Early protein intake predicts functional connectivity and neurocognition in preterm born children.

Nutritional intake can promote early neonatal brain development in very preterm born neonates (< 32 weeks' gestation). In a group of 7-year-old very preterm born children followed since birth, we examined whether early nutrient intake in the first weeks of life would be associated with long-term brain function and neurocognitive skills at school age. Children underwent resting-state functional MRI (fMRI), intelligence testing (Wechsler Intelligence Scale for Children, 5th Ed) and visual-motor processing (Beery-Buktenica, 5th Ed) at 7 years. Relationships were assessed between neonatal macronutrient intakes, functional connectivity strength between thalamic and default mode networks (DMN), and neuro-cognitive function using multivariable regression. Greater functional connectivity strength between thalamic networks and DMN was associated with greater intake of protein in the first week (ß = 0.17; 95% CI 0.11, 0.23, p < 0.001) but lower intakes of fat (ß = - 0.06; 95% CI - 0.09, - 0.02, p = 0.001) and carbohydrates (ß = - 0.03; 95% CI - 0.04, - 0.01, p = 0.003). Connectivity strength was also associated with protein intake during the first month (ß = 0.22; 95% CI 0.06, 0.37, p = 0.006). Importantly, greater thalamic-DMN connectivity strength was associated with higher processing speed indices (ß = 26.9; 95% CI 4.21, 49.49, p = 0.02) and visual processing scores (ß = 9.03; 95% CI 2.27, 15.79, p = 0.009). Optimizing early protein intake may contribute to promoting long-term brain health in preterm-born children.

Association of early skin breaks and neonatal thalamic maturation: A modifiable risk?

OBJECTIVE: To test the hypothesis that a strategy of prolonged arterial line (AL) and central venous line (CVL) use is associated with reduced neonatal invasive procedures and improved growth of the thalamus in extremely preterm neonates (<28 weeks' gestation). METHODS: Two international cohorts of very preterm neonates (n = 143) with prolonged (≥14 days) or restricted (<14 days) use of AL/CVL were scanned serially with MRI. General linear models were used to determine the association between skin breaks and thalamic volumes, accounting for clinical confounders and site differences. Children were assessed at preschool age on standardized tests of motor and cognitive function. Outcome scores were assessed in relation to neonatal thalamic growth. RESULTS: Prolonged AL/CVL use in neonates (n = 86) was associated with fewer skin breaks (median 34) during the hospital stay compared to restricted AL/CVL use (n = 57, median 91, 95% confidence interval [CI] 60.35-84.89). Neonates with prolonged AL/CVL use with fewer skin breaks had significantly larger thalamic volumes early in life compared to neonates with restricted line use (B = 121.8, p = 0.001, 95% CI 48.48-195.11). Neonatal thalamic growth predicted preschool-age cognitive (B = 0.001, 95% CI 0.0003-0.001, p = 0.002) and motor scores (B = 0.01, 95% CI 0.001-0.10, p = 0.02). Prolonged AL/CVL use was not associated with greater incidence of sepsis or multiple infections. CONCLUSIONS: Prolonged AL/CVL use in preterm neonates may provide an unprecedented opportunity to reduce invasive procedures in preterm neonates. Pain reduction in very preterm neonates is associated with optimal thalamic growth and neurodevelopment.

Early Procedural Pain Is Associated with Regionally-Specific Alterations in Thalamic Development in Preterm Neonates.

Very preterm human neonates are exposed to numerous invasive procedures as part of life-saving care. Evidence suggests that repetitive neonatal procedural pain precedes long-term alterations in brain development. However, to date the link between pain and brain development has limited temporal and anatomic specificity. We hypothesized that early exposure to painful stimuli during a period of rapid brain development, before pain modulatory systems reach maturity, will predict pronounced changes in thalamic development, and thereby cognitive and motor function. In a prospective cohort study, 155 very preterm neonates (82 males, 73 females) born 24-32 weeks' gestation underwent two MRIs at median postmenstrual ages 32 and 40 weeks that included structural, metabolic, and diffusion imaging. Detailed day-by-day clinical data were collected. Cognitive and motor abilities were assessed at 3 years, corrected age. The association of early (skin breaks, birth-Scan 1) and late pain (skin breaks, Scans 1-2) with thalamic volumes and N-acetylaspartate (NAA)/choline (Cho), and fractional anisotropy of white-matter pathways was assessed. Early pain was associated with slower thalamic macrostructural growth, most pronounced in extremely premature neonates. Deformation-based morphometry analyses confirmed early pain-related volume losses were localized to somatosensory regions. In extremely preterm neonates early pain was associated with decreased thalamic NAA/Cho and microstructural alterations in thalamocortical pathways. Thalamic growth was in turn related to cognitive and motor outcomes. We observed regionally-specific alterations in the lateral thalamus and thalamocortical pathways in extremely preterm neonates exposed to more procedural pain. Findings suggest a sensitive period leading to lasting alterations in somatosensory-system development.SIGNIFICANCE STATEMENT Early exposure to repetitive procedural pain in very preterm neonates may disrupt the development of regions involved in somatosensory processing, leading to poor functional outcomes. We demonstrate that early pain is associated with thalamic volume loss in the territory of the somatosensory thalamus and is accompanied by disruptions thalamic metabolic growth and thalamocortical pathway maturation, particularly in extremely preterm neonates. Thalamic growth was associated with cognitive and motor outcome at 3 years corrected age. Findings provide evidence for a developmentally sensitive period whereby subcortical structures in young neonates may be most vulnerable to procedural pain. Furthermore, results suggest that the thalamus may play a key role underlying the association between neonatal pain and poor neurodevelopmental outcomes in these high-risk neonates.

