Each year 15 million infants are born preterm (PT). Even without severe comorbidities, they are exposed to sensory stress during the Neonatal Intensive Care Unit (NICU) stay and are at greater risk of neurodevelopmental problems compared to full-term (FT) counterparts in the short- and long-term period. Altered biobehavioral interpersonal synchrony patterns are documented in PT parent-infant dyads and might contribute to detrimental outcomes. Electroencephalographic (EEG) hyperscanning provides innovative real-time central biomarkers of brain-to-brain co-regulation; it was never applied to PT mother-infant dyads. Early parenting video-feedback (VF) interventions promote at-risk infants' neurodevelopment, yet action mechanisms are partially unknown. The present longitudinal project aims (a) to compare indexes of brain-to-brain co-regulation between dyads of full-term (FT) and VPT infants interacting with their mothers and (b) to investigate the effect of an early post-discharge VF intervention on the brain-to-brain co-regulation indexes of VPT dyads. This study will establish translational hyperscanning as a new field of innovative research with crucial clinical implications.

Very preterm (VPT) birth is a major risk condition for child neurological and behavioral development and as well as for parental well-being, mainly due to multiple sources of stress (e.g., separation and pain exposure) during the hospitalization. Even in absence of severe critical medical comorbidities, VPT infants and their parents are exposed to multiple stress sources during the stay in the hospitalization in the Neonatal Intensive Care Unit (NICU), including early parent-infant separation and pain. Early parenting video-feedback (VF) interventions focused on promoting parent-infant closeness through the video-feedback (VF) approach methodology have proven effective in promoting child development and parental well-being. Electroencephalography (EEG) hyperscanning paradigms allow the assessment of brain-to-brain co-regulation during live interaction between infants and parents and hold promises to highlight mechanisms behind the interactive benefits of early VF parenting interventions. The 2-Brain Regulation to Achieve Improved Neuroprotection during Early Development (2-BRAINED) research project aims (a) to compare indexes of brain-to-brain co-regulation between dyads of full-term (FT) and VPT infants interacting with their mothers and (b) to investigate the effect of an early post-discharge VF intervention on the brain-to-brain co-regulation indexes of VPT dyads.

The 2-BRAINED project is a randomized-controlled trial (RCT) with three arms (see arm description). VPT (gestational age below 35 weeks) and FT (gestational age above 37 weeks) dyads will be enrolled at birth and the former will be randomly allocated to one of two arms: VF intervention or care as usual. The VF intervention will be delivered during the first three months after NICU discharge, consisting of and consists of 8 weekly remote VF sessions focused on sensory, behavioral, cognitive, and affective dimensions of parenting. Before and after the intervention, videotaped mother-infant interaction will provide pre-post behavioral data to assess the short-term effectiveness of the VF intervention. Videos will be micro-analytically coded for infant's and caregivers' target behaviors.

Mothers of VPT and FT infants will fill in questionnaires focused on maternal well-being (symptoms of depression [Beck Depression Inventory, BDI; Beck et al.,1961] and anxiety [State-Trait Anxiety Inventory, STAI-Y, Spielberg, 1983]), parenting (parental stress and mother-infant bonding [Parenting Stress Index, PSI; Abidin, 1983]), and infant development (language [Italian adaptation of the MacArthur-Bates Communicative Development Inventory; Caselli & Casadio, 1995]; temperament [Infant Behavior Questionnaire Revised, IBQ-R, Gartstein et al., 2003] and sensory profile [Sensory Profile 2, SP-2, Dunn, 2014]) at 3, 6 and 9 months (corrected age, CA).

At 9 months CA, all dyads will take part in a lab-based 5-min EEG- hyperscanning Still-Face task (Tronick et al., 1978; Provenzi et al., 2016) in the laboratory to assess brain-to-brain co-regulation, during which EEG activity from both the interactive partners will be recorded using two 32-electrode caps linked with two PC-connected wireless amplifiers (Smarting mBrainTrain) that will assure complete freedom of movements. Several indexes used to measure of brain-to-brain co-regulation will be tested and compared, including Phase-Locking Value (PLV), Amplitude-Amplitude Coupling (AAC) and imaginary coherence (ICoh). These indexes will be used to compare brain-to-brain co-regulation indexes (a) between PT and FT infants to test difference in interpersonal neurophysiological attunement in typical and at-risk infants as well as (b) between PTCU and PTVF. Moreover, best-fitting synchrony indexes will be used in a path analysis model testing the mediating role of brain-to-brain co-regulation indexes on the effects of VF early parental intervention on the short- and long-term outcomes. A prediction model will be implemented to predict outcomes on the basis of both clinical and EEG measures.

Inclusion Criteria:

• infants' (corrected) age between birth and 3 months;
• parental age greater than 18 years;
• parental mastery of Italian language;
• parents living together with the infant;

Exclusion Criteria:

• infant's major comorbidities (e.g., genetic syndromes, malformations, brain injuries);
• parental psychiatric diagnoses;

Raw data will be made available upon request through Zenodo repository

After study completion

Researchers will be able to access the raw data and the supporting information through the Zenodo repository upon request and after sharing an analysis plan