be many reasons for these discrepancies, including the heterogeneity of the populations studied (i.e., severe vs. less severe forms of schizophrenia, acute vs. chronic forms, or inpatients vs. outpatients), the lack of continuous scale for the measurement of dependence (subjects are often classified as heavy, mild or non-smokers), the use of inadequate measurements of nicotine dependence for schizophrenic patients [START_REF] Steinberg | Applicability of the Fagerstrom test for nicotine dependence in smokers with schizophrenia[END_REF], and the influence of pharmacological treatment [START_REF] Mcevoy | Haloperidol increases smoking in patients with schizophrenia[END_REF].

However, these conflicting results also suggest that self-medication is not the only explanatory hypothesis and that schizophrenic patients smoke due to a combination of factors including self-medication and genetic susceptibility. It has been suggested that some susceptibility genes for schizophrenia and nicotine dependence are common to these two conditions [START_REF] Dalack | Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings[END_REF], and there is genetic evidence to support this hypothesis.

Strong genetic components have been found for both predisposition to tobacco use [START_REF] Saccone | Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs[END_REF] and susceptibility to schizophrenia [START_REF] Owen | The molecular genetics of schizophrenia: new findings promise new insights[END_REF][START_REF] Harrison | Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence[END_REF]. Several nicotinic receptor gene variants have recently been reported to be associated with an increase in the risk of nicotine dependence [START_REF] Saccone | Cholinergic nicotinic receptor genes implicated in a nicotine dependence association study targeting 348 candidate genes with 3713 SNPs[END_REF]. [START_REF] Faraone | A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families[END_REF] also found evidence for linkage between smoking in schizophrenia and the nicotinic receptor 2 (8p21), 2 (1q21), and 7 (15q14) subunit genes. The locus of the 7 subunit gene has also been linked to the P50 deficit in schizophrenia, with a LOD score of 5.3 [START_REF] Freedman | Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus[END_REF]. Linkage between this locus and schizophrenia has also been demonstrated in a number of other studies (Freedman et al., 2001a(Freedman et al., , 2001b;;[START_REF] Tsuang | Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample[END_REF][START_REF] Liu | Suggestive evidence for linkage of schizophrenia to markers at chromosome 15q13-14 in Taiwanese families[END_REF].

By studying nicotine consumption in individuals with a high genetic risk of developing schizophrenia, it may be possible to avoid some of the methodological problems of previous studies and to improve our understanding of the relationship between smoking and schizophrenia. Studies of relatives of schizophrenic subjects are free from several problems that can potentially confound studies in schizophrenic patients, including the effects of longterm and (usually) ongoing medication, multiple hospital admissions or institutionalization, prolonged functional impairment due to chronic disease and a deterioration of social skills.

Only a few studies have investigated nicotine consumption in the first-degree relatives of schizophrenic subjects. This group has been reported to contain a higher proportion of smokers than control groups [START_REF] Lyons | Nicotine and familial vulnerability to schizophrenia: a discordant twin study[END_REF][START_REF] Smith | Elevated rates of substance use disorders in non-psychotic siblings of individuals with schizophrenia[END_REF]. Studies of the relationship between nicotine consumption and schizotypy in the relatives of schizophrenic patients could thus provide indirect information about the relationship between smoking and schizophrenic symptoms. Indeed, genetic and developmental links have already been found between schizotypy and schizophrenia [START_REF] Kendler | Evaluating the spectrum concept of schizophrenia in the Roscommon Family Study[END_REF], and these two conditions are composed of the same symptomatic dimensions [START_REF] Vollema | The multidimensionality of schizotypy[END_REF].

Furthermore, the symptoms in schizophrenic probands are predictive of similar schizotypal traits in relatives [START_REF] Mata | Childhood schizotypy and positive symptoms in schizophrenic patients predicts schizotypy in relatives[END_REF][START_REF] Fanous | Relationship between positive and negative symptoms of schizophrenia and schizotypal symptoms in nonpsychotic relatives[END_REF].

To our knowledge, only one study has investigated the relationship between nicotine dependence and schizotypy in a sample of 42 first-degree relatives of schizophrenic probands, most of whom were African-American. The authors found a positive relationship between smoking status and the level of schizotypy in relatives [START_REF] Esterberg | Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls[END_REF].

We aimed to replicate the results of [START_REF] Esterberg | Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls[END_REF] in a large Caucasian sample. We therefore investigated the relationship between specific dimensions of schizotypy and tobacco smoking in unaffected first-degree relatives of schizophrenic subjects and in healthy controls.

We assessed the proportion of smokers and the severity of nicotine dependence in our two samples, and then investigated the association between schizotypal traits (positive, negative and disorganized) and the severity of nicotine dependence.

Method

Subjects

We recruited Caucasian probands meeting the DSM-IV-TR (APA, 2000) criteria for schizophrenia, consecutively admitted to a university hospital (Psychiatry Department, Paris-Est University). For confirmation of the diagnosis, patients were interviewed directly by an experienced psychiatrist using the French version of the Diagnostic Interview for Genetic Studies (DIGS), which has a high inter-rater and test-retest reliability [START_REF] Nurnberger | Diagnostic interview of genetic studies. Rationale, unique features and training. NIMH Genetics Initiative[END_REF][START_REF] Preisig | Diagnostic interview of genetic studies (DIGS): inter-rater and test-retest reliability of the French version[END_REF].

