Gilles Martinez

Elise Mosconi

Claire Daban-Huard

Mara Parellada

Lourdes Fananas

Mar Raphaël Gaillard

Marie-Odile Krebs

Isabelle Amado

"A circle and a triangle dancing together": Alteration of social cognition in schizophrenia compared to autism spectrum disorders

Keywords: Neurodevelopment, Asperger, Autistic, Psychosis, Early onset psychosis, theory of mind

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

INTRODUCTION

Schizophrenia (SCZ) and autism spectrum disorders (ASD) are neurodevelopmental disorders. Our understanding of the links between the two diseases has evolved over time.

Since the 1970s, these two conditions have been considered as distinct despite the proximity of some clinical features. More recently and following the literature supporting the neurodevelopmental hypothesis of SCZ, the nature of these links was re-examined. Common vulnerability factors, particularly genetic (Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium, 2017; [START_REF] Crespi | Association testing of copy number variants in schizophrenia and autism spectrum disorders[END_REF][START_REF] Sullivan | Family history of schizophrenia and bipolar disorder as risk factors for autism[END_REF]; [START_REF] Soler | Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review[END_REF], epidemiological [START_REF] Chisholm | The association between autism and schizophrenia spectrum disorders: A review of eight alternate models of co-occurrence[END_REF][START_REF] Rapoport | Autism spectrum disorders and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited[END_REF], cognitive [START_REF] Eack | Commonalities in social and non-social cognitive impairments in adults with autism spectrum disorder and schizophrenia[END_REF] as well as neuroimaging studies [START_REF] Baribeau | A comparison of neuroimaging findings in childhood onset schizophrenia and autism spectrum disorder: a review of the literature[END_REF][START_REF] Cheung | Autistic disorders and schizophrenia: related or remote? An anatomical likelihood estimation[END_REF] support the hypothesis of an autism-schizophrenia continuum. Persons with either SCZ or ASD share difficulties in social interaction with incidence on their quality of life [START_REF] Barneveld | Quality of life: a case-controlled long-term follow-up study, comparing young high-functioning adults with autism spectrum disorders with adults with other psychiatric disorders diagnosed in childhood[END_REF][START_REF] Maat | Social cognition and quality of life in schizophrenia[END_REF]. These difficulties are driven by impairments in social cognition [START_REF] Couture | Comparison of social cognitive functioning in schizophrenia and high functioning autism: more convergence than divergence[END_REF][START_REF] Couture | The functional significance of social cognition in schizophrenia: a review[END_REF], a concept that refers to the ability to construct representations of the relationships between oneself and others and to use those representations to guide social behavior [START_REF] Adolphs | The neurobiology of social cognition[END_REF]. Social cognition encompasses Theory of Mind (ability to infer thoughts, beliefs, desires, emotions to oneself and others, ToM), emotional processing, attributional style, perception and social knowledge [START_REF] Green | Social cognition in schizophrenia: an NIMH workshop on definitions, assessment, and research opportunities[END_REF]. Social cognition has been widely explored in SCZ and ASD using various tests; however, few studies directly compared these persons in adulthood and results are contrasted, possibly due to differences in global functioning. Some studies found common alterations in ToM [START_REF] Chung | A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder[END_REF][START_REF] Couture | Comparison of social cognitive functioning in schizophrenia and high functioning autism: more convergence than divergence[END_REF][START_REF] Craig | Persecutory beliefs, attributions and theory of mind: comparison of patients with paranoid delusions, Asperger's syndrome and healthy controls[END_REF][START_REF] Murphy | Theory of mind in Asperger's syndrome, schizophrenia and personality disordered forensic patients[END_REF], and in emotion recognition tests [START_REF] Eack | Commonalities in social and non-social cognitive impairments in adults with autism spectrum disorder and schizophrenia[END_REF][START_REF] Sasson | Orienting to social stimuli differentiates social cognitive impairment in autism and schizophrenia[END_REF][START_REF] Sasson | Context Effects on Facial Affect Recognition in Schizophrenia and Autism: Behavioral and Eye-Tracking Evidence[END_REF] in both disorders. Others found more severe difficulties in ASD [START_REF] Bölte | The recognition of facial affect in autistic and schizophrenic subjects and their first-degree relatives[END_REF][START_REF] Ciaramidaro | Schizophrenia and autism as contrasting minds: neural evidence for the hypo-hyper-intentionality hypothesis[END_REF][START_REF] Ozguven | Theory of Mind in Schizophrenia and Asperger's Syndrome: Relationship with Negative Symptoms[END_REF][START_REF] Pilowsky | Theory of mind abilities of children with schizophrenia, children with autism, and normally developing children[END_REF][START_REF] Sachse | Facial emotion recognition in paranoid schizophrenia and autism spectrum disorder[END_REF] or in SCZ [START_REF] Lugnegård | Social cognition impairments in Asperger syndrome and schizophrenia[END_REF][START_REF] Tobe | Differential profiles in auditory social cognition deficits between adults with autism and schizophrenia spectrum disorders: A preliminary analysis[END_REF]. According to C. Frith, alterations in ToM should differ between ASD and SCZ, since the diseases impact ToM at different ages: very early in ASD, and later in SCZ [START_REF] Frith | Exploring "theory of mind" in people with schizophrenia[END_REF]. Moreover, in SCZ, the links between clinical profiles and performance in ToM remains contraversial. C.

Frith [START_REF] Frith | The Cognitive Neuropsychology of Schizophrenia[END_REF] suggested that some symptoms of SCZ could emerge from aberrations in the attribution of mental states. Paranoid patients tend to "hypermentalize", that is, to attribute intentions excessively and erroneously, whereas persons with prominent negative symptoms or disorganization "hypomentalize" [START_REF] Frith | Schizophrenia and theory of mind[END_REF].

Following Medalia and Bowie (2016), over or under mentalizing are associated with insufficient hypotheses or guesses about a person or an event often associated to the mechanism of 'jumping to conclusion'. Actually, cognitive remediation programs, such as social cognition and interaction training (SCIT) provides mentalizing exercices in order to learn to generate alternative hypotheses when facing to an event, contributing to reduce jumping to conclusion mechanisms. SCIT method has been used in schizophrenia [START_REF] Roberts | A randomized, controlled trial of Social Cognition and Interaction Training (SCIT) for outpatients with schizophrenia spectrum disorders[END_REF], and in few persons with autism [START_REF] Turner-Brown | Brief report: feasibility of social cognition and interaction training for adults with high functioning autism[END_REF]. Animated geometric shapes tasks allow an exploration of the ToM, with non verbal support.

These tasks consist in the attribution of actions and mental states to geometric shapes moving according to different conditions of actions: random, goal-directed and involving a mental state, with evaluation of four dimensions: degree of intentionality, appropriateness, degree of certainty and length of the answer. Groups of persons with ASD [START_REF] Bal | Do social attribution skills improve with age in children with high functioning autism spectrum disorders?[END_REF][START_REF] Bliksted | Discriminating autism spectrum disorders from schizophrenia by investigation of mental state attribution on an on-line mentalizing task: A review and meta-analysis[END_REF][START_REF] Castelli | Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes[END_REF][START_REF] Marsh | Dissociation of mirroring and mentalising systems in autism[END_REF][START_REF] Salter | Can autistic children read the mind of an animated triangle?[END_REF] or with SCZ [START_REF] Bourgou | Theory of mind in adolescents with early-onset schizophrenia: correlations with clinical assessment and executive functions[END_REF][START_REF] Das | Mentalizing in male schizophrenia patients is compromised by virtue of dysfunctional connectivity between task-positive and task-negative networks[END_REF][START_REF] Horan | Disturbances in the spontaneous attribution of social meaning in schizophrenia[END_REF]Koelkebeck et al., 2013a;[START_REF] Pedersen | Theory of mind in patients with schizophrenia: Is mentalizing delayed?[END_REF][START_REF] Russell | Do you see what I see? Interpretations of intentional movement in schizophrenia[END_REF] were tested, objectivizing an impairment in the attribution of mental states. To our knowledge, only one study directly compared ASD and SCZ and correlations with clinical dimensions were not explored [START_REF] Lugnegård | Social cognition impairments in Asperger syndrome and schizophrenia[END_REF].

This study intends firstly to characterize Theory of Mind impairments and their relationships with clinical profiles in young adults with recent onset SCZ compared to HC; and secondly, to compare them to matched young adults with high functioning ASD.

