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

Abstract

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.

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

“…Next, we wanted to see if sleep-related network dynamics, or change in network strengths between sleep states, is affected by SRI exposure. This approach was motivated by our recent works where comparable sleep-related network dynamics was shown to disclose significant effects from prematurity ( Tokariev et al, 2019a ) and in utero exposure to maternal antiepileptic medication ( Tokariev et al, 2021 ). Such analysis of relative individual level change is more powerful in detecting salient effects because it automatically calibrates to the individual baseline levels of network strengths.…”

“…The procedure outputs a binary template that rejects the same subset of unreliable connections (about 32%) from all empirical networks. Then, in line with our previous work (Tokariev et al, 2019a(Tokariev et al, , 2021, we focused on the sleepby-group interaction that holds important information about infant brain function (Figure 2). To isolate frequency-specific network patterns with altered sleep-related dynamics due to SRI exposure, we used network-based statistics (Zalesky et al, 2010).…”

“…Our study was prospective with a stringent psychiatric evaluation of the maternal state ( Videman et al, 2017 ), which provides a good clinical characterization of the patient cohort. Our analytical methods for computing cortical networks are also well characterized and openly available ( Tokariev et al, 2019a , 2021 ) to allow direct benchmarking across methodologies. However, there are limitations arising from the limited numbers of study subjects available for such work, and further cohorts with prospective patient recruitments are needed to validate the present findings.…”

“…Here, we hypothesized that in utero exposure to SRIs in the human newborn infants would change cortical frequencyspecific and cross-frequency interactions measured by PPC and PAC, respectively. This hypothesis was motivated by the globallevel PAC findings from the scalp EEG data in the same infant cohort (Videman et al, 2017), as well as by the many other PPC findings in infants after other drug exposures or neonatal adversities (Tokariev et al, 2019b(Tokariev et al, , 2021Yrjola et al, 2021). All these prior studies have suggested that PAC and PPP may be sensitive in disclosing early neurodevelopmental effects.…”

“…All these requirements can be met by studying cortical activity—estimated from reconstruction of the scalp-recorded EEG—and analysis of phase-phase correlations (PPC) for remote cortico-cortical interactions, and phase-amplitude coupling (PAC) for local interactions. PPC is considered to support large-scale communications at high temporal precision and is sensitive to various adversities including drug exposure ( Palva et al, 2005 , 2010 ; Engel et al, 2013 ; Tokariev et al, 2019b , 2021 ). PAC is taken as a measure of cross-frequency interaction that is found in most brain functions and structures ( Cohen et al, 2009 ; Canolty and Knight, 2010 ; Liu et al, 2015 ; Palva and Palva, 2018 ; Siebenhühner et al, 2020 ).…”