Cortical Cross-Frequency Coupling Is Affected by in utero Exposure to Antidepressant Medication

Up to five percent of human infants are exposed to maternal antidepressant medication by serotonin reuptake inhibitors (SRI) during pregnancy, yet the SRI effects on infants' early neurodevelopment are not fully understood. Here, we studied how maternal SRI medication affects cortical frequency-specific and cross-frequency interactions estimated, respectively, by phase-phase correlations (PPC) and phase-amplitude coupling (PAC) in electroencephalographic (EEG) recordings. We examined the cortical activity in infants after fetal exposure to SRIs relative to a control group of infants without medical history of any kind. Our findings show that the sleep-related dynamics of PPC networks are selectively affected by in utero SRI exposure, however, those alterations do not correlate to later neurocognitive development as tested by neuropsychological evaluation at two years of age. In turn, phase-amplitude coupling was found to be suppressed in SRI infants across multiple distributed cortical regions and these effects were linked to their neurocognitive outcomes. Our results are compatible with the overall notion that in utero drug exposures may cause subtle, yet measurable changes in the brain structure and function. Our present findings are based on the measures of local and inter-areal neuronal interactions in the cortex which can be readily used across species, as well as between different scales of inspection: from the whole animals to in vitro preparations. Therefore, this work opens a framework to explore the cellular and molecular mechanisms underlying neurodevelopmental SRI effects at all translational levels.Peer reviewe

Evidence for spared attention to faces in 7-month-old infants after prenatal exposure to antiepileptic drugs

Introduction: Prenatal antiepileptic drug (AED) exposure is associated with an increased risk of cognitive impairment and autism spectrum disorders detected mainly at the age of two to six years. We examined whether the developitiental aberrations associated with prenatal AED exposure-could be-detected already in infancy and whether effects on visual attention can be observed at this early age. Material and methods: We compared a prospective cohort of infants with in utero exposure to AED (n = 56) with infants without drug exposures (n = 62). The assessments performed at the age of seven months included standardized neurodevelopmental scores (Griffiths Mental Developmental Scale and Hammersmith Infant Neurological Examination) as well as a novel eye-tracking-based test for visual attention and orienting to faces. Background information included prospective collection of AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, and information on maternal epilepsy type. Results: Carbamazepine, oxcarbazepine, and valproate, but not lamotrigine or levetiracetam, were associated with impaired early language abilities at the age of seven months. The general speed of visuospatial orienting or attentional bias for faces measured by eye-tracker-based tests did not differ between AED-exposed and control infants. Discussion: Our findings support the idea that prenatal AED exposure may impair verbal abilities, and this effect may be detected already in infancy. In contrast, the early development of attention to faces was spared after in utero AED exposure. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds

Introduction: Prenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. Material and methods: Data on AED exposure. pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. Results: Frontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. Conclusions: These preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information. (C) 2019 Elsevier Inc. All rights reserved.Peer reviewe

Healthy full-term infants' brain responses to emotionally and linguistically relevant sounds using a multi-feature mismatch negativity (MMN) paradigm

We evaluated the feasibility of a multi-feature mismatch negativity (MMN) paradigm in studying auditory processing of healthy newborns. The aim was to examine the automatic change-detection and processing of semantic and emotional information in speech in newborns. Brain responses of 202 healthy newborns were recorded with a multi-feature paradigm including a Finnish bi-syllabic pseudo-word/ta-ta/as a standard stimulus, six linguistically relevant deviant stimuli and three emotionally relevant stimuli (happy, sad, angry). Clear responses to emotional sounds were found already at the early latency window 100-200 ms, whereas responses to linguistically relevant minor changes and emotional stimuli at the later latency window 300-500 ms did not reach significance. Moreover, significant interaction between gender and emotional stimuli was found in the early latency window. Further studies on using multi-feature paradigms with linguistic and emotional stimuli in newborns are needed, especially those containing of follow-ups, enabling the assessment of the predictive value of early variations between subjects.Peer reviewe

Healthy full-term infants’ brain responses to emotionally and linguistically relevant sounds using a multi-feature mismatch negativity (MMN) paradigm

