2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED): A translational hyperscanning research project

2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED): A translational hyperscanning research project | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol 2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED): A translational hyperscanning research project Lucia Billeci, Valentina Riva, Elena Capelli, Serena Grumi, Miriam Paola Pili, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4501473/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Introduction. Very preterm (VPT) birth is a major risk condition for child development and parental well-being, mainly due to multiple sources of stress (e.g., separation and pain exposure) during the Neonatal Intensive Care Unit (NICU) stay. Early video-feedback (VF) interventions proved effective in promoting VOT infants’ development and parental well-being. Electroencephalography (EEG) hyperscanning allows the assessment of brain-to-brain co-regulation during live interaction between infants and parents and holds promises to highlight mechanisms behind the interactive benefits of early VF interventions. Goals. To compare indexes of brain-to-brain co-regulation between dyads of full-term (FT) and VPT infants interacting with their mothers. To investigate the effect of an early post-discharge VF intervention on the brain-to-brain co-regulation indexes of VPT dyads. Methods and analysis. VPT and FT dyads will be enrolled at birth and the former will be randomly allocated to one of two arms: VF intervention or care as usual. Short-term effectiveness will be assessed through ratings of mother-infant interaction videotaped before and after the VF intervention or care as usual. Mothers of VPT and FT infants will report on their mental state, parenting stress and bonding, and infant temperament and sensory profile at 3 and 6 months (corrected age, CA). At 9 months CA, all dyads will participate in a lab-based EEG-hyperscanning paradigm to assess brain-to-brain co-regulation through phase-locking value (PLV) and other explorative indexes. Ethics and dissemination. This study is funded by the Italian Ministry of Health and received approval by the Ethics Committee of Pavia (Italy) and participating hospitals. Research findings will be reported in scientific publications, presented at international conferences, and disseminated to the general public. Study registration number. GR-2021-12375213 (Italian Ministry of Health registry) EEG hyperscanning infant parent preterm synchrony video-feedback Figures Figure 1 Figure 2 INTRODUCTION Very preterm (VPT) birth is a major challenge for healthcare systems worldwide [ 1 ], representing the leading cause of long-lasting chronic diseases in childhood and child mortality [ 2 ]. While VPT infants are exposed to heightened medical risk and to several stress sources from the Neonatal Intensive Care Unit (NICU) environment [ 3 , 4 ] their parents also may face critical levels of psychological distress leading to increased risk for depression, anxiety, and parenting stress in the postpartum period [ 5 ]. Notably, biobehavioral dysregulation patterns have been observed in dyads of VPT infants and their caregivers in the first months of life [ 6 – 9 ] suggesting that VPT birth and NICU-related stress might affect child development and parental adjustment by altering critical processes of dyadic co-regulation during the first thousand days [ 10 , 11 ]. Early interventions promoting parent-infant closeness might contribute to promote the establishment of the same psychobiological co-regulatory processes [ 12 – 15 ] with buffering and protective benefits for child development and parental well-being [ 16 – 18 ]. Video-feedback (VF) interventions are well-validated parenting support programs that focus on parent-infant closeness, promote parental sensitivity, facilitate co-regulatory processes, and provide neuroprotective effects for child development [ 19 – 22 ]. VF interventions include a diverse set procedures and methodologies aimed at promoting positive parenting and capitalize from allowing the parents to observe themselves and the interaction with their infant “from the outside”, thus facilitating mentalization and reflexive functions [ 23 , 24 ]. Although different theoretical and methodological VF approaches have been described [ 21 ], previous research highlighted benefits for child development and the quality of parent-child interaction in different clinical contexts and populations, including preterm infants and their caregivers [ 25 , 26 ]. More recently, a clinical trial by Pisoni and colleagues [ 27 ] highlighted long-term improvement in the developmental quotient scores of 24-month-old VPT infants of age following a VF intervention, adding to the evidence that remote video-consultation might be an effective home care approach [ 28 , 29 ]. Hyperscanning is a relatively recent approach to the study of brain-to-brain co-regulation in live interactive partners using different electrophysiological and neuroimaging techniques [ 30 , 31 ]. By simultaneously recording of multiple brains’ activity, hyperscanning allows the acquisition of neurophysiological measures of human dyadic or group-based neurophysiological coordination [ 32 ]. Among the different available techniques, EEG offers special advantages when the hyperscanning paradigm is applied to pediatric and even newborn populations. Wireless EEG devices are relatively non-invasive and allow freedom of movement, thus facilitating the study of mother-infant interactions in laboratory as well as in ecological settings during the first months of life. By using EEG hyperscanning paradigms, Leong and colleagues [ 33 ] highlighted how gaze direction during face-to-face interactions between adults and 8-month-old infants affect patterns of dyadic neural connectivity. Similarly, different patterns of theta power fluctuations were observed when 12-month-old infants play in solo in the presence of the caregiver or when they actively interact together [ 34 ]. More recently, the phase-locking values (PLVs) indicating the strength of brain-to-brain co-regulation in theta and alpha frequency bands were computed during 7-month-old infants’ interaction with the caregiver compared to an adult stranger [ 35 ]. The study reported greater inter-brain attunement when infants were interacting with the mother, despite the addition of maternal chemo-signals in the setting of infant-stranger interaction attenuated the significant difference. As the field of parent-infant hyperscanning research is rapidly growing, the accumulating knowledge is contributing to a pivotal epistemic and theoretical shift in developmental neurosciences from a mono-personal account to a strongly relational perspective [ 36 ]. The application of hyperscanning paradigms to the study of parent-infant brain-to-brain co-regulation in at-risk and clinical pediatric populations holds promises to acquire innovative data on the mechanisms by which the early caregiving environment fosters and promotes child neurodevelopment [ 37 ]. Moreover, as specific indexes of brain-to-brain co-regulation become validated in typical development, they may also be embedded into a novel set of neurobehavioral markers to assess the benefit of early interventions. Such translational hyperscanning vision has been recently framed in the affective neuroscience literature ([ 37 ]); yet there is lack of research on the brain-to-brain co-regulation of VPT infants and their parents and on the potentially beneficial neuroprotective effects of early parenting interventions in this population. STUDY AIMS General and specific aims The 2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED) research project is funded by Italian Ministry Health under the Ricerca Finalizzata 2021 program (research line: Giovani Ricercatori, project code: GR-2021-12375213). It is aimed at assessing brain-to-brain co-regulation patterns in dyads of VPT infants and their caregivers and to further explore how an early VF intervention might facilitate specific interbrain regulatory indexes. The first specific aim (Aim 1) is to assess the presence of statistically significant differences in a set of brain-to-brain co-regulation indexes – primarily, PLV measure – between dyads of caregivers and VPT compared to FT infants. Previous research gave evidence of specific markers of lower co-regulation in behavioral synchrony [ 7 ] physiological coupling [ 38 , 39 ] and neuroendocrine attunement [ 40 ] in dyads of VPT infants during the first year of life. Consistently, we hypothesized that VPT infants and their caregivers would show less strong brain-to-brain co-regulation indexes compared to dyads of FT counterparts at 9 months (corrected age for prematurity, CA). The second specific aim (Aim 2) is to investigate the effect of an early VF intervention for parents of VPT infants on the selected indexes of brain-to-brain co-regulation at 9 months CA. By comparing EEG hyperscanning-derived indexes of interbrain coupling between dyads of VPT infants exposed to the VF intervention and dyads exposed to care as usual during the three months following NICU discharge, we hypothesize to describe greater brain-to-brain co-regulation in the former group. Additional exploratory aims The longitudinal nature of this study and the possibility to collect a multi-layer set of data for what pertains the neurobehavioral development of FT and VPT infants as well as the parenting environment during the first year of life allow us to set the stage for a number of exploratory analyses that will further guide future spin-off studies stemming from the 2-BRAINED research project. Here we highlight five main exploratory aims that appear relevant for future translational research in the field of affective neuroscience and developmental psychobiology. First, the availability of behavioral and EEG physiological data from the 9-month interactive procedure (see below, Study design and procedures ) will allow for the exploration of patterns of bio-neurophysiological coupling within dyads. Previous research produced limited evidence for the presence of correlations between specific interactive behaviors and EEG signaling during interactive tasks [ 41 ]. Similarly, in VPT infants and their caregivers the presence of a matched coupling or overlapping regulatory profiles between interactive behaviors and neuroendocrine or physiological oscillations is debated [ 40 ]. This study will provide a suitable data setup to further explore the presence of significant coupling between interactive behaviors and neurophysiological brain activity in typically developing and at-risk pediatric populations. Second, it will be possible to explore how brain-to-brain co-regulation in typically developing FT infants and their caregivers is affected by different dimensions that characterized infants’ development (e.g., sensory profile, temperament) and the caregiving environment (e.g., affective symptoms, parenting stress, parent-infant bonding). It is well known that different behavioral indexes of caregiver-infant co-regulation (e.g., matching, synchrony, dyadic reparation; [ 4 ]) are shaped by individual characteristics and contributions by parent and infant behavior. For instance, Fuertes and colleagues [ 42 ] have suggested that infant temperament may play a critical role in the emergence of early attachment patterns and co-regulation of socio-emotional stress in full-term infants. Similarly, maternal affective symptoms may result in different dyadic organization of critical behaviors signaling reciprocal attention and socio-emotional availability, such as gaze direction [ 43 ] and emotional cues [ 44 ] Third, the role of sensory profile and environmental sensitivity to sensory inputs is recognized as an important contributor of child socio-emotional stress regulation [ 45 , 46 ]. Previous research highlighted how infants with diverse sensory profiles (e.g., sensation seekers or passive encoders) may differ in their resting state EEG activity [ 47 ], whereas FT and VPT infants’ sensory reactivity at 12 months was found to associate with later behavioral problems in toddlerhood [ 48 ]. The role of infants’ sensory profile in setting the stage for different gradients of brain-to-brain co-regulation is yet to be explored and such investigation might shed light into genetic-informed individual differences in the early establishment of parent-infant relationship. Fourth, consistent with the previous exploratory goal it might be speculated that VPT infants – due to early adverse sensory stimulations during the NICU stay [ 49 , 50 ] – might exhibit specifically altered profiles of sensory regulation compared to FT counterparts. Niutanen and colleagues [ 51 ] recently conducted a review of the literature highlighting how VPT infants might exhibit abnormal regulation of sensory inputs with consequences for sensory-motor integration and stress regulation. As the sensory regulation profile of VPT infants might be at least partially learned from attempts to adapt to the NICU, the present study might also help in identifying how early alterations in the sensory environment might shape the emergence of precocious forms of brain-to-brain co-regulation with the caregiver. Finally, by collecting quantitative data on the parents’ experience of the NICU hospitalization – including both psychological stress and perceived support from the staff – it will be possible to estimate how caring for parents’ well-being during the NICU stay might promote later electrophysiological caregiver-infant attunement. Previous research has highlighted that mothers of VPT infants might show lower sensitivity to infants’ facial and bodily cues [ 52 ]; nonetheless, their brain reactivity to emotional pictures of their own VPT infant appears to be heightened when compared to that of FT infants’ mothers [ 53 ]. These preliminary available data suggests that the brains of VPT infants’ caregivers might elaborate interactive-salient stimuli differently and this might be at least partially affected by the stressful experience of NICU hospitalization and early parent-infant separation. The present