Cognitive outcomes after fetal exposure to carbamazepine, lamotrigine, valproate or levetiracetam monotherapy: Data from the EURAP neurocognitive extension protocol.

PURPOSE: Prenatal exposure to antiseizure medications (ASMs) has been associated with an increased risk of major malformations and neurodevelopmental disorders, with the latter being mainly associated with valproate (VPA). Our aim was to compare neurocognitive outcome at age 6-7 years in children exposed prenatally to lamotrigine (LTG), carbamazepine (CBZ), valproate (VPA) or levetiracetam (LEV) monotherapy. METHODS: Eligible mother-child pairs were identified from the observational prospective multinational EURAP cohort study. Assessor-blinded testing was conducted at age 6-7 years using WISC-III and NEPSY-II. Verbal IQ (VIQ), performance IQ (PIQ), full scale IQ (FSIQ) and performance in neuropsychological tasks were compared across ASM groups by ANOVA. Scores were adjusted for maternal IQ, paternal education, maternal epilepsy type and child sex. RESULTS: Of 169 children enrolled in the study, 162 (LTG n = 80, CBZ n = 37, VPA n = 27, LEV n = 18) had sufficient data from WISC-III, NEPSY-II or both, and were included in the analyses. Observed (unadjusted) PIQ and FSIQ did not differ across exposure groups, but a difference was identified for VIQ (P<0.05), with children exposed to VPA having lower scores than children exposed to LEV (P<0.05) and children from all groups combined (P<0.01). Adjusted VIQ, PIQ and FSIQ scores did not differ significantly across groups, but VPA-exposed children had borderline significantly lower adjusted VIQ scores than children from all groups combined (P=0.051). VPA-exposed children had lower scores in comprehension of instructions before and after adjustment for confounding variables than children exposed to LTG (P<0.001), LEV (P<0.01) or children from all groups combined (p < 0.001). The VPA-exposed group also had lower scores in immediate and delayed memory for faces compared to children exposed to CBZ (P<0.05 and P<0.001, respectively) and LTG (P<0.05 and P<0.02, respectively), and children from all groups combined (P<0.02 and P<0.001, respectively). LEV-exposed children had lower scores in delayed memory for names than children exposed to LTG (P<0.001), CBZ (P<0.001), VPA (P<0.05) and children from all groups combined (P<0.001). CONCLUSIONS: Consistent with previous reports, our results provide evidence for an adverse effect of prenatal exposure to valproate on verbal development. Our finding of relatively weaker performance of VPA-exposed children compared to other ASM exposures in both comprehension of instructions and face memory also suggest that children of mothers treated with VPA are at increased risk for compromised memory functions or altered processing of socially relevant information.

Phase-Based Cortical Synchrony Is Affected by Prematurity.

Inter-areal synchronization by phase-phase correlations (PPCs) of cortical oscillations mediates many higher neurocognitive functions, which are often affected by prematurity, a globally prominent neurodevelopmental risk factor. Here, we used electroencephalography to examine brain-wide cortical PPC networks at term-equivalent age, comparing human infants after early prematurity to a cohort of healthy controls. We found that prematurity affected these networks in a sleep state-specific manner, and the differences between groups were also frequency-selective, involving brain-wide connections. The strength of synchronization in these networks was predictive of clinical outcomes in the preterm infants. These findings show that prematurity affects PPC networks in a clinically significant manner, suggesting early functional biomarkers of later neurodevelopmental compromise that may be used in clinical or translational studies after early neonatal adversity.

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.

Preterm Birth Changes Networks of Newborn Cortical Activity.

