Mental development is associated with cortical connectivity of the ventral and nonspecific thalamus of preterm newborns

The thalamus is a key hub for regulating cortical connectivity. Dysmaturation of thalamocortical networks that accompany white matter injury have been hypothesized as neuroanatomical correlate of late life neurocognitive impairment following preterm birth. Our objective was to find a link between thalamocortical connectivity measures at term equivalent age and two year neurodevelopmental outcome in preterm infants. Diffusion tensor MRI of 58 infants (postmenstrual age at birth, mean (SD), 29.71 (1.47) weeks) was used to trace connections between the cortex and thalami. We found strong correlation between mental developmental index and two complementary measures of thalamocortical networks: connectivity strength projected to a cortical skeleton and pathway length emerging from thalamic voxels (partial correlation, R=0.552 and R=0.535, respectively, threshold-free cluster enhancement, corrected p-value<0.05), while psychomotor development was not associated with thalamocortical connectivity. Post hoc stepwise linear regression analysis revealed that parental socioeconomic scale, postmenstrual age and the duration of mechanical ventilation at the intensive care unit contribute to the variability of outcome. Our findings independently validated previous observations in preterm infants, providing additional evidence injury or dysmaturation of tracts emerging from ventral specific and various non-specific thalamus projecting to late-maturing cortical regions are predictive of mental, but not psychomotor developmental outcomes.

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Factors associated with neurodevelopment in preterm infants with systematic inflammation

BMC Pediatrics ◽

10.1186/s12887-021-02583-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Eun Sun Lee ◽

Ee-Kyung Kim ◽

Seung han Shin ◽

Young-Hun Choi ◽

Young Hwa Jung ◽

...

Keyword(s):

White Matter ◽

Preterm Infants ◽

Systemic Inflammation ◽

Head Circumference ◽

Brain Mri ◽

White Matter Injury ◽

Social Emotional ◽

Postmenstrual Age ◽

Neurodevelopmental Impairment ◽

Near Term

Abstract Background Several studies have suggested that adverse neurodevelopment could be induced by systemic inflammation in preterm infants. We aimed to investigate whether preterm infants with systemic inflammation would have impaired neurodevelopment and which biomarkers and neurophysiologic studies during inflammation are associated with poor neurodevelopment. Methods This prospective cohort study enrolled infants born before 30 weeks of gestation or with birth weight < 1250 g. Infants were grouped according to the presence of systemic inflammation: Control (no inflammation, n = 49), I (systemic inflammation, n = 45). Blood and cerebrospinal fluid samples for markers of brain injury and inflammation were collected and amplitude-integrated electroencephalography (aEEG) was performed within 4 h of septic workup. We evaluated aEEG at 35 weeks postmenstrual age (PMA), head circumference at 36 weeks PMA, and brain MRI at discharge. The Bayley Scales of Infant and Toddler Development III (Bayley-III) was performed at a corrected age (CA) of 18 months. Results The I group had more white matter injuries (2 vs. 26.7%, Control vs. I, respectively) at the time of discharge, lower brain functional maturation (9.5 vs. 8), and smaller head size (z-score − 1.45 vs. -2.12) at near-term age and poorer neurodevelopment at a CA of 18 months than the control (p < 0.05). Among the I group, the proportion of immature neutrophils (I/T ratios) and IL-1 beta levels in the CSF were associated with aEEG measures at the day of symptom onset (D0). Seizure spike on aEEG at D0 was significantly correlated with motor and social-emotional domains of Bayley-III (p < 0.05). The I/T ratio and CRP and TNF-α levels of blood at D0, white matter injury on MRI at discharge, head circumference and seizure spikes on aEEG at near-term age were associated with Bayley-III scores at a CA of 18 months. Conclusions Systemic inflammation induced by clinical infection and NEC are associated with neurodevelopmental impairment in preterm infants. The seizure spike on aEEG, elevated I/T ratio, CRP, and plasma TNF-alpha during inflammatory episodes are associated with poor neurodevelopment.

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Nutritional Intake, White Matter Integrity, and Neurodevelopment in Extremely Preterm Born Infants

Nutrients ◽

10.3390/nu13103409 ◽

2021 ◽

Vol 13 (10) ◽

pp. 3409

Author(s):

Lisa M. Hortensius ◽

Els Janson ◽

Pauline E. van van Beek ◽

Floris Groenendaal ◽

Nathalie H. P. Claessens ◽

...

