A Novel Method for ECG Artifact Removal from EEG without Simultaneous ECG.

The electrocardiogram (ECG) is a common source of electrical artifact in electroencephalogram (EEG). Here, we present a novel method for removing ECG artifact that requires neither simultaneous ECG nor transformation of the EEG signals. The approach relies upon processing a subset of EEG channels that contain ECG artifact to identify the times of each R-wave of the ECG. Within selected brief epochs, data in each EEG channel is signal-averaged ± 60 ms around each R-wave to derive an ECG template specific to each channel. This template is subtracted from each EEG channel which are aligned with the R-waves. The methodology was developed using two cohorts of infants: one with 128-lead EEG including an ECG reference and another with 32-lead EEG without ECG reference. The results for the first cohort validated the methodology the ECG reference and the second demonstrated its feasibility when ECG was not recorded. This method does not require independent, simultaneous recording of ECG, nor does it involve creation of an artifact template based on a mixture of EEG channel data as required by other methods such as Independent Component Analysis (ICA). Spectral analysis confirms that the method compares favorably to results using simultaneous recordings of ECG. The method removes ECG artifact on an epoch by epoch level and does not require stationarity of the artifact. Clinical Relevance - This approach facilitates the removal of ECG noise in frequency bands known to play a central role in brain mechanisms underlying cognitive processes.

Family nurture intervention increases term age forebrain EEG activity: A multicenter replication trial.

OBJECTIVE: This trial (RCT-2) sought to replicate the EEG findings of a randomized controlled trial of Family Nurture Intervention in the NICU (FNI-NICU) (RCT-1) comparing infants receiving standard care (SC) with infants receiving SC plus FNI . METHODS: RCT-2 (NCT02710474) was conducted at two NICUs. Subjects were randomly assigned to receive SC or FNI during their NICU stay. The primary outcome was EEG power in the frontal polar region at 39-41 weeks gestational age (GA). Sixty preterm infants (26-34 weeks GA; 33 SC, 27 FNI) were assessed. FNI-NICU consisted of repeated calming sessions (∼4 times/week) facilitated by Nurture Specialists during which mothers engaged in emotional expression during clothed or skin-to-skin holding, vocal soothing, and eye contact. EEGs were collected from 128 leads. EEG power was computed using Fast Fourier Transforms. RESULTS: RCT-2 replicated RCT-1 results; FNI-NICU led to significantly increased frontal polar power at frequencies > 12 Hz. Effects were spatially more widespread than in RCT-1, with substantial effect sizes (∼0.50) in frontal and parietal regions. CONCLUSIONS: RCT-2 results provide further evidence that FNI-NICU increases term age brain activity. SIGNIFICANCE: FNI-NICU is designed to facilitate autonomic emotional connection and coregulation between mothers and infants in the NICU resulting in profound effects on early brain development.

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.

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.

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.

Integrated information in the EEG of preterm infants increases with family nurture intervention, age, and conscious state.

A putative quantifier of consciousness, integrated information, was applied to preterm infant EEG data after novel pre-processing. Integrated information had a non-random structure as a function of the time lag over which it was computed. For most lags, it increased with age in early life, but even more so in infants exposed to Family Nurture Intervention (FNI), providing further evidence that FNI advances brain maturation in preterm infants. Also, it discriminated between conscious states (awake, REM sleep, NREM sleep), providing empirical support for the Integrated Information Theory of Consciousness in human infants.

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.

Depression and anxiety symptoms of mothers of preterm infants are decreased at 4 months corrected age with Family Nurture Intervention in the NICU.