Unaffected first-degree relatives of the probands were contacted and asked to participate in the study. We recruited healthy Caucasian controls from blood donors. Relatives and controls were also interviewed with the French version of the DIGS to confirm the absence of schizophrenia. Controls were interviewed with the FIGS (Family Interview for Genetic Studies) [START_REF] Maxwell | Family Interview for Genetic Studies[END_REF] to confirm the absence of psychiatric disorders in their family history.

None of the subjects had a history of neurological disease, or was currently dependent on any substance other than nicotine, as evaluated with the DIGS, which has a detailed section for assessing current and past episodes of substance abuse or dependence (alcohol, cocaine, cannabis, hallucinogens, opiates, sedatives, inhalants, etc.). Written informed consent was obtained from each subject.

Measurements

Information about age, sex, level of education and other demographic characteristics was collected from the DIGS for each subject.

We used the validated French translation of the Schizotypal Personality Questionnaire (SPQ) [START_REF] Raine | The SPQ: A scale for the assessment of schizotypal personality based on DSM-III-R criteria[END_REF][START_REF] Dumas | Traduction et adpatation Française du questionnaire de personnalité schizotypique de Raine[END_REF][START_REF] Dumas | Validation de la version française du questionnaire de personnalité schizotypique de Raine -approche catégorielle et dimensionnelle des traits de personnalité schizotypique dans une population d'étudiants[END_REF] to assess schizotypal dimensions (positive, negative and disorganized dimensions). Subjects also completed the French translation of the Fagerström Test for Nicotine Dependence (FTND) [START_REF] Heatherton | The Fagerström test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire[END_REF][START_REF] Etter | Validity of the Fagerström test for nicotine dependence and of the Heaviness of Smoking Index among relatively light smokers[END_REF]. This six-item instrument assesses nicotine dependence: it is widely used in the general population and has been shown to be highly reliable and valid [START_REF] Heatherton | The Fagerström test for nicotine dependence: a revision of the Fagerström Tolerance Questionnaire[END_REF].

Former smokers were included in the non-smoker group for two main reasons: 1) former smokers were considered to be non-smokers in previous studies; and 2) smoking dependence was evaluated with the Fagerström test, which investigates current dependence.

For inclusion in the study, relatives and controls had to be euthymic as evaluated with the MADRS [START_REF] Montgomery | A new depression scale designed to be sensitive to change[END_REF] and the Bech-Rafaelson (Beck et al., 1978) mania rating scale (MAS).

Statistical analysis

Differences between groups (controls and relatives) were assessed with the Mann-Whitney test for continuous variables and with chi-squared or Fischer's exact tests for discrete variables. Partial correlation analysis (Spearman's rank correlation coefficient) was carried out to investigate the relationships between schizotypal dimensions and smoking dependence, making it possible to control for the potentially confounding influences of sex, age and level of education.

Results

The final samples consisted of 98 first-degree relatives of schizophrenic subjects and 110 healthy controls. Most of the relatives were the parents of patients (70.4%). All subjects were euthymic at the time of the study, with MADRS and MAS scores < 5. The demographic and clinical characteristics of these subjects are displayed in Table 1. The relatives were older than the controls (51.7  14.7 vs. 41.9  11.7; p < 0.0001). Sex ratios were similar for relatives and controls (48.9% and 55.4% men, respectively). The highest completed school grade (level of education) was recorded, according to the usual conventions [START_REF] Pichot | L'estimation du niveau intellectuel prémorbide à la WAIS-R. Comparaison entre la méthode de Barona et l'ndex de détérioration de Wechsler[END_REF] as a trichotomous variable (1 = elementary school; 3 = completion of high school or above; 2 = intermediate between 1 and 3). However, we finally decided to merge levels 1 and 2 because level 1 was infrequent in both groups. Level of education did not differ significantly between the two samples (p = 0.33).

The proportion of smokers were more higher among the relatives than among the controls (44.9% vs. 23.6%; p = 0.001) and nicotine dependence was greater among the relatives than among the controls that smoked, as shown by FTND scores (2.66  2 vs. 1.65  1.99; p = 0.04) (Table 1).

Schizotypy levels were low, with similar values obtained for the two groups (11.36  10.9 for controls and 10.58  7.98 for relatives) (Table 1).

INSERT TABLE 1

Mean schizotypal (SPQ) scores did not differ between smokers and non-smokers in either group (9.84  9.1 vs. 12.59  12.2 in relatives; 10.7  8.6 vs. 10.74  7.8 in controls) (Table 2).

INSERT TABLE 2

We found no correlation between nicotine dependence and SPQ score (full score, or scores for the positive, negative and disorganized dimensions) in either relatives or healthy controls (Table 3).

INSERT TABLE 3

Discussion

The goal of our study was to examine the relationship between nicotine dependence and schizotypy in a sample of healthy first-degree relatives of schizophrenic patients and healthy controls without a family history of schizophrenia. The only previous study of this relationship, to our knowledge, is that of [START_REF] Esterberg | Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls[END_REF], which dealt with a smaller sample.

