Lucie Jurek

Yannick Longuet

Matias Baltazar

Anouck Amestoy

Vicky Schmitt

Michel Desmurget

Marie-Maude Geoffray

How did I get so late so soon? A review of time processing and management in autism

Keywords: Autism, Time processing, Circadian rhythm, Remediation, Time assessment

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

INTRODUCTION

Autism spectrum Disorder (ASD) is a common and life-long neurodevelopmental disorder characterized by difficulty with communication and social interaction and stereotyped, repetitive behaviors. Cognitive functioning is highly heterogeneous across individuals with ASD. ASD generally appears in the first two years of life (American Psychiatric Association, 2013). Current classifications of the core diagnostic criterion in ASD include atypical sensory and perception behaviors. However, despite being emphasized upon by clinicians and researchers, time management and perception atypicalities are not included in those criterion [START_REF] Stevenson | Keeping time in the brain: Autism spectrum disorder and audiovisual temporal processing[END_REF][START_REF] Wing | The Autistic Spectrum: A Guide for Parents and Professionals[END_REF]. Nonetheless, temporal issues in ASD are observed in daily clinical practice. Moreover, several recent studies have reported that a significant proportion of cognitive processes involve the encoding and precise treatment of temporal information [START_REF] Allman | Possible evolutionary and developmental mechanisms of mental time travel (and implications for autism[END_REF]Christine M. Falter, Elliott, & Bailey, 2012a;[START_REF] Lambrechts | Diminished neural resources allocation to time processing in Autism Spectrum Disorders[END_REF]. Some authors have even suggested that deficits in time processing could be central to the pathological pathways leading to ASD phenotypes (Allman, 2011a;[START_REF] Allman | Possible evolutionary and developmental mechanisms of mental time travel (and implications for autism[END_REF][START_REF] Allman | Developmental neuroscience of time and number: implications for autism and other neurodevelopmental disabilities[END_REF]. It is possible then, that a "temporal" point of view could lead to a better understanding of the neurodevelopment pathways found in ASD and help to develop new early targeted interventions to improve the prognostic of this disorder. Time processing is a broad construct. During the last decade, a consensus has emerged to differentiate between three kinds of time measurement, each having different neural mechanisms involved: circadian, interval and millisecond timing [START_REF] Buhusi | What makes us tick? Functional and neural mechanisms of interval timing[END_REF]. Circadian timing intervenes on a 24-hour based duration and allows control of sleep-wake rhythms. This system is present in a multitude of different species. In humans, it is regulated by the supra-chiasmatic nucleus, which detects perceived light, to synchronize diurnal and nocturnal behaviors with day-night alternations [START_REF] Panda | Circadian rhythms from flies to human[END_REF]. Interval Timing operates within a spectrum spanning from less than one second to a few minutes and refers to conscious time estimation. It is involved in the decision-making processes. The precise neural mechanisms involved in interval timing are currently under debate, yet there is strong evidence for the implication of cortico-striatal networks and dopamine neurons. Millisecond Timing refers to the measurement of time by intervals of under one second and contributes to crucial functions such as motor control and speech. Millisecond timing relies on different cerebral structures depending on the sensory modality. For example, the cerebellum is involved in motor control [START_REF] De Zeeuw | Spatiotemporal firing patterns in the cerebellum[END_REF], and the auditory cortex participates in speech processing [START_REF] Nourski | Representation of temporal sound features in the human auditory cortex[END_REF]. This review aims to discuss the current scientific literature about time processing in ASD, at its different levels. We present an overview of recent scientific data and knowledge gaps on time processing in ASD compared to individuals with a typical development (TD).

For this purpose, we searched for articles on PubMed and PsycINFO databases and included studies or reviews written in English andFrench, published between 1980 and2019. Articles were searched using a combination of keywords related to ASD, time processing, synchrony or order judgment, circadian time and time assessment. After the removal of duplicate articles, a first selection was then made based on screening title and abstract by one of the authors (LJ). Full-texts were then read and classified according to their main topic (time perception, circadian time or clinical assessment), and reference lists were also screened for additional relevant papers to insure completeness. Beginning with a total of 1074 articles, 298 were excluded as duplicates, 776 were screened on title and abstract, 605 were excluded (not related to time processing or circadian system, wrong study population, case report…) and 171 full-text articles were ultimately included in the review.

ASD AND TIME PROCESSING: CLINICAL OVERVIEW Time processing is in an important but neglected feature of ASD, as much in its clinical definition as in daily practice. Few clinicians have reported or assessed this feature as essential for daily adaptive behavior. It has been reported that participants with ASD without Intellectual disability (i.e. with IQ superior or equal to 70) have difficulties making chronological sense of their memories [START_REF] Bennetto | Intact and Impaired Memory Functions in Autism[END_REF]. Adults with ASD also reported a lack of sense of time, and difficulty understanding continuity in time, even in their own personal history [START_REF] Vogel | Interrupted Time Experience in Autism Spectrum Disorder: Empirical Evidence from Content Analysis[END_REF]. While telling time on a clock was not a problem for them, they mentioned difficulty in associating specific hours to related activities, or in managing the allotted time for that activity (J. [START_REF] Boucher | Time-parsing and autism[END_REF]. Clinical studies are also limited. Two parent-report studies showed a significant alteration in time perception in ASD children compared to typically developing children (Allman & Wearden, 2011), and also encountered difficulties thinking in a diachronic fashion (i.e. to think about past or future stages of a current situation) or in considering successive discrete events as being part of a whole [START_REF] Boucher | Temporal Cognition in Children with Autistic Spectrum Disorders: Tests of Diachronic Thinking[END_REF]. Two other authors indirectly reported time difficulties. One suggested that repetitive behaviors could be an effective way for people with ASD to create a sense of rhythmicity where there is none exists [START_REF] Tordjman | Autism as a Disorder of Biological and Behavioral Rhythms: Toward New Therapeutic Perspectives[END_REF]. A qualitative study, including the statements of 26 adult participants with ASD, indicated that routine and repetitive behaviors were used to accentuate the impression of fading time and prevent from the impression of "interrupted time" [START_REF] Vogel | Interrupted Time Experience in Autism Spectrum Disorder: Empirical Evidence from Content Analysis[END_REF]. Indeed, those symptoms could reflect compensating mechanisms used to bypass inefficient time processing. Studies evaluating the correlation between time perception and the severity and frequency of those repetitive symptoms could help understand the relationship between these two features.

In parallel with the thin "clinical" literature about time perception difficulties, there are few tools available to measure time management and processing. Some well-known tests, developed to measure daily adaptive behavior, have included few/minimal items for evaluating time perception. For instance, the Vineland Adaptive Behavior Scales (VABS-II; [START_REF] Sparrow | Vineland Adaptive Behavior Scales, Second Edition (Vineland TM -II)[END_REF]), is a scale scored by a clinician while interviewing a caretaker or filled in by caretakers themselves. It includes items pertaining to time reading on analog or digital devices, and an observance of appointments and schedules. These items are included under a broader construct named "Community," which pertains to skills necessary for interacting with and navigating in the community (such as money management, use of a telephone, autonomy in taking public transportation, etc.). However, since these items are not aggregated in a separate dimension, one cannot derive a standardized score indexing time perception from such a tool.

