A Jeanne

Tatiana

-8 Term D 1 Preterm D 9 Preterm D 6-8 Preterm

humour noir, ta clarté d'esprit, merci pour nos danses endiablées ! On a quand même bien évolué depuis ces après-midis jogging-révisions-pâtes carbo, je suis fière de nous ! Aux Zazas, merci de m'avoir accueillie dans cette équipe Trézir recomposée ! merci pour toutes les soirées, pour le ski : « le Malaysia représente !!! », les croisières ! C'est bon de vous avoir les copains !!! A mes co-internes brestois, merci d'avoir été une joyeuse team pendant ces 4 années ! Petite dédicace à la soeur Lisa, merci de m'avoir fait rire quand l'internat devenait parfois pesant.

mon humble capacité à relativiser et ainsi à profiter de la vie que l'on m'offre. A Papa, merci pour ton assiduité à rendre chacun de tes trois enfants épanouis. Tu es, je crois, notre plus grand supporteur et c'est à toi que je dois le développement de ma combativité et la conviction de mériter tout autant que les autres. C'est à toi que je dois d'être médecin aujourd'hui.

A ma grande soeur et à mon petit frère, merci d'être ma tribu. A Morgane, merci pour ta tendresse et ton ouverture d'esprit, c'est à travers nos échanges que je grandis le plus. Pour moi, ta sensibilité est une force, elle sait repousser mes nuages les plus sombres. Merci pour ta protection, discrète mais farouche lorsque nécessaire. Merci pour nos conversations et rires de soeurs. Merci pour les moments en montagne, passés et à venir. A Hugues, merci d'être mon ADN. Aujourd'hui, tu suis ton propre chemin et je sais, que je ne serais plus l'indéfectible complice de toutes ses étapes. Cependant, ce que l'innocence de l'enfance a su créer, rien ne saurait le défaire. Ainsi, je veux te rappeler que je n'oublie pas la fille dans l'avion. Vous êtes mes deux tas de cellules préférés.

A Diane, merci de m'avoir appris à écrire mon prénom, de m'avoir fait croire que Morgane et toi étiez des loups-garous, de m'avoir fait élever des crevettes, de m'avoir fait adorer les chaises volantes alors que je vomissais, merci pour Lacanau, merci pour le DME, merci pour ma première soirée mousse, merci d'être toujours aussi pétillante.

A Olivier, merci d'avoir été une figure emblématique de mon enfance, merci d'avoir toujours aimé jouer avec nous « les petits » ; merci pour les soirées parisiennes, merci d'être mon grand cousin, merci de me faire savoir que tu es toujours là, pas loin, si besoin.

A Brigitte et Jean-Marc, merci pour votre gentillesse et vos encouragements, merci pour les réunions de famille, merci pour les cravates de Noël et les corrections de TPE.

A Anne, merci d'être la plus cool des tatas, merci pour ton état d'esprit, merci pour tes doux conseils.

A Romain, Julie et Arnaud, merci d'être des « pièces rapportées » vraiment sympathiques, merci d'aimer cette famille malgré ses petits caractères.

A Mamée, merci d'avoir insufflé à tes petites filles le besoin d'indépendance, merci d'avoir été un personnage de cette famille. Quand les regrets me guettent, je me dis que tu savais que je serais toujours ta douce, malgré tout.

A Lucien, pour l'initiation précoce à l'apprentissage difficile mais nécessaire du pardon.

A Pépé, merci d'avoir été le plus cool des grands-pères, merci de m'avoir fait croire aux fantômes, merci pour le petit fer à cheval.

A Oma et Opa, les souvenirs qui me restent de vous sont marqués par la tendresse de l'enfance et par l'admiration pour les personnes épatantes que vous sembliez être. Je pense que pour une anesthésiste et un pédiatre, mon choix pour la réanimation néonatale vous aurait plu ! An Martin. Endlich bin ich Ärztin geworden. Ich werde auch zu Dir: "Mein lieber Kollege!" sagen dürfen. An Charlotte, Julia und Markus und alle Maager, meine Wiener Sommer haben mich mit Sicherheit für immer geprägt! Ich kann es kaum erwarten, mehr Zeit zu haben, um euch wieder zu besuchen! A Catherine, ça fait 23 ans ! Nous nous sommes apprivoisées malgré tout et je me réjouis de la belle amitié que nous avons su faire perdurer.

A Maureen, si j'avais su ce qui m'attendait en m'asseyant devant toi en ces premiers jours de rentrée en Seconde… Merci de m'avoir fait si souvent mourir de rire ! Il est par contre temps d'assumer ta part de responsabilité dans le fait que je sois aussi nulle en histoire-géographie ! Merci de m'avoir fait évoluer en m'attirant hors des sentiers battus.

Aux Matounes (Charlotte, Lucie, Gaëlle-Anne, Maureen et Max), merci de m'avoir fait passer un lycée et des étés des plus tarés ! on a quand même pu partir très loin dans nos délires … J'espère vous retrouver davantage ! A Amies P2 groupe de oooouuuuffff !!! je sais plus s'il y a 3 « o » ou plus de « u » ! Bon, il faut tout de même mentionner que ce « groupe » sera cité dans 8 thèses de docteur en Médecine et c'est au moins ce qu'il mérite !! Merci les filles pour cet externat que vous avez su rendre inoubliable ! A Charlotte, je suis heureuse que tu m'aies finalement acceptée dans le groupe, merci d'avoir autant de répartie que tu as de coeur. A ma petite Marie, merci pour les apéros corpo, merci pour tes tenues toujours assorties, bleu marine de préférence ! merci pour les we surfs, merci de m'avoir accompagnée à la piscine pendant cette longue année de D4, en vrai on a progressé en crawl ! A Justine, je ne me justifierai pas ! ce qui se passe en Guyane reste en Guyane… merci pour ton équilibre sur cette pirogue, on ne serait peut-être plus là sans lui ! Depuis la P1, merci de me faire toujours autant rire, merci de ne toujours PAS comprendre les blagues, merci pour l'orga de plein de we de folie ! A Fanny d'enfer, merci d'être toujours aussi adorable et déjantée à la fois ! J'ai hâte que quelqu'un te donne un ti punch ! A Barzic, merci pour tes gâteaux de mémé et tes tartes aux thon, merci d'être un co-pilier toujours aussi fiable ! Quand nous reviens tu ? A Sandrine, entre les études et nos voyages, les souvenirs se bousculent et sont souvent improbables voire carrément hors du temps pour certains (#Tahaa) ! Merci pour les fous rires, merci d'avoir été un acolyte de soirée toujours enthousiaste, merci pour nos longues conservations sur toutes les plages du monde, j'ai hâte à nos prochaines aventures, il y a encore plein de sommets à Magnum ! promis. A Claire. Ce fameux été 2013 … Comme quoi arracher les échalotes pendant 2 semaines pour dépenser tout son argent en 7 jours à Rome, ça crée des liens ! Merci pour ces 3 ans de coloc, merci pour ton

