Multimodal assessment shows misalignment of structural and functional thalamocortical connectivity in children and adolescents born very preterm.

Thalamocortical connections are altered following very preterm birth but it is unknown whether structural and functional alterations are linked and how they contribute to neurodevelopmental deficits. We used a multimodal approach in 27 very preterm and 35 term-born children and adolescents aged 10-16 years: Structural thalamocortical connectivity was quantified with two measures derived from probabilistic tractography of diffusion tensor data, namely the volume of thalamic segments with cortical connections and mean fractional anisotropy (FA) within the respective segments. High-density sleep EEG was recorded and sleep spindles were identified at each electrode. Sleep spindle density and integrated spindle activity (ISA) were calculated to quantify functional thalamocortical connectivity. In term-born participants, the volume of the global thalamic segment with cortical connections was strongly related to sleep spindles across the entire head (mean r â€‹= â€‹.53 â€‹± .10; range â€‹= â€‹0.35 to 0.78). Regionally, the volume of the thalamic segment connecting to frontal brain regions correlated with sleep spindle density in two clusters of electrodes over fronto-temporal brain regions (.42 â€‹± .06; 0.35 to 0.51 and 0.43 â€‹± .08; 0.35 to 0.62) and the volume of the thalamic segment connecting to parietal brain regions correlated with sleep spindle density over parietal brain regions (mean r â€‹= â€‹.43 â€‹± .07; 0.35 to 0.61). In very preterm participants, the volume of the thalamic segments was not associated with sleep spindles. In the very preterm group, mean FA within the global thalamic segment was negatively correlated with ISA over a cluster of frontal and temporo-occipital brain regions (mean r â€‹= â€‹-.53 â€‹± .07; -.41 to -.72). No association between mean FA and ISA was found in the term-born group. With this multimodal study protocol, we identified a potential misalignment between structural and functional thalamocortical connectivity in children and adolescents born very preterm. Eventually, this may shed further light on the neuronal mechanisms underlying neurodevelopmental sequelae of preterm birth.

Creative music therapy to promote brain function and brain structure in preterm infants: A randomized controlled pilot study.

Cognitive and neurobehavioral problems are among the most severe adverse outcomes in very preterm infants. Such neurodevelopmental impairments may be mitigated through nonpharmacological interventions such as creative music therapy (CMT), an interactive, resource- and needs-oriented approach that provides individual social contact and musical stimulation. The aim was to test the feasibility of a study investigating the role of CMT and to measure the short- and medium-term effects of CMT on structural and functional brain connectivity with MRI. In this randomized, controlled clinical pilot feasibility trial, 82 infants were randomized to either CMT or standard care. A specially trained music therapist provided CMT via infant-directed humming and singing in lullaby style. To test the short-term effects of CMT on brain structure and function, diffusion tensor imaging data and resting-state functional imaging data were acquired. Clinical feasibility was achieved despite moderate parental refusal mainly in the control group after randomization. 40 infants remained as final cohort for the MRI analysis. Structural brain connectivity appears to be moderately affected by CMT, structural connectomic analysis revealed increased integration in the posterior cingulate cortex only. Lagged resting-state MRI analysis showed lower thalamocortical processing delay, stronger functional networks, and higher functional integration in predominantly left prefrontal, supplementary motor, and inferior temporal brain regions in infants treated with CMT. This trial provides unique evidence that CMT has beneficial effects on functional brain activity and connectivity in networks underlying higher-order cognitive, socio-emotional, and motor functions in preterm infants. Our results indicate the potential of CMT to improve long-term neurodevelopmental outcomes in children born very preterm.

NICU Diet, Physical Growth and Nutrient Accretion, and Preterm Infant Brain Development.

Half of very preterm infants experience neurodevelopmental impairments after NICU discharge. These adverse outcomes result in part from abnormal brain development and injury that occur during the NICU hospitalization. Although many factors influence infant brain development, nutritional determinants are of particular interest because they are highly modifiable within clinical care. Physical growth of preterm infants in the NICU continues to lag behind the reference fetus, suggesting reduced nutrient accretion during a critical period for brain development. Nutrient accretion is driven by intake of specific nutrients such as macro- and micronutrients as well as non-nutritional factors such as systemic inflammation. Most often, anthropometric indicators, such as weight, length, and head circumference, are used as proxies for nutrient accretion. A limitation of weight is that it does not differentiate the healthy growth of specific organs and tissues from excess fat accumulation. Body length provides information about skeletal growth, and linear growth stunting predicts neurodevelopmental impairment. Head circumference is only a crude proxy for brain size. More recently, application of new technologies such as air displacement plethysmography and magnetic resonance imaging has allowed the direct estimation of lean tissue accretion and brain growth in the NICU. These newer techniques can facilitate research to improve our understanding of the links among the NICU diet, inflammation, physical growth, and brain development. These new measures may also be relevant within clinical care to identify infants who may benefit from specific interventions to enhance nutrient accretion and brain development.