We evaluated the feasibility of a multi-feature mismatch negativity (MMN) paradigm in studying auditory processing of healthy newborns. The aim was to examine the automatic change-detection and processing of semantic and emotional information in speech in newborns. Brain responses of 202 healthy newborns were recorded with a multi-feature paradigm including a Finnish bi-syllabic pseudo-word/ta-ta/as a standard stimulus, six linguistically relevant deviant stimuli and three emotionally relevant stimuli (happy, sad, angry). Clear responses to emotional sounds were found already at the early latency window 100–200 ms, whereas responses to linguistically relevant minor changes and emotional stimuli at the later latency window 300–500 ms did not reach significance. Moreover, significant interaction between gender and emotional stimuli was found in the early latency window. Further studies on using multi-feature paradigms with linguistic and emotional stimuli in newborns are needed, especially those containing of follow-ups, enabling the assessment of the predictive value of early variations between subjects.</p

Infant brain function after fetal exposure to neuroactive drugs

Background: In utero exposure to antiepileptic drugs (AEDs) or to serotonin reuptake inhibitors (SRIs) is associated with structural and functional teratogenesis. The aim of this thesis was to investigate whether prenatal SRI or AED exposure changes newborn brain activity. In addition, we wanted to evaluate the effects of prenatal AED exposure on visual attention and emotion-related attention in infancy and to characterize functional connectivity in healthy term newborns. Material and Methods: A prospective cohort of infants with in utero AED exposure (n=56) and similar cohort with in utero SRI exposure (n=22) were compared to infants without drug exposure (n=67). Background information, exposure data, pregnancy outcome, neuropsychological evaluation of the mothers (AED), mood and anxiety of mothers (SRI), and neurological status of the infants were assessed at neonatal age and at 7 months-of-age. Electroencephalography (EEG) was used to evaluate newborn cortical function and an eye-tracking-based test to assess the infants visual attention and orienting to faces. Results: Neurological assessment showed subtle abnormalities in both the AED- and the SRI-exposed newborns. Early language abilities were impaired at 7 month-of-age in infants with in utero carbamazepine, oxcarbazepine, and valproate exposure. The general speed of visuospatial orienting or attentional bias for faces did not differ between AED-exposed and control infants. Computational EEG analyses demonstrated several differences between the exposed and control newborns. AED-exposed newborns had lower amplitudes at multiple frequencies, higher interhemispheric synchrony in frontal versus posterior parts of the brain, more even distribution of interhemispheric interval durations, and fewer frontal alpha bouts of typical duration. In the SRI-exposed newborns, interhemispheric connectivity was reduced, cross-frequency integration was lower, and frontal activity at low-frequency oscillations was reduced. These effects were unrelated to maternal depression or anxiety. In unexposed newborns, functional connectivity was shown to vary significantly between vigilance states and to mature rapidly after normal birth. Conclusions: The results suggest that prenatal AED and SRI treatment may change newborn brain function and affect early neonatal neurologic status. In addition, AED exposure may impair verbal abilities in a way that can be detected already in infancy. Early development of visual attention as well as orienting and face perception were spared after in utero AED exposure. Results in the newborn connectivity study support the view that emerging functional connectivity exhibits fundamental differences between sleep states during the neonatal period. The findings suggest that interference in the development of an activity-dependent network may be a possible mechanism to explain the link from prenatal AED and SRI exposure to later adverse functional effects.Taustaa: Sikiöaikainen altistuminen antiepileptiselle lääkitykselle ja serotoniinin takaisinotonestäjälääkitykselle saattaa aiheuttaa rakenteellisia ja toiminnallisia kehityshäiriöitä. Tämän väitöskirjatyön tavoitteena oli tutkia, aiheuttaako sikiöaikainen altistuminen näille lääkkeille muutoksia vastasyntyneiden aivojen toiminnassa. Lisäksi halusimme arvioida epilepsialääkealtistuksen vaikutuksia näönvaraisen tarkkaavuuden suuntaamiseen imeväisiässä ja arvioida aivojen eri osien välistä yhteistoimintaa terveillä vastasyntyneillä. Tällä koeasetelmalla pyrimme erottelemaan lääkkeiden aiheuttamat sikiöaikaiset vaikutukset syntymän jälkeen tulevista ympäristövaikutuksista. Menetelmät: Seurantatutkimukseemme osallistui 56 sikiöaikana epilepsia- ja 22 serotoniinin takaisinotonestäjälääkkeille altistunutta imeväistä sekä 67 verrokkia. Keräsimme tausta-, altistumis-, synnytys- ja vastasyntyneisyyskauden sairauskertomustiedot. Lisäksi epilepsiaa sairastaville äideille tehtiin neuropsykologinen ja serotoniinin takaisinotonestäjälääkityille äideille psykiatrinen tutkimus. Lastenneurologi tutki lapset sekä vastasyntyneenä että 7 kk iässä käyttäen strukturoituja menetelmiä. Vastasyntyneen aivojen toimintaa arvioitiin elektroenkefalografian (EEG) avulla ja imeväisikäisen näönvaraista tarkkaavuutta ja tarkkaavuuden suuntaamista eri tunnetiloja ilmentäviin kasvoihin mitattiin silmänliikekameratekniikkaan perustuvalla menetelmällä. Tulokset: Neurologisessa arviossa todettiin vähäisiä eroja altistuneissa vastasyntyneissä verrattuna verrokkilapsiin. Varhaisten kielellisten taitojen todettiin olevan heikommat tietyille epilepsialääkkeille (karbamatsepiini, okskarbatsepiini ja valproaatti) sikiöaikana altistuneilla lapsilla 7 kk iässä. Näönvaraisen tarkkaavuuden suuntaamisen nopeudessa ei todettu eroa epilepsialääkkeille altistuneiden ja verrokkilasten välillä. Tietokonepohjaiset EEG analyysit toivat esille useita muutoksia sekä epilepsia- että masennuslääkkeille altistuneiden vastasyntyneiden aivosähkötoiminnassa. Muutokset näkyivät sekä paikallisesti että eri aivoalueiden yhteistoiminnassa. Masennuslääketutkimuksessa muutokset eivät vaikuttaneet liittyvän äitien masennukseen tai ahdistuneisuuteen. Lisäksi verrokkilapsilla tutkittuna aivojen eri osien välisen yhteistoiminnan eroavan merkittävästi eri vireystilojen välillä ja kypsyvän nopeasti ajan myötä. Päätelmät: Tulosten perusteella on pääteltävissä, että sikiöaikainen altistuminen epilepsia- tai SRI-lääkitykselle näkyy vastasyntyneen aivojen toiminnassa ja kliinisessä neurologisessa arviossa. Lisäksi epilepsialääkitys saattaa heikentää kielellisiä taitoja imeväisiässä tavalla, joka on todettavissa jo 7 kk iässä. Toisaalta epilepsialääkitys ei näytä vaikuttavan heikentävästi varhaiseen näönvaraiseen tarkkaavuuteen tai kasvojen tunnistamiskykyyn. Aivojen eri alueiden yhteistoiminnan muutokset vastasyntyneen ensiviikkoina vahvistavat ajatusta siitä, että vireystila ja aivojen kypsyminen vaikuttavat merkittävästi varhaiseen tähän toimintaan. Löydösten perusteella voidaan ajatella, että aivojen varhaisen verkostoitumisen häiriintyminen saattaisi olla yksi mekanismi, jolla sikiöaikaisen lääkealtistuksen myöhemmin esille tulevat haittavaikutukset syntyvät

