Cortical morphology variations during the menstrual cycle in individuals with and without premenstrual dysphoric disorder.

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.

Grey matter morphology in women with premenstrual dysphoric disorder treated with a selective progesterone receptor modulator.

Premenstrual dysphoric disorder (PMDD) is characterized by severe cyclic mood symptoms emerging in the luteal phase of the menstrual cycle. The variation in progesterone levels and its metabolites during the luteal phase seems critical to the occurrence of PMDD symptoms. Notably, the efficacy of selective progesterone receptor modulator (SPRM) treatment on the mental symptoms of PMDD has been recently demonstrated. In the present study, structural magnetic resonance imaging was used to assess the effects of SPRM treatment, compared with placebo, on grey matter morphology in women with PMDD. In total, 35 women were scanned during the luteal phase, before and after three months of treatment with SPRM or placebo. Symptom severity was assessed using the Daily Record of Severity of Problems (DRSP), while gonadal hormone levels were measured by liquid chromatography-tandem mass spectrometry. Region-of-interest and whole-brain approaches were employed to perform voxel-based morphometry analyses, subcortical volumetric analyses, and surface-based morphometry analyses. No interaction or main effects of treatment and time were observed on grey matter volume and cortical surface measures (cortical thickness, gyrification index, sulcal depth, and fractal dimension). The relationship between change in brain morphology and symptom severity was also explored but no treatment-dependant grey matter structure change was related to symptom severity change. These findings suggest that SPRM treatment does not impart macrostructural changes onto grey matter structure, at least in the short term.

Grey matter correlates of affective and somatic symptoms of premenstrual dysphoric disorder.

Ovarian hormones fluctuations across the menstrual cycle are experienced by about 58% of women in their fertile age. Maladaptive brain sensitivity to these changes likely leads to the severe psychological, cognitive, and physical symptoms repeatedly experienced by women with Premenstrual Dysphoric Disorder (PMDD) during the late luteal phase of the menstrual cycle. However, the neuroanatomical correlates of these symptoms are unknown. The relationship between grey matter structure and PMDD symptom severity was delineated using structural magnetic resonance imaging during the late luteal phase of fifty-one women diagnosed with PMDD, combined with Voxel- and Surface-Based Morphometry, as well as subcortical volumetric analyses. A negative correlation was found between depression-related symptoms and grey matter volume of the bilateral amygdala. Moreover, the severity of affective and somatic PMDD symptoms correlated with cortical thickness, gyrification, sulcal depth, and complexity metrics, particularly in the prefrontal, cingulate, and parahippocampal gyri. The present findings provide the first evidence of grey matter morphological characteristics associated with PMDD symptomatology in brain regions expressing ovarian hormone receptors and of relevance to cognitive-affective functions, thus potentially having important implications for understanding how structural brain characteristics relate to PMDD symptomatology.

Altered resting-state functional networks in patients with premenstrual syndrome: a graph-theoretical based study.

Premenstrual syndrome (PMS) is a menstrual cycle-related disorder. Previous studies have indicated alterations of brain functional connectivity in PMS patients. However, little is known about the overall organization of brain network in PMS patients. Functional magnetic resonance imaging data deriving from 20 PMS patients and 21 healthy controls (HCs). Pearson correlation between mean time-series was used to estimate connectivity matrix between each paired regions of interest, and the connectivity matrix for each participant was then binarized. Graph theory analysis was applied to assess each participant's global and local topological properties of brain functional network. Correlation analysis was performed to evaluate relationships between the daily rating of severity of problems (DRSP) and abnormal network properties. PMS patients had lower small-worldness values than HCs. PMS-related alterations of nodal properties were mainly found in the posterior cingulate cortex, precuneus and angular gyrus. The PMS-related abnormal connectivity components were mainly associated with the thalamus, putamen and middle cingulate cortex. In the PMS group, the DRSP score were negatively correlated with the area under the curves of nodal local efficiency in the posterior cingulate cortex. Our study suggests that the graph-theory method may be one potential tool to detect disruptions of brain connections and may provide important evidence for understanding the PMS from the disrupted network organization perspective.