Keyword(s):

White Matter ◽

Preterm Infants ◽

Motor Development ◽

Protein Intake ◽

Diffusion Tensor ◽

Neurodevelopmental Outcome ◽

White Matter Integrity ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Preterm Born

Background: Determining optimal nutritional regimens in extremely preterm infants remains challenging. This study aimed to evaluate the effect of a new nutritional regimen and individual macronutrient intake on white matter integrity and neurodevelopmental outcome. Methods: Two retrospective cohorts of extremely preterm infants (gestational age <28 weeks) were included. Cohort B (n = 79) received a new nutritional regimen, with more rapidly increased, higher protein intake compared to cohort A (n = 99). Individual protein, lipid, and caloric intakes were calculated for the first 28 postnatal days. Diffusion tensor imaging was performed at term-equivalent age, and cognitive and motor development were evaluated at 2 years corrected age (CA) (Bayley-III-NL) and 5.9 years chronological age (WPPSI-III-NL, MABC-2-NL). Results: Compared to cohort A, infants in cohort B had significantly higher protein intake (3.4 g/kg/day vs. 2.7 g/kg/day) and higher fractional anisotropy (FA) in several white matter tracts but lower motor scores at 2 years CA (mean (SD) 103 (12) vs. 109 (12)). Higher protein intake was associated with higher FA and lower motor scores at 2 years CA (B = −6.7, p = 0.001). However, motor scores at 2 years CA were still within the normal range and differences were not sustained at 5.9 years. There were no significant associations with lipid or caloric intake. Conclusion: In extremely preterm born infants, postnatal protein intake seems important for white matter development but does not necessarily improve long-term cognitive and motor development.

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Deep Multimodal Learning From MRI and Clinical Data for Early Prediction of Neurodevelopmental Deficits in Very Preterm Infants

Frontiers in Neuroscience ◽

10.3389/fnins.2021.753033 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lili He ◽

Hailong Li ◽

Ming Chen ◽

Jinghua Wang ◽

Mekibib Altaye ◽

...

Keyword(s):

Preterm Infants ◽

Clinical Data ◽

Diffusion Tensor ◽

Neurodevelopmental Outcome ◽

Motor Deficits ◽

Individual Data ◽

Very Preterm Infants ◽

Very Preterm ◽

Neurodevelopmental Deficits ◽

Multimodal Mri

The prevalence of disabled survivors of prematurity has increased dramatically in the past 3 decades. These survivors, especially, very preterm infants (VPIs), born ≤ 32 weeks gestational age, are at high risk for neurodevelopmental impairments. Early and clinically effective personalized prediction of outcomes, which forms the basis for early treatment decisions, is urgently needed during the peak neuroplasticity window—the first couple of years after birth—for at-risk infants, when intervention is likely to be most effective. Advances in MRI enable the noninvasive visualization of infants' brains through acquired multimodal images, which are more informative than unimodal MRI data by providing complementary/supplementary depicting of brain tissue characteristics and pathology. Thus, analyzing quantitative multimodal MRI features affords unique opportunities to study early postnatal brain development and neurodevelopmental outcome prediction in VPIs. In this study, we investigated the predictive power of multimodal MRI data, including T2-weighted anatomical MRI, diffusion tensor imaging, resting-state functional MRI, and clinical data for the prediction of neurodevelopmental deficits. We hypothesize that integrating multimodal MRI and clinical data improves the prediction over using each individual data modality. Employing the aforementioned multimodal data, we proposed novel end-to-end deep multimodal models to predict neurodevelopmental (i.e., cognitive, language, and motor) deficits independently at 2 years corrected age. We found that the proposed models can predict cognitive, language, and motor deficits at 2 years corrected age with an accuracy of 88.4, 87.2, and 86.7%, respectively, significantly better than using individual data modalities. This current study can be considered as proof-of-concept. A larger study with external validation is important to validate our approach to further assess its clinical utility and overall generalizability.

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Delayed Achievement of Oral Feedings Is Associated with Adverse Neurodevelopmental Outcomes at 18 to 26 Months Follow-up in Preterm Infants

American Journal of Perinatology ◽

10.1055/s-0039-1681059 ◽

2019 ◽

Vol 37 (05) ◽

pp. 483-490 ◽

Cited By ~ 1

Author(s):

Shabnam Lainwala ◽

Natalia Kosyakova ◽

Kimberly Power ◽

Naveed Hussain ◽

James E. Moore ◽

...