Preterm birth is the greatest risk factor for lifelong neurocognitive deficits, globally. The effect of prematurity on early cortical network function has, however, remained poorly understood. Here, we developed a novel methodology that allows reliable assessment of functional connectivity in neonatal brain activity at millisecond and multisecond scales in terms of cortical phase and amplitude correlations, respectively. We measured scalp electroencephalography at term-equivalent age in infants exposed to very early prematurity as well as in healthy controls. We found that newborn cortical activity organizes into multiplex networks that differ significantly between vigilance states. As compared with healthy control infants, prematurity was found to cause frequency-specific patterns of dysconnectivity in cortical network, changes that were distinct for networks of phase and amplitude correlations. Neuroanatomically, the most prominent markers of prematurity were found in connections involving the frontal regions. Phase synchrony in frontally connected networks was correlated with newborn neurological performance, suggesting the first measure of cortical functional coupling that correlates with neurological performance in human infant.

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.

Newborn Brain Function Is Affected by Fetal Exposure to Maternal Serotonin Reuptake Inhibitors.

Recent experimental animal studies have shown that fetal exposure to serotonin reuptake inhibitors (SRIs) affects brain development. Modern recording methods and advanced computational analyses of scalp electroencephalography (EEG) have opened a possibility to study if comparable changes are also observed in the human neonatal brain. We recruited mothers using SRI during pregnancy (n = 22) and controls (n = 62). Mood and anxiety of mothers, newborn neurology, and newborn cortical function (EEG) were assessed. The EEG parameters were compared between newborns exposed to drugs versus controls, followed by comparisons of newborn EEG features with maternal psychiatric assessments. Neurological assessment showed subtle abnormalities in the SRI-exposed newborns. The computational EEG analyses disclosed a reduced interhemispheric connectivity, lower cross-frequency integration, as well as reduced frontal activity at low-frequency oscillations. These effects were not related to maternal depression or anxiety. Our results suggest that antenatal serotonergic treatment might change newborn brain function in a manner compatible with the recent experimental studies. The present EEG findings suggest links at the level of neuronal activity between human studies and animal experiments. These links will also enable bidirectional translation in future studies on the neuronal mechanisms and long-term neurodevelopmental effects of early SRI exposure.

Visual fixation in human newborns correlates with extensive white matter networks and predicts long-term neurocognitive development.

Infants are well known to seek eye contact, and they prefer to fixate on developmentally meaningful objects, such as the human face. It is also known, that visual abilities are important for the developmental cascades of cognition from later infancy to childhood. It is less understood, however, whether newborn visual abilities relate to later cognitive development, and whether newborn ability for visual fixation can be assigned to early microstructural maturation. Here, we investigate relationship between newborn visual fixation (VF) and gaze behavior (GB) to performance in visuomotor and visual reasoning tasks in two cohorts with cognitive follow-up at 2 (n = 57) and 5 (n = 1410) years of age. We also analyzed brain microstructural correlates to VF (n = 45) by voxel-based analysis of fractional anisotropy (FA) in newborn diffusion tensor imaging. Our results show that newborn VF is significantly related to visual-motor performance at both 2 and 5 years, as well as to visual reasoning at 5 years of age. Moreover, good newborn VF relates to widely increased FA levels across the white matter. Comparison to motor performance indicated that early VF is preferentially related to visuocognitive development, and that early motor performance relates neither to white matter integrity nor to visuocognitive development. The present findings suggest that newborn VF is supported by brainwide subcortical networks and it represents an early building block for the developmental cascades of cognition.

Effects of prenatal antiepileptic drug exposure on newborn brain activity.

OBJECTIVE: Prenatal exposure to antiepileptic drugs (AEDs) is associated with an increased risk of cognitive dysfunction at early school age. Our aim was to investigate whether signs of adverse drug effects on brain function could be detected already during the first 2 weeks of life. METHODS: We studied prospectively 56 full-term newborns with prenatal exposure to AEDs and 67 unexposed newborns for the following characteristics: Background information, AED exposure data, pregnancy outcome, neuropsychological evaluation of the mothers, clinical neurologic status with Hammersmith Neonatal Neurological Examination and early cortical activity using electroencephalography (EEG). For EEG assessment, we developed and provide automated quantitation algorithms of several earlier described features: oscillatory bouts at theta and alpha frequencies, frequency spectra, interhemispheric synchrony, and interburst intervals (IBIs). RESULTS: The AED-exposed newborns had lower limb and axial tone and were less irritable than the unexposed newborns. EEG assessment disclosed significant differences in alpha bouts, in the frequency spectra, as well as in the spatial distributions of interhemispheric synchrony and IBIs. SIGNIFICANCE: The results indicate that fetal AED exposure may affect early neonatal neurologic status and several features of early cortical activity. The findings suggest that interference of activity-dependent network development may be a possible mechanism to explain the link from fetal AED exposure to later neurocognitive sequelae.