Preterm delivery can precipitate maternal psychological morbidities. Family Nurture Intervention (FNI) was designed to minimize these by facilitating the emotional connection between mother and infant, beginning early in the infant's neonatal intensive care unit (NICU) stay. We examined depression and anxiety symptoms of mothers of preterm infants at 4 months infant corrected age (CA). One hundred fifteen mothers who delivered between 26 and 34 weeks gestational age were randomized to receive standard care (SC) or standard care plus FNI. Mothers' self-reported depressive symptoms (Center for Epidemiologic Studies Depression Scale: CES-D) and state anxiety (Spielberger State-Trait Anxiety Inventory: STAI) symptoms were assessed at enrollment, near to term age, and 4 months (CA). At 4 months CA, mean CES-D and STAI scores were significantly lower in FNI mothers compared to SC mothers. Effectiveness of FNI can only be evaluated as an integrated intervention strategy as it was not possible to control all aspects of FNI activities. Although there was considerable loss to follow-up, analyses suggest that resulting biases could have masked rather than inflated the measured effect size for depressive symptoms. FNI may be a feasible and practicable way to diminish the impact of premature delivery on maternal depressive and anxiety symptoms.

Family Nurture Intervention in the Neonatal Intensive Care Unit improves social-relatedness, attention, and neurodevelopment of preterm infants at 18 months in a randomized controlled trial.

BACKGROUND: Preterm infants are at high risk for adverse neurodevelopmental and behavioral outcomes. Family Nurture Intervention (FNI) in the Neonatal Intensive Care Unit (NICU) is designed to counteract adverse effects of separation of mothers and their preterm infants. Here, we evaluate effects of FNI on neurobehavioral outcomes. METHODS: Data were collected at 18 months corrected age from preterm infants. Infants were assigned at birth to FNI or standard care (SC). Bayley Scales of Infant Development III (Bayley-III) were assessed for 76 infants (SC, n = 31; FNI, n = 45); the Child Behavior Checklist (CBCL) for 57 infants (SC, n = 31; FNI, n = 26); and the Modified Checklist for Autism in Toddlers (M-CHAT) was obtained for 59 infants (SC, n = 33; FNI, n = 26). RESULTS: Family Nurture Intervention significantly improved Bayley-III cognitive (p = .039) and language (p = .008) scores for infants whose scores were greater than 85. FNI infants had fewer attention problems on the CBCL (p < .02). FNI improved total M-CHAT scores (p < .02). Seventy-six percent of SC infants failed at least one of the M-CHAT items, compared to 27% of FNI infants (p < .001). In addition, 36% of SC infants versus 0% of FNI infants failed at least one social-relatedness M-CHAT item (p < .001). CONCLUSIONS: Family Nurture Intervention is the first NICU intervention to show significant improvements in preterm infants across multiple domains of neurodevelopment, social-relatedness, and attention problems. These gains suggest that an intervention that facilitates emotional interactions between mothers and infants in the NICU may be key to altering developmental trajectories of preterm infants.

Prenatal nicotine exposure selectively affects nicotinic receptor expression in primary and associative visual cortices of the fetal baboon.

Exposure to nicotine during pregnancy via maternal cigarette smoking is associated with visual deficits in children. This is possibly due to the activation of nicotinic acetylcholine receptors (nAChRs) in the occipital cortex, which are important in the development of visual mapping. Using a baboon model, we explored the effects of prenatal nicotine on parameters in the primary and associated visual cortices. Pregnant baboons were infused with nicotine (0.5 mg/h, intravenous) or saline from 86 days gestation. At 161 days gestation, fetal brains were collected (n = 5 per group) and the occipital lobe assessed for nAChRs and markers of the serotonergic and catecholaminergic systems using tissue autoradiography and/or high-performance liquid chromatography. Neuronal nAChRs and serotonergic markers were expressed in a region- and subunit-dependent manner. Prenatal nicotine exposure was associated with increased binding for (3) H-epibatidine sensitive nAChRs in the primary visual cortex [Brodmann areas (BA) 17] and BA 18, but not BA 19, of the associative visual cortex (P < 0.05). Markers of the serotonergic or catecholaminergic systems were not significantly altered. Thus, prenatal nicotine exposure is associated with alterations in the cholinergic system in the occipital lobe, which may aid in the explanation of the appearance of visual deficits in children from mothers who smoke during pregnancy.