Regulated aberrant amygdala functional connectivity in premenstrual syndrome via electro-acupuncture stimulation at sanyinjiao acupoint（SP6）.

Background: Acupuncture is an effective therapy for premenstrual syndrome (PMS). However, the mechanisms behind this method are still unclear. Our previous study found that aberrant amygdala resting-state functional networks were involved in PMS. Thereby, a deep investigation on the alterations of amygdala resting-state functional networks induced by acupuncture stimulation might contribute to a better understanding of the intricate mechanisms of acupuncture treatment on PMS. Methods: Twenty three PMS patients were recruited in this study. All patients received a 6-minute electro-acupuncture stimulation (EAS) at Sanyinjiao acupoint (SP6) and underwent two 6-minute resting-state fMRI scannings before and after EAS. With amygdala as the seed region, functional connectivity (FC) method was adopted to examine EAS-related modulation of intrinsic connectivity in PMS patients by comparing pre-EAS. Results: The results showed that EAS at SP6 induced increased FC between the left amygdala and brainstem, right hippocampus, and decreased FC between the left amygdala and left thalamus, bilateral supplementary motor area (SMA). Moreover, the results also showed that EAS at SP6 induced increased FC between the right amygdala and brainstem, right hippocampus, right orbitofrontal cortex, bilateral anterior cingulate cortex (ACC), and decreased FC between the right amygdala and right SMA. Conclusions: Based on the results of our previous study, our findings might improve our understanding of neural mechanisms behind acupuncture effects on PMS.

Neural evidence of dysfunction of reward processing in women with premenstrual syndrome.

BACKGROUND: Most studies on the mechanism behind premenstrual syndrome (PMS) have focused on negative emotional overreaction, but little evidence exists regarding the weakening of positive emotions. Given the close relationship between positive emotions and reward processing, the aim of this study is to investigate the dysfunction of reward processing in women with PMS. METHOD: Seventeen women with PMS and seventeen healthy women were scanned during a card guessing task in the late luteal phase. By selecting bilateral caudate and orbitofrontal cortex (OFC) as seed regions, region-of-interest (ROI) analysis and functional connectivity (psycho-physiological interaction [PPI]) analysis were conducted to compare the difference between two groups. Exploratory whole brain analysis was also conducted to examine the group differences in other reward-related brain regions. RESULTS: ROI analysis revealed that healthy women showed stronger activation at the bilateral caudate and OFC when gains were contrasted to losses feedback, whereas women with PMS showed no significant difference between these two conditions. Whole brain analysis indicated that healthy women showed stronger activation at the right middle frontal gyrus (MFG) when gains were contrasted to losses feedback, whereas women with PMS showed no significant difference between these two conditions. Furthermore, separate analysis on healthy women revealed significant clusters of greater activation to gains minus losses that included the bilateral caudate, right middle temporal gyrus, and left inferior occipital gyrus; conversely, no significant clusters of activations to gains minus losses were observed in women with PMS. PPI analysis results revealed that women with PMS exhibited lower functional connectivity between the right caudate and the right cerebellum than healthy women when experiencing gains versus losses. CONCLUSIONS: Our findings provide one of the first evidence that PMS is related to dysfunction in reward processing, which could be associated with the weakening of positive emotions.

Trait-related changes in brain network topology in premenstrual dysphoric disorder.

