Using EEG to Assess Neural Effects of Blood Sex Steroid Ratios: Progesterone and Allopregnanolone to Estradiol in Females with and without Epilepsy

Abstract

Background: Catamenial epilepsy (CE) is a poorly understood menstrual cycle-specific exacerbation of seizures (1), affecting up to 70% of females with epilepsy (EF) (2). Sex steroid 17β-estradiol (E2) is seizure-enhancing via neural excitation (3). Progesterone (P4) via its metabolite allopregnanolone (ALLO) is seizure-protective, by promoting GABAergic neural inhibition (4). Visual gamma (VG) is an evoked visual cortex oscillation, which can be recorded using electroencephalography (EEG) (191,192). VG varies in frequency across the menstrual cycle in healthy females (HF), mirroring changes in GABA-related inhibition (180). Objectives: To increase understanding of CE’s pathophysiology, this study assessed relationships between blood sex steroid ratios (P4/E2; ALLO/E2) and VG parameters and seizure severity across the menstrual cycle. Methods: Participants (n=43 HF, n=20 EF) completed study sessions at differing phases of their menstrual cycle. Blood samples were taken to derive plasma sex steroid ratios. EEG was recorded and VG peak frequency and amplitudes were determined. EF used seizure diaries to record seizure severity. Results: The only significant relationship between blood sex steroid ratios and VG parameters in the HFs was a positive one between P4/E2 and peak VG frequency when viewing moving stimuli. In the EFs, the only significant relationship between these was a negative one between ALLO/E2 and VG amplitude when viewing moving stimuli. The only significant relationship between seizure intensity and frequency probability with the other study variables was a positive one between intensity and VG frequency. Discussion: Changes in VG frequency did not match changes in amplitude, potentially due to differing neural mechanisms. Several expected relationships between sex steroid ratios and changes to neural signalling were not corroborated here, which may indicate that it is the denovo expression of neurosteroids directly altering neural firing, or that external factors like stress influence this relationship. However, some differences in the sex-steroid and VG relationships were seen between HF and EF. Further research should attempt to clarify this difference. For the first time, this study showed the effects of VG in females with epilepsy and measured the effect of the blood sex steroid ratios on neural excitation and inhibition, across the menstrual cycle.