Electroencephalographic activity of preterm infants is increased by Family Nurture Intervention: a randomized controlled trial in the NICU.

OBJECTIVE: To assess the impact of Family Nurture Intervention (FNI) on electroencephalogram (EEG) activity in preterm infants (26-34 weeks gestation). METHODS: Two groups were tested in a single, level IV neonatal intensive care unit (NICU; standard care or standard care plus FNI) using a randomized controlled trial design. The intervention consists of sessions designed to achieve mutual calm and promote communication of affect between infants and their mothers throughout the NICU stay. EEG recordings were obtained from 134 infants during sleep at ∼35 and ∼40 weeks postmenstrual age (PMA). Regional brain activity (power) was computed for 10 frequency bands between 1 and 48 Hz in each of 125 electrodes. RESULTS: Near to term age, compared to standard care infants, FNI infants showed robust increases in EEG power in the frontal polar region at frequencies 10 to 48 Hz (20% to 36% with p-values <0.0004). Effects were significant in both quiet and active sleep, regardless of gender, singleton-twin status, gestational age (26-30 or 30-35 weeks) or birth weight (<1500 or >1500 g). CONCLUSION: FNI leads to increased frontal brain activity during sleep, which other investigators find predictive of better neurobehavioral outcomes. SIGNIFICANCE: FNI may be a practicable means of improving outcomes in preterm infants.

Randomized controlled trial of Family Nurture Intervention in the NICU: assessments of length of stay, feasibility and safety.

BACKGROUND: While survival rates for preterm infants have increased, the risk for adverse long-term neurodevelopmental and behavioral outcomes remains very high. In response to the need for novel, evidence-based interventions that prevent such outcomes, we have assessed Family Nurture Intervention (FNI), a novel dual mother-infant intervention implemented while the infant is in the Neonatal Intensive Care Unit (NICU). Here, we report the first trial results, including the primary outcome measure, length of stay in the NICU and, the feasibility and safety of its implementation in a high acuity level IV NICU. METHODS: The FNI trial is a single center, parallel-group, randomized controlled trial at Morgan Stanley Children's Hospital for mothers and their singleton or twin infants of 26-34 weeks gestation. Families were randomized to standard care (SC) or (FNI). FNI was implemented by nurture specialists trained to facilitate affective communication between mother and infant during specified calming interactions. These interactions included scent cloth exchange, sustained touch, vocal soothing and eye contact, wrapped or skin-to-skin holding, plus family-based support interactions. RESULTS: A total of 826 infants born between 26 and 34 weeks during the 3.5 year study period were admitted to the NICU. After infant and mother screening plus exclusion due to circumstances that prevented the family from participating, 373 infants were eligible for the study. Of these, we were unable to schedule a consent meeting with 56, and consent was withheld by 165. Consent was obtained for 150 infants from 115 families. The infants were block randomized to groups of N = 78, FNI and N = 72, SC. Sixteen (9.6%) of the randomized infants did not complete the study to home discharge, 7% of those randomized to SC and 12% of FNI infants. Mothers in the intervention group engaged in 3 to 4 facilitated one- to two-hour sessions/week. Intent to treat analyses revealed no significant difference between groups in medical complications. The mean length of stay was not significantly affected by the intervention. CONCLUSION: There was no significant effect demonstrated with this intervention amount on the primary short-term outcome, length of stay. FNI can be safely and feasibly implemented within a level IV NICU. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01439269.

Toward an electrocortical biomarker of cognition for newborn infants.

The event-related potential (ERP) effect of mismatch negativity (MMN) was the first electrophysiological probe to evaluate cognitive processing (change detection) in newborn infants. Initial studies of MMN predicted clinical utility for this measure in identification of infants at risk for developmental cognitive deficits. These predictions have not been realized. We hypothesized that in sleeping newborn infants, measures derived from wavelet assessment of power in the MMN paradigm would be more robust markers of the brain's response to stimulus change than the ERP-derived MMN. Consistent with this premise, we found increased power in response to unpredictable and infrequent tones compared to frequent tones. These increases were present at multiple locations on the scalp over a range of latencies and frequencies and occurred even in the absence of an ERP-derived MMN. There were two predominant effects. First, theta band power was elevated at middle and late latencies (200 to 600 ms), suggesting that neocortical theta rhythms that subserve working memory in adults are present at birth. Second, late latency (500 ms) increased power to the unpredictable and infrequent tones was observed in the beta and gamma bands, suggesting that oscillations involved in adult cognition are also present in the neonate. These findings support the expectation that frequency dependent measures, such as wavelet power, will improve the prospects for a clinically useful test of cortical function early in the postnatal period.

Family nurture intervention (FNI): methods and treatment protocol of a randomized controlled trial in the NICU.

BACKGROUND: The stress that results from preterm birth, requisite acute care and prolonged physical separation in the Neonatal Intensive Care Unit (NICU) can have adverse physiological/psychological effects on both the infant and the mother. In particular, the experience compromises the establishment and maintenance of optimal mother-infant relationship, the subsequent development of the infant, and the mother's emotional well-being. These findings highlight the importance of investigating early interventions that are designed to overcome or reduce the effects of these environmental insults and challenges. METHODS: This study is a randomized controlled trial (RCT) with blinded assessment comparing Standard Care (SC) with a novel Family Nurture Intervention (FNI). FNI targets preterm infants born 26-34 weeks postmenstrual age (PMA) and their mothers in the NICU. The intervention incorporates elements of mother-infant interventions with known efficacy and organizes them under a new theoretical context referred to collectively as calming activities. This intervention is facilitated by specially trained Nurture Specialists in three ways: 1) In the isolette through calming interactions between mother and infant via odor exchange, firm sustained touch and vocal soothing, and eye contact; 2) Outside the isolette during holding and feeding via the Calming Cycle; and 3) through family sessions designed to engage help and support the mother. In concert with infant neurobehavioral and physiological assessments from birth through 24 months corrected age (CA), maternal assessments are made using standard tools including anxiety, depression, attachment, support systems, temperament as well as physiological stress parameters. Quality of mother-infant interaction is also assessed. Our projected enrolment is 260 families (130 per group). DISCUSSION: The FNI is designed to increase biologically important activities and behaviors that enhance maternally-mediated sensory experiences of preterm infants, as well as infant-mediated sensory experiences of the mother. Consequently, we are enlarging the testing of preterm infant neurodevelopment beyond that of previous research to include outcomes related to mother-infant interactions and mother-infant co-regulation. Our primary objective is to determine whether repeated engagement of the mother and her infant in the intervention's calming activities will improve the infant's developmental trajectory with respect to multiple outcomes. Our secondary objective is to assess the effectiveness of FNI in the physiological and psychological co-regulation of the mother and infant. We include aspects of neurodevelopment that have not been comprehensively measured in previous NICU interventions. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01439269.

Techniques for in utero, longitudinal MRI of fetal brain development in baboons at 3T.

Magnetic Resonance Imaging (MRI) is a promising tool for the noninvasive, longitudinal study of developing primate brains. We developed a protocol to scan pregnant baboons serially at 3T for up to 3h per session. This protocol includes procedures for animal preparation, anesthesia, MRI scanning, and post-scan animal care. We applied this protocol to scan 5 baboons multiple times across the latter 70% of gestation-from as early as 56 days post-conceptional age to as late as 185 days (term approximately 180 days). We successfully acquired high-resolution anatomical images and maps of relaxation times (T(1) and T(2)) of the fetal brains at multiple time points across gestation. These images and maps demonstrated the convergence of gray and white matter contrast near term, and furthermore demonstrated that the convergence of contrast is a consequence of the continuous change in relaxation times during fetal brain development. We estimated the rates of decrease of T(1) and T(2) in white matter and gray matter, respectively. In addition, we measured the volumes of fetal brain at different gestational ages and calculated the growth rates of whole brain (0.91+/-0.08 cm(3)/day) and cortical gray matter (0.40+/-0.04 cm(3)/day). We also measured the mean diffusivity in white matter and deep gray matter using diffusion tensor imaging. In conclusion, in utero MRI of fetal baboon brains greatly enhances the use of nonhuman primate models to study fetal brain development longitudinally.

Prenatal nicotine-exposure alters fetal autonomic activity and medullary neurotransmitter receptors: implications for sudden infant death syndrome.

During pregnancy, exposure to nicotine and other compounds in cigarette smoke increases the risk of the sudden infant death syndrome (SIDS) two- to fivefold. Serotonergic (5-HT) abnormalities are found, in infants who die of SIDS, in regions of the medulla oblongata known to modulate cardiorespiratory function. Using a baboon model, we tested the hypothesis that prenatal exposure to nicotine alters 5-HT receptor and/or transporter binding in the fetal medullary 5-HT system in association with cardiorespiratory dysfunction. At 87 (mean) days gestation (dg), mothers were continuously infused with saline (n = 5) or nicotine (n = 5) at 0.5 mg/h. Fetuses were surgically instrumented at 129 dg for cardiorespiratory monitoring. Cesarean section delivery and retrieval of fetal medulla were performed at 161 (mean) dg for autoradiographic analyses of nicotinic and 5-HT receptor and transporter binding. In nicotine-exposed fetuses, high-frequency heart rate variability was increased 55%, possibly reflecting increases in the parasympathetic control of heart rate. This effect was more pronounced with greater levels of fetal breathing and age. These changes in heart rate variability were associated with increased 5-HT(1A) receptor binding in the raphé obscurus (P = 0.04) and increased nicotinic receptor binding in the raphé obscurus and vagal complex (P < 0.05) in the nicotine-exposed animals compared with controls (n = 6). The shift in autonomic balance in the fetal primate toward parasympathetic predominance with chronic exposure to nicotine may be related, in part, to abnormal 5-HT-nicotine alterations in the raphé obscurus. Thus increased risk for SIDS due to maternal smoking may be partly related to the effects of nicotine on 5-HT and/or nicotinic receptors.

Anesthetic-specific electroencephalographic patterns during emergence from sevoflurane and isoflurane in infants and children.

BACKGROUND: Devices that monitor the depth of anesthesia are increasingly used to titrate sedation and avoid awareness during anesthesia. Many of these monitors are based upon electroencephalography (EEG) collected from large adult reference populations and not pediatric populations (Anesthesiology, 86, 1997, 836; Journal of Anaesthesia, 92, 2004, 393; Anesthesiology, 99, 2003, 34). We hypothesized that EEG patterns in children would be different from those previously reported in adults and that they would show anesthetic-specific characteristics. METHODS: This prospective observational study was approved by the Institutional Review Board, and informed written consent was obtained. Patients were randomized to receive maintenance anesthesia with isoflurane or sevoflurane. EEG data collection included at least 10 min at steady-state maintenance anesthesia. The EEG was recorded continuously through emergence until after extubation. A mixed model procedure was performed on global and regional power by pooled data analysis and by analyzing each anesthetic group separately. Statistical significance was defined as P < 0.05. RESULTS: Thirty-seven children completed the study (ages 22 days-3.6 years). Isoflurane and sevoflurane had different effects on global and regional EEG power during emergence from anesthesia, and frontal predominance patterns were significantly different between these two anesthetic agents. CONCLUSIONS: The principal finding of the present study was that there are anesthetic-specific and concentration-dependent EEG effects in children. Depth-of-anesthesia monitors that utilize algorithms based on the EEGs of adult reference populations therefore may not be appropriate for use in children.

EEG functional connectivity in term age extremely low birth weight infants.

OBJECTIVE: The hypothesis is tested that electrocortical functional connectivity (quantified by coherence) of extremely low birth weight (ELBW) infants, measured at term post-menstrual age, has regional differences from that of full term infants. METHODS: 128 lead EEG data were collected during sleep from 8 ELBW infants with normal head ultrasound exams and 8 typically developing full term infants. Regional spectral power and coherence were calculated. RESULTS: No significant regional differences in EEG power were found between infant groups. However, compared to term infants, ELBW infants had significantly reduced interhemispheric coherence (in frontal polar and parietal regions) and intrahemispheric coherence (between frontal polar and parieto-occipital regions) in the 1-12Hz band but increased interhemispheric coherence between occipital regions in the 24-50Hz band. CONCLUSIONS: ELBW infants at term post-menstrual age manifest regional differences in EEG functional connectivity as compared to term infants. SIGNIFICANCE: Distinctive spatial patterns of electrocortical synchrony are found in ELBW infants. These regional patterns may presage regional alterations in the structure of the cortex.

Cross-frequency phase coupling of brain rhythms during the orienting response.

A critical function of the brain's orienting response is to evaluate novel environmental events in order to prepare for potential behavioral action. Here, measures of synchronization (power, coherence) and nonlinear cross-frequency phase coupling (m:n phase locking measured with bicoherence and cross-bicoherence) were computed on 62-channel electroencephalographic (EEG) data during a paradigm in which unexpected, highly-deviant, novel sounds were randomly intermixed with frequent standard and infrequent target tones. Low frequency resolution analyses showed no significant changes in phase coupling for any stimulus type, though significant changes in power and synchrony did occur. High frequency resolution analyses, on the other hand, showed significant differences in phase coupling, but only for novel sounds compared to standard tones. Novel sounds elicited increased power and coherence in the delta band together with m:n phase locking (bicoherence) of delta:theta (1:3) and delta:alpha (1:4) rhythms in widespread fronto-central, right parietal, temporal, and occipital regions. Cross-bicoherence revealed that globally synchronized delta oscillations were phase coupled to theta oscillations in central regions and to alpha oscillations in right parietal and posterior regions. These results suggest that globally synchronized low frequency oscillations with phase coupling to more localized higher frequency oscillations provide a neural mechanism for the orienting response.

Placental transfer and fetal elimination of morphine-3-beta-glucuronide in the pregnant baboon.

The glucuronide metabolites of several widely used drugs are detected in fetal plasma after maternal drug administration. However, the disposition of these metabolites is poorly understood and clinical concerns have been raised about accumulation of active metabolites in the fetus. For this reason, morphine-3-beta-glucuronide (M3G), an active metabolite of morphine, was studied to provide quantitative data on disposition. Maternal, fetal, and bidirectional placental clearances of M3G were measured in three pregnant baboons. During maternal infusion of M3G to steady-state, the glucuronide metabolite readily appeared in fetal plasma achieving a mean +/- S.D. fetal-to-maternal concentration ratio of 0.79 +/- 0.04. In paired maternal and fetal infusions, steady-state clearances were 53 +/- 3 (maternal), 1.5 +/- 0.5 (maternal-to-fetal), 2.6 +/- 0.1 (fetal-to-maternal), and -0.70 +/- 0.6 ml x min(-1) (fetal). These clearance values support bidirectional transfer of M3G across the placenta and indicate negligible direct clearance from the fetus. The clearance of M3G across the placenta is more than 20-fold less than that of morphine. Despite this low index of permeability, placental transfer contributes significantly to the glucuronide pool in the fetus. Placental transfer emerges as the major clearance pathway for the glucuronide from the fetus and suggests a component of active efflux. What is more, the results do not support the concept of sequestration in the fetal intestine as a significant route of clearance. Together these results clarify the distribution and clearance of glucuronides in the pregnant primate and facilitate prediction of fetal exposure to active metabolites.