study will allow us to study how the brain activity of VPT infants’ mothers process relevant social cues during real-life face-to-face interactions, further contributing to understanding how caregivers’ brain adapt to preterm birth and hospitalization. In this context, NICU-related stress and perceived support from staff could be considered as potential moderators of the caregivers’ EEG activity when interacting with their VPT infant – with relevant consequences for the observed brain-to-brain co-regulation. METHODS AND PROCEDURES Study design and procedures The 2-BRAINED project is a randomized-controlled trial (RCT) with three arms. The first arm includes VPT infants and their caregivers randomly allocated to the intervention arm (VPT-VF). The second arm includes VPT infants and their caregivers randomly allocated to the care as usual arm (VPT-CU). This arm will act as a control group matched to preterm conditions of VPT-VF. The third arm includes FT infants and their caregivers and will act as an additional control group unmatched to preterm conditions. Both VPT-CU and FT arms will receive no VF intervention. Population, enrolment, and arm allocation VPT and FT infants will be enrolled at birth by contacting their caregivers within the first 48 hours after delivery. Informed consent will be obtained. VPT infants will be considered eligible in the presence of the following conditions: gestational age below 35 weeks, absence of major brain lesions as documented by cerebral ultra-sound, no neuro-sensory deficits including retinopathy of prematurity (ROP) equal or above stage 2, absence of genetic syndromed or malformations involving the central nervous system. FT infants will be considered eligible in the presence of the following conditions: gestational age equal to or above 37 weeks, healthy, with no evident signs of neurodevelopmental risk or morbidities. For both groups, single-parent family, less than 18-year-old parental age, lack of Italian language mastery, and the presence of documented psychiatric disorder will constitute exclusion criteria. Study timeline The 2-BRAINED study features five data collection waves (see Fig. 1 ). The VF intervention is delivered after wave T1 (NICU discharge) and before wave T2 (3 months CA) to subjects allocated to the VPT-VF arm. The EEG hyperscanning task will occur for all subjects at wave T4 (9 months CA) and will feature the videotaping of mother-infant interaction according to a modified Face-to-Face Still-Face (FFSF) procedure [ 54 ] and the simultaneous EEG data collection from both the interactive partner. At each wave parents will receive questionnaires by email using RedCap ( https://www.project-redcap.org/ ). Please, insert Fig. 1 here VF intervention Remote videotaping. Before (T1) and after (T2) the VF intervention sessions for participants allocated to VPT-VF – and at the same timepoints for participants allocated to VPT-CU – a 15-minute mother-infant interaction will be videotaped remotely. Before videotaping, mothers will be asked to position the webcam or smartphone to have the widest possible view of the play area and to see the entire body of both the mother and the infant. The interaction paradigm includes 10-minute unrestrained face-to-face play followed by a 6-minute FFSF procedure [ 54 ] as described here: during the 2-minute Play episode, mothers will be asked to play with the infant as they usually do (e.g., the infant can stay in an infant seat or on a carpet); during the 2-minute Still-Face episode mothers will be asked to interrupt any communication and to maintain a still, poker face while keeping eye-contact with their infant; unconstrained interaction will be resumed during the 2-minute Reunion episode. Intervention details. The remote VF intervention has been adapted according to previous research from our group [ 55 ]. It comprises six weekly 1-hour sessions organized in two subsequent phases: 4 sharing the focus sessions and 2 integration sessions. Sharing the focus sessions are dedicated to the discussion between the psychologist and the mother of specific themes related to parenting and parent–infant interaction: physical stimulation, responsiveness, teaching, and parenting experience (see Table 1 ). During these sessions, a purposively trained psychologist proposes to the mother to jointly review and discuss brief clips obtained from the pre-intervention videotaped interaction, usually starting from potential curiosity, comments, or requests from the mother herself. The goal of the sharing the focus sessions is to develop insights about the infants’ behavioral signals, how to respond contingently and appropriately, how to promote emotion regulation and to sustain cognitive and behavioral achievements. In the subsequent two integration sessions, the mother plays with the infant while the psychologist provides guidance based on insights co-developed during the previous four sessions. The goal is to promote a pragmatical translation of the insights into interactive skills. Table 1 Description of the thematic focus of the four sharing the focus sessions of the video-feedback (VF) intervention. Thematic cluster Key topic Goal Sensory stimulation and regulation Sensory channels Highlighting infant preference or avoidance of specific sensory channels and stimuli. Intensity of stimulation Regulating intensity of physical stimulation and understanding infant sensory thresholds. Affective social touch Facilitating parental affective touch to promote infant state regulation, postural stability, and attention orientation. Nurturing and sensitive caregiving Parental sensitivity Promoting parental perception, interpretation and appropriate responsiveness to infant communicative signals. Sense of agency Detecting and supporting the infant interactive initiatives (e.g., vocalizations, attention orienting). Exploration and safety Supporting the infant exploration of the environment and building safety and trust in parental secure base. Rhythm and reparation Facilitating the emergence of a proto-conversational rhythm in the dyad and supporting reparative actions of interactive perturbations. Cognitive sensitivity and scaffolding Attention skills Supporting and scaffolding infant sustained and focused attention to the physical and social environment. Modelling and guidance Providing a model to foster observational learning and the functional use of tools and toys. Proximal development zone Improving caregiver awareness of the cognitive abilities of the infant to make appropriate play proposals and to support infant emerging abilities. Parenting experience and mental state Mindmindedness Improving awareness about parental representations of the infant mind and keeping high levels of curiosity about infant behaviors. Self-care and self-regulation Highlighting the importance of parental psychological well-being and reflective functions; promoting parental psychological self-care and compassion. Self-efficacy Strengthening caregiver sense of efficacy as a parent and nourishing trust in parent own experience and mental representations of the infant. Please, insert Table 1 here FFSF procedure At 9 months (CA for VPT participants), mothers and infants will take part in a FFSF procedure in the lab. The FFSF will include three episodes: during the Play episode (2 minutes), mothers and infants will interact face-to-face avoiding use of toys and pacifier; during the Still-Face episode (1 minute), mothers will be asked to interrupt any communication toward the infant, to maintain a still, poker face, while maintaining eye-contact; during the Reunion episode (2 minutes), unconstrained interaction will be resumed. The procedure has been previously adopted to assess biobehavioral dimensions [ 9 , 56 ] and physiological underpinnings [ 7 , 57 ] of socio-emotional stress regulation in VPT infants. The entire procedure will be videotaped for the off-line coding of specific maternal and infant interactive behaviors (see Measures for details). Neurophysiological procedures EEG data acquisition will occur at 500 Hz sampling frequency during the 9-month FFSF procedure employing the Smarting Pro (mBrainTrain, Belgrade, Serbia) system equipped with two 32-channel EEG caps featuring wireless Bluetooth connection between the amplifiers and the mBrainTrain Streamer software installed on two separate laptops. The laptops receiving data will be linked to each other via a network cable to ensure synced data collection. The use of wireless EEG caps will allow greater flexibility and comfort for participating dyads. Upon arrival, the infant will be familiarized with the setting: a play mat and toys will be available to aid in acclimatization to the environment. The researchers will debrief parents with a comprehensive explanation of the study aims and procedures. Caps sizing will be selected to fit participants' head circumference. The caps fitting process will commence with the caregiver to ensure greater infant's comfort and familiarity with the equipment. Conductive gel will be applied to optimize signal conductivity and minimize artifacts. Measures Parent-report questionnaires are summarized and described in Table 2 . As for behavioral coding purposes, the videotapes obtained from two cameras during the lab FFSF procedure will be edited offline using Movavi Video Suite 2020 software and a single synced video showing both frontal views of the caregiver and the infant face, hands, and torso will be produced. Videos will be micro-analytically coded for infant’s and caregivers' target interactive behaviors according to an adaptation of the Parent-Infant Coding Scheme (PICS, Version 4.0; Brambilla et al., 2023) as reported in Table 2 . PICS codes will be computed as percentage of time for each FFSF episode. Plan of EEG data elaboration Pre-processing pipeline Dyadic EEG data will be pre-processed with a fully automated pipeline built using the MATLAB-based (The MathWorks Inc., 2024) interacting toolbox EEGLAB [ 58 ] A brief description of the main pre-processing steps is available in Fig. 2 . Table 2 Details of questionnaires included in the study. Construct Questionnaire Reference Item N Likert scale Description Study wave(s) Parental NICU-related stress Parental Stressor Scale – NICU (PSS-NICU) Miles, 1993 46 5-point Three main factor scores representing stress related to infants’ appearance, environmental sights and sounds, and parental role alteration T1 (only VPT) Sensory profile Sensory Profile-2 (SP-2) Dunn, 2014 54 5-point The infant version (0–6 months) identifies 5 sensory patterns. The toddler version (7–35 months) identifies four sensory patterns. T2, T3, T4 Anxiety symptoms State-Trait Anxiety Inventory (STAI-Y) Spielberger et al., 1983 40 4-point One trait score representing tendency to feel anxiety and one state score representing the present levels of anxiety T2, T4 Depression symptoms Beck Depression Inventory (BDI-II) Beck et al., 1996 21 4-point Global score representing a quantitative appreciation of the severity of symptoms of depression T2, T4 Parenting stress Parenting Stress Index - Short Form (PSI-SF) Abidin, 1995 36 5-point Three subscale scores addressing parental distress, parent–child dysfunctional interaction, stress related to difficult child behavior. A global score is also obtained. T2, T3, T4 Temperament Infant Behavior Questionnaire-Revised (IBQ-R) very short form Gartstein & Rothbart, 2003 37 7-point Three subscale factor scores addressing negative affectivity, surgency and regulatory capacity. T2, T3, T4 Note. VPT, very preterm; NICU, neonatal intensive care unit. Table 3 Selection of codes from the Parent-Infant Coding Scheme (PICS, Version 4.0). Variable Levels Description A. Both interactive partners Emotional state Negative Clear display of negative emotionality (e.g., eyes, mouth, general movements of the face or the body, and other vocal or non-vocal signals) including fussing and crying. Neutral No clear display of negative or positive emotionality. Positive Clear display of positive emotionality (e.g., eyes, mouth, general movements of the face or the body, and other vocal or non-vocal signals) including smiles and laughs. Gaze direction Face-directed Attention focus is on the interactive partner face Object-directed Attention focus is on the interactive partner body (e.g., hands, torso) or other objects. Avoiding The subject is actively avoiding eye-contact as displayed by head and body movements/posture. Approach/withdrawal Withdrawal Evident leaning backwards and/or turning the head away in order to avoid interaction Neutral No evident backward or forward movements. Approach Evident leaning forward and/or reaching forward to engage in interactive behaviors. B. Parental specific codes Vocal inputs No voice No vocal productions. Negative Vocal comments that convey explicit critique or rejection of infants' behaviors or state. Pragmatic Vocal comments finalized at modifying or instructing the interactive partner cognitive state, such as requests, attention getting, explanations. Social Vocal comments that convey playful and social engagement such as singing, laughing, playing nursery rhymes. Nurturing Vocal comments that express appreciation or acceptance of infants' behaviors or state or are finalized to sooth infants' stress. These also include mind-related comments (e.g., "you think", "you want") and mirroring of infants' communicative bids. Tactile inputs No touch No tactile stimulations. Negative Tactile stimulations that clearly appear intrusive and/or provoke or increase a negative emotionality state in the interactive partner. Pragmatic Tactile stimulations finalized at modifying or instructing the interactive partner posture or movements in the environment, such as holding, shadowing, attention getting. Social Tactile stimulations that convey playful and social engagement such as tickling, squeezing, and any other appropriate entertaining tactile stimulations that is fast-paced, dynamic, repetitive, and/or characterized by quick cinematic features. Nurturing Tactile stimulations that are finalized to sooth or regulate the behavioral state of the interactive partners. These include stroking, kissing, massaging and any other appropriate tactile