Keyword(s):

Cerebral Palsy ◽

Retrospective Study ◽

Preterm Infants ◽

Neurodevelopmental Outcome ◽

Oral Intake ◽

Neurodevelopmental Outcomes ◽

Motor Delay ◽

Postmenstrual Age ◽

Multivariable Analyses

Abstract Objective This study aimed to compare neurodevelopmental outcomes in preterm infants at 18 to 26 months corrected age (CA) who did versus did not achieve full oral feedings at 40 weeks postmenstrual age (PMA). Study Design This retrospective study included infants born between 2010 and 2015 with gestational age <32 weeks and followed between 18 and 26 months CA. Achievement of full oral feedings was defined as oral intake >130 mL/kg/d for >72 hours by 40 weeks PMA. Incidence of cognitive, language, or motor delay, or cerebral palsy at 18 to 26 months CA was compared in multivariable analyses for infants in the two feeding groups. Results Of 372 included infants, those achieving full oral feedings had lower incidence of any adverse neurodevelopmental outcome (p < 0.001) compared with those who did not achieve full oral feedings. In multivariable analyses, achievement of full oral feedings by 40 weeks PMA was associated with decreased odds of cognitive, language, and motor delays, cerebral palsy, and any adverse neurodevelopmental outcome at follow-up. Conclusion Achievement of full oral feedings by 40 weeks PMA was associated with better adjusted neurodevelopmental outcomes at 18 to 26 months CA. Inability to fully feed orally at 40 weeks PMA may be a simple, clinically useful marker for risk of adverse neurodevelopmental outcomes.

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Neurodevelopmental outcomes following preterm birth and the association with postmenstrual age at discharge

American Journal of Perinatology ◽

10.1055/a-1733-2690 ◽

2022 ◽

Author(s):

Polly Kellner ◽

Jenny Kwon ◽

Joan Smith ◽

Roberta G Pineda

Keyword(s):

Risk Factors ◽

Preterm Infants ◽

Ductus Arteriosus ◽

Neurodevelopmental Outcome ◽

Cognitive Outcome ◽

Composite Score ◽

Neurodevelopmental Outcomes ◽

Medical Risk ◽

Medical Risk Factors ◽

Postmenstrual Age

Objective: To 1) define the prevalence of motor, cognitive, and language delays in preterm infants born < 32 weeks estimated gestational age (EGA) and 2) identify the relationship between the timing of discharge from the NICU and neurodevelopmental outcome in early childhood. Study Design: This retrospective study of 176 preterm infants born < 32 weeks EGA and hospitalized in a level IV NICU captured medical factors, including timing of discharge, from the NICU stay. Standardized developmental testing at 1-2 years corrected age was conducted in the newborn follow-up clinic. Results: At 1-2 years corrected age, the sample had an average cognitive composite score of 91.5 ± 17.4, language composite score of 84.5 ± 17.3, and motor composite score of 88.9 ± 18.4. Lower EGA at birth, necrotizing enterocolitis, patent ductus arteriosus, and oxygen requirement for > 28 days were independently associated with higher postmenstrual age (PMA) at NICU discharge. After controlling for known risk factors, higher PMA at discharge was associated with poorer cognitive outcome [p < 0.001, (-0.16, -0.07), β = -0.35], poorer language outcome [p = 0.049 (-0.10, 0.00), β = -0.15] and poorer motor outcome [p < 0.001, (-0.14, -0.05), β = -0.30]. Conclusion: Poorer cognitive, language, and motor outcomes were associated with longer hospitalization, even after controlling for medical risk factors known to be associated with poorer outcome. This provides further evidence for the potential role of the environment that may be impacting the developmental outcomes of infants hospitalized in the NICU.

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Epigenome-wide Analysis Identifies Genes and Pathways Linked to Neurobehavioral Variation in Preterm Infants

10.1101/445130 ◽

2018 ◽

Author(s):

Todd M. Everson ◽

Carmen J. Marsit ◽

T. Michael O’Shea ◽

Amber Burt ◽

Karen Hermetz ◽

...

