Poster No:
1332
Submission Type:
Abstract Submission
Authors:
Rachael Sumner1, Malak Alshakhouri1, Suresh Muthukumaraswamy2, Alexander Shaw3, Khalid Hamandi4, Paul Hofman5, Peter Bergin6, Cynthia Sharpe7
Institutions:
1The University of Auckland, Auckland, Auckland, 2University of Auckland, Auckland, Auckland, 3University of Exeter, Exeter, Exeter, 4Cardiff University, Cardiff, Cardiff, 5Liggins Institute, Auckland, Auckland, 6Neurology, Auckland Hospital, Auckland, Auckland, 7Paediatric Neurology, Starship Children’s Health, Auckland, Auckland
First Author:
Co-Author(s):
Peter Bergin
Neurology, Auckland Hospital
Auckland, Auckland
Cynthia Sharpe
Paediatric Neurology, Starship Children’s Health
Auckland, Auckland
Introduction:
Epilepsy is one of the most common debilitating neurological disorders globally (World Health Organization, 2019). For 40% of women with epilepsy, the menstrual cycle increases their seizure frequency two-fold or more (Herzog et al., 2015). The main subtype, perimenstrual catamenial epilepsy accounts for ~70% of cases. A leading theory on its cause is naturally occurring rapid withdrawal from the neurosteroid allopregnanolone (ALLO) during the perimenstrual phase (Alshakhouri et al., 2023a, 2023b). ALLO, a metabolite of progesterone (P4), enhances the brain's major inhibitory system via GABA-A receptors. This withdrawal allows oestradiol (E2) to dominate. E2 is excitatory and thus can exacerbate seizures (Woolley, 2007). This study visually induced long-term potentiation (LTP) to assess E2 dominance at different phases of the menstrual cycle of people with epilepsy.
Methods:
Twenty-five females (age 14-45) with uncontrolled epilepsy took part in a within-subject, repeated-measures, counterbalanced study. Three study visits were timed to capture the mid-follicular trough in hormones (days +5 to +8), the mid-luteal peak (days -9 to -5), and the withdrawal from the peak in the late-luteal and early menses or perimenstrual phase (days -25 to +2). Timing was confirmed with blood E2 and P4 concentration, confirming ovulation.
A 64-channel Brain Products ActiCap system recorded electroencephalography at each visit. The visual LTP task was used to assess changes in evoked potentials associated with shifts in plasticity over the menstrual cycle. Generative thalamocortical modelling (Sumner et al., 2020) probed the mechanism – whether an increase in E2 driven excitation, or a decrease in GABAergic inhibition is dominant.
Results:
Mean hormone concentrations for the follicular phase were 192 pmol/L E2 and 0.46 nmol/L P4. For the luteal phase 485 pmol/L E2 and 29 nmol/L P4 (all from ovulatory cycles). In the perimenstrual phase: 191 pmol/L E2 and 3.76 nmol/L P4 demonstrates all were collected when hormones were withdrawing from peak levels.
In the evoked potential analysis there was a significant interaction between phase and time (F(2, 216)=13.78, p=0.002). This was driven by significantly higher LTP-driven potentiation of the P2 visually evoked potential 40-mins after induction. Specifically in the luteal phase compared to the follicular phase (T(216)=4.55, p=0.003) and to a lesser extent in the perimenstrual phase compared to the follicular phase (T(216)=4.06, p=0.020). There were no significant differences in potentiation of P2 between the luteal and perimenstrual phase.
The thalamocortical model provided an excellent fit for the data (98% variance explained). The difference between follicular and luteal potentiation was driven by an increase in modulation of excitatory spiny stellate (layer 4) input to superficial interneurons (layer 2/3) (exceedance probability; Ep=0.11), decrease in self-gain in superficial pyramidal cells (layer 2/3) (Ep=-0.13), and increase in relay input into spiny stellates (Ep=0.13). The difference in the follicular to perimenstrual phase was modulated to a lesser extent and only a decrease in self-gain into superficial pyramidal cells was seen (Ep=0.22). Posterior probabilities all >0.99.
Conclusions:
Higher P2 potentiation in the luteal and perimenstrual phase is consistent with when many of our participants report worsening seizures. Further, a healthy control cohort showed the opposite, a suppression of potentiation in the luteal phase. In epilepsy, a breakthrough of E2 driven excitation may be the dominating influence on seizure threshold in the luteal and perimenstrual phases.
Modelling revealed an increase in excitatory parameters, rather than a decrease in inhibitory parameters in the luteal phase driving this effect. The leading neurosteroid withdrawal theory of catamenial epilepsy predicts a decrease in ALLO driven inhibition, making our finding important to understanding catamenial epilepsy pathophysiology.
Modeling and Analysis Methods:
EEG/MEG Modeling and Analysis 1
Novel Imaging Acquisition Methods:
EEG
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission 2
Keywords:
Computational Neuroscience
Electroencephaolography (EEG)
Epilepsy
GABA
1|2Indicates the priority used for review
By submitting your proposal, you grant permission for the Organization for Human Brain Mapping (OHBM) to distribute your work in any format, including video, audio print and electronic text through OHBM OnDemand, social media channels, the OHBM website, or other electronic publications and media.
I accept
The Open Science Special Interest Group (OSSIG) is introducing a reproducibility challenge for OHBM 2025. This new initiative aims to enhance the reproducibility of scientific results and foster collaborations between labs. Teams will consist of a “source” party and a “reproducing” party, and will be evaluated on the success of their replication, the openness of the source work, and additional deliverables. Click here for more information.
Propose your OHBM abstract(s) as source work for future OHBM meetings by selecting one of the following options:
I am submitting this abstract as an original work to be reproduced. I am available to be the “source party” in an upcoming team and consent to have this work listed on the OSSIG website. I agree to be contacted by OSSIG regarding the challenge and may share data used in this abstract with another team.
Please indicate below if your study was a "resting state" or "task-activation” study.
Task-activation
Healthy subjects only or patients (note that patient studies may also involve healthy subjects):
Patients
Was this research conducted in the United States?
Yes
Are you Internal Review Board (IRB) certified?
Please note: Failure to have IRB, if applicable will lead to automatic rejection of abstract.
Yes, I have IRB or AUCC approval
Were any human subjects research approved by the relevant Institutional Review Board or ethics panel?
NOTE: Any human subjects studies without IRB approval will be automatically rejected.
Yes
Were any animal research approved by the relevant IACUC or other animal research panel?
NOTE: Any animal studies without IACUC approval will be automatically rejected.
Not applicable
Please indicate which methods were used in your research:
EEG/ERP
Computational modeling
Provide references using APA citation style.
Alshakhouri, M., Sharpe, C., Bergin, P., & Sumner, R. L. (2023a). Female sex steroids and epilepsy: Part 1. A review of reciprocal changes in reproductive systems, cycles, and seizures. Epilepsia, n/a(n/a). https://doi.org/10.1111/epi.17842
Alshakhouri, M., Sharpe, C., Bergin, P., & Sumner, R. L. (2023b). Female sex steroids and epilepsy: Part 2. A practical and human focus on catamenial epilepsy. Epilepsia, n/a(n/a). https://doi.org/10.1111/epi.17820
Herzog, A. G., Fowler, K. M., Sperling, M. R., Massaro, J. M., & Progesterone Trial Study, G. (2015). Distribution of seizures across the menstrual cycle in women with epilepsy. Epilepsia, 56(5), e58-62. https://doi.org/10.1111/epi.12969
Sumner, R. L., Spriggs, M. J., & Shaw, A. D. (2020). Modelling thalamocortical circuitry shows visually induced LTP changes laminar connectivity in human visual cortex. bioRxiv, 2020.2002.2008.940155. https://doi.org/10.1101/2020.02.08.940155
Woolley, C. S. (2007). Acute Effects of Estrogen on Neuronal Physiology. Annual Review of Pharmacology and Toxicology, 47(1), 657-680. https://doi.org/10.1146/annurev.pharmtox.47.120505.105219
World Health Organization. (2019). Epilepsy: a public health imperative. Retrieved from: https://www.who.int/publications/i/item/epilepsy-a-public-health-imperative
No