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Premenstrual dysphoric disorder (PMDD) afflicts 3%-5% of women of childbearing age, and is characterised by recurrent negative mood symptoms (eg, irritability, depression, anxiety and emotional lability) during the luteal phase of the menstrual cycle. The aetiology of PMDD is unknown, although a temporal association with circulating ovarian steroids, in particular progesterone and its metabolite allopregnanolone, has been established during the luteal phase. Allopregnanolone is a positive modulator of the GABA(A) receptor: it is sedative in high concentrations but may precipitate paradoxical adverse effects on mood at levels corresponding to luteal phase concentrations in susceptible women. Saccadic eye velocity (SEV) is a measure of GABA(A) receptor sensitivity; in experimental studies of healthy women, i.v. allopregnanolone decreases SEV. Women with PMDD display an altered sensitivity to an i.v. injection of allopregnanolone compared to healthy controls in this model. In functional magnetic resonance imaging (fMRI) studies, women with PMDD react differently to emotional stimuli in contrast to controls. A consistent finding in PMDD patients is increased amygdala reactivity during the luteal phase. Post-mortem studies in humans have revealed that allopregnanolone concentrations vary across different brain regions, although mean levels in the brain also reflect variations in peripheral serum concentrations. The amygdala processes emotions such as anxiety and aggression. This is interesting because allopregnanolone is detected at high concentrations within the region into which marked increases in blood flow are measured with fMRI following progesterone/allopregnanolone administration. Allopregnanolone effects are antagonised by its isomer isoallopregnanolone (UC1010), which significantly reduces negative mood symptoms in women with PMDD when administered s.c. in the premenstrual phase. This was shown in a randomised, placebo-controlled clinical trial in which the primary outcome was change in symptom scoring on the Daily Rating of Severity of Problems (DRSP): the treatment reduced negative mood scores (P<.005), as well as total DRSP scores (P<.01), compared to placebo in women with PMDD. In conclusion, the underlying studies of this review provide evidence that allopregnanolone is the provoking factor behind the negative mood symptoms in PMDD and that isoallopregnanolone could ameliorate the symptoms as a result of its ability to antagonise the allopregnanolone effect on the GABA(A) receptor.

Background: Premenstrual dysphoric disorder (PMDD) is hypothesized to stem from maladaptive neural sensitivity to ovarian steroid hormone fluctuations. Recently, we found thinner cortices in individuals with PMDD, compared to healthy controls, during the symptomatic phase. Here, we aimed at investigating whether such differences illustrate state-like characteristics specific to the symptomatic phase, or trait-like features defining PMDD.

Methods: Patients and controls were scanned using structural magnetic resonance imaging during the mid-follicular and late-luteal phase of the menstrual cycle. Group-by-phase interaction effects on cortical architecture metrics (cortical thickness, gyrification index, cortical complexity, and sulcal depth) were assessed using surface-based morphometry.

Results: Independently of menstrual cycle phase, a main effect of diagnostic group on surface metrics was found, primarily illustrating thinner cortices (0.3 < Cohen's d > 1.1) and lower gyrification indices (0.4 < Cohen's d > 1.0) in patients compared to controls. Furthermore, menstrual cycle-specific effects were detected across all participants, depicting a decrease in cortical thickness (0.4 < Cohen's d > 1.7) and region-dependent changes in cortical folding metrics (0.4 < Cohen's d > 2.2) from the mid-follicular to the late luteal phase.

Limitations: Small effects (d = 0.3) require a larger sample size to be accurately characterized.

Conclusions: These findings provide initial evidence of trait-like cortical characteristics of the brain of individuals with premenstrual dysphoric disorder, together with indications of menstrual cycle-related variations in cortical architecture in patients and controls. Further investigations exploring whether these differences constitute stable vulnerability markers or develop over the years may help understand PMDD etiology.

