Rapid cortical oscillations and early motor activity in premature human neonate.

International audienceDelta-brush is the dominant pattern of rapid oscillatory activity (8-25 Hz) in the human cortex during the third trimester of gestation. Here, we studied the relationship between delta-brushes in the somatosensory cortex and spontaneous movements of premature human neonates of 29-31 weeks postconceptional age using a combination of scalp electroencephalography and monitoring of motor activity. We found that sporadic hand and foot movements heralded the appearance of delta-brushes in the corresponding areas of the cortex (lateral and medial regions of the contralateral central cortex, respectively). Direct hand and foot stimulation also reliably evoked delta-brushes in the same areas. These results suggest that sensory feedback from spontaneous fetal movements triggers delta-brush oscillations in the central cortex in a somatotopic manner. We propose that in the human fetus in utero, before the brain starts to receive elaborated sensory input from the external world, spontaneous fetal movements provide sensory stimulation and drive delta-brush oscillations in the developing somatosensory cortex contributing to the formation of cortical body maps

The development of motor activity: observing spontaneous behavior in fetuses, preterm and term infants

Nowadays, ultrasound examinations in 3D and 4D are promoting the concept of continuity in human motor behavior. The most recent studies on the central nervous have focused both on the general movements of the body and on facial expressions, in order to identify additional evaluation criteria to understand the neuro-behavioral development. The aim of this study is to observe spontaneous motor behavior from the beginning of movement during prenatal life. The observation of human motor behavior is related to the normal function of central nervous system and it can detect early, or even before birth, the integrity of central nervous system (Di Pietro, 2005). In order to describe spontaneous behavior before and after birth, we are going to dedicate the first experiment to code spontaneous motor activity in a group of fetuses and preterm infants at the same gestational age. To code behavior we adopted a new coding scale made by 21 behavioral motor patterns, deriving from the descriptive categories of behavior observed in fetuses, preterm and full-term infants. Comparison between preterm infants and fetuses at the same gestational age was allowed to understand the ontogeny of spontaneous motor activity, but it also helped us to highlight the differences in behavior from the prenatal period to postnatal life. In the second experiment we investigate how appetite condition, as a primary motivational factor, modulates behavior in premature newborns. Results suggest that we can find a modulation in behavior expression also during preterm development and that this modulation is functional to attention seeking and to nutrition. The third experiment compares behavior between full-term and preterm newborns at the same post-conceptional age. Results state there are differences in behavioral motor patterns, as a result of the different behavioral state regulation and coming from the different types of maturational and environmental development. Thanks to these experiments we can confirm that our new behavioral motor patterns coding scale is sensitive to behavior exhibited by fetuses, preterm and full-term infants. Spontaneous behavior is an activity endogenously generated by the CNS which reflects the state of neural development. Behaviors is sensitive to changes in physiological and motivational functions. The study of spontaneous behavior allows us to understand the evolutionary trajectories of specific functions and to inquire into newborn well-being. The value of these observations is twofold, because it opens the way for a new approach both scientific and diagnostic

Sleep State Modulates Resting-State Functional Connectivity in Neonates.

The spontaneous cerebral activity that gives rise to resting-state networks (RSNs) has been extensively studied in infants in recent years. However, the influence of sleep state on the presence of observable RSNs has yet to be formally investigated in the infant population, despite evidence that sleep modulates resting-state functional connectivity in adults. This effect could be extremely important, as most infant neuroimaging studies rely on the neonate to remain asleep throughout data acquisition. In this study, we combine functional near-infrared spectroscopy with electroencephalography to simultaneously monitor sleep state and investigate RSNs in a cohort of healthy term born neonates. During active sleep (AS) and quiet sleep (QS) our newborn neonates show functional connectivity patterns spatially consistent with previously reported RSN structures. Our three independent functional connectivity analyses revealed stronger interhemispheric connectivity during AS than during QS. In turn, within hemisphere short-range functional connectivity seems to be enhanced during QS. These findings underline the importance of sleep state monitoring in the investigation of RSNs