The female predominance in the prevalence of depression is partially accounted by reactivity to hormonal fluctuations. Premenstrual dysphoric disorder (PMDD) is a reproductive subtype of depression characterized by cyclic emotional and somatic symptoms that recur before menstruation. Despite the growing understanding that most psychiatric disorders arise from dysfunctions in distributed brain circuits, the brain's functional connectome and its network properties of segregation and integration were not investigated in PMDD. To this end, we examined the brain's functional network organization in PMDD using graph theoretical analysis. 24 drug naïve women with PMDD and 27 controls without premenstrual symptoms underwent 2 resting-state fMRI scans, during the mid-follicular and late-luteal menstrual cycle phases. Functional connectivity MRI, graph theory metrics, and levels of sex hormones were computed during each menstrual phase. Altered network topology was found in PMDD across symptomatic and remitted stages in major graph metrics (characteristic path length, clustering coefficient, transitivity, local and global efficiency, centrality), indicating decreased functional network segregation and increased functional network integration. In addition, PMDD patients exhibited hypoconnectivity of the anterior temporal lobe and hyperconnectivity of the basal ganglia and thalamus, across menstrual phases. Furthermore, the relationship between difficulties in emotion regulation and PMDD was mediated by specific patterns of functional connectivity, including connections of the striatum, thalamus, and prefrontal cortex. The shifts in the functional connectome and its topology in PMDD may suggest trait vulnerability markers of the disorder.

Cortical and subcortical changes in patients with premenstrual syndrome.

BACKGROUND: Premenstrual syndrome (PMS) is characterized by a series of emotional, physical and behavioral symptoms. Although PMS is related to dysfunctions of the central nervous system, the neuropathological mechanism of PMS still has not been clearly established. The aim of this study is to evaluate potential differences in both cortical thickness and subcortical volumes in PMS patients compared to healthy controls (HCs). METHODS: Twenty PMS patients and twenty HCs underwent a structural magnetic resonance imaging scan and clinical assessment. Cortical thickness and subcortical volumes were computed using the FreeSurfer image analysis suite. Relationships between cortical thickness/subcortical volumes and the daily rating of severity of problems (DRSP) score were then measured in patients. RESULTS: Compared to HCs, PMS patients exhibited reduced cortical thickness in the medial prefrontal cortex (MPFC), orbitofrontal cortex (OFC) and insula, and increased subcortical volumes of the amygdala, thalamus and pallidum. Furthermore, negative correlations were detected between the DRSP and cortical thickness in the anterior cingulate cortex and precuneus. LIMITATIONS: The study is limited by a small sample size and narrow age range of participants. CONCLUSIONS: Our findings indicate that the abnormal morphological changes are mainly implicated in emotional regulation and visceral perception in PMS patients. We hope that our study may contribute to a better understanding of PMS.

Menstrual cycle effects on amygdala reactivity to emotional stimulation in premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) with luteal phase related anxiety and mood swings compromise quality of life in around 4% of reproductive women. While anxiety is related to amygdala function, prior studies on amygdala reactivity both in healthy controls and women with PMDD are inconsistent with respect to menstrual cycle effects. Here women with PMDD and healthy controls were exposed to emotional faces during the mid-follicular and late luteal phase, and mean blood-oxygen-level dependence (BOLD) signal changes in the amygdala were determined with functional magnetic resonance imaging (fMRI). Women with PMDD had enhanced bilateral amygdala reactivity in the follicular phase in comparison with healthy controls, but there was no difference between groups during the luteal phase. In contrast, healthy controls displayed higher left amygdala reactivity in the luteal than in their follicular phase. However, among women with PMDD follicular phase progesterone serum concentrations were positively correlated with bilateral amygdala reactivity while depression scores were positively correlated with right amygdala reactivity in the luteal phase. In addition, women with PMDD and high scores on trait anxiety had increased right amygdala reactivity in the luteal as compared to the follicular phase. Finally, amygdala reactivity was more prone to habituation in women with PMDD, as they had enhanced amygdala reactivity in comparison with controls at the first, but not the second scanning session. Thus, while the study failed to indicate increased luteal phase amygdala reactivity in women with PMDD, our findings suggest that anxiety proneness and progesterone levels modulate menstrual cycle related amygdala reactivity in women with PMDD.