INTRODUCTION

The major advances in obstetrics and neonatology practices throughout the last decades had led to a significant improvement in the rates of survival without severe neonatal morbidities in preterm infants [START_REF] Ancel | Survival and Morbidity of Preterm Children Born at 22 through 34 Weeks' Gestation in France in 2011: Results of the EPIPAGE-2 Cohort Study[END_REF]. Mild or moderate neurodevelopmental impairments were found to be significantly higher in children born preterm at school age. All cognitive domains were involved (IQ, language, reading-writing, mathematics, behavior), and impairments may persist at secondary school age [START_REF] Allotey | Cognitive, Motor, Behavioural and Academic Performances of Children Born Preterm: A Meta-Analysis and Systematic Review Involving 64 061 Children[END_REF]. To date, no reference method has been identified for early detection of neurodevelopmental impairments during hospital stay or at hospital discharge.

Habituation to external stimuli is a form of innate learning. If the stimulus is harmless, the infant will get used to it. The repetition of the stimulus will lead to a gradual decrease of its response [START_REF] Thompson | Habituation: A Model Phenomenon for the Study of Neuronal Substrates of Behavior[END_REF][START_REF] Rankin | Habituation Revisited: An Updated and Revised Description of the Behavioral Characteristics of Habituation[END_REF]). Development of this sensory homeostasis is essential to the individual's survival by avoiding the exhaustion of its energy resources. Infant's habituation paradigm is believed to be a fundamental basis for the processing of cognitive functions and is suggested to be efficient to predict infants' neuro-developmental outcomes [START_REF] Rose | Prediction of Childhood Intelligence from Habituation in Early Infancy[END_REF][START_REF] Slater | Can measures of infant habituation predict later intellectual ability?[END_REF][START_REF] Kavšek | Predicting Later IQ from Infant Visual Habituation and Dishabituation: A Meta-Analysis[END_REF][START_REF] Weber | Habituation as Parameter for Prediction of Mental Development in Healthy Preterm Infants: An Electrophysiological Pilot Study[END_REF]. Habituation has been explored in many sensory modalities and responses generated by a stimulus can be studied through different components of the organism: motor, vegetative or hemodynamic [START_REF] Martinius | Habituation of the Optic Blink Reflex in Infants in Sleep. A Longitudinal Study[END_REF].

The encephalopathy of prematurity refers to all damages resulting from the brain's injuries related to preterm birth. Its specific underlying physiological mechanisms are still only partially understood [START_REF] Volpe | Encephalopathy of Prematurity Includes Neuronal Abnormalities[END_REF]2009). Recent studies highlighted the relationship between fetal or postnatal systemic inflammation and brain lesions in premature infant [START_REF] Fleiss | Neuroprotection of the Preterm Brain[END_REF]. The inflammation during the perinatal period was suggested to act as a predisposing factor that makes the central nervous system (CNS) more "susceptible" to secondary stresses (« Néonatologie : bases scientifiques » 2016). Brain condition and stage of cerebral development determine the level of responses to stressors: effective or maladaptive [START_REF] Mcewen | Recognizing resilience: Learning from the effects of stress on the brain[END_REF]. In clinical practice, the vulnerability of preterm infants to their environment is frequently observed in the neonatal intensive care units (NICU). The "susceptibility" to external stimuli seems to fade away only when they reach a near-term corrected age [START_REF] Castillo | Habituation Responses to External Stimuli: Is the Habituation of Preterm Infants at a Postconceptual Age of 40 Weeks Equal to That of Term Infants? » Archives of Disease in Childhood[END_REF]. We hypothesized that preterm newborns may exhibit in their first weeks of life, lower capacity of habituation to external stimuli than term newborns.

The short-term objectives were, firstly, to assess the habituation abilities to visual and auditory stimuli of preterm neonates and to compare them with those of full-term neonates. The secondary objectives were to study the habituation paradigm, by a multimodal assessment and by analyzing the relationship between clinical, vegetative and brain responses. The long-term objectives are to determine the association between habituation skills in the neonatal period and psychomotor development at 2 years of age.

METHOD

A prospective, observational study was conducted in the Maternity Ward and the Department of Neonatal Medicine of the University hospital of Brest, France. Patients were enrolled from February 2020 to March 2021.

Population

Hospitalized preterm infants with gestational ages ranging from 25+0 to 33+6 weeks of gestational age (GA) were eligible for the study when they reached 35 weeks of post menstrual age (PMA). Term newborn infants born after 38 weeks of GA were eligible between 24 to 48 hours of life during their hospital stay.

Exclusion criteria included: maternal drug abuse; maternal treatment with psychotropic or antiepileptic drugs during the last month of pregnancy; infants with life-threatening prognosis; chromosomal abnormality; deafness; severe neurological disease; caffeine treatment at the time of inclusion; opioids, sedative or anticonvulsant treatment within 24 hours prior to the Habituation-test (H-test); infant with caput succedaneum on the day of the H-test.

Ethics

The study protocol was approved by the local Ethics Committee (Comité de Protection des Personnes (CPP)) in 2014. Any protocol changes were approved by relevant ethical review boards. Informed written consents were obtained from each parent.