Early development of sleep and brain functional connectivity in term-born and preterm infants

The proper development of sleep and sleep-wake rhythms during early neonatal life is crucial to lifelong neurological well-being. Recent data suggests that infants who have poor quality sleep demonstrate a risk for impaired neurocognitive outcomes. Sleep ontogenesis is a complex process, whereby alternations between rudimentary brain states-active vs. wake and active sleep vs. quiet sleep-mature during the last trimester of pregnancy. If the infant is born preterm, much of this process occurs in the neonatal intensive care unit, where environmental conditions might interfere with sleep. Functional brain connectivity (FC), which reflects the brain's ability to process and integrate information, may become impaired, with ensuing risks of compromised neurodevelopment. However, the specific mechanisms linking sleep ontogenesis to the emergence of FC are poorly understood and have received little investigation, mainly due to the challenges of studying causal links between developmental phenomena and assessing FC in newborn infants. Recent advancements in infant neuromonitoring and neuroimaging strategies will allow for the design of interventions to improve infant sleep quality and quantity. This review discusses how sleep and FC develop in early life, the dynamic relationship between sleep, preterm birth, and FC, and the challenges associated with understanding these processes. Impact Sleep in early life is essential for proper functional brain development, which is essential for the brain to integrate and process information. This process may be impaired in infants born preterm. The connection between preterm birth, early development of brain functional connectivity, and sleep is poorly understood. This review discusses how sleep and brain functional connectivity develop in early life, how these processes might become impaired, and the challenges associated with understanding these processes. Potential solutions to these challenges are presented to provide direction for future research.Peer reviewe

Pharmacological aspects of neonatal antidepressant withdrawal

Depression is common in reproductive age women, and continued pharmacologic treatment of depression during pregnancy may be necessary to prevent relapse, which could be harmful for both the fetus and the mother. Although data on drug safety are imperfect and incomplete, the benefits of antidepressant therapy during pregnancy generally outweigh the risks. Neonates who are exposed to antidepressant medications during gestation are at increased risk to have neonatal withdrawal syndrome, although the exact incidence of this complication is unknown because the definition of the syndrome is not clear and withdrawal reactions are probably underreported. Tricyclic antidepressant withdrawal syndrome is most likely related to muscarinergic activity and individual drug half-lives, and selective serotonin reuptake inhibitor withdrawal may be due to a decrease in available synaptic serotonin in the face of down-regulated serotonin receptors, the secondary effects of other neurotransmitters, and biological or cognitive sensitivity. Other factors that influence neonatal toxicity or withdrawal include the normal physiologic changes of pregnancy, the altered activity of CYP450 enzymes during pregnancy, drug-drug transporter (PgP and OCT3) interaction, and the presence of genetic polymorphisms in genes influencing drug metabolism. Further research is necessary

Modulation of EEG spectral edge frequency during patterned pneumatic oral stimulation in preterm infants

Background—Stimulation of the nervous system plays a central role in brain development and neurodevelopmental outcome. Thalamocortical and corticocortical development is diminished in premature infants and correlated to electroencephalography (EEG) progression. The purpose of this study was to determine the effects of orocutaneous stimulation on the modulation of spectral edge frequency, fc=90% (SEF-90) derived from EEG recordings in preterm infants. Methods—Twenty two preterm infants were randomized to experimental and control conditions. Pulsed orocutaneous stimulation was presented during gavage feedings begun at around 32 weeks postmenstrual age (PMA). The SEF-90 was derived from 2-channel EEG recordings. Results—Compared to the control condition, the pulsed orocutaneous stimulation produced a significant reorganization of SEF-90 in the left (p = 0.005) and right (p \u3c 0.0001) hemispheres. Notably, the left and right hemisphere showed a reversal in the polarity of frequency shift, demonstrating hemispheric asymmetry in the frequency domain. Pulsed orocutaneous stimulation also produced a significant pattern of short term cortical adaptation and a long term neural adaptation manifest as a 0.5 Hz elevation in SEF-90 after repeated stimulation sessions. Conclusion—This is the first study to demonstrate the modulating effects of a servo-controlled oral somatosensory input on the spectral features of EEG activity in preterm infants