One of the most striking findings of this study was the differences in the proportion of smokers and the level of nicotine dependence between the two groups. The proportion of smokers was higher and the level of nicotine dependence was greater in first-degree relatives than in controls. The proportion of smokers in our control group is similar to that reported for the general population (20-30%) [START_REF] Lyons | Nicotine and familial vulnerability to schizophrenia: a discordant twin study[END_REF]. The proportion of smokers in the group of relatives was intermediate between that in samples of schizophrenic patients (70% or greater) and that in the general population. Our results are consistent with those of previous studies [START_REF] Lyons | Nicotine and familial vulnerability to schizophrenia: a discordant twin study[END_REF][START_REF] Smith | Elevated rates of substance use disorders in non-psychotic siblings of individuals with schizophrenia[END_REF]. However, [START_REF] Esterberg | Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls[END_REF] reported a higher proportion of smokers in their control group, with similar levels of nicotine dependence in the two groups. The prevalence of smoking among healthy controls (66%) in the study by Esterberg et al. was much higher than the prevalence of smoking in the general population (20-30%), suggesting a possible recruitment biases. Furthermore, 90.2% of the subjects included in their sample were African-American, whereas our sample was entirely Caucasian. These two ethnic groups metabolize nicotine differently and have different specific smoking habits, with African-American reported to have higher levels of nicotine dependence and lower smoking cessation rates despite smoking fewer cigarettes per day [START_REF] Benowitz | Clinical pharmacology of nicotine: implications for understanding, preventing, and treating tobacco addiction[END_REF][START_REF] Gandhi | Lower quit rates among African American and Latino menthol cigarette smokers at a tobacco treatment clinic[END_REF]. The level of nicotine dependence in study by Esterberg et al. may therefore have been underestimated. Our results suggest that familialpossibly geneticfactors may make a major contribution to the relationship between schizophrenia and smoking. This hypothesis is clearly supported by several lines of genetic, biological and clinical evidence. The heritability of smoking behavior [START_REF] Spitz | Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients[END_REF][START_REF] Shields | Dopamine D4 receptors and the risk of cigarette smoking in African-Americans and Caucasians[END_REF][START_REF] Kendler | A population-based twin study in women of smoking initiation and nicotine dependence[END_REF] and the linkage demonstrated between schizophrenia and specific nicotinic receptor genes or nicotine-metabolizing enzyme genes confirm this genetic susceptibility [START_REF] Freedman | Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus[END_REF](Freedman et al., , 2001b;;[START_REF] Leonard | Association of promoter variants in the α7 nicotine acetylcholine receptor gene with an inhibitory deficit found in schizophrenia[END_REF][START_REF] Yoshimasu | Genetic influences on smoking behaviour and nicotine dependence: a review[END_REF][START_REF] Leonard | Smoking, genetics and schizophrenia: evidence for self medication[END_REF]. Furthermore, genetic linkage studies of smoking in schizophrenia have shown that these linkage sites coincide with replicated sites of linkage in schizophrenia [START_REF] Faraone | A novel permutation testing method implicates sixteen nicotinic acetylcholine receptor genes as risk factors for smoking in schizophrenia families[END_REF]. However, environmental factors common to schizophrenic patients and their relatives may contribute to the higher prevalence of smoking in these two groups. The hypothesis that relatives are mimicking the behaviour of schizophrenic subjects by smoking is unlikely, as most of the relatives in our sample were parents, who presumably started smoking before the probands.

We found no correlation between either smoking status or nicotine dependence and the level of schizotypy in either group of subjects. Several studies have reported a positive correlation between schizotypy and smoking status in the general population [START_REF] Williams | Tobacco smoking correlates with schizotypal and borderline personality traits[END_REF][START_REF] Larrison | Nicotine, caffeine, alcohol and schizotypy[END_REF][START_REF] Joseph | Personality, smoking motivation, and selfefficacy to quit[END_REF]. Interestingly, [START_REF] Esterberg | Nicotine consumption and schizotypy in first-degree relatives of individuals with schizophrenia and non-psychiatric controls[END_REF] found a positive relationship between smoking status and the level of schizotypy in their sample of first-degree relatives of schizophrenic subjects, but not in the control group. Our findings, conducted in a larger sample, do not support the hypothesis that relatives use nicotine as a form of "self-medication" to improve schizotypal traits. Unaffected first-degree relatives probably carry schizophrenia susceptibility genes, but, typically, do not suffer from the confounding effects of chronic illness and ongoing treatment. They are therefore, ideal subjects for studies of the possible trait-related markers of susceptibility to schizophrenia. Our results argue against the self-medication theory of smoking in schizophrenia, consistent with previous findings, including the observation that 90% of schizophrenic subjects begin smoking before they become ill, even before the prodromal phase [START_REF] De Leon | Initiation of daily smoking and nicotine dependence in schizophrenia and mood disorders[END_REF][START_REF] Gurpegui | Smoking initiation and schizophrenia: a replication study in a Spanish sample[END_REF]. The convincing evidence that smoking does not greatly alleviate schizophrenic symptoms is probably the absence of major changes to schizophrenic symptom scores in most trials in which schizophrenic subjects either stopped smoking or smoked less [START_REF] Dalack | Nicotine withdrawal and psychiatric symptoms in cigarette smokers with schizophrenia[END_REF][START_REF] Evins | A pilot trial of bupropion added to cognitive behavioral therapy for smoking cessation in schizophrenia[END_REF][START_REF] Evins | Independent effects of tobacco abstinence and bupropion on cognitive function in schizophrenia[END_REF][START_REF] Smith | Effects of cigarette smoking and nicotine nasal spray on psychiatric symptoms and cognition in schizophrenia[END_REF][START_REF] Fatemi | A double-blind placebo-controlled cross over trial of bupropion in smoking reduction in schizophrenia[END_REF].