One team designed a specific tool in order to assess time perception in children with disabilities aged 5 to 10 years old, the Kit for assessing Time Processing Ability (KaTid) (G. [START_REF] Janeslätt | Development of a new assessment of time processing ability in children, using Rasch analysis[END_REF][START_REF] Janeslätt | Measurement of time processing ability and daily time management in children with disabilities[END_REF]. The tool assesses three dimensions: time perception (experiencing and assessing the length and passage of time, including interval timing), time orientation (awareness of the day, date, month and year, as well as the ability to situate events in a timeline), and time management (the ability to prioritize one task among others, to order a set of tasks, and to allocate the optimum amount of time to each task). The latter dimension seems to develop at a later age according to one study (i.e. between seven and nine years old; [START_REF] Janeslätt | Patterns of Time Processing Ability in Children with and without Developmental Disabilities[END_REF] and has been theorized to rely on the development of the first two dimensions (G. [START_REF] Janeslätt | Validity in assessing time processing ability, test equating of KaTid-Child and KaTid-Youth[END_REF]. The tool includes 51 items in the form of a combined visual and verbal presentation for allowing assessment of children with communication or reading impairments. Depending on the item, the child answers verbally or by pointing at a picture. It is of note that the validation study for this tool is in favor of a unidimensional construct (named Time Processing Ability), thus limiting the conclusions that can be drawn on the effects restricted to one or two dimensions. A version for older children and adolescents aged 10 to 17 years old (the KaTid-Youth) has also been designed by the same team (G. [START_REF] Janeslätt | Validity in assessing time processing ability, test equating of KaTid-Child and KaTid-Youth[END_REF][START_REF] Wennberg | Effectiveness of time-related interventions in children with ADHD aged 9-15 years: A randomized controlled study[END_REF].

The same team designed a self-rated questionnaire for parents to assess their child's time management ability (Parent Scale of the Child's Time Management in Daily Life; (G. [START_REF] Janeslätt | Development of a new assessment of time processing ability in children, using Rasch analysis[END_REF][START_REF] Janeslätt | Measurement of time processing ability and daily time management in children with disabilities[END_REF]). This scale includes 13 items investigating various aspects of time perception, from the adherence to a regular sleep-wake pattern to the ability to use calendars and clocks. KaTid and the Parent Scale have been found to be highly correlated in several studies (G. [START_REF] Janeslätt | Development of a new assessment of time processing ability in children, using Rasch analysis[END_REF][START_REF] Janeslätt | Measurement of time processing ability and daily time management in children with disabilities[END_REF].

A self-rated questionnaire for children aged from 10 to 17 years old was also designed (the Time S questionnaire; [START_REF] Sköld | Self-rating of daily time management in children: Psychometric properties of the Time-S[END_REF]). The questionnaire includes 21 statements which are rated with a Likert-like frequency scale, with four response alternatives. It is of note that scores from this questionnaire were not significantly correlated with scores from the KaTid-Youth in the validation study [START_REF] Sköld | Self-rating of daily time management in children: Psychometric properties of the Time-S[END_REF], which raises questions about children and adolescents with disabilities assessing their own time management capacities reliably, and/or casting doubt upon the fact that both tools (the KaTid and the Time S) measure the same construct.

These questionnaires could improve clinical assessment of time perception. Information on temporal perception and processing in ASD could be add to global functional assessments. This could lead to a better understanding of time perception difficulties impact in daily life. But if a clinical perspective is important, a view of cognitive mechanisms may allow a better understanding of clinical observations.

"MILLISECOND" AND "INTERVAL TIMING" IN ASD

Interval timing: A deficit induced by atypical but modifiable cognitive strategies?

Many different approaches exist to evaluate interval timing [START_REF] Grondin | Timing and time perception: A review of recent behavioral and neuroscience findings and theoretical directions[END_REF]. In ASD research, the majority of experiments have used temporal reproduction tasks (where the subject is asked to reproduce a standard interval of time by manipulating a device, e.g. pressing a button or pulling a lever) and temporal comparison tasks (where the subject is asked to compare two intervals of time and to indicate if these intervals are similar or not). Other experiments use a temporal bisection task, in which subjects are asked to compare temporal stimuli to two references, between a "long" and "short" stimuli. After being trained on the reference stimuli, probe stimuli are then introduced. The subject must indicate with which reference stimulus they believe the probe stimulus is most similar to, the long or the short one. From the data collected during the task experimenters are able to construct a psychometric curve. This curve shows the point of indifference (i.e. the stimulus length at which participants show a 50/50 chance of picking the long or short reference), offering insight on how time is represented and processed [START_REF] Kopec | Human Performance on the Temporal Bisection Task[END_REF].

Using this framework, Szelag et al. first demonstrated a very clear alteration of precision and accuracy in temporal reproduction tasks in children with ASD compared to typically developing controls (TD), with an overestimation of a longer duration and an underestimation of a shorter duration in ASD group [START_REF] Szelag | Temporal processing deficits in highfunctioning children with autism[END_REF]) (N = 14; 7 ASD and TD, average age of 12 years).

Similar results have been found in several studies during the last two decades and a synthesis is presented in Table 1. Most of the studies found a significant difference in interval timing processing in ASD group compared to typically developing controls, with ASD individuals showing higher detection thresholds (relating to the minimum interval between sequential stimuli needed for individuals to perceive an interruption between the stimuli) [START_REF] Bhatara | Impaired Timing and Frequency Discrimination in High-functioning Autism Spectrum Disorders[END_REF][START_REF] Foss-Feig | Auditionspecific temporal processing deficits associated with language function in children with autism spectrum disorder[END_REF][START_REF] Isaksson | Is there a generalized timing impairment in Autism Spectrum Disorders across time scales and paradigms[END_REF][START_REF] Karaminis | Central tendency effects in time interval reproduction in autism[END_REF][START_REF] Lambrechts | Diminished neural resources allocation to time processing in Autism Spectrum Disorders[END_REF], less accurate and more variable responses on duration reproduction [START_REF] Brenner | Time reproduction performance is associated with age and working memory in high-functioning youth with autism spectrum disorder[END_REF][START_REF] Martin | Brief Report: Impaired Temporal Reproduction Performance in Adults with Autism Spectrum Disorder[END_REF][START_REF] Salunkhe | Examining the Overlap Between ADHD and Autism Spectrum Disorder (ASD) Using Candidate Endophenotypes of ADHD[END_REF] or poorer sensitivity to duration on a temporal bisection task [START_REF] Allman | Deficits in temporal processing associated with autistic disorder[END_REF][START_REF] Brodeur | Time Estimation Among Low-Functioning Individuals With Autism Spectrum Disorders: Evidence of Poor Sensitivity to Variability of Short Durations[END_REF]. Decrease in auditory gap detection abilities were associated with lower phonological processing scores but also weaker receptive language skills [START_REF] Foss-Feig | Auditionspecific temporal processing deficits associated with language function in children with autism spectrum disorder[END_REF] or higher communication impairment score (Christine Michaela [START_REF] Falter | More consistent, yet less sensitive: Interval timing in autism spectrum disorders[END_REF]. Autistic traits in a TD population, as measured by the Autistic Quotient [START_REF] Ruzich | Measuring autistic traits in the general population: A systematic review of the Autism-Spectrum Quotient (AQ) in a nonclinical population sample of 6,900 typical adult males and females[END_REF] were found to be positively correlated to duration discrimination thresholds, extending the applicability of this finding to the broader autistic spectrum [START_REF] Stewart | Autistic Traits and Enhanced Perceptual Representation of Pitch and Time[END_REF].

Table 1 about here

In contrast, some studies failed to report differences between ASD and control groups concerning interval timing [START_REF] Edey | Brief Report: Typical Auditory-Motor and Enhanced Visual-Motor Temporal Synchronization in Adults with Autism Spectrum Disorder[END_REF][START_REF] Gil | Children with Autism Spectrum Disorders have "the working raw material" for time perception[END_REF][START_REF] Jones | Auditory discrimination and auditory sensory behaviors in autism spectrum disorders[END_REF][START_REF] Jones | Using Time Perception to Explore Implicit Sensitivity to Emotional Stimuli in Autism Spectrum Disorder[END_REF][START_REF] Mostofsky | Evidence for a deficit in procedural learning in children and adolescents with autism: Implications for cerebellar contribution[END_REF][START_REF] Wallace | Time perception in autism spectrum disorders[END_REF].