MATERIAL AND METHODS

PARTICIPANTS

One hundred and six persons aged 18 to 30 were recruited in this cross-sectional comparative study between 2012 and 2016, including (i) 51 persons meeting the DSM-IV-TR criteria for SCZ (American Psychiatric Association et al., 2000) but no history of ASD, (ii) 32 persons with ASD (High Functioning Autism and Asperger's syndrome) and (iii) 23 healthy control persons (HC) matched for age, sex and education level (number of years since first year of primary school). 75 participants had already been included in our previous study (recruitment until September 2015) [START_REF] Martinez | Phenotypic continuum between autism and schizophrenia: Evidence from the Movie for the Assessment of Social Cognition (MASC)[END_REF]. Patients were recruited in the hospitaluniversity department of the Sainte-Anne hospital and healthy control persons by advertising.

Diagnostic Interview for Genetics Studies (DIGS 3.0, French version Krebs, 2003) [START_REF] Nurnberger | Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative[END_REF] was used to confirm SCZ diagnosis and to exclude comorbidity in ASD and axis 1 disorder in HC. ASD diagnosis was confirmed using the Autism Diagnostic Interview -Revised [START_REF] Lord | Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders[END_REF].

Exclusion criteria for all participants were intellectual disability (IQ <70, assessed with WAIS-III (Wechsler, 1997); substance misuse or dependence (except nicotine) or use for more than 5 years, bipolar disorder, current or recent severe depression, suicidal risk, central neurological disease, treatment with benzodiazepines, antipsychotic dosage > 400 mg Chlorpromazine equivalents, antidepressants started less than 3 weeks before the beginning of the study. For HC, additional exclusion criteria were personal psychiatric history, family history of SCZ or ASD in first-and second-degree relatives.

This study was approved by the ethics committee CPP IDF3 (clinical trial number EudraCT 2011-A00812-39). All participants received written and verbal information about the project and written consent was obtained before inclusion.

PSYCHOPATHOLOGICAL AND COGNITIVE ASSESSMENTS

All participants were assessed for general psychopathology with the Brief Psychiatric Rating Scale (BPRS). General intellectual efficiency was evaluated with WAIS-III (Weshler, 1997).

This psychometric test leads to determine the intellectual quotient (IQ), calculated through two indices. The verbal IQ includes verbal reasoning, working memory and vocabulary tasks; and the performance IQ comprises non verbal reasoning and abstraction, and processing speed tasks.

Patients with SCZ were evaluated with the Positive and Negative Symptom Scale (PANSS) [START_REF] Kay | The positive and negative syndrome scale (PANSS) for schizophrenia[END_REF] and with the Scale for Assesment of Negative Symptoms (SANS) [START_REF] Andreasen | The Scale for the Assessment of Negative Symptoms (SANS): conceptual and theoretical foundations[END_REF]. Disorganization was assessed with the Thought Language and Communication Scale (TLC) [START_REF] Andreasen | Scale for the assessment of thought, language, and communication (TLC)[END_REF]. Symptom Onset in Schizophrenia (SOS) [START_REF] Perkins | Characterizing and dating the onset of symptoms in psychotic illness: the Symptom Onset in Schizophrenia (SOS) inventory[END_REF] was used to date onset of prodromal symptoms, and to determine age of first-episode psychosis, and DIGS was used for global psychiatric disease's history, including age at first contact with psychiatrist and first psychotropic drug. All clinical evaluations and WAIS-III were assessed by trained psychiatrist (GM) and psychologists (NB, CD).

EVALUATION OF SOCIAL COGNITION: THE ANIMATED SHAPES

In this study, we used the Animated Shapes task developed by Pouillès et al. (Pouillès, 2007), stemming from Triangles task [START_REF] Abell | Do triangles play tricks? Attribution of mental states to animated shapes in normal and abnormal development[END_REF]. Twelve silent animations, lasting 10 seconds each, are presented on a computer screen. Each animation shows two simple geometric figures (triangles, circles, squares) moving in a minimal environment (wall, door, enclosure).

This task has been designed to minimize the intervention of complex cognitive functions.

Three types of modalities govern interactions between shapes: (i) 'random' (R): object movements involving neither goal nor mental state (for example: a ball is rolling freely, before decelerating to stop), (ii) 'goal-directed' action (G): movements of living beings involving a goal, but no mental state (for example: a square attempts to break a wall at three times before make it through), (iii) Theory of mind 'ToM': movements of living beings involving a goal and a mental state (for example: a mother is trying to bring out her child of a room, but he refuse. Finally, she pushes her out.). Four animated sequences are developed for each modality.

First, the persons were informed that they were going to see sequences of moving shapes, representing objects or living beings, and be asked to describe and interpret them. Each animated sequence was presented twice on a computer screen. The presentation order was random but identical for all persons.

Participants' verbal answers were recorded to be rated later by two psychiatrists (GM + EM), including one blind to the clinical status of the participant (EM). Meeting for training quotation with discussion, and readjustment were organized throughout the study, in order to maintain homogeneity of scoring. For each sequence, four scores were attributed: (i) intentionality, according to the degree of intentional mental states described (0 = non deliberate action; 1 = deliberate action, alone; 2 = deliberate action with somebody; 3 = deliberate action in response to other's action; 4 = deliberate action in response to other's mental state; 5 = deliberate action to influence other's mental state) ; (ii) appropriateness, according to the degree of correctness of answers (0 = no answer; 1 = inappropriate answer, wrong type of interaction; 2 = partially correct answer, good type of interaction but confused description; 3 = appropriate and clear answer); (iii) certainty, meaning the degree of certainty based on intonation (0 = silence; 1 = just a few words, incomplete sentences; 2 = hesitations, alternative answers; 3 = no hesitation, quick response) ; (iv) score for length of answers (0 = no answer; 1 = 1 sentence; 2 = 2 sentences; 3 = 3 or 4 sentences; 4 = more than 4 sentences).

A total score per dimension was calculated for each type of animations, by adding the scores of the four corresponding sequences.

STATISTICAL ANALYSES

Statistical analyses were performed with IBM SPSS 20.0 software. Normal distribution of variables was tested by Kolmogorov-Smirnov test. Group differences on the Animated Shapes scores for clinical and cognitive variables were analyzed using 1-factor ANOVA, Tukey test for post-hoc analysis and univariate variance analysis to include gender as covariate Associations between variables were evaluated with Pearson correlation coefficients.

Considering the exploratory nature of the second objective, Bonferroni corrections for multiple comparisons were applied only for post-hoc analysis between SCZ and HC.

RESULTS

DEMOGRAPHIC AND CLINICAL CHARACTERISTICS

Demographic and clinical characteristics are presented in Table 1.

No significant differences existed between the groups for age, gender and intellectual quotient (verbal IQ VIQ; performance IQ, PIQ and full scale IQ, FSIQ). Education level was higher in HC compared to ASD and SCZ, without differences between these two groups. The clinical symptoms severity score was similar in ASD and SCZ, as reflected by BPRS' scores.

SOCIAL COGNITION

The Animated Shapes results are presented in Table 2.

In the 'random' condition, the appropriateness score was significantly lower in SCZ compared to HC (p = 0.007), with a trend for more intentionality in SCZ than HC (p = 0.085).

In the 'goal-directed' condition, appropriateness and intentionality scores were lower in SCZ compared to HC (respectively p = .016 and p = .024).

In the 'ToM' condition, appropriateness and intentionality scores were lower in both patient's groups as compared to HC (SCZ: p = 0.001, p =0.002; ASD: p = 0.018 and p = 0.026).

In the three conditions, there were no significant differences between ASD and SCZ for appropriateness scores and intentionality. Scores for certainty and length of answers were similar in the three groups (Table 3).

The results were similar when gender was included as covariate (ANOVA p values: 0.009 and 0.084 / 0.022 and 0.033 / 0.002 and 0.002 for random / goal-directed / ToM appropriateness and intentionality, respectively).

CORRELATIONS

In SCZ, in the random condition, the score in TLC was negatively correlated with appropriateness score (r = -0.410, p = 0.008) and positively correlated with intentionality score (r = 0.404, p = 0.009). Age of the first episode psychosis was also positively correlated with appropriateness score (r = 0.344; p = 0.034) and tends to be negatively correlated with intentionality score (r = -0.288, p = 0.08). There was no significant correlation between performance on Animated Shapes and SANS or PANSS total scores.