stimulations with clear regulatory functions and conveying a sense of affective closeness. Note. The complete coding manual is available upon request to the corresponding author. Please, insert Fig. 2 here The parent and infant signals will be pre-processed separately with the same steps and parameters for both. First, data filtering will be performed with the application of a bandpass 1–30 Hz filter, as the planned analyses (see below) will be conducted on the lower (theta and alpha) frequency bands. Subsequently, flat and outlier channels will be detected using the NEAR (Neonatal EEG Artifact Removal) plugin [ 59 ] and retained (i.e., put in a separate temporary matrix) for later interpolation. Dyads in which at least one of the members displays a signal with more than 15% (N > 5) of flagged channels will be excluded from further analyses. The EEG signal from all non-flagged channels will undergo noise correction through the Artifact Subspace Reconstruction (ASR; [ 60 ]), with burst criterion (k) set at 10; subsequently, analysis of the components of the signal will be performed through the Independent Component Analysis (ICA; runica function with default settings), producing as many components as the number of good channels. The resulting components will be then classified through the ICLabel [ 61 ] plugin. Every component flagged as having 50% or more of probability of being an ocular artifact will be rejected. At this stage, the matrix containing the flat and outlier channels will be re-merged with the EEG matrix and the bad channels will be interpolated through spherical interpolation using the pre-processed signal. The signal will be then re-referenced to the average signal of the channels and split into three different sets containing each phase of the experimental procedure (Play, Still-Face, Reunion): each of these sets will be subsequently segmented into 1000 ms epochs avoiding overlaps. Bad data segments containing residual artifacts in each of the three phases will be identified. All segments in which at least one of the target channels used for estimates of dyadic co-regulation (see below) displays a voltage exceeding ± 150 µV [ 62 ] will be marked as rejected. The rejected epochs in the infant’s and parent’s signals will be merged to obtain the final pool of rejected epochs for the dyad. This ensures that all the rejected epochs for one interactive member of the dyad will be similarly mirrored for the other partner. Dyadic data will undergo further analyses if their signal contains at least 30 good epochs in both Play and Reunion phases; if this criterion will not be met, their signal will undergo manual epoch rejection performed by an expert EEG coder. In case after the manual epoch rejection, the dyad will result having less than 30 good merged epochs in at least one of the FFSF episodes, the signal will be excluded from further analyses. Estimating indexes of inter-brain co-regulation Several inter-brain synchronization indices have been proposed so far to estimate the coupling between two brains [ 32 ]. Since there is still debate on the appropriateness of each inter-brain synchronization measure, we plan to compute and compare several indices (see Table 4 ). To further check for spurious findings and get stronger evidence that the obtained co-regulation estimations are not artifact production, we will compare the synchronization indexes obtained from the real dyads to surrogate data generated by randomly pairing mothers and infants from different dyads. Table 4 Indexes of inter-brain co-regulation adopted in the 2-BRAINED study. Index Description Notes Reference Phase-Locking Value (PLV) Frequency-specific transients of phase locking independent of amplitude. The value ranges from 0 to 1: values closer to 0 indicate random signals with unsynchronized phases; values closer to 1 indicate stronger coupling between the two signals. While previous studies focused mainly on infant frequency bands, cross-frequency PLV indexes will be obtained for the purposes of the 2-BRAINED study. Lachaux et al., 1999: Canolty & Knight (2010) Imaginary Coherence (ICoh) Computed through spectral density (power) of each participant and cross-spectral density between them to estimate the average phase difference and consistency of phase difference synchronization. ICoh is expressed as a complex number: the real part represents how much the coherence is driven by instantaneous interactions; the imaginary part shows how much the coherence is based on lagged interactions. Dikker et al., 2021; Turk et al., 2022 Amplitude-Amplitude Coupling (AAC) Expressed as Person's correlation coefficient between normalized power time courses of the two signals. Amplitude coupling was suggested as a valid alternative to phase coupling for three main reasons: amplitude changes are more easily estimated; amplitude modulations are more extensively characterized across EEG studies; amplitude modulations are more sensitive to neural coupling phenomena non detectable with other phase-related measures Haresign et al., 2022; Koul et al., 2023 The computation of synchronization measures will preferentially occur considering homologous channels for the sake of interpretability and computational costs. However, as an exploratory analysis, we will also compute synchronization between non homologous channels because we can hypothesize that synchronization tasks between mother and infant can involve different brain areas in the two actors [ 35 ]. Please, insert Table 4 here Regarding the frequency bands on which the synchronization measures will be computed, we will mainly consider alpha and theta. Indeed, these frequencies have been found to be involved in parent–infant social task, with theta fluctuations linked to changes in shared attention during joint play of parent and infant [ 34 ], enhancement of alpha and theta power linked to changes in directed gaze [ 33 ], and fluctuations in alpha band linked to changes in emotional states of mother and child [ 63 ]. Moreover, since we are interested in the dynamic evolution of brain-to-brain synchronization, we plan to evaluate the trend of each synchronization index over time (i.e., over the epochs). In particular we are interested in the change between an asynchronous to a synchronous state, which is defined as reparation. Reparation is a dyadic process in which unmatched dyadic states are transformed into matched dyadic states. We will compute the rate and the latency of reparation considering the EEG synchronization indices as previously performed in synchronized behaviors assessment [ 64 ]. Statistical power and sample size estimates The sample size has been estimated according to over-arching Aim 2, setting parameters as follows: medium effect size, f = .25, alpha = .05, beta = .20, number of groups = 3 (VPT-VF, VPT-CU, FT). The procedure yielded a total sample size of 159 subjects (53 subjects per RCT arm). Nonetheless, considering the longitudinal nature of the study and the attrition rate related to EEG tasks with infants, an oversampling of n = 80 ( ~ + 50%) subjects per RCT arm was planned to secure the minimum sample size for appropriately powered statistical analyses. Plan of statistical analyses Preliminary analyses Specific aim 1. General linear models (GLMs) will be carried out to compare VPT and FT dyadic brain-to-brain co-regulation indexes during the experimental procedure phases. Theoretically relevant (e.g., gestational age) and statistically identified (e.g., any variable significantly linked with the outcome variables) confounding variables will be controlled for in the analytical model. Specific aim 2 . Separate analyses of variance (ANOVA) will be used with dyadic brain-to-brain co-regulation indexes as dependent variable and groups (FT, VPT-VF, VPT-CU) as an independent variable. Theoretically relevant (e.g., gestational age) and statistically identified (e.g., any variable significantly linked with the outcome variables) confounding variables will be controlled for in the analytical model. Additional aims. Models to track early developmental trajectories will be estimated in Mplus by latent class growth analysis with inter-individual variations in time of assessment and mixed-effect linear models with repeated measures to assess group differences in rates of temperament, emotional, and sensory profiles. DISCUSSION The present protocol describes an RCT study that aims at assessing the benefits of an early post-discharge video-feedback intervention to enhance and promote both parental and VPT infants’ outcomes. By collecting dual-source EEG data in a hyper-scanning paradigm and from face-to-face real-time interactions between parents and infants, the study also aims at providing estimations of the effects of such intervention not only for the individual adjustment of caregivers and infants, but also for the emergence of dyadic co-regulatory biobehavioral processes. Such co-regulation profiles are meant to be critical indicators of a nurturing caregiving environment during the first months of life fostering affective well-being and stress resilience [ 65 , 66 ] Sources of bias and mitigation strategies The heterogeneity of VPT infants’ conditions should not be underestimated. Even in the absence of severe comorbidities and brain injuries, the experience of NICU hospitalization might be very different for each infant and their parents. To avoid extreme variations, gestational age range will be constrained between 28 and 35 weeks. Moreover, stress related to the NICU environment will be evaluated and quantified with a well-validated questionnaire [ 67 ]. Selection issues might affect random allocation plans in RCT arms. The allocation to VPT-VF and VPT-CU arms will occur by using an automatically generated list of binary codes that will be consecutively matched with the enrolled families across consecutive sampling. This will reduce the risk of self-selection. To further avoid confounding by infant sex and to assure sex distribution balancing, the random allocation will be stratified by infant sex by post-hoc controls every 20 enrollments. Parental gender will also be unconstrained, inviting the primary caregiver – and not explicitly the mother – to participate in the study, in the VF intervention and in the observational procedures. EEG procedural steps and artifacts might easily result in loss of subjects in a longitudinal study; a 50% oversampling was planned to achieve the minimum sample size for adequately powered statistical analyses. Expected results and impact The project represents a translational application of the emerging field of hyper-scanning in developmental neuroscience [ 37 ]. As neuroscience is moving toward a radical shift in considering the interpersonal exchanges as the primary unit of analysis and observation [ 68 , 69 ], clinical applications are meant to be implemented to innovate healthcare. Previous proposals have been advanced to apply such bi-personal neuroscientific approach to the field of adult psychiatry [ 70 ] and child development [ 31 ]. Here, we aim to innovate the field of family-centered care in pediatric settings by embedding a cutting-edge approach to the study of parent-infant interaction and co-regulation processes into well-validated approaches to parental support and child development promotion. As the video-feedback intervention is well-acknowledged for its beneficial implications for parental well-being, child development, and quality of the early parent-child relationship [ 71 , 72 ], it represents an élite clinical setting to test the advantages of new neuroscientific-inspired metrics that specifically focus on the assessment of brain-to-brain co-regulatory processes. In this context, the present study has multifaceted implications. From a scientific perspective, this study will provide first-of-a-kind quantitative estimations of inter-brain coupling and co-regulation in a sample of VPT infants and their caregivers. While previous research has highlighted functional and structural alterations in VPT infants’ brain [ 73 – 75 ], very little is known about VPT neurophysiological functioning in real-life settings. Moreover, the study will provide insights into “how much” inter-brain synchrony should be expected in typical and atypical developmental trajectories. As medium levels of attunement and matching have been suggested to be optimal in terms of behavioral co-regulation during the first months [ 76 ], similar expectations appear to be plausible for what pertains inter-brain coupling. From a clinical point of view, the 2-BRAINED project is expected to produce evidence on the efficacy of an early intervention for VPT infants and their parents that is delivered after NICU discharge. This is a critical window for continuity of care, as parents transit from potentially high-quality family-centered care during NICU stay to lack of appropriate and tailored support at home [ 77 , 78 ]. In this perspective, this study will explore the efficacy of an intervention aimed at granting continuity of care from the hospital to the house, extending and empowering family-centered care for VPT infants’ parents. From a translational neuroscience perspective, the study will also offer unprecedented opportunity to get first-hand dyadic neurophysiological target outcomes of well-validated early family-centered VF intervention. While the road to develop qualitative and quantitative measures of effectiveness and efficacy of such family-centered interventions is yet to be fully implemented, the integration of behavioral, self-report, and neurobiological markers is promising for future advances. Patient and public involvement Active engagement of families will be pursued through public dedicated web/social communications, digital content, and newsletter describing the achieved goals and implications of the study. Parental associations and professionals orders will be engaged through online webinars to capitalize from the data obtained from the present study to further fuel a culture of family-centered care for preterm infants and their parents. ETHICS AND DISSEMINATION Ethics, privacy, and data management The Ethics Committee Pavia and collaborating partners granted approval