Fantastic voyage: Chasing oxytocin from the bedside to the bench and back again.

This is the story of my 50-year career in medicine and research, and the people who influenced and helped me most along the way. I recount the way in which I became interested in oxytocin early in my career as a child psychiatrist, and how it led me back to Columbia University, my alma mater, to study oxytocin's role in mother-child innate behaviors. I recount how oxytocin/oxytocin receptor signaling was central to my basic and clinical research and present a new theory on mother-infant emotional behaviors that challenges 400 years of brain-centric science. My history underscores the important and unique perspective women bring to science and why women are especially needed in the sciences. I hope to inspire young women (and young men) who are beginning their careers in research.

Qualitative insights from a randomized clinical trial of a mother-child emotional preparation program for preschool-aged children.

BACKGROUND: Early life stress and adversity conveys risk for emotional, behavioral, and developmental disorders. To address this risk in the preschool population, Mother-Child Emotional Preparation (MCEP) was tested as an in-school dyadic intervention for facilitating mother-child emotional connection through mother-child calming cycles. In a computer-generated block randomized controlled trial enrolling preschool-aged children and their mothers, in partnership with an early childhood learning center, we at Columbia University Irving Medical Center tested effects of MCEP across multiple domains. Within this RCT we designed a qualitative sub-study to understand how MCEP aligns with calming cycle theory and its impact on mothers and the mother-child relationship. METHODS: A qualitative researcher observed 14 group MCEP sessions consisting of nurture specialists facilitating reciprocal calming interactions through shared emotional expression between mothers and their preschool-aged children. We conducted two waves of participant interviews in English or Spanish, per participant preference. Participants (n = 8) were majority Hispanic at or below the federal poverty level. Group session observations were coded and analyzed for frequency, co-occurrence, variance by session, and alignment with calming cycle theory, incorporating demographic variables and attendance. Interview transcripts were translated from Spanish to English if needed, then coded and analyzed using thematic analysis. RESULTS: Qualitative analysis revealed mothers' experiences of MCEP. Data demonstrated that calming position and emotional expression were mutually supportive, and that barriers to connection were calming cycle entry-points, not barriers. At the group level, supported by nurture specialists, fellow participants helped each other progress through calming cycles. Moreover, MCEP adapted to meet individual dyad needs, and mothers described its far-reaching impact. CONCLUSIONS: Qualitative methods show that MCEP helps mother-child dyads emotionally connect through the calming cycle and fills a gap in early childhood education services. This study generated insights for quantitative studies and suggested implications for MCEP dissemination. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03908268 , Registered April 9, 2019-Retrospectively registered.

Assessment of Neurodevelopment in Infants With and Without Exposure to Asymptomatic or Mild Maternal SARS-CoV-2 Infection During Pregnancy.

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding. Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months. Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants. Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection. Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language. Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (ß = 0.31; 95% CI, -2.97 to 3.58), gross motor (ß = 0.82; 95% CI, -1.34 to 2.99), fine motor (ß = 0.36; 95% CI, -0.74 to 1.47), expressive language (ß = -1.00; 95% CI, -4.02 to 2.02), or receptive language (ß = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores. Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

Pandemic beyond the virus: maternal COVID-related postnatal stress is associated with infant temperament.

BACKGROUND: Studies have shown that infant temperament varies with maternal psychosocial factors, in utero illness, and environmental stressors. We predicted that the pandemic would shape infant temperament through maternal SARS-CoV-2 infection during pregnancy and/or maternal postnatal stress. To test this, we examined associations among infant temperament, maternal prenatal SARS-CoV-2 infection, maternal postnatal stress, and postnatal COVID-related life disruptions. METHODS: We tested 63 mother-infant dyads with prenatal maternal SARS-CoV-2 infections and a comparable group of 110 dyads without infections. To assess postnatal maternal stress, mothers completed the Perceived Stress Scale 4 months postpartum and an evaluation of COVID-related stress and life disruptions 6 months postpartum. Mothers reported on infant temperament when infants were 6-months-old using the Infant Behavior Questionnaire-Revised (IBQ-R) Very Short Form. RESULTS: Maternal SARS-CoV-2 infection during pregnancy was not associated with infant temperament or maternal postnatal stress. Mothers with higher self-reported postnatal stress rated their infants lower on the Positive Affectivity/Surgency and Orienting/Regulation IBQ-R subscales. Mothers who reported greater COVID-related life disruptions rated their infants higher on the Negative Emotionality IBQ-R subscale. CONCLUSIONS: Despite no effect of prenatal maternal SARS-CoV-2 infection, stress and life disruptions incurred by the COVID-19 pandemic were associated with infant temperament at 6-months. IMPACT: SARS-CoV-2 infection during pregnancy is not associated with postnatal ratings of COVID-related life disruptions, maternal stress, or infant temperament. Postnatal ratings of maternal stress during the COVID-19 pandemic are associated with normative variation in maternal report of infant temperament at 6 months of age. Higher postnatal ratings of maternal stress are associated with lower scores on infant Positive Affectivity/Surgency and Orienting/Regulation at 6 months of age. Higher postnatal ratings of COVID-related life disruptions are associated with higher scores on infant Negative Emotionality at 6 months of age.