Altered functional network connectivity relates to motor development in children born very preterm.

Individuals born very preterm (<32 weeks gestation) are at increased risk for neuromotor impairments. The ability to characterize the structural and functional mechanisms underlying these impairments remains limited using existing neuroimaging techniques. Resting state-functional magnetic resonance imaging (rs-fMRI) holds promise for defining the functional network architecture of the developing brain in relation to typical and aberrant neurodevelopment. In 58 very preterm and 65 term-born children studied from birth to age 12 years, we examined relations between functional connectivity measures from low-motion rs-fMRI data and motor skills assessed using the Movement Assessment Battery for Children, 2nd edition. Across all subscales, motor performance was better in term than very preterm children. Examination of relations between functional connectivity and motor measures using enrichment analysis revealed between-group differences within cerebellar, frontoparietal, and default mode networks, and between basal ganglia-motor, thalamus-motor, basal ganglia-auditory, and dorsal attention-default mode networks. Specifically, very preterm children exhibited weaker associations between motor scores and thalamus-motor and basal ganglia-motor network connectivity. These findings highlight key functional brain systems underlying motor development. They also demonstrate persisting developmental effects of preterm birth on functional connectivity and motor performance in childhood, providing evidence for an alternative network architecture supporting motor function in preterm children.

Assessing bone development in preterm infants using quantitative ultrasonography showed a decline in the early postnatal period.

AIM: Preterm infants have an insufficient bone mineral store at birth and this study explored their bone development during the early postnatal period. METHODS: The metacarpal speed of sound (mcSOS) and metacarpal bone transmission time (mcBTT) were used to assess bone development in 277 preterm infants, admitted to the neonatal intensive care unit of the VU University Medical Center, Amsterdam, the Netherlands from 2007-2012. RESULTS: During the first nine postnatal weeks, the mcSOS declined from 10 to 38 m per second per week and the mcBTT declined from 20 to 71 nanoseconds per week. The pattern of change in both of these measurements showed a significant difference between infants born before 32 weeks of gestation (p = 0.048) and those born between 28 and 32 weeks of gestation (p = 0.008). There was a borderline significant difference in the pattern of change of the mcBTT in infants with a protein intake below 2 g/kg per day versus a higher intake (p = 0.050). CONCLUSION: The mcSOS and mcBTT of preterm infants showed a small to moderate decline during the early postnatal period. Future studies should explore the clinical relevance of this decline and develop interventions to halt it.

Plasticity of neonatal neuronal networks in very premature infants: Source localization of temporal theta activity, the first endogenous neural biomarker, in temporoparietal areas.

Temporal theta slow-wave activity (TTA-SW) in premature infants is a specific signature of the early development of temporal networks, as it is observed at the turning point between non-sensory driven spontaneous local processing and cortical network functioning. The role in development and the precise location of TTA-SW remain unknown. Previous studies have demonstrated that preterms from 28 weeks of gestational age (wGA) are able to discriminate phonemes and voice, supporting the idea of a prior genetic structural or activity-dependent fingerprint that would prepare the auditory network to compute auditory information at the onset of thalamocortical connectivity. They recorded TTA-SW in 26-32 wGA preterms. The rate of TTA-SW in response to click stimuli was evaluated using low-density EEG in 30 preterms. The sources of TTA-SW were localized by high-density EEG using different tissues conductivities, head models and mathematical models. They observed that TTA-SW is not sensory driven. Regardless of age, conductivities, head models and mathematical models, sources of TTA-SW were located adjacent to auditory and temporal junction areas. These sources become situated closer to the surface during development. TTA-SW corresponds to spontaneous transient endogenous activities independent of sensory information at this period which might participate in the implementation of auditory, language, memory, attention and or social cognition convergent and does not simply represent a general interaction between the subplate and the cortical plate. Hum Brain Mapp 38:2345-2358, 2017. © 2017 Wiley Periodicals, Inc.

Functional Maps at the Onset of Auditory Inputs in Very Early Preterm Human Neonates.

During the last trimester of human gestation, neurons reach their final destination and establish long- and short-distance connections. Due to the difficulties obtaining functional data at this age, the characteristics of the functional architecture at the onset of sensory thalamocortical connectivity in humans remain largely unknown. In particular, it is unknown to what extent responses evoked by an external stimulus are general or already sensitive to certain stimuli. In the present study, we recorded high-density event-related potentials (ERPs) in 19 neonates, tested ten weeks before term (28-32 weeks gestational age (wGA), that is, at an average age of 30 wGA) by means of a syllable discrimination task (i.e., a phonetic change: ba vs. ga; and a voice change: male vs. female voice). We first observed that the syllables elicited 4 peaks with distinct topographies implying a progression of the sensory input along a processing hierarchy; second, repetition induced a decrease in the amplitude (repetition suppression) of these peaks, but their latencies and topographies remained stable; and third, a change of stimulus generated mismatch responses, which were more precisely time-locked to event onset in the case of a phonetic change than in the case of a voice change. A hierarchical and parallel functional architecture is therefore able to process environmental sounds in a timely precise fashion, well before term birth. This elaborate functional architecture at the onset of extrinsic neural activity suggests that specialized areas weakly dependent on the environment are present in the perisylvian region as part of the genetic endowment of the human species.