for the study on February 16, 2023 (protocol number: 0008588/23) and officially launched on April 24, 2023 (GR-2021-12375213). All procedures align with the ethical principles outlined in the Declaration of Helsinki for research involving human subjects, ensuring no harm to participants. The study intervention offers additional opportunities for families without altering standard mother–infant care programs. Infants will undergo planned diagnostic and therapeutic interventions at the child neurology and psychiatric unit IRCCS Mondino Foundation, Pavia, Italy, and the Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy. Data management will occur in accordance with the General Data Protection Regulation (Regulation 2016/279, commonly known as GDPR), in order to guarantee the privacy and the security of the gathered data. In this sense, all the infants’ parents will sign an informed consent module after that the study’s aims and modalities will be clearly explained and eventual doubts will be solved. Each subject will be assigned with a code and data will be stored in a pseudonymized form. After the period of conservation (25 years), data will be made completely anonymous. In line with the open science principle, the anonymized data collected for the study will be published on a publicly accessible “repository” (i.e., Zenodo) in order to promote the dissemination of research results with a view to furthering the research itself and the scientific community. Dissemination The dissemination strategy involves presenting findings at national and international scientific meetings, publishing in developmental psychology journals, and engaging in outreach activities with families and healthcare specialists. This aims to promote early family-centered intervention and share insights with the wider public. Declarations Competing interests: none declared. Patient consent for publication: not required. Ethical Approval The study was approved by the Ethics Committee Pavia on February 16, 2023 (protocol number: 0008588/23). Funding This study is supported by the Italian Ministry of Health through Ricerca Finalizzata grant GR-2021-12375213 (Principal Investigator: LP). Work supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) – A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022). Author Contribution LP conceived the study, obtained funding, and prepared the first draft of the manuscript; VR contributed to study conception, behavioral methodology, and manuscript drafting; LB contributed to study conception, neurophysiological methodology, and manuscript drafting; ES and MC contributed critically to manuscript preparation and behavioral methodology; EC and MPP contributed to neurophysiological methodology and manuscript drafting; ER contributed to defining neurophysiological methods and technical details; SG, contributed to the clinical intervention design and manuscript drafting; MC contributed to behavioral methodology and manuscript drafting. Acknowledgement The authors are thankful to the following project collaborators: Renato Borgatti, Giacomo Cremaschi, Silvia D’Alfonso, Sara De Monti, Stefano Ghirardello, Yaren Gunay, Giulia Libardo, Cecilia Naboni, Giacomo Novembre, Simona Orcesi, Camilla Pisoni, and Elise Torterolo. Availability of data and materials: Not applicable References Beam AL, Fried I, Palmer N, Agniel D, Brat G, Fox K, et al. Estimates of healthcare spending for preterm and low-birthweight infants in a commercially insured population: 2008–2016. J Perinatol. 2020;40:1091–9. https://doi.org/10.1038/s41372-020-0635-z . Ohuma EO, Moller A-B, Bradley E, Chakwera S, Hussain-Alkhateeb L, Lewin A, et al. National, regional, and global estimates of preterm birth in 2020, with trends from 2010: a systematic analysis. Lancet. 2023;402:1261–71. https://doi.org/10.1016/S0140-6736(23)00878-4 . Cong X, Wu J, Vittner D, Xu W, Hussain N, Galvin S, et al. 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A Comparison of Maternal and Paternal Experiences of Becoming Parents of a Very Preterm Infant. J Obstet Gynecol Neonatal Nurs. 2016;45:528–41. https://doi.org/10.1016/j.jogn.2016.04.004 . Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4501473","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":313500405,"identity":"b8d17593-526f-43a5-819b-ad232ff2b4fb","order_by":0,"name":"Lucia Billeci","email":"","orcid":"","institution":"National Research Council of Italy (IFC-CNR)","correspondingAuthor":false,"prefix":"","firstName":"Lucia","middleName":"","lastName":"Billeci","suffix":""},{"id":313500408,"identity":"6fd52f70-649f-48cc-9ce9-b81291f5617c","order_by":1,"name":"Valentina Riva","email":"","orcid":"","institution":"Scientific Institute IRCCS E. Medea","correspondingAuthor":false,"prefix":"","firstName":"Valentina","middleName":"","lastName":"Riva","suffix":""},{"id":313500409,"identity":"6aec190c-7813-41c7-8271-530bfea64047","order_by":2,"name":"Elena Capelli","email":"","orcid":"","institution":"University of Pavia","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Capelli","suffix":""},{"id":313500410,"identity":"eab161a0-689d-4ea2-b430-a7c8a65026cb","order_by":3,"name":"Serena Grumi","email":"","orcid":"","institution":"IRCCS Mondino Foundation","correspondingAuthor":false,"prefix":"","firstName":"Serena","middleName":"","lastName":"Grumi","suffix":""},{"id":313500411,"identity":"fab8b950-642f-4db7-b380-5aea508dc37a","order_by":4,"name":"Miriam Paola Pili","email":"","orcid":"","institution":"University of Pavia","correspondingAuthor":false,"prefix":"","firstName":"Miriam","middleName":"Paola","lastName":"Pili","suffix":""},{"id":313500412,"identity":"518a2d79-c269-4b27-a96f-b67125d953df","order_by":5,"name":"Maddalena Cassa","email":"","orcid":"","institution":"Scientific Institute IRCCS E. Medea","correspondingAuthor":false,"prefix":"","firstName":"Maddalena","middleName":"","lastName":"Cassa","suffix":""},{"id":313500413,"identity":"2d0e6714-1afc-4287-9d4e-33a803b186f1","order_by":6,"name":"Eleonora Siri","email":"","orcid":"","institution":"Scientific Institute IRCCS E. Medea","correspondingAuthor":false,"prefix":"","firstName":"Eleonora","middleName":"","lastName":"Siri","suffix":""},{"id":313500414,"identity":"3cad4145-f12e-4e23-b27f-94790b87ed56","order_by":7,"name":"Elisa Roberti","email":"","orcid":"","institution":"IRCCS Mondino Foundation","correspondingAuthor":false,"prefix":"","firstName":"Elisa","middleName":"","lastName":"Roberti","suffix":""},{"id":313500415,"identity":"560c4f3b-4a16-476a-a068-cdfab666511d","order_by":8,"name":"Livio Provenzi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIie3SvQrCMBSG4QOBusR2TQe9hlMKBUG8lpZCHXV0FARdvIB6F93ELSWgS7UXoIMunTuJQwd/ir8Q6+iQd8o3PHCGAKhUf5hOAPhzYhuA3B5yon2Q4E7kRvvY4oHlpEYtnsOuZzB/eTj1U29eqy8Z9Isvh1GMQ8haszDoIsOttxjpAft6GNFcQUEgJonD8EIiQW38kaRH5uLmF0J4SVZTjXHkV2Ltq0gcYobmZOyYQ/TtSOje3kVbSgwjHuX5YIcGIZl5KjqNKF1znhdNKSlD/roogFsB4O0D3IhKpVKpXjoDnSBMGPPvJgAAAAAASUVORK5CYII=","orcid":"","institution":"University of Pavia","correspondingAuthor":true,"prefix":"","firstName":"Livio","middleName":"","lastName":"Provenzi","suffix":""}],"badges":[],"createdAt":"2024-05-30 08:23:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4501473/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4501473/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":58386163,"identity":"138e0d68-1dfc-4789-a67a-4ee7106a3ba9","added_by":"auto","created_at":"2024-06-14 18:43:37","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":106379,"visible":true,"origin":"","legend":"\u003cp\u003eStudy design.\u003c/p\u003e\n\u003cp\u003eNote. NICU, Neonatal Intensive Care Unit; VF, video-feedback intervention; CU, care as usual; CA, corrected age.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4501473/v1/c898474528aeb4bdb70d261b.png"},{"id":58386165,"identity":"5c427f61-bf1e-4e74-b701-eb03bfaac365","added_by":"auto","created_at":"2024-06-14 18:43:37","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":69625,"visible":true,"origin":"","legend":"\u003cp\u003eEEG data pre-processing pipeline.\u003c/p\u003e\n\u003cp\u003eNote. NEAR = Neonatal EEG Artifact Removal, ASR = Artifact Subspace Reconstruction, ICA = Independent Component Analysis.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4501473/v1/102e08888f2c7d681952c389.png"},{"id":63257566,"identity":"915e5f6a-0875-4f1d-835f-911824cfb243","added_by":"auto","created_at":"2024-08-26 08:30:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1005937,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4501473/v1/3114a618-96e9-4baf-98f8-ab4e5e6bc19a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED): A translational hyperscanning research project","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eVery preterm (VPT) birth is a major challenge for healthcare systems worldwide [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], representing the leading cause of long-lasting chronic diseases in childhood and child mortality [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While VPT infants are exposed to heightened medical risk and to several stress sources from the Neonatal Intensive Care Unit (NICU) environment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] their parents also may face critical levels of psychological distress leading to increased risk for depression, anxiety, and parenting stress in the postpartum period [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNotably, biobehavioral dysregulation patterns have been observed in dyads of VPT infants and their caregivers in the first months of life [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] suggesting that VPT birth and NICU-related stress might affect child development and parental adjustment by altering critical processes of dyadic co-regulation during the first thousand days [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Early interventions promoting parent-infant closeness might contribute to promote the establishment of the same psychobiological co-regulatory processes [\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] with buffering and protective benefits for child development and parental well-being [\u003cspan additionalcitationids=\"CR17\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eVideo-feedback (VF) interventions are well-validated parenting support programs that focus on parent-infant closeness, promote parental sensitivity, facilitate co-regulatory processes, and provide neuroprotective effects for child development [\u003cspan additionalcitationids=\"CR20 CR21\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. VF interventions include a diverse set procedures and methodologies aimed at promoting positive parenting and capitalize from allowing the parents to observe themselves and the interaction with their infant \u0026ldquo;from the outside\u0026rdquo;, thus facilitating mentalization and reflexive functions [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Although different theoretical and methodological VF approaches have been described [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], previous research highlighted benefits for child development and the quality of parent-child interaction in different clinical contexts and populations, including preterm infants and their caregivers [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. More recently, a clinical trial by Pisoni and colleagues [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] highlighted long-term improvement in the developmental quotient scores of 24-month-old VPT infants of age following a VF intervention, adding to the evidence that remote video-consultation might be an effective home care approach [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHyperscanning is a relatively recent approach to the study of brain-to-brain co-regulation in live interactive partners using different electrophysiological and neuroimaging techniques [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. By simultaneously recording of multiple brains\u0026rsquo; activity, hyperscanning allows the acquisition of neurophysiological measures of human dyadic or group-based neurophysiological coordination [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Among the different available techniques, EEG offers special advantages when the hyperscanning paradigm is applied to pediatric and even newborn populations. Wireless EEG devices are relatively non-invasive and allow freedom of movement, thus facilitating the study of mother-infant interactions in laboratory as well as in ecological settings during the first months of life. By using EEG hyperscanning paradigms, Leong and colleagues [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e] highlighted how gaze direction during face-to-face interactions between adults and 8-month-old infants affect patterns of dyadic neural connectivity. Similarly, different patterns of theta power fluctuations were observed when 12-month-old infants play in solo in the presence of the caregiver or when they actively interact together [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. More recently, the phase-locking values (PLVs) indicating the strength of brain-to-brain co-regulation in theta and alpha frequency bands were computed during 7-month-old infants\u0026rsquo; interaction with the caregiver compared to an adult stranger [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The study reported greater inter-brain attunement when infants were interacting with the mother, despite the addition of maternal chemo-signals in the setting of infant-stranger interaction attenuated the significant difference.