Modulation of EEG spectral edge frequency during patterned pneumatic oral stimulation in preterm infants

Background—Stimulation of the nervous system plays a central role in brain development and neurodevelopmental outcome. Thalamocortical and corticocortical development is diminished in premature infants and correlated to electroencephalography (EEG) progression. The purpose of this study was to determine the effects of orocutaneous stimulation on the modulation of spectral edge frequency, fc=90% (SEF-90) derived from EEG recordings in preterm infants. Methods—Twenty two preterm infants were randomized to experimental and control conditions. Pulsed orocutaneous stimulation was presented during gavage feedings begun at around 32 weeks postmenstrual age (PMA). The SEF-90 was derived from 2-channel EEG recordings. Results—Compared to the control condition, the pulsed orocutaneous stimulation produced a significant reorganization of SEF-90 in the left (p = 0.005) and right (p \u3c 0.0001) hemispheres. Notably, the left and right hemisphere showed a reversal in the polarity of frequency shift, demonstrating hemispheric asymmetry in the frequency domain. Pulsed orocutaneous stimulation also produced a significant pattern of short term cortical adaptation and a long term neural adaptation manifest as a 0.5 Hz elevation in SEF-90 after repeated stimulation sessions. Conclusion—This is the first study to demonstrate the modulating effects of a servo-controlled oral somatosensory input on the spectral features of EEG activity in preterm infants

