Maternal dexamethasone and EEG hyperactivity in preterm fetal sheep

Abstract

Non-technical summary Long-acting glucocorticoids such as dexamethasone are commonly given to women at risk of preterm labour. While they significantly improve survival of the prematurely born infant, their effects on preterm brain activity is surprisingly unclear. We found that, in sheep, a conventional clinical course of maternal dexamethasone treatment was associated with dramatic, evolving low-frequency hyperactivity of the fetal EEG. This activity reflected a striking shift to less-frequent but higher amplitude EEG waveforms, and unexpectedly, EEG waveforms whose duration and pattern were highly consistent with seizure activity. After resolution of hyperactivity, the EEG showed changes consistent with maturation of sleep architecture, and reassuringly there was no histological evidence of brain injury 5 days after first exposure. The long-term implications are uncertain, but these effects may contribute to improved neonatal outcomes.Abstract Maternal treatment with synthetic corticosteroids such as dexamethasone (DEX) significantly reduces neonatal morbidity and mortality, but its effects on the fetal brain remain unclear. In this study we evaluated the effects of DEX on EEG activity in preterm fetal sheep. Ewes at 103 days gestation received two intramuscular injections of DEX (12 mg, n = 8) or saline vehicle (n = 7) 24 h apart. Fetal EEG activity was recorded from 6 h before until 120 h after the first injection (DEX-1). DEX-1 was associated with a marked transient rise in total EEG power, maximal at 12 h (P < 0.001), with a relative increase in delta and reduced theta, alpha and beta activity, resolving by 24 h. Continuous EEG records showed a shift to larger but less frequent transient waveforms (P < 0.001). Unexpectedly, evolving epileptiform activity, consistent with electrographic and clinical seizures, developed from 178 ± 44 min after DEX-1. Similar but smaller changes were seen after the second injection. Following the injections, total power returned to control values, but the proportion of alpha activity progressively increased vs. controls (P < 0.001), with reduced interburst interval duration and number (P < 0.001). No histological neural injury or microglial activation was seen. In summary, exposure to maternal dexamethasone was associated with dramatic, evolving low-frequency hyperactivity on fetal cortical EEG recordings, followed by sustained changes consistent with maturation of fetal sleep architecture. We postulate that these effects may contribute to improved neonatal outcomes. Abbreviations DEX-1 and -2, first and second dexamethasone injections; IBI, interburst interval; HPA, hypothalamic-pituitary-adrenal; REM, rapid-eye movement.

Maternal treatment with glucocorticoids modulates gap junction protein expression in the ovine fetal brain

“…Recent evidence suggests that maternal treatment with dexamethasone in doses similar to those in our study was associated with increased epileptiform activity, consistent with electrographic and clinical seizures on fetal cortical EEG recordings, and with later changes in the fetal EEG indicative of increased maturation of fetal sleep architecture (Davidson et al, 2011). The increases in cerebral cortical connexin-36 and -43 that we detected potentially reflect increases in neuronal and astrocytic gap junction channels that could facilitate increased cell-to-cell electrical communication (Eugenin et al, 2012) and have allowed for the recently reported increased epileptiform activity observed after maternal dexamethasone treatment (Davidson et al, 2011).…”

“…The increases in cerebral cortical connexin-36 and -43 that we detected potentially reflect increases in neuronal and astrocytic gap junction channels that could facilitate increased cell-to-cell electrical communication (Eugenin et al, 2012) and have allowed for the recently reported increased epileptiform activity observed after maternal dexamethasone treatment (Davidson et al, 2011). …”

Limited predictive value of early changes in EEG spectral power for neural injury after asphyxia in preterm fetal sheep

“…Brain development at this age is broadly consistent with 28 to 32 wk in humans, before the development of cortical myelination (14). The fetal EEG at this age is consistent with that of the preterm human infant, with discontinuous mixed-frequency activity with periods of quiescence (the so called interburst interval) alternating with periods of high-amplitude slowwave activity (15,16).…”

“…Total EEG power (µV 2 ) was calculated from the intensity spectra. Quantitative EEG measurements for each waveform were performed to quantify power in the Δ (0-3.9 Hz), θ (4-7.9 Hz), α (8-12.9 Hz), and β (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) bands. This involved calculating power spectra (by fast Fourier transform) of the EEG on sequential epochs, using a 10 s Hanning window to minimize spectral leakage.…”

Effects of Neonatal Dexamethasone Exposure on Adult Neuropsychiatric Traits in Rats

“…Tapered neonatal dexamethasone in rats alters cortical spreading depression velocity (an evoked propagating wave) in mature animals, but not cortical potentiation [83]. Whilst maternal exposure to dexamethasone in fetal sheep produces changes in EEG power bands lasting at least several days in utero [84], however it is unknown if these changes extend into adulthood, or for more than a few days. Therefore, perinatal glucocorticoids may have effects on brain function, but they do not appear to enduring changes specific to neuropsychiatric traits in electrophysiology measures of brain function.…”