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.

Facilitating early parent-infant emotional connection improves cortical networks in preterm infants.

Exposure to environmental adversities during early brain development, such as preterm birth, can affect early brain organization. Here, we studied whether development of cortical activity networks in preterm infants may be improved by a multimodal environmental enrichment via bedside facilitation of mother-infant emotional connection. We examined functional cortico-cortical connectivity at term age using high-density electroencephalography recordings in infants participating in a randomized controlled trial of Family Nurture Intervention (FNI). Our results identify several large-scale, frequency-specific network effects of FNI, most extensively in the alpha frequency in fronto-central cortical regions. The connectivity strength in this network was correlated to later neurocognitive performance, and it was comparable to healthy term-born infants rather than the infants receiving standard care. These findings suggest that preterm neurodevelopmental care can be improved by a biologically driven environmental enrichment, such as early facilitation of direct human connection.

Wired to Connect: The Autonomic Socioemotional Reflex Arc.

We have previously proposed that mothers and infants co-regulate one another's autonomic state through an autonomic conditioning mechanism, which starts during gestation and results in the formation of autonomic socioemotional reflexes (ASRs) following birth. Theoretically, autonomic physiology associated with the ASR should correlate concomitantly with behaviors of mother and infant, although the neuronal pathway by which this phenomenon occurs has not been elucidated. In this paper, we consider the neuronal pathway by which sensory stimuli between a mother and her baby/child affect the physiology and emotional behavior of each. We divide our paper into two parts. In the first part, to gain perspective on current theories on the subject, we conduct a 500-year narrative history of scientific investigations into the human nervous system and theories that describe the neuronal pathway between sensory stimulus and emotional behavior. We then review inconsistencies between several currently accepted theories and recent data. In the second part, we lay out a new theory of emotions that describes how sensory stimuli between mother and baby unconsciously control the behavior and physiology of both. We present a theory of mother/infant emotion based on a set of assumptions fundamentally different from current theories. Briefly, we propose that mother/infant sensory stimuli trigger conditional autonomic socioemotional reflexes (ASRs), which drive cardiac function and behavior without the benefit of the thalamus, amygdala or cortex. We hold that the ASR is shaped by an evolutionarily conserved autonomic learning mechanism (i.e., functional Pavlovian conditioning) that forms between mother and fetus during gestation and continues following birth. We highlight our own and others research findings over the past 15 years that support our contention that mother/infant socioemotional behavior is driven by mutual autonomic state plasticity, as opposed to cortical trait plasticity. We review a novel assessment tool designed to measure the behaviors associated with the ASR phenomenon. Finally, we discuss the significance of our theory for the treatment of mothers and infants with socioemotional disorders.

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.

Effects of Family Nurture Intervention in the NICU on Theory of Mind Abilities in Children Born Very Preterm: A Randomized Controlled Trial.

Preterm infants are at risk for socioemotional deficits, neurodevelopmental disorders, and potentially theory of mind (ToM) deficits. Preterm infants enrolled in a randomized controlled trial in the neonatal intensive care unit (NICU) received Standard Care (SC) or Family Nurture Intervention (FNI). Children (N = 72; median age 61.8 ± 2.6 months; FNI: 35 (55%), SC:2 9 (45%)) completed a ToM task, of whom 64 (54% male; born to White (43.8%), Black (18.7%), and Hispanic (25.0%) mothers) contributed to this analysis. FNI and SC infants born extremely preterm to very preterm differed significantly: 78% (14 of 18) of FNI children passed vs. 30% (3 of 10) SC children (p = 0.01, effect size = 1.06). This large effect size suggests that FNI in the NICU may ameliorate deficits in social-cognitive skills of extreme to very preterm infants by school age.