Studying connectivity in the neonatal EEG

In humans the few months surrounding birth comprise a developmentally critical period characterised by the growth of major neuronal networks as well as their initial tuning towards more functionally mature large-scale constellations. Proper wiring in the neonatal brain, especially during the last trimester of pregnancy and the first weeks of postnatal life, relies on the brain’s endogenous activity and remains critical throughout one’s life. Structural or functional abnormalities at the stage of early network formation may result in a neurological disorder later during maturation. Functional connectivity measures based on an infant electroencephalographic (EEG) time series may be used to monitor these processes. A neonatal EEG is temporally discrete and consists of events (e.g., spontaneous activity transients (SATs)) and the intervals between them (inter-SATs). During early maturation, communication between areas of the brain may be transmitted through two distinct mechanisms: synchronisation between neuronal oscillations and event co-occurrences. In this study, we proposed a novel algorithm capable of assessing the coupling on both of these levels. Our analysis of real data from preterm neonates using the proposed algorithm demonstrated its ability to effectively detect functional connectivity disruptions caused by brain lesions. Our results also suggest that SAT synchronisation represents the dominant means through which inter-areal cooperation occurs in an immature brain. Structural disturbances of the neuronal pathways in the brain carry a frequency selective effect on the functional connectivity decreasing at the event level. Next, we used mathematical models and computational simulations combined with real EEG data to analyse the propagation of electrical neuronal activity within the neonatal head. Our results show that the conductivity of the neonatal skull is much higher than that found in adults. This leads to greater focal spread of cortical signals towards the scalp and requires high-density electrode meshes for quality monitoring of neonatal brain activity. Additionally, we show that the specific structure of the neonatal skull fontanel does not represent a special pathway for the spread of electrical activity because of the overall high conductivity of the skull. Finally, we demonstrated that the choice of EEG recording montage may strongly affect the fidelity of non-redundant neuronal information registration as well as the output of functional connectivity analysis. Our simulations suggest that high-density EEG electrode arrays combined with mathematical transformations, such as the global average or current source density (CSD), provide more spatially accurate details about the underlying cortical activity and may yield results more robust against volume conduction effects. Furthermore, we provide clear instruction regarding how to optimise recording montages for different numbers of sensors.Lähikuukaudet ennen ja jälkeen syntymää ovat ihmisillä hermoston kehityksen kannalta kriittisiä vaiheita, joita luonnehtii mittavien hermostollisten verkostojen kasvu sekä niiden alustava virittäytyminen toiminnallisesti kypsiksi suuren mittakaavan yhteenliittymiksi. Vastasyntyneen aivojen koko loppuelämään vaikuttavien hermoverkostojen muodostuminen määräytyy ensimmäisten syntymän jälkeisten viikkojen mutta erityisesti raskauden viimeisen kolmanneksen aikaisen aivojen sisäsyntyisen aktiivisuuden mukaan. Rakenteelliset tai toiminnalliset epämuodostumat näiden varhaisten hermoverkostojen muodostumisvaiheessa voi johtaa neurologisiin häiriöihin myöhemmässä kypsymisessä. Varhaisen kehityksen vaiheita voidaan valvoa vastasyntyneillä mittaamalla hermoyhteyksien toiminnallista liittyvyyttä aivosähkökäyrien (EEG) aikasarjojen avuilla. Vastasyntyneen aivosähkökäyrä on ajallisesti epäjatkuva ja koostuu lyhytkestoisista spontaanin aktiivisuuden tapahtumista, SATeista (Spontaneous Activity Transients) sekä niiden välisistä ajanhetkistä, inter-SATeista. Varhaisessa hermostollisessa kypsymisessä aivoalueiden välinen yhteydenpito voi tapahtua kahdella eri mekanismilla: hermostollisten oskillaatioiden välisellä synkronisaatioilla ja tapahtumien samanaikaisuudella. Tässä tutkimuksessa me kehitimme uuden matemaattisen mallin, algoritmin, jolla voi arvioida näiden kahden mekanismin välistä kytkeytymistä. Vastasyntyneiden keskosten mittausdataan pohjautuva analyysimme osoitti, että kehittämämme algoritmi on toimiva väline aivovaurioiden aiheuttamien toiminnallisten liittyvyyskatkoksien havaitsemisessa. Tuloksemme osoittavat myös, että SAT-synkronisaatio on aivoalueiden pääasiallisin yhteydenpitokeino kypsymättömissä vastasyntyneen aivoissa. Hermostollisten yhteyksien rakenteelliset epämuodostumat heikentävät toiminnallista liittyvyyttä taajuuskohtaisesti tapahtumatasolla. Seuraavaksi me käytimme matemaattisia malleja ja tietokonesimulaatioita yhdistettynä varsinaiseen EEG-mittausdataan analysoidaksemme sähköisen hermostollisen aktiivisuuden leviämistä vastasyntyneen päässä. Tulostemme mukaan vastasyntyneen kallon sähkönjohtavuus on paljon korkeampi kuin aikuisilla ihmisillä. Tämä aiheuttaa aivokuoren signaalien suurempaa paikallista leviämistä päänahkaa kohti, minkä takia vastasyntyneen aivoaktiivisuuden luotettava rekisteröinti vaatii enemmän ja tiheämmin mittauselektrodeja kuin aikuisilla. Lisäksi todistimme, että vastasyntyneen kallon aukileet eivät muodosta erityistä reittiä sähköisen aktiivisuuden leviämiselle, kallon suuren johtavuuden takia. Lopuksi osoitimme, että EEG-mittausasetelman valinta voi vahvasti vaikuttaa ei-päällekkäisen hermostollisen datan mittaustarkkuuteen ja sitä seuraaviin liittyvyysanalyyseihin. Simulaatiomme mukaan suuritiheyksinen EEG-mittauselektrodiasetelma yhdistettynä matemaattisiin muunnoksiin, kuten virtalähdetiheyden (Current Source Density) globaalikeskiarvoon, tarjoavat spatiaalisesti tarkkoja yksityiskohtia alla sijaitsevasta aivokuoren aktiivisuudesta ja voi erottaa selkeästi sekundääristen virtatihentymien osuuden. Lisäksi laadimme selkeät ohjeet kuinka optimoida mittausasetelma eri elektrodimäärille

Investigating the Impact of Maternal Antiviral Responses on Pregnancy and Fetal Development