GSK-3ß inhibitor TDZD-8 reduces neonatal hypoxic-ischemic brain injury in mice.

AIMS: Glycogen synthase kinase 3ß (GSK-3ß) is activated following hypoxic-ischemic (HI) brain injury. TDZD-8 is a specific GSK-3ß inhibitor. Currently, the impact of inhibiting GSK-3ß in neonatal HI injury is unknown. We aimed to investigate the effect of TDZD-8 following neonatal HI brain injury. METHODS: Unilateral common carotid artery ligation followed by hypoxia was used to induce HI injury in postnatal day 7 mouse pups pretreated with TDZD-8 or vehicle. The infarct volume, whole-brain imaging, Nissl staining, and behavioral tests were used to evaluate the protective effect of TDZD-8 on the neonatal brain and assess functional recovery after injury. Western blot was used to evaluate protein levels of phosphorylated protein kinase B (Akt), GSK-3ß, and cleaved caspase-3. Protein levels of cleaved caspase-3, neuronal marker, and glial fibrillary acidic protein were detected through immunohistochemistry. RESULTS: Pretreatment with TDZD-8 significantly reduced brain damage and improved neurobehavioral outcomes following HI injury. TDZD-8 reversed the reduction of phosphorylated Akt and GSK-3ß, and the activation of caspase-3 induced by hypoxia-ischemia. In addition, TDZD-8 suppressed apoptotic cell death and reduced reactive astrogliosis. CONCLUSION: TDZD-8 has the therapeutic potential for hypoxic-ischemic brain injury in neonates. The neuroprotective effect of TDZD-8 appears to be mediated through its antiapoptotic activity and by reducing astrogliosis.

Magnetoencephalography reveals slowing of resting peak oscillatory frequency in children born very preterm.

Resting cortical activity is characterized by a distinct spectral peak in the alpha frequency range. Slowing of this oscillatory peak toward the upper theta-band has been associated with a variety of neurological and neuropsychiatric conditions and has been attributed to altered thalamocortical dynamics. Children born very preterm exhibit altered development of thalamocortical systems. To test the hypothesis that peak oscillatory frequency is slowed in children born very preterm, we recorded resting magnetoencephalography (MEG) from school age children born very preterm (≤ 32 wk gestation) without major intellectual or neurological impairment and age-matched full-term controls. Very preterm children exhibit a slowing of peak frequency toward the theta-band over bilateral frontal cortex, together with reduced alpha-band power over bilateral frontal and temporal cortex, suggesting that mildly dysrhythmic thalamocortical interactions may contribute to altered spontaneous cortical activity in children born very preterm.

Neonatal watershed brain injury on magnetic resonance imaging correlates with verbal IQ at 4 years.

OBJECTIVE: We have previously described patterns of neonatal brain injury that correlate with global cognitive and motor outcomes. We now examine, in survivors of neonatal encephalopathy (presumed secondary to hypoxia-ischemia) without functional motor deficits, whether the severity and neuroanatomical involvement on neonatal MRI are associated with domain-specific cognitive outcomes, verbal and performance IQ, at 4 years of age. METHODS: In this prospective study, neonatal MRIs of 81 term infants with neonatal encephalopathy were scored for degree of injury in 2 common patterns: watershed distribution and basal ganglia distribution. Follow-up evaluation at 4 years of age by examiners blinded to clinical history and MRIs included a 5-point neuromotor score and the Wechsler Preschool and Primary Scale of Intelligence-Revised. In 64 subjects with no functional motor impairment, test of trend was used to examine the association of ordered watershed-distribution and basal ganglia-distribution MRI scores with mean verbal and performance IQ. RESULTS: Lower verbal and performance IQs were seen with increasing degree of injury on both watershed-distribution and basal ganglia-distribution scales in univariate analyses. When each MRI pattern score was adjusted for the other, only the association of decreasing verbal IQ with increasing watershed-distribution injury remained significant. A suggestion of decreasing verbal IQ with increasing basal ganglia-distribution injury was also seen in the multivariate model, whereas no association was seen between performance IQ and severity of injury in either MRI pattern. CONCLUSIONS: In survivors of neonatal encephalopathy without functional motor deficits at 4 years of age, an increasing severity of watershed-distribution injury is associated with more impaired language-related abilities.