\u003c/p\u003e \u003cp\u003eAs the field of parent-infant hyperscanning research is rapidly growing, the accumulating knowledge is contributing to a pivotal epistemic and theoretical shift in developmental neurosciences from a mono-personal account to a strongly relational perspective [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The application of hyperscanning paradigms to the study of parent-infant brain-to-brain co-regulation in at-risk and clinical pediatric populations holds promises to acquire innovative data on the mechanisms by which the early caregiving environment fosters and promotes child neurodevelopment [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Moreover, as specific indexes of brain-to-brain co-regulation become validated in typical development, they may also be embedded into a novel set of neurobehavioral markers to assess the benefit of early interventions. Such \u003cem\u003etranslational hyperscanning\u003c/em\u003e vision has been recently framed in the affective neuroscience literature ([\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]); yet there is lack of research on the brain-to-brain co-regulation of VPT infants and their parents and on the potentially beneficial neuroprotective effects of early parenting interventions in this population.\u003c/p\u003e"},{"header":"STUDY AIMS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGeneral and specific aims\u003c/h2\u003e \u003cp\u003eThe \u003cem\u003e2-Brain Regulation to Achieve Improved Neuroprotection during Early Development\u003c/em\u003e (2-BRAINED) research project is funded by Italian Ministry Health under the Ricerca Finalizzata 2021 program (research line: Giovani Ricercatori, project code: GR-2021-12375213). It is aimed at assessing brain-to-brain co-regulation patterns in dyads of VPT infants and their caregivers and to further explore how an early VF intervention might facilitate specific interbrain regulatory indexes.\u003c/p\u003e \u003cp\u003eThe first specific aim (Aim 1) is to assess the presence of statistically significant differences in a set of brain-to-brain co-regulation indexes \u0026ndash; primarily, PLV measure \u0026ndash; between dyads of caregivers and VPT compared to FT infants. Previous research gave evidence of specific markers of lower co-regulation in behavioral synchrony [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] physiological coupling [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] and neuroendocrine attunement [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e] in dyads of VPT infants during the first year of life. Consistently, we hypothesized that VPT infants and their caregivers would show less strong brain-to-brain co-regulation indexes compared to dyads of FT counterparts at 9 months (corrected age for prematurity, CA).\u003c/p\u003e \u003cp\u003eThe second specific aim (Aim 2) is to investigate the effect of an early VF intervention for parents of VPT infants on the selected indexes of brain-to-brain co-regulation at 9 months CA. By comparing EEG hyperscanning-derived indexes of interbrain coupling between dyads of VPT infants exposed to the VF intervention and dyads exposed to care as usual during the three months following NICU discharge, we hypothesize to describe greater brain-to-brain co-regulation in the former group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eAdditional exploratory aims\u003c/h2\u003e \u003cp\u003eThe longitudinal nature of this study and the possibility to collect a multi-layer set of data for what pertains the neurobehavioral development of FT and VPT infants as well as the parenting environment during the first year of life allow us to set the stage for a number of exploratory analyses that will further guide future spin-off studies stemming from the 2-BRAINED research project. Here we highlight five main exploratory aims that appear relevant for future translational research in the field of affective neuroscience and developmental psychobiology.\u003c/p\u003e \u003cp\u003eFirst, the availability of behavioral and EEG physiological data from the 9-month interactive procedure (see below, \u003cem\u003eStudy design and procedures\u003c/em\u003e) will allow for the exploration of patterns of bio-neurophysiological coupling within dyads. Previous research produced limited evidence for the presence of correlations between specific interactive behaviors and EEG signaling during interactive tasks [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Similarly, in VPT infants and their caregivers the presence of a matched coupling or overlapping regulatory profiles between interactive behaviors and neuroendocrine or physiological oscillations is debated [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. This study will provide a suitable data setup to further explore the presence of significant coupling between interactive behaviors and neurophysiological brain activity in typically developing and at-risk pediatric populations.\u003c/p\u003e \u003cp\u003eSecond, it will be possible to explore how brain-to-brain co-regulation in typically developing FT infants and their caregivers is affected by different dimensions that characterized infants\u0026rsquo; development (e.g., sensory profile, temperament) and the caregiving environment (e.g., affective symptoms, parenting stress, parent-infant bonding). It is well known that different behavioral indexes of caregiver-infant co-regulation (e.g., matching, synchrony, dyadic reparation; [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]) are shaped by individual characteristics and contributions by parent and infant behavior. For instance, Fuertes and colleagues [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] have suggested that infant temperament may play a critical role in the emergence of early attachment patterns and co-regulation of socio-emotional stress in full-term infants. Similarly, maternal affective symptoms may result in different dyadic organization of critical behaviors signaling reciprocal attention and socio-emotional availability, such as gaze direction [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e] and emotional cues [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]\u003c/p\u003e \u003cp\u003eThird, the role of sensory profile and environmental sensitivity to sensory inputs is recognized as an important contributor of child socio-emotional stress regulation [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. Previous research highlighted how infants with diverse sensory profiles (e.g., sensation seekers or passive encoders) may differ in their resting state EEG activity [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e], whereas FT and VPT infants\u0026rsquo; sensory reactivity at 12 months was found to associate with later behavioral problems in toddlerhood [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. The role of infants\u0026rsquo; sensory profile in setting the stage for different gradients of brain-to-brain co-regulation is yet to be explored and such investigation might shed light into genetic-informed individual differences in the early establishment of parent-infant relationship.\u003c/p\u003e \u003cp\u003eFourth, consistent with the previous exploratory goal it might be speculated that VPT infants \u0026ndash; due to early adverse sensory stimulations during the NICU stay [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] \u0026ndash; might exhibit specifically altered profiles of sensory regulation compared to FT counterparts. Niutanen and colleagues [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] recently conducted a review of the literature highlighting how VPT infants might exhibit abnormal regulation of sensory inputs with consequences for sensory-motor integration and stress regulation. As the sensory regulation profile of VPT infants might be at least partially learned from attempts to adapt to the NICU, the present study might also help in identifying how early alterations in the sensory environment might shape the emergence of precocious forms of brain-to-brain co-regulation with the caregiver.\u003c/p\u003e \u003cp\u003eFinally, by collecting quantitative data on the parents\u0026rsquo; experience of the NICU hospitalization \u0026ndash; including both psychological stress and perceived support from the staff \u0026ndash; it will be possible to estimate how caring for parents\u0026rsquo; well-being during the NICU stay might promote later electrophysiological caregiver-infant attunement. Previous research has highlighted that mothers of VPT infants might show lower sensitivity to infants\u0026rsquo; facial and bodily cues [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e]; nonetheless, their brain reactivity to emotional pictures of their own VPT infant appears to be heightened when compared to that of FT infants\u0026rsquo; mothers [\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. These preliminary available data suggests that the brains of VPT infants\u0026rsquo; caregivers might elaborate interactive-salient stimuli differently and this might be at least partially affected by the stressful experience of NICU hospitalization and early parent-infant separation. The present study will allow us to study how the brain activity of VPT infants\u0026rsquo; mothers process relevant social cues during real-life face-to-face interactions, further contributing to understanding how caregivers\u0026rsquo; brain adapt to preterm birth and hospitalization. In this context, NICU-related stress and perceived support from staff could be considered as potential moderators of the caregivers\u0026rsquo; EEG activity when interacting with their VPT infant \u0026ndash; with relevant consequences for the observed brain-to-brain co-regulation.\u003c/p\u003e \u003c/div\u003e"},{"header":"METHODS AND PROCEDURES","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and procedures\u003c/h2\u003e \u003cp\u003eThe 2-BRAINED project is a randomized-controlled trial (RCT) with three arms. The first arm includes VPT infants and their caregivers randomly allocated to the intervention arm (VPT-VF). The second arm includes VPT infants and their caregivers randomly allocated to the care as usual arm (VPT-CU). This arm will act as a control group matched to preterm conditions of VPT-VF. The third arm includes FT infants and their caregivers and will act as an additional control group unmatched to preterm conditions. Both VPT-CU and FT arms will receive no VF intervention.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003ePopulation, enrolment, and arm allocation\u003c/h2\u003e \u003cp\u003e VPT and FT infants will be enrolled at birth by contacting their caregivers within the first 48 hours after delivery. Informed consent will be obtained. VPT infants will be considered eligible in the presence of the following conditions: gestational age below 35 weeks, absence of major brain lesions as documented by cerebral ultra-sound, no neuro-sensory deficits including retinopathy of prematurity (ROP) equal or above stage 2, absence of genetic syndromed or malformations involving the central nervous system. FT infants will be considered eligible in the presence of the following conditions: gestational age equal to or above 37 weeks, healthy, with no evident signs of neurodevelopmental risk or morbidities. For both groups, single-parent family, less than 18-year-old parental age, lack of Italian language mastery, and the presence of documented psychiatric disorder will constitute exclusion criteria.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStudy timeline\u003c/h2\u003e \u003cp\u003eThe 2-BRAINED study features five data collection waves (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The VF intervention is delivered after wave T1 (NICU discharge) and before wave T2 (3 months CA) to subjects allocated to the VPT-VF arm. The EEG hyperscanning task will occur for all subjects at wave T4 (9 months CA) and will feature the videotaping of mother-infant interaction according to a modified Face-to-Face Still-Face (FFSF) procedure [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] and the simultaneous EEG data collection from both the interactive partner. At each wave parents will receive questionnaires by email using RedCap (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.project-redcap.org/\u003c/span\u003e\u003cspan address=\"https://www.project-redcap.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003ePlease, insert\u003c/em\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003ehere\u003c/em\u003e\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eVF intervention\u003c/h2\u003e \u003cp\u003e \u003cb\u003eRemote videotaping.\u003c/b\u003e Before (T1) and after (T2) the VF intervention sessions for participants allocated to VPT-VF \u0026ndash; and at the same timepoints for participants allocated to VPT-CU \u0026ndash; a 15-minute mother-infant interaction will be videotaped remotely. Before videotaping, mothers will be asked to position the webcam or smartphone to have the widest possible view of the play area and to see the entire body of both the mother and the infant. The interaction paradigm includes 10-minute unrestrained face-to-face play followed by a 6-minute FFSF procedure [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e] as described here: during the 2-minute Play episode, mothers will be asked to play with the infant as they usually do (e.g., the infant can stay in an infant seat or on a carpet); during the 2-minute Still-Face episode mothers will be asked to interrupt any communication and to maintain a still, poker face while keeping eye-contact with their infant; unconstrained interaction will be resumed during the 2-minute Reunion episode.\u003c/p\u003e \u003cp\u003e \u003cb\u003eIntervention details.\u003c/b\u003e The remote VF intervention has been adapted according to previous research from our group [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e]. It comprises six weekly 1-hour sessions organized in two subsequent phases: 4 \u003cem\u003esharing the focus\u003c/em\u003e sessions and 2 \u003cem\u003eintegration\u003c/em\u003e sessions. \u003cem\u003eSharing the focus\u003c/em\u003e sessions are dedicated to the discussion between the psychologist and the mother of specific themes related to parenting and parent\u0026ndash;infant interaction: physical stimulation, responsiveness, teaching, and parenting experience (see Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During these sessions, a purposively trained psychologist proposes to the mother to jointly review and discuss brief clips obtained from the pre-intervention videotaped interaction, usually starting from potential curiosity, comments, or requests from the mother herself. The goal of the \u003cem\u003esharing the focus\u003c/em\u003e sessions is to develop insights about the infants\u0026rsquo; behavioral signals, how to respond contingently and appropriately, how to promote emotion regulation and to sustain cognitive and behavioral achievements. In the subsequent two \u003cem\u003eintegration\u003c/em\u003e sessions, the mother plays with the infant while the psychologist provides guidance based on insights co-developed during the previous four sessions. The goal is to promote a pragmatical translation of the insights into interactive skills.