Association of Birth During the COVID-19 Pandemic With Neurodevelopmental Status at 6 Months in Infants With and Without In Utero Exposure to Maternal SARS-CoV-2 Infection.

Importance: Associations between in utero exposure to maternal SARS-CoV-2 infection and neurodevelopment are speculated, but currently unknown. Objective: To examine the associations between maternal SARS-CoV-2 infection during pregnancy, being born during the COVID-19 pandemic regardless of maternal SARS-CoV-2 status, and neurodevelopment at age 6 months. Design, Setting, and Participants: A cohort of infants exposed to maternal SARS-CoV-2 infection during pregnancy and unexposed controls was enrolled in the COVID-19 Mother Baby Outcomes Initiative at Columbia University Irving Medical Center in New York City. All women who delivered at Columbia University Irving Medical Center with a SARS-CoV-2 infection during pregnancy were approached. Women with unexposed infants were approached based on similar gestational age at birth, date of birth, sex, and mode of delivery. Neurodevelopment was assessed using the Ages & Stages Questionnaire, 3rd Edition (ASQ-3) at age 6 months. A historical cohort of infants born before the pandemic who had completed the 6-month ASQ-3 were included in secondary analyses. Exposures: Maternal SARS-CoV-2 infection during pregnancy and birth during the COVID-19 pandemic. Main Outcomes and Measures: Outcomes were scores on the 5 ASQ-3 subdomains, with the hypothesis that maternal SARS-CoV-2 infection during pregnancy would be associated with decrements in social and motor development at age 6 months. Results: Of 1706 women approached, 596 enrolled; 385 women were invited to a 6-month assessment, of whom 272 (70.6%) completed the ASQ-3. Data were available for 255 infants enrolled in the COVID-19 Mother Baby Outcomes Initiative (114 in utero exposed, 141 unexposed to SARS-CoV-2; median maternal age at delivery, 32.0 [IQR, 19.0-45.0] years). Data were also available from a historical cohort of 62 infants born before the pandemic. In utero exposure to maternal SARS-CoV-2 infection was not associated with significant differences on any ASQ-3 subdomain, regardless of infection timing or severity. However, compared with the historical cohort, infants born during the pandemic had significantly lower scores on gross motor (mean difference, -5.63; 95% CI, -8.75 to -2.51; F1,267 = 12.63; P<.005), fine motor (mean difference, -6.61; 95% CI, -10.00 to -3.21; F1,267 = 14.71; P < .005), and personal-social (mean difference, -3.71; 95% CI, -6.61 to -0.82; F1,267 = 6.37; P<.05) subdomains in fully adjusted models. Conclusions and Relevance: In this study, birth during the pandemic, but not in utero exposure to maternal SARS-CoV-2 infection, was associated with differences in neurodevelopment at age 6 months. These early findings support the need for long-term monitoring of children born during the COVID-19 pandemic.

Preterm infant heart rate is lowered after Family Nurture Intervention in the NICU: Evidence in support of autonomic conditioning.

BACKGROUND: Cardiac complications after premature birth are associated with negative long-term consequences to health. The Family Nurture Intervention (FNI) has been designed to support mother-infant parasympathetic calming sessions in the neonatal intensive care unit (NICU). FNI has shown neurodevelopmental and autonomic benefit across infant development. AIMS: We tested the hypothesis that heart rate (HR) will decrease after FNI over the course of the NICU stay, compared to matched controls. STUDY DESIGN: We used a case-matched design. The intervention included on average four ~1-hour facilitated mother-infant 'calming' sessions per week. We collected 24/7 real time heart rate data from a central monitoring system and analyzed data from two time-periods. SUBJECTS: The intervention group comprised 37 infants born ~30 weeks gestational age (GA) in a level IV NICU, treated with FNI. From the same NICU and time-period, we created a contemporaneous comparison group of 32 infants who were case-matched to each intervention infant for sex, age-at-birth, singleton or twin status, month of admission and length of stay. OUTCOME MEASURES: Using generalized estimating equation (GEE) modeling, we analyzed 24/7 HR data during a 1-hour period between 4:30 and 5:30 am each day in the NICU, when all infants were least disturbed. Using repeated measures ANOVA, we analyzed 24/7 HR data during a 6-week period starting 1 week prior to the start of FNI and ending 5 weeks after start. RESULTS: GEE modeling of the 1-hour data from all subjects showed significant lower HR in the FNI group, compared with controls. ANOVA modeling on a subset of subjects over the five-week period showed that FNI infant HR decreased in a dose-response manner relative to SC HR. CONCLUSION: This study suggests FNI may condition lower infant HR in a dose-response manner during the NICU stay.

