Using LTP to investigate the Neurosteroid Withdrawal Hypothesis of Perimenstrual Catamenial Epilepsy
Poster No:
1095
Submission Type:
Abstract Submission
Authors:
Malak Alshakhouri1, Rachael Sumner1, Farheen Kothiwala1, Suresh Muthukumaraswamy1, Khalid Hamandi2, Paul Hofman3, Peter Bergin4, Cynthia Sharpe5
Institutions:
1The University of Auckland, Auckland, New Zealand, 2CUBRIC, University Hospital of Wales and Cardiff University, Cardiff, Wales., 3Liggins Institute, The University of Auckland, Auckland, New Zealand, 4Neurology Auckland Hospital, Te Whatu Ora, Auckland, New Zealand, 5Starship Hospital, Auckland District Health Board, Auckland, New Zealand
First Author:
Co-Author(s):
Introduction:
Catamenial epilepsy refers to seizure exacerbations during certain phases of the menstrual cycle, a condition affecting 40% of women with epilepsy (WWE) that is often treatment-resistant (Herzog, 2015). Perimenstrual catamenial epilepsy (PCE) is the most common pattern, exemplified by a two-fold increase in seizure frequency around menstruation (Herzog, 2004). Female sex steroids are involved in modulating cortical excitability. Very broadly, oestradiol enhances glutamatergic excitation, while progesterone enhances GABAergic inhibition via its neuroactive metabolite, allopregnanolone (ALLO) (Reddy, 2016). The current hypothesis, which has only been tested in rodents, suggests PCE could be a withdrawal symptom caused by the rapid premenstrual decline of ALLO following prolonged exposure during the luteal phase (Reddy, 2016). Long-term potentiation (LTP) is a model of neural plasticity that allow us to non-invasively investigate changes in cortical excitability (Sumner, 2020b). This study utilised an established visual LTP and electroencephalography (EEG) paradigm to investigate the effect of ALLO withdrawal directly in humans.
Methods:
This study used a within-subject, repeated-measures, counterbalanced, observational design. Twenty-one WWE with uncontrolled seizers and 25 healthy controls attended 3 sessions timed to their perimenstrual (day -3 to +2), mid-follicular (day 5 to 8), and mid-luteal (day -5 to -9) phases, with day 1 being the first day of menstrual bleeding. Cycle timing was confirmed using ovulation and blood tests. Blood will be analysed for changes in progesterone, oestradiol, ALLO and GABAA receptor (GABAAR) mRNA. At each session, participants were presented with repetitive sine gratings at low frequency (1Hz) for 4 minutes, preceding a 2-minute high-frequency photic tetanus (9Hz) to induce LTP (Fig 1). The low-frequency condition was repeated at 2- and 40-minutes post-tetanus to record early and sustained LTP changes, respectively. EEG was recorded using a 64-channel actiCAP system. Data was pre-processed using Fieldtrip and analysed using SPM12 in MATLAB. LTP was assessed as changes in visual evoked potential (VEP) amplitude between pre-tetanus and post-tetanus recordings.
·Fig 1. Diagram of the LTP paradigm timing and sequence. Adapted from Sumner, et al., (2020a).
Results:
The data from the entire control cohort and the first nine WWE were included in the analysis. Initial analysis revealed a significant enhancement of the P2 peak of the VEP in the late post-tetanus condition at 183ms in the control cohort (F(1,288) = 76.8, p < 0.05 FWE-c) and at 215ms in the epilepsy cohort (F(1,96) = 73.3, p < 0.05 FWE-c). The timing of these peaks was used to inform the main within-subject analysis of menstrual cycle phase effect. A significant effect of menstrual cycle phase on visual LTP was found in the control cohort (F(2, 288) = 12.1, p < 0.05 FWE-c). P2 enhancement was significantly greater during the mid-follicular phase than the perimenstrual phase (t(48) = 4.41, p < 0.05 FWE-c) (Fig 2a). In the epilepsy cohort, exploratory analyses revealed a trend in the opposite direction. P2 enhancement was greater during the perimenstrual phase than the mid-follicular phase (t(16) = 3.23, p < 0.01 unc) (Fig 2b).
· 2. Topographies of the P2 peak during the perimenstrual and mid-follicular phases for (A) the healthy control cohort and (B) the epilepsy cohort.
Conclusions:
We found greater LTP enhancement during the mid-follicular phase compared to the perimenstrual phase in healthy females, although both phases are associated with low serum hormone levels. The latter is however associated with higher progesterone to oestradiol ratio, potentially leading to dominating effects of GABAergic inhibition and thus reduced cortical excitation (Reddy, 2004). It is too early to interpret the epilepsy findings, given the small sample size at the time of analysis. Yet, our preliminary finding shows some promise as it appears to align with rodent findings of increased cortical excitation during the perimenstrual phase (Reddy, 2007). This could reflect heightened sensitivity of women with PCE to ALLO withdrawal, possibly underlined by dysregulation of GABAAR as the current hypothesis suggests.
Learning and Memory:
Neural Plasticity and Recovery of Function 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Receptors
Transmitter Systems
Novel Imaging Acquisition Methods:
EEG 2
Physiology, Metabolism and Neurotransmission :
Physiology, Metabolism and Neurotransmission Other
Keywords:
Blood
Electroencephaolography (EEG)
Epilepsy
GABA
Glutamate
Neurotransmitter
Plasticity
1|2Indicates the priority used for review
Provide references using author date format
Herzog, A. G. (2004), 'Frequency of catamenial seizure exacerbation in women with localization-related epilepsy', Ann Neurol, vol 56, no. 3, pp. 431-4.
Reddy, D. S. (2016), 'Catamenial Epilepsy: Discovery of an Extrasynaptic Molecular Mechanism for Targeted Therapy', Front Cell Neurosci, vol 10, pp. 101.
Sumner, L. R. (2020a). 'Ketamine enhances visual sensory evoked potential long-term potentiation in patients with major depressive disorder', Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, vol 5, pp. 45-55.
Sumner, L. R. (2020b). 'The role of Hebbian learning in human perception: a methodological and theoretical review of the human Visual Long-Term Potentiation paradigm', Neuroscience & Biobehavioral Reviews, vol 115, pp. 220-37