DISCUSSION

This study compared ToM abilities of young adults with SCZ to those of persons with ASD and healthy controls, using the Animated Shapes task. Our results confirmed that SCZ are significantly impaired in the attribution of intentions to others, and did not differ from persons with ASD. In SCZ, appropriateness and intentionality in the 'random' condition were related to disorganization and age of onset of the disease, indicating that among SCZ, 'overmentalizing' is related to earlier and more disorganized forms of the disease. Altogether, Animated Shapes revealed a mixed ToM impairment in SCZ combining undermentalizing (for intentional actions states) and overmentalizing (for random movements).

UNDERMENTALIZING IN SCZ

In 'ToM' sequences, persons with SCZ attributed less mental states and therefore produced less appropriate answers compared to HC. This 'undermentalization' is concordant with other studies [START_REF] Bliksted | Social cognition and neurocognitive deficits in first-episode schizophrenia[END_REF].

Undermentalizing was also found for 'goal-directed' sequences. Data from the literature are inconsistent : some studies [START_REF] Lugnegård | Social cognition impairments in Asperger syndrome and schizophrenia[END_REF][START_REF] Pedersen | Theory of mind in patients with schizophrenia: Is mentalizing delayed?[END_REF] showing no differences between HC and SCZ, while other studies reported either a reduction in intentionality in SCZ [START_REF] Bourgou | Theory of mind in adolescents with early-onset schizophrenia: correlations with clinical assessment and executive functions[END_REF][START_REF] Horan | Disturbances in the spontaneous attribution of social meaning in schizophrenia[END_REF][START_REF] Koelkebeck | Theory of Mind in first-episode schizophrenia patients: Correlations with cognition and personality traits[END_REF], or an increase in intentionality [START_REF] Russell | Do you see what I see? Interpretations of intentional movement in schizophrenia[END_REF].

The general cognitive impairment reported in SCZ might question the existence of a specific deficit in ToM. Indeed, Animated Shapes involves verbal memory and abstract reasoning.

Their alterations could bias ToM assessment. However, general cognitive impairment has a moderate impact on social cognition [START_REF] Bliksted | Social cognition and neurocognitive deficits in first-episode schizophrenia[END_REF][START_REF] Fanning | Is it possible to have impaired neurocognition but good social cognition in schizophrenia?[END_REF]. Only 10 to 20% of the variance of social cognition, with the exception of emotion recognition (34%), depends on neurocognition [START_REF] Fanning | Is it possible to have impaired neurocognition but good social cognition in schizophrenia?[END_REF]. Here, the selection of a task without involvement of verbal comprehension skills, the lack of difference between groups in the length of answers, and lastly the comparable IQ (especially verbal IQ) might suggest that the sole neurocognitive alteration in SCZ cannot account for the observed impairment in ToM.

COMPARISON OF TOM ABILITIES IN SCZ AND ASD

In the same way, in the "ToM" condition, ASD attributed less intentionality with less appropriate answers compared to HC. This folllows results in previous studies, which found lower intentionality scores in children and adults with ASD compared to HC [START_REF] Castelli | Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes[END_REF][START_REF] Lugnegård | Social cognition impairments in Asperger syndrome and schizophrenia[END_REF][START_REF] Marsh | Dissociation of mirroring and mentalising systems in autism[END_REF][START_REF] Salter | Can autistic children read the mind of an animated triangle?[END_REF][START_REF] White | Developing the Frith-Happé animations: a quick and objective test of Theory of Mind for adults with autism[END_REF].

Only one previous study directly compared persons with SCZ or ASD and HC (respectively n = 36, 53 and 50) using the Animated Shapes [START_REF] Lugnegård | Social cognition impairments in Asperger syndrome and schizophrenia[END_REF]: lower intentionality and appropriateness scores were found both in SCZ and ASD compared to HC, in the 'ToM' condition. These deficits were more severe in SCZ compared to ASD [START_REF] Lugnegård | Social cognition impairments in Asperger syndrome and schizophrenia[END_REF]. Our study did not replicate this later result. However, several factors limit the comparability of the present sample with the former one, including the lack of information on psychopathology, IQ and level of education as well as the inclusion of persons with schizoaffective disorder, older age for patients with SCZ and restriction to persons with Asperger syndrome for patients with ASD. In addition, a meta-analysis from 10 studies assessing ToM abilities in SCZ (N = 206) or ASD (N = 98) using Animated Shapes did not show more severe impairments in SCZ [START_REF] Bliksted | Discriminating autism spectrum disorders from schizophrenia by investigation of mental state attribution on an on-line mentalizing task: A review and meta-analysis[END_REF]. Furthermore, in this meta analysis, the intentionality scores in the 'ToM' condition,were similar in ASD and SCZ, whereas ASD gave less appropriate answers than SCZ.

The results of studies comparing ASD to SCZ using other ToM tasks (Strange Stories, False Beliefs, Hinting task, Reading the Mind in the Eyes test, etc.) are contrasted, with either no significant differences [START_REF] Chung | A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder[END_REF][START_REF] Couture | Comparison of social cognitive functioning in schizophrenia and high functioning autism: more convergence than divergence[END_REF][START_REF] Craig | Persecutory beliefs, attributions and theory of mind: comparison of patients with paranoid delusions, Asperger's syndrome and healthy controls[END_REF][START_REF] Murphy | Theory of mind in Asperger's syndrome, schizophrenia and personality disordered forensic patients[END_REF] or more severe deficits in ASD [START_REF] Ciaramidaro | Schizophrenia and autism as contrasting minds: neural evidence for the hypo-hyper-intentionality hypothesis[END_REF][START_REF] Ozguven | Theory of Mind in Schizophrenia and Asperger's Syndrome: Relationship with Negative Symptoms[END_REF][START_REF] Pilowsky | Theory of mind abilities of children with schizophrenia, children with autism, and normally developing children[END_REF][START_REF] Sachse | Facial emotion recognition in paranoid schizophrenia and autism spectrum disorder[END_REF].

OVERMENTALIZING IN SCZ

In random sequences, answers were significantly less appropriate in SCZ compared to HC, these persons tending to introduce a higher degree of intentionality in their interpretations. This trend to overmentalize in random modality has already been reported (meta-analysis [START_REF] Bliksted | Discriminating autism spectrum disorders from schizophrenia by investigation of mental state attribution on an on-line mentalizing task: A review and meta-analysis[END_REF]), or identified only within subgroups of persons with paranoid SCZ or with predominant negative symptoms or thought disorganization [START_REF] Russell | Do you see what I see? Interpretations of intentional movement in schizophrenia[END_REF].

Although not statistically significant, the nature of ToM impairment was different in ASD and SCZ. Both had difficulties in the perception of mental states. However, SCZ tended to attribute goals to actions or mental states when they did not exist, in concordance with Frith and Corcoran' postulate (1996), suggesting that age of onset, which differs in ASD and SCZ, causes distinct deficits in ToM. persons with SCZ would develop ToM abilities in childhood.

At the onset of the disease, awareness that others have intentions and beliefs would be preserved, but mentalization abilities would be used inadequately [START_REF] Frith | Exploring "theory of mind" in people with schizophrenia[END_REF].

Here, the mistakes in mental state attribution result in a trend of hyper-and undermentalizing.

In ASD, the development of ToM would putatively be disrupted earlier in childhood, leading to a lack of awareness of others' desires and intentions that would result in a predominant undermentalizing.

A recent fMRI study investigated neural pattern associated with social cognition deficits assessed with Animated Triangles Task in 17 first-episode SCZ. Unlike healthy controls, persons with SCZ showed increased activity in a region of anterior medial prefrontal cortex (amPFC) while studying 'random' movements of shapes, as compared to the conditionof movements normally interpreted as 'intentional'. The authors concluded that these results were consistent with deficits in the ability to switch off mentalizing processes in potentially social contexts, instead increasing them when intentionality is not forthcoming [START_REF] Emborg | Hyper-and Hypomentalizing in Patients with First-Episode Schizophrenia: fMRI and Behavioral Studies[END_REF]. The hypo-hyper-intentionality hypothesis was also tested in another fMRI study that found opposed connectivity patterns between the right posterior superior temporal sulcus and amPFC in the clinical groups, i.e. increased for SCZ, decreased for ASD [START_REF] Ciaramidaro | Schizophrenia and autism as contrasting minds: neural evidence for the hypo-hyper-intentionality hypothesis[END_REF]

CORRELATIONS BETWEEN ToM IMPAIRMENT AND CLINICAL

PROFILES IN SCZ

We did not replicate the associations between ToM impairments and positive or negative symptoms in SCZ , contrasting with other studies [START_REF] Bliksted | Discriminating autism spectrum disorders from schizophrenia by investigation of mental state attribution on an on-line mentalizing task: A review and meta-analysis[END_REF][START_REF] Horan | Disturbances in the spontaneous attribution of social meaning in schizophrenia[END_REF][START_REF] Koelkebeck | Theory of Mind in first-episode schizophrenia patients: Correlations with cognition and personality traits[END_REF]. In these previous studies, the association of ToM deficits with negative symptoms could be accounted for by illness chronicity [START_REF] Pousa | Theory of mind deficits in chronic schizophrenia: evidence for state dependence[END_REF]. Here, the participants were young and most of them had experienced only one episode. Moreover, they were stabilized and poorly symptomatic, and they constituted a relatively homogeneous group, as reflected by the low level and narrow distribution of PANSS and SANS scores.

