Effects of in utero exposure to antiepileptics are still observed in cortical networks at six years
Poster No:
284
Submission Type:
Abstract Submission
Authors:
Anton Tokariev1, Sebastian König2, Pauliina Yrjölä1, Sami Auno1, Mari Videman3, Sampsa Vanhatalo1
Institutions:
1University of Helsinki, Helsinki, Finland, 2Aalto University, Espoo, Finland, 3Helsinki University Hospital, Helsinki, Finland
First Author:
Co-Author(s):
Introduction:
The fetal brain undergoes dynamic self-organization during late gestation, guided mostly by endogenous activity. At this time brain is extremely sensitive to environmental and pharmacological effects, including maternal drug treatments. Our previous research demonstrated that in utero exposure to antiepileptic drugs (AEDs) disrupts functional cortical networks in newborns. However, it remained unclear whether these functional effects persist into later childhood. In this follow-up study, we compared the cortical networks of children who were exposed to AEDs in utero with their control peers at six years of age. We also tested if AED-induced alterations in brain networks correlate with neurocognitive performance.
Methods:
We collected 64-channel EEG during sleep from N = 46 six-year-old children (6.34 ± 0.25 years). This dataset included N = 25 children those were exposed to AEDs in utero as a result of maternal treatment and they did not have any signs of epilepsy. Another subgroup included N = 21 children who experienced a normal pregnancy and were thus classified as healthy controls (HC). Next, we selected artifact-free two-minute-long EEG epochs during sleep states N1 and N2 for each subject. Scalp EEG signals were filtered into five frequency bands of interest: low delta (0.4–1.5 Hz), high delta (1.5–4 Hz), theta (4–8 Hz), alpha (8–13 Hz), beta (13–22 Hz); and further source-reconstructed into 58 cortical parcels using an age-adjusted head model. Cortical connectivity networks were computed as phase-phase correlations between all parcel pairs using weighted phase lag index. We examined group differences (AED vs. HC) in frequency- and state-specific networks using the Wilcoxon rank-sum test and assessed interaction effects (how each group transitions from N1 to N2) using network-based statistics. The network patterns showing statistical differences were correlated (Spearman test) with neuropsychological assessment scores: Verbal Comprehension Index (VCI), Perceptual Reasoning Index (PRI), Working Memory Index (WMI), Processing Speed Index (PSI), and full-scale Intelligence Quotient (full IQ).
Results:
We observed significant differences between groups in large-scale cortical networks, which were both frequency- and sleep-specific (Fig.1). During N1 stage, AED group showed stronger connectivity at low delta and beta frequencies in ~5-8% of connections (p < 0.05, FDR-corrected) that were uniformly distributed over the cortex. In turn, at theta-alpha frequency range posterior networks in AED were robustly weaker (~6-7% of edges). However, during N2 sleep, we observed hyperconnectivity in the alpha network, comprising almost 22% of all edges in the AED group. Low delta network was similar to N1 (AED > HC, 7.2%) and high delta-theta networks showed differences in sparser cortical patterns (AED < HC, ~2-5%). We also observed robust interaction effects between groups during their transition between states at low delta and alpha frequencies (Fig.2). Interestingly, that connectivity changes in low delta network positively correlated to PSI, WMI, and Full IQ (rho ≥ 0.37; p ≤ 0.04), whereas alpha changes negatively correlated to PRI (rho = −0.48, p = 0.01). In addition, we analyzed the coincidence on spindles in the alpha frequency network, which showed no statistical difference between the groups.
Conclusions:
Our current results show that the effects of prenatal AED exposure on cortical sleep networks and their dynamics persist at the age of six years. Importantly, our previous work on the same AED group at newborn age also revealed disruptions in functional networks supporting early sleep. (Tokariev et al., 2022). At both time points these effects correlate with neurodevelopment. These studies suggest that the analysis of cortical-level networks holds promise for disclosing clinically informative effects of early exposure to pharmacological therapies.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism) 1
Lifespan Development:
Lifespan Development Other 2
Keywords:
Cognition
Cortex
Development
Electroencephaolography (EEG)
Epilepsy
PEDIATRIC
Sleep
1|2Indicates the priority used for review
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