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 developmental 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.

Epilepsies with onset during the first year of life: A prospective study on syndromes, etiologies, and outcomes.

OBJECTIVE: Infantile seizures cause great concern for both doctors and parents. In addition to modern neuroimaging and genetics, clinical tools helpful in predicting the course of the disease are needed. We prospectively studied the incidence, electroclinical characteristics and etiologies of epilepsy syndromes with onset before the age of 12 months and looked for prognostic determinants of outcome by age 24 months. METHODS: From February 2017 through May 2019, we recruited all eligible infants diagnosed with epilepsy at our unit. Data on electroclinical studies, genetic investigations and drug response were gathered prospectively. The infants were given a structured neurological examination (Hammersmith Infantile Neurological examination [HINE] and Griffiths scales) at predetermined intervals until age 24 months at which age neurocognitive evaluation with Bayley scales was performed. RESULTS: Included were 60 infants (27 female). The mean onset age of epilepsy was 5.3 (±2.5 standard deviation) months. The incidence of epilepsy in the population-based cohort was 131 (95% confidence interval 99-172)/100 000. Epilepsy syndrome was identified in 80% and etiology in 58% of infants. Self-limited infantile epilepsy was the second most common syndrome (incidence 18/100 000) after infantile epileptic spasms syndrome. PRRT2 was the most common monogenic cause. At age 24 months, 37% of the infants had drug-resistant epilepsy (DRE) and half had a global developmental delay (GDD). Abnormal first HINE was the strongest predictor of GDD, followed by DRE and identified etiology. DRE was associated with structural etiology and GDD. Those with normal first HINE and good response to treatment had favorable outcomes, irrespective of the identified etiology. SIGNIFICANCE: Our results support a high incidence of self-limited epilepsy in infancy and PRRT2 as the genetic cause in the first year of life. Notwithstanding the advances in etiological discovery, we want to highlight the importance of clinical evaluation as standardized neurological examination with HINE proved a valuable tool in prognostication. PLAIN LANGUAGE SUMMARY: One in every 700-800 babies develop epilepsy within the first year after birth. Our study identified an epilepsy syndrome in 80% and the cause of epilepsy in 60% of the participants. By age 2 years, over one-third of the children still experienced seizures, and almost half faced significant developmental delay. Structural brain abnormalities increased the likelihood of difficult epilepsy and developmental challenges. Babies whose epilepsy was caused by a gene defect varied widely in development and response to medications. Babies with normal neurological examination at first visit, especially if their seizures stopped quickly, had favorable development.

Use of complex visual stimuli allows controlled recruitment of cortical networks in infants.

OBJECTIVE: To characterize cortical networks activated by patterned visual stimuli in infants, and to evaluate their potential for assessment of visual processing and their associations with neurocognitive development. METHODS: Three visual stimuli, orientation reversal (OR), global form (GF), and global motion (GM), were presented to cohort of five-month-old infants (N = 26). Eye tracker was used to guide the stimulation and to choose epochs for analysis. Visual responses were recorded with electroencephalography and analysed in source space using weighted phase lag index as the connectivity measure. The networks were quantified using several metrics that were compared between stimuli and correlated to cognitive outcomes. RESULTS: Responses to OR/GF/GM stimuli were observed in nearly all (96/100/100%) recordings. All stimuli recruited cortical networks that were partly condition-specific in their characteristics. The more complex GF and GM conditions recruited wider global networks than OR. Additionally, strength of the GF network showed positive association with later cognitive performance. CONCLUSIONS: Network analysis suggests that visual stimulation recruits large-scale cortical networks that extend far beyond the conventional visual streams and that differ between stimulation conditions. SIGNIFICANCE: The method allows controlled recruitment of wide cortical networks, which holds promise for the early assessment of visual processing and its related higher-order cognitive processes.