These features could explain the differences between our observations and previous studies.

On the other hand, previous observations could also be driven by the disorganization symptoms embedded in positive and negative subscales of SANS-SAPS and PANSS.

Unfortunately, these symptoms were not analysed in these previous studies.

In SCZ, in the random condition, thought disorganization (TLC score) was positively correlated with intentionality and negatively correlated with appropriateness of the response: the more disorganized the thought and language, the more intentionality and inappropriate answers. To our knowledge, no previous studies using Animated Shapes explored the links between disorganization and ToM. We previously found a similar association between disorganisation and ToM using another social cognition task: the MASC test [START_REF] Dziobek | Introducing MASC: a movie for the assessment of social cognition[END_REF][START_REF] Martinez | Phenotypic continuum between autism and schizophrenia: Evidence from the Movie for the Assessment of Social Cognition (MASC)[END_REF]. Association between disorganisation and ToM was already reported with comics tasks in SCZ (Sarfati and Hardy-Baylé, 1999;Sarfati et al., 1999[START_REF] Sarfati | Attribution of intentions to others in people with schizophrenia: a non-verbal exploration with comic strips[END_REF] and in two meta-analyses [START_REF] Sprong | Theory of mind in schizophrenia: meta-analysis[END_REF][START_REF] Ventura | Neurocognition and symptoms identify links between facial recognition and emotion processing in schizophrenia: meta-analytic findings[END_REF]. Disorganization was evaluated using either the TLC scale, which explores specifically thought and language output [START_REF] Andreasen | Scale for the assessment of thought, language, and communication (TLC)[END_REF], or with PANSS disorganization factor extracted from the scale [START_REF] Kay | The positive and negative syndrome scale (PANSS) for schizophrenia[END_REF]. These studies concluded that ToM impairments were more severe in disorganized persons.

Severity of disorganization could be related to the developmental weight in the individuals since it was negatively correlated with age at onset (of prodrome and first episode). We found a positive correlation between age of first episode psychosis and ToM performance in the 'random' condition, reinforcing the idea that age of onset influences social cognition : the earlier the symptoms, the more disorganization and the more intentionality and inappropriate answers in the random condition. These correlations suggest a tendency to overmentalize in persons with early onset of disease.

In SCZ, few studies explored the relationships existing between age of onset and impairments in social cognition. Late age at onset was associated with better performance in an emotion recognition test in 151 persons with SCZ [START_REF] Linke | Age or age at onset? Which of them really matters for neuro and social cognition in schizophrenia?[END_REF]. In addition, the performance was particularly impaired when the onset occured before 20 years of age, suggesting that development of social skills during adolescence is crucial for future social functioning.

Another study compared older persons with either 'early' (before 40 years) or late-onset paranoid SCZ (between 40 and 60 years) and healthy persons, using the Hinting Task [START_REF] Smeets-Janssen | Theory of Mind differences in older patients with early-onset and late-onset paranoid schizophrenia[END_REF]. While the severity of symptoms was comparable in both groups, ToM abilities were better in the late-onset than in the early-onset groups.

Disorganisation was not explored. The authors suggested that differences in ToM abilities were related to the duration of the disease [START_REF] Smeets-Janssen | Theory of Mind differences in older patients with early-onset and late-onset paranoid schizophrenia[END_REF]. However, the literature is controversial, reporting either gradual decline in social cognition during the disease [START_REF] Brüne | Theory of mind" in schizophrenia: a review of the literature[END_REF][START_REF] Drury | Theory of mind" skills during an acute episode of psychosis and following recovery[END_REF][START_REF] Sarfati | Can verbalization remedy the theory of mind deficit in schizophrenia?[END_REF], or stability of deficit [START_REF] Bora | Theory of mind impairments in first-episode psychosis, individuals at ultra-high risk for psychosis and in first-degree relatives of schizophrenia: systematic review and meta-analysis[END_REF][START_REF] Green | Social cognition in schizophrenia, Part 1: performance across phase of illness[END_REF][START_REF] Mazza | New evidence in theory of mind deficits in subjects with chronic schizophrenia and first episode: correlation with symptoms, neurocognition and social function[END_REF]. A meta-analysis based on six studies using Animated Shapes (206 participants) reported higher intentionality score in the 'ToM' condition in persons with a first episode psychosis (duration of the disease between 0.35 and 0.36 years) compared to chronic SCZ (duration of the disease between 5.6 and 17.4 years) [START_REF] Bliksted | Discriminating autism spectrum disorders from schizophrenia by investigation of mental state attribution on an on-line mentalizing task: A review and meta-analysis[END_REF].

LIMITATIONS

The first limitation of this study is the rather small size of the ASD group, accounting for possible lack of statistical power. Despite our satisfactory interrater coefficient (alpha coefficient of Cronbach from 0.725 to 0.909), the scoring method of the Animated shapes remains subjective. Some studies, like our, provided two raters to diminish subjectivity [START_REF] Abell | Do triangles play tricks? Attribution of mental states to animated shapes in normal and abnormal development[END_REF][START_REF] Castelli | Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes[END_REF][START_REF] Horan | Disturbances in the spontaneous attribution of social meaning in schizophrenia[END_REF], while others provided only one [START_REF] Das | Mentalizing in male schizophrenia patients is compromised by virtue of dysfunctional connectivity between task-positive and task-negative networks[END_REF]Koelkebeck et al., 2013b;[START_REF] Pedersen | Theory of mind in patients with schizophrenia: Is mentalizing delayed?[END_REF]. Moreover, medications received by participants could influence performances in ToM [START_REF] Savina | Schizophrenic patients treated with clozapine or olanzapine perform better on theory of mind tasks than those treated with risperidone or typical antipsychotic medications[END_REF]. However, here, all SCZ received atypical antipsychotics, with very low dosages (<400 mg Eq chlorpromazine). In addition, the persons were young and most of them had experienced only one episode.

CONCLUSION

Animated shapes showed mental state attribution impairments in young adults with recent onset SCZ and high functioning ASD, as compared with healthy persons. Although persons with SCZ could not be statistically discriminated from those with ASD based on their ToM abilities, the nature of mentalizing impairments seems different, suggesting the existence of distinct pathophysiological mechanisms in both disorders. A trend to overmentalize was found in SCZ, related to thought and language dizorganization, and precocity of the first psychotic episode. On the other hand, undermentalizing was a common feature to both disorders. Noteworthy, both under or overmentalizing can actively be reduced with specific cognitive remediation programs that benefit to persons with schizophrenia as well as persons with autism [START_REF] Roberts | A randomized, controlled trial of Social Cognition and Interaction Training (SCIT) for outpatients with schizophrenia spectrum disorders[END_REF]. This suggests at least that the two disorders might share common cognitive abnormalities and mechanisms for rehabilitation.