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDescription of the thematic focus of the four \u003cem\u003esharing the focus\u003c/em\u003e sessions of the video-feedback (VF) intervention.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThematic cluster\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eKey topic\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGoal\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eSensory stimulation and regulation\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSensory channels\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHighlighting infant preference or avoidance of specific sensory channels and stimuli.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eIntensity of stimulation\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRegulating intensity of physical stimulation and understanding infant sensory thresholds.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eAffective social touch\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFacilitating parental affective touch to promote infant state regulation, postural stability, and attention orientation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e \u003cp\u003e\u003cem\u003eNurturing and sensitive caregiving\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eParental sensitivity\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003ePromoting parental perception, interpretation and appropriate responsiveness to infant communicative signals.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSense of agency\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDetecting and supporting the infant interactive initiatives (e.g., vocalizations, attention orienting).\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eExploration and safety\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSupporting the infant exploration of the environment and building safety and trust in parental secure base.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eRhythm and reparation\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFacilitating the emergence of a proto-conversational rhythm in the dyad and supporting reparative actions of interactive perturbations.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eCognitive sensitivity and scaffolding\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eAttention skills\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSupporting and scaffolding infant sustained and focused attention to the physical and social environment.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eModelling and guidance\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eProviding a model to foster observational learning and the functional use of tools and toys.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eProximal development zone\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eImproving caregiver awareness of the cognitive abilities of the infant to make appropriate play proposals and to support infant emerging abilities.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eParenting experience and mental state\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eMindmindedness\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eImproving awareness about parental representations of the infant mind and keeping high levels of curiosity about infant behaviors.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSelf-care and self-regulation\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHighlighting the importance of parental psychological well-being and reflective functions; promoting parental psychological self-care and compassion.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSelf-efficacy\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eStrengthening caregiver sense of efficacy as a parent and nourishing trust in parent own experience and mental representations of the infant.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003ePlease, insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cem\u003ehere\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003eFFSF procedure\u003c/h2\u003e \u003cp\u003eAt 9 months (CA for VPT participants), mothers and infants will take part in a FFSF procedure in the lab. The FFSF will include three episodes: during the Play episode (2 minutes), mothers and infants will interact face-to-face avoiding use of toys and pacifier; during the Still-Face episode (1 minute), mothers will be asked to interrupt any communication toward the infant, to maintain a still, poker face, while maintaining eye-contact; during the Reunion episode (2 minutes), unconstrained interaction will be resumed. The procedure has been previously adopted to assess biobehavioral dimensions [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e] and physiological underpinnings [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e] of socio-emotional stress regulation in VPT infants. The entire procedure will be videotaped for the off-line coding of specific maternal and infant interactive behaviors (see \u003cem\u003eMeasures\u003c/em\u003e for details).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eNeurophysiological procedures\u003c/h2\u003e \u003cp\u003eEEG data acquisition will occur at 500 Hz sampling frequency during the 9-month FFSF procedure employing the Smarting Pro (mBrainTrain, Belgrade, Serbia) system equipped with two 32-channel EEG caps featuring wireless Bluetooth connection between the amplifiers and the mBrainTrain Streamer software installed on two separate laptops. The laptops receiving data will be linked to each other via a network cable to ensure synced data collection. The use of wireless EEG caps will allow greater flexibility and comfort for participating dyads.\u003c/p\u003e \u003cp\u003eUpon arrival, the infant will be familiarized with the setting: a play mat and toys will be available to aid in acclimatization to the environment. The researchers will debrief parents with a comprehensive explanation of the study aims and procedures. Caps sizing will be selected to fit participants' head circumference. The caps fitting process will commence with the caregiver to ensure greater infant's comfort and familiarity with the equipment. Conductive gel will be applied to optimize signal conductivity and minimize artifacts.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMeasures\u003c/h2\u003e \u003cp\u003eParent-report questionnaires are summarized and described in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. As for behavioral coding purposes, the videotapes obtained from two cameras during the lab FFSF procedure will be edited offline using Movavi Video Suite 2020 software and a single synced video showing both frontal views of the caregiver and the infant face, hands, and torso will be produced. Videos will be micro-analytically coded for infant\u0026rsquo;s and caregivers' target interactive behaviors according to an adaptation of the Parent-Infant Coding Scheme (PICS, Version 4.0; Brambilla et al., 2023) as reported in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. PICS codes will be computed as percentage of time for each FFSF episode.\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePlan of EEG data elaboration\u003c/h2\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003ePre-processing pipeline\u003c/h2\u003e \u003cp\u003eDyadic EEG data will be pre-processed with a fully automated pipeline built using the MATLAB-based (The MathWorks Inc., 2024) interacting toolbox EEGLAB [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e] A brief description of the main pre-processing steps is available in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDetails of questionnaires included in the study.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConstruct\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eQuestionnaire\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eItem N\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eLikert scale\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eStudy wave(s)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eParental NICU-related stress\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParental Stressor Scale \u0026ndash; NICU (PSS-NICU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMiles, 1993\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5-point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThree main factor scores representing stress related to infants\u0026rsquo; appearance, environmental sights and sounds, and parental role alteration\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT1 (only VPT)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eSensory profile\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSensory Profile-2 (SP-2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDunn, 2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5-point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThe infant version (0\u0026ndash;6 months) identifies 5 sensory patterns. The toddler version (7\u0026ndash;35 months) identifies four sensory patterns.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT2, T3, T4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAnxiety symptoms\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eState-Trait Anxiety Inventory (STAI-Y)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpielberger et al., 1983\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4-point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOne trait score representing tendency to feel anxiety and one state score representing the present levels of anxiety\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT2, T4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eDepression symptoms\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBeck Depression Inventory (BDI-II)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBeck et al., 1996\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4-point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eGlobal score representing a quantitative appreciation of the severity of symptoms of depression\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT2, T4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eParenting stress\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenting Stress Index - Short Form (PSI-SF)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbidin, 1995\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5-point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThree subscale scores addressing parental distress, parent\u0026ndash;child dysfunctional interaction, stress related to difficult child behavior. A global score is also obtained.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT2, T3, T4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cem\u003eTemperament\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInfant Behavior Questionnaire-Revised (IBQ-R) very short form\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGartstein \u0026amp; Rothbart, 2003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7-point\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eThree subscale factor scores addressing negative affectivity, surgency and regulatory capacity.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eT2, T3, T4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote. VPT, very preterm; NICU, neonatal intensive care unit.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSelection of codes from the Parent-Infant Coding Scheme (PICS, Version 4.0).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLevels\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eA. Both interactive partners\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eEmotional state\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClear display of negative emotionality (e.g., eyes, mouth, general movements of the face or the body, and other vocal or non-vocal signals) including fussing and crying.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNeutral\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo clear display of negative or positive emotionality.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePositive\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eClear display of positive emotionality (e.g., eyes, mouth, general movements of the face or the body, and other vocal or non-vocal signals) including smiles and laughs.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eGaze direction\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eFace-directed\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAttention focus is on the interactive partner face\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eObject-directed\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAttention focus is on the interactive partner body (e.g., hands, torso) or other objects.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eAvoiding\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eThe subject is actively avoiding eye-contact as displayed by head and body movements/posture.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cem\u003eApproach/withdrawal\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eWithdrawal\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEvident leaning backwards and/or turning the head away in order to avoid interaction\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNeutral\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo evident backward or forward movements.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eApproach\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEvident leaning forward and/or reaching forward to engage in interactive behaviors.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"3\" nameend=\"c3\" namest=\"c1\"\u003e \u003cp\u003eB. Parental specific codes\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cem\u003eVocal inputs\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNo voice\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo vocal productions.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVocal comments that convey explicit critique or rejection of infants' behaviors or state.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePragmatic\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVocal comments finalized at modifying or instructing the interactive partner cognitive state, such as requests, attention getting, explanations.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSocial\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVocal comments that convey playful and social engagement such as singing, laughing, playing nursery rhymes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNurturing\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVocal comments that express appreciation or acceptance of infants' behaviors or state or are finalized to sooth infants' stress. These also include mind-related comments (e.g., \"you think\", \"you want\") and mirroring of infants' communicative bids.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003e\u003cem\u003eTactile inputs\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNo touch\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNo tactile stimulations.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNegative\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTactile stimulations that clearly appear intrusive and/or provoke or increase a negative emotionality state in the interactive partner.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003ePragmatic\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTactile stimulations finalized at modifying or instructing the interactive partner posture or movements in the environment, such as holding, shadowing, attention getting.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eSocial\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTactile stimulations that convey playful and social engagement such as tickling, squeezing, and any other appropriate entertaining tactile stimulations that is fast-paced, dynamic, repetitive, and/or characterized by quick cinematic features.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eNurturing\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTactile stimulations that are finalized to sooth or regulate the behavioral state of the interactive partners. These include stroking, kissing, massaging and any other appropriate tactile stimulations with clear regulatory functions and conveying a sense of affective closeness.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eNote. The complete coding manual is available upon request to the corresponding author.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003ePlease, insert\u003c/em\u003e Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e \u003cem\u003ehere\u003c/em\u003e\u003c/p\u003e \u003cp\u003eThe parent and infant signals will be pre-processed separately with the same steps and parameters for both. First, data filtering will be performed with the application of a bandpass 1\u0026ndash;30 Hz filter, as the planned analyses (see below) will be conducted on the lower (theta and alpha) frequency bands. Subsequently, flat and outlier channels will be detected using the NEAR (Neonatal EEG Artifact Removal) plugin [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e] and retained (i.e., put in a separate temporary matrix) for later interpolation. Dyads in which at least one of the members displays a signal with more than 15% (N\u0026thinsp;\u0026gt;\u0026thinsp;5) of flagged channels will be excluded from further analyses. The EEG signal from all non-flagged channels will undergo noise correction through the Artifact Subspace Reconstruction (ASR; [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]), with burst criterion (k) set at 10; subsequently, analysis of the components of the signal will be performed through the Independent Component Analysis (ICA; runica function with default settings), producing as many components as the number of good channels. The resulting components will be then classified through the ICLabel [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e] plugin. Every component flagged as having 50% or more of probability of being an ocular artifact will be rejected. At this stage, the matrix containing the flat and outlier channels will be re-merged with the EEG matrix and the bad channels will be interpolated through spherical interpolation using the pre-processed signal. The signal will be then re-referenced to the average signal of the channels and split into three different sets containing each phase of the experimental procedure (Play, Still-Face, Reunion): each of these sets will be subsequently segmented into 1000 ms epochs avoiding overlaps. Bad data segments containing residual artifacts in each of the three phases will be identified. All segments in which at least one of the target channels used for estimates of dyadic co-regulation (see below) displays a voltage exceeding\u0026thinsp;\u0026plusmn;\u0026thinsp;150 \u0026micro;V [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e] will be marked as rejected. The rejected epochs in the infant\u0026rsquo;s and parent\u0026rsquo;s signals will be merged to obtain the final pool of rejected epochs for the dyad. This ensures that all the rejected epochs for one interactive member of the dyad will be similarly mirrored for the other partner. Dyadic data will undergo further analyses if their signal contains at least 30 good epochs in both Play and Reunion phases; if this criterion will not be met, their signal will undergo manual epoch rejection performed by an expert EEG coder. In case after the manual epoch rejection, the dyad will result having less than 30 good merged epochs in at least one of the FFSF episodes, the signal will be excluded from further analyses.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eEstimating indexes of inter-brain co-regulation\u003c/h2\u003e \u003cp\u003eSeveral inter-brain synchronization indices have been proposed so far to estimate the coupling between two brains [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Since there is still debate on the appropriateness of each inter-brain synchronization measure, we plan to compute and compare several indices (see Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). To further check for spurious findings and get stronger evidence that the obtained co-regulation estimations are not artifact production, we will compare the synchronization indexes obtained from the real dyads to surrogate data generated by randomly pairing mothers and infants from different dyads.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eIndexes of inter-brain co-regulation adopted in the 2-BRAINED study.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIndex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNotes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eReference\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhase-Locking Value (PLV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFrequency-specific transients of phase locking independent of amplitude. The value ranges from 0 to 1: values closer to 0 indicate random signals with unsynchronized phases; values closer to 1 indicate stronger coupling between the two signals.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWhile previous studies focused mainly on infant frequency bands, cross-frequency PLV indexes will be obtained for the purposes of the 2-BRAINED study.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eLachaux et al., 1999: Canolty \u0026amp; Knight (2010)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImaginary Coherence (ICoh)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eComputed through spectral density (power) of each participant and cross-spectral density between them to estimate the average phase difference and consistency of phase difference synchronization.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eICoh is expressed as a complex number: the real part represents how much the coherence is driven by instantaneous interactions; the imaginary part shows how much the coherence is based on lagged interactions.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDikker et al., 2021; Turk et al., 2022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmplitude-Amplitude Coupling (AAC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExpressed as Person's correlation coefficient between normalized power time courses of the two signals.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAmplitude coupling was suggested as a valid alternative to phase coupling for three main reasons: amplitude changes are more easily estimated; amplitude modulations are more extensively characterized across EEG studies; amplitude modulations are more sensitive to neural coupling phenomena non detectable with other phase-related measures\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHaresign et al., 2022; Koul et al., 2023\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe computation of synchronization measures will preferentially occur considering homologous channels for the sake of interpretability and computational costs. However, as an exploratory analysis, we will also compute synchronization between non homologous channels because we can hypothesize that synchronization tasks between mother and infant can involve different brain areas in the two actors [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cem\u003ePlease, insert\u003c/em\u003e Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e \u003cem\u003ehere\u003c/em\u003e\u003c/p\u003e \u003cp\u003eRegarding the frequency bands on which the synchronization measures will be computed, we will mainly consider alpha and theta. Indeed, these frequencies have been found to be involved in parent\u0026ndash;infant social task, with theta fluctuations linked to changes in shared attention during joint play of parent and infant [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], enhancement of alpha and theta power linked to changes in directed gaze [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], and fluctuations in alpha band linked to changes in emotional states of mother and child [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMoreover, since we are interested in the dynamic evolution of brain-to-brain synchronization, we plan to evaluate the trend of each synchronization index over time (i.e., over the epochs). In particular we are interested in the change between an asynchronous to a synchronous state, which is defined as reparation. Reparation is a dyadic process in which unmatched dyadic states are transformed into matched dyadic states. We will compute the rate and the latency of reparation considering the EEG synchronization indices as previously performed in synchronized behaviors assessment [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eStatistical power and sample size estimates\u003c/h2\u003e \u003cp\u003eThe sample size has been estimated according to over-arching Aim 2, setting parameters as follows: medium effect size, \u003cem\u003ef\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.25, \u003cem\u003ealpha\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.05, \u003cem\u003ebeta\u003c/em\u003e\u0026thinsp;=\u0026thinsp;.20, number of groups\u0026thinsp;=\u0026thinsp;3 (VPT-VF, VPT-CU, FT). The procedure yielded a total sample size of 159 subjects (53 subjects per RCT arm). Nonetheless, considering the longitudinal nature of the study and the attrition rate related to EEG tasks with infants, an oversampling of n\u0026thinsp;=\u0026thinsp;80 (\u0026thinsp;~\u0026thinsp;+\u0026thinsp;50%) subjects per RCT arm was planned to secure the minimum sample size for appropriately powered statistical analyses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003ePlan of statistical analyses\u003c/h2\u003e \u003cdiv id=\"Sec18\" class=\"Section3\"\u003e \u003ch2\u003ePreliminary analyses\u003c/h2\u003e \u003cp\u003e \u003cem\u003eSpecific aim 1.\u003c/em\u003e General linear models (GLMs) will be carried out to compare VPT and FT dyadic brain-to-brain co-regulation indexes during the experimental procedure phases. Theoretically relevant (e.g., gestational age) and statistically identified (e.g., any variable significantly linked with the outcome variables) confounding variables will be controlled for in the analytical model.\u003c/p\u003e \u003cp\u003e \u003cem\u003eSpecific aim 2\u003c/em\u003e. Separate analyses of variance (ANOVA) will be used with dyadic brain-to-brain co-regulation indexes as dependent variable and groups (FT, VPT-VF, VPT-CU) as an independent variable. Theoretically relevant (e.g., gestational age) and statistically identified (e.g., any variable significantly linked with the outcome variables) confounding variables will be controlled for in the analytical model.\u003c/p\u003e \u003cp\u003e \u003cem\u003eAdditional aims.\u003c/em\u003e Models to track early developmental trajectories will be estimated in Mplus by latent class growth analysis with inter-individual variations in time of assessment and mixed-effect linear models with repeated measures to assess group differences in rates of temperament, emotional, and sensory profiles.