Keyword(s):

Preterm Infants ◽

Developmental Trajectories ◽

P Value ◽

Buccal Cells ◽

Neurobehavioral Performance ◽

Very Preterm Infants ◽

Equivalent Age ◽

Epigenetic Age ◽

Postmenstrual Age ◽

Near Term

AbstractBackground & ObjectivesNeonatal neurobehavioral performance measures, such as the NICU Network Neurobehavioral Scale (NNNS), have been developed to assess the neurobehavioral characteristics of infants and provide insights into future developmental trajectories. The identification of molecular biomarkers of very early life neurobehavioral experiences could lead to better predictions of the long-term developmental outcomes of high-risk infants including preterm infants. To this end, we aimed to examine whether variability in DNA methylation (DNAm) or epigenetic age from surrogate tissues are associated with NNNS profiles in a cohort of infants born less than 30 weeks postmenstrual age (PMA).MethodsThis study was performed within the Neonatal Neurobehavior and Outcomes in Very Preterm Infants (NOVI) Study and included those infants with complete NNNS assessment data and DNAm measured from buccal cells, collected at near term-equivalent age using the Illumina EPIC array (N=536). We tested whether epigenetic age and age acceleration differed between infants based on their NNNS profile classifications. Then we performed an epigenome-wide association study, to test whether DNAm at individual epigenetic loci varied between these NNNS profile groupings. Models were adjusted for recruitment site, infant sex, postmenstrual age, and estimated tissue heterogeneity.ResultsWe found that infants with an optimal NNNS profile had slightly older epigenetic age than other NOVI infants (β1 = 0.201, p-value = 0.026), and that infants with an atypical NNNS profile had differential methylation at 29 CpG sites (FDR < 10%). The genes annotated to these differentially methylated CpGs included PLA2G4E, TRIM9, GRIK3, and MACROD2, which have previously been associated with neurological structure and function, or with neurobehavioral disorders.ConclusionsGreater epigenetic age is associated with optimal NNNS responses while altered DNAm of multiple genes are associated with an atypical neurobehavioral profile at near-term equivalent age. These findings build upon the existing evidence that epigenetic variations in buccal cells may serve as markers of neonatal neurobehavior and might facilitate early identification of children at risk for abnormal developmental outcome.

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Effectiveness of Cue-Based Feeding Versus Scheduled Feeding in Preterm Infants Using Comprehensive Feeding Assessment Scales: A Randomized Clinical Trial

Iranian Journal of Pediatrics ◽

10.5812/ijp.107475 ◽

2020 ◽

Vol 30 (6) ◽

Author(s):

Farideh Kamran ◽

Ahmad Reza Khatoonabadi ◽

Mahshid Aghajanzadeh ◽

Abbas Ebadi ◽

Yaser Faryadras ◽

...

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Preterm Infants ◽

Neonatal Intensive Care ◽

Oral Feeding ◽

P Value ◽

Readiness Assessment ◽

Feeding Group ◽

Postmenstrual Age ◽

Duration Of Hospitalization

Background: One of the most critical criteria in making ready an infant for discharge from the neonatal intensive care unit (NICU) is full oral feeding attainment. Objectives: The present study aimed at investigating the effectiveness of cue-based feeding in preterm infants. Methods: A randomized clinical trial study was designed to compare 37 preterm infants at a gestational age of ≤ 34 weeks in the cue-based feeding group (n = 18) and the scheduled feeding group (n = 19). All participants were evaluated by the Preterm Infant Oral Feeding Readiness Assessment Scale (PIOFRAS) and Early Feeding Skill (EFS) scale in four different stages. Outcome measures were weight (grams per day), duration of full oral feeding achievement, duration of hospitalization, postmenstrual age (PMA), and the score of PIOFRAS and EFS. A P-value of less than 0.05 has been considered statistically significant. Results: The duration of full oral feeding achievement was shorter in the cue-based feeding group (3.55 ± 1.24 vs 6.68 ± 2.00, P < 0.001). Infants were discharged earlier in the cue-based feeding group (15.55 ± 5.38 vs 27.10 ± 7.90, P < 0.001). The mean score of PIOFRAS only on the day of discharge in the cue-based feeding group was more than the scheduled feeding group (32.61 ± 1.14 vs 31.90 ± 0.87, P = 0.03). The score of EFS in each dimension was inconsistent in each stage, and differences were observed between two groups in the full oral feeding stage. Conclusions: Although PIOFRAS and EFS demonstrated no difference significantly in most of the stages of achievement in oral feeding between the cue-based feeding group and the scheduled feeding, the process of attainment of oral feeding and discharge from the hospital was more rapid in the cue-based feeding group.