Table 2 : Animated Shapes performances in ASD, SCZ and HC

 2

		ASD	SCZ	HC	Overall a	SCZ vs	SCZ vs
		N = 28	N = 51	N = 23		ASD b	HC b
	Random	10.4 (1.45)	9.74 (1.89)	11.07 (0.88)	p = 0.01*	NS	0.007**
	Appropriateness
	Random	1.08 (1.19)	1.38 (1.67)	0.58 (0.75)	p = 0.103	NS	NS 0.085
	Intentionnality
	Goal-directed	9.68 (1.60)	9.33 (1.87)	10.52 (1.01)	p = 0,032*	NS	0.024**
	Appropriateness
	Goal-directed	6.34 (1.62)	5.90 (2.00)	7.25 (1.26)	p = 0.022*	NS	0,016**
	Intentionnality
	ToM	7.1 (2.3)	6.77 (2.25)	8.90 (1.4)	p = 0.002*	NS	0.001**
	Appropriateness
	ToM	12.62 (3.08) 12.10 (3.25) 14.95 (1.79)	p = 0.002*	NS	0.002**
	Intentionnality
	Mean (SD) scores for animated shapes are presented
	a One factor ANOVA, b Post hoc Tukey test, * p < 0,05, ** p < 0,025 (Bonferroni correction) NS : not
	significant

Table 3 : Certainty and length of answers in ASD, SCZ and HC

 3 SD) scores for animated shapes are presented a One factor ANOVA, b Post hoc Tukey test, * p < 0,05, ** p < 0,025 (Bonferroni correction) NS : not significant

			ASD	SCZ	HC	Overall a
			N = 28	N = 51	N = 23
	Random	Certainty	10.3 (2.03)	10.05 (1.13)	10.25 (0.92)	NS
		Length	7.67 (2.41)	8.58 (2.91)	8.3 (2.28)	NS
	Goal-directed	Certainty	9.86 (2.44)	9.95(1.61)	10.57 (1.10)	NS
		Length	8.9 (2.51)	9.39 (2.8)	9.32 (3.09)	NS
	ToM	Certainty	10.09 (2.31)	9.93 (1.29)	10.75 (0.92)	NS
		Length	10.68 (2.71)	11.25 (2.36)	11.62 (2.68)	NS
	Mean (


MD Clément Dondé

PhD Marine Mondino

PhD David I Leitman

MD, PhD Daniel C Javitt

PhD Marie-Françoise Suaud-Chagny

' Amato

PhD Jérôme Brunelin

MD, PhD Frédéric Haesebaert

MD, PhD Thierry D ' Amato

Are basic auditory processes involved in source-monitoring deficits in patients with schizophrenia?

Keywords: Schizophrenia, Tone-matching, Basic auditory processing, Sourcemonitoring, Positive symptoms

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

INTRODUCTION

Schizophrenia is a severe neuropsychiatric disorder that stands as the third leading cause of worldwide morbidity amongst neurological, mental, and substance use disorders [START_REF] Collins | the Executive Committee of the Grand Challenges on Global Mental[END_REF]. Schizophrenia is characterized by profound disruption in emotion, cognition and perception abilities, leading to several clinical manifestations. Among them, misperceptions of the self, as described in the RDoC "Agency" subconstruct, are core features of the illness [START_REF] Ford | Studying hallucinations within the NIMH RDoC framework[END_REF].

Source-monitoring is a cognitive mechanism that tracks the origin of perceptual materials such as thoughts, speech or motor actions to allow their correct sourcing. Cognitive models suggest that patients with schizophrenia (SZ) are impaired in monitoring the source of their own speech and thoughts, resulting in confusion between externally perceived events and self-generated materials [START_REF] Frith | The cognitive neuropsychology of schizophrenia[END_REF][START_REF] Harvey | Reality monitoring in mania and schizophrenia. The association of thought disorder and performance[END_REF][START_REF] Harvey | Linguistic and cognitive failures in schizophrenia. A multivariate analysis[END_REF]. SZ individuals, particularly those with auditory hallucinations, tend to misattribute internallygenerated events to an external source (i.e., externalization bias), which have been hypothesized to be a mechanism from which these symptoms may stem [START_REF] Waters | Selfrecognition deficits in schizophrenia patients with auditory hallucinations: a meta-analysis of the literature[END_REF].

Mechanistically, when this externalization bias occurs, subjects become unable to correctly label self-generated material as such. This results in their conclusion that this material came from an external source, which manifests to the clinician as auditory hallucinations [START_REF] Bentall | Reality monitoring and psychotic hallucinations[END_REF][START_REF] Brebion | Positive symptomatology and source-monitoring failure in schizophrenia--an analysis of symptom-specific effects[END_REF]Brunelin et al., 2006b;[START_REF] Keefe | Source monitoring deficits in patients with schizophrenia; a multinomial modelling analysis[END_REF][START_REF] Stirling | Self-monitoring dysfunction and the positive symptoms of schizophrenia[END_REF][START_REF] Waters | Selfrecognition deficits in schizophrenia patients with auditory hallucinations: a meta-analysis of the literature[END_REF][START_REF] Woodward | Source monitoring biases and auditory hallucinations[END_REF]. Nevertheless, source-monitoring disturbances have also been demonstrated in schizophrenia participants despite their prominent symptoms [START_REF] Brebion | Source monitoring impairments in schizophrenia: characterisation and associations with positive and negative symptomatology[END_REF]Brunelin et al., 2006a;[START_REF] Keefe | Source monitoring deficits in patients with schizophrenia; a multinomial modelling analysis[END_REF], highlighting the importance of source-monitoring mechanisms in the pathophysiology of the disease, even if they are not directly related to one single specific clinical dimension. Namely, two types of source-monitoring processes are impaired in SZ: (i) "reality monitoring", which enables individuals to discriminate between internally generated and externally perceived events, and (ii) "internal monitoring", which enables individuals to discriminate between two different internal sources, for instance, one in inner space (i.e., own thoughts) and one in outer space (i.e., self-generated vocal speech).

Additionally, several strands of evidence show that non-verbal basic auditory functions are also impaired in SZ. For instance, patients present with large significant disturbances in tone-matching tasks consisting of discriminating non-verbal sounds according to their psychoacoustic features, such as pitch [START_REF] Donde | Tone-matching ability in patients with schizophrenia: A systematic review and meta-analysis[END_REF][START_REF] Donde | Hierarchical deficits in auditory information processing in schizophrenia[END_REF], location [START_REF] Olsson | Contralateral induction by frequency spectrum in hallucinating schizophrenics[END_REF], intensity [START_REF] Holcomb | Tone discrimination performance in schizophrenic patients and normal volunteers: impact of stimulus presentation levels and frequency differences[END_REF] and dynamic streaming [START_REF] Mclachlan | Auditory processing and hallucinations in schizophrenia[END_REF] perception. Critically, such basic perceptual impairments can lead to misinterpretation of the social intent conveyed through speech prosody [START_REF] Leitman | Getting the cue: sensory contributions to auditory emotion recognition impairments in schizophrenia[END_REF].

However, associations between basic auditory processing and clinical symptoms remain heterogeneous. For instance, a recent study have reported poorer basic auditory performances in a group of patients with auditory hallucinations compared with a non-hallucinating group [START_REF] Mclachlan | Auditory processing and hallucinations in schizophrenia[END_REF]. Other studies have found that these performances were significantly correlated with negative symptoms [START_REF] Bruder | Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits[END_REF] or with each of the 3 factors of the Positive And Negative Syndrome Scale [START_REF] Kay | The positive and negative syndrome scale (PANSS) for schizophrenia[END_REF]) in SZ [START_REF] Javitt | Associated deficits in mismatch negativity generation and tone matching in schizophrenia[END_REF].

From a hierarchical perspective, source-monitoring can be acknowledged as a "higher order" mechanism than basic auditory processes. Supporting this notion, basic auditory processing impairments have been specifically tied to auditory cortex dysfunction in SZ [START_REF] Javitt | Auditory dysfunction in schizophrenia: integrating clinical and basic features[END_REF], while source-monitoring has been correlated with broader brain networks involving the temporal superior gyrus, the temporo-parietal junction, the anterior cingular cortex [START_REF] Mechelli | Misattribution of speech and impaired connectivity in patients with auditory verbal hallucinations[END_REF][START_REF] Vercammen | Functional connectivity of the temporo-parietal region in schizophrenia: effects of rTMS treatment of auditory hallucinations[END_REF] and the prefrontal cortex [START_REF] Vinogradov | Deficit in a neural correlate of reality monitoring in schizophrenia patients[END_REF][START_REF] Wang | Aberrant connectivity during self-other source monitoring in schizophrenia[END_REF].

Several strands of evidence suggest that basic sensory features, as perceived during basic sensory processing, are key elements for optimal sourcing of a sensory event [START_REF] Johnson | Source monitoring[END_REF][START_REF] Sugimori | The effects of cognitive activity and perceptual details on speech source monitoring[END_REF]. In SZ, this contribution has been put forward in the auditory domain by a previous study showing that contrary to healthy controls, SZ individuals with prominent auditory verbal hallucinations did not require the distortion of their feedback to misattribute their own speech to an external source, indicating that basic auditory processes were impaired in these patients [START_REF] Johns | Verbal self-monitoring and auditory verbal hallucinations in patients with schizophrenia[END_REF].