Functional brain connectivity develops rapidly around term age and changes between vigilance states in the human newborn

Large-scale coupling in neuronal activity is essential in all cognitive functions, but its emergence and functional correlates are poorly known in the human newborn. This study aimed to characterize functional connectivity in the healthy human newborn, and to identify the changes in connectivity related to vigilance states and to maturation during the early postnatal weeks. We recorded active and quiet sleep of 38 sleeping newborn babies using multichannel electroencephalography (EEG) at 2 neonatal time points. Functional connectivity between brain areas was quantified with 3 different metrics: phase–phase correlations, amplitude–amplitude correlations (AACs), and phase–amplitude correlations. All functional connectivity measures changed significantly between vigilance states and matured rapidly after normal birth. The observed changes were frequency-specific, most salient in AAC coupling, and their development was compatible with the known development of structural cortico-cortical connectivity. The present findings support the view that emerging functional connectivity exhibits fundamental differences between sleep states months before the onset of genuine EEG signatures of sleep states. Moreover, our findings also support the idea that early cortical events entail different mechanisms of functional coupling needed to provide endogenous guidance for early activity-dependent development of brain networks

Child growth and neurodevelopment after maternal antenatal antibiotic treatment

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Impact of In Utero Exposure to Antiepileptic Drugs on Neonatal Brain Function

In utero brain development underpins brain health across the lifespan but is vulnerable to physiological and pharmacological perturbation. Here, we show that antiepileptic medication during pregnancy impacts on cortical activity during neonatal sleep, a potent indicator of newborn brain health. These effects are evident in frequency-specific functional brain networks and carry prognostic information for later neurodevelopment. Notably, such effects differ between different antiepileptic drugs that suggest neurodevelopmental adversity from exposure to antiepileptic drugs and not maternal epilepsy per se. This work provides translatable bedside metrics of brain health that are sensitive to the effects of antiepileptic drugs on postnatal neurodevelopment and carry direct prognostic value