Perinatal antibiotics alter preterm infant EEG and neurobehavior in the Family Nurture Intervention trial.

Early exposure to antibiotics has been shown to increase risk for poor neurobehavioral development, particularly with regard to attention deficit disorders. Clinically, electroencephalography (EEG) is increasingly used as a biomarker of these deficits. Less is known about the effects of antibiotics on neurobehavioral and neurophysiological outcomes in preterm infants, a population at particularly high risk for attention deficits and perinatal antibiotic exposure. This study examines the effects of perinatal antibiotic exposure on neonatal EEG and attention deficits as measured by the Child Behavior Checklist in 4- to 5-year-old children who were enrolled in an NICU-based randomized controlled trial comparing Family Nurture Intervention (FNI) to standard care. Antibiotic-exposed infants had increased attention problems and there was a main effect of antibiotic exposure such that exposed infants had higher EEG power. This effect was fourfold greater in infants who received standard NICU care compared to those who received the intervention, suggesting a buffering effect of the intervention. We hypothesize that the relationship between antibiotic exposure and altered neurodevelopment may be due to effects of antibiotics on the microbiome, and that FNI may buffer these adverse consequences.

Family nurture intervention in preterm infants increases early development of cortical activity and independence of regional power trajectories.

AIM: Premature delivery and maternal separation during hospitalisation increase infant neurodevelopmental risk. Previously, a randomised controlled trial of Family Nurture Intervention (FNI) in the neonatal intensive care unit demonstrated improvement across multiple mother and infant domains including increased electroencephalographic (EEG) power in the frontal polar region at term age. New aims were to quantify developmental changes in EEG power in all brain regions and frequencies and correlate developmental changes in EEG power among regions. METHODS: EEG (128 electrodes) was obtained at 34-44 weeks postmenstrual age from preterm infants born 26-34 weeks. Forty-four infants were treated with Standard Care and 53 with FNI. EEG power was computed in 10 frequency bands (1-48 Hz) in 10 brain regions and in active and quiet sleep. RESULTS: Percent change/week in EEG power was increased in FNI in 132/200 tests (p < 0.05), 117 tests passed a 5% False Discovery Rate threshold. In addition, FNI demonstrated greater regional independence in those developmental rates of change. CONCLUSION: This study strengthens the conclusion that FNI promotes cerebral cortical development of preterm infants. The findings indicate that developmental changes in EEG may provide biomarkers for risk in preterm infants as well as proximal markers of effects of FNI.

Family nurture intervention alters relationships between preterm infant EEG delta brush characteristics and term age EEG power.

OBJECTIVE: Family Nurture Intervention (FNI) facilitates mother/infant emotional connection, improves neurodevelopmental outcomes and increases electroencephalogram (EEG) power at term age. Here we explored whether delta brushes (DB), early EEG bursts that shape brain development, are altered by FNI and mediate later effects of FNI on EEG. METHODS: We assessed DB characteristics in EEG data from a randomized controlled trial comparing infants with standard care (SC, n = 31) versus SC + FNI (n = 33) at ~35 and ~40 weeks GA. RESULTS: Compared to SC infants, FNI infant DB amplitude increased more from ~35 to ~40 weeks, and FNI infants had longer duration DBs. DB parameters (rate, amplitude, brush frequency) at ~35 weeks were correlated with power at ~40 weeks, but only in SC infants. FNI effects on DB parameters do not mediate FNI effects on EEG power or coherence at term. CONCLUSIONS: DBs are related to subsequent brain activity and FNI alters DB parameters. However, FNI's effects on electrocortical activity at term age are not dependent on its earlier effects on DBs. SIGNIFICANCE: While early DBs can have important effects on later brain activity in preterm infants, facilitating emotional connection with FNI may allow brain maturation to be less dependent on early bursts.

Family nurture intervention in the NICU increases autonomic regulation in mothers and children at 4-5 years of age: Follow-up results from a randomized controlled trial.

BACKGROUND: Maturation of multiple neurobehavioral systems, including autonomic regulation, is altered by preterm birth. The purpose of this study was to determine the long-term effects of Family Nurture Intervention (FNI) in the NICU on autonomic regulation of preterm infants and their mothers. METHOD: A subset of infants and mothers (48% of infants, 51% of mothers) randomly assigned to either standard are (SC), or SC plus the FNI in the NICU in a prior RCT (ClincalTrials.gov; NCT01439269) returned for follow-up assessments when the children were 4 to 5 years corrected age (CA). ECGs were collected for 10 minutes in mothers and their children while children were in their mothers' laps. Heart rate, standard deviation for heart rate, respiratory sinus arrhythmia (RSA)-an index of parasympathetic regulation, and a measure of vagal efficiency were quantified. RESULTS: Both children and mothers in the FNI group had significantly greater levels of RSA compared to the SC group (child: mean difference = 0.60, 95% CI 0.17 to 1.03, p = 0.008; mother: mean difference = 0.64, 95% CI 0.07 to 1.21, p = 0.031). In addition, RSA increased more rapidly in FNI children between infancy and the 4 to 5-year follow-up time point (SC = +3.11±0.16 loge msec2, +3.67±0.19 loge msec2 for FNI, p<0.05). These results show that the rate of increase in RSA from infancy to childhood is more rapid in FNI subjects. CONCLUSION: Although these preliminary follow-up results are based on approximately half of subjects originally enrolled in the RCT, they suggest that FNI-NICU led to healthier autonomic regulation in both mother and child, when measured during a brief face-to-face socioemotional interaction. A Pavlovian autonomic co-conditioning mechanism may underly these findings that can be exploited therapeutically.

Early Life Maternal Separation and Maternal Behaviour Modulate Acoustic Characteristics of Rat Pup Ultrasonic Vocalizations.

Early separation of preterm infants from their mothers has adverse, long-term neurodevelopmental consequences. We investigated the effects of daily maternal separation (MS) of rat pups from postnatal days 2-10 (PND2-10) on neurobehavioural responses to brief isolation at PND12 compared with pups receiving controlled handling without MS. Ultrasonic vocalizations (USV) were measured at PND12 during two, 3-minute isolations occurring immediately before and after a 3-minute maternal reunion. There were no significant differences in acoustic characteristics between MS and control animals in the first isolation. However, in the second isolation, MS pups produced a greater proportion of high (~60 kHz) vs low (~40 kHz) frequency calls. During this isolation, control pups made longer and louder low frequency calls compared to the first isolation, whereas MS pups did the opposite. Maternal behaviour of control and MS mothers modulated pup acoustic characteristics in opposite directions; higher maternal care was associated with more low frequency calls in control pups but more high frequency calls in MS pups. We hypothesize that MS results in USV emission patterns reflective of a greater stress response to isolation. This translational model can be used to identify mechanisms and interventions that may be exploited to overcome the negative, long-term effects of MS.