Females with epilepsy show abnormal changes to perimenstrual sensory induced long-term potentiation

Abstract

IntroductionCatamenial epilepsy refers to a cyclical exacerbation of seizure frequency and/or severity linked to stages of the menstrual cycle. To investigate the contribution of underlying excitatory and inhibitory mechanisms of this exacerbation we induced and measured long-term potentiation (LTP). Oestradiol modulates primarily NMDA receptor driven excitation and would enhance visual LTP. Allopregnanolone modulates GABA receptor mediated inhibition and would suppress visual LTP. MethodA control cohort (n = 25) and a cohort with epilepsy (n = 20) were recruited. Participants took part in a visual LTP task while EEG was recorded. Three study visits were timed to capture the mid-follicular (days +5 to +8), mid-luteal (days -9 to -5) phases, as well as the hormone withdrawal in the perimenstrual phase (days -3 to +2). Blood samples confirmed session timing. Generative computational modelling of thalamocortical changes in the EEG was paired with standard evoked potential analysis. Result17 (age 26 {+/-} 9.40) participants with epilepsy, and a control cohort of 25 (age 30 {+/-} 7.06) without epilepsy completed the study. The P2 visually evoked potential (a positive-going component of the visual event related potential waveform) was significantly more enhanced by LTP induction in the mid-follicular phase than the mid-luteal or perimenstrual phases in the control cohort (F(2, 144) =11.54, p = 0.004 corrected). In contrast, in the epilepsy cohort the P2 was significantly more potentiated in the perimenstrual phase than the mid-follicular or mid-luteal phases (F(2,108) = 12.21, p = 0.005 corrected). The effect of cycle on visual LTP was robust, with only 3/17 participants with epilepsy showing highest P2 modulation in the mid-follicular phase (which is the pattern the healthy cohort showed). The computational modelling showed that in epilepsy, the perimenstrual phase was associated with a decrease in superficial pyramidal grain control as well as decreased LTP driven modulation of feed-forward superficial connections to layer 5 and layer 6 to thalamus. DiscussionOur finding of enhanced visual LTP in the luteal phase and perimenstrual phase of females with epilepsy indicates a breakthrough of glutamatergic excitation. Given the relationship between oestrogen and n-methyl-D-aspartate (NMDA) receptor dependent LTP this is plausibly NMDA receptor driven. Several thalamocortical model parameter changes observed warrant further investigation in studies stratifying participants by catamenial epilepsy type. Overall, while research into allopregnanolone and its inhibitory effects dominate perimenstrual catamenial epilepsy research, this study justifies consideration of the role of seizure exacerbating oestradiol.