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Value of Cranial Ultrasound and Magnetic Resonance Imaging in Predicting Neurodevelopmental Outcome in Preterm Infants

PEDIATRICS ◽

10.1542/peds.90.2.196 ◽

1992 ◽

Vol 90 (2) ◽

pp. 196-199

Author(s):

Margot van de Bor ◽

Lya den Ouden ◽

Gerard L. Guit

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Preterm Infants ◽

Predictive Factor ◽

Intraventricular Hemorrhage ◽

Periventricular Leukomalacia ◽

Neurodevelopmental Outcome ◽

Cranial Ultrasound ◽

Resonance Imaging ◽

Postmenstrual Age

In this prospective study, cranial ultrasound was performed to detect periventricular-intraventricular hemorrhage and periventricular leukomalacia in 33 preterm infants of less than 32 weeks' gestation. At 44 weeks postmenstrual age magnetic resonance imaging was performed to detect the stage of myelination. Neurodevelopmental outcome was assessed at 3 years of age in 31 children (2 children died in the first year of life). Significant correlations were found between neurodevelopmental outcome and ultrasound findings (χ2 = 32.8; P < .0001) and stage of myelination (χ2 = 20.5; P < .0005). To establish the criterion with the best predictive factor, multiple regression analysis was performed with outcome as dependent variable and periventricular-intraventricular hemorrhage, periventricular leukomalacia, and stage of myelination as independent variables. It appeared that the detection of periventricular leukomalacia with ultrasound showed the best predictive factor for neurodevelopmental outcome. Routine magnetic resonance imaging at 44 weeks postmenstrual age should not be performed just for the purpose of predicting neurodevelopmental outcome more reliably.

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Isoprostanes as Biomarker for White Matter Injury in Extremely Preterm Infants

Frontiers in Pediatrics ◽

10.3389/fped.2020.618622 ◽

2021 ◽

Vol 8 ◽

Author(s):

Caterina Coviello ◽

Serafina Perrone ◽

Giuseppe Buonocore ◽

Simona Negro ◽

Mariangela Longini ◽

...

Keyword(s):

Lipid Peroxidation ◽

White Matter ◽

Preterm Infants ◽

Neurodevelopmental Outcome ◽

Area Under The Curve ◽

White Matter Injury ◽

Roc Curve Analysis ◽

Extremely Preterm ◽

Extremely Preterm Infants ◽

Early Biomarker

Background and Aim: Preterm white matter is vulnerable to lipid peroxidation-mediated injury. F2-isoprostanes (IPs), are a useful biomarker for lipid peroxidation. Aim was to assess the association between early peri-postnatal IPs, white matter injury (WMI) at term equivalent age (TEA), and neurodevelopmental outcome in preterm infants.Methods: Infants with a gestational age (GA) below 28 weeks who had an MRI at TEA were included. IPs were measured in cord blood (cb) at birth and on plasma (pl) between 24 and 48 h after birth. WMI was assessed using Woodward MRI scoring system. Multiple regression analyses were performed to assess the association between IPs with WMI and then with BSITD-III scores at 24 months corrected age (CA). Receiver operating characteristic (ROC) curve analysis was used to evaluate the predictive value of pl-IPs for the development of WMI.Results: Forty-four patients were included. cb-IPs were not correlated with WMI score at TEA, whereas higher pl-IPs and lower GA predicted higher WMI score (p = 0.037 and 0.006, respectively) after controlling for GA, FiO2 at sampling and severity of IVH. The area under the curve was 0.72 (CI 95% = 0.51–0.92). The pl-IPs levels plotted curve indicated that 31.8 pg/ml had the best predictive threshold with a sensitivity of 86% and a specificity of 60%, to discriminate newborns with any WMI from newborns without WMI. IPs were not associated with outcome at 24 months.Conclusion: Early measurement of pl-IPs may help discriminate patients showing abnormal WMI score at TEA, thus representing an early biomarker to identify newborns at risk for brain injury.

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