Intervention: the habituation test (H-test)

Preterm infants were exposed to the H-test between 36 and 38 weeks of PMA. Term newborn infants were tested at the age of 2 days (i.e. at least 48 hours after birth). The H-test was carried out according to the following organization. First, the required equipment was set up in the infant's and parents' room (Figure 1). All the sensors were then placed on the infant (Figure 2). The ECG electrodes were located on the chest. NIPE Monitor™ (MN-NIPE-V1, Mdoloris Medical Systems, Loos, France) was connected to the cardio-respiratory monitor; the signal was checked and a 20-minute calibration was performed. The three-plantar skin conductance electrodes were placed on the right foot, the contact signal was checked via the Pain Monitor ™ (SN 1001-0940-1287 Med-Storm Innovation Oslo, Norway) software. The head-cap (EasyCap® BioniX) adapted to the head circumference, to which the functional Near Infra-Red Spectroscopy (fNIRS) probes have been previously attached, was fitted by first placing it on the frontal area and then sliding it over the occipital area. To limit light artifacts, a black opaque towel was placed around the fNIRS head-cap. The infant was placed on its back in its cradle or incubator. To promote good contact between probes and scalp, the head was placed on a water-filled bag. The contact signal was then tested by calibration via the NIRStar™15.0 software. Contact anomalies were corrected. Once a correct signal has been obtained from all measurement devices, the infant was left to rest until obtaining a 1-2 sleep state [START_REF] Prechtl | The Behavioural States of the Newborn Infant (a Review)[END_REF][START_REF] Als | Toward a Research Instrument for the Assessment of Preterm Infants' Behavior (APIB)[END_REF]. Afterwards, the environmental conditions of the room were collected by a lux meter (RS-PRO 123-8776) and a sound level meter (MASTECH MS6701). The blinds of the shutters were lowered to obtain a maximum brightness of 6 Lux.

Once the desired conditions have been met, with the infant in the sleep state required, the H-test could begin. An APIB-certified research nurse exposed the infant to two blocks of stimuli. The first block of stimuli was visual (maneuver = Light): a standard 8-inch flashlight was passed quickly (3 seconds) about 3cm in front of the infant's right and then left eyes; the second was auditory (maneuver = Rattle): a small plexi-container one-third filled with corn kernels was shaken three times (3 seconds) about 30cm away from the center of the face.

The APIB-certified research nurse performs the maneuvers and simultaneously notes the infant's behavioral responses to stimuli according to APIB's package number 1 [START_REF] Als | Toward a Research Instrument for the Assessment of Preterm Infants' Behavior (APIB)[END_REF]. If the infant gets used to visual stimuli before ten repetitions, auditory stimuli were started. If the infant does not show habituation after ten repetitions, the absence of habituation was noted and auditory stimuli were then initiated. Auditory stimuli can also be reproduced up to ten times, depending on the observed behavioral response. Stimuli should be presented approximately at least 5 seconds after the end of the previous behavioral response. If the infant moved to sleep-awake state 3 or greater and needs to be comforted (e.g. holding infant's hand or using a pacifier), the H-test was stopped.

H-test stimuli are considered non-invasive: the light intensity of the flashlight used is about 85 Lux and the sound intensity of the rattle is about 70 dB [START_REF] Philbin | The Influence of Auditory Experience on the Behavior of Preterm Newborns[END_REF][START_REF] Lasky | Noise and Light Exposures for Extremely Low Birth Weight Newborns during Their Stay in the Neonatal Intensive Care Unit[END_REF]. Monitoring of vital functions was carried out throughout the whole procedure and allowed the staff to rapidly take necessary actions in case of poor tolerance (e.g. bradycardia in premature infants). All sensors are designed to be non-invasive and safe. The only possible adverse effect was a mild skin irritation possibly linked to adhesive electrodes or fNIRS probes.

In addition to behavioral responses, signals from NIPE, skin conductance and fNIRS were continuously recorded during the H-test.

The H-tests were always carried out in the infant's private rooms using the same equipment and by the same APIB-certified research nurse.

Number of patients required

The standard deviation (SD) of the APIB (package n°1) scores was evaluated between 0.5 and 0.9 among ten premature children and four term newborn infants assessed in the unit during clinical routine assessment. Based on an absolute reduction of 1 in the APIB score in the preterm group, a power of 90%, an estimated standard deviation of 1 point and a two-sided type I error of 0.05, the target sample size was 21 in each group, or 42 in total. The final sample size was set at 30 in each group, i.e. 60 in total taking into account 10% missing data.

Data collection, processing and analysis

The statistical analyses were carried out using Excel and GraphpadPrsim-8.

Demographic characteristics

Comparisons between groups were made with Mann Whitney for quantitative data and with Fisher's exact test for qualitative data.

Assessment of Preterm Infants' Behavior (APIB)

The APIB is designed to document the spectrum of full-term as well as preterm newborn infants' neurobehavioral state [START_REF] Als | Toward a Research Instrument for the Assessment of Preterm Infants' Behavior (APIB)[END_REF]. The maneuvers of the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) [START_REF] Als | The Brazelton Neonatal Behavioral Assessment Scale (BNBAS)[END_REF] are used in the APIB as increasingly demanding environmental packages of distal and proximal stimuli. The maneuvers presented to the infant are organized in six packages and should gradually bring him/her to awakening. On Package n° I Sleep/Distal, the only one evaluated in this study protocol, an attempt is made to measure the infant's capacity to maintain a sleep state and decrease the responses to at least two repeated distal stimuli. Infant's responses are first monitored along five physiological subsystems in interaction with each other and with the environment (Score-Sheet I). The response of each sub-system to the administration of the maneuver (Light/Rattle) is rated from 1 to 9. Secondary, the infant's ability to deal with each maneuver (Light/Rattle) is assessed through different criteria (Score-Sheet II). The criterion Degree of decrement was considered the most appropriate for clinical habituation assessment and was chosen as primary endpoint. It is rated from 1 to 9 for each block of visual and auditory stimuli (see Appendix). The criterion Degree of disorganization was also scored. The comparison of the APIB ratings of the two groups was done using a Mann-Whitney test. All the correlations were studied by a unilateral Spearman's test.

Heart rate and Newborn Infant Parasympathetic Evaluation (NIPE)

The NIPE is a heart rate variability (HRV) index adjusted to the newborn and the infant up to 2 years of age which is used to study the parasympathetic branch of the autonomic nervous system arousal's. NIPE is calculated by using the ECG signal extracted from the standard monitoring system. The NIPE index ranges from 0 to 100. According to the manufacturer, the higher the NIPE is, the more comfortable the patient is. The NIPE monitor calculates two types of NIPE indices: the NIPEm computed as a mean value over 20 minutes and the instantaneous NIPEi (mean value over a time window of 64 seconds with adjustments each second). These indices are supposed to reflect chronic and acute pain/stress, respectively [START_REF] De Jonckheere | Heart Rate Variability Analysis for Newborn Infants Prolonged Pain Assessment[END_REF]; « Mdoloris Medical Systems -NIPE » 2020). NIPE (one value per second) and heart rate data (one value per second), recorded during the H-test were extracted directly from the NIPE monitor. Only heart rate and NIPEi data were processed. For each of the subjects, values 15 seconds before and 30 seconds after each stimulus were isolated. Comparisons were done using a Wilcoxon test