However, despite the suggested relationship between basic auditory functions and higher-order source-monitoring, more evidence is required to further establish the link between source-monitoring of speech, basic auditory disturbances and symptom severity in SZ. According to the above-mentioned literature, one can hypothesize that both cognitive processes are involved in the same pathophysiological framework leading to the clinical symptoms of the illness. To explore these linkages, we investigated the relationship between source-monitoring (i.e., internal and reality monitoring) and basic auditory processes among a large range of acoustic features (i.e., pitch, intensity, amplitude and length) in SZ. As prior studies have reported heterogeneous associations between basic auditory processing and clinical symptoms of schizophrenia, we investigated these associations as exploratory to clarify the link between these deficits and different domains of symptoms. We first hypothesized that patients would display lower performances in both source-monitoring tasks and in basic auditory tasks involving all acoustic features perception, compared to control subjects. Second, we predicted that basic auditory and source-monitoring deficits would be positively associated across groups.

METHOD

Design and participants

A between-subjects design compared 30 participants with a diagnosis of schizophrenia according to DSM-5.0 and 30 healthy controls without any current or history of a section-II disorder. Patients were recruited from both inpatient (8/30) and outpatient (22/30) settings associated with the Centre Hospitalier Le Vinatier (Bron, France).

Patient diagnoses were established using the Mini-International Neuropsychiatric Interview [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]. All controls were examined by a trained psychiatrist to make sure they were free of a current DSM disorder and had no lifetime history of schizophrenia-spectrum disorder. Inclusion criteria were age 18-65 years and fluent spoken French. Exclusion criteria were history of intellectual disability, auditory or neurological impairment, substance use disorder (except for tobacco) and brain neuromodulation procedures in the last 3 months. We also excluded participants who were professional musicians, as musicians display superior ability to discriminate fine auditory changes [START_REF] Bianchi | Subcortical and cortical correlates of pitch discrimination: Evidence for two levels of neuroplasticity in musicians[END_REF][START_REF] Micheyl | Influence of musical and psychoacoustical training on pitch discrimination[END_REF].

All participants provided written informed consent. The experiment was approved by the local ethics committee (Comité de Protection des Personnes Sud-Est 6, Lyon, France).

The study consisted of a single visit. Participants were first informed of the protocol and signed the consent. The absence of severe hearing impairment was confirmed by a simplified audiogram. Then, participants were assessed with the basic auditory and source-monitoring tasks in an isolated room. In the group of patients, the severity of symptoms was assessed using the PANSS. This scale, which is divided in positive, negative and general psychopathology subscores, was administered by trained psychiatrists (authors CD and FH).

Source-monitoring tasks

Source-monitoring was assessed using two French source memory tasks that were developed by our group (Brunelin et al., 2006a) from those described by Keefe and colleagues [START_REF] Keefe | Source monitoring deficits in patients with schizophrenia; a multinomial modelling analysis[END_REF] (Fig. 1a).

Words presented in the source-monitoring tasks were current French words with same neutral emotional valence and length. During each task, an instruction was followed by a word that remained on a computer screen for 3 seconds. In the internal monitoring task (Say-Imagine), participants had to distinguish 8 words that they had imagined themselves saying from 8 words they had spoken aloud. In the reality monitoring task (Hear-Imagine), participants had to distinguish 8 words that they had imagined hearing from 8 words they had heard (said by the experimenter). At the end of each task, a response grid including the 16 presented words plus 8 words that were not presented during the task ('new words') was given to the participant. The whole source-monitoring testing procedure lasted approximately 15 minutes.

A variety of information embedded in a memory event at the time it occurs later serves as the basis of judgements about the origin of this event [START_REF] Johnson | Source monitoring[END_REF]. Thus, despite the fact that source-monitoring is an immediate, on-going experience rather than a memory defect, our tasks are suitable for revealing on-going source-monitoring deficits [START_REF] Waters | Selfrecognition deficits in schizophrenia patients with auditory hallucinations: a meta-analysis of the literature[END_REF]. Additionally, the 'new word' condition allows eliminating a possible confounding effect of memory functioning on actual source discrimination performances.

Basic auditory processing tasks

Four basic auditory sensory processing tasks (Length, Pitch, Intensity, and Amplitude) and 1 control task (Length-distractor) were employed. All tasks are based on a behavioural "simple tone-matching paradigm" originally described by [START_REF] Strous | Auditory sensory ("echoic") memory dysfunction in schizophrenia[END_REF]. In this paradigm, participants are presented with series of pairs of short, non-verbal, pure tones.

Within each pair, tones are either identical or different in one acoustic feature. Auditory stimulus presentation was controlled by a laptop computer with the sound volume fixed at 70 dB. Participants listened to tones binaurally through headphones (Sennheiser HD 558 model) connected to the laptop. The task sequence is described in Fig. 1b. To avoid learning and fatigability effects, the order of presentation of tasks was randomized across participants. The whole basic auditory testing procedure lasted approximately 30 minutes, with 5-minute breaks between each task.

Sound feature discrimination of pure tones

Length discrimination task: 40 randomized pairs of short, serial, non-verbal tones (300 ms) with a short inter-tone interval (500 ms) were presented. The pairs were divided into six randomized blocks. Within each pair, tones differed in length (i.e., duration) by specified amounts in each block (Δl 15%, Δl 33%, Δl 66%, Δl 133%, Δl 266%, and Δl 533%).

Participants had to listen to the pairs of tones and then respond by pressing "first tone was the shortest" or "second tone was the shortest" on a 2-button press.

Pitch discrimination task: 140 randomized pairs of short, serial, non-verbal tones (300 ms) with a short inter-tone interval (500 ms) were presented. The pairs were divided into six randomized blocks. Within each pair, tones were either identical or differed in frequency by specified amounts in each block (Δf 1.5%, Δf 2.5%, Δf 5%, Δf 10%, Δf 20%, and Δf 50%).

Tones were derived from three reference base frequencies (2000, 1000 and 500 Hz) to avoid learning effects. Participants had to listen to the pairs of tones and then respond by pressing "the two tones were identical" or "the two tones were different" on a 2-button press.

Intensity discrimination task: 80 randomized pairs of short, serial, non-verbal tones (300 ms) with a short inter-tone interval (500 ms) are presented. The pairs are divided into six randomized blocks. Within each pair, tones differed in intensity by specified amounts in each block (Δi 10%, Δi 20%, Δi 30%, Δi 40%, Δi 50%, and Δi 60%). Participants had to listen to the pairs of tones and then respond by pressing "first tone had the lowest intensity" or "second tone had the lowest intensity" on a 2-button press.

Modulation discrimination of pure tones

Amplitude task (See [START_REF] Goswami | Amplitude envelope onsets and developmental dyslexia: A new hypothesis[END_REF] for details): 80 randomized pairs of short, serial, non-verbal tones (786 ms) with a short inter-tone interval (500 ms) were presented. All sounds were sinusoidal carriers at 500 Hz, amplitude-modulated at a rate of 0.7 Hz, and had a depth of 50%. The fall time was fixed at 350 ms, and the rise time could be varied from 15 to 300 ms (logarithmically spaced over a continuum of 80 stimuli). Participants had to listen to the pairs of tones and then respond by pressing "first tone had the softest rise" or "second tone had the softest rise" on a 2-button press.

Control for attention functioning

These basic auditory tasks required participants' sustained attention for several minutes. As attentional processes are known to be impaired in SZ [START_REF] Carter | Attention deficits in schizophrenia--preliminary evidence of dissociable transient and sustained deficits[END_REF][START_REF] Fioravanti | Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence[END_REF], we designed a control task called the Length-distractor to eliminate a possible confounding effect of these processes on basic auditory performance. This task was exactly the same as the Length task, with the exception of presenting a short (300 ms) white noise as distractor in the intervening period between tones of each pair (i.e., a sequence "tone -white noise -tone"). By disrupting the sustained attention with an irrelevant stimulus, this task would control for attentional functioning during basic auditory performance effort.

Analyses

All statistical analyses were carried out using R (R Development Core Team, 2008). For all tests, significance was set at p-value<.05. Cohen's d effect sizes for mean comparisons were calculated with a d value of 0.2, 0.5 and 0.8 reflecting the cut-off for small, medium and large effect sizes, respectively. Socio-demographic characteristics between groups were compared using independent-sample two-sided Student's t-tests for continuous variables and Fisher's exact F-tests for categorical variables. Illness duration, medication dosage (expressed in chlorpromazine -CPZ-equivalents) and socio-demographic variables revealing group differences were subjected to exploratory correlational analyses to assess their inclusion as covariates in between-group comparisons.

Source-monitoring comparisons

Participants who identified fewer than 4 'new words' in at least one of the two sourcemonitoring tasks were excluded from the study to eliminate a possible confounding effect of memory capacities or lack of attention towards the task during the encoding phase on sourcemonitoring performances.