Maister and al. suggested that these contradictions could be explained by the variety of measurement methods. Starting from this hypothesis the authors tried to assess temporal processing on a large spectrum of various duration in children with and without ASD in a procedure that addressed the methodological concerns associated with previous research. The study was divided into two experiments. The first one was conducted with 42 children (21 with ASD and 21 TD, 8-13 years-old, normal IQ) for several durations (0.5, 1, 2, 4, 10, 30, and 45 seconds). Each duration was evaluated twice in order to measure variability between the first and the second trial for each subject, which could reflect changes in attentional levels. The results showed a statistically significant alteration in temporal reproduction abilities, but only for very short (0.5, 1 and 2 seconds) or very long (45 seconds) periods of time. The inter-subject variability showed an attentional bias for short to average durations (0.5, 1, 2, 4 and 10 seconds) in subjects with ASD. For longer duration, a positive correlation between duration reproduction accuracy and short-term memory capacity was demonstrated [START_REF] Maister | Time perception and its relationship to memory in Autism Spectrum Conditions[END_REF] and was confirmed in another study [START_REF] Brenner | Time reproduction performance is associated with age and working memory in high-functioning youth with autism spectrum disorder[END_REF]. Those results suggest that, in order to perform temporal judgements, individuals with ASD use different cognitive strategies (and different neural substrates) compared to TDC individuals.

Consistent with this conclusion, a recent comparative MEG study (19 subjects with ASD and 19 TD) using an auditory temporal comparison task confirmed the attentional deficit presented by ASD subjects for short duration discrimination [START_REF] Lambrechts | Diminished neural resources allocation to time processing in Autism Spectrum Disorders[END_REF]. Participants were told to evaluate either the length (300, 600 or 900ms) or the pitch (490 Hz, 500 Hz or 510 Hz) of a target stimulus compared to a standard stimulus. A significant deficit in sensitivity to temporal duration was found in subjects with ASD compared to controls. In MEG evaluations, auditory evoked responses elicited by the presentation of the standard stimulus in duration tasks were different between groups. ASD presented a significantly longer neuronal response to the standard stimuli, going beyond its actual length. A slower decrease in MEG activity after the end of the sound was also reported. These results might indicate that from the standard stimulus a less precise encoding of the offset may be found in ASD, underlying the diminished sensitivity to duration.

Additionally, because of the very nature of pitch and duration, pitch discrimination could be resolved shortly after the onset of the tone, whereas duration comparison could only be resolved after the offset of the tone. Participants with ASD presented an enhanced and sustained evoked response to the pitch instruction whereas their evoked response to duration instruction were diminished and imprecise. The opposite pattern was found in control participants. These results suggest that ASD participants, unlike TD controls, do not allocate the relevant attentional resources to the processing of the target duration.

In terms of cortical regions, different activation patterns were found between ASD and TD groups. In the control group, MEG evoked responses for duration were significantly higher in the right hemisphere although responses for pitch were higher in the left hemisphere. In the ASD group, brain activation was similar in the left and right hemispheres regardless of the given instructions, pointing toward a less differentiated allocation of neural resources in ASD.

Therefore, there is growing evidence of an impairment of interval timing in ASD. Scientific literature emphasizes ASD's atypical cognitive strategies when processing time. Attentional functions and short-term memory may be implied in this impairment and could be targeted by cognitive remediation. Though, a mediation analysis evaluating the benefits of cognitive remediation on interval timing in relation to attention or memory could be of great use in the understanding of the interval timing process.

Arguments for impairment in specific sensory modalities

Certain authors have suggested that differences in processing of visual information in people with ASD explains the heterogeneity of the results found in the literature concerning time processing. They have argued that processing visual time information might be preserved, or even improved, in subjects with autism, while processing information in other sensory (particularly auditory) modalities might be degraded [START_REF] Edey | Brief Report: Typical Auditory-Motor and Enhanced Visual-Motor Temporal Synchronization in Adults with Autism Spectrum Disorder[END_REF][START_REF] Falter | Enhanced Visual Temporal Resolution in Autism Spectrum Disorders[END_REF][START_REF] Foss-Feig | Auditionspecific temporal processing deficits associated with language function in children with autism spectrum disorder[END_REF].

For instance, using a visual temporal bisection task, no difference was found between ASD and TD participants [START_REF] Gil | Children with Autism Spectrum Disorders have "the working raw material" for time perception[END_REF][START_REF] Jones | Using Time Perception to Explore Implicit Sensitivity to Emotional Stimuli in Autism Spectrum Disorder[END_REF], even in populations with auditory temporal processing impairment [START_REF] Foss-Feig | Auditionspecific temporal processing deficits associated with language function in children with autism spectrum disorder[END_REF][START_REF] Kwakye | Altered auditory and multisensory temporal processing in autism spectrum disorders[END_REF]. More importantly, several authors reported enhanced time processing performance of ASD subjects with the use of visual tasks [START_REF] Edey | Brief Report: Typical Auditory-Motor and Enhanced Visual-Motor Temporal Synchronization in Adults with Autism Spectrum Disorder[END_REF][START_REF] Falter | Enhanced Visual Temporal Resolution in Autism Spectrum Disorders[END_REF][START_REF] Karaminis | Central tendency effects in time interval reproduction in autism[END_REF].

A neuroimaging study also supports this hypothesis [START_REF] Lukito | Neural Correlates of Duration Discrimination in Young Adults with Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder and Their Comorbid Presentation[END_REF]. A visual duration discrimination task showed no difference in terms of performance between TD, ASD, Attention Deficit/Hyperactivity disorder (ADHD) or co-morbid ASD and ADHD young adults. The authors demonstrated a neurofunctional deficit in the typical duration discrimination brain region, when comparing ASD+ADHD group to ASD only or TD, but not to ADHD only. ASD only groups didn't show any significant difference in cerebral activation patterns.

To conclude on this section, it appears that time perception is dependent on sensory modality. Based on their preserved-to-enhanced visual capacities, individuals with ASD seem to be efficient in measuring time through visual cues. But because of anomalies in auditory processing, time perception is altered when relying on auditory cues. It remains to be studied how other modalities with good temporal resolution (such as touch or even interoceptive modalities) are affected in ASD.

It is also interesting to note that this data fits within the empirical clinical practices, in which visual aids are used to help ASD individuals to better represent time intervals and schedules. It could be interesting to design studies profiling ASD individuals on their visual and auditory capacities, and then assessing their responses to visual aid interventions.

Autism and multimodal temporal integration

There are an accumulation of studies supporting the hypothesis of impairment in multisensory integration in ASD [START_REF] Chan | Temporal integration of multisensory stimuli in autism spectrum disorder: A predictive coding perspective[END_REF][START_REF] Feldman | Audiovisual multisensory integration in individuals with autism spectrum disorder: A systematic review and meta-analysis[END_REF][START_REF] Stevenson | Keeping time in the brain: Autism spectrum disorder and audiovisual temporal processing[END_REF]. This capacity is based on multimodal temporal integration, which is the capacity of the central nervous system to temporally integrate different external events (perceived by different sensory modalities) into a single percept. This cerebral capacity is notably involved in the McGurk effect [START_REF] Mcgurk | Hearing lips and seeing voices[END_REF]. In this illusion, a manipulated video shows a speaker saying the syllable "ga" while an audio clip produces the syllable "ba", leading viewers to hear "da" or "that" syllables.