Premenstrual dysphoric disorder (PMDD) is a female-specific condition classified in the Diagnostic and Statical Manual—5th edition under depressive disorders. Alterations in grey matter volume, cortical thickness and folding metrics have been associated with a number of mood disorders, though little is known regarding brain morphological alterations in PMDD. Here, women with PMDD and healthy controls underwent magnetic resonance imaging (MRI) during the luteal phase of the menstrual cycle. Differences in grey matter structure between the groups were investigated by use of voxel- and surface-based morphometry. Machine learning and multivariate pattern analysis were performed to test whether MRI data could distinguish women with PMDD from healthy controls. Compared to controls, women with PMDD had smaller grey matter volume in ventral posterior cortices and the cerebellum (Cohen’s d = 0.45–0.76). Region-of-interest analyses further indicated smaller volume in the right amygdala and putamen of women with PMDD (Cohen’s d = 0.34–0.55). Likewise, thinner cortex was observed in women with PMDD compared to controls, particularly in the left hemisphere (Cohen’s d = 0.20–0.74). Classification analyses showed that women with PMDD can be distinguished from controls based on grey matter morphology, with an accuracy up to 74%. In line with the hypothesis of an impaired top-down inhibitory circuit involving limbic structures in PMDD, the present findings point to PMDD-specific grey matter anatomy in regions of corticolimbic networks. Furthermore, the results include widespread cortical and cerebellar regions, suggesting the involvement of distinct networks in PMDD pathophysiology.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a mood disorder characterized by psychological and physical symptoms. Differences in white matter have been associated with affective and anxiety disorders, which share some symptoms with PMDD. However, whether white matter structure differs between the brains of individuals with PMDD and healthy controls is not known, nor is its relation to symptom severity.

METHODS: We performed tract-based spatial statistics and voxel-based morphometry analyses of diffusion tensor imaging metrics and white matter volume, using 2 neuroimaging data sets (n = 67 and n = 131) and a combined whole-brain and region-of-interest approach. We performed correlation analyses to investigate the relationship between regions with different white matter microstructure and volume and PMDD symptom severity.

RESULTS: We found greater fractional anisotropy in the left uncinate fasciculus (d = 0.69) in individuals with PMDD compared to controls. Moreover, the volume of the right uncinate fasciculus was higher in individuals with PMDD compared to controls (d = 0.40). As well, the severity of premenstrual depression was positively correlated with fractional anisotropy in the right superior longitudinal fasciculus (r = 0.35).

LIMITATIONS: It is challenging to interpret group differences in diffusion tensor imaging metrics in terms of their underlying biophysical properties. The small size of the control group in the diffusion tensor imaging study may have prevented effects of interest from being detected.

CONCLUSION: The findings of the present study provide evidence of differential cerebral white matter structure associated with PMDD and its symptoms.

Background Premenstrual dysphoric disorder (PMDD) is an ovarian hormone-bound disorder, characterized by mood symptoms which occur exclusively during the luteal phase of the menstrual cycle. Previous neuroimaging studies of PMDD have primarily reported functional brain differences during the luteal phase in regions of the salience network (SN), which is commonly implicated in mood and anxiety disorders. SN dysfunction may mediate affective and behavioral deficits by leading to enhanced detection and inappropriate assignment of salience to stimuli. What drives altered brain function in PMDD is unknown. However, one influential hypothesis implicates the luteal phase hormone progesterone, and in particular its neurosteroid metabolites. Progesterone-derived neurosteroids increase transmission at the g- aminobutyric acid type A (GABAA) receptor, leading to increased inhibitory tone at the neuronal level. This thesis aimed to i) investigate structural and functional characteristics of the brain in PMDD, ii) relate functional measures to levels of neurosteroids during the luteal phase, and iii) investigate how gene expression of GABAA receptor subunits is altered across the menstrual cycle in PMDD.

Results In Study I, we found that women with PMDD had thinner cortices in widespread brain regions, including regions of the SN. In Studies II and III, we found that increases in functional brain measures are most prominent during the symptomatic luteal phase in regions belonging to the SN and in other networks commonly involved in the psychopathology of mood disorders. Furthermore, we could show that increased activity in key nodes of the SN was apparent in the follicular phase and related to the severity of affective symptoms experienced during the luteal phase. Additionally, in Study II, we found that functional activity in the amygdala, a key region of the SN, was differentially associated with serum levels of GABAA receptor- active neurosteroids between PMDD and controls during the luteal phase. Lastly, in Study IV, we found seminal evidence of reduced mRNA expression of the d-GABAA subunit, which imbues GABAA receptors with increased sensitivity to progesterone’s neurosteroid metabolites. Lower expression of d subunits was related to higher amygdala reactivity.

Conclusion In this thesis, I provide evidence for altered structure and function in multiple brain networks, particularly the SN in PMDD. Accentuated SN dysfunction during the symptomatic luteal phase may be mediated by the amygdala, and related to abnormal deficits in the expression of neurosteroid-sensitive d- GABAA receptors in response to ovarian hormone fluctuations.