Skin conductance

The skin conductance measurement is a non-invasive technique, reflecting the sympathetic system arousal's. Skin conductance can be separated into several component measures. The number of skin conductance responses (SCRs) over time expressed as peaks/second were reported as the most sensitive parameter for newborn infant's pain and stress assessment and were processed using Pain Monitor™ software [START_REF] Storm | Skin conductance and the stress response from heel stick in preterm infants[END_REF][START_REF] Storm | Changes in Skin Conductance as a Tool to Monitor Nociceptive Stimulation and Pain[END_REF][START_REF] Hellerud | Skin Conductance and Behaviour during Sensory Stimulation of Preterm and Term Infants[END_REF][START_REF] Harrison | Skin Conductance as a Measure of Pain and Stress in Hospitalised Infants[END_REF].Two values were obtained: a pre-stimulus value (B: pre-stimulus baseline) and a post stimulus value which corresponds to the mean of the peaks/sec over the 30 seconds before and the 20 seconds following each stimulus. Comparisons were done using a Wilcoxon test.

Functional Near Infra-Red Spectroscopy (fNIRS)

fNIRS is a non-ionizing neuro-functional imagery technique, abled to apply tomographic approaches. It employs low-energy optical radiation for measuring absorption changes in sub-surface tissues. It's based on the principle that biological tissues are relatively transparent to light in the near-infrared spectrum (650-1,000 nm) while oxygenated-(O2Hb) and deoxygenated (HHb) hemoglobin are strong absorbers in this region. Raw light intensities data are first converted into optical densities data and then into changes in concentration through the modified Beer-Lambert law. The definitions and the impact of the different parameters involved in the process underlying optical imaging are fully explained in the literature [START_REF] Scholkmann | A Review on Continuous Wave Functional Near-Infrared Spectroscopy and Imaging Instrumentation and Methodology[END_REF][START_REF] Pinti | Current Status and Issues Regarding Pre-processing of fNIRS Neuroimaging Data: An Investigation of Diverse Signal Filtering Methods Within a General Linear Model Framework[END_REF].

In the NIRx system used in this study, the light is guided by optical fibers bundles from detector (technology: PD) to emitter (technology: LED emitting light at 760 and 850nm) probes named optodes which can be set up by appropriate optode-holders on the head-cap. The optode topo layout used was designed to match the infant's brain structures spotted in MRI with the international 10-20 EEG placement system [START_REF] Kabdebon | Anatomical Correlations of the International 10-20 Sensor Placement System in Infants[END_REF][START_REF] Zores | Etude de la sensibilité visuelle du nouveau-né grand prématuré à son environnement[END_REF]. Different sizes of caps to fit the infant's head were available (28, 30, 32, 34, 36cm), with individualized recommended inter-optode distance ranging from 2,5 to 3,5cm [START_REF] Gervain | Near-Infrared Spectroscopy: A Report from the McDonnell Infant Methodology Consortium[END_REF]). The optodes topo layout was made up of 8 emitters and 8 detectors probes arranged in a configuration creating 12 channels (Figure 3), measuring the oxygenated-hemoglobin (O2Hb) et deoxygenated-hemoglobin (HHb) variations in the cortical regions of interest (ROI). The sampling rate of data acquisition was 7,812Hz. The data recording was done with NIRStar software. Data treatment were realized with HOMER2 on MATLAB. The combination of Spline interpolation and Wavelet filtering was used to motion correction (Di [START_REF] Lorenzo | Recommendations for Motion Correction of Infant FNIRS Data Applicable to Multiple Data Sets and Acquisition Systems[END_REF]. The band pass filter used was 0,01 -1 Hz [START_REF] Gervain | Near-Infrared Spectroscopy: A Report from the McDonnell Infant Methodology Consortium[END_REF][START_REF] Scholkmann | A Review on Continuous Wave Functional Near-Infrared Spectroscopy and Imaging Instrumentation and Methodology[END_REF]). The block average function was used to extract a graphical representation of the mean response to each block of stimuli.

9

RESULTS

Demographic characteristics

From February 2020 to March 2021, 36 couples of parents were offered to enroll their infant in the study and 24 newborn infants were finally included. Figure 4 shows the flow chart. Maternal and neonatal characteristics are reported on Table 1.

Test characteristics

The mean value of brightness in the room was 2.7 Lux (SD = 1). The mean measured environmental noise was 40,7 dB (SD = 2,7) at the beginning of the H-test. Table 2 shows the infant's characteristics on the H-test day. When the H-test could be performed, the children were all in the sleep stage 2A.

Assessment of Preterm Infants' Behavior (APIB)

APIB scores are presented on Tables 3a and3b.

Except for the Physiological system (preterm infants had poorer scores than term newborns infants), no significant differences in performances of each sub-system were found during the administration of the package I (Score-Sheet I).

Although preterm infants habituated (Degree of decrement -Light = 9) less often (23%) than term newborns infants (50%), no significant difference in abilities to decrease the response to the visual stimuli was found between the two groups. In contrast, among those who could be tested with auditory stimulus, preterm infants habituated significantly better than term infants (Degree of decrement -Rattle). Preterm infants were significantly more "disorganized" at the end of the visual stimuli than term newborns (Score Sheet II-Degree of disorganization-Light). No significant difference in the intensity of the disorganization of the response to the auditory stimuli (Degree of Disorganization -Rattle) were found between the two groups. No significant correlation was found between the gestational age at birth or the post menstrual age and the Degree of decrement.

For the following data analysis, term and preterm groups were divided into 3 categories (see Appendix):

-D 9: those who have become "completely" habituated to the stimuli.

-D 6-8: those who have become "partially" habituated to the stimuli.

-D 1: those who have woken up. D = Degree of decrement. Six percent of heart rate and NIPE data collected could not be analyzed due to poor quality signal at the time of acquisition.

Figure 5 shows the heart rate during the H-test. Over the duration of the H-test, the preterm newborn's heart rate was significantly higher than that of the term newborns infants (p < 0,001). Repeated visual stimuli tended to decrease preterm newborn's heart rate and to increase that of term newborns. Repeated auditory stimuli tended to increase preterm newborn's heart rate and to decrease that of term newborns. There does not seem to be a relation between clinical habituation (Degree of decrement) and the value of the slope.