Our study has several limitations. Firstly, the relatives had SPQ scores that were similar to those of the controls and therefore, lower than expected. There are several possible reasons for this. The relatives of schizophrenic patients may be more defensive in their responses to schizotypy questionnaires [START_REF] Calkins | Multiple dimensions of schizotypy in first-degree biological relatives of schizophrenia patients[END_REF] and there may be a selection effect, with only relatives with fewer schizotypal traits agreeing to participate in research studies. Secondly, although all relatives were euthymic at the time of assessment, we cannot not rule out the hypothesis that they smoke to improve their mood [START_REF] Berlin | Monoamine oxidase A and B activities in heavy smokers[END_REF][START_REF] Lerman | Depression and self-medication with nicotine: the modifying influence of the dopamine D4 receptor gene[END_REF], as being the parent of a schizophrenic patient may lead to depressive states. Similarly, we could not exclude the possibility of relatives smoking to improve cognitive deficits or due to a low socio-economic status, as shown for schizophrenic subjects. Thirdly, we did not take into account the fact that the relatives were older than the controls, and have therefore probably been exposed to more antismoking campaigns.

Our results provide support for the hypothesis that familial factors increase the prevalence of smoking in first-degree relatives of schizophrenic subjects, who have a "high genetic risk" of schizophrenia. If it can be confirmed that genetic factors make people at risk of schizophrenia more likely to smoke, this would have major implications for our understanding of the aetiology of schizophrenia.

The relatives of schizophrenic patients are at greater risk of becoming cigarette smokers. They therefore also have a greater risk of developing chronic health problems.

Efforts should therefore be made to prevent nicotine dependence in these relatives and, if necessary, to help them quit smoking if they have already started. Moreover, as some studies have suggested that nicotine may play a role in conversion to psychosis [START_REF] Kristensen | Cannabis abuse and risk for psychosis in a prodromal sample[END_REF] and that heavier smoking is associated with a greater risk of schizophrenia [START_REF] Weiser | Higher rates of cigarette smoking in male adolescents before the onset of schizophrenia: a historical-prospective cohort study[END_REF], special psychiatric monitoring could be proposed for young heavy smokers related to schizophrenic subjects, who are at greater risk of developing schizophrenia.

Acknowledgments

We thank M.J. Pereira-Gomes and E. Abadie for technical assistance.

We also thank the FondaMental foundation for technical support.


Delphin Levasseur
email: levasseur.d@icmcb-bordeaux.cnrs.fr

Heba Badr

El Din Badr

El-Din El-Shaarawi
email: heba_elshaarawy@yahoo.com

Sébastien Pacchini
email: spacchini@ntu.edu.sg

Anthony Rousseau
email: rousseau@icmcb-bordeaux.cnrs.fr

Sandrine Payan
email: payan@icmcb-bordeaux.cnrs.fr

Guillaume Guegan
email: guillaume.guegan@st.com

Mario Maglione
email: maglione@icmcb-bordeaux.cnrs.fr

H B El-Shaarawi

Systematic investigation of the annealing temperature and composition effects on the dielectric properties of solgel BaxSr1-xTiO3 thin films

Keywords: Films, Grain size, Dielectric Properties, BaTiO3 and titanates, Capacitors

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

1-Introduction

Over the past few years, ferroelectric thin films have been widely considered for tunable microwave devices. A good lead free candidate is Ba x Sr 1-x TiO 3 (BST), showing a high permittivity, a good tunability, and low dielectric losses. It is well known that downsizing ceramic to thin film, these dielectric properties are affected.

BST thin films can be prepared by several techniques such as MOCVD, RF-magnetron sputtering, pulsed laser ablation and sol-gel processes [START_REF] Baniecki | Dielectric relaxation of Ba 0.7 Sr 0.3 TiO 3 thin films from 1 mHz to 20 GHz[END_REF][START_REF] Horikawa | Dielectric properties of (Ba,Sr)TiO 3 thin films deposited by RF sputtering[END_REF][START_REF] Chrisey | Pulsed Laser Deposition of Thin Films[END_REF][START_REF] Burhanuddin | Ba x Sr l-x TiO 3 thin films by a chemical process[END_REF]. Among these techniques, sol-gel deposition is of a great industrial interest, using simple equipment and fast process. In addition, it offers some advantages, such as good film homogeneity and stoichiometry and large area deposition.