Background: Premenstrual dysphoric disorder (PMDD) has been hypothesized to be related to an abnormal sensitivity of the g-aminobutyric acid type A (GABAA) receptor to progesterone-derived neurosteroids. GABAA receptor sensitivity to neurosteroid-modulation is dependent on its subunit composition.

Methods: In the present study, we used quantitative reverse transcription polymerase chain reactions (RT-qPCR) to compare messenger ribonucleic acid (mRNA) expression of GABAA receptor subunits in peripheral mononuclear cells (PBMCs) across the menstrual cycle in 29 women with PMDD and 27 controls. We related mRNA subunit expression to serum levels of neurosteroids, and to functional activation of the amygdala, a key brain region involved in emotion generation, measured using functional magnetic resonance imaging (fMRI).

Results: Women with PMDD had lower mRNA expression of the delta GABAA receptor subunit during the luteal phase of the menstrual cycle. Lower delta mRNA expression was related to higher amygdala activation in PMDD women.

Conclusion: GABAA receptor incorporating the delta subunit are especially sensitive to neurosteroids modulation. It is possible that the mood symptoms of PMDD are mediated by an inability to effectively adjust the expression of this receptor type in response to neurosteroids fluctuations, leading to dysregulation GABAergic tone and increased activity in emotion-generating brain circuits.

Background: Emotion regulation deficits have been highlighted as a transdiagnostic feature of multiple psychiatric disorders. Deficient prefrontal “top-down” regulation of key nodes of the salience network (SN) associated with emotion generation, has previously been hypothesized to be relevant also in premenstrual dysphoric disorder (PMDD).

Methods: In the present study, we used functional magnetic resonance imaging (fMRI) to investigate menstrual-cycle related variations in brain activity and connectivity in response to two separate emotional tasks (emotion reactivity and regulation) in 29 women with PMDD and 27 controls. We also examined whether differential brain activation between groups is related to premenstrual symptom severity and serum levels of progesterone-derived neuroactive steroids.

Results: We did not find convincing evidence for reduced activity in regions associated with the conscious control of emotion in PMDD. However, women with PMDD showed increased reactivity in key nodes of the SN and the default mode network (DMN) during the luteal phase compared to control women. Furthermore, SN hyperactivity was apparent also during the follicular phase and related to PMDD symptom severity. We found no evidence of altered network connectivity across the menstrual cycle in PMDD women.

Conclusion: SN dysfunction during the luteal phase may mediate multiple network aberrations. Furthermore, higher baseline (follicular) SN activity may render PMDD women more susceptible to severe mood symptoms in response to hormonal fluctuations. What drives increased SN activity in the follicular phase is unknown, but innate and neuroplastic mechanisms are proposed.

Premenstrual dysphoric disorder (PMDD) is a debilitating disorder characterized by severe mood symptoms in the luteal phase of the menstrual cycle. PMDD symptoms are hypothesized to be linked to an altered sensitivity to normal luteal phase levels of allopregnanolone (ALLO), a GABAA-modulating progesterone metabolite. Moreover, the endogenous 3β-epimer of ALLO, isoallopregnanolone (ISO), has been shown to alleviate PMDD symptoms through its selective and dose-dependent antagonism of the ALLO effect. There is preliminary evidence showing altered recruitment of brain regions during emotion processing in PMDD, but whether this is associated to serum levels of ALLO, ISO or their relative concentration is unknown. In the present study, subjects with PMDD and asymptomatic controls underwent functional magnetic resonance imaging (fMRI) in the mid-follicular and the late-luteal phase of the menstrual cycle. Brain responses to emotional stimuli were investigated and related to serum levels of ovarian steroids, the neurosteroids ALLO, ISO, and their ratio ISO/ALLO. Participants with PMDD exhibited greater activity in brain regions which are part of emotion-processing networks during the late-luteal phase of the menstrual cycle. Furthermore, activity in key regions of emotion processing networks - the parahippocampal gyrus and amygdala - was differentially associated to the ratio of ISO/ALLO levels in PMDD subjects and controls. Specifically, a positive relationship between ISO/ALLO levels and brain activity was found in PMDD subjects, while the opposite was observed in controls. In conclusion, individuals with PMDD show altered emotion-induced brain responses in the late-luteal phase of the menstrual cycle which may be related to an abnormal response to physiological levels of GABAA-active neurosteroids.