Figure 6 shows the NIPE during the H-test. Over the duration of the H-test, the preterm newborn's NIPE was significantly higher than that of the term newborn infants (p < 0,001); except during auditory stimuli for group D 6-8. Repeated stimuli tended to increase the NIPE in almost all cases. Except during visual stimuli for group D1, there does not seem to be a relation between clinical habituation (Degree of decrement) and the value of the slope. Individually NIPE's analysis of each subject showed that in habituated (D 9) or nearly habituated (D 6-8) newborn infants, the NIPE was either stable or reached its maximum after the last visual or auditory stimulus. In contrast, in subjects who awoke (D 1), the NIPE was either stable or reached its nadir after the last visual or auditory stimulus.

Skin conductance

Skin conductance data collected from 2 patients could not be analyzed due to poor quality signal at the time of acquisition.

Figures 7a and7b show the mean SCRs changes in response to each visual and auditory stimulus. Concerning the visual stimuli, the mean post-stimulus SCRs values were significantly higher in the preterm group (p = 0,006). Concerning the auditory stimuli, the mean poststimulus SCRs values were higher in the term group without significant difference. Subjects who finally woke up (D 1) generally had the highest SCRs values compared to those who partially (D 6-8) or completely (D 9) habituated.

A negative correlation was found between the last visual post-stimulus SCRs value and the score Degree of Decrement (Light) of each patient (Spearman r -0, 68; 95% CI: -0,87 to -0,33; p = 0,0009). A same negative correlation was found for the auditory stimuli (Spearman r -0,82; 95% CI -0,95 to -0,48; p = 0,002). Functional Near Infra-Red Spectroscopy (fNIRS)

Figure 8a and 8b show the neuronal hemodynamic response (nHR) to a block of visual stimuli in the cortical regions of interest (ROI) of a term and a preterm infant who had obtained a Degree of decrement at 9. For these channels, a typical pattern of nHR could be extracted: a rapid increase in [O2Hb] with a mirrored decrease in [HHb] followed by a gradual return to baseline.

The range of changes in hemoglobin concentration was wide (0.5 to 9µmol/L) between subjects but preterm infants had overall responses with less intense variations.

The viewing of the video provided a dynamic 3D map of the brain and showed the activation of the different cortical areas in real time. During visual stimuli, it was sometimes possible to observe the activation of the primary occipital areas followed by those of the prefrontal cortex, possibly indicating the presence of a fronto-temporal-occipital functional connectivity. This could also be seen in figures 8a and 8b: an nHR appears in the frontal channels quickly after that in the occipital channels. The ordinate is the hemoglobin concentration in µmol/L and the abscissa is the time in seconds. T0 corresponds to the stimuli.

DISCUSSION

In this preliminary study, we reported that behavioral habituation to visual stimuli seemed to be better in full-term newborns infants tested at two days of life than in preterm infants tested between 36 and 38 weeks of PMA. This was reversed for the auditory stimulus. This was consistent with the literature on neonatal habituation [START_REF] Leijon | Assessment of Behaviour on the Brazelton Scale in Healthy Preterm Infants from 32 Conceptional Weeks until Full-Term Age[END_REF][START_REF] Paludetto | Behaviour of Preterm Newborns Reaching Term without Any Serious Disorder[END_REF][START_REF] Castillo | Habituation Responses to External Stimuli: Is the Habituation of Preterm Infants at a Postconceptual Age of 40 Weeks Equal to That of Term Infants? » Archives of Disease in Childhood[END_REF], which describe that preterm infants assessed at term habituated more slowly to light and tactile stimuli as compared to term newborns, but similarly to auditory stimuli. In preterm infants, the quality of responses to external stimuli is variable: a deficiency in the inhibitory mechanisms leading to recycling of the initial response is commonly observed [START_REF] Als | Toward a Research Instrument for the Assessment of Preterm Infants' Behavior (APIB)[END_REF]. It is widely admitted that the interaction between the individual and his environment is necessary for the development of the CNS. NICU may expose preterm infants to disturbances in their neuro-sensory development, by over-stimulating systems that develop later during ontogeny and under-stimulating systems that develop earlier [START_REF] Lickliter | The Integrated Development of Sensory Organization[END_REF]). It follows a fixed time sequence: first appear the somatosensory structures, then the oral and nasal followed by the vestibular and auditory structures and, finally, the visual system (Granier-Deferre 2005). This raises complex questions about how to best manage the sensory environment of the preterm infant (Koenig-Zores 2016).

Studies [START_REF] Leijon | Assessment of Behaviour on the Brazelton Scale in Healthy Preterm Infants from 32 Conceptional Weeks until Full-Term Age[END_REF][START_REF] Paludetto | Behaviour of Preterm Newborns Reaching Term without Any Serious Disorder[END_REF][START_REF] Castillo | Habituation Responses to External Stimuli: Is the Habituation of Preterm Infants at a Postconceptual Age of 40 Weeks Equal to That of Term Infants? » Archives of Disease in Childhood[END_REF] also suggested that the scores improved with advancing post postmenstrual age and that preterm infants assessed at 40 weeks of PMA had the same habituation skills as term newborns. We did not find significant correlations between the Degree of decrement and the gestational age at birth or the post menstrual age. Instead, it appeared that, extreme preterm infants (born before 28 weeks of GA) who had the longest hospital stays, generally showed good habituation skills in the H-test. It is possible that time spent exposed to intense stimuli such as those present in the NICU has an impact, shaping long-term habituation [START_REF] Van Heteren | Fetal Learning and Memory[END_REF].

At 36-38 weeks of post-menstrual age, Bueno et al. found that preterm infants (birth < 32 weeks of GA) with intra-ventricular hemorrhage had poorer habituation responses to external stimuli than those without intra-ventricular hemorrhage [START_REF] Bueno | Preterm Infants with Peri/Intraventricular Hemorrhage Have Poorer Habituation Responses to External Stimuli[END_REF]. In this study, the preterm infants had few comorbidities (Table 1) which may partly explain their relatively good results in the Habituation Test (H-test).

A review [START_REF] Als | The Assessment of Preterm Infants' Behavior (APIB): Furthering the Understanding and Measurement of Neurodevelopmental Competence in Preterm and Full-Term Infants[END_REF] suggested that the APIB offered the most solid theoretical foundation and the best evidence of wide-ranging scientific value (high test-retest reliability, high sensitivity in identifying neurobehavioral differences associated with gestational ages at birth, high concurrent validity of APIB, EEG, and MRI measures). APIB requires that the timing of maneuvers be adjusted to the infant's integration capabilities [START_REF] Als | The Assessment of Preterm Infants' Behavior (APIB): Furthering the Understanding and Measurement of Neurodevelopmental Competence in Preterm and Full-Term Infants[END_REF]. Thus, the inter-stimulus intervals were highly variable within and between subjects. The smallest ISI reported is 17 seconds but the medians were otherwise around 30 seconds; which according to the literature [START_REF] Boucsein | et Society for Psychophysiological Research Ad Hoc Committee on Electrodermal Measures[END_REF][START_REF] Roever | Investigation of the Pattern of the Hemodynamic Response as Measured by Functional Near-Infrared Spectroscopy (fNIRS) Studies in Newborns, Less Than a Month Old: A Systematic Review[END_REF] allows time for the stimulus-evoked component of the fNIRS and SC signals to manifest itself but not always to go back to his baseline.