Use of eye tracking improves the detection of evoked responses to complex visual stimuli during EEG in infants.

OBJECTIVE: To improve the reliability of detecting EEG responses evoked by complex visual stimuli to the level required for clinical use by integrating an eye tracker to the EEG setup and optimizing the analysis protocol. METHODS: Infants were presented with continuous orientation reversal (OR), global form (GF), and global motion (GM) stimuli. Eye tracking was used to control stimulus presentation and exclude epochs with disoriented gaze. The spectral responses were estimated from 13 postcentral EEG channels using a circular variant of Hotelling's T2 test statistic. RESULTS: Among 39 healthy infants, statistically significant (p < 0.01) responses to OR/GF/GM stimuli were found from 92%/100%/95% recordings, respectively. The specificity test of the detection algorithm, using non-stimulated baseline EEG, did not yield any false-positive findings. Taken together, this yields 15% improvement on average in the detection performance compared to that in the current literature. CONCLUSIONS: Changes to the test protocol and incorporation of the eye tracking information improves the detection of responses to complex visual stimuli in infants. SIGNIFICANCE: This work presents a test protocol suitable for use in a clinical environment at a level of reliability that allows individual diagnostics.

Dynamic eye tracking based metrics for infant gaze patterns in the face-distractor competition paradigm.

OBJECTIVE: To develop new standardized eye tracking based measures and metrics for infants' gaze dynamics in the face-distractor competition paradigm. METHOD: Eye tracking data were collected from two samples of healthy 7-month-old (total n = 45), as well as one sample of 5-month-old infants (n = 22) in a paradigm with a picture of a face or a non-face pattern as a central stimulus, and a geometric shape as a lateral stimulus. The data were analyzed by using conventional measures of infants' initial disengagement from the central to the lateral stimulus (i.e., saccadic reaction time and probability) and, additionally, novel measures reflecting infants gaze dynamics after the initial disengagement (i.e., cumulative allocation of attention to the central vs. peripheral stimulus). RESULTS: The results showed that the initial saccade away from the centrally presented stimulus is followed by a rapid re-engagement of attention with the central stimulus, leading to cumulative preference for the central stimulus over the lateral stimulus over time. This pattern tended to be stronger for salient facial expressions as compared to non-face patterns, was replicable across two independent samples of 7-month-old infants, and differentiated between 7 and 5 month-old infants. CONCLUSION: The results suggest that eye tracking based assessments of infants' cumulative preference for faces over time can be readily parameterized and standardized, and may provide valuable techniques for future studies examining normative developmental changes in preference for social signals. SIGNIFICANCE: Standardized measures of early developing face preferences may have potential to become surrogate biomarkers of neurocognitive and social development.

Sleep wake cycling in early preterm infants: comparison of polysomnographic recordings with a novel EEG-based index.

OBJECTIVE: To document the occurrence of genuine sleep stages in the early preterm babies, and to develop an EEG-based index for following sleep wake cyclicity. METHODS: Twelve preterm babies were recruited from a study that assessed ventilator strategies. We used altogether 18 polysomnography recordings that were collected at mean conceptional age of 29.3 (25.9-32.7) weeks. Spontaneous activity transients (SAT) were detected automatically and their cumulative coverage in each 20s interval was computed from the EEG derivations C3-A2 and O2-A1. Mean SAT% values between sleep stages were compared. RESULTS: All babies exhibited all sleep stages, however the sleep was remarkably fragmentary in infants due to their respiratory issues. The EEG index, SAT% showed temporal behavior that strikingly well compared with the sleep stage fluctuations in the hypnogram. In the statistical analysis we found significant differences in all recordings between the deep (quiet) sleep and the REM sleep. CONCLUSION: Genuine sleep states exist in the early preterm babies, and changes in sleep stages are reflected in the EEG activity in a way that can be readily measured by assessing fluctuation of the automatically detected, EEG based index, the SAT%. SIGNIFICANCE: The findings open a possibility to construct automated analysis or monitoring of sleep wake cyclicity into brain monitors in neonatal intensive care unit.