The main goal for applications is to understand and control the effect of the composition and of process parameters on the properties. Many studies have been carried out concerning the Ba/Sr ratio effect, on the optical properties [START_REF] Tian | Determination of the optical properties of sol-gel-derived Ba x Sr 1-x TiO 3 thin film by spectroscopic ellipsometry[END_REF][START_REF] Yang | Spectroscopic Ellipsometry of Ba x Sr 1x TiO 3 Thin Films Prepared by the Sol-Gel[END_REF][START_REF] Leng | Structural and optical properties of Ba x Sr 1-x TiO 3 thin films on indium tin oxide/quartz substrates prepared by radiofrequency magnetron sputtering[END_REF][START_REF] Wang | Composition dependence of structural and optical properties for sol-gel derived (100)-oriented Ba 1-x Sr x TiO 3 thin films[END_REF], on nanomechanical characteristics [START_REF] Jian | Nanomechanical characteristics of Ba x Sr 1-x TiO 3 thin films[END_REF], on the electrical properties [START_REF] Kribalis | Structural and electrical characterization of barium strontium titanate films prepared by sol-gel technique on brass (CuZn) substrate[END_REF][START_REF] Panda | Thickness and temperature dependent electrical characteristics of crystalline Ba x Sr 1-x TiO 3 thin films[END_REF] or dielectric properties at low frequencies [START_REF] Wang | Dielectric and Ferroelectric Properties of Ba 1-x Sr x TiO 3 Thin Films Prepared by Pulsed Laser Deposition[END_REF] and microwave frequencies [START_REF] Zhu | Recent Progress of (Ba,Sr)TiO 3 Thin Films for Tunable Microwave Devices[END_REF][START_REF] Ioachim | Barium strontium titanate-based perovskite materials for microwave applications[END_REF][START_REF] Costa | Microwave dielectric properties of the system Ba 1-x Sr x TiO 3[END_REF].

The most influential process parameter common in many synthesis or deposition techniques is the temperature [START_REF] Knauss | structure and dielectric properties of Ba x Sr 1-x TiO 3 ferroelectric thin films[END_REF][START_REF] Nayak | Electrical and dielectric properties of (Ba 0.5 Sr 0.5 )TiO 3 thin films prepared by a hydroxide-alkoxide precursor-based sol-gel method[END_REF][START_REF] Lu | Influence of annealing temperature on the band structure of sol-gel Ba 0.65 Sr 0.35 TiO 3 thin films on n-type Si(100)[END_REF]. Wu et al explored the effect of the annealing temperature for various compositions [START_REF] Wu | Dielectric tunable properties of (Ba 1-x Sr x )TiO 3 thin films on LaAlO 3 substrate[END_REF] on the dielectric properties but only at low frequency.

In this paper, a study of the structure, microstructure and of the dielectric properties at low and high frequencies of BST sol-gel thin films deposited by spin coating is presented, in which the effects of post-deposition annealing temperature and composition are investigated. To our knowledge, for the first time, a systematic behavior in terms of grain sizes, ferroelectric to paraelectric transitions and dielectric properties of three different Ba x Sr 1-x TiO 3 film compositions is reported, with x=0.7 (BST70), x=0.5 (BST50) and x=0.3 (BST 30). Radio Frequency measurements are also presented: a very high tunability at 10GHz is reported.

2-Experimental procedure

The Ba x Sr 1-x TiO 3 precursor sols used in this study were purchased from Mitsubishi Material Corporation, Japan. Thin films of approximately the same thickness were prepared by spin coating using three different compositions with x equal to 0.7/0.5/0.3. The films were deposited on Pt/Si substrate. Each coated layer was pyrolyzed, and the process was repeated in order to obtain the desired thickness. Finally the whole films were post-annealed under oxygen at various temperatures from 600 to 800°C. The phase formation and the film crystallinity were analyzed using a Panalytical X'pert MDP X-ray diffractometer in Bragg-Brentano geometry, with a 40kV working voltage. The grain size and morphology were investigated by scanning electron microscopy (SEM) using a Nova NanoLab 600 microscope at 15kV for the top view images, and a JEOL 6700 at 5kV for the cross section image.

So as to study the dielectric properties at low frequencies of our films, Metal-Insulator-Metal (MIM) structures were formed by depositing top electrodes by RF-magnetron sputtering at room temperature through a shadow mask. These 100 nm thick top electrodes were circular with a diameter of 600µm. The capacitance-voltage (C-V) characteristic of MIM capacitors were investigated at room temperature using a Süss Microtec PM5 probe system and a Hewlett Packard 4194A Impedance/Gain Phase Analyzer. The C-V curves were measured at 100 kHz and 0.1 V AC signal, and the dielectric permittivity was then calculated using capacitance, and the dimensional parameters: the thickness d obtained from cross section SEM images, and top electrode areas A measured with an optical microscope. The capacitance-temperature (C-T) characteristics were carried out in a home built measurement cell. The samples were mounted inside a furnace, in a vacuum chamber equipped with a cryogenic cooler. The furnace temperature was regulated with a Eurotherm device and a platinum resistance temperature sensor fixed on the furnace. A second Pt sensor was fixed in the substrate holder to give the sample temperature. The measurements were performed under helium atmosphere providing a good thermal contact. This system can afford a large temperature control range from -200°C to 150°C. Capacitance-Frequency (C-F) characteristics were measured with a Wayne Kerr 6500B Impedance Analyzer each 15 seconds during the sample temperature ramp up rate (0.5K/min) thereby giving C-T curves at many frequencies.