Temporal integration is important in everyday life, as illustrated by the case of patient AWF [START_REF] Hamilton | An acquired deWcit of audiovisual speech processing[END_REF]. Following a brain injury of unknown etiology associated with bilateral parietal hypoperfusion, AWF started perceiving what he heard and saw as being unsynchronized, like "watching a movie with the audio out of sync". Interestingly AWS was incapable of perceiving the McGurk effect. He coped with this asynchrony by limiting face-to-face conversations and looking away during conversations, which could give the impression of social avoidance.

The past twenty years of research has revealed impairment in temporal integration in subjects with ASD, with a notably decreased susceptibility to the McGurk effect (de Gelder, Vroomen, & Van der Heide, 1991; E. G. [START_REF] Smith | Audiovisual speech integration and lipreading in autism[END_REF][START_REF] Stevenson | Multisensory Temporal Integration in Autism Spectrum Disorders[END_REF][START_REF] Williams | Visualauditory integration during speech imitation in autism[END_REF] Atypical patterns of cerebral connectivity are proposed as neurobiological foundations of those temporal integration impairments [START_REF] Martínez-Sanchis | Neurobiological foundations of multisensory integration in people with autism spectrum disorders: The role of the medial prefrontal cortex[END_REF], with hyper-connectivity in some unimodal sensory regions, such as visual cortex, while hypo-connectivity between sensory region and attentional network is reported. Those particular patterns are correlated to ASD severity [START_REF] Martínez | Sensory-to-Cognitive Systems Integration Is Associated With Clinical Severity in Autism Spectrum Disorder[END_REF].

Temporal processing abnormalities are probably not the sole ontogenetic cause of ASD but subtle impairments in low-level neuronal functions could have cascading effects on the development of higher-level functions [START_REF] Stein | Multisensory integration: Current issues from the perspective of the single neuron[END_REF]). An association between impaired temporal processing mechanisms and other cognitive functions (such as social cognition, language processing and understanding of causality) support this hypothesis (Christine Michaela Falter et al., 2012;[START_REF] Foss-Feig | Auditionspecific temporal processing deficits associated with language function in children with autism spectrum disorder[END_REF]. Increased audiovisual integration in individuals with ASD has been associated with better language, communication abilities and reduced autism symptom severity [START_REF] Feldman | Audiovisual multisensory integration in individuals with autism spectrum disorder: A systematic review and meta-analysis[END_REF], emphasizing the importance of this mechanism in neurodevelopment.

Going a bit further, Stevenson et al. recently proposed a mediation analysis to explore the eventual causality of temporal processing impairment on speech perception. Through a series of tasks assessing multisensory temporal processes, multisensory integration and speech perception in children with and without ASD, the authors demonstrated that the relationship between temporal processing and speech perception was significantly mediated by abilities to correctly integrate social information across auditory and visual modalities [START_REF] Stevenson | The cascading influence of multisensory processing on speech perception in autism[END_REF].

Indeed, alteration of multimodal temporal integration in ASD is a robust finding, mostly concerning audio-visual integration. This impairment is linked with higher-cognitive skills dysfunction, such as language comprehension. Imagery studies are a new step in multimodal temporal integration studies, focusing on regions of cerebral sensory connectivity. Combined functional imagery with cognitive tasks for multimodal temporal integration will provide further evidence of ASD neurobiological particularities.

Considerations for future studies

At this point, there is growing evidence of an alteration in temporal processing in ASD at different levels: duration estimation, temporal reproduction and simultaneity judgement, leading to multimodal temporal integration impairment, in turn leading to cascading effects on time management, speech processing and possibly on repetitive behavior. Nevertheless, because of the heterogeneity in the design of the studies and the small sample sizes, cross-study comparisons should be done with caution. Several factors must be considered in the designing of future ASD time processing studies.

Given that ASD is a neurodevelopmental disorder, a particular attention should be given to the developmental age. Performance in interval reproduction is highly related to developmental age in TD [START_REF] Sciutti | Development of context dependency in human space perception[END_REF] and ASD subjects have shown altered performances compared to age matched TD, and comparable to younger TD [START_REF] Karaminis | Central tendency effects in time interval reproduction in autism[END_REF]. Concerning temporal multisensory integration, impairment displayed in young ASD children tends to normalize by adulthood, with adolescence being the pivotal point of transition [START_REF] Beker | Ripe for solution: Delayed development of multisensory processing in autism and its remediation[END_REF].

In addition, as the term "spectrum" indicates, the ASD population is highly heterogeneous regarding symptomatology. Recent diagnostic classifications highlight the differences in clinical presentations in terms of cognitive or behavioral competencies (American Psychiatric Association, 2013).

Impairments in ASD could be preeminent in some domains and absent in others, such as communication, socialization, repetitive behavior, etc. Overall severity does not reflect the diversity of the ASD phenotype and scale subscores are necessary to evaluate the different domains of difficulties. Subgrouping individuals (including non-clinical participants with autistic traits) according to their clinical and cognitive profile is required to better understand the sources of discrepancies between reported data.

Cognitive function deficits and potential intellectual disabilities, frequently associated with ASD, could also be confounding factors [START_REF] Brodeur | Time Estimation Among Low-Functioning Individuals With Autism Spectrum Disorders: Evidence of Poor Sensitivity to Variability of Short Durations[END_REF]. Observed deficits might reflect cognitive limitations as non-autistic subjects with ID also have difficulties in perceiving and processing time [START_REF] Haldemann | Performance on auditory and visual temporal information processing is related to psychometric intelligence[END_REF][START_REF] Rammsayer | Performance on temporal information processing as an index of general intelligence[END_REF]. To date, the available corpus of data does not allow for the comparison between ASD with or without ID and no studies have been designed for this purpose. A deficit in short-term memory, visuo-spatial abilities or attentional system, which are highly related to temporal processing [START_REF] Allman | Psychophysical assessment of timing in individuals with autism[END_REF][START_REF] Bauermeister | Time estimation and performance on reproduction tasks in subtypes of children with attention deficit hyperactivity disorder[END_REF][START_REF] Brenner | Time reproduction performance is associated with age and working memory in high-functioning youth with autism spectrum disorder[END_REF][START_REF] Maister | Time perception and its relationship to memory in Autism Spectrum Conditions[END_REF]) should be controlled.

ADHD, another frequent comorbidity in ASD [START_REF] Ghirardi | The familial co-aggregation of ASD and ADHD: A register-based cohort study[END_REF], has been largely studied in the "temporal processing" field. Individuals with ADHD exhibit a strong alteration of time duration perception and temporal judgement [START_REF] Hart | Meta-analysis of fMRI studies of timing in attention-deficit hyperactivity disorder (ADHD)[END_REF][START_REF] Toplak | Temporal information processing in ADHD: Findings to date and new methods[END_REF]). As presented above, Lukito et al. found significant differences in brain activity during temporal processing tasks in ASD+ADHD subgroups but not in the ASD only subgroup [START_REF] Lukito | Neural Correlates of Duration Discrimination in Young Adults with Autism Spectrum Disorder, Attention-Deficit/Hyperactivity Disorder and Their Comorbid Presentation[END_REF]. A recent study confirmed those results and reported an alteration in temporal reproduction in ADHD and ADHD+ASD groups, but not in ASD only group [START_REF] Salunkhe | Examining the Overlap Between ADHD and Autism Spectrum Disorder (ASD) Using Candidate Endophenotypes of ADHD[END_REF]. Indeed, ADHD symptoms may have an impact on the temporal processing tasks and should be considered when studying temporal performances in ASD.

Lastly, it should be noted that prescriptions are seldom represented in population characteristics.