The maternal-fetal interface during pregnancy is an underexplored environment rich in immunological factors that must propel developmental processes while simultaneously providing protection from invading pathogens such as viruses. Almost half of all cells in the maternal decidua in pregnancy are leukocytes, which are required for successful pregnancy, and the placenta has increasingly become recognized as an immunological organ. Viral infections during pregnancy are associated with significant mortality and morbidity, both for the pregnant female and the developing fetus. Notably, impacts on fetal development have typically been attributed to direct viral damage to cells and tissues during the course of infection, without a deep consideration of the potential collateral damage incurred upon the activation of antiviral immune responses. In this dissertation, I characterize the contribution of the immune system and antiviral responses to pathologies of pregnancy and fetal development, using both mouse models of maternal immune activation and human studies of viral infection and immunization during the coronavirus disease 2019 (COVID-19) pandemic. First, I establish and characterize a novel model of maternal immune activation (MIA) in early pregnancy that leads to a high rate of neural tube defects (NTDs) and craniofacial abnormalities in the affected offspring. Using systemic administration of the double-stranded RNA mimic poly(I:C) to pregnant mice, I demonstrate that the activation of antiviral immune responses alone is capable of driving fetal birth defects. These phenotypes mirror human NTDs, among the most common birth defects seen worldwide. I identify key immunological pathways and factors driving pathogenesis, which is TLR3- and STAT1-dependent. Strikingly, mice deficient in γδ T cells are protected from the development of MIA-induced NTDs. Together with collaborators, I use immunofluorescence imaging and a spatial gene expression approach to show that γδ T cells are associated with laminin loss at the ectoplacental cone of the primitive placenta. I demonstrate that these changes at the maternal-fetal interface are associated with decreased proliferation of neural progenitors in the developing fetus, resulting in the failure of neural tube closure. We thus uncover a previously unrecognized role for γδ T cells at the maternal-fetal interface and novel mechanism underlying NTD pathogenesis. Next, I interrogate the impact of antiviral responses on outcomes in human pregnancy. The emergence of SARS-CoV-2 and the ongoing COVID-19 pandemic has highlighted the importance of studying the unique consequences of viral infections during pregnancy, as pregnant individuals are at much greater risk for severe COVID-19 disease than nonpregnant individuals. Working with a multidisciplinary team, I help to identify one of the first reports worldwide showing that SARS-CoV-2 is capable of infecting the placenta. I discover that SARS-CoV-2 is capable of infecting the placenta at the syncytiotrophoblast layer, the multinucleated layer of trophoblast derived from stem cell cytotrophoblasts, and that infection, while rare, is restricted to this region of the maternal-fetal interface. In pregnancies affected by asymptomatic SARS-CoV-2, the vast majority of placentas are not infected due to a robust antiviral response at the maternal-fetal interface. However, I find that this powerful antiviral defense includes a distinct inflammatory profile at the placenta that is directly associated with preeclampsia and other inflammatory disorders of pregnancy, suggesting that antiviral immunity mounted to effectively shield the fetus from viral infection may come at the price of dysregulation of the maternal-fetal interface. This observation lends insight as to why pathogens typically are not able to invade the placenta during pregnancy and how even asymptomatic or mild infections limited to the respiratory tract can lead to severe maternal outcomes at a distant organ site. Finally, I directly address some of the most prevalent vaccine misinformation encountered by the public today, including false theories that the COVID-19 mRNA vaccines cause infertility and harm developing fetuses in utero when administered in pregnancy. With a mouse model of vaccination during early pregnancy, I show that administration of the mRNA-1273 vaccine has no impact on fetal size at term and does not lead to birth defects. In contrast, poly(I:C) administration, which unlike the mRNA vaccines activates TLR3 pathways, significantly reduces crown-rump length and weight at term. I further demonstrate that mRNA-1273 vaccination even in the earliest stages of pregnancy, prior to formation of the definitive placenta, leads to high levels of protective antibodies in fetuses at term. In a large study of human volunteers, we challenge a common infertility myth by providing direct evidence that COVID-19 vaccination with either mRNA-1273 or BNT162b2 does not lead to an increase in circulating anti-syncytin-1 antibodies. Together, these contributions dispel a number of the most common vaccine rumors fueling vaccine hesitancy worldwide