We investigated two variables source-monitoring outcomes based on the literature (Brunelin et al., 2006a;[START_REF] Mondino | Anodal tDCS targeting the left temporo-parietal junction disrupts verbal reality-monitoring[END_REF]. In order to separate guessing bias and actual sourcemonitoring measures, we used analysis of covariance (ANCOVA) with count of false positives (i.e., 'said', 'heard', 'imagined as said' and 'imagined as heard' responses to 'new word') entered as covariate [START_REF] Woodward | Source monitoring biases and auditory hallucinations[END_REF].

1) The percent of correct responses was entered in a three-way analysis of covariance (ANOVA) ANCOVA with group (control and patient) as inter-subject factor, and type of task (Say-Imagine and Hear-Imagine), and task condition (internal ('imagined as said' or 'imagined as heard'), external ('heard' or 'said')) as within-subject factors, and false positive rate as covariate.

2) The percent of source-inversions between presented source information (i.e., in the Say-Imagine test, misattributing an internal source to an external source (externalization) and misattributing an external source to an internal event (internalization)) was entered in a threeway ANOVA ANCOVA with group as inter-subject factor, and type of task and type of inversion (internalization, externalization) as within-subject factors, and false positive rate as covariate.

Basic auditory processing comparisons

We measured percentages of correct responses from each basic auditory task (Pitch, Intensity, Length, Amplitude, Length-distractor) according to the literature [START_REF] Donde | Tone-matching ability in patients with schizophrenia: A systematic review and meta-analysis[END_REF].

Percentages of correct responses were divided into three conditions for static feature tasks, related to feature differences of tones: 'Difficult' (2 smallest Δ%), 'Intermediate' (2 intermediate Δ%) and 'Easy' (2 widest Δ%). Amplitude scores were isolated in three equal categories according to the level of difficulty of corresponding stimuli. Then, the percentage of correct responses was entered in a two-way ANOVA with group (control and patient) as inter-subject factor and type of task (Pitch, Intensity, Length and Amplitude) as within-subject factor. As a specific control analysis, covariance (ANCOVA) was computed to assess the independence of basic auditory perception (Length) from attention performance (Lengthdistractor).

Relationships between measures

Pearson correlations were used to compare relationships among variables across groups and within the schizophrenia group. Bonferroni corrections for multiple comparisons were applied, as indicated. In addition, to build a parsimonious model for the prediction of sourcemonitoring regarding basic auditory performances in SZ, we conducted a backward step-wise regression analysis to condense the variables and thus identify the best predictors of sourcemonitoring performance among a large number of variables. The candidate predictors were each basic auditory task score, PANSS dimension scores, illness duration, medication (CPZ) dosage and variables revealing group differences. 'New words' correct recognitions scores in both source-monitoring tasks were excluded from these analyses.

RESULTS

One patient with schizophrenia and one healthy participant did not adequately perform the source-monitoring tasks (more than 4 'new words' not recognized in one of the tasks) and were thus excluded from the analyses. The final analysed sample consisted of 29 SZ and 29 healthy controls. A significantly lower level of education was observed in the patient group (Table 1). Mean task scores and comparisons are detailed in S1.

Source-monitoring comparisons

The three-way ANOVA ANCOVA involving the total numbers of correct responses in source-monitoring tasks revealed a significant main effect of group (F(4,224)=42.49; p<.0005).

(F(8,223)=19.0; p<.0005). No other main effects or interactions were reported.

Post hoc between-group comparisons (Fig. 2) revealed that patients showed significantly less correct recognition of imagined (p<.005; d=0.91) and spoken aloud (p<.05; d=0.53) words in the internal monitoring task, and less correct recognition of imagined (p<.005; d=0.87) and heard (p<.0005; d=1.13) words in the reality monitoring task compared to controls. The total of these correct recognitions was significant within tasks (internal monitoring: p<.005, d=0.87; reality monitoring: p<.00005, d=1.34) and across tasks (p<.00005, d=1.24), with large effect sizes. No significant between-group differences were observed for correct recognition of 'new words' in either source-monitoring task.

Basic auditory processing comparisons

The two-way ANOVA on the percentage of basic auditory correct responses revealed a significant main effect of group (F(4,227)=45.5; p<.0001) and type of basic auditory task (F(4,227)=5.3; p<.0001), but no significant interaction between group and type of basic auditory task.

Post hoc between-group comparisons (Fig. 3) revealed that patients were significantly impaired in all auditory tasks, from more to less impaired: Length (p<.0005; d=1.15), Amplitude (p<.005; d=0.91), Pitch (p<.005; d=0.90) and Intensity (p<.05; d=0.78). We also found a large significant deficit in patients for total correct basic auditory responses (p<.0005; d=1.16).

The ANCOVA of basic auditory length perception ability controlling for attention performance revealed that patients' basic auditory length perception deficits were significant overall (F(2,55)=4.8; p<.05), but that there was a significant attention effect between groups (F(4,227)=30.9; p<.0001). According to this result, we conducted a complementary post hoc ANOVA with groups and tasks (Length and Length-distractor) to explore for an additional deficit in one these tasks versus the other. No significant interaction was observed between task and group.

Relationships between measures

Basic auditory global performance (i.e., the average performance percent of the four basic auditory tasks Length, Pitch, Intensity, and Amplitude -Fig. 3e) was significantly correlated with correct recognition in both internal monitoring (across groups: rpartial=.48,p<.0005,N=58;patients group: r=.48,p<.05,N=29;Fig.4a) and reality monitoring tasks (across groups: rpartial=.43,p<.005,N=58;patients group: r=.40,p<.05,N=29;Fig.4b). Across groups, these correlations remained significant following Bonferroni correction. Within tasks, significant correlations were observed between basic auditory and all word conditions, except for 'said' words.

Within the patient group, a significant negative correlation was observed between performance at the Pitch test (intermediate condition) and PANSS-Positive sub score (r=-.40, p<.05, N=29, but did not survive Bonferroni correction). Examination of relationships with specific PANSS-Positive symptoms showed that delusion and suspiciousness were the most negatively correlated with basic auditory processing (Average performance). However, these correlations lost significance when applying Bonferroni correction.

There was no correlation between global basic auditory performance and PANSS-Negative (r=.09, p>.05, N=29) and PANSS-General psychopathology subscores (r=-.19, p>.05, N=29).

In addition, no correlations between source-monitoring tasks and positive, negative, general psychopathology symptom measures were significant (all p>.05).

Basic auditory processing and source-monitoring scores did not correlate with illness duration or medication (CPZ) dosage (all p>.05). However, there was a significant correlation between education and both sets of task scores. Regression analysis using the same ANOVA models controlling for this covariate revealed that basic auditory and source-monitoring task score differences remained significant between groups.

The step-wise regression analysis studied the influence of candidate predictor variables on the total number of correct recognitions in both source-monitoring tasks: 12 that reflect basic auditory processing (3 levels of Length, Pitch, Intensity and Amplitude percentages of correct responses) and 6 socio-demographic/clinical measures (PANSS subscores, illness duration, CPZ, education). Within the patient group, only Pitch Intermediate (b=0.20; p<.05) was a significant predictor.

DISCUSSION

Source-monitoring deficits and basic auditory processing in SZ

This exploratory study conducted in 29 SZ and 29 healthy participants corroborated our primary hypothesis by showing that patients displayed lower performances in both basic auditory functions and source-monitoring processes in comparison to controls.

