Changes in Visual Long-Term Potentiation Show Preserved Cyclicity in Human Females Taking Combined Oral Contraceptives

Abstract

Introduction: The combined oral contraceptive pill (COC) is often employed to address physical and neurological symptoms in menstrual cycle-related disorders by suppressing shifts in endogenous gonadal hormone fluctuations. Symptom persistence, especially in the lead up to the hormone free interval (HFI) suggests an underlying neurobiological mechanism of preserved cycling. Our study utilised a non-invasive method of visually inducing long-term potentiation (LTP) to index changes in neural plasticity in the absence of hormonal fluctuations. Methods: Visually induced LTP was recorded using electroencephalography in 24 healthy female COC users across three sessions; day 3 and 21 during active hormone pills, and day 24 during the HFI. The Daily Record of the Severity of Problems (DRSP) questionnaire tracked premenstrual symptoms. Dynamic causal modelling (DCM) was used to elucidate the neural connectivity and receptor activity changes associated with LTP across different days of COC. Results: Visually induced LTP was greater on day 21 than day 3 (p=0.011) and was localised to the P2 visually evoked potential. There was no effect of the HFI (day 24) on LTP. DCM of differences between day 3 and 21 showed changes to inhibitory interneuronal gating of LTP in cortical layer VI. The DRSP only showed a significant increase in symptoms in the HFI, meaning the LTP result appeared more sensitive to cyclicity. Conclusions: This study provides objective evidence of preserved cyclicity in COC users through enhanced LTP on day 21 compared to day 3 of a 28-day COC regimen, indicating that relatively higher excitation in the brain despite peripheral gonadal suppression may underlie and exacerbate menstrual cycle-related disorders.

Modulation of long-term potentiation following microdoses of LSD captured by thalamo-cortical modelling in a randomised, controlled trial

“…Placebo was associated with greater modulation of self-gain on stellates in later 4. Modulation of inhibitory interneuronal input into stellates was also seen in a previous application to this model to LTP sessions conducted over the preserved menstrual cycle of women on hormonal birth control, with a reduction seen in the perimenstrual-like relative to the mid-follicular-like phase [ 22 ]. GABAergic interneuronal inhibition has been shown to provide a gating mechanism preventing the induction of LTP from layer 4 to 3 [ 55 ].…”

“…Given the study was a randomised trial there was no systematic difference for placebo participants that can explain this. However, it does raise the question of the test-retest reliability of the Teyler protocol, for which three repeated measures has rarely been employed previously (one example: [ 22 ]). Outside of this study counterbalancing has always been applied in our own groups’ research to mitigate order effects as a potential confound.…”

“…These were then used in the main analyses of a repeated measures ANOVA of Group (Placebo vs. LSD) x Session (Baseline vs. Treatment/Final) in separate Early and Late analyses. Main and post-hoc effects were considered significant if they achieved a FWE-c p -value < 0.05, while interaction effects were less conservatively considered significant with an uncorrected p -value < 0.001, in line with previous literature [ 22 ]. In both cases FWE-c p- values are reported, and these values are not further corrected in the post-hoc tests.…”

“…Based on previous LTP research [ 21 , 22 ], an occipital-parietal ROI was defined, consisting of electrodes P1, P2, P3, P4, P5, P6, P7, P8, Pz, PO3, PO4, PO7, PO8, PO9, PO10, POz, O1, O2 and Oz. Initial parameter-finding analyses of Time (Early/Late) x Stimulus (Tetanised/Non-tetanised) were conducted in SPM12 on each analysis with planned contrasts to confirm LTP was occurring (Additional file 1 : Table S1), identify the time windows of interest, and test for specificity (altered potentiation of the Tetanised vs. Non-tetanised stimulus).…”

“…Critically, the paradigms induce an LTP-like effect with repeated visual stimulation and record the product of the induced changes as enhanced VEPs in response to the same stimuli. Of these, the Teyler protocol used in the current study [ 16 ], has been shown to produce VEP components which are modulated in relation to ageing [ 17 – 19 ], autism spectrum disorder [ 20 ], depression [ 21 ], and in combined oral contraceptive use [ 22 ]. Crucially, these changes have been associated with pro-plasticity genetic polymorphisms and shown to be predictive of memory task performance [ 23 ].In place of direct electrical stimulation, the Teyler protocol uses high-contrast visual stimuli that are administered as a high frequency photic tetanus, leading to observable changes to VEP components: the N1b (lateralized trailing edge of the negative N1 component occurring around 132–200ms) and P2 (centralized positivity occurring around 178-240ms) [ 14 ].…”