Abnormal luteal phase excitability of the motor cortex in women with premenstrual syndrome
Introduction
There is evidence suggesting that an abnormal brain response to an essentially normal secretion pattern of the ovarian steroids, estradiol and progesterone, forms the physiological basis of the premenstrual syndrome (PMS; Schmidt et al 1998). These hormones and their metabolites have potent effects on brain function. For example, estradiol increases neuronal excitability Wong et al 1996, Woolley 1999 and lowers the threshold for epileptic seizures (Morrell 1999) by increasing the activity of glutamate, the principal excitatory neurotransmitter in the brain. Progesterone is metabolized to neuroactive compounds, the neurosteroids, some of which bind to a site on the alpha subunit of the γ-aminobutyric acid A (GABAA) receptor, increasing its activity in response to GABA binding (Paul and Purdy 1992) in a manner analogous to the action of the benzodiazepine sedatives and anxiolytics. Like other GABA agonists, neurosteroids reduce neuronal excitability in the cerebral cortex, raising the seizure threshold (Morrell 1999) and blocking anxiety (Brot et al 1997).
Indirect data suggest that in PMS, a disorder of neurosteroid metabolism or action leads to a luteal phase deficit in GABA-mediated inhibition. For instance, women with PMS are reported to have decreased serum GABA levels in the late luteal phase (Halbreich et al 1996). Drug challenge studies have shown decreased behavioral sensitivity both to benzodiazepines (Sundstrom et al 1997) and to the GABA agonist neurosteroid pregnenolone (Sundstrom et al 1998) and greater sensitivity to benzodiazepine receptor antagonism with flumazenil relative to control subjects (Le Melledo et al 2000). Recently, Epperson et al (2002), using magnetic resonance spectroscopy, found that GABA levels in the occipital cortex were abnormally low in the follicular phase and increased abnormally in the luteal phase. They interpreted this increase as implying a possible luteal phase defect in GABA function. Despite these results, convincing physiologic evidence of a defect in luteal phase GABAergic function has yet to be obtained.
Recently adopted noninvasive techniques can test the function of specific neuronal circuits and are beginning to be used to analyze the effects of drugs and other agents in vivo in humans. The amplitude of the muscle response, or motor evoked potential (MEP), produced by transcranial magnetic stimulation (TMS) of the motor cortex reflects the integration of synaptic inputs by the cortical and spinal motoneurons (Figure 1 A). The MEP can be modulated by a preceding “conditioning” stimulus delivered with an intensity below the MEP threshold (Kujirai et al 1993). This occurs even when the conditioning pulse is too weak to produce spinal cord activity, indicating a purely cortical site of interaction between the stimuli. Depending on the interstimulus interval (ISI), the predominant effect of the first stimulus on the second is inhibition or facilitation (Figure 1, B and C). The relative degree of inhibition and facilitation, summed over ISIs, is affected by GABAergic drugs, for example, the benzodiazepines (Ziemann et al 1998). In earlier studies of healthy women Smith et al 1999, Smith et al 2002, we showed that there is less inhibition and more facilitation in the follicular phase under the unopposed excitatory influence of estrogen, which facilitates the action of glutamate, the principal excitatory neurotransmitter in the cerebral cortex; however, in the luteal phase, the balance shifts in favor of inhibition, presumably reflecting the added effect of the progesterone-derived neurosteroids. The theory of a luteal phase deficiency in GABAergic function in PMS predicts that affected women should show less inhibition and more facilitation than matched control subjects. In the study described here, we compared women with and without PMS in a TMS experiment to test the hypothesis that the increase in paired-pulse inhibition, seen and attributed to progesterone in our earlier studies, would be attenuated in women with PMS. Some of these data have been published in abstract form (Smith et al 2000).
Section snippets
Methods and materials
Medication-free women with regular menstrual cycles were selected from respondents to newspaper advertisements for healthy volunteers and women with menstrual-cycle-related mood changes. For 3 months before entry into the study, all prospective participants were screened with a daily visual analog scale for self-rating of affective symptoms including sadness, anxiety, irritability, and mood stability and of somatic symptoms including breast discomfort, bloating, and fatigue. The diagnostic
Results
As expected, the women with PMS had a significantly greater increase in symptoms in the luteal phase than did the control women, both when the scores were collapsed across all scales [group * phase interaction: F(1,21) = 23.8; p = .0002] and on the individual scales (all ps ≤ .01).