Ovarian morphology in premenstrual dysphoria.

Ovarian cyclicity is a prerequisite for premenstrual dysphoria (PMD), as illustrated by the fact that this condition is effectively eliminated by ovariectomy or by treatment with a GnRH agonist. Despite the possibility of differences in ovarian function between women with and without PMD, no study comparing ovarian morphology in these two groups has ever been published. Fifty-two women were recruited for this study; 26 had premenstrual dysphoria, fulfilling criteria slightly modified from those of the premenstrual dysphoric disorder, and 26 were asymptomatic age-matched controls. Ovarian morphology was assessed using transvaginal 7 MHz ultrasonography on day 5 after the start of menses, and venous blood was sampled for hormone analysis on days 3 and 8, the expected day of ovulation, and day -4 of the menstrual cycle. There were no significant differences between the groups with respect to the prevalence of polycystic ovaries (PCO), the total number of follicles, the total ovarian volume or serum levels of androgen hormones. In addition, serum free testosterone levels in late premenstrual phase showed an inverse association to premenstrual symptoms of irritability and a similar inverse association trend to symptoms of depressed mood. Unexpectedly, the prevalence of ovaries with fewer than five antral or growing follicles was significantly higher in women with PMD than in controls (p=0.016). While the results do not support a role for PCO or androgen hormones in eliciting late luteal phase irritability, the possible relationship between oligofollicular ovaries and PMD deserves further study.

Neuroimaging evidence of cerebellar involvement in premenstrual dysphoric disorder.

BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a debilitating cyclic disorder that is characterized by affective symptoms, including irritability, depression, and anxiety, which arise in the luteal phase of the menstrual cycle and resolve soon after the onset of menses. Despite a prevalence of up to 8% in women of reproductive age, few studies have investigated the brain mechanisms that underlie this disorder. METHODS: We used positron emission tomography with [(18)F] fluorodeoxyglucose and self-report questionnaires to assess cerebral glucose metabolism and mood in 12 women with PMDD and 12 healthy comparison subjects in the follicular and late luteal phases of the menstrual cycle. The primary biological end point was incorporated regional cerebral radioactivity (scaled to the global mean) as an index of glucose metabolism. Relationships between regional brain activity and mood ratings were assessed. Blood samples were taken before each session for assay of plasma estradiol and progesterone concentrations. RESULTS: There were no group differences in hormone levels in either the follicular or late luteal phase, but the groups differed in the effect of menstrual phase on cerebellar activity. Women with PMDD but not comparison subjects showed an increase in cerebellar activity (particularly in the right cerebellar vermis) from the follicular phase to the late luteal phase (p = .003). In the PMDD group, this increase in cerebellar activity was correlated with worsening of mood (p = .018). CONCLUSIONS: These findings suggest that the midline cerebellar nuclei, which have been implicated in other mood disorders, also contribute to negative mood in PMDD.

A PET study of 5-HT1A receptors at different phases of the menstrual cycle in women with premenstrual dysphoria.

The cause of premenstrual dysphoric disorder (PMDD) is largely unknown. It has been hypothesized that normal ovarian function triggers PMDD-related biochemical events within the brain and that serotonin plays an important role. In the present study, positron emission tomography (PET) and [carbonyl-(11)C]WAY-100635 were used to examine serotonin 5-HT(1A) receptors in a control group of women and in a group of women with PMDD. Two PET examinations were performed in each subject, one before (follicular phase) and one after ovulation (luteal phase). Each subject's menstrual cycle was confirmed by ultrasonography of the ovaries as well as with hormone levels in blood and urine. The 5-HT(1A) binding potential was measured in six regions of interest and calculated according to the simplified reference tissue model. In the raphe nuclei, the 5-HT(1A) binding potential changed from the follicular to the luteal phase of the menstrual cycle in asymptomatic controls. In women with PMDD, the observed change between phases was significantly smaller. The results are in concordance with previously reported challenge studies of 5-HT(1A) receptor-mediated effects indicating different serotonergic responses between women with PMDD and controls. The study principally provides new support, in vivo, for a serotonergic dysregulation in women with PMDD.