The RF properties were investigated on Parallel Plate Capacitors (PPC) shown in Fig. 1. A design consisting of two imbricate gold circle patches as signal and ground electrodes is patterned over BST layer. Two PPCs have been fabricated of dimensions given by: These dimensions take into account the RF probes pitch (150µm) needed to be satisfied for the measurement process (Fig. 1 (b)). One port reflection measurements of the parallel plate varactors at frequency ranges from 800 MHz to 30 GHz are carried out by using the Anritsu 37397C vector network analyzer (VNA) and Picoprobes with 150 µm GSG coplanar pitch. The bias voltage is supplied via the internal bias tee of the VNA that allows biasing up to 40V, while SOLT calibration is used. This method was first proposed by Ma et al. in [START_REF] Ma | RF Measurement Technique for Characterizing Thin Dielectric Films[END_REF]. One of the advantages of this test structure is its minimized parasitic R and L, in addition to its easy fabrication. A simplified model of this PPC may be given as shown in Fig. 2. Where the values of the capacitance and the resistance may be obtained from:

(1)

3-Results and discuss

3.1-Structure and microstructure analysis

The crystallinity of the films was studied by X-ray analysis. Fig. 3 shows diffractograms of BST70, BST50 and BST30 annealed at the same temperature (Fig. 3(a)) and BST70 annealed at different temperatures (Fig. 3(b)). As we can see, pure BST phase as been synthesized and the thin films are polycrystalline without preferential orientation. Silicon and Platinum diffraction peak can be seen on the XRD pattern, belonging to the substrate. The cell parameters, calculated from the diffractograms and shown in Table 1, are in good agreement with the bulk parameters [START_REF] Mcquarrie | Structural Behavior in the System (Ba, Ca, Sr) TiO 3 and its relation to certain dielectric characteristics[END_REF]. For the BST70 samples, a cubic structure pattern has been obtained, which let us think that the films are in paraelectric state at ambient temperature. Fig. 4 shows a better definition scan of the (110) peak of BST70. The intensity of the (110) peak increases from 600 to 700 °C and is then stabilizing between 700 and 800°C meaning that the crystallinity is improved with the temperature, reaching its maximum at 800°C. The full width at half medium (FWHM), decreasing with temperature increase, is associated with the grain size increase. Fig. 5 presents the SEM images of the surface of the BST70, BST50 and BST30 films annealed at 600, 700 and 800°C. For each composition, an increase of the grain size with the temperature can readily be seen, which is in agreement with the XRD analysis. For the BST70, the grain size around 30nm at 600°C, is up to 150nm at 800°C. At 600°C, the majority of the grains are separated by porosity, and the increase of temperature allows then the coalescence of those small grains. The coalescence also leads to a size increase of the intergranular porosity. Moreover, for a same annealing temperature, the grain size increases with raising the Ba/Sr ratio . BaTiO 3 melting temperature (T melt =1618°C) is indeed smaller than that of SrTiO 3 (T melt =2080°C), then when the Ba/Sr ratio is increased, the T anneal./ T melt ratio is increased and the grain growth improved. All these surface mappings were confirmed by cross section analysis shown in Fig. 6. As we can see, the out-of-plane grain sizes and morphologies are approximately the same than the top surface: the grains are spherical and disordered.

3.2-Dielectric measurements at low frequency

The permittivity vs. temperature curves of the thin films measured at 10kHz are shown in Fig. 7. Diffuse ferroelectric to paraelectric transitions can be seen. For each composition, the same behavior is observed with the increase of the annealing temperature: a global enhancement of the permittivity, sharper transition peaks, and a shift of the transition maxima T m toward higher temperature. Despite this temperature shift of T m , for the highest temperature annealed samples the maxima are approximately 25°C to 30°C lower than the bulk Curie temperature T c ( T c respectively 30°C, -25°C and -100°C for BST70, BST50 and BST30 [START_REF] Smolenskii | Ferroelectric Properties of Solid Solutions of Barium Stannate in Barium Titanate[END_REF]). This result confirms the cubic pattern obtain for BST70 in XRD analysis at ambient temperature. With the increase of the annealing temperature, the films tend to a bulk like behavior. This can be correlated with crystallinity increase and with the grain growth observed on Fig. 4 and Fig. 5. Assuming that the grain core is a high permittivity material and the grain boundary is a low permittivity material, increasing the grain size will decrease the low permittivity volume fraction in the layer and improve the global permittivity.

Sinnamon et al investigated the possibility that the dielectric collapse could be due to a grain boundary dead layer, rather than a dead layer interface [START_REF] Sinnamon | Exploring grain size as a cause for ''dead-layer'' effects in thin film capacitors[END_REF]. This hypothesis is correlated with the dielectric losses at 10kHz vs. temperature plot presented in Fig. 8. After a 600°C heat treatment, there isn't any losses peak at the transition temperature, corroborating the presence of a low losses material. The losses anomaly appears for the 700°C annealed sample and can be clearly seen after an 800°C heat treatment, showing the decreasing of the non-ferroelectric volume fraction such as grain boundaries.

On the other hand, the shift of the transition maximum has been previously discussed using a layered composite model [START_REF] Tagantsev | Ferroelectric materials for microwave tunable applications[END_REF], with inclusions of low permittivity layer by Berge et al. [START_REF] Berge | The effect of growth temperature on the nanostructure and dielectric response of BaTiO 3 ferroelectric films[END_REF]. It is shown that the appearing Curie temperature is strongly reduced by increasing the thickness of a dead layer. The presence of an interfacial dead layer could be confirmed by a study with thin films of different thickness, increasing the contribution of the dead layer in the permittivity [START_REF] Zhou | Intrinsic dead layer effect and the performance of ferroelectric thin film capacitors[END_REF][START_REF] Lee | Influences of interfacial intrinsic low-dielectric layers on the dielectric properties of sputtered (Ba,Sr)TiO 3 thin films[END_REF][START_REF] Park | Film-thickness-dependent Curie-Weiss behavior of (Ba,Sr)TiO 3 thin-film capacitors having Pt electrodes[END_REF], coupled with Transmission Electronic Microscopy at the interface region [START_REF] Liao | The interfacial structures of (Ba,Sr)TiO 3 films deposited by radio frequency magnetron sputtering[END_REF][START_REF] Chen | Effects of interface on the dielectric properties of Ba 0.6 Sr 0.4 TiO 3 thin film capacitors[END_REF]. Dielectric permittivity and losses measured at 10kHz as a function of external dc electric field at ambient conditions have been performed (Fig. 9). For each composition, the annealing temperature increase leads to an increase of the permittivity and losses at 0V, and also of the tunability (Table 2).

Such behavior is in perfect agreement with the crystallinity and grain size improvement reported in XRD and SEM analysis, and with the presence of low permittivity material with lower temperature heat treatment. The transition shift toward higher temperature observed with the annealing temperature increase also contributes to this dielectric properties improvement.

An increase of the permittivity, losses and tunability is also observed when the Ba/Sr ratio is increased. The higher the Ba content is, the higher is the transition temperature, so at ambient condition the measurement is performed at a temperature closer to the peak. It is well known that the non linearity of a ferroelectric material will be maximal at the Curie temperature; thereby we observe greater tunability when the Ba content is higher. Nevertheless, a raise of the dielectric losses is also obtained (Fig. 9). A tunability of the losses is observed for the well crystallized sample, confirming a higher ferroelectric material volume fraction. This result is in good agreement with the grain size growth and temperature dependence dielectric measurements.

On the Fig. 9 showing the permittivity and dielectric loss field dependences, a butterfly hysteresis shape that is typical of the ferroelectricity can be observed for the BST70 and BST50. Since the measurement were performed at room temperature, both BST70 and BST50 sample should be in the paraelectric state, as shown in Fig. 7. Different reasons can be found in the literature to explain the origin of this ferroelectric-like behavior in paraelectric thin films. One model proposed by Pontes et al is associated with oxygen vacancies and other space charges effect at the interface between the film and the substrate and/or at the grain boundaries [START_REF] Pontes | Effects of the postannealing atmosphere on the dielectric properties of (Ba,Sr)TiO 3 capacitors: Evidence of an interfacial space charge layer[END_REF]. Such space charges have been observed by TEM by Zhu et al [START_REF] Zhu | The origin of the weak ferroelectric-like hysteresis effect in paraelectric Ba 0.5 Sr 0.5 TiO 3 thin films grown epitaxially on LaAlO 3[END_REF]. Another explanation could be the appearance of local regions of ferroelectric polarization. Those polar nanoregions, which have been studied by Raman spectroscopy by Tenne et al [START_REF] Tenne | Raman study of Ba x Sr 1-x TiO 3 films: Evidence for the existence of polar nanoregions[END_REF] would be correlated with the broad peak of the permittivity in the temperature dependence.

3.3-RF characterization

RF measurements of the permittivity under different bias of the samples annealed at the higher temperature 800°C are presented in Fig. 10. Without bias, the extracted permittivity is constant on the whole frequency range. Under an electric field, resonances appear around 1, 3 and 5GHz, that may be due to an electrostrictive effect [START_REF] Gevorgian | dc field and temperature dependent acoustic resonances in parallel-plate capacitors based on SrTiO 3 and Ba 0.25 Sr 0.75 TiO 3 films: Experiment and modeling[END_REF]. As shown on Table 3, a very good continuity is obtained between the permittivity at low and high frequency. Moreover, very close values of tunability are measured at low and high frequency. A huge tunability of 70% is obtained under a 600kV.cm -1 electric field at10GH, for the BST70 sample annealed at 800°C.

4-Conclusions

This study has shown the effects of the annealing temperature and the composition of BST solgel thin films on the structure, microstructure and dielectric properties. A good correlation between the crystallinity, the grain size and the dielectric properties has been found. As expected, the increase of the heat treatment temperature increased the crystallinity, the grain size, and also restricted the contribution of non ferroelectric materials such as grain boundaries. These results corroborate the increase of the film permittivity, dielectric losses and tunability at low frequency. A shift of the ferroelectric to paraelectric transition toward the bulk Curie temperature has been observed with the increase of the annealing temperature, suggesting the decrease of a dead layer thickness.

A very reproductive behavior with the annealing temperature has been found for each BST composition. Furthermore, for a given annealing temperature, a clear effect of the Ba/Sr ratio has been seen: increasing the Sr content increases the melting point of the material, and mitigates the effect of the heat treatment. Thus, a decrease of the grain size, the dielectric permittivity, losses and tunability has been shown.

