Unexpected Findings in PMDD Research
From gene expression to gamma response
Research suggests several biological distinctions between women with premenstrual dysphoric disorder (PMDD) and controls, that persist across menstrual cycle phase.
These findings are unexpected because PMDD symptoms only occur in the premenstrual phase of the cycle - lasting from ovulation until menstruation. The theme of ‘we’re different all of the time’ seems to ring true in my personal experiences with PMDD, and in several bodies of research.
While this phenomena is not well understood, it should be considered as researchers design studies and develop new hypotheses. PMDD may be a hormonally triggered condition, but very little is known about the biological mechanisms that underpin this complex condition. Perhaps, the premenstrual phase isn’t telling the complete story, so let’s get into the nitty gritty.
Epigenetics
In 2017, a study conducted by the National Institute of Health found variations in gene expression in a gene complex responsible for epigenetic processes related to sex hormones and stressors in women with PMDD vs. study controls.
Divergence in gene expression was demonstrated in cell line cultures from women with PMDD, both with and without the presence of ovarian hormones:
“These findings demonstrate that LCLs [lymphoblastoid cell line cultures] from women with PMDD manifest a cellular difference in ESC/E(Z) complex function both in the untreated [ovarian hormone free] condition and in response to ovarian hormones.”
Brain Connectivity
Neuroimaging of PMDD patients, suggests divergence of functional activity in the brain across all phases of the cycle, not just during the luteal phase when symptoms are present.
fMRI and PET scans have demonstrated a greater activation in the dorsolateral prefrontal cortex while performing cognitive tasks in women with PMDD compared to controls across the cycle.
“Since these correlations were present during all three experimental hormone conditions, our findings suggest that these persistent effects, even in the clinically asymptomatic phase of the hormone manipulation paradigm (i.e., leuprolide alone), may represent an enduring “trait-like” predisposition to this hormonally triggered disorder.”
Greater prefrontal cortex activation is important for evolutionary hypotheses related to PMDD. The prefrontal cortex is considered a key area of the brain for cognitive functions such as empathy and compassion. The prefrontal cortex is believed to be the most recent area of the brain to develop in our evolutionary history, so studying women with PMDD may help scientists better understand the role of this area in the brain.
Gamma Frequency
Brain oscillations measure the speed of neural circuits and are implicated in controlling the connectivity between brain regions, a critical component for memory, emotion and perception.
Visual peak gamma frequency has been demonstrated to fluctuate over the course of the menstrual cycle in the general female population, as demonstrated by Sumner et al.
PMDD research suggests gamma response in the visual cortex is elevated across the menstrual cycle phase in women with PMDD compared to controls, further increasing during the luteal phase. Results from this study were unexpected as the researchers hypothesized inhibitory neuron dysfunction would be implicated in PMDD:
“The atypical modulation of GR power suggests that neuronal excitability in the visual cortex is constitutively elevated in PMDD and that this E/I imbalance is further exacerbated during the luteal phase. However, the unaltered GR frequency does not support the hypothesis of inhibitory neuron dysfunction in PMDD.”
Unexpected findings in research further alludes to the need for new hypotheses and thinking outside of the box on hormonally triggered conditions such as PMDD. As researchers develop new hypotheses for PMDD, a broader lens outside of the symptomatic window may be helpful in exploring causal factors and new treatment options.