The Welch Emotional Connection Screen: Adapting observational methods to pediatric primary care via resident training.

The Welch Emotional Connection Screen (WECS) is a novel instrument that is a brief, practicable, evidenced-based observational screening tool for assessing relationship health between parent and child. The WECS requires observing 2-3 min of face-to-face interactions between parent and child, without toys, prompts, paradigms or technology. Here, we describe a translational project from the coding lab to the primary care provider via a residency training program conducted with 50 residents during a 30-day developmental and behavioral pediatrics medical resident education rotation. The aims of this study were to evaluate the efficacy of WECS pediatric resident training: 1) to improve residents' accuracy in recognizing the dyadic behaviors of emotional connection (EC) via WECS training; and 2) to improve residents' attitudes, self-efficacy, and perceived professional norms (ASPPN) pertaining to Early Relational Health in Pediatrics. Results indicate that using a rapid prototyping approach to training, residents improved in their identification of dyads showing low to midrange levels of emotional connection. As well, resident attitudes about the importance of relationship health in pediatrics and their self-efficacy in identifying emotional connection improved significantly after this brief resident training.

How babies learn: The autonomic socioemotional reflex.

BACKGROUND: Human and animal research has long documented the negative effects of early traumatic events on long-term development and socioemotional behavior. Yet, how and where the body stores these memories remains unclear. Current theories propose that the brain stores such memory in the subcortical limbic system. However, a clear theory of change with testable hypothesis has yet to emerge. AIMS: In this paper, we review the classical Pavlovian conditioning learning tradition, along with its functional variant. Then, we review calming cycle theory, which builds upon the idea that mother/infant learning is distinct from other types of learning, requiring a new set of assumptions in light of functional Pavlovian conditioning. CONCLUSION: Calming cycle theory states that learning of behaviors associated with subcortical autonomic physiology is separate and distinct from learning of behaviors associated with cortical physiology. Mother/infant autonomic learning starts in the uterine environment via functional Pavlovian co-conditioning that is stored as conditional reflexes within the dyad's autonomic nervous systems. These reflexes are preserved transnatally as autonomic socioemotional reflexes (ASRs), which can be used to monitor mother-infant relational health. The functional Pavlovian co-conditioning mechanism can be exploited to change the physiological/behavioral reflex response. The theory provides a well established learning mechanism, a theory of change and a method of change, along with a set of hypotheses with which to test the theory. We present evidence from a randomized controlled trial with prematurely born infants and their mothers that supports calming cycle theory.

A review of newborn outcomes during the COVID-19 pandemic.

As the COVID-19 pandemic continues to spread worldwide, it is crucial that we determine populations that are at-risk and develop appropriate clinical care policies to protect them. While several respiratory illnesses are known to seriously impact pregnant women and newborns, preliminary data on the novel SARS-CoV-2 Coronavirus suggest that these groups are no more at-risk than the general population. Here, we review the available literature on newborns born to infected mothers and show that newborns of mothers with positive/suspected SARS-CoV-2 infection rarely acquire the disease or show adverse clinical outcomes. With this evidence in mind, it appears that strict postnatal care policies, including separating mothers and newborns, discouraging breastfeeding, and performing early bathing, may be more likely to adversely impact newborns than they are to reduce the low risk of maternal transmission of SARS-CoV-2 or the even lower risk of severe COVID-19 disease in otherwise healthy newborns.

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.

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.

Nurturescience versus neuroscience: A case for rethinking perinatal mother-infant behaviors and relationship.