No significant differences were found in hormone levels between the groups (see Table 1) and there were no significant correlations between the serum levels of either hormone and the symptom ratings or the
Discussion
In this study, women with PMS showed neurophysiological changes from the follicular to the luteal phase that were significantly different from those of a control group. Specifically, in the PMS group, the luteal phase increase in circulating progesterone was accompanied by an increase in the excitability of the output cells of the motor cortex. This contrasts with the decreased excitability shown by the control subjects in this study and two similar groups of healthy women in our previous
Acknowledgements
The work was supported by National Institute of Neurological Disorders and Stroke and National Institute of Mental Health intramural program funding.
References (37)
- et al.
Mechanisms influencing stimulus-response properties of the human corticospinal system
Clin Neurophysiol
(2001) - et al.
The anxiolytic-like effects of the neurosteroid allopregnanoloneInteractions with GABA(A) receptors
Eur J Pharmacol
(1997) - et al.
Short-term exposure to a neuroactive steroid increases alpha4 GABA(A) receptor subunit levels in association with increased anxiety in the female rat
Brain Res
(2001) Premenstrual syndrome. Advances in diagnosis and treatment
Obstet Gynecol Clin North Am
(2000)- et al.
Progesterone metabolite allopregnanolone in women with premenstrual syndrome
Obstet Gynecol
(1997) - et al.
Patients with premenstrual syndrome have reduced sensitivity to midazolam compared to control subjects
Neuropsychopharmacology
(1997) - et al.
Motor cortex excitability correlates with an anxiety-related personality trait
Biol Psychiatry
(2001) - et al.
Transcranial magnetic stimulationIts current role in epilepsy research
Epilepsy Res
(1998) - et al.
An inventory for measuring depression
Arch Gen Psychiatry
(1961) - et al.
Allopregnanolone in women with premenstrual syndrome
Horm Metab Res
(1998)
Insensitivity to anaesthetic agents conferred by a class of GABA(A) receptor subunit
Nature
A diagnostic interviewThe schedule for affective disorders and schizophrenia
Arch Gen Psychiatry
A placebo-controlled study of effects of oral progesterone on performance and mood
Br J Clin Pharmacol
Altered cortical excitability in obsessive-compulsive disorder
Neurology
Low plasma gamma-aminobutyric acid levels during the late luteal phase of women with premenstrual dysphoric disorder
Am J Psychiatry
Glutamate and GABA systems as targets for novel antidepressant and mood-stabilizing treatments
Mol Psychiatry
Corticocortical inhibition in human motor cortex
J Physiol (Lond)
Cited by (70)
Premenstrual dysphoric disorder: Mental disorder or adjustment difficulty?
2020, Annales Medico-PsychologiquesGender does not matter: Add-on repetitive transcranial magnetic stimulation treatment for female methamphetamine dependents
2019, Progress in Neuro-Psychopharmacology and Biological PsychiatryPreliminary evidence of an association between increased cortical inhibition and reduced suicidal ideation in adolescents treated for major depression
2019, Journal of Affective DisordersCitation Excerpt :Although we assessed the ΔLICI–ΔSI relationship while controlling for change in depression severity, the small sample did not permit controlling for additional covariates such as age and sex. LICI has been found to vary with age in children and adolescents (Croarkin et al., 2014), while other TMS measures of GABAergic cortical inhibition have been found to vary with menstrual phase in adult women (Smith et al., 1999; Smith et al., 2003). Additionally, prior work in adults indicates that LICI has good reliability over time (Farzan et al., 2010), but studies in children and adolescents are lacking.
Cortical inhibitory and excitatory correlates of depression severity in children and adolescents
2016, Journal of Affective DisordersCitation Excerpt :Other considerations for future studies would be to control for effects of sex and menstrual status. While the previous adult literature has found little difference between hemispheres (in relation to handedness) or genders on paired-pulse TMS measures of inhibition and facilitation (Cahn et al., 2003), other studies have indicated a relative cortical facilitation effect during the luteal phase in adult women with premenstrual syndrome (Smith et al., 2003), which is theorized to be related to the activity of neuroactive progesterone metabolites at GABA receptors. These effects, as well as the considerable variation in circulating levels of sex steroids during the adolescent years, should be considered in future work attempting to characterize TMS measures of cortical inhibition and excitability in adolescents.
Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study
2015, Psychiatry Research - NeuroimagingElevated gray matter volume of the emotional cerebellum in women with premenstrual dysphoric disorder
2013, Journal of Affective Disorders