The prenatal period must be properly deemed to fully understand the development of the central nervous system (CNS) [1]. The intrauterine signals influence brain structure, cognitive and motor function, and emotional regulation in the offspring [1]. Adverse events in the early stages of development could have lasting consequences on the individual structure, physiology, and metabolism according to the phenomenon of “fetal programming” [2]. The Predictive Adaptive Response (PAR) model suggests that the developing organism makes adjustment based on predictions of the postnatal environment [3,4,5]. A maternal depression among the prenatal period, for example, leads the fetus to habituate and to “adjust” the trajectory of her/his development during the first year of life [6,7]. The fetal environment is modulated by the placenta, which integrates and transduces information from the maternal environment to the fetal developmental program rapidly adapting to changes through epigenetic mechanisms [8] that respond to internal (hereditary) and external (environmental and social) signals. As a result, fetal behaviors can epigenetically maximize intrauterine environmental adaptation, shape the sensory, skeletal, and nervous systems, and provide the basis for effective transition to the postnatal environment [9,10,11]. The placenta synthesize serotonin in automatic way [12]. It holds many components of the serotonergic system such as the serotonin reuptake receptor (SERotonin Transporter, SERT), enzymes that metabolize the neurotransmitter (Monoamino Oxidase A, MAOA), and the 5-HT1A and 5-HT2A receptors [13]. The serotonergic system is involved in two key stress response systems: the HPA (Hypothalamic-Pituitary-Adrenal axis) and the LC-NA (Locus Coeruleus–Norepinephrine) [14,15]. The process of maternal and fetal programming involves multiple features (e.g., biological, environmental, psychosocial, and genetic) [1] with long-term consequences. Pathways between placenta programming and neurodevelopmental outcomes are depicted in Figure 1.

In the prenatal programming the placenta plays a key role orchestrating several maternal-fetal interactions rapidly adapting to the environment through epigenetic variations [16] such as histone modifications, DNA methylation, and microRNA (miRNA) actions that essentially modify the structure of genetic material without altering the nucleotide’s sequence [16,17]. Changes in placental DNA methylation have been recently explored with respect to sex differences [1,4].

Brain development varies basing on the environment hearing stimuli [6]. Functional development of the auditory system proceeds gradually during the third trimester of gestation. Between the 25th and 28th week of gestational age (GA) appear the first reactions to sounds, such as behavioral (muscle contractions), neurovegetative (heart rate accelerations) and electrophysiological responses [1,10] until the maturation of cochlear biomechanics, at about 32nd weeks GA, which allows the fine coding of sound. At 33rd week, GA, fetus can attentively process higher order auditory stimuli, such as music [18]. Prenatal auditory experiences, particularly those of the maternal voice and singing are endowed with critical adaptive value [19,20]. The auditory cortex is a highly plastic epigenetic area crucial for prenatal learning, located in the posterior-medial part of Heschl’s gyrus, a region corresponding with the Brodmann’s area 41 [21] and acoustic environments are essential for shaping the functional organization and processing capabilities of the auditory cortex. Indeed, functional maturation of the auditory system cannot be achieved in presence of a congenital sound deprivation [21,22] whereas exposure of rat pups to an enriched auditory environment enhanced discrimination skills and auditory learning [23]. Some newborns might develop early in response to events such as prematurity, which occurs in a period when the brain has the capacity to re-organize. Compared to full-term, preterm neonates evidenced a decreased connectivity between thalamus and prefrontal, insular, and anterior cingulate cortex, but an augmented functional connectivity between thalamus and lateral primary sensory cortex, suggesting the effect of early experiences of premature extra-uterine life [24]. In the womb the fetus listens to internal sounds coming from the mother’s body (particularly heartbeats and breathing) described as rhythmic, periodic, organized, and predictable, whereas the primary auditory environment in the Neonatal Intensive Care Units (NICUs) is aperiodic (white noise), unorganized, and unpredictable (alarms). Only 2% to 5% of the sounds reaching the ears of the preterm newborn are vocal [25]. Considering the comforting effect of the rhythmic vestibular stimulation, scientists have developed rocking systems in neonatal care units [26]. The acoustic environment of the NICU contains High Frequency (HF > 500 Hz) noise from medical equipment and activities [27]. Increased exposure to HF noise in the NICU as most cochlear neurons are still migrating [28] and cortical folding is still in flux, can disrupt usual tonotopic tuning of cochlear hair cells and hinder subcortical and cortical auditory development [29]. A lack of perception of maternal speech sounds in the NICU can alter brain structure. It is estimated that half of all neonates born very prematurely (i.e., before 32 full weeks GA), in the infancy will show neurodevelopmental impairments [30,31,32] or disorders, such as Attention Deficit/Hyperactivity Disorder (ADHD), Autism Spectrum Disorders (ASD), anxiety, and depression [33,34,35].

Listening to music triggers several emotional and cognitive responses among distinct and interconnected neural substrates [36] not attributable at the simple sound processing [37,38,39,40,41]. Thus, music can be a valuable tool for multisensory stimulation [42,43]. The effects of music interventions have been explored in relation to cardiorespiratory parameters, growth and feeding, or on behavioral status and pain. Sound stimulation may also alter neural connectivity in the early postnatal life to improve cognitive function or repair secondary damage in various neurological and psychiatric disorders [44]. Music would similarly be able to affect the social-emotional development because it induces activity in the limbic and paralimbic structures involved in the emotion regulation [39]. Therefore, emotions evoked by music implies the core of evolutionarily adaptive neuroaffective mechanisms [38]. Music and singing also promote to the production of endorphins for both the mother and the fetus contributing to lower anxieties and regularize blood pressure and heart rate [45]. Full-term newborns in the first few days of life exhibit emotional neural responses to musical stimuli [46,47]. Therefore, the auditory histories, in the form of excessive noise, acoustic deprivation or sound training can affect auditory processes throughout the lifespan [48].

Prenatal life affects the development of the fetal nervous system with long-term neurobehavioral consequences. Fetal vulnerabilities caused by the maternal environment depend on several factors. First, the time and period of exposure to environmental risks will have different effects on the fetus depending on her/his developmental stage. Second, female become progressively less sensitive to perturbations in their environments as gestation progresses. Indeed, male fetuses, in contrast with females, experience delays in brain maturation when exposed to prenatal adversity. In addition, depending on the gender of the fetus, there will be differences in placental structure and function, including gene methylation and glucocorticoid receptor expression and function that may result in variations in response to environmental adversity. The schedule of maternal and fetal vulnerabilities also explains how the same signal can have opposite effects depending on the timing of exposure.

The sound environment plays a key role in the growth of the CNS because all stimuli present in the environment in which the fetus grows contribute to the development of the acoustic sensory pathways, also promoting the process of structural and functional maturation of the CNS. Prenatal brain development is largely dependent on the environment. The occurrence of meaningful sounds is essential for a correct maturation of the auditory system. Music can be a valuable aid in promoting positive auditory stimulation. In clinical practice, prenatal exposure to music could be employed to reduce in-hospital drug therapy considering its simplicity, non-invasiveness, cheapness, and lack of harmful effects on both the mother and the fetus [53]. The intravaginal application of the stimulus can facilitate, and shorten ultrasound examinations, since it induces early excitatory responses in the fetus, as early as the 16th week GA [62] but its scientific soundness is questionable.

A review of music therapy in the NICU discovered unimagined perceptual, adaptive, and active engagement abilities of preterm babies during music intervention [89]. The scholars summarized several music or auditory stimulation interventions that incorporated musical elements-such as sounds and rhythm-established on the acoustic intrauterine environment, such as recorded womb sounds, the maternal voice, breathing sounds, and heartbeats. The paper indicated that music has encouraging effects on the preterm newborns, calming, and relaxing them and reducing their stress level. A second systematic review of music-based intervention published from 2010 to 2015 indicated poor quality of music intervention investigations [90]. Finally, a meta-analysis of randomized controlled trials showed that prenatal music therapy did not change fetal heart rate, number of fetal movements, or number of accelerations in different intervention phases, probably due to the heterogeneity of music therapy strategies applied during pregnancy [19]. In the NICU, high levels of stress and instability due to deprivation of contact with the mother and the presence of unnatural stimuli, such as loud mechanical noises, unsettle normal brain development [57]. Thereby, premature newborns are at high risk of developing neurological, cognitive, and behavioral harms due to functional impairment of the prefrontal cortex, hippocampus, amygdala (of the limbic system), and the fiber tracts that connect them to these centers [42]. These consequences on the preterm organism might be reduced by controlling the levels of the sound environment and providing structured auditory stimulation [54,56,57,58,60]. Several studies included have considered the effects of listening to music on premature newborns’ physiological data [54,55,56,57,60,68,69]. Early enrichment of NICUs environment by music have utilized distinct types of music and several protocols concerning the amount of music exposure, type of music intervention, delivery method, GA of the participants, leading to results showing a stabilizing effect of music on heart and respiratory rhythms, a decrease in apnea and bradycardia counts per day, an improvement in weight gain, and more mature sleep patterns [45,56,57,58,69]. These findings indicate an influence of NICUs sound enrichment on preterm brain maturation. Preterm babies with music intervention showed brain functional connectivity comparable to those of full-term newborns in the same regions [54,57,60,68]. Lastly, emotional regulation was assessed at 12 and 24 months [55]. Preterm infants in the music condition revealed more comparable fear reactivity at 12 months of age and anger reactivity at 24 months of age to full-term babies than preterm control babies. Therefore, early music intervention in NICU appears to have long-lasting influences on emotion regulation and neurodevelopment among preterm newborns. Nevertheless, the effect the music interventions in the NICU, including the type of music and amount of exposure, bone conduction of acoustic vibrations and music processing ability on future brain development and subsequent cognitive-behavioral outcomes deserves additional investigation.

Neonatal care is progressing towards integrating the approach of precision medicine, which intends identifying early precursors of developmental troubles as well as early windows of opportunities for prematurely born newborns. The main atypical neurodevelopmental trajectories of prematurity, such as cognitive and socio-emotional difficulties, are the target for a precision medicine approach in newborn care. One of the keys of prevention in perinatal medicine is the timing of the intervention: neuronal plasticity is maximal during the third trimester of life so any intervention in this period will be more effective than later ones. These motives recently led researchers to highlight the potential effects of auditory stimulation in the NICU as resilience-inducing actions, which share the important auditory sensory medium as a basis and that the trained medical staff and nurses can implement in their routine. 

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