Rational behind using Music to promote early brain development

not only for the maturation of the auditory circuits, which require a particular auditory input, but influences also the maturation of distinct brain neural networks.

This process is highly dependent on intrinsic and extrinsic multisensory activity:

during initial developmental stages, spontaneous activity from the immature

43 cochlea drives the maturation of networks in the auditory cortex, whereas further remodelling is experience-dependent (Blankenship and Feller, 2010; Kiss et al., 2014b; Sameroff, 2010; Shonkoff, 2010; Swingler et al., 2015). Indeed, from 24-26 weeks GA, with the invasion of the thalamocortical afferents into the cortical plate, the brain starts receiving thalamic input and becomes sensory-driven, mainly in sensory cortical regions as the auditory cortex, what results in an intense dendrite and axonal growth accompanied by synaptogenesis and remodeling (Mire et al., 2012; Mizuno et al., 2010). Also by the third trimester, all the major auditory structures are developed and anatomically functional (Hall, 2000; Polin et al., 2011).

The cochlea matures slowly during the third trimester, undergoing “tuning”, which is sensitive to changes in sound environment (Benfield, 2004). During this period occurs myelination of the auditory pathway, running from the cochlea, through the auditory nerve, to the cochlear nuclei in brainstem, passing then mainly via the superior olivary complex, the inferior colliculus of the midbrain and the auditory thalamus and from the thalamus, through the acoustic radiations, to the contralateral areas of the primary auditory cortex in the temporal lobe (Moore and Linthicum, 2007).

Figure 1.6.1 – Timing of main developmental stages in the human cerebral cortex and auditory circuitry. Prematurity occurs during the third trimester of pregnancy, a period of important cortical wiring, activity-dependent neuroplasticity and auditory circuitry development. The activity-dependent dendritic and axonal growth occurring during this period are mainly regulated by the early cortical synaptic activity. The auditory environment contributes thus not only for the maturation of the auditory circuits, which require a particular auditory input, but influences also the maturation of distinct brain neural networks, a process dependent on extrinsic multisensory activity. (Adapted from Kiss et al., 2014b).

Synaptogenesis+ Myelinationof auditory pathway:

cochlea - brainstem - auditory thalamus - auditory cortex 28-30

Neuronal connections to temporal lobe are functional

Tunning of hair cells of cochlea

Conception Birth

Weeks GA

months Years

44 Studies measuring fetal movement or heart rate response to sound have shown that, although not fully mature yet, the developing auditory system enables responses to sound in utero from around 25 weeks GA (Birnholz and Benacerraf, 1983) and fetal auditory-evoked responses, evaluated with magnetoencephalography (MEG), have been identified from 27 weeks GA in preterm infants (Draganova et al., 2007).

By the third trimester, preterm infants are thus capable of processing sound, which will be crucial for the normal development of the auditory system, and consequently for the maturation of distinct related brain neural networks.

The sound environment in the NICU is one of the environmental drastic changes that preterm infants have to face, exposing them to direct, erratic, unpredictable and noisy sounds, different from the rhythmical, coherent and familiar auditory stimuli inside the mother’s womb. The high noise associated with premature infant’s basic care in the NICU can damage the infant’s auditory system and impact early brain development. Indeed, studies using pulsed noise exposition in rat pups have shown a substantial impairment in the formation of cortical tonotopic maps and local cortical circuits (Zhang et al., 2002), while sound deprivation studies in rat pups have proven that is necessary to experience spectrally and temporally patterned rich sound to wire brain circuits for pitch processing (Chang and Merzenich, 2003). Deprivation of meaningful sounds or exposition to specific auditory stimuli in the NICU have also been shown to impact auditory cortex maturation (Pineda et al., 2014). On the other hand, auditory experience has been shown to shape the auditory system in the developing brain, namely through studies on reintroduction of the auditory sensation via a cochlear implant in profoundly deaf children, which enabled to restore some or all aspects of normal cortical function (Ponton and Eggermont, 2001).

Music, in contrast to the auditory stressors present in the NICU, is a rich auditory stimulus with elements such as melody, rhythm, harmony, timbre, form and style, comprising both sound and silence expressively organized in time. Through its acoustic properties, music may serve as a masking agent for much of the typical noise present in the NICU (Standley, 2003). Additionally, music listening implies a complex brain processing (Phillips-Silver and Trainor, 2005), triggering both cognitive and emotional components with distinct neural substrates (Zatorre et al., 2009). Indeed, besides brain areas analysing the basic acoustic cues of sound, music is known to activate areas involved in higher order musical features, attention, working memory, episodic memory, experiencing of emotions and sensory-motor regions (Sarkamo et al., 2013). The human neural processing of music involves thus

45 a widespread bilateral network of cortical and subcortical areas, extending well beyond the auditory cortex and including temporal, frontal, parietal, subcortical and limbic and paralimbic regions, integrating several auditory, cognitive, sensory-motor and emotional functions (Koelsch et al., 2004; Koelsch, 2010; Popescu et al., 2004). In particular, functional neuroimaging studies have proven that music listening triggers many neural substrates involved in socio-emotional functions, comprising amygdala, hippocampal formation, ventral striatum (including nucleus accumbens), cingulate cortex, insula and the OFC, which constitute brain core regions involved in emotion processing (Koelsch et al., 2004; Koelsch, 2010;

Koelsch, 2014; Popescu et al., 2004; Zatorre et al., 2009) and are also key areas of deficits in preterm infants (Fischi-Gomez et al., 2015; Lordier et al., 2019b; Spittle et al., 2009; Witt et al., 2014). In fact, literature shows that premature newborns present an atypical socio-emotional development, comprising diminished social competences and self-esteem, emotional dysregulation, shyness and timidity (Bhutta et al., 2002; Hille et al., 2001; Hughes et al., 2002; Montagna and Nosarti, 2016; Spittle et al., 2009), accompanied by structural and functional alterations in brain areas involved in processing emotion and social stimuli (Cismaru et al., 2016;

Fischi-Gomez et al., 2016; Peterson et al., 2000; Witt et al., 2014).

Figure 1.6.2 – Key brain areas associated with music processing based in neuroimaging studies of healthy subjects. Each color represents a subgroup of brain areas activated during music processing. In green are regions known to perceive the basic features of music; in blue, regions perceiving higher-order musical features; in yellow, regions implied in attention and working memory, for keeping track of music in time; in purple are areas important for episodic memory, in order to recognize music and recall associated memories; in grey, regions important for motor functions; and in red regions related to emotional processing and experience pleasure and reward. (Adapted from Sarkamo et al., 2013).

Basic acoustic features

High-order acoustic features / Language Attention

Memory Motor Socio-emotion

46 Given its rich brain processing, with the recruitment of regions implicated in functions known to be affected by prematurity, music has been implemented in the past years as a meaningful sensory stimulation approach during NICU stay, thought to be relevant for activity-dependent brain plasticity during a critical period of auditory and brain networks maturation (Graven and Browne, 2008; Kiss et al., 2014b; Lasky and Williams, 2005).

An early music therapy program intervention during preterm infants NICU stay might thus impact the auditory system maturation, as well as its associated brain networks, which are important for language processing, attention, memory, emotion, mood and motor skills.

1.6.3. Effects of Music interventions in preterm infants’ early brain