Even if no pharmacological treatment is actually recommended in ASD, neuroleptics and stimulants are commonly prescribed to subjects with ASD. It has been proposed that time processing mechanisms are based on the dopaminergic system [START_REF] Lewis | Remembering the time: A continuous clock[END_REF][START_REF] Soares | Midbrain dopamine neurons control judgment of time[END_REF]. It is then mandatory to control related medications, such as haloperidol or methylphenidate, which have been implicated in timing performances [START_REF] Soares | Midbrain dopamine neurons control judgment of time[END_REF][START_REF] Toplak | Temporal information processing in ADHD: Findings to date and new methods[END_REF].

CIRCADIAN TIME

Circadian time has a very different temporal scale than the previously stated mechanisms of time measurement. As will be discussed in this section, recent research has emphasized the potential disruption of circadian rhythms in individuals with ASD.

What is "circadian time"?

Circadian time is a near-24-hour cycle present in mammalian species. While it is genetically coded, the period, phase and amplitude of the cycle is influenced by many other environmental factors, such as light exposure and social cues, and by endogenous factors, such as physical activity. The circadian cycle is managed by a general clock located in the supra-chiasmatic nucleus (SCN). This pacemaker sets the time using neuronal activity, body temperature and hormonal secretions; one of the major hormones being melatonin. Melatonin results from the enzymatic transformation of serotonin, synthesized in the pineal gland during the night. As a biological signal of light/dark cycles, this hormone is an important synchronizer of human physiology [START_REF] Pagan | The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders[END_REF][START_REF] Pagan | Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders[END_REF]. In the periphery, independent clocks are found in different organs, regulated by varying external factors and then re-synchronized by the SCN [START_REF] Logan | Rhythms of life: Circadian disruption and brain disorders across the lifespan[END_REF][START_REF] Marco | Disrupted Circadian Rhythm as a Common Player in Developmental Models of Neuropsychiatric Disorders[END_REF]. At the cellular level, this timing is set by a complex molecular clock composed of transcriptional-translational feedback loops driven by CLOCK and BMAL1 genes [START_REF] Geoffray | Are circadian rhythms new pathways to understand Autism Spectrum Disorder?[END_REF][START_REF] Marco | Disrupted Circadian Rhythm as a Common Player in Developmental Models of Neuropsychiatric Disorders[END_REF][START_REF] Schuch | The role of CLOCK gene in psychiatric disorders: Evidence from human and animal research[END_REF].

In human development, there is evidence that the circadian system forms as early as the 18th week of gestation, with the emergence of melatonin receptors in fetal SCN (Logan et al., Jin et al., Marco et al.). Melatonin, which is known to pass through the placenta and the blood-brain barrier, at this time of development is probably the main relay of time-of-day information via the increase of circulating maternal melatonin [START_REF] Jin | The Relationship between Autism Spectrum Disorder and Melatonin during Fetal Development[END_REF][START_REF] Logan | Rhythms of life: Circadian disruption and brain disorders across the lifespan[END_REF]. In full-term infants, temperature rhythms appear immediately after birth, whereas other rhythms (including restactivity, sleep-wake and hormonal cycles) typically develop between 3 and 6 months of age [START_REF] Logan | Rhythms of life: Circadian disruption and brain disorders across the lifespan[END_REF].

In homeostasis, the circadian system modulates multiple functions, such as the sleep/wake cycle, feeding schedules, and body temperature. The hormones involved, notably melatonin, also have antioxidative functions, which are important to brain development. Moreover, the genes involved in these processes are known to manage various significant bodily activities such as neurogenesis, cortical development, neurotransmission, synaptic homeostasis, neuronal metabolism and oxidative stress [START_REF] Charrier | Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders[END_REF][START_REF] Logan | Rhythms of life: Circadian disruption and brain disorders across the lifespan[END_REF].

Dysfunction of such an essential regulatory system has obvious severe pathological behavioral consequences and may also be implicated in pathological neurodevelopmental pathways.

Evidence of impaired circadian rhythm in ASD

It is well known that sleep disorders are heavily linked to circadian rhythm dysfunction and are more frequent in children with ASD than in neurotypical children (Díaz-Román, Zhang, Delorme, Beggiato, & Cortese, 2018; [START_REF] Tordjman | Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder[END_REF]. Different types of sleep issues are found in ASD; anxiety related to falling asleep, higher sleep-onset delay, and circadian rhythm disturbances are more frequent in children with ASD compared to those with general intellectual disability [START_REF] Geoffray | Are circadian rhythms new pathways to understand Autism Spectrum Disorder?[END_REF][START_REF] Jin | The Relationship between Autism Spectrum Disorder and Melatonin during Fetal Development[END_REF][START_REF] Reynolds | Sleep Problems in 2-to 5-Year-Olds With Autism Spectrum Disorder and Other Developmental Delays[END_REF]. Compared to controls without neurodevelopmental disorders, a decrease in total sleep duration and a greater percentage of night-awakenings are reported in ASD between 30 months of age into adolescence [START_REF] Díaz-Román | Sleep in youth with autism spectrum disorders: Systematic review and meta-analysis of subjective and objective studies[END_REF][START_REF] Elrod | Sleep Differences Among Children With Autism Spectrum Disorders and Typically Developing Peers: A Meta-analysis[END_REF][START_REF] Humphreys | Sleep patterns in children with autistic spectrum disorders: A prospective cohort study[END_REF]. Recently reported is a prevalence of sleep disturbance, particularly during early life, occurring at a rate between 64% -93% or a recent systematic review, see [START_REF] Carmassi | Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop[END_REF]. In terms of sleep patterns, recent literature shows evidence of increased rapid eye movement (REM) sleep latency, immature organization of REM sleep or a decreased total of REM sleep associated to an increased proportion of stage 1 sleep [START_REF] Díaz-Román | Sleep in youth with autism spectrum disorders: Systematic review and meta-analysis of subjective and objective studies[END_REF][START_REF] Maruani | Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume[END_REF]. These sleep issues are present from young age to adulthood and tend to increase with ASD severity [START_REF] Adams | The relationship between autism symptom severity and sleep problems: Should bidirectionality be considered?[END_REF].

Different underlying pathways have been explored to account for these observations. The most robust account relates to the decrease in melatonin levels in ASD compared to controls [START_REF] Geoffray | Are circadian rhythms new pathways to understand Autism Spectrum Disorder?[END_REF][START_REF] Logan | Rhythms of life: Circadian disruption and brain disorders across the lifespan[END_REF][START_REF] Maruani | Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume[END_REF][START_REF] Melke | Abnormal melatonin synthesis in autism spectrum disorders[END_REF][START_REF] Pagan | The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders[END_REF]. The decreased levels may result from an alteration of the enzymatic pathway (composed of acetylserotonin methyltransferase (ASMT) and arylalkylamine N-acetyltransferase (AANAT)) which drives the conversion of serotonin into melatonin [START_REF] Carmassi | Systematic Review of Sleep Disturbances and Circadian Sleep Desynchronization in Autism Spectrum Disorder: Toward an Integrative Model of a Self-Reinforcing Loop[END_REF].

At a behavioral level, sleep disorders and decreased levels of melatonin appear to be correlated to specific symptoms in ASD. In two different studies, Tordjman et al. [START_REF] Tordjman | Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder[END_REF][START_REF] Tordjman | Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents with autistic disorder[END_REF] observed a negative correlation between the excretion of 6-SM (a melatonin urine metabolite) and the repetitive use of objects. Lower melatonin excretion was also significantly associated with social communication impairments, especially for verbal communication and social imitative play, which are core symptoms of ASD (American Psychiatric Association, 2013). Furthermore, a decrease of autistic symptoms (such as social withdrawal, stereotyped behaviors or communication dysfunction) after the administration of melatonin strengthens the hypothesis of the role of the circadian system in ASD physiopathology [START_REF] Malow | Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes[END_REF][START_REF] Tordjman | Autism as a Disorder of Biological and Behavioral Rhythms: Toward New Therapeutic Perspectives[END_REF].

At a genetic level, dysregulation of circadian rhythm pathway genes is also reported in ASD [START_REF] Bourgeron | The Possible Interplay of Synaptic and Clock Genes in Autism Spectrum Disorders[END_REF][START_REF] Hu | Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: Evidence for circadian rhythm dysfunction in severe autism[END_REF][START_REF] Nicholas | Association of Per1 and Npas2 with autistic disorder: Support for the clock genes/social timing hypothesis[END_REF][START_REF] Olde Loohuis | Altered expression of circadian rhythm and extracellular matrix genes in the medial prefrontal cortex of a valproic acid rat model of autism[END_REF][START_REF] Yang | Circadian-relevant genes are highly polymorphic in autism spectrum disorder patients[END_REF] and linked to autism severity [START_REF] Hu | Gene expression profiling differentiates autism case-controls and phenotypic variants of autism spectrum disorders: Evidence for circadian rhythm dysfunction in severe autism[END_REF].

To better understand the cascading consequences of this complex physiopathology, [START_REF] Vilches | Gestational Chronodisruption Impairs Hippocampal Expression of NMDA Receptor Subunits Grin1b/Grin3a and Spatial Memory in the Adult Offspring[END_REF] and [START_REF] Smarr | Maternal and Early-Life Circadian Disruption Have Long-Lasting Negative Consequences on Offspring Development and Adult Behavior in Mice[END_REF] analyzed the effect of constant light exposure during pregnancy on the circadian genes and behavior in mice offspring. The results showed that light induced maternal circadian disruption, generating an alteration in circadian gene expression in the hippocampus of their offspring. This alteration was associated with long-lasting spatial memory dysfunction, an increase in stereotyped behaviors and a decrease in social activities. More interestingly, pregnant mice exposed to constant light but given a melatonin supplement, corrected the previously described gene alterations and led to normal development of the offspring [START_REF] Vilches | Gestational Chronodisruption Impairs Hippocampal Expression of NMDA Receptor Subunits Grin1b/Grin3a and Spatial Memory in the Adult Offspring[END_REF].

In summary, the circadian rhythm pathways is altered in ASD at different levels. Indeed, an overall decrease in melatonin levels, a dysfunction of melatonin enzyme pathways and a dysregulation of circadian genes are reported, not only with sleep/wake disorders but also linked to an increase in autistic symptoms and cognitive dysfunctions. Yet, even if several studies are available, none of them offer a global view on the circadian system.

Future studies should assess circadian system alterations at multiple levels but also their interdependence (from clock genes, to plasmatic level of melatonin and electrophysiological sleep markers) on well characterized ASD populations. This could allow a better identification of mechanisms explaining circadian rhythm dysfunction in autism.

Developmental implications of an impaired circadian rhythm: a bidirectional hypothesis

A WRONG TIMING IN PLASTICITY ONSET [START_REF] Tordjman | Autism as a Disorder of Biological and Behavioral Rhythms: Toward New Therapeutic Perspectives[END_REF] hypothesized that given the major role of melatonin in the ontogenetic establishment of diurnal rhythms, the synchronization of peripheral oscillators (also termed "clocks") and the regulation of human circadian rhythms, melatonin might also be involved in the synchrony of motor, emotional, and relational rhythms which are crucial in the early development of social communication.

More recently, [START_REF] Kobayashi | Clock Genes Control Cortical Critical Period Timing[END_REF] found evidence for the implication of circadian genes in the timing of brain development [START_REF] Kobayashi | Clock Genes Control Cortical Critical Period Timing[END_REF]. Notably, they demonstrated that circadian clock genes could control the onset of a critical period of plasticity in the neocortex by acting on GABAergic interneurons expressing the calcium binding protein parvalbumin (PV+ cells). PV+ cells constitute an essential factor in neuronal plasticity, particularly by maintaining the excitation/inhibition balance, which may be dysfunctional in ASD [START_REF] Butt | A role for GABAergic interneuron diversity in circuit development and plasticity of the neonatal cerebral cortex[END_REF]. It was also recently reported that PV knockout mice (PV-/-) or heterozygous (PV+/-) mice display behavioral phenotypes in accordance with all core symptoms present in human ASD individuals [START_REF] Wöhr | Lack of parvalbumin in mice leads to behavioral deficits relevant to all human autism core symptoms and related neural morphofunctional abnormalities[END_REF]. Moreover, in their meta-analysis, Gogolla et al. found a PV-cell decrease in the neocortex across multiple ASD mouse models and further replicated the results in a chemical and a genetic model of ASD [START_REF] Gogolla | Common circuit defect of excitatory-inhibitory balance in mouse models of autism[END_REF].

Considering the importance of brain plasticity in the etiology of ASD, [START_REF] Kobayashi | Clock Genes Control Cortical Critical Period Timing[END_REF] linked this feature to circadian gene pathways. His team showed, in clock-deficient mice, that clock genes intrinsic to PV+ interneurons coordinate postnatal maturation of cells, and consequently, the onset of critical periods of plasticity. Clock-deficient mice exhibited delayed onset of these critical periods despite having a normal systemic circadian rhythm. This delay was rectified by the pharmacological enhancement of GABAergic transmission [START_REF] Kobayashi | Clock Genes Control Cortical Critical Period Timing[END_REF]. As highlighted earlier, activity of CLOCK-BMAL1 is tightly linked to environmental conditions. In this way, some environmental conditions, such as sleep deprivation, can impact the timing of critical periods of plasticity and disturb neurodevelopment. A few days of circadian rhythm disorganization can be enough to impact the maturation and specialization of certain brain structures during specific developmental periods, and therefore have a cascade effect on several brain functions [START_REF] Butt | A role for GABAergic interneuron diversity in circuit development and plasticity of the neonatal cerebral cortex[END_REF][START_REF] Charrier | Clock Genes and Altered Sleep-Wake Rhythms: Their Role in the Development of Psychiatric Disorders[END_REF].

VERY EARLY SLEEP ISSUES AND COGNITIVE FUNCTIONS

If the hypothesis of a direct implication between the alteration of circadian rhythms on ASD etiology is seductive, the complementary (and potentially mutually reinforcing) "sleep disorder bias" must not be disregarded. As mentioned above, sleep issues occur early on in the life of an ASD individual and are proposed as a predictive risk factor for developing ASD [START_REF] Nguyen | Prospective Associations Between Infant Sleep at 12 Months and Autism Spectrum Disorder Screening Scores at 24 Months in a Community-Based Birth Cohort[END_REF]. It is therefore difficult, if not impossible, to propose a unique etiology, as sleeping issues may also have a strong impact on cognitive function and may lead to autistic symptoms. In fact, sleep disturbances significantly impact the daily functioning of individuals, affecting their cognitive resources and altering their abilities to regulate their emotions and behaviors [START_REF] Maruani | Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume[END_REF]. Several studies describe the relationship between poor sleep duration or quality, and an alteration of cognitive functions such as executive functions [START_REF] Astill | Sleep, cognition, and behavioral problems in school-age children: A century of research meta-analyzed[END_REF]).

Longitudinal studies assessing early life sleep duration and their impact on development exposed the dramatic consequences of sleep disorders. To illustrate, [START_REF] Smithson | Shorter sleep duration is associated with reduced cognitive development at two years of age[END_REF] found that short sleepers between birth and two years of age had a 5.2-points lower cognitive development score at two years of age compared to intermediate and long sleepers. Regarding language development, short sleepers between two and six years of age present poor receptive vocabulary at ages between six and ten [START_REF] Seegers | Short persistent sleep duration is associated with poor receptive vocabulary performance in middle childhood[END_REF]. Tomisaki et al. reported an association between proper development of social competence with short sleep onset and sufficient sleep duration in early life [START_REF] Tomisaki | The relationship between the development of social competence and sleep in infants: A longitudinal study[END_REF]. Similarly, [START_REF] Weisman | Sleep-Wake Transitions in Premature Neonates Predict Early Development[END_REF] showed that infants whose sleep-wake transitions were more organized (mainly characterized by shifts between quiet sleep and wakefulness) exhibited the most favorable development, including greater neonatal neuromaturation, less negative emotionality, better cognitive development, and better verbal, symbolic, and executive competences at five years of age.