Changes in cerebral blood flow associated with premenstrual syndrome: a preliminary study.

The purpose of this study was to determine changes in regional cerebral blood flow (rCBF) associated with premenstrual syndrome (PMS). Regional CBF was examined using single photon emission computed tomography (SPECT) in seven women who sought treatment for PMS and seven control subjects. Confirmation of PMS was based on the Daily Symptom Report (DSR) of 17 common symptoms associated with PMS. A first SPECT scan was performed near the peak of premenstrual symptoms based on DSR reports from the two previous cycles. A second scan was performed in the postmenstrual period. Prior to scanning, each subject had a Hamilton Depression Rating Scale (Ham-D) obtained. Regions of interest were drawn on the images to generate mean counts per pixel, and normalized to the cerebellum. Activity in the frontal, temporal and parieto-occipital cortices, and the thalami and basal ganglia, were compared between the two scans. Correlations between activity in each region of interest and Ham-D values were also determined. There were marked decreases in rCBF in the temporal lobes on the premenstrual scan compared to the postmenstrual scan in PMS patients. Significant correlations were observed between the change in rCBF in the right and left temporal lobes and the changes in Ham-D scores (r = 0.91, p < 0.01 and r = 0.86, p = 0.01 respectively). No rCBF changes were observed in controls. We conclude that SPECT imaging demonstrates modest decreases in rCBF in the temporal lobes that correlate with the level of depression in subjects with PMS.

The effects of low-dose testosterone treatment on lipid metabolism, clotting factors and ultrasonographic ovarian morphology in women.

INTRODUCTION: Low doses of androgen are used in women for the symptomatic treatment of sexual dysfunction and premenstrual syndrome (PMS). However, little is known about the long-term safety of androgen use in women. This study investigated the effects of low dose exogenous testosterone (T) on lipid metabolism, markers of activation of the coagulation system and ultrasonographic ovarian morphology in women. PATIENTS: Twenty-two patients with severe PMS (age 39.6 +/- 3.1 years, mean +/- SD) treated with subcutaneous T implants (100 mg six monthly) for at least two years (mean duration 3.3 (+/- 0.9 years) were compared with 22 age-matched (age 37.7 +/- 2.9 years) control patients with severe PMS who had not previously received T treatment. All women continued to have regular menses. MEASUREMENTS: Fasting blood samples were obtained for measurement of lipids and clotting factors and ovarian ultrasound examination carried out between days 1-4 of the menstrual cycle (2.3 +/- 1.2 months after the T implant in T-treated group). RESULTS: Mean plasma T was 4.5 +/- 2.2 nmol/l, and 1.9 +/- 0.6 nmol/l in the treated and control groups, respectively. In the T-treated group apolipoprotein-A1 (Apo-A1) (treated 99.2 +/- 12 vs controls 116.2 +/- 27.7 g/l, P < 0.01) and high density lipoprotein cholesterol (HDL-C) (treated 1.3 +/- 0.3 vs controls 1.5 +/- 0.4 nmol/l, P < 0.01) were significantly decreased. In addition very low density lipoprotein cholesterol (VLDL-C) (treated 0.4 +/- 0.3 vs controls 0.2 +/- 0.1 nmol/l, P < 0.05) was increased in T-treated patients. There were no differences in total serum cholesterol and triglyceride or low density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo-B), lipoprotein(a), lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein activity. There was no difference in clotting factors between the two groups which included prothrombin time, fibrinogen, antithrombin-III, protein-C, protein-S (total and free), tissue plasminogen activator, plasminogen activator inhibitor, beta-thromboglