Sarah Terrien

Nicolas Stefaniak

Yannick Morvan

Chrystel Besche-Richard
email: chrystel.besche@univ-reims.fr

Factor structure of the French version of the Hypomanic Personality Scale (HPS) in nonclinical young adults

Keywords: hypomanic personality, HPS, general population, vulnerability, bipolar disorders

Hypomanic Personality Scale (HPS) is a self-report questionnaire designed to identify vulnerable individuals at high risk of bipolar disorders in non-clinical samples. Our aim was to identify the factorial structure of HPS in a French non-clinical sample and to compare this with different factor solutions described in the literature. We carried out a survey in a French population using a French version of HPS. A total of 698 participants were included in the study. They completed the HPS, the Schizotypal Personality Questionnaire-Brief (SPQ-B), the Positive And Negative Affect Schedule (PANAS), and the Beck Depression Inventory (BDI-II). We tested the 1, 3 and 4-factor solutions with a Confirmatory Factor Analysis to compare this with the factor solutions suggested by Rawling et al. and Schalet et al. Goodness-of-fit indices showed that Schalet et al.'s solution "fits" our data better than Rawling et al.'s factorial solutions. HPS scores correlated with the PANAS Positive score and the SPQ-B Total score. We confirmed the 3-factor structure of the HPS in a large non-clinical population of young adults and found consistent correlations with BDI, affectivity and schizotypal traits.

Introduction

Several clinical scales have been developed to detect and identify mental disorders [START_REF]Handbook of Psychiatric Measures[END_REF][START_REF] Maruish | The use of psychological testing for treatment planning and outcomes assessment[END_REF]. The development of these scales is also essential in order to detect high-risk individuals as soon as possible so that intervention is not delayed and the likelihood of patients receiving appropriate treatment and therapeutic care is increased [START_REF] Angst | The mood spectrum: improving the diagnosis of bipolar disorder[END_REF][START_REF] Miettunen | Identifying schizophrenia and other psychoses with psychological scales in the general population[END_REF]. This perspective is particularly relevant in the case of Bipolar Disorder (BD I and II) which is a cause of premature death and leads to a significant impairment of both social and cognitive functioning [START_REF] Angst | Mortality of 403 patients with mood disorders 48 to 52 years after their psychiatric hospitalisation[END_REF]. Indeed, Waugh et al., advocate that it is necessary to increase the level of screening in populations at high risk of developing bipolar disorders [START_REF] Waugh | A review of self-rating instruments to identify young people at risk of bipolar spectrum disorders[END_REF]. This view is corroborated by Angst et al.'s study which showed that many young adults (about 9% of the young adult population) seem to belong to a minor BD group who could be erroneously treated for depression due to the rigidity of the categorical diagnostic system used to identify BD [START_REF] Angst | Diagnostic issues in bipolar disorder[END_REF].

This problem is due to the fact that, while a scale for the identification of hypomanic components in unipolar depressive disorders exists [START_REF] Angst | The HCL-32: towards a self-assessment tool for hypomanic symptoms in outpatients[END_REF], there has been a lack of validated tools capable of identifying individuals with hypomanic personality in the general population.

Indeed, the lack of detection of hypomanic states in depression could explain the heterogeneity of the clinical forms of unipolar depressive disorders [START_REF] Hoertel | Subthreshold bipolar disorder in a U.S. national representative sample: prevalence, correlates and perspectives for psychiatric nosography[END_REF].

Whereas some individuals with high levels of hypomanic personality trait and unipolar depression are erroneously treated as a classical unipolar depressive patient whereas they would need a specific clinical supervision, others are not treated at all. However, several studies have also shown that individuals with high levels of hypomania are at higher risk of developing bipolar disorder [START_REF] Kwapil | A longitudinal study of high scorers on the Hypomanic Personality Scale[END_REF], including both BD I and II [START_REF] Savitz | Hypomanic, cyclothymic and hostile personality traits in bipolar spectrum illness: a family-based study[END_REF], and are at the highest risk of hospitalization due to various forms of psychosis [START_REF] Miettunen | Identifying schizophrenia and other psychoses with psychological scales in the general population[END_REF], manic symptoms [START_REF] Blechert | Are measures of hypomanic personality, impulsive nonconformity and rigidity predictors of bipolar symptoms?[END_REF] or internalizing symptomatology [START_REF] Klein | Hypomanic personality traits in a community sample of adolescents[END_REF].

In line with this finding, researchers have long proposed that normal mood states and bipolar disorder are situated on the same continuum [START_REF] Kretschmer | Physique and character[END_REF][START_REF] Wittman | A proposed classification of psychotic behavior reactions[END_REF] and this interpretation is still relevant today. According to Walsh et al., the bipolar spectrum model is more relevant for the treatment of BD than the current classification system [START_REF] Walsh | Looking for bipolar spectrum psychopathology: identification and expression in daily life[END_REF]. Moreover, Judd and Akiskal state that "The structure of bipolar disorder in the population appears to be dimensional in nature" [START_REF] Judd | The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases[END_REF] and therefore consider hypomanic personality to be possibly a sub-syndromal state of bipolarity [START_REF] Parker | The hypomanic personality scale: a measure of personality and/or bipolar symptoms?[END_REF].

The risk of developing BD among individuals presenting high levels of hypomania is so great that it prompted Eckblad and Chapman to propose the Hypomanic Personality Scale (HPS) in order to assess the risk of healthy people developing BD [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF]. This scale has been developed in the field of the personality trait conception and not in the field of temperament conception.

Indeed, this 48 true-false items self-report scale which reflecting the features of hypomanic personality have been constructed with the Jackson's recomendations (1970) for the construction of personality scale. This scale explores the usual features conventionally associated with hypomanic personality: being cheerful, optimistic, extraverted, self-confident, energetic, irritability, rude, reckless, irresponsible (e.g. [START_REF] Kwapil | A longitudinal study of high scorers on the Hypomanic Personality Scale[END_REF][START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF][START_REF] Akhtar | Hypomanic personality disorder[END_REF][START_REF] Evans | Familiality of temperament in bipolar disorder: support for a genetic spectrum[END_REF][START_REF] Young | A comparison of Tridimensional Personality Questionnaire dimensions in bipolar disorder and unipolar depression[END_REF]). The HPS has been shown to exhibit good internal consistency ( = .87) and good test-retest stability over a period of 15 weeks as well as over a period of 7 months (r = .81 and r = .77, respectively) [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF][START_REF] Meyer | Screening for bipolar disorders using the Hypomanic Personality Scale[END_REF]. [START_REF] Meyer | Screening for bipolar disorders using the Hypomanic Personality Scale[END_REF] . Beyond good indices of validity, the HPS have a good clinical sensibility. Indeed, seventy-eight percent of people scoring more than two standard deviations present criteria for mood disorders whereas none people presenting low score meet mood disorders criteria [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF]. A more recent study shows that high scores on the HPS are correlated with current mania symptoms [START_REF] Klein | Hypomanic personality traits in a community sample of adolescents[END_REF]. Finally, a 13year follow-up study have shown that HPS scores predict the risk for developing bipolar disorders (Kwappil et al., 2000HPS seems to be also a good tool to conduct cognitive study on hypomanic personality. Indeed, scores on this scale were associated to cognitive facets of mania (Eisner, Johnson, & Carver, 2008;Trevisani, Johnson, & Carver, 2008).

Moreover, Meyer et al. have shown cross-cultural validity for a German version of the HPS

From a theoretical perspective, Walsh et al. suggest that hypomanic personality is characterized by dysregulations in mood, cognition and behavior [START_REF] Walsh | Looking for bipolar spectrum psychopathology: identification and expression in daily life[END_REF]. Dysregulation in mood refers to euphoria, dysphoria, irritability and lability of affect. Dysregulation in cognition refers to racing thoughts, fullness of thought, grandiosity and unrealistic plans. Dysregulation in behavior refers to increased energy and sociability, behavioral disinhibition, impulsivity, and decreased need for sleep. Interestingly, while Walsh et al. consider that bipolar spectrum consists of three components, they only used the total HPS score in their analyses [START_REF] Walsh | Looking for bipolar spectrum psychopathology: identification and expression in daily life[END_REF]. This choice could be due to the fact that the items of the HPS can belong to different components and it is not possible to assign them to one component only. For instance, the item "I often have moods where I feel so energetic and optimistic that I feel I could" could be considered as referring to a behavioral dysregulation or a mood dysregulation. This approach is consistent with Eckblad and Chapman's initial theoretical view, which considered hypomanic personality as an homogenous construct. This view might find support in the high internal consistency of the HPS [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF][START_REF] Meyer | Screening for bipolar disorders using the Hypomanic Personality Scale[END_REF].

However, according to Schalet et al., the HPS must also be analyzed separately on its different subscales and not only on the total score. In line with this view, two studies have proposed a multifactor structure for the HPS [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF]. Rawlings et al. suggested a four-factor solution for the HPS: Affective component, cognitive component, hypersociability component and normality component [START_REF] Rawlings | A factor analytic study of the Hypomanic Personality Scale in British, Spanish and Australian samples[END_REF]. The affective component explores moodiness in the form of the irritability and restlessness of hypomanic personality. The cognitive component explores the cognitive elements of hypomania such as creativity, productivity and "grandiosity". The hypersociability component explores aspects such as the need for attention. Finally, the normality component explores one's ability to see oneself as normal.

Subsequently, Schalet et al. proposed a 3-factor model of the HPS which included the factors Social Vitality, Mood Volatility and Excitement [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF]. According to Schalet et al., Mood Volatility explores negative, unpredictable mood states and hypomanic cognition; the Excitement dimension explores the energetic, extremely cheerful mood exhibited by such individuals; and Social Vitality explores social potency and vivaciousness [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF].

Nevertheless, up to now, the different studies (i.e., [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF][START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF][START_REF] Rawlings | A factor analytic study of the Hypomanic Personality Scale in British, Spanish and Australian samples[END_REF]) which have analyzed the factor structure of the HPS have only performed exploratory factor analyses. The problem with an exploratory factor structure (or cluster) analysis lies in the fact that these analyses are guided by the data [START_REF] Goldgberg | Revealing structure in the data: Principles of exploratory factor analysis[END_REF]. This problem explains why there are discrepancies in the factor structure of the HPS between the different studies.

The aim of the present study is to compare the different factor structures proposed in the literature in order to determine which is the optimal theoretical approach for the use of the HPS.

2. Method 2.1. Participants and procedure XXXX students were included in our study with XXX responding on paper-and-pencil test and XXX responding in online study Altogether, 698 participants were included (79% women; mean age in years = 22.1 ±8.2; education level in years = 13.1±1.8). They all received self-rated questionnaires, including questions on socio-demographic variables, and self-administered scales. There was no financial or course credit compensation for the participants. The study was anonymous and all participants gave written or electronic informed consent using methods approved by the Ethics Committee of the Cognition, Health and Socialization Laboratory of Reims Champagne-Ardenne University. The study was designed in accordance with the Declaration of Helsinki.

Measures

Hypomanic Personality Scale (HPS)

Eckblad and Chapman developed this scale to assess the risk of developing BD among healthy populations [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF]. It is a self-report scale which contains 48 true-false items reflecting the features of hypomanic personality. The distribution of the items to the different factors is presented separately in Table 1 for both the three-and four-factor models. The translation of the HPS's items was carried out as follows: we translated the items from English to French.

After this first stage, a bilingual English-French speaker back translated the translated items into English. Discrepancies emerging between the back translated and the original English versions were discussed, and translation adjustments were consensually made.

Please Insert Table 1

Beck Depression Inventory (BDI-II)

The BDI-II [START_REF] Beck | Comparison of Beck Depression Inventories -IA and -II in psychiatric outpatients[END_REF] is a 21-item self-report measure administered to determine the presence and severity of depressive symptoms.

Schizotypal Personality Questionnaire-Brief (SPQ-B)

The SPQ-B [START_REF] Raine | The SPQ-B: a brief screening instrument for schizotypal personality disorder[END_REF] is a self-report scale which contains 22 true-false items relating to the features of schizotypal personality. This scale is subdivided into three subscales: cognitive perceptual deficits (magical thinking, paranoid ideation, unusual perceptual experiences and reference ideas), interpersonal deficits (anxiety, emotional blunting and difficulty in having close friends) and disorganization (odd behavior and odd language).

Positive and Negative Affect Schedule (PANAS)

The PANAS is a self-report scale which contains 20 adjectives that measure general dimensions of negative or positive affectivity [START_REF] Watson | Development and validation of brief measures of positive and negative affect: the PANAS scales[END_REF]. Participants rate how they have felt up to the present moment using a five-point rating scale, ranging from 1 ("very slightly or not at all") to 5 ("extremely"). There are 10 items in the negative affect scale (e.g., "nervous", "guilty") and 10 items in the positive affect scale (e.g., "alert", "proud").

Statistical analyses

Descriptive statistics, internal consistency reliability (Cronbach's α) coefficients, and Bravais-Pearson correlations between HPS, SPQ-B, BDI and PANAS scores were computed using Statistica 7.1. R (package Lavaan and psych) was then used for a Confirmatory Factor Analysis (CFA) and to compute the internal consistency of the HPS. This CFA was conducted on the whole sample (n=698). The level of significance was fixed at 0.05 and the indices used to assess the fit of the measurement model to the data were similar to those used by Compton [START_REF] Compton | An examination of the factorial structure of the Schizotypal Personality Questionnaire-Brief (SPQ-B) among undergraduate students[END_REF], i.e. ²/df <5, RMSEA <.08, GFI and AGFI >.90. We also conducted correlation analyzes on a partial sample (n = 590) to evaluate the construct validity of the HPS. Test-retest analyses were conducted on a sample of 58 participants.

Results

Factor validity

In the analyses, we first used a confirmatory factor analysis to try to replicate either Schalet et al.'s [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF] or Rawlings et al.'s [START_REF] Rawlings | A factor analytic study of the Hypomanic Personality Scale in British, Spanish and Australian samples[END_REF] exploratory factor structure or the one-factor model resulting from the theoretical point of view proposed by Eckblad and Chapman [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF].

We explored both these models using confirmatory factor analyses. The confirmatory factor analysis was performed on the tetrachoric correlations using the Means and variance Adjusted Weighted Least Squares (WLSMV) parameter estimation method in order to assess the factor structure of the HPS in the French-speaking adult population. When performing the analyses, we first treated residual errors as uncorrelated. In the light of Schalet et al.'s factorial structure, we excluded items 12, 14 and 24 because they did not load well on any factor in the three-factor solution [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF]. This analysis revealed that the data were fitted to the model. These different indices revealed a reasonably good fit between the data and the model since the ² value was not greater than five times the degree of freedom, the RMSEA was close to .05, and both the GFI and the AGFI were greater than 0.95. The different fit indices are summarized in Table .

Please insert Table 2

Rawlings et al.'s (2000) model does not suggest which items should be assigned to the four factors. On the basis of Rawling et al's results, we assigned each item to the factor on which it had the highest loading [START_REF] Rawlings | A factor analytic study of the Hypomanic Personality Scale in British, Spanish and Australian samples[END_REF]. Two items (items 30 and 39) were excluded from the model because their loadings were very low on all four factors (less than .20). Moreover, item 7 was also excluded because the highest loading was low (.21) and was identical on Factor 2 and on Factor 3. This analysis revealed that the data fitted the model slightly less well. As with the 3factor structure, these different indices revealed a reasonably good fit between the data and the model but were marginally lower than those provided by the three-factor structure. ² was lower in the three-factor model, while there were more degrees of freedom (see Table 2).

Finally, an analysis on the one-factor structure, which corresponds to the theoretical point of view proposed by Eckblad and Chapman [START_REF] Eckblad | Development and validation of a scale for hypomanic personality[END_REF], revealed that the data also fitted the model reasonably well. Even though there was a reasonably good fit between the data and the model, the statistical indices were marginally lower than those provided by the three and the fourfactor structures. ² was higher in the one-factor model than in the three and the four-factor models (see Table 2).

Overall, it appears that the three-factor structure provides a slightly better or equivalent fit compared to the four-factor structure. However, the three-factor structure might be preferable because it is more parsimonious and contains more items with a loading lower than .30.

Internal consistency

In order to determine the internal consistency of the HPS, we computed Cronbach's alpha for 45 items. Cronbach's α was 0.90 for the overall scale, .85 for the Social Vitality factor .83 for the Mood Volatility factor and .80 for the Excitement factor (see Table 3).

Please Insert Table 3

Construct validity

Finally, we looked at the construct validity of the HPS by analyzing the correlation between HPS scores and scores for measures of variables linked to hypomania, such as depression in the BDI, the affective state dimension of participants in the PANAS, and the level of schizotypy in the SPQ-B (see Table 4).

Please Insert Table 4

The total HPS score revealed a significant positive correlation with the PANAS Positive score In order to better characterize whether the size of the correlations between each subscale of the HPS and the different other questionnaires, we performed pairwise correlation comparisons. This analysis allows to determine whether, when several subscales are correlated to another questionnaire, the size of the correlation could be considered as similar.

Bonferroni's correction has been applied to the p values in order to avoid multiplication of Type I error. The results of these comparisons are provided in Table 5.

Please Insert Table 5.

Table 5 suggests that PANAS positive score is significantly less related to mood volatility subscale that to the other subscales. Conversely, the correlations between the different subscales of the HPS and the PANS negative score appear quite similar. The SPQ is significantly more correlated to the mood volatility than to the other subscales. Finally, it appears that the absence of correlation between the the BDI and the HPS total score is due to the fact that the BDI is negatively correlated to the social vitality subscale while it is positively related to the mood volatility and the difference between both these correlation is significant. Conversely, Excitement is not related to the BDI, and this absence of correlation is signicantly different from both correlations between the social vitality and the mood volatility subscales with the BDI.

Test-retest validity

After three weeks, the HPS was again administered to 56 participants. The test-retest reliability was assessed by Bravais-Pearson correlation and, for this sample, was .86 for both the Social Vitality factor and the Mood Volatility factor, .88 for the Excitement factor and .82 for the Total scale.

Moreover, given that Meyer and Hautzinger (2001) showed that older individuals would present lower scores to the HPS than youngers, we also tested the stability of the mean by computing ICC (Shrout & Fleiss, 1979). The ICCs are 0.92 for the total scale, 0.86 for the Social Volatility subscale, 0.84 for Mood Volatility, and 0.87 for Excitment.

Discussion

The goal of this study was to compare the different factor model structures presented in different studies in order to ascertain the optimum theoretical approach by using the HPS in a large non-clinical sample of young adults in France. To answer this question, we conducted Volatility and Excitement. Regarding the items included in the Mood Volatility factor, we found that the name of this factor does not accurately reflect the variables measured as part of this factor. Indeed, it seems that only two items (out of 16) actually explored the lability of participant's mood. Furthermore, these two items were moderately correlated with the factor: namely item 21. "My moods do not seem to fluctuate any more than most people's do" (-.115); and 37. " I seem to be a person whose mood goes up and down easily" (.286). Thus, we suggest that the name "Hypomanic mood" might be more appropriate for items such as: "I frequently get into moods where I feel very speeded-up and irritable" (.442), "There have often been times when I had such an excess of energy that…" (.522); "I very frequently get into moods where I wish I could be everywhere and do everything . . ." (.479). This proposal is consistent with the result of Parker et al.'s study even though this was not conducted in a healthy population but in a group of bipolar and unipolar patients [START_REF] Parker | The hypomanic personality scale: a measure of personality and/or bipolar symptoms?[END_REF]. Indeed, these latter authors named the first factor in their analysis "Hypomanic Mood" and this factor consisted of 14 items, eight of which are also present in our Mood Volatility factor.

The fact that the three-factor model [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF] fits our data better than the one-factor structure shows that, when studying the HPS, it is necessary to analyze the results in the light of the different factors involved in the scale and not on the basis of the total score alone.

Furthermore, recent studies have shown that the "Mood Volatility" factor is the factor which best predicts the risk of developing BD [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF] and that this score is the only one that is linked to cognitive ToM performances in a general male population [START_REF] Terrien | Theory of mind and hypomanic traits in general population[END_REF]. Thus, it appears that is necessary to take into account the different factors of the HPS, and especially the Mood Volatility factor, if we are to study the functioning of individuals evaluated using this scale.

Concerning the internal consistency of the HPS with the three-factor model, only one Cronbach's α value was just below 0.70, thus complying with the usual rule of thumb for good reliability. This can be attributed to the fact that this factor has more reversed items. The alphas for the overall scale and the other two factors can be considered as good. The results also show a very good test-retest stability and therefore indicate the good internal validity of the HPS.

An examination of the correlations between the HPS scores and measures of variables that could be linked to hypomania showed that the total HPS score and all the HPS subscales are positively related to the positive affective state dimension of the PANAS. These correlations seem to be consistent with the nature of the dimension we wish to measure. Indeed, positive affectivity is described as a high-energy, pleasurable engagement that can be found in hypomania. Concerning the positive correlation between the Mood Volatility and the BDI, Mood Volatility is the subscale of the HPS that should best predict the risk of developing bipolar disorder [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF]. It is therefore no surprise to find a positive correlation between the subscale which best predicts the risk of developing bipolar disorder and a depression scale. Indeed, the HPS predicts not only the risk of developing BD but also the risk of experiencing major depressive episodes [START_REF] Kwapil | A longitudinal study of high scorers on the Hypomanic Personality Scale[END_REF].Observation of an inverse correlation between the negative dimension of the PANAS and the HPS Mood Volatility subscale could be surprising "au regard de la correlation précédente". However, this negative correlation makes sense because negative affectivity is described in terms of distress, pleasureless energy and aversive mood states [START_REF] Watson | Development and validation of brief measures of positive and negative affect: the PANAS scales[END_REF], which were opposites terms of hypomania and positive dimension of PANAS. Furthemore, the PANAS was originally constructed to determine the different types of affectivity in individuals and not to predict the risk of developing bipolar depression. Indeed, individuals who scored high on Mood volatility subscale could were not presented negative affectivity but depression traits. Concerning the negative relationship between the BDI and Social Vitality, this is consistent with Schalet et al.'s results which showed that people who scored high on the Social Volatility subscale might be less likely to develop depression [START_REF] Schalet | Multidimensional structure of the Hypomanic Personality Scale[END_REF]. Furthermore, the Social Volatility factor corresponds to the second factor in Parkers et al.'s study, which is named "grandiosity" [START_REF] Parker | The hypomanic personality scale: a measure of personality and/or bipolar symptoms?[END_REF]. The concept of "grandiosity" is opposed to some BDI items like: "I feel I am a complete failure as a person", "I hate myself". HPS total score and two subscales out of three (Excitement and Mood Volatility) are linked with another measure of personality referred to as schizotypal personality. Schizotypal traits are frequently found in the general population [START_REF] Stefanis | Factorial composition of self-rated schizotypal traits among young males undergoing military training[END_REF][START_REF] Mata | Schizotypal Personality Questionnaire-Brief: factor structure and influence of sex and age in a nonclinical population[END_REF][START_REF] Fonseca-Pedrero | Validation of the Schizotypal Personality Questionnaire-Brief Form in adolescents[END_REF][START_REF] Esterberg | The psychosis continuum and categorical versus dimensional diagnostic approaches[END_REF] and are viewed as the subclinical expression of the 'schizophrenia spectrum' [START_REF] Raine | Schizotypal personality: neurodevelopmental and psychosocial trajectories[END_REF][START_REF] Van Os | A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis pronenesspersistence-impairment model of psychotic disorder[END_REF]. Indeed, this result is consistent with a newly emerging area of research that defends the idea of a continuum between the bipolar and schizophrenia spectra [START_REF] Hill | Neurocognitive allied phenotypes for schizophrenia and bipolar disorder[END_REF][START_REF] Angst | Diagnosis and course of affective psychoses: was Kraepelin right?[END_REF][START_REF] Van Snellenberg | Meta-analytic evidence for familial coaggregation of schizophrenia and bipolar disorder[END_REF][START_REF] Craddock | The Kraepelinian dichotomy -going, going... but still not gone[END_REF]. 2009) study indicated that high HPS score were associated to enhancement of positive affect and irritability. All of these authors dealing with cognition and hypomanic personality in their conclusion associated an high score on HPS to a risk to develop mania, which could be reinforced the idea "selon laquelle" the HPS measures a stable trait.

Nevertheless, our study has several limitations. First, the analysis was carried out in a large sample of students, with a high proportion of women (79%). The nature of the French education system, where there are no selection criteria for the first year of university, means that first-year students can be considered to be fairly representative of the general population [START_REF] Vredenburg | Analogue versus clinical depression: a critical reappraisal[END_REF] and therefore suitable for the study of psychiatric symptoms as exhibited by college students. Second, we did not assess for the presence of hypomanic/manic symptoms, for example with the Young Mania Rating scale which is commonly used in bipolar disorders, because our sample was not clinical. However, Parker et al. have recently pointed out that the "hypomanic mood" factor of the HPS could be similar to the hypomanic/manic mood states that occur during bipolar disorders [START_REF] Parker | The hypomanic personality scale: a measure of personality and/or bipolar symptoms?[END_REF]. The binary answers to the HPS did not make it easy to discriminate between hypomanic traits and symptoms and did not allow us to evaluate the intensity of the traits. Furthermore, the observation of an overlap between certain items of the HPS and manic symptoms does not necessarily contradict the idea of a "hypomanic traits personality". Indeed, the idea of a continuum between normal mood states and bipolar disorder has been around for more than 50 years [START_REF] Kretschmer | Physique and character[END_REF][START_REF] Wittman | A proposed classification of psychotic behavior reactions[END_REF]. Furthermore, a recent study has placed this continuum at center stage by asking the question of whether the "bipolar spectrum model" might be more relevant for the treatment of bipolar disorder than the current categorybased classification [START_REF] Walsh | Looking for bipolar spectrum psychopathology: identification and expression in daily life[END_REF]. Last, and as a consequence of the results of Parker et al.'s study, it was necessary to use a standard tool, such as the MINI [START_REF] Sheehan | The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10[END_REF], in order to eliminate past or current diagnoses of bipolar disorder or major depression from our sample. However, as suggested by Parker et al., it will also be necessary in the future to fine-tune the instructions used for the HPS in order to center on the identification of personality traits.

Conclusion

The confirmatory factor analysis in a non-clinical sample supported Schalet et al.'s model and confirmed the three-factor structure of the HPS consisting of the factors: Social Vitality, Mood Volatility and Excitement. We suggest changing the name of the second factor to "Hypomanic Mood" in order to illustrate the content of this factor more clearly. The results also suggest that it might be better to examine the three factors of this scale separately. The correlation between the HPS score and the BDI supports the idea of a continuum between hypomanic personality and depressive disorder. In addition, the correlation between the HPS score and the SPQ score supports the hypothesis according to which there is a continuum, and possible overlap, between the bipolar and schizophrenia spectra. Overall, we have provided further confirmation of the validity of the HPS in its French translation and this should constitute a valuable tool for studies that wish to identify hypomanic endophenotypes in nonclinical samples.

  and the SPQ-B Total score. Concerning the HPS subscale scores, we found a significant positive correlation between the HPS Social Vitality score and the PANAS Positive score; and a negative correlation with the BDI Total score. For the HPS Mood Volatility subscale, we observed a positive correlation with the PANAS Positive score, the SPQ-B Total score and the BDI Total score; and a negative correlation with the PANAS Negative score. Finally, we found a positive correlation between the HPS Excitement score and the PANAS Positive score and SPQ-B Total score.

  three separate exploratory factor analyses on: the four factor model proposed by Rawling et al., the three factor model proposed by Schalet et al. and the one-factor model which corresponds to the theoretical viewpoint advocated by Eckblad and Chapman [19, 24, 25]. The indices revealed a reasonably good fit between our data and Rawling et al.'s model (2000) and the one-factor model, but were lower than those provided by Schalet et al.'s (2011) threefactor structure. Schalet et al.'s (2011) structure therefore seems to provide a better fit for a sample taken from the French population. The three factors are: Social Vitality, Mood

  Most of studies dealing with cognitive and emotional abilities in general population who presented risk to develop bipolar disorders have used the HPS. Deldulca et al. (2010) have shown that people who scored high on HPS seems to have particularities in autobiographical memory: they recalled more frequently and more faster specific autobiographical memories in response to unpleasant cues than individuals who scored low on HPS. Trevisani et al. (2008) demonstrated that individuals who scored high on HPS have facilities to detect subtly positive facial expressions. Fulford et al. (2009) have shown that during positive mood, people who scored high on HPS were associated present an enhancement of cognitive flexibility. Gruber et al.'s (

Table 1

 1

	Factor	Items
		Rawlings et al. (2000)
	1	8, 10, 11, 15, 17, 18, 20, 21, 22, 24, 31, 33, 35, 37, 38, 44, 45, 46
	2	5, 9, 12, 13, 19, 23, 26, 28, 34, 36, 41, 42, 43, 47, 48
	3	2, 3, 4, 6, 25, 29, 32, 40
	4	1, 14, 16, 27
		Schalet et al. (2011)
	Social vitality	1, 2, 4, 6, 7, 13, 16, 18, 23, 25, 26, 27, 29, 30, 34, 36, 39, 40, 42, 47, 48
	Mood volatility	5, 8, 9, 10, 19, 20, 21, 22, 28, 31, 35, 37, 38, 41, 43, 44, 45
	Excitement	3, 11, 15, 17, 32, 33, 46

Table 2 .

 2 Results of the confirmatory factor analyses conducted with the 1, 3 and 4-factor models.

	Fit indices	1-factorstructure	3-factor structure	4-factor structure
	² (df)	3745.57 (1080)	3153.96 (942)	3271.71 (939)
	p value	<.001	<.001	<.001
	RMSEA (C.I.)	0.06 (0.57-0.062)	.058 (.056-.060)	.060 (.057-.062)
	GFI	0.993	.994	.994
	AGFI	0.992	.993	.993
	²df	3.47	3.34	3.48

Table 3 .

 3 Loading for items split on the 3-factor structure.

		Social	Mood
	Item	Vitality	Volatility Excitement
	1. I consider myself to be pretty much an average
	kind of person	-0.237
	2. It would make me nervous to play the clown in
	front of other people	-0.289
	4. I think I would make a good nightclub comedian	0.401
	6. When with groups of people, I usually prefer to
	let someone else be the center	-0.282
	7. In unfamiliar surroundings, I am often so
	assertive and sociable that I surprise myself	0.362
	13. People often come to me when they need a
	clever idea	0.289
	16. I can't imagine that anyone would ever write a
	book about my life	-0.333
	18. I often have moods where I feel so energetic and
	optimistic that I feel I could ...	0.423
	23. I expect that someday I will succeed in several
	different professions	0.38
	25. When I go to a gathering where I don't know
	anyone, it usually takes me a while ...	-0.311
	26. I think I would make a good actor, because I can
	play many roles convincingly	0.427
	27. I like to have others think of me as a normal
	kind of person	-0.286
	29. I have often persuaded groups of friends to do
	something really adventurous or crazy	0.531
	30. I would really enjoy being a politician and
	hitting the campaign trail	0.246
	34. There are so many fields I could succeed in that
	it seems a shame to have to pick	0.314
	36. I find it easy to get others to become sexually
	interested in me	0.312
	39. I am so good at controlling others that it
	sometimes scares me	0.339
	40. At social gatherings, I am usually the "life of the
	party"	0.386
	42. I seem to have an uncommon ability to persuade
	and inspire others	0.467
	47. I would rather be an ordinary success in life than
	a spectacular failure	-0.263
	48. A hundred years after I'm dead, my
	achievements will probably have been forgotten	-0.301
	5. Sometimes ideas and insights come to me so fast
	that I cannot express them all	1	0.453
	8. There are often times when I am so restless that it
	is impossible for me to sit still	1	0.461
	9. Many people consider me to be amusing but kind	1	0.452

Table 4 .

 4 Two-tailed correlations between total and sub-scores for HPS and Affectivity, Schizotypy and Depression (n = 589).

		HPS Total	HPS Social	HPS Mood	HPS
		score	Vitality	Volatility	Excitement
	PANAS	.340**	.371**	.161**	.295**
	Positive

* p < .05. ** p < .01.

Acknowledgments

This work was supported by the French Agence Nationale de la Recherche (ANR) (Grant number ANR-11-EMCO-001 01). We thank to Marine Blondel and Andrei Hadjiu for their help in the collection of the data. We are grateful to Tim Pownall for reviewing the English style.

Contributors

ST wrote the manuscript, collected data and contributed to the elaboration of this research.

NS realized statistical analysis.

YM contributed to the elaboration of this research as a data manager.

CBR supervised data collection and took the lead role in the preparation and the writing of the manuscript.

PANAS


Nicolas Stefaniak

Stéphanie Caillies

Christelle Declercq

Fiorine Preto

Thierry Meulemans

The semantic priming effect: how to explain individual differences?

come   L'archive ouverte pluridisciplinaire

Experiment 1

-For 30 years, SP studies focused item features which influenced the size of the SP effect, in particular the association strength between the prime and the target words (e.g., [START_REF] Chwilla | Three strep-priming in lexical decision[END_REF].

-More recently, SP studies focused on individual differences in the SP effect: Yap et al. showed that the association strength had no impact in participants with high vocabulary knowledge, but had an impact in participants with low vocabulary knowledge. They argued that people with high vocabulary knowledge were able to create equally strong associations between concepts even when they were less semantically related. -This explanation has never been directly tested.

-The aim of Experiment 1 is to determine whether, when vocabulary is maintained constant, the ability to create more association between concepts can explain the size of the SP effect.

Abstract

Several studies have shown that semantic priming (SP) is directly associated to the association strength between the prime and the target words (e.g., [START_REF] Chwilla | Three strep-priming in lexical decision[END_REF]. However, Yap et al. (2010) showed that this phenomenon was only observed in people with little vocabulary knowledge. They argued that participants with more vocabulary knowledge made equally strong representations for weak and strong related stimuli. However, this explanation is not sufficient because individual differences in SP have been shown even when vocabulary is controlled. We hypothesize that the SP effect should be larger for participants who are more able to identify similarities between words, independently of their vocabulary knowledge, and that this ability would depend on implicit learning processes (see [START_REF] Kaufman | Implicit learning as an ability[END_REF]. In Experiment 1, participants performed two tasks. In the first one, they were presented a pair of words for which they were asked to identify as many words as possible which could associate both these words. In the second one, they performed an SP task (i.e., a lexical decision task in which some prime and target pairs were semantically related). In Experiment 2, they performed an implicit learning task (i.e, serial reaction time task) and an SP task. Results show that, when vocabulary is controlled, the SP effect is determined by the ability to identify similarities between concepts and by implicit learning abilities. These results are discussed in the context of Ullman's ( 2001

Results

Experiment 2

Can implicit learning abilities predict the size of the semantic priming effect?

Results

Contact: nicolas.stefaniak@univ-reims.fr -Given that the ability to create many associations between concepts is directly involved in the size of SP effect (Experiment 1), the SP effect should depend on implicit learning abilities.

-The aim of Experiment 2 is to determine whether implicit learning abilities can predict the SP effect

  of words provided during the FAT a predictor of the size of semantic priming?

-

  Tell me as many words which could relate both the following words as possible Are both letter strings French words?Press the corresponding key of the stimulus as fast and as accurately as possible. 50 pairs -15 semantically related (e.g., skirt and pants), 15 semantically related by a mediator (e.g., lion -tiger [not seen]-stripe), 15 non related pairs (e.g;: package -oil) 50 pairs -15 semantically related, 15 counterbalanced, 15 filler and 45 pseudoword pairs SOC sequences: 342312143241 (SOC1) or 341243142132 (SOC2) 8 presentations by block Block 1-13: learning blocks Block14 : transfer block: Block 15: learning block Discussion -Support the idea that free association is a good measure of semantic relatedness -Support the fact that semantic priming depends on the strength of associations between the prime and the target, even in -Contrary to Ullman's (2001) view, lexicon, and more specifically relationships between concepts, is not only supported by declarative memory but also by the procedural memory -The fact that associations between concepts are underlied by implicit learning abilities support the dual-process theory (Evans & Frankish, 2009) Perspectives -Does implicit learning abilities can explain the ability to create associations between concepts? -Modeling (SEM) the relationships between implicit learning abilities, creating associations between concepts and the size of the semantic priming effect? -What about with a probabilistic sequence? -Can differences in semantic priming effect explain the ability to better understand figurative language? Experiment 2 According to the dual-process theory, associative learning is sustained by implicit learning mechanisms. -According to Kaufman et al. (2010), implicit learning is involved in verbal analogical reasoning.


Mélanie Labalestra
email: melanie.labalestra@umons.ac.

Nicolas Stefaniak
email: nicolas.stefaniak@univ-reims.fr

Laurent Lefebvre
email: laurent.lefebvre@umons.ac.be

Chrystel Besche-Richard
email: chrystel.besche@univ-reims.fr

Mélanie Labalestra

Labalestra Mélanie

Dr Stefaniak Nicolas

Lefebvre Laurent

Pr Besche-Richard Chrystel

Mlle Labalestra

Pr Lefebvre

La mémoire sémantique dans le trouble bipolaire : une revue de la littérature

Keywords: mémoire sémantique, trouble bipolaire, amorçage sémantique, fluences verbales semantic memory, bipolar disorder, semantic priming, verbal fluency

teaching and research institutions in France or abroad, or from public or private research centers.

Résumé

L'existence de similitudes symptomatiques et cognitives entre la schizophrénie et les épisodes maniaques du trouble bipolaire a mené certains auteurs à émettre l'hypothèse d'une altération de certaines fonctions cognitives dans la schizophrénie qui pourraient également l'être dans le trouble bipolaire. C'est notamment le cas pour la mémoire sémantique. L'origine des dysfonctionnements sémantiques est différente entre les deux troubles alors qu'ils sont associés aux troubles formels de la pensée dans la schizophrénie, cela ne semble pas être le cas dans le trouble bipolaire. Par ailleurs, alors que les processus sémantiques altérés sont clairement identifiés dans la schizophrénie, des résultats contradictoires et peu comparables sont obtenus chez les patients bipolaires. Les études semblent néanmoins se diriger vers une atteinte probable des processus d'activation/inhibition sémantique durant les phases maniaques qui pourrait persister durant les périodes de rémission. Une atteinte de processus plus généraux tels que les processus d'inhibition et/ou les processus émotionnels ayant un impact sur la mémoire sémantique n'est cependant pas exclue.

Abstract

Symptomatic and cognitive similarities between manic states in bipolar disorder and schizophrenia have led some authors to explore the functioning of semantic memory in bipolar disorder in order to assess whether the semantic memory alterations observed in schizophrenia are found in bipolar disorder. While the dysfunctions of semantic processes are associated with formal thought disorders in schizophrenia, it appears that it is not the case in bipolarity. Moreover, while altered semantic processes are clearly identified in schizophrenia, discrepancies between studies are observed in bipolar patients. The lack of consensus could be due to heterogeneity of methodology or to the sample of patients who participated to the study. However, the studies suggest a probable impairment of semantic activation / inhibition processes during the manic phases that could persist during periods of remission. During Pourtant, des altérations de ce système sont connues dans la schizophrénie [3]. En effet, elles sont liées aux troubles formels de la pensée [START_REF] Spitzer | Associative semantic network dysfunction in thought-disordered schizophrenic patients: Direct evidence from indirect semantic priming[END_REF], symptômes pouvant être également présents au cours des phases maniaques dans le TB [START_REF] Andreasen | Thought, language, and communication disorders. II. Diagnostic significance[END_REF]. Il semble donc probable que la mémoire sémantique soit altérée en phase maniaque dans le TB.

Nous commencerons par développer les arguments en faveur du continuum clinique entre TB de type 1 et schizophrénie, notamment des caractéristiques cliniques communes, qui étayent l'idée d'une atteinte de la mémoire sémantique (dans son fonctionnement ou dans sa structure). Nous nous intéressons spécifiquement au TB de type 1 dans la première section puisqu'il se caractérise par la survenue de phases maniaques contrairement aux autres soustypes de bipolarité. Nous présenterons ensuite les études explorant la mémoire sémantique dans les TB de façon plus générale en précisant les sous-types de TB qui ont été étudiés dans chacune de ces études.

Schizophrénie et TB de type 1 : hypothèse d'un continuum clinique et cognitif

En termes de similitudes cliniques, Schûroff [START_REF] Schürhoff | Troubles bipolaires et schizophrénie : troubles distincts ou continuum[END_REF] rappelle que 40 à 70% des patients schizophrènes présentent des symptômes thymiques et que 50% des patients bipolaires présentent des symptômes psychotiques, principalement lors d'épisodes maniaques. Parmi les similitudes symptomatiques, on observe également que les troubles formels de la pensée sont présents durant les épisodes maniaques des TB ainsi que dans la schizophrénie. A ce titre, bien qu'il existe des divergences sur la sévérité des troubles formels de la pensée entre les deux troubles, Andreasen montrait dès 1979 [START_REF] Andreasen | Thought, language, and communication disorders. II. Diagnostic significance[END_REF] que, aussi bien dans les TB que dans la schizophrénie, plus les troubles formels de la pensée étaient fréquents, plus ils étaient intenses.

Au-delà des similitudes cliniques, il existe des similitudes cognitives entre les patients schizophrènes et bipolaires, bien que les atteintes cognitives soient plus marquées dans la schizophrénie [START_REF] Krabbendam | Cognitive functioning in patients with schizophrenia and bipolar disorder: A quantitative review[END_REF]. Dans ces deux populations, des dysfonctionnements sont observés pour la mémoire verbale, la mémoire de travail, l'attention, mais aussi certaines composantes de la cognition sociale [START_REF] Bora | Cognitive impairment in affective psychoses: A metaanalysis[END_REF][START_REF] Tsitsipa | The neurocognitive functioning in bipolar disorder : a systematic review of data[END_REF]. En revanche, alors qu'il existe un consensus concernant l'atteinte de la mémoire sémantique dans la schizophrénie, les études explorant la mémoire sémantique dans le TB mènent à des résultats contradictoires. Notre objectif est de faire une synthèse de la littérature pour comprendre l'hétérogénéité de ces résultats et de s'interroger sur l'existence possible d'une association entre perturbations de la mémoire sémantique et troubles formels de la pensée, comme dans la schizophrénie.

Troubles formels de la pensée : expression clinique des troubles de la mémoire sémantique ?

La mémoire sémantique a largement été explorée dans la schizophrénie à l'aide du paradigme d'amorçage sémantique. Si certaines études montrent une diminution ou une absence de différence de cet effet d'amorçage entre les patients et le groupe de participants sains, les méta-analyses suggèrent plutôt un effet d'hyperamorçage [START_REF] Pomarol-Clotet | Semantic priming in schizophrenia: Systematic review and meta-analysis[END_REF]. Pour rendre compte des résultats en fonction des différents processus évalués en mémoire sémantique dans la schizophrénie, un modèle intégratif basé sur le modèle attentionnel de Posner et Snyder [START_REF] Posner | Attention and cognitive control[END_REF] a été proposé par Callaway et Naghdi [START_REF] Callaway | An Information Processing Model for Schizophrenia[END_REF]. Selon leur conception, il existerait une dissociation entre les processus automatiques (diffusion automatique de l'activation) qui seraient préservés chez les patients schizophrènes et les processus contrôlés (appariement sémantique) qui seraient déficitaires.

Un des résultats les plus stables dans la littérature portant sur l'amorçage sémantique dans la schizophrénie est que les troubles formels de la pensée seraient la conséquence de déficits de l'activation ou de l'inhibition des associations en mémoire sémantique [START_REF] Gouzoulis-Mayfrank | Semantic hyperpriming in thought-disordered patients with schizophrenia: State or trait? -A longitudinal investigation[END_REF][START_REF] Niznikiewicz | Abnormal inhibitory processes in semantic networks in schizophrenia[END_REF]. Pour d'autres auteurs, les troubles formels de la pensée résulteraient de difficultés pour intégrer des informations contextuelles en mémoire sémantique en raison d'un dysfonctionnement des processus contrôlés d'appariement sémantique [START_REF] Besche-Richard | Semantic context-processing deficit in thoughtdisordered schizophrenic patients: Evidence from new semantic priming paradigms[END_REF]. Par ailleurs, certains ont avancé que la mémoire sémantique pourraient organisée différemment chez les patients schizophrènes par rapport à des individus sains [START_REF] Tan | Assessing the Relationship between Semantic Processing and Thought Disorder Symptoms in Schizophrenia[END_REF].

Au regard du lien entre perturbations de la mémoire sémantique et les troubles formels de la pensée dans la schizophrénie et du continuum clinique entre schizophrénie et TB, il apparait pertinent d'analyser les études ayant exploré la mémoire sémantique dans le TB. Notre revue critique considérera les études qui ont considéré les différents éléments du continuum psychotique (symptômes positifs, troubles formels de la pensées). Cela implique de distinguer les différents sous-types de TB et leurs différentes phrases (maniaque, dépressive, rémission).

L'exploration de la mémoire sémantique dans les TB

Les premières recherches qui ont suggéré une atteinte de la mémoire sémantique dans le TB se sont appuyées sur le test des fluences verbales qui se divise en deux sous-épreuves : les fluences verbales sémantiques et les fluences verbales phonémiques. Ce test est généralement utilisé pour évaluer les capacités de flexibilité spontanée [START_REF] Rende | Cognitive flexibility: theory, assesment, and treatment[END_REF]. Il peut également nous renseigner sur l'intégrité du stock lexico-sémantiques ainsi que sur des processus fonctionnels en mémoire sémantique [START_REF] Shao | What do verbal fluency tasks measure? Predictors of verbal fluency performance in older adults[END_REF]. Les processus de regroupements correspondent à la production de mots appartenant à des sous-catégories sémantiques ou phonémiques impliqueraient la préservation du stock des connaissances sémantiques et du lexique phonologique [START_REF] Gierski | Les Fluences Verbales: Aspects Théoriques et Nouvelles Approches[END_REF]. La capacité de passer d'un regroupement à un autre impliquerait davantage les processus exécutifs, notamment la mise en place de stratégies de recherche en mémoire sémantique ainsi que la flexibilité spontanée [START_REF] Gierski | Les Fluences Verbales: Aspects Théoriques et Nouvelles Approches[END_REF]. La méta-analyse de Raucher-Chéné, Achim, Kaladjian et Besche-Richard [START_REF] Raucher-Chéné | Verbal fluency in bipolar disorders: a systematic review and meta-analysis[END_REF] révèle un fonctionnement moins efficient pour les deux types de fluences dans le TB en comparaison aux participants sains (taille d'effet d=.61). Pour affiner l'analyse et apporter des précisions quant à l'organisation de la mémoire sémantique, Sung, Gordon, Vannorsdall, Ledoux et Schretlen, [START_REF] Sung | Impaired retrieval of semantic information in bipolar disorder: A clustering analysis of category-fluency productions[END_REF] ont réalisé une analyse qualitative des réponses fournies au test des fluences. Ils ont montré que les catégorisations utilisées par les patients bipolaires étaient moins cohérentes que celles utilisées par les participants sains.

Selon ces auteurs, ces stratégies non optimales résulteraient d'une atteinte fonctionnelle de la mémoire sémantique pouvant prendre différentes formes : 1) une atteinte des processus d'activation/inhibition, 2) une propagation de l'activation qui serait insuffisante ou 3) une atteinte des capacités à contrôler ces différentes fonctions.

Ainsi, ce premier niveau de l'analyse suggère l'existence d'une atteinte de la mémoire sémantique dans le TB [START_REF] Raucher-Chéné | Verbal fluency in bipolar disorders: a systematic review and meta-analysis[END_REF][START_REF] Sung | Impaired retrieval of semantic information in bipolar disorder: A clustering analysis of category-fluency productions[END_REF]. Néanmoins, amalgamer l'ensemble des patients bipolaires comme appartenant à un seul et même groupe, sans distinguer les sous-types de la maladie, la période ou les caractéristiques de celle-ci, ne permet pas d'associer les dysfonctionnements aux symptômes cliniques. Nous allons donc aborder, lorsqu'ils sont disponibles, les résultats en fonction des différentes phases du TB.

Dysfonctionnement de la mémoire sémantique durant l'épisode maniaque.

Les résultats en fluences verbales obtenus auprès de patients bipolaires en phase maniaque comparés aux résultats obtenus auprès de patients en période d'euthymie révèlent un dysfonctionnement plus marqué chez les patients euthymiques [START_REF] Raucher-Chéné | Verbal fluency in bipolar disorders: a systematic review and meta-analysis[END_REF]. Ces résultats sont surprenants. En effet, au regard du recouvrement symptomatique entre TB et schizophrénie et de la présence d'un difficultés de production dans les tâches de fluences chez les patients schizophrènes, nous nous attendions à des résultats similaires chez les patients en phase maniaque [START_REF] Chen | Verbal fluency in schizophrenia: Reduction in semantic store[END_REF]. Cependant, pour les fluences sémantiques, les patients bipolaires en phase maniaque parviennent à produire significativement plus de mots que ceux en phase d'euthymique. L'atteinte plus marquée des fluences sémantiques par rapport aux fluences phonémiques est classiquement retrouvée chez les patients atteints de pathologies neurodégénératives et résulterait d'une atteinte du stock des connaissances sémantique [START_REF] Henry | Verbal fluency performance in dementia of the Alzheimer's type: a meta-analysis[END_REF].

La différence en termes de production entre l'état maniaque et la période d'euthymie peut s'expliquer par une atteinte fonctionnelle différente en fonction de la période de la maladie.

L'hypothèse avancée par les auteurs pour expliquer cette différence de productivité entre les deux phrases de la maladie est la suractivation en mémoire sémantique durant l'épisode maniaque qui permettrait aux patients de récupérer davantage de mots qu'en période d'euthymie [START_REF] Raucher-Chéné | Verbal fluency in bipolar disorders: a systematic review and meta-analysis[END_REF].

Bien que l'approche quantitative en fluences verbales puissent évoquer l'existence de difficultés sémantiques durant l'épisode maniaque, une analyse qualitative permet d'identifier les processus pouvant être altérés. Dans cette optique, Chang et al. [START_REF] Chang | Differential pattern of semantic memory organization between bipolar I and II disorders[END_REF] ont comparé les réponses fournies par des patients présentant un TB de type 1 (TB1) ou un TB de type 2 (TB2) en période d'euthymie à celles fournies par un groupe de participants sains. Il apparaît que les patients TB1 utilisent des stratégies de regroupement inhabituelles par rapport aux TB2 et au groupe de participants sains. Ainsi, la mémoire sémantique présenterait une désorganisation uniquement chez les patients qui ont présenté une symptomatologie maniaque (TB1). Les productions désorganisées en fluences verbales étant associées aux troubles formels de la pensée dans la schizophrénie, il est probable que celles observées dans le TB1 soient liées à ces mêmes symptômes. Parmi ces recherches, deux d'entre elles comparent le fonctionnement de la mémoire sémantique entre patients schizophrènes, patients bipolaires en phase maniaque et un groupe de participants sains [START_REF] Jamadar | Impairment in Semantic Retrieval is Associated with Symptoms in Schizophrenia but not Bipolar Disorder[END_REF][START_REF] Ryu | Differential alteration of automatic semantic processing in treated patients affected by bipolar mania and schizophrenia: An N400 study[END_REF]. La première étude explore le fonctionnement de la mémoire sémantique en combinant mesures comportementales et électrophysiologiques [START_REF] Ryu | Differential alteration of automatic semantic processing in treated patients affected by bipolar mania and schizophrenia: An N400 study[END_REF]. Sur le plan comportemental, une tâche de jugement de congruence sémantique entre un mot amorce et un mot cible était implémentée dans un paradigme d'amorçage sémantique. Les paires pouvaient être congruentes (ex : aujourd'huidemain) ou incongruentes (ex : aujourd'huiforme). Pendant la réalisation de la tâche, l'activité cérébrale était mesurée à l'aide d'un EEG de sorte à pouvoir identifier des composantes de potentiels évoqués, en particulier la N400. La N400 refléterait l'effort nécessaire pour intégrer un mot (cible) à son contexte (amorce) [START_REF] Holcomb | Semantic priming and stimulus degradation: Implications for the role of the N400 in language processing[END_REF].

Habituellement, l'effet N400 est plus élevé pour des paires non congruentes que pour des paires congruentes. En effet, plus la représentation sémantique du mot cible est pré-activée par la présentation d'un mot amorce relié sémantiquement, moins la quantité d'activation supplémentaire nécessaire au traitement de l'item est importante, ce qui entraine une réduction de l'amplitude de la N400. Les résultats comportementaux révèlent qu'un effet d'amorçage sémantique a été observé pour les différents groupes. Par ailleurs, aucune différence entre les groupes n'est observée suggérant la préservation des capacités de jugement de congruence sémantique dans la schizophrénie et dans le TB. En revanche, les résultats électrophysiologiques révèlent une amplitude de la N400 plus importante pour les paires congruentes dans le TB comparativement au groupe de patients schizophrènes et au groupe de participants sains. Ces résultats suggèrent que, en phase maniaque, les patients avec un TB traitent les stimuli congruents sémantiquement comme s'ils n'étaient pas liés. En d'autres termes, le contexte (l'amorce) ne semble pas faciliter la récupération du mot cible en mémoire sémantique. Selon ces auteurs, leurs résultats pourraient s'expliquer par une altération des processus de désinhibition et d'impulsivité observés lors des épisodes maniaques et/ou de la diminution des capacités de sélection et de traitements d'informations externes. Les ressources attentionnelles se focaliseraient sur la cible qui serait traitée comme un stimulus nouveau, indépendamment de l'amorce présentée avant qui ne recevrait plus aucune attention. Selon cette explication, le dysfonctionnement observé pourrait résulter d'une atteinte de la mémoire de travail plutôt que de la mémoire sémantique. Néanmoins, puisque la manière dont le paradigme est construit implique davantage les processus d'appariement sémantique (jugement conscient de la congruence sémantique) plutôt que les processus de propagation automatique de l'activation, et que, au niveau comportemental, l'effet d'amorçage est présent, les capacités attentionnelles devraient être préservées.

Enfin, l'analyse des liens entre troubles formels de la pensée et les différentes mesures réalisées ne révèle pas d'association entre ces symptômes et la mémoire sémantique, que ce soit pour les patients schizophrènes ou le TB. Cependant, cette absence de résultat pourrait s'expliquer par le manque de sensibilité de l'outil utilisé étant donné que les sous scores « langage » et « troubles de la pensée et contenu » ont été évalués à l'aide de la Young Mania Rating Scale.

La deuxième étude ayant pour objectif de comparer le fonctionnement de la mémoire sémantique entre patients bipolaires maniaques et patients schizophrènes a utilisé une tâche d'association sémantique en Imagerie par Résonnance Magnétique fonctionnelle (IRMf) auprès de patients schizophrènes, de patients bipolaires présentant des troubles formels de la pensée et des participants sains [START_REF] Jamadar | Impairment in Semantic Retrieval is Associated with Symptoms in Schizophrenia but not Bipolar Disorder[END_REF]. La tâche d'association sémantique consiste en la présentation de deux mots sémantiquement reliés qui, ensemble, sont censés évoquer un troisième mot non présenté. La tâche du participant est de décider si les deux mots présentés évoquent un troisième mot ou non. Cette épreuve permet d'évaluer la capacité à rechercher des relations sémantiques entre des paires de mots jusqu'à la convergence vers un troisième mot (processus d'appariement sémantique). Les résultats comportementaux révèlent des difficultés pour les deux groupes de patients, bien qu'elles soient plus marquées chez les patients schizophrènes. Les résultats neurophysiologiques révèlent quant à eux une réduction similaire du lobe pariétal inférieur bilatéral chez les patients schizophrènes et bipolaires. La réduction de l'activation au niveau de cette zone cérébrale refléterait la perte des relations entre les représentations en mémoire sémantique. De manière intéressante, au niveau des caractéristiques cliniques, la réduction de l'activation cérébrale est associée à la sévérité des troubles formels de la pensée uniquement chez les patients schizophrènes, bien que la sévérité de ces troubles formels de la pensée ne semble pas se différencier entre patients schizophrènes et bipolaires.

En résumé, ces deux premières études s'accordent sur l'absence d'association entre troubles formels de la pensée et mémoire sémantique dans le TB. Les dysfonctionnements de la mémoire sémantique dans le TB pourrait donc être d'une nature différente de ceux observés dans la schizophrénie. Cependant, une limite qu'on peut adresser à ces deux études est l'utilisation de protocoles expérimentaux qui s'éloignent de l'utilisation naturelle du langage.

Une étude sur l'exploration de la mémoire sémantique dans un cadre plus écologique a été proposé par Cermolacce et al. [START_REF] Cermolacce | Natural speech comprehension in bipolar disorders: An event-related brain potential study among manic patients[END_REF]. La compréhension verbale était évaluée par une écoute passive de phrases. Ces phrases pouvaient se terminer par un mot congruent (ex : « la voiture était conduite par un conducteur") ou non congruent ("Je suis venu pour voir les bateaux sur la porte"). L'objectif de ce protocole était d'explorer les capacités de traitement contextuel en mémoire sémantique. Tout comme dans l'étude de Ryu et al. [START_REF] Ryu | Differential alteration of automatic semantic processing in treated patients affected by bipolar mania and schizophrenia: An N400 study[END_REF], la mémoire sémantique était également évaluée sur le plan électrophysiologique par la N400. Une attention particulière était également accordée à la composante « Late Positive Component » (LPC) qui est influencée par des traitements cognitifs plus généraux. Les résultats révèlent davantage d'erreurs pour le groupe de patients en période maniaque en comparaison au groupe de participants sains. Cette différence n'est pas retrouvée par les mesures d'amplitude de la N400. En revanche, l'apparition de la LPC est retardée chez les patients, ce qui permet d'interpréter les différences observées sur le plan comportemental comme une atteinte de processus cognitifs généraux tels que les processus d'inhibition, et non comme une atteinte spécifique de la mémoire sémantique.

En résumé, au niveau comportemental, les difficultés pour les tâches impliquant la mémoire sémantique ne sont pas systématiquement retrouvées chez les patients bipolaires maniaques.

Alors que les capacités d'appariement sémantique semblent préservées dans l'étude de Ryu et al. [START_REF] Ryu | Differential alteration of automatic semantic processing in treated patients affected by bipolar mania and schizophrenia: An N400 study[END_REF] elles semblent perturbées dans celle de Jamadar et al. [START_REF] Jamadar | Impairment in Semantic Retrieval is Associated with Symptoms in Schizophrenia but not Bipolar Disorder[END_REF]. Des difficultés sont également observées pour une tâche plus écologique proposée [START_REF] Cermolacce | Natural speech comprehension in bipolar disorders: An event-related brain potential study among manic patients[END_REF]. Sur le plan électrophysiologique, les résultats sont peu clairs mais il semble que la symptomatologie maniaque ne perturbent pas les traitements sémantiques. Par ailleurs, les patients avec TB ne semble pas présenter une altération des processus sémantiques identiques à ceux des patients schizophrènes. En effet, dans le TB il est possible que des processus cognitifs d'ordre plus général soient perturbés durant la manie.

Dysfonctionnement de la mémoire sémantique durant les périodes dépressives et de rémission

Mémoire sémantique et épisodes dépressifs

Les déficits cognitifs durant les épisodes dépressifs majeurs ont largement été étudiés ces dernières années. Ces atteintes sont spécifiquement observées lorsque les tâches utilisées sollicitent des processus cognitifs dits « contrôlés » en opposition aux processus « automatiques » qui sont globalement préservés dans la dépression [START_REF] Hartlage | Automatic and effortful processing in depression[END_REF]. Cette dissociation se retrouve aussi au niveau de la mémoire sémantique. En effet, à une tâche de fluences verbales sémantiques (qui implique des processus contrôlés, stratégiques), les patients dépressifs sont moins productifs que des participants sains [START_REF] Fossati | Qualitative analysis of verbal fluency in depression[END_REF], suggérant une possible atteinte des processus contrôlés en mémoire sémantique. En revanche, pour les processus automatiques, évalués par le paradigme d'amorçage sémantique, différentes études suggèrent une préservation de l'effet d'amorçage sémantique chez des patients présentant une dépression unipolaire ou bipolaire [START_REF] Manschreck | Semantic priming in thought disordered schizophrenic patients[END_REF][START_REF] Kwapil | Facilitation of word recognition by semantic priming in schizophrenia[END_REF], des patients dépressifs présentant une symptomatologie psychotique [START_REF] Chapin | Investigation of the associative network in schizophrenia using the semantic priming paradigm[END_REF], et chez des patients dépressifs évalués au début et à la fin de l'épisode dépressif majeur [START_REF] Besche-Richard | Lexical decision tasks in depressive patients: Semantic priming before and after clinical improvement[END_REF].

Mémoire sémantique durant les périodes de rémission

Une seule étude a été publiée chez les patients bipolaires en période de rémission partielle [START_REF] Andreou | Semantic priming in remitted patients with bipolar disorder[END_REF]. Les 14 patients recrutés étaient considérés comme étant en rémission sur base de l'évaluation des symptômes maniaques (score < 10 à la Young Mania Rating Scale) et dépressifs (score < 10 à la Montgomery-Asberg Depression Rating Scale [START_REF] Montgomery | A new depression scale designed to be sensitive to change[END_REF]). Une tâche d'amorçage sémantique classique était proposée aux patients bipolaires en rémission et à un groupe de participants sains appariés. Les participants devaient réaliser une tâche de décision lexixale, c'est-à-dire décider si le stimulus présenté en cible était un mot ou un pseudo-mot. L'objectif de cette étude était d'évaluer le processus de propagation automatique de l'activation et d'établir s'il existe une association entre l'amplitude des effets d'amorçage et les troubles formels de la pensée évalués par la Thought Language and Communication scale (TLC [START_REF] Andreasen | Scale for the assessment of thought, language, and communication (TLC)[END_REF]). Les troubles formels de la pensée étant associés à l'hyperamorçage dans la schizophrénie, les auteurs ont fait l'hypothèse qu'un hyperamorçage serait observé chez les patients bipolaires puisqu'ils présentent eux aussi des troubles formels de la pensée.

Contrairement à leur hypothèse, une réduction de l'effet d'amorçage était observée chez les patients bipolaires par rapport aux participants sains. Pour ces auteurs, ces résultats étaye l'idée que le dysfonctionnement des processus de propagation automatique de l'activation est d'une nature différente du dysfonctionnement observé dans la schizophrénie. Cependant, cette interprétation est sujette à caution. En effet, bien que les troubles formels de la pensée aient été évalués, les patients avec TB étaient en période de rémission partielle. Ils présentaient donc peu ces symptômes, qui n'étaient par ailleurs pas associés à la réduction de l'effet d'amorçage. Un autre candidat potentiel aux dysfonctionnements sémantiques dans le TB serait la difficulté des traitements émotionnels. En effet, à ce jour, une seule étude a testé l'hypothèse d'une influence de l'émotion sur les processus de propagation automatique en mémoire sémantique [START_REF] Kim | Emotional priming with facial exposures in euthymic patients with bipolar disorder[END_REF]. Dans cette étude, les auteurs ont utilisé un paradigme d'amorçage utilisant des expressions faciales émotionnelles. Cette étude suggère que les processus automatiques de propagation de l'activation sont préservés, alors que, le contrôle cognitif des processus émotionnels semble altéré.

conclusions

Compte

La présence de déficits cognitifs chez les patients bipolaires étant un des indices les plus solides pour prédire le fonctionnement psychosocial à long terme [START_REF] Jaeger | Neurocognitive test performance predicts functional recovery from acute exacerbation leading to hospitalization in bipolar disorder[END_REF], l'identification des processus altérés constitue un enjeu majeur dans la prise en charge de la maladie. La compréhension des interactions entre mémoire sémantique, processus d'inhibition et processus émotionnels permettra de préciser le profil cognitif des patients bipolaires et contribuera à l'amélioration de la prise en charge cognitive et psychoéducative. Des exercices de remédiation basés sur l'apprentissage de stratégies visant à être plus attentif à un contexte sémantique ont notamment déjà été développés auprès de patients schizophrènes [START_REF] Besche-Richard | Remediation of context-processing deficits in schizophrenia: preliminary data with ambiguous sentences[END_REF][START_REF] Besche-Richard | Double-decision lexical tasks in thought-disordered schizophrenic patients: A path towards cognitive remediation?[END_REF]

IntroductionL

  'exploration des particularités cliniques du fonctionnement cognitif dans le trouble bipolaire (TB) constitue un champ de recherche à part entière. L'objectif de ces études est de comprendre la manière dont certains dysfonctionnements se manifestent dans l'expression clinique des troubles. La littérature sur le fonctionnement cognitif dans le TB permet de dégager que 1) les fonctions cognitives altérées dans les TB sont les mêmes que celles observées dans la schizophrénieil existe donc une similitude qualitative -2) la comparaison entre TB et troubles schizophréniques révèle généralement que les troubles cognitifs chez les patients bipolaires sont moins sévères que ceux des patients schizophrènesil existe donc une différence quantitative -[1]. Ainsi, les similitudes cliniques et cognitives entre TB et schizophrénie suggèrent l'existence d'un continuum entre ces deux troubles [2]. Bien que le profil cognitif dans les TB et dans la schizophrénie aient été largement explorés dans les deux troubles, certains domaines, comme la mémoire sémantique, l'ont moins été dans le TB.

  Le test des fluences verbales a permis d'identifier l'existence probable d'une désorganisation de la mémoire sémantique dans le TB1. Néanmoins, cette tâche sollicite aussi bien les fonctions exécutives que la mémoire sémantique. Elle ne permet donc pas d'identifier clairement les processus en mémoire sémantique susceptibles d'être altérés au contraire d'autres méthodologies plus adaptées pour explorer la mémoire sémantique. C'est le cas du paradigme d'amorçage sémantique qui a été utilisé dans différentes études explorant le fonctionnement de la mémoire sémantique dans le TB.

  tenu du continuum clinique et cognitif entre TB et schizophrénie, nous pouvions émettre l'hypothèse de perturbations de la mémoire sémantiques similaires dans les deux pathologies. Pourtant, plusieurs études suggèrent une atteinte différente. Alors que les troubles sémantiques sont associés à la sévérité des troubles formels de la pensée dans la schizophrénie, ce résultat n'est pas retrouvé dans le TB. Néanmoins, les troubles formels ne se manifestent pas de la même manière dans les deux troubles. Il semble donc nécessaire d'examiner les différents facteurs des échelles mesurant ces symptômes plutôt que de réaliser des analyses sur les scores totaux. L'hétérogénéité des résultats peut s'expliquer par les différences méthodologiques et/ou par l'hétérogénéité clinique du TB (voir tableau 1). Il semble en effet probable que les caractéristiques du TB puissent engendrer des perturbations différentes de la mémoire sémantique. Les patients avec davantage d'épisodes dépressifs pourraient présenter des altérations plus marquées des processus contrôlés alors que les patients présentant davantage d'épisodes maniaques pourraient plutôt présenter une suractivation en mémoire sémantique. Sur le plan méthodologique, il existe différentes formes de paradigmes d'amorçage évaluant différents processus en mémoire sémantique et menant à des résultats peu comparables. Enfin, il semble nécessaire d'envisager que les dysfonctionnements sémantiques dans le TB soient dus à une atteinte de processus plus généraux. Parmi ces processus plus généraux, l'inhibition est un des candidats probables. En effet, des difficultés exécutives sont observées à différents niveaux dans le TB , y compris lors du test de complétion de phrases de Hayling connu pour évaluer les capacités d'inhibition sémantique. Durant cette épreuve, les patients font davantage d'erreurs et sont plus lents dans les deux sous-épreuves du test de Hayling (initation et inhibition) [38]. Le ralentissement durant la phase d'initiation peut s'expliquer par la nécessité de fournir un effort cognitif par les patients pour choisir une réponse adéquate dans leur réseau de connaissances. Durant la deuxième partie, cette stratégie n'est plus suffisante puisque l'intervention des processus d'inhibition et de planification est nécessaire. La mise en place de ces stratégies implique également la mémoire de travail qui peut également être perturbée dans le TB.

  et pourraient être adaptés aux spécificités des patients bipolaires lorsque la nature des perturbations sémantiques sera plus clairement identifiée. Bibliographie [1] Jabben N, Arts B, Van Os J, Krabbendam L. Neurocognitive Functioning as Intermediary Phenotype and Predictor of Psychosocial Functioning Across the Psychosis Continuum: Studies in Schizophrenia and Bipolar Disorder. J Clin Psychiatry 2010;716. doi:10.4088/JCP.08m04837yel. [2] Craddock N, Owen MJ. The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005;186:364-6. doi:10.1192/bjp.186.5.364. [3] Chen EYH, Wilkins AJ, McKenna PJ. Semantic memory is both impaired and anomalous in schizophrenia. Psychol Med 1994;24:193.


Nemo Fournier

Stanley Durrleman

Covariate-Aware Longitudinal Modelling for Neurodegenerative Diseases

Keywords:

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

Introduction

Methods

Validation on Synthetic Data

Our model has been thoroughly validated on synthetic data. We generated data via synthetic disease models. The influence of covariates was simulated by instanciating multiple models with slightly different dynamics. For each subject we first sampled its time-fixed covariates, and then used them to select the model for data generation. Continuous covariates were modeled by combining slightly different models. We also included covariates irrelevant to the disease dynamics to validate the robustness of our approach.

For example, we consider a fictive disease having two different progression patterns, depending on the status of a given mutation (binary covariate). We use two distinct generative models (bold line) to model a standard form (top) and a motor form of the disease (down). We consider a binary covariate (think: mutation status) that defines whether a patient suffers from the standard (no mutation) or the motor form (mutation) of the pathology. Longitudinal modelling is of pivotal interest for the study of neurodegenerative diseases. The Disease Course Mapping 1 is a multivariate Bayesian mixed-effect progression model that is able to recover the course of a disease from a cohort with multimodal longitudinal observations (imaging variables, cognitive and clinical scores) and to extract interpretable parameters to describe each patient. It has been validated on multiple diseases and on multiple applications settings (cohort study, trial enrichment, data simulation, ...) However, its statistical formulation relies only on time-dependent observations. It thus fail to integrate time-independent information (gender, education levels, genetic factors, ...) in its modelling, even though such covariates are known to modulate clinical disease courses. We propose a mixed-effect formulation that captures the influence of such covariates over the dynamic of the disease.

Results on Clinical Data

Memory Motor

During calibration, the original model learns a set of population parameters characterizing the average progression of the pathology. Averaging is defined as learning a geodesic in a multi-dimensional Riemannian space which minimizes the cost of non-linear identifiable registrations of the average curve onto all individual observations. A Bayesian framework is used in order to include regularize registration costs: each registration is driven both by individual data attachment and information learned from the whole cohort.

We then calibrated our new model on such synthetic datasets and made sure that we could recover the link between covariates and dynamic effects. The example presented here is a simple binary setting, but multiple, continuous and slighter dynamics effects were also considered with success. Covariates that were artificially added but without any dynamic effects were also correctly discarded by our model.

Top: average progression from a standard model calibrated on this heterogenous cohort. Bottom: average progression from our covariate aware model.

The standard model averaged the cohort onto an intermediate dynamic that does not account for the heterogeneity of the cohort, while our new model was able to recover the dynamic effect that was associated to the mutation status.

We ran our model on the ADNI dataset, which is an Alzheimer's Disease cohort. We showed that we can recover clinically established effects of covariates such as sex, APOE mutation. Calibration over ADNI. Here we emphasize the effect of the APOE4 mutation. In solid line the average progression for patients without the APOE4 mutation. The dotted line shows the expected progression of a patient homozygous for the APOE4 mutation. We recover the clinically known effect of the mutation with patients affected earlier and faster.

M M S E

Analysis of the link function learned during calibration.

Here is represented the effect of the APOE4 mutation on the progression speed of some biomarkers and cognitive scores. A positive value is associated to an «accelerating» effect, while a negative value stands for a «slowing» effect.

+

Comparison between the original approach (left) and our new formulation (right). The link function of the new model diagrammatically corresponds to the arrow between the green and the blue areas.

2 [Kunkle et al -2019] Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nature genetics.

We adapt this model to explicit the dependancy between covariates and biomarker evolution. We learn a parametrized function linking covariates to population parameters. While the original model learned a fixed average trajectory, we now learn a function that associates a set of covariates, to a proposal average trajectory. Individual effects are retained to account for patient variability even within a "similar covariate class". This link function is modelled as a linear map between covariates and the geodesic parameters. We thus obtain an interpretable link between each covariate and the dynamic of the pathology (such as progression speed for each biomarker, onset age, etc). The total likelihood of the model thereby formulated can be shown to lie in the curved exponential family. This allows using algorithms of the MCMC-SAEM family for calibration.

We then ran our model on a wider number of SNP selected using a reference GWAS 2 . Our findings suggest that even though those SNPs have some of the highest effect size in the GWAS, their association with dynamics effect of the disease -such as speed of progression -is not always significant. This is because in most standard GWAS, SNP are associated with diagnosis and not with dynamic aspects of pathologies. This suggests that polygenic risk scores derived from regular GWAS do not efficiently target and inform about disease dynamics and that our approach could be a first step toward designing finer risk scores.

  Trajectories of patients are pooled into a single synthetic cohort, where two disease modes coexist and depends on a mutation status.

-

  A D A S 1 3 V e n t r i c l e s V o l u m e H i p p o c a m p u s V o l u m e P E T A m y l o i d l o a d P E T T a u l o a d

P

  t r i c l e s V o l u m e H i p p o c a m p u s V o l u m e P E T A m y l o i d l o a d speed Effect of rs11932324_A Effect of rs114812713_C Effect of rs138190086_A Effect of rs138727474_T Effect of rs28660482_A M M S E A D A S 1 3 V e n t r i c l e s V o l u m e H i p p o c a m p u s V o l u m e P E T A m y l o i d l o a d P E T T a u l o a d M M S E A D A S 1 3 V e n t r i c l e s V o l u m e H i p p o c a m p u s V o l u m e P E T A m y l o i d l o a d M M S E A D A S 1 3 V e n t r i c l e s V o l u m e H i p p o c a m p u s V o l u m e P E T A m y l o i d l o a d P E T T a u l o a d

D

  is e a se M o d e l t Di se as e M od el t Pe rso na lize d Mo de l Leaspy synthetizes longitudinal observations from a cohort into a descriptive model (left). Once presented with observations from a new patient, it finds descriptive parameters that register the population model onto the observed data, thus obtaining a personalized progression model. Priors learned during the initial calibration over the cohort help regularizing the model. While performing this registration of the population model onto the personalized model, no information about covariates are taken into account. We propose to change this behaviour.