Even more concerning, insufficient sleep during the first few years of life may have long-standing consequences. It was found that high hyperactivity scores at age six were strongly associated with a pattern of short sleep duration at two and a half years of age, even in children showing normative sleep in the interim period (from three and a half to six years of age). Inconsistent sleep-wake cycles during early development might be contributing to the steadily rising rates of emotional and behavioral problems in young children [START_REF] Touchette | Associations Between Sleep Duration Patterns and Behavioral/Cognitive Functioning at School Entry[END_REF][START_REF] Touchette | Risk factors and consequences of early childhood dyssomnias: New perspectives[END_REF]. Thus, it is tempting to speculate that early sleep disorders could lead to autistic symptoms and neurodevelopmental disorders. In a "cascade" model, those symptoms are further exacerbated by persisting sleep difficulties. In addition, many studies outlined the fact that sleep problems tend to compound autism symptomatology and repetitive or aggressive behavior in individuals diagnosed with ASD. [For a review, see [START_REF] Cohen | The relationship between sleep and behavior in autism spectrum disorder (ASD): A review[END_REF]]

Consequently, dysregulation of the circadian system and consequent sleep disorders are being increasingly recognized as aggravating factors in ASD etiology. In regard to recent scientific knowledge, circadian time and ASD seem to be involved in a bidirectional manner one reinforcing the other. Either way, assessing and acting on the circadian pathway by promoting efficient sleep/wake patterns in early life may be central to the treatment of the condition. For future studies, controlling the quality and duration of sleep is mandatory, as the association between circadian rhythm dysfunction and the reported clinical symptoms could be explained by a lack of sleep.

TIME THEORY, A GUIDE TO NEW THERAPEUTIC PERSPECTIVES

Evaluating time processing among children with ASD is the first step in reeducation. In this perspective, some research teams evaluated a time processing training program. Since very few studies involved interventions in ASD individuals, we also reported studies concerning individuals with Attention Deficit/Hyperactivity Disorder (ADHD) or Intellectual Disability (ID). Both neurodevelopmental disorders are often comorbid with ASD (American Psychiatric Association, 2013), and are also associated with difficulties in time perception or management (American Psychiatric Association, 2013;[START_REF] Sharp | A matter of time[END_REF][START_REF] Toplak | Temporal information processing in ADHD: Findings to date and new methods[END_REF].

TRAINING AND COMPENSATION OF TIME PERCEPTION

Wennberg et al., who worked on the KaTid, tested a 12-week time processing training program on children with ADHD, across the ages of nine to 15 years old [START_REF] Wennberg | Effectiveness of time-related interventions in children with ADHD aged 9-15 years: A randomized controlled study[END_REF]. Three to four treatment sessions, lasting 30 minutes each, focused on finding compensating strategies for the child, structuring the physical environment and identifying adequate time assisting devices. These devices could be alarm clocks, weekly schedules or step-by-step-schedules with text or pictures, and timers representing time visually. Remediation techniques were also used and involved training time perception, orientation and management through the completion of tasks (e.g. assessing the time necessary to complete five daily activities and then identifying which activity could fit within a 45minute interval, etc.). After 24 weeks, results showed a higher score increase across all exercises of the KaTid program (except for the Time Management dimension) for the treatment group compared to the control group (with 12 weeks of intervention and 12 additional weeks for favoring the use of learned techniques in the everyday environment). The Parent Scale also showed a significant improvement, but not the Time S self-rated questionnaire.

Another method of intervention is derived from the My Time program [START_REF] Aberg | Manual för Min Tid; verktyg för att unders€oka, första och hantera tid [Manual for My Time; Tool for examining[END_REF]. It includes five steps: examine, visualize, document, process and discuss. The first step involves focusing on the duration of activities that are of interest to the child and associated experiences. Time is measured using a special quarter-hour stopwatch that makes time visible in the form of dots that fill-in at 15minute intervals. Only four dots are displayed, which facilitates the understanding and communication of time duration for people who have difficulty with calculations, including those with an intellectual development disorder. The child documents the duration of each measured activity in a time book, drawing black dots. When documentation is completed, differences in duration can be experienced and processed through exercises or playful activities of various durations. and he documented activities are then discussed (e.g., how two activities take the same number of black dots even though their durations feel subjectively different). One study assessed the efficacy of this intervention on children with mild to moderate intellectual disabilities [START_REF] Janeslätt | Intervention in time-processing ability, daily time management and autonomy in children with intellectual disabilities aged 10-17 years -A cluster randomised trial[END_REF]. Results showed better improvement in time perception after eight weeks of intervention, compared to the group with no intervention, as assessed by the KaTid.

No effect was found on the Parent Scale.

Other time devices have been evaluated in small population studies: the timer software (the Tic Tac tool) which represents the passing of time intervals visually [START_REF] Campillo | Using Tic-Tac software to reduce anxiety-related behaviours in adults with autism and learning difficulties during waiting periods: A pilot study[END_REF] but also the quarter hour watch, the time rule [START_REF] Arvidsson | The impact of time aids on independence and autonomy in adults with developmental disabilities[END_REF], the Time Timer [START_REF] Grey | Using a Time Timer TM to increase appropriate waiting behavior in a child with developmental disabilities[END_REF] or visual calendars [START_REF] Koyama | Use of activity schedule to promote independent performance of individuals with autism and other intellectual disabilities: A review[END_REF]. Different beneficial outcomes were reported, either related to time (regulating the duration of their activities, observing an appointment) or to autism severity (impulsivity, stereotypies). Some teams also propose to use music as a rhythmic temporal reference [START_REF] Hardy | Rhythm, movement, and autism: Using rhythmic rehabilitation research as a model for autism[END_REF].

These time reeducation activities should be offered as early as possible during children's development in order to favor a typical brain maturation during critical developmental stages. Such early intervention may positively impact the emergence of higher-level functions based on time processing.

RESYNCHRONIZING

Another way to improve time processing in children with ASD is to help the synchronization of their internal clock. As a first-line treatment, parent-directed behavioral sleep interventions are recommended. These interventions educate parents about sleep hygiene and behavioral responses to their child's sleep problems and help restoration of a physiological sleep rhythm [START_REF] Cuomo | Effectiveness of Sleep-Based Interventions for Children with Autism Spectrum Disorder: A Meta-Synthesis[END_REF][START_REF] Gringras | Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder[END_REF]. Attention to circadian synchronizers (or so called zeitgebers) is also crucial. As reported previously, the internal clock needs to be guided by external factors in order to be well synchronized. A good balance of daylight and darkness, regular meal times and physical activity are needed to reinforce internal clock synchronization [START_REF] Gringras | Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder[END_REF][START_REF] Logan | Rhythms of life: Circadian disruption and brain disorders across the lifespan[END_REF].

When sleep hygiene and behavioral intervention are insufficient, supplementation in melatonin could be offered. Melatonin treatment has been evaluated in several small studies with promising efficiency for sleep issues, and also has beneficial effects on autism severity (for a review see [START_REF] Tordjman | Autism as a Disorder of Biological and Behavioral Rhythms: Toward New Therapeutic Perspectives[END_REF].