Heart rate and NIPE data were inconsistent. Schematically, if the baby is habituated, we would expect that during the repetition of the stimuli, the heart rate would decrease and the NIPE would increase. When an individual is exposed to stressful stimuli, variations in heart rate are one of the early signs of neuro-psychological activation which aims to prepare the bodyto act and protect itself [START_REF] Sander | A Systems Approach to Appraisal Mechanisms in Emotion[END_REF]. The autonomic nervous system is one of the main reflex regulatory systems and exerts major control over the cardiovascular system, particularly the sinus node [START_REF]Autonomic and Endocrine Control of Cardiovascular Function[END_REF] . A meta-analysis found that HRV indices (like the NIPE) changed in responses to stress [START_REF] Kim | Stress and Heart Rate Variability: A Meta-Analysis and Review of the Literature[END_REF]. In adults as well as in infants in development, stress modifies the sympatho-vagal balance in favor of sympathetic influence. The drop in parasympathetic tone leads to a decrease in spectral power in the HF band [START_REF] Oberlander | The Developmental Character of Cardiac Autonomic Responses to an Acute Noxious Event in 4and 8-Month-Old Healthy Infants[END_REF][START_REF] Appelhans | Heart Rate Variability and Pain: Associations of Two Interrelated Homeostatic Processes[END_REF]. Preterm newborn infants have physiologically higher basal heart rate than term newborns, which explains the difference between the two groups. Caution must be exercised with absolute NIPE values. In fact, the NIPE, even before the test began, was in the low range (mean term group = 59, mean preterm group = 61). Baseline values may be low due to the discomfort induced by equipment set up. In agreement with the manufacturer, if the instantaneous index (NIPEi) falls below 50 then staff can conclude that the current situation is painful or stressful for the patient (« Mdoloris Medical Systems -NIPE » 2020). The instantaneous NIPEi, developed for acute pain monitoring, provides a value based on a 64-s moving window analysis, which is updated every 1 second [START_REF] Faye | Newborn Infant Pain Assessment Using Heart Rate Variability Analysis[END_REF][START_REF] Butruille | Development of a Pain Monitoring Device Focused on Newborn Infant Applications: The NeoDoloris Project[END_REF]F. Weber et al. 2019). The H-test stimuli may not have been intense enough to cause a significant drop in the index. They may also have been too closely spaced to allow the values to be related to the stimulus preceding them. The means were carried out on subgroups of different sample sizes including infants not receiving the same number of stimuli. This was probably a reason for the inconsistency between the slope of the curves and the clinical habituation. The individual analysis of each subject seemed to show that the NIPE during the H-test was more stable in term newborns than in preterm infants during the H-test. In the context of studying habituation, in addition to the NIPE absolute values, it is maybe the intensity of its fluctuations that should be kept in mind, as it may reflect the inability of the immature autonomic nervous system of preterm infants to modulate its activity [START_REF] Patural | Autonomic Cardiac Control of Very Preterm Newborns: A Prolonged Dysfunction[END_REF].

Skin conductance responses (SCRs) have mostly been studied for pain assessment in infants [START_REF] Hellerud | Skin Conductance and Behaviour during Sensory Stimulation of Preterm and Term Infants[END_REF][START_REF] Oji-Mmuo | Skin Conductance at Baseline and Postheel Lance Reflects Sympathetic Activation in Neonatal Opiate Withdrawal[END_REF][START_REF] Hu | The Validity of Skin Conductance For Assessing Acute Pain in Infants[END_REF]. A recent study showed that preterm birth changed skin conductance signal and behavioral response to pain at termequivalent age [START_REF] Maillard | Prematurity Alters Skin Conductance and Behavioural Scoring after Acute Stress in Term-Equivalent Age Infants[END_REF]. The results of the present study seemed to show an increased reactivity of the sympathetic system to visual stimuli in preterm infants compared to term newborn infants. Little is known about the SCRs of neonates to "non-painful" stimuli. A study had compared the SCRs of a preterm and a term group to tactile and nociceptive stimuli: no significant differences could be found between the groups. However, in preterm infants, tactile stimulation produced significantly higher SCRs than nociceptive stimulation [START_REF] Hellerud | Skin Conductance and Behaviour during Sensory Stimulation of Preterm and Term Infants[END_REF]. SCRs was sensitive enough to discriminate responses to high sound level stimuli from responses to baseline sound level stimuli in a preterm population [START_REF] Salavitabar | Preterm Infants' Sympathetic Arousal and Associated Behavioral Responses to Sound Stimuli in the Neonatal Intensive Care Unit[END_REF]. As with NIPE, our stimuli may have been not intense enough to obtain significant SCRs changes from the baseline. Indeed, a significant part of the collected signal was below 0.2 peaks/sec, but according to the classification proposed by the manufacturer (Med-Storm Innovation Oslo, Norway): below 0.21 peaks/sec, the infant is calm and stress-less. In the present study, SCRs correlated well with behavioral reactions. This supports the use of SCRs to measure habituation because it allows the sympathetic system activity to be quantified on a stimulus-by-stimulus approach. In fact, skin conductance is often used in adult's psychiatric studies about stimulus-induced stress [START_REF] Walker | Habituation of the electrodermal response -A biological correlate of resilience?[END_REF]).

In the present study, the initial fNIRS data are globally supportive of a more intense cortical hemodynamic response in the term group than in the preterm group. It is difficult to establish whether a neuronal hemodynamic response (nHR) pattern is specific to one of the groups. Monitoring functional brain activity of preterm and term newborn infants is of increasing interest to improve knowledge of brain development and to derive prognostic markers of neurodevelopment following perinatal brain injury [START_REF] Sood | Near-Infrared Spectroscopy: Applications in Neonates[END_REF][START_REF] Roever | Investigation of the Pattern of the Hemodynamic Response as Measured by Functional Near-Infrared Spectroscopy (fNIRS) Studies in Newborns, Less Than a Month Old: A Systematic Review[END_REF]. fNIRS has been used to measure hemodynamic changes occurring during auditory or visual stimulation in newborn infants [START_REF] Sakatani | Cerebral Blood Oxygenation Changes Induced by Auditory Stimulation in Newborn Infants Measured by near Infrared Spectroscopy[END_REF][START_REF]Illuminating the Developing Brain: The Past, Present and Future of Functional near Infrared Spectroscopy[END_REF][START_REF] Karen | Cerebral hemodynamic responses in preterm-born neonates to visual stimulation: classification according to subgroups and analysis of frontotemporal-occipital functional connectivity[END_REF]. It also has been used to study the activation of different brain regions during habituation in infants, highlighting the preferential involvement of the prefrontal cortex during this process [START_REF] Nakano | Prefrontal Cortical Involvement in Young Infants' Analysis of Novelty[END_REF]. Like fMRI, fNIRS can detect neuro-functional activity indirectly via detection of hemodynamic changes. fNIRS can differentiate O2Hb and HHb, providing additional hemodynamic and oxygenation information. The fNIRS signals represents a combination of evoked and non-evoked systemic physiological processes [START_REF] Scholkmann | A Review on Continuous Wave Functional Near-Infrared Spectroscopy and Imaging Instrumentation and Methodology[END_REF]. One of the great challenges of NIRS data processing, is to reliably remove undesired signal components to extract the signal component of interest: the evoked neuronal hemodynamic response (nHR) [START_REF] Pfeifer | Signal Processing in Functional Near-Infrared Spectroscopy (fNIRS): Methodological Differences Lead to Different Statistical Results[END_REF][START_REF] Pinti | Current Status and Issues Regarding Pre-processing of fNIRS Neuroimaging Data: An Investigation of Diverse Signal Filtering Methods Within a General Linear Model Framework[END_REF]. Schematically, neural activity increase (e.g stimulus-evoked) requires additional metabolic supplies insured by local vasodilation to the functional localized area. This is known as the neuro-metabolic-vascular coupling. This leads to a regional increase in [O2Hb] with a corresponding decrease in [HHb], which constitutes a typical pattern of the nHR in fNIRS [START_REF] Scholkmann | A Review on Continuous Wave Functional Near-Infrared Spectroscopy and Imaging Instrumentation and Methodology[END_REF]. Investigation of the nHR patterns in newborn infants is a major challenge, given the multiple factors that can influence it [START_REF] Issard | Variability of the Hemodynamic Response in Infants: Influence of Experimental Design and Stimulus Complexity[END_REF]. A large inter-subject variability in the magnitude and shape of the nHRs in preterm infants is found in the literature [START_REF] Karen | Cerebral hemodynamic responses in preterm-born neonates to visual stimulation: classification according to subgroups and analysis of frontotemporal-occipital functional connectivity[END_REF]. The origin of these inter-subject differences is unclear, it could be due to multiple technical and physiological factors. Among them, different states of neurovascular coupling development and different states of consciousness are often mentioned [START_REF] Wolf | Advances in Near-Infrared Spectroscopy to Study the Brain of the Preterm and Term Neonate[END_REF][START_REF] Scholkmann | A Review on Continuous Wave Functional Near-Infrared Spectroscopy and Imaging Instrumentation and Methodology[END_REF][START_REF] Roever | Investigation of the Pattern of the Hemodynamic Response as Measured by Functional Near-Infrared Spectroscopy (fNIRS) Studies in Newborns, Less Than a Month Old: A Systematic Review[END_REF]. A study in sedated newborn infants have shown a slower hemodynamic response as compared to adults during motor stimulation [START_REF] Isobe | Functional Imaging of the Brain in Sedated Newborn Infants Using near Infrared Topography during Passive Knee Movement[END_REF]). In the present study, peak latency was about 5 seconds which is comparable to that of the adult.

Strengths and Limitations

The methods used in this study are non-invasive and have already yielded significant results in exploring the habituation process in newborn infants. Compared to a unique behavioral evaluation, multimodal assessment is likely to provide a better understanding of the process and give greater robustness to the results.

The environmental conditions of the H-test and the stimuli themselves could not be strictly standardized. The date and time of the procedure were obviously dependent on the infant but also on the availability of the only APIB-certified research nurse. The devices set up, waiting period to reach the required sleep stage and the H-test itself required time: the total time spent in the room varied from 2 to 4 hours.

In some of the infants included, the test could not be performed because stage 1-2 sleep could never be obtained. Although the fNIRS head-cap was fitted to infants and not supposed to be painful, it was still often difficult to get infants to fall asleep with it and it seemed to make them more uncomfortable. Regarding the term newborn infants: as the discharge from maternity ward is generally on day 3 of life, the H-test had to be carried out before, i.e. on the 2nd day of life. Yet, full-term newborn infants physiologically present between 48 and 72 hours of life a period of agitation where they constantly solicit attention and soothe only at the breast or when held in arms. This could lead to an assessment bias: the habituation skills of the term newborn infants may therefore have been underestimated because the H-test took place at the least favorable time for them.

Overall, data acquisition was not disrupted by dysfunctions of the numerous measurement devices. However, some of the acquired data could not be analyzed due to poor signal quality. Indeed, once the H-test had started, if the infant moved e.g, it was no longer possible to replace the different electrodes and optodes in the event of loss of contact. Besides, while the fNIRS is less sensitive to motion than the EEG, we lost a significant amount of data due to artifact release. Unfortunately, but logically the movement artefacts occurred during the stimuli when the neuronal hemodynamic response is expected to be observed.

The analysis presented here is based on preliminary data. The results will have to be confirmed on the final sample. The long-term goal of the project is to develop a method, based on multimodal assessment, for the early detection of neurodevelopmental disorders in the most vulnerable newborn infants. For each enrolled infant, a phone follow-up call is planned for the completion of the Brief Infant Sleep Questionnaire (BISQ) at 6 and 12 months and the Ages and Stages Questionnaires (ASQ) at 24 months (of corrected age for preterm infants).

CONCLUSION

Premature birth abruptly interrupts the development of the fetus and exposes it to an unsupportive external environment in which his organism is not yet fully functional. These preliminary results are in favor on an impact of prematurity on the infant's mechanisms of integration and habituation to external stimuli. These results need to be confirmed within the whole sample of patients that are currently being enrolled. APPENDIX APIB manual [START_REF] Als | Toward a Research Instrument for the Assessment of Preterm Infants' Behavior (APIB)[END_REF] Degree of decrement:

1) Increase of response over course of presentation and sleep state disrupted.