Source-monitoring deficit in patients is consistent with the previous literature regarding internal monitoring [START_REF] Brebion | Positive symptomatology and source-monitoring failure in schizophrenia--an analysis of symptom-specific effects[END_REF][START_REF] Henquet | Confusing thoughts and speech: source monitoring and psychosis[END_REF], reality monitoring disruption [START_REF] Vinogradov | Clinical and neurocognitive aspects of source monitoring errors in schizophrenia[END_REF], and both [START_REF] Keefe | Source monitoring deficits in patients with schizophrenia; a multinomial modelling analysis[END_REF]. Although recent memory retention differences between groups may account for these differences in source-monitoring performance, the absence of group difference in the recognition of 'new words' does not support this interpretation. In addition, source-monitoring differences remained significant after regression analysis controlling for the same potential covariates as controlled for basic auditory tasks. An important caveat is that our patient group did not show significant source inversions in source-monitoring tasks in comparison to controls (e.g., misattributing an internal, self-generated item to an external source; S1). Even if one study corroborates this result [START_REF] Seal | Deficits in Source Monitoring in Subjects with Auditory Hallucinations May be Due to Differences in Verbal Intelligence and Verbal Memory[END_REF], this non-significant difference strongly contrasts with the recent literature (Brunelin et al., 2006b;[START_REF] Waters | Selfrecognition deficits in schizophrenia patients with auditory hallucinations: a meta-analysis of the literature[END_REF][START_REF] Woodward | Source monitoring biases and auditory hallucinations[END_REF] Moreover, we observed that patients displayed abnormalities for processing several psychoacoustic parameters, regarding both sound feature (length, pitch, intensity) and modulation discrimination (amplitude). This is consistent with patients' pitch discrimination impairments reported in our recent meta-analysis [START_REF] Donde | Tone-matching ability in patients with schizophrenia: A systematic review and meta-analysis[END_REF]. Additionally, we calculated an increasing magnitude of the effect size between groups as the level of pitch test difficulty decreased (Table 2, S1), supporting the auditory discrimination threshold reduction related to schizophrenia that was previously underlined in some studies [START_REF] Kantrowitz | The 5% difference: early sensory processing predicts sarcasm perception in schizophrenia and schizo-affective disorder[END_REF][START_REF] Rabinowicz | Auditory sensory dysfunction in schizophrenia: imprecision or distractibility?[END_REF]. The analysis of length perception ability controlled for attention revealed that higher attention performance predicts better auditory processing scores, but that auditory processing cannot be accounted for solely by attention differences between groups. This is important especially since patients usually display large attention deficits [START_REF] Carter | Attention deficits in schizophrenia--preliminary evidence of dissociable transient and sustained deficits[END_REF][START_REF] Fioravanti | Cognitive deficits in schizophrenia: an updated metanalysis of the scientific evidence[END_REF]. Furthermore, patients' basic auditory deficits remained significant after controlling for education, illness duration and CPZ dosages; this outcome was not the case in a basic auditory study of Leitman and colleagues (Leitman et al., 2006). These regression analyses may support the consideration of basic auditory processing deficits as a full-blown dimension of schizophrenia, which would be distinct from the attention domain and likely underpinned by specific pathophysiological neural pathways [START_REF] Javitt | When doors of perception close: bottom-up models of disrupted cognition in schizophrenia[END_REF][START_REF] Javitt | Auditory dysfunction in schizophrenia: integrating clinical and basic features[END_REF].

Basic auditory processing correlates with source-monitoring and clinical symptoms

Our results showed significant correlations between basic auditory processing and source-monitoring scores, for both internal ('imagined as said' and 'imagine as heard' words) and external ('heard' words) events across groups. Furthermore, our step-wise regression analysis suggested that pitch processing is a strong predictor of source-monitoring performances, even when socio-demographic and clinical variables are taken into account.

These results support the hypothesis of an incorrect identification of the basic auditory cues that are related to a specific auditory source (internal or external) in SZ. Such deficits would lead to an impaired recognition of these events and then to source-monitoring disruption, as each auditory source is related to specific psychoacoustic parameters.

As well as being consistent with previous studies [START_REF] Bruder | Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits[END_REF][START_REF] Javitt | Associated deficits in mismatch negativity generation and tone matching in schizophrenia[END_REF][START_REF] Mclachlan | Auditory processing and hallucinations in schizophrenia[END_REF], the correlation we observed between pitch discrimination and positive symptoms (as measured by the PANSS scale) suggests that basic auditory deficits are involved in source-monitoring impairments, as such deficits were identified as more disrupted in subsamples more prone to positive symptoms [START_REF] Brebion | Positive symptomatology and source-monitoring failure in schizophrenia--an analysis of symptom-specific effects[END_REF]Brunelin et al., 2006a;[START_REF] Keefe | Source monitoring deficits in patients with schizophrenia; a multinomial modelling analysis[END_REF][START_REF] Stirling | Self-monitoring dysfunction and the positive symptoms of schizophrenia[END_REF]. However, the association between pitch discrimination and positive symptoms was no longer significant after correction for multiple comparisons and thus should be considered with caution.

These findings provide new insights into the corollary discharge model [START_REF] Ford | Assessing corollary discharge in humans using noninvasive neurophysiological methods[END_REF], in that source-monitoring disruption may arise from wrong sensory feedforward of the auditory signal that mismatches with the efference copy, resulting in a loss of the sense of thought agency in patients. However, we must note that consistent with prior studies [START_REF] Szoke | Correlations between cognitive performances and psychotic or schizotypal dimensions[END_REF][START_REF] Vinogradov | Clinical and neurocognitive aspects of source monitoring errors in schizophrenia[END_REF], no significant correlations were observed between sourcemonitoring tasks scores and psychometric scales in SZ. Likewise, the absence of significant correlation between source inversions and basic auditory processing shows that auditory disruption may rather be involved in decreased accuracy of source recognition than in specific incorrect externalization/internalization of this source.

Methodological bias and limits

This is the first experiment to explore both basic auditory processing and sourcemonitoring in SZ, as well as clinical symptoms. However, this study has some notable and methodological limitations.

First, the small sample size did not allow performing subgroup comparisons to investigate if both deficits are more pronounced between prominent clinical dimensions.

Additionally, hallucinations occurring simultaneously with the tests were not possible to determine, but they may have biased the performances.

Second, indirect measure of self-monitoring through source memory tasks prevents us from determining if monitoring deficits occur simultaneously with the auditory stimulus encoding or when the information is recalled. Real-time self-monitoring assessments showed deficits in SZ [START_REF] Allen | Misattribution of external speech in patients with hallucinations and delusions[END_REF], but these results were not systematically replicated [START_REF] Versmissen | Verbal self-monitoring in psychosis: a non-replication[END_REF]. Nevertheless, short-term memory recall deficits in patients were eliminated by the absence of differences in 'new words' recognition between groups.

Third, several parameters that we did not evaluate in our study may be involved in source-monitoring abilities, such as metacognitive beliefs about own thoughts [START_REF] Aleman | Hallucinations : the science of idiosyncratic perception, 1st ed[END_REF] and emotional state presented during source-monitoring assessment [START_REF] Johnson | Memory and reality[END_REF][START_REF] Morrison | A cognitive model of hallucinations[END_REF].

CONCLUSION

Our study shows that both basic auditory processing and internal/reality sourcemonitoring of auditory stimuli are impaired in SZ and cannot be accounted for solely by attention (estimated by auditory performance with distractor noise) or memory deficits (measured with short-term 'new words' recall). We hypothesize that primarily auditory disruption at the brain level, as indexed by basic auditory skills, may be involved in larger neural networks underpinning source-monitoring abilities and positive symptoms in patients.

Further validation of the present findings is certainly warranted, including studies measuring brain function and general cognitive abilities, controlling for potential bias of both behavioural paradigms. Nevertheless, this study contributes to the literature by demonstrating that early sensory processing may be a key feature of schizophrenia and a potential contributor of cognitive deficits and positive symptoms of the illness. A. Source monitoring assessment. 1: an instruction is presented on the screen (Internal monitoring: "Say this word aloud" or "Imagine this word"; Reality monitoring: "Listen to this word" -the experimenter say the word -or "Imagine that you are hearing this word"), 2: a word is presented, and the participant has to apply the instruction to the word, 3: response grid: for example, in the 'Internal monitoring' task, a participant had to note for each word if he said the word, if he imagined saying the word or if the word did not appear on the computer's screen.

FIGURES CAPTIONS

B.

Basic auditory processing assessment. 1: a short visual cue is present on the screen to capture the participant's attention, 2: a pair of short tones is presented through headphones, 3: participant has to respond to the instruction on a 2-button press.

Figure 1 :

 1 Figure 1: Models of behavioural paradigms.

Figure 2 :

 2 Figure 2: Behavioural assessment of source monitoring. Bar graph (Mean +/-SD) of % correct for source monitoring tasks. Total scores exclude control task ('New words') scores. *p<.05, **p<.005, ***p<.0005.

Figure 3 :

 3 Figure 3: Behavioural assessment for basic auditory processing.Bar graph (Mean +/-SD) of % correct by acoustic feature against level of task difficulty.

  (e) Average refers to the average performance percent of the four basic auditory tasks (Length, Pitch, Intensity, and Amplitude).

*

  p<.05, **p<.005, ***p<.0005, ****p<.00005.

Figure 4 :

 4 Figure 4: Scatter plots of A. % total correct for Internal monitoring and B. % total correct for Reality monitoring by basic auditory processing % total correct. : Healthy controls (red circles), : Patients with schizophrenia (blue triangles).