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Background: Emotion regulation deficits have been highlighted as a transdiagnostic feature of multiple psychiatric disorders, including premenstrual dysphoric disorder (PMDD). In this study, we hypothesized that deficient prefrontal top-down regulation of key nodes of the salience network (SN) is a characteristic of PMDD, driven by increased levels of progesterone-derived neuroactive steroids.

Methods: Functional magnetic resonance imaging was used to investigate menstrual cycle–related variations in brain activity and connectivity during 2 emotional tasks (emotion generation and regulation) in 29 women with PMDD and 27 control women. We also examined whether differential brain activation between groups was related to serum levels of progesterone-derived neuroactive steroids and premenstrual symptom severity.

Results: Women with PMDD showed increased reactivity in key nodes of the SN and, at subthreshold level, in the default mode network during the luteal phase when passively viewing negative emotional stimuli. Intriguingly, SN hyperactivity in patients with PMDD was also apparent during the follicular phase and related to premenstrual symptom severity. Women with PMDD and control women had similar network connectivity patterns and activity in regions associated with the conscious control of emotion in PMDD. No link to progesterone-derived neuroactive steroids was found.

Conclusions: Multiple network aberrations during the luteal phase may explain the development of mood symptoms during the luteal phase. Furthermore, higher baseline (follicular) SN activity may render women with PMDD 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 have been proposed.

Background Premenstrual dysphoric disorder (PMDD) is common, with at least 3% of the female population affected by one or more of the typical mood symptoms of depression, irritability, mood swings and anxiety. The cyclicity and close relationship to the luteal phase of the menstrual cycle is characteristic for this syndrome and positive allosteric modulators (PAMs) on the GABAA receptor, especially allopregnanolone, are believed to be involved in the symptomatology.

Aim To summarise the research on the role of PAMs and other neuroactive steroids in the pathophysiology of PMDD.

Method PubMed was searched for articles including the terms Premenstrual syndrome, AND neurosteroids OR allopregnanolone OR GABA OR oestradiol. Many additional publications were previously known to the authors and basic animal research was covered in a secondary step through reference lists.

Results There is evidence that allopregnanolone, like other PAMs of the GABAA receptor, is sedative in high concentrations and, in a minor proportion of the population, causes anxiety and irritability at lower levels, pointing to an inter-individual difference in sensitivity. In research comparing women with PMDD and healthy controls, differences in brain function and subcomposition of GABAA receptors related to levels of allopregnanolone have been found. Also, the varying levels of neuroactive steroids in general seem to worsen the symptoms. Supressed ovulation is effective but add-back hormones are necessary to prevent severe side-effects and could cause adverse mood in these individuals.

Conclusions There is yet no effective treatment for PMDD available. Allopregnanolone seems to be a key provocateur of PMDD symptoms in susceptible individuals. Future research should focus on interventions that interfere with the effects of neurosteroids or the plasticity of the GABAA receptor itself.

Background: Premenstrual dysphoric disorder (PMDD) is characterized by symptoms of irritability, affective lability, anxiety, and depression, which occur only in the luteal phase of ovulatory menstrual cycles. This offers an ideal model to assess the neural correlates of the on and off switch of mood symptoms. Recently, we highlighted differences in grey matter volume between individuals with PMDD and healthy controls during the luteal phase, depicting smaller volumes in those diagnosed with the condition. However, it is unknown whether such alterations represent state-like changes specific to the symptomatic phase, or trait-like characteristics.

Methods: Here, 28 patients with PMDD and 26 controls underwent anatomical magnetic resonance imaging during the mid-follicular and the late-luteal phases of the menstrual cycle. For each time point, we assessed grey matter volumes over the whole brain using voxel-based morphometry.

Results: We found no group-by-phase interaction effect on grey matter volumes, but a main effect of group across menstrual cycle phases, suggesting trait rather than state structural markers of PMDD. Patients displayed smaller volumes compared to controls, primarily in the cerebellum and cuneus, and at a trend-level in ventral occipito-temporal, parietal, paracentral and orbitofrontal areas, as well as the putamen (Cohen’s d range: 0.4–1.1).

Conclusions: These findings suggest that the differences in grey matter volumes found in PMDD are stable across the menstrual cycle and could represent trait-like, vulnerability markers of PMDD.

Premenstrual dysphoric disorder (PMDD) has been hypothesized to be related to an altered sensitivity of the γ-aminobutyric acid type A (GABAA) receptor to progesterone-derived neurosteroids. GABAA receptor sensitivity to neurosteroid-modulation is dependent on its subunit composition. 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). Women with PMDD had lower mRNA expression of the delta GABAA receptor subunit during the symptomatic, luteal phase (compared to the asymptomatic, follicular phase) of the menstrual cycle. Lower delta mRNA expression was related to higher amygdala activation in PMDD women. GABAA receptors incorporating the delta subunit are especially sensitive to neurosteroid 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 neurosteroid fluctuations, leading to dysregulation GABAergic tone and increased activity in emotion-generating brain circuits.

Background: Premenstrual dysphoric disorder (PMDD) is an understudied, debilitating, and hormone-related mental disorder. Recent evidence suggests alterations in white matter structure during the symptomatic luteal phase in PMDD. In this study, white matter volumes (WMVs) in the brains of women with PMDD versus control women were compared across the menstrual cycle, to determine whether these differences reflect state- or trait-like characteristics.

Methods: Anatomical magnetic resonance imaging was performed during the midfollicular phase and the late luteal phase of the menstrual cycle in 28 women with PMDD and 27 control women. WMVs were assessed using voxel-based morphometry, employing both region-of-interest (ROI) and exploratory whole-brain approaches.

Results: No group-by-phase interaction effects on WMVs were found. Across menstrual cycle phases, women with PMDD exhibited greater WMVs than control women within ROIs (in the bilateral uncinate fasciculus, right inferior fronto-occipital fasciculus, and left crus and fimbria of the fornix) and across the whole brain (in inferior occipital areas and near the angular gyrus), indicating trait- rather than state-like structural markers of PMDD.

Conclusions: These findings suggest that women with PMDD exhibit larger WMVs than healthy control women, during both the symptomatic and asymptomatic phases of the menstrual cycle, in white matter tracts involved in emotion processing and regulation, memory, and connecting limbic and prefrontal regions of relevance to mood disorders.

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.

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.

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.

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.