Preterm EEG: a multimodal neurophysiological protocol.

Since its introduction in early 1950s, electroencephalography (EEG) has been widely used in the neonatal intensive care units (NICU) for assessment and monitoring of brain function in preterm and term babies. Most common indications are the diagnosis of epileptic seizures, assessment of brain maturity, and recovery from hypoxic-ischemic events. EEG recording techniques and the understanding of neonatal EEG signals have dramatically improved, but these advances have been slow to penetrate through the clinical traditions. The aim of this presentation is to bring theory and practice of advanced EEG recording available for neonatal units. In the theoretical part, we will present animations to illustrate how a preterm brain gives rise to spontaneous and evoked EEG activities, both of which are unique to this developmental phase, as well as crucial for a proper brain maturation. Recent animal work has shown that the structural brain development is clearly reflected in early EEG activity. Most important structures in this regard are the growing long range connections and the transient cortical structure, subplate. Sensory stimuli in a preterm baby will generate responses that are seen at a single trial level, and they have underpinnings in the subplate-cortex interaction. This brings neonatal EEG readily into a multimodal study, where EEG is not only recording cortical function, but it also tests subplate function via different sensory modalities. Finally, introduction of clinically suitable dense array EEG caps, as well as amplifiers capable of recording low frequencies, have disclosed multitude of brain activities that have as yet been overlooked. In the practical part of this video, we show how a multimodal, dense array EEG study is performed in neonatal intensive care unit from a preterm baby in the incubator. The video demonstrates preparation of the baby and incubator, application of the EEG cap, and performance of the sensory stimulations.

Evaluation of an easy, standardized and clinically practical method (SurePrep) for the preparation of electrode-skin contact in neurophysiological recordings.

The aim of this study was to assess the practicality, reliability and safety of a recently introduced method of skin preparation for EEG recordings. We compared the traditional skin abrasion (SA) method to a method called SurePrep (SP), which creates tiny incisions through the upper epithelial layers. The study comprised three parts. In part 1, forearm recordings (n = 400; ten healthy volunteers) were conducted to examine acute and late (24 h) impedances, skin reactions, as well as the effects on electrode movement artefacts. In part 2, the effect of repeated (up to nine) SP sticks on impedances was examined on the forearm skin in two subjects (n = 99). In part 3, preparation speed and skin impedances were measured from preparation of a standard EEG cap in four subjects (n = 74). Immediately after preparation, skin impedances were a little lower (n.s.) after SA, but the variability in impedances was significantly less after SP (p < 0.01). After one day, there was no mean impedance difference but a greater proportion of SP sites were >10 kOmega. The frequency of immediate skin irritations (93.5%) was much higher after SA compared to 42.5% after SP, but there was no clinically significant difference observed after one day. The SP method exposed interstitial fluid in 5% of cases, while SA caused a wound-like lesion in 4.5% of the sites. No macroscopic blood was observed in any case (n = 400). Three sticks with the SP device produced clinically sufficient (<10 kOmega) impedances in 85% of the cases, and a total of five to six sticks secured a sufficient skin contact in all skin sites examined (n = 99). Preparation of skin contacts in the EEG cap was faster by SP compared to SA in all four study subjects. Our results demonstrate that skin contacts of sufficient quality can be reliably, easily and quickly prepared by the SP method. SP is a useful alternative for EEG recordings in general, although SA may provide the slightly better preserved skin contacts needed for long-term recordings. Notably, SP could facilitate emergency care units, peripheral hospitals and after-hours EEG acquisition by people without special EEG training.