MRI features correlate with clinical outcome in preterm infants

TEA, with the objective of identifying cerebral lesions and predict long-term developmental outcomes.

38 In general, total and regional volumetric reductions in premature infants at TEA, mainly in central and parieto-occipital regions, cerebellum and CSF, have been related to poorer neurodevelopmental impairments in early childhood (Inder et al., 2005; Lind et al., 2011; Thompson et al., 2008). Preterm infants’ brain tissue volumes at TEA were shown to contribute to the prediction of motor outcomes at 18–24 months and, together with volume growth rates, to the prediction of cognitive scores at 5 years of age (Gui et al., 2019). Significant associations were detected at TEA between WM volume reductions in the right sensorimotor and mid-temporal regions and measures of cognitive and motor development assessed between 18 and 20 months of corrected age (Peterson et al., 2003). Additionally, reduced volumes in premotor, sensorimotor and parieto-occipital regions, as well as increased CSF, were shown to correlate with performance in an object working memory task (Woodward et al., 2005). Thus, alterations in brain tissue volumes due to preterm birth appear to be associated with later neurodevelopmental impairments.

Besides brain tissue volumes alterations, moderate to severe WM abnormalities on MRI at TEA were shown to predict cerebral palsy and motor function in very preterm neonates (van't Hooft et al., 2015).

Diffusion-based WM microstructural measures have also been used to link WM maturation features to brain function, offering a potential as biomarkers for early prognosis of subsequent neurodevelopmental outcome (Arzoumanian et al., 2003; Limperopoulos, 2010; Rose et al., 2007; Rose et al., 2009).

In normal pediatric population, WM maturation evaluated by DTI has been correlated with the development of cognitive functions. For example, in 12-month-old infants and in children between 8 and 18 years, working memory was correlated with DTI parameters in left frontal lobe regions and WM tracts connecting brain regions involved in working memory (such as the genu of CC, anterior and superior thalamic radiations, anterior cingulate gyrus and arcuate fasciculus), whereas reading ability was correlated with FA in the left temporal lobe and tempo-parietal WM (Beaulieu et al., 2005; Deutsch et al., 2005; Klingberg et al., 2000; Nagy et al., 2004; Short et al., 2013). Positive correlations have also been reported in normal pediatric population between IQ (intelligence quotient) and FA in several structures, such as the left arcuate fasciculus, genu of CC and right parietal and frontal regions, suggesting that increases in fiber organization are related to increased cognitive capacity (Schmithorst et al., 2005).

In prematurely born infants, DTI measures indicative of WM microstructural alterations have been generally associated with cognitive, motor and

socio-39 behavioral impairments. A positive association has been reported between FA and NDI in several WM tracts, with intelligence, socio-behavioral, gross-motor, fine-motor and visuofine-motor skills, whereas a negative association was found between ODI, MD, AD and RD and these abilities (Fischi-Gomez et al., 2015; Kelly et al., 2016;

van Kooij et al., 2012; Young et al., 2019).

Regarding cognitive function, DTI parameters within the CC and fronto-striatal WM fibers have shown associations with later cognitive capacity in preterm infants (Counsell et al., 2008; Duerden et al., 2013; Rose et al., 2009). FA values within the CC, in particular, have been shown to be linearly correlated with developmental quotient at 2-years corrected age (Counsell et al., 2008), while whereas diffusivity in superior temporal gyrus was correlated with language scores at 2-years corrected age (Aeby et al., 2013). In addition, mean FA of the whole-brain WM was correlated with mathematical ability and working memory at 5 years (Ullman et al., 2015) and with full IQ scores in preterm children aged between 8 and 11 years (Yung et al., 2007). In preterm born adolescents, a low IQ was associated with low FA in the external capsule, ILF and SLF, whereas performance IQ was positively correlated with FA in the right PLIC and right SLF (Skranes et al., 2007).

Regarding motor function, DTI parameters within CST/PLIC have shown associations with later motor impairment (Drobyshevsky et al., 2007; Rose et al., 2007; Rose et al., 2009). In particular, in preterm infants with cerebral palsy, DTI has shown that, in addition to lower FA in CST/PLIC, also thalamocortical connections were disrupted, correlating with poor motor and sensory outcome measures (Arzoumanian et al., 2003; Hoon et al., 2009). Fine motor impairment was related to low FA in the internal, external capsule and SLF in preterm born adolescents (Skranes et al., 2007).

Behavioral and socio-emotional function has also been related to DTI parameters. In particular, alterations in FA-weighted structural connectivity in the cortico-basalganglia-thalamo-cortical loop and in short cortico-cortical connectivity (involving namely the superior frontal gyrus, lateral OFC and cingulate gyrus), following preterm birth, were associated with poorer social behavior, recognition of social context and simultaneous information processing at school age (Fischi-Gomez et al., 2015). Additionally, increased diffusivity in right orbitofrontal cortex has been associated with an increased rate of peer problems at 5 years old (Rogers et al., 2012). In preterm born adolescents, mild social deficits were correlated with reduced FA in the external capsule and SLF, while inattention symptoms and the diagnosis of ADHD were related to lower FA in several WM areas. In fact, impairments in more complex functioning such as attention, arithmetic and visual

40 motor integration seemed to be related to more extensive WM injury (Skranes et al., 2007).

Furthermore, an impaired visual function in premature infants at TEA has been associated with lower FA values in the optic radiations (Bassi et al., 2008).

NODDI parameters have also been applied to study preterm brain development and correlation with clinical outcomes. A higher axon dispersion was found in very preterm infants in various tracts, comprising the CC, CST, corona radiata, internal capsule, external capsule, cingulum, ILF, SLF and uncinate fasciculus. Lower axon density of these WM tracts was correlated with worse neurodevelopmental outcomes in these infants, whereas a worse behavioral/emotional outcome was associated with lower axon density and higher axon dispersion in tracts such as the CC and forceps minor (Kelly et al., 2016).

Regarding structural whole-brain network topology in preterm infants at TEA, global efficiency and clustering coefficient have been found, respectively, to be significantly correlated with later cognitive performance (Keunen et al., 2017) and internalizing and externalizing behaviours assessed in early childhood (Wee et al., 2017).

1.6. Music as an intervention to promote early brain structural