2) Increase of response over course of presentation, yet sleep state generally maintained.

3) Startles still present at end of 10 trials. 4) Large body movement still present at end of 10 trials. 5) Medium body movement and/or head movement still present at end of 10 trials. 6) Facial grimaces and/or small sounds and/or minute body movements (finger, foot) still present at end of 10 trials. 7) Blinks still present at end of trials. 8) Moderate respiration response still present at end of 10 trials. 9) Shut-down achieved within 10 trials.

Degree of disorganization:

1) Gradual diminution of high level to low level response maintenance without fluctuation; shutdown achieved.

2) Gradual diminution of high level to low level response, or low level response maintenance without fluctuation, and without shutdown; or high level responses without sleep state disruption.

3) Periods of sustained low level responses with occasional return of a high level response, followed by shutdown. 4) Periods of sustained low level responses with occasional return of a high level response, without achievement of shutdown. 5) Variable high and low level responses followed by shutdown. 6) Signs of disorganization may be present repeatedly between trials, yet shutdown is achieved. 7) Repeated fluctuation between high and low level responses with some disorganization and without meeting shutdown. 8) Signs of disorganization may be present repeatedly between trials and shutdown is not achieved. 9) Attains increasing disorganization with succeeding stimulus presentations. Unable to proceed with decrement item(s). PELLAE (Elisabeth) -Multimodal assessment of habituation responses to visual and auditory stimuli in the neonatal period: impact of preterm birth. Th. : Méd. : Brest 2021 RESUME: Introduction: According to the World Health Organization (WHO) and based on reliable data, 15 million infants are born preterm every year and rates are increasing in almost all countries. Few methods are available for the early detection of neuro-cognitive disorders related to encephalopathy of prematurity. Habituation abilities have been suggested to be efficient to predict the level of cognitive developmental of preterm and term newborn infants. We assume that premature birth is responsible for poorer habituation skills. Objectives: We aim to compare habituation abilities of preterm infants born between 25 and 34 weeks of gestational age reaching 36 weeks of post conceptual age to those of full term newborns, by studying the behavioral, vegetative and cortical responses to visual and auditory stimuli in both groups. Methods: This prospective study was planned to enroll 30 patients in each group. During infants' sleep, the responses to successive visual and auditory stimuli, defining the Habituation-test, were simultaneously measured using a multimodal assessment including the Assessment of Preterm Infants' Behavior (APIB), the heart rate and heart rate variability (NIPE), the skin conductance and the functional near-infrared spectroscopy. Results: From February 2020 to March 2021, 36 couples of parents were offered to enroll their child in the study and 24 newborns were finally included. Full-term newborns seem to habituate better to visual stimuli, whereas preterm infants habituate significantly better to auditory stimuli. Significant correlations were reported between the APIB and the other parameters, especially for the skin conductance responses. Discussion: In this preliminary study, differences between preterm and term infants are reported in the way they integrate and become accustomed to external stimuli. These results need to be confirmed within the whole sample of patients that are currently being enrolled. Care must be taken in processing and analyzing the data to ensure that the desired signal component is studied.

Figure 1

 1 Figure 1 Picture of the set up used for the study.

Figure 2

 2 Figure 2 Schematic representation of the multimodal assessment model used during the H-test.

Figure 3

 3 Figure 3 Optodes Montage Setup Template.

Figure 5

 5 Figure5Heart rate during the H-test. Visual stimulus (V) 1 to 11. Auditory stimulus (A) 1 to 11. D: degree of decrement.

Figure 5 Figure 7a

 57a Figure 5 NIPE during the H-test. Visual stimulus (V) 1 to 11. Auditory stimulus (A) 1 to 11. D: degree of decrement.

Figure 7b

 7b Figure 7bThe mean SC changes in response to auditory stimulus (A) 1 to 10. B: pre-stimulus baseline. D: degree of decrement.

Figure 8a

 8a Figure 8aNeuronal hemodynamic response to visual stimuli of a term newborn.[O2Hb] corresponds to the solid line and [HHb] corresponds to the dotted line. The ordinate is the hemoglobin concentration in µmol/L and the abscissa is the time in seconds. T0 corresponds to the stimuli.

Figure 8b

 8b Figure 8bNeuronal hemodynamic response to visual stimuli of a preterm infant.[O2Hb] corresponds to the solid line and [HHb] corresponds to the dotted line. The ordinate is the hemoglobin concentration in µmol/L and the abscissa is the time in seconds. T0 corresponds to the stimuli.

  DE SOUTENANCE : 22 Octobre 2021

Table des matières :

	ABRÉVIATIONS
	Abréviations APIB: assessment of preterm infants' behavior
	ASQ : ages and stages questionnaires
	Introduction BISQ : brief infant sleep questionnaire
	Method BNBAS: Brazelton neonatal behavioral assessment scale
	Population CNS: central nervous system
	Ethics Intervention: the habituation test (H-test) dB: decibels
	Number of patients required ECG: electrocardiogram
	Data collection, processing and analysis EEG: electroencephalogram
	Demographic characteristics Assessment of Preterm Infants' Behavior (APIB) GA: gestational age
	Heart rate and Newborn Infant Parasympathetic Evaluation (NIPE) HF: high-frequency
	Skin conductance HHb: deoxygenated-hemoglobin
	Functional Near Infra-Red Spectroscopy (fNIRS) HRV: heart rate variability
	Result H-test: Habituation test	9
	Demographic characteristics Hz: hertz
	Test characteristics IQ: intellectual quotient
	Assessment of Preterm Infants' Behavior (APIB) Heart rate and Newborn Infant Parasympathetic Evaluation (NIPE) LED: light emitting diode
	Skin conductance NICU: neonatal intensive care units
	Functional Near Infra-Red Spectroscopy (fNIRS) nHR: neuronal hemodynamic response
	Discussion fNIRS: functional near infra read spectroscopy
	Strengths and Limitations NIPE: newborn infant parasympathetic evaluation
	fMRI: functional magnetic resonance imaging
	Conclusion O2Hb: oxygenated-hemoglobin
	Appendix PD: photodiode
	PMA: post menstrual age
	Bibliography SD : standard deviation
	SCRs : skin conductance responses
		1

Table 1

 1 Maternal and neonatal characteristics. * Mann-Whitney test. ** Fisher's exact test.

	Figure 4 Flow chart.

Table 2 Infant's characteristics on the H-test day. * Mann-Whitney test. ISI: Inter-Stimuli-Intervals.