More recently, pediatric prolonged-release melatonin has been evaluated in a larger population. The long-and short-term efficacy of pediatric prolonged-release melatonin has been reported on total sleep duration, sleep latency and quality of life, with satisfying safety and good acceptability of treatment [START_REF] Gringras | Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder[END_REF][START_REF] Maras | Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder[END_REF]. A decrease in externalizing behavior (i.e. aggressive behaviors) as well as an increase in family quality of life was also reported [START_REF] Schroder | Pediatric Prolonged-Release Melatonin for Sleep in Children with Autism Spectrum Disorder: Impact on Child Behavior and Caregiver's Quality of Life[END_REF]. This could be a promising step to regulate circadian rhythm early in the development of ASD individuals where this process is altered, as well as its associated symptoms.

In a different way, time remediation may be "naturally" included in some global developmental and early relational intervention, such as the Early Start Denver Model (ESDM) or more communication focused intervention, such as Pediatric Autism Communication Therapy (PACT) [START_REF] Dawson | Randomized, Controlled Trial of an Intervention for Toddlers With Autism: The Early Start Denver Model[END_REF][START_REF] Green | Parent-mediated communication-focused treatment in children with autism (PACT): A randomised controlled trial[END_REF]. These therapies have the common aim of establishing dyadic, sustained and synchronized interactions between ASD toddlers and their caregivers, in order to improve the toddler's reciprocal social interaction skills. Because such interventions increase the opportunities for the child to integrate multisensory social stimuli and to adjust one's behavior in synchrony to others' cues, i.e. two main features associated with time perception, we should expect an improvement of time perception, as well, in such children.

DISCUSSION

There is growing evidence of impaired time processing in ASD compared to TDC no matter the evaluated "time level." This review is the first to gather information about time processing and management across the time spectrum. Different scientific fields have been covered here to allow a global view of time processing and management impairments in ASD.

Time interval perception is likely to be impacted by atypical cognitive strategies which involve attentional network and short-term memory capacity and is dependent on sensory modalities. So far, individuals with ASD seem to be efficient in measuring time through visual cues, with preserved-toenhanced visual, but not auditive, time processing abilities. In the same way, multimodal temporal integration is impaired in ASD with difficulties concerning audio-visual integration. This has been linked to socio-communication impairment. Along these lines, alterations of circadian pathway have been found on multiple levels; from genetic dysregulation to biological imbalance and behavioral features, circadian pathway and ASD are involved in a bidirectional manner, one reinforcing the other.

A neurodevelopmental point of view with a cascading effect of "temporal processing" impairment on higher-level cognitive skills, is adopted in recent scientific literature as millisecond, interval and circadian timing are entangled in many crucial functions. A small defect in these processes could have a cascading effect on development, and lead to, or worsen, symptoms of autism. Resulting from correlations or mediation analysis, this hypothesis needs longitudinal studies to be validated, as none has been found within this literature review.

There is a lack of information concerning the interdependence of the different "time systems" (i.e. millisecond, interval or circadian timing) and global explaining models are only speculative; future studies should assess time processing at multiple levels while taking care of essential confounding factors such as developmental age, symptom heterogeneity, cognitive functions, comorbidities or medication. Multidisciplinary approaches could be of great use to allow the concomitant exploration of the severity of autistic symptoms, time perception and biological rhythms. Electronic devices could be the support of some "time" assessment such as sleep/wake rhythm or time perception tasks. This could improve the feasibility of multidisciplinary studies at a higher scale in space, but also in time!

To conclude, this review shows that it would be highly relevant to systematically assess temporal perception and processing in ASD, and to add this data to global functional assessments before intervention. The reeducation of time perception as well as resynchronization of circadian rhythms could consistently improve ASD symptoms. This knowledge may also guide parents to better help their children on a daily basis with simple advice, such as the use of visual aids are used to help ASD individuals to better represent time intervals and schedules, but also by promoting essential behavior such as efficient sleep/wake patterns in early life.

ANNEXES 1.

  Studies of time perception (duration, reproduction and bisectional task) in ASD compared to TD. FSIQ = Full Scale Intellectual Quotient, WMI = Working Memory Index, RPM = Raven's Progressive Matrices, PIQ = Performance Intellectual Quotient, VIQ = Verbal Intellectual Quotient, n.s. = non significant

  or worsened judgement of simultaneity in an audiovisual task (de Boer-Schellekens,[START_REF] De Boer-Schellekens | Diminished sensitivity of audiovisual temporal order in autism spectrum disorder[END_REF][START_REF] Foxe | Severe Multisensory Speech Integration Deficits in High-Functioning School-Aged Children with Autism Spectrum Disorder (ASD) and Their Resolution During Early Adolescence[END_REF][START_REF] Noel | Atypical rapid audiovisual temporal recalibration in autism spectrum disorders[END_REF][START_REF] Smith | Temporal synchrony and audiovisual integration of speech and object stimuli in autism[END_REF].

TABLE 1 .

 1

							Results
	Article	Population	Mean Age (ASD/TD)	Mean IQ (ASD/TD)	Modality	Time range	DDT: Duration discrimination thresholds DR: Duration reproduction
							TBT: Temporal bissection task
	Mostofsky, 2000	17 TD 11 ASD	13.3 / 12.5	FSIQ 101/ 105	auditive	550ms	DDT: n.s.
	Szelag, 2004	7 ASD 7 TD	12.6 / ?	PIQ 82-102 / 95-145	visual auditive	1000-5500ms	DR: overestimation of longer duration, underestimation of shorter duration in ASD group
	Wallace, 2008	25 ASD / 25 TD (including 4 DI)	14.10 / 13.84	FSIQ 96.36 / 100.08	none ?	2-45s	DDT: n.s. DR: n.s.
	Jones, 2009	72 ASD / 52 TD	15.6 / 15.6	84/87 FSIQ 88/89 PIQ 93/93 VIQ	auditive		DDT: n.s.
	Martin, 2009	20 ASD / 20 TD	36 / 35	FSIQ 106/108 PIQ 105/106 VIQ 107/108	auditive	0.5 -4.1s	DR: ASD group less accurate with an increase variability
							TBT : ASD experienced greater difficulty
	Allman, 2011	13 ASD / 12 TD	10.3 / 10.3	VIQ 100 / ?	visual	1-8s	discriminating between longer durations, less
							acurate, descrease sensibility to duration
	Maister, 2011	21 ASD / 21 TD and 15 ASD/15TD	11.3/10.7 and 11.8/11.2	RPM 40/38 and 40/40	visual	0.5-45s	DR: lower performances in ASD group for shorter and longer durations, increased intraindividual variability
							DDT: lower sensitivity to duration in ASD group
	Falter, 2012	18 ASD / 19 TD	25,3 / 26,1	FSIQ 112 / 113	visual and / or auditive	600-1000ms	in both modalities, with better results in visual modality Lower performance are correlated to severity
							of communication impairment
						0.5 to 1 s /	TBT: n.s.
				FSIQ 94.37 / 101.45		1.25 to 2.5 s /
	Gil, 2012	12 ASD / 12 TD	9-17 / 8-16	WMI 91.37 / 100.81	visual	3.12 to 6.25 s
				PSI 83.25 / 101.45		/ 7.81 to
						16.62 s

Table 1 .

 1

AUTHORS' CONTRIBUTIONS L. J. screened the articles, made the table, contributed to the writing of the discussion and wrote the "circadian" part. Y. L. wrote the introduction and the "millisecond and interval timing" part and participated in minor editing throughout other sections of the paper. M. B. mainly contributed to the writing of the "Assessing time perception in autistic patients" and participated in minor editing throughout other sections of the paper.

A. E. participated in rereading and in editing throughout the manuscript.

V. S. participated in rereading and in editing throughout the manuscript. M. D. participated in rereading and in editing throughout the manuscript. MM. G. participated in rereading and in editing throughout the manuscript and contributed to the writing of clinical overview.

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.