Immediate effects of phototherapy on sleep in very preterm neonates: an observational study.

Process C (internal clock) and Process S (sleep-wake homeostasis) are the basis of sleep-wake regulation. In the last trimester of pregnancy, foetal heart rate is synchronized with the maternal circadian rhythm. At birth, this interaction fails and an ultradian rhythm appears. Light exposure is a strong factor influencing the synchronization of sleep-wake processes. However, little is known about the effects of phototherapy on the sleep rhythm of premature babies. It was hypothesized that sleep in preterm infants would not differ during phototherapy, but that a maturation effect would be seen. Sleep states were studied in 38 infants born < 32 weeks gestational age and/or < 1 500 g birth weight. Videos of 3 h were taken over the first 5 days of life. Based on breathing and movement patterns, behavioural states were defined as: awake; active sleep; or quiet sleep. Videos with and without phototherapy were compared for amounts of quiet sleep and active states (awake + active sleep). No significant association between phototherapy and amount of quiet sleep was found (P = 0.083). Analysis of videos in infants not under phototherapy revealed an increase in time spent awake with increasing gestational age. The current data suggest that the ultradian rhythm of preterm infants seems to be independent of phototherapy, supporting the notion that sleep rhythm in this population is mainly driven by their internal clock.

The impact of premature birth on the mandibular cortical bone of children.

SUMMARY: Children born prematurely often have reduced skeletal mineralization. The aim in this study was to compare the cortical thickness of the lower jaw on radiographs of 8- to 10-year-old children with histories of preterm or full term births. There were no significant differences in cortical thickness between full term and preterm children at this age. INTRODUCTION: The purpose of this study was to compare the cortical thickness of the mandible on panoramic radiographs of 8- to 10-year-old children with histories of preterm or full term births. METHODS: Panoramic radiography was performed on 36 extremely preterm, 38 very preterm and 42 full term children at the age of 8 to 10 years. Five observers independently measured the mandibular cortical width on the panoramic radiographs at four defined sites bilaterally. Altogether, 928 sites were available. Measurements were performed twice on a random 24% of the sites by four observers. One-way analysis of variance with Tukey's post hoc test was used to test differences between groups. Intraclass correlation coefficient (ICC) was calculated for interobserver agreement while intra-observer agreement was expressed as measurement precision. RESULTS: Significant differences of mandibular cortical width were found between extremely preterm and very preterm children for five of the eight measurement sites with the very preterm showing the highest value. No significant differences were found between full term and either very preterm or extremely preterm except for one measurement site, with the extremely preterm showing the lowest value. ICC varied between 0.30 and 0.83 for the different sites (mean 0.62). The precision of a single measurement varied between 0.11 and 0.45 mm (mean 0.25 mm). CONCLUSIONS: From the evidence that very preterm children had significantly thicker mandibular cortices than extremely preterm children, we suggest that these findings may reflect the effect of mineral supplementation provided to premature infants, causing a 'shifting up' of bone mineral status relative to the full term peer group while maintaining the difference between very preterm and extremely preterm born children.

Exposure to biological maternal sounds improves cardiorespiratory regulation in extremely preterm infants.

OBJECTIVE: Preterm infants experience frequent cardiorespiratory events (CREs) including multiple episodes of apnea and bradycardia per day. This physiological instability is due to their immature autonomic nervous system and limited capacity for self-regulation. This study examined whether systematic exposure to maternal sounds can reduce the frequency of CREs in NICU infants. METHODS: Fourteen preterm infants (26-32 weeks gestation) served as their own controls as we measured the frequency of adverse CREs during exposure to either Maternal Sound Stimulation (MSS) or Routine Hospital Sounds (RHS). MSS consisted of maternal voice and heartbeat sounds recorded individually for each infant. MSS was provided four times per 24-h period via a micro audio system installed in the infant's bed. Frequency of adverse CREs was determined based on monitor data and bedside documentation. RESULTS: There was an overall decreasing trend in CREs with age. Lower frequency of CREs was observed during exposure to MSS versus RHS. This effect was significantly evident in infants ≥ 33 weeks gestation (p=0.03), suggesting an effective therapeutic window for MSS when the infant's auditory brain development is most intact. CONCLUSION: This study provides preliminary evidence for short-term improvements in the physiological stability of NICU infants using MSS. Future studies are needed to investigate the potential of this non-pharmacological approach and its clinical relevance to the treatment of apnea of prematurity.