The RF results show values of permittivity and tunability in very good agreement with the low frequency results.

Capacitor 1 (

 1 Denoted by C a ): a a =20 µm, b a =60 µm, c a =280µm. Capacitor 2 (Denoted by C b ): a a =30 µm, b a =60 µm, c a =280µm.

Fig. 1 :

 1 Fig. 1 : (a) Layout of the fabricated MIM capacitors for the RF measurements, (b) Microscopic top view picture of the structure.

Fig. 2 :

 2 Fig. 2 : The equivalent series R-C model of a tunable MIM capacitor where "a" and "b" are suffix denoting the first and second capacitor, respectively.

Fig. 3 :

 3 Fig. 3 : XRD pattern of solgel BST thin films, (a) with different compositions annealed at the same temperature: 800°C, (b) for BST70 annealed at different temperatures: 600°C, 700°C and 800°C.

Fig. 4 :

 4 Fig. 4 : XRD centered on the 110 BST70 diffraction peak for different annealing temperature. Inset: table of the intensities and FWHM.

Fig. 5 :

 5 Fig. 5 : SEM images of top surface of solgel BST thin films with different compositions and different annealing temperatures.

Fig. 6 :

 6 Fig. 6 : SEM images of the cross section of solgel BST thin films with different compositions and different annealing temperatures.

Fig. 7 :Fig. 8 :

 78 Fig. 7 : Permittivity at 10kHz as a function of temperature of solgel BST thin films with different compositions and different annealing temperatures.

Fig. 9 :

 9 Fig. 9 : Permittivity and dielectric losses at 10kHz as a function of external electric field for solgel BST thin films with different compositions and different annealing temperatures.

Fig. 10 :

 10 Fig. 10 : Permittivity from 800MHz to 30GHz, under different bias, of the BST70, BST50 and BST30 samples annealed at 800°C. BST70 (800°C) BST50 (800°C) BST30 (800°C) Frequency 10kHz 10GHz 10kHz 10GHz 10kHz 10GHz Permittivity 410 325 250 200 160 140 Tunability @150kV/cm 49% 53% 40% 39% 19% 20%

Figure captions :Fig. 1 :Fig. 2 :

 12 Figure captions :Fig. 1 : (a) Layout of the fabricated MIM capacitors for the RF measurements, (b) Microscopic top view picture of the structure Fig. 2 : The equivalent series R-C model of a tunable MIM capacitor where "a" and "b" are suffix denoting the first and second capacitor, respectively.

Fig. 3 :

 3 Fig. 3 : XRD pattern of solgel BST thin films, (a) with different compositions annealed at the same temperature: 800°C, (b) for BST70 annealed at different temperatures: 600°C, 700°C and 800°C.

Fig. 4 :

 4 Fig.4: XRD centered on the 110 BST70 diffraction peak for different annealing temperature. Inset: table of the intensities and FWHM.

Fig. 5 :

 5 Fig. 5 : SEM images of top surface of solgel BST thin films with different compositions and different annealing temperatures.

Fig. 6 :

 6 Fig. 6 : SEM images of the cross section of solgel BST thin films with different compositions and different annealing temperatures.

Fig. 7 :

 7 Fig. 7 : Permittivity at 10kHz as a function of temperature of solgel BST thin films with different compositions and different annealing temperatures.

Fig. 8 :

 8 Fig.8: Dielectric losses at 10kHz as a function of temperature for solgel BST70 thin films annealed at different temperatures.

Fig. 9 :

 9 Fig. 9 : Permittivity and dielectric losses at 10kHz as a function of external electric field for solgel BST thin films with different compositions and different annealing temperatures.

Fig. 10 :

 10 Fig.10: Permittivity from 800MHz to 30GHz, under different bias, of the BST70, BST50 and BST30 samples annealed at 800°C.

Table 1 :

 1 table of the intensities and FWHM. Cell parameter of solgel BST thin films with different compositions and different annealing temperatures.

	Anneal. T	a (BST70)	a (BST50)	a (BST30)
	800°C	3.97(8) Å	3.95(3) Å	3.93(9) Å
	700°C	3.97(5) Å	3.95(4) Å	3.93(6) Å
	600°C	3.97(5)Å	3.95(3) Å	3.93(6) Å
	Bulk	3.974	3.952	3.932

Table 2 :

 2 Tunability for a 150kV/cm external electric field, for solgel BST thin films with different compositions and different annealing temperatures.

Table 3 :

 3 Comparison of the low and high frequency values of permittivity and tunability at 150kV/cm.

Table Captions :Table 1 :

 Captions1 Cell parameter of solgel BST thin films with different compositions and different annealing temperatures.

Table 2 :

 2 Tunability for a 150kV/cm external electric field, for solgel BST thin films with different compositions and different annealing temperatures.

Table 3 :

 3 Comparison of the low and high frequency values of permittivity and tunability at 150kV/cm.

Acknowledgement

The authors would like to thank Fabien Allanic from STMicroelectronics for the top surface SEM analysis, Céline Bondoux from STMicroelectronics for the thin film depositions, and Mitsubishi Material Corporation for the solgel solutions. Part of this work was supported by the French National Agency for Research under contract ABSYS2.