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe present protocol describes an RCT study that aims at assessing the benefits of an early post-discharge video-feedback intervention to enhance and promote both parental and VPT infants\u0026rsquo; outcomes. By collecting dual-source EEG data in a hyper-scanning paradigm and from face-to-face real-time interactions between parents and infants, the study also aims at providing estimations of the effects of such intervention not only for the individual adjustment of caregivers and infants, but also for the emergence of dyadic co-regulatory biobehavioral processes. Such co-regulation profiles are meant to be critical indicators of a nurturing caregiving environment during the first months of life fostering affective well-being and stress resilience [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]\u003c/p\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSources of bias and mitigation strategies\u003c/h2\u003e \u003cp\u003eThe heterogeneity of VPT infants\u0026rsquo; conditions should not be underestimated. Even in the absence of severe comorbidities and brain injuries, the experience of NICU hospitalization might be very different for each infant and their parents. To avoid extreme variations, gestational age range will be constrained between 28 and 35 weeks. Moreover, stress related to the NICU environment will be evaluated and quantified with a well-validated questionnaire [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. Selection issues might affect random allocation plans in RCT arms. The allocation to VPT-VF and VPT-CU arms will occur by using an automatically generated list of binary codes that will be consecutively matched with the enrolled families across consecutive sampling. This will reduce the risk of self-selection. To further avoid confounding by infant sex and to assure sex distribution balancing, the random allocation will be stratified by infant sex by post-hoc controls every 20 enrollments. Parental gender will also be unconstrained, inviting the primary caregiver \u0026ndash; and not explicitly the mother \u0026ndash; to participate in the study, in the VF intervention and in the observational procedures. EEG procedural steps and artifacts might easily result in loss of subjects in a longitudinal study; a 50% oversampling was planned to achieve the minimum sample size for adequately powered statistical analyses.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eExpected results and impact\u003c/h2\u003e \u003cp\u003eThe project represents a translational application of the emerging field of hyper-scanning in developmental neuroscience [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. As neuroscience is moving toward a radical shift in considering the interpersonal exchanges as the primary unit of analysis and observation [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e], clinical applications are meant to be implemented to innovate healthcare. Previous proposals have been advanced to apply such bi-personal neuroscientific approach to the field of adult psychiatry [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e] and child development [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHere, we aim to innovate the field of family-centered care in pediatric settings by embedding a cutting-edge approach to the study of parent-infant interaction and co-regulation processes into well-validated approaches to parental support and child development promotion. As the video-feedback intervention is well-acknowledged for its beneficial implications for parental well-being, child development, and quality of the early parent-child relationship [\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e, \u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e72\u003c/span\u003e], it represents an \u0026eacute;lite clinical setting to test the advantages of new neuroscientific-inspired metrics that specifically focus on the assessment of brain-to-brain co-regulatory processes. In this context, the present study has multifaceted implications.\u003c/p\u003e \u003cp\u003eFrom a scientific perspective, this study will provide first-of-a-kind quantitative estimations of inter-brain coupling and co-regulation in a sample of VPT infants and their caregivers. While previous research has highlighted functional and structural alterations in VPT infants\u0026rsquo; brain [\u003cspan additionalcitationids=\"CR74\" citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR75\" class=\"CitationRef\"\u003e75\u003c/span\u003e], very little is known about VPT neurophysiological functioning in real-life settings. Moreover, the study will provide insights into \u0026ldquo;how much\u0026rdquo; inter-brain synchrony should be expected in typical and atypical developmental trajectories. As medium levels of attunement and matching have been suggested to be optimal in terms of behavioral co-regulation during the first months [\u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e], similar expectations appear to be plausible for what pertains inter-brain coupling.\u003c/p\u003e \u003cp\u003eFrom a clinical point of view, the 2-BRAINED project is expected to produce evidence on the efficacy of an early intervention for VPT infants and their parents that is delivered after NICU discharge. This is a critical window for continuity of care, as parents transit from potentially high-quality family-centered care during NICU stay to lack of appropriate and tailored support at home [\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e, \u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e78\u003c/span\u003e]. In this perspective, this study will explore the efficacy of an intervention aimed at granting continuity of care from the hospital to the house, extending and empowering family-centered care for VPT infants\u0026rsquo; parents.\u003c/p\u003e \u003cp\u003eFrom a translational neuroscience perspective, the study will also offer unprecedented opportunity to get first-hand dyadic neurophysiological target outcomes of well-validated early family-centered VF intervention. While the road to develop qualitative and quantitative measures of effectiveness and efficacy of such family-centered interventions is yet to be fully implemented, the integration of behavioral, self-report, and neurobiological markers is promising for future advances.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003ePatient and public involvement\u003c/h2\u003e \u003cp\u003eActive engagement of families will be pursued through public dedicated web/social communications, digital content, and newsletter describing the achieved goals and implications of the study. Parental associations and professionals orders will be engaged through online webinars to capitalize from the data obtained from the present study to further fuel a culture of family-centered care for preterm infants and their parents.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eETHICS AND DISSEMINATION\u003c/h2\u003e \u003cdiv id=\"Sec24\" class=\"Section4\"\u003e \u003ch2\u003eEthics, privacy, and data management\u003c/h2\u003e \u003cp\u003e The Ethics Committee Pavia and collaborating partners granted approval for the study on February 16, 2023 (protocol number: 0008588/23) and officially launched on April 24, 2023 (GR-2021-12375213). All procedures align with the ethical principles outlined in the Declaration of Helsinki for research involving human subjects, ensuring no harm to participants. The study intervention offers additional opportunities for families without altering standard mother\u0026ndash;infant care programs. Infants will undergo planned diagnostic and therapeutic interventions at the child neurology and psychiatric unit IRCCS Mondino Foundation, Pavia, Italy, and the Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy.\u003c/p\u003e \u003cp\u003eData management will occur in accordance with the General Data Protection Regulation (Regulation 2016/279, commonly known as GDPR), in order to guarantee the privacy and the security of the gathered data. In this sense, all the infants\u0026rsquo; parents will sign an informed consent module after that the study\u0026rsquo;s aims and modalities will be clearly explained and eventual doubts will be solved. Each subject will be assigned with a code and data will be stored in a pseudonymized form. After the period of conservation (25 years), data will be made completely anonymous. In line with the open science principle, the anonymized data collected for the study will be published on a publicly accessible \u0026ldquo;repository\u0026rdquo; (i.e., Zenodo) in order to promote the dissemination of research results with a view to furthering the research itself and the scientific community.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eDissemination\u003c/h2\u003e \u003cp\u003eThe dissemination strategy involves presenting findings at national and international scientific meetings, publishing in developmental psychology journals, and engaging in outreach activities with families and healthcare specialists. This aims to promote early family-centered intervention and share insights with the wider public.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e none declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent for publication:\u003c/strong\u003e not required.\u003c/p\u003e\n\n\u003ch2\u003eEthical Approval\u003c/strong\u003e \u003cp\u003e The study was approved by the Ethics Committee Pavia on February 16, 2023 (protocol number: 0008588/23).\u003c/p\u003e \u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study is supported by the Italian Ministry of Health through Ricerca Finalizzata grant GR-2021-12375213 (Principal Investigator: LP). Work supported by #NEXTGENERATIONEU (NGEU) and funded by the Ministry of University and Research (MUR), National Recovery and Resilience Plan (NRRP), project MNESYS (PE0000006) \u0026ndash; A Multiscale integrated approach to the study of the nervous system in health and disease (DN. 1553 11.10.2022).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLP conceived the study, obtained funding, and prepared the first draft of the manuscript; VR contributed to study conception, behavioral methodology, and manuscript drafting; LB contributed to study conception, neurophysiological methodology, and manuscript drafting; ES and MC contributed critically to manuscript preparation and behavioral methodology; EC and MPP contributed to neurophysiological methodology and manuscript drafting; ER contributed to defining neurophysiological methods and technical details; SG, contributed to the clinical intervention design and manuscript drafting; MC contributed to behavioral methodology and manuscript drafting.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eThe authors are thankful to the following project collaborators: Renato Borgatti, Giacomo Cremaschi, Silvia D\u0026rsquo;Alfonso, Sara De Monti, Stefano Ghirardello, Yaren Gunay, Giulia Libardo, Cecilia Naboni, Giacomo Novembre, Simona Orcesi, Camilla Pisoni, and Elise Torterolo.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials:\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBeam AL, Fried I, Palmer N, Agniel D, Brat G, Fox K, et al. 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J Obstet Gynecol Neonatal Nurs. 2016;45:528\u0026ndash;41. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jogn.2016.04.004\u003c/span\u003e\u003cspan address=\"10.1016/j.jogn.2016.04.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"EEG, hyperscanning, infant, parent, preterm, synchrony, video-feedback","lastPublishedDoi":"10.21203/rs.3.rs-4501473/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4501473/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eIntroduction. \u003c/strong\u003eVery preterm (VPT) birth is a major risk condition for child development and parental well-being, mainly due to multiple sources of stress (e.g., separation and pain exposure) during the Neonatal Intensive Care Unit (NICU) stay. Early video-feedback (VF) interventions proved effective in promoting VOT infants’ development and parental well-being. Electroencephalography (EEG) hyperscanning allows the assessment of brain-to-brain co-regulation during live interaction between infants and parents and holds promises to highlight mechanisms behind the interactive benefits of early VF interventions. \u003cstrong\u003eGoals. \u003c/strong\u003eTo compare indexes of brain-to-brain co-regulation between dyads of full-term (FT) and VPT infants interacting with their mothers. To investigate the effect of an early post-discharge VF intervention on the brain-to-brain co-regulation indexes of VPT dyads.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods and analysis.\u003c/strong\u003e VPT and FT dyads will be enrolled at birth and the former will be randomly allocated to one of two arms: VF intervention or care as usual. Short-term effectiveness will be assessed through ratings of mother-infant interaction videotaped before and after the VF intervention or care as usual. Mothers of VPT and FT infants will report on their mental state, parenting stress and bonding, and infant temperament and sensory profile at 3 and 6 months (corrected age, CA). At 9 months CA, all dyads will participate in a lab-based EEG-hyperscanning paradigm to assess brain-to-brain co-regulation through phase-locking value (PLV) and other explorative indexes. \u003cstrong\u003eEthics and dissemination.\u003c/strong\u003e This study is funded by the Italian Ministry of Health and received approval by the Ethics Committee of Pavia (Italy) and participating hospitals. Research findings will be reported in scientific publications, presented at international conferences, and disseminated to the general public.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy registration number.\u003c/strong\u003e GR-2021-12375213 (Italian Ministry of Health registry)\u003c/p\u003e","manuscriptTitle":"2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED): A translational hyperscanning research project","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-14 18:43:32","doi":"10.21203/rs.3.rs-4501473/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"794c7dd3-b716-4890-8465-5ab5bd658ec5","owner":[],"postedDate":"June 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-26T08:22:01+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-14 18:43:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4501473","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4501473","identity":"rs-4501473","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}