Behavioral and emotional outcomes for babies who experienced maternal separation due to prematurity or birth defects have not improved significantly for the last 20 years. Current theories and treatment paradigms based on neuroscience have not generated explanatory mechanisms that work, or provided testable hypotheses. This article proposes a new field of scientific investigation, "nurturescience" within which new hypotheses can be tested with novel instruments. Key distinctions between neuroscience and nurturescience are described. Our definition of nurturescience is based on the basic needs of all newborns and of the needs of mothers and their families. This understanding is drawn from biology, anthropology, sociology, physiological, and clinical research. Mechanisms are described from studies on microbiota, epigenetics, allostasis, brain imaging, and developmental origins of health and adult disease. The converging message from these and other fields is that the mother-infant dyad should not be separated. Ongoing emotional connection is the cornerstone of development, leading to life-long resilience. This has implications for making the correct diagnosis (emotional disconnection vs. attachment disorder), providing the appropriate care (infant and family centered developmental care) in the biologically expected place (skin-to-skin contact), and potential for rehabilitation (calming cycle theory). Nurturescience has particular relevance to the care of "small and sick" infants, with profound potential for decreasing the "likelihood of developing developmental problems."

Darwin's Other Dilemmas and the Theoretical Roots of Emotional Connection.

Modern scientific theories of emotional behavior, almost without exception, trace their origin to Charles Darwin, and his publications On the Origin of Species (1859) and The Expression of the Emotions in Man and Animals (1872). The most famous dilemma Darwin acknowledged as a challenge to his theory of evolution through natural selection was the incomplete Sub-Cambrian fossil record. However, Darwin struggled with two other rarely referenced theoretical and scientific dilemmas that confounded his theories about emotional behavior. These included (1) the origin of social instincts (e.g., altruism, empathy, reciprocity and cooperation) and the reasons for their conservation in evolution and (2) the peripheral control of heart rate vis-à-vis emotional behavior outside of consciousness. Darwin acknowledged that social instincts are critical to the survival of some species, but had difficulty aligning them with his theory of natural selection in humans. Darwin eventually proposed that heart rate and emotions are controlled via one's intellect and cortical mechanisms, and that instinctive behavior is genetically programmed and inherited. Despite ongoing efforts, these two theoretical dilemmas are debated to this day. Simple testable hypotheses have yet to emerge for the biological mechanisms underlying instinctive behavior or the way heart rate is controlled in infants. In this paper, we review attempts to resolve these issues over the past 160 years. We posit that research and theories that supported Darwin's individualistic brain-centric and genetic model have become an "orthodox" Western view of emotional behavior, one that produced the prevailing behavioral construct of attachment as developed by John Bowlby. We trace research and theories that challenged this orthodoxy at various times, and show how these challenges were repeatedly overlooked, rejected, or misinterpreted. We review two new testable theories, emotional connection theory and calming cycle theory, which we argue resolve the two dilemmas We show emerging scientific evidence from physiology and a wide variety of other fields, as well from clinical trials among prematurely born infants, that supports the two theories. Clinical implications of the new theories and possible new ways to assess risk and intervene in emotional, behavioral and developmental disorders are discussed.

Autonomic regulation of preterm infants is enhanced by Family Nurture Intervention.

Preterm infants have maturational delays in several neurobehavioral systems. This study assesses the impact of the Family Nurture Intervention (FNI) in the neonatal intensive care unit (NICU) on the maturation of autonomic regulation of preterm infants. Preterm infants born at 26-34 weeks postmenstrual age (PMA) were assigned to groups receiving either standard care (SC) or SC plus FNI, using a randomized controlled trial design. At two collection time points, approximately 35 weeks and 41 weeks PMA, electrocardiograms (ECG) were monitored for approximately 1 hour during sleep. Heart rate and respiratory sinus arrhythmia (RSA) were quantified from the ECG. Across the two time points, the FNI group exhibited greater increases in RSA (Cohen's d = 0.35) and slope between RSA and heart rate, as a measure of vagal efficiency (Cohen's d = 0.62). These results document that FNI resulted in enhanced autonomic regulation consistent with greater maturation of cardiac function. These and previous findings strongly suggest that facilitating early nurturing interactions and emotional connection between preterm infants and their mothers is a practicable and effective means of optimizing postnatal development in preterm infants. Interpretation of these autonomic function results also enriches our understanding of the potential long-term beneficial outcomes of FNI by drawing upon polyvagal theory, which explains how autonomic state provides a neurophysiological platform for optimal co-regulation between infant and caregiver, and by drawing upon calming cycle theory, which provides a model for understanding how repeated mother/infant calming interactions positively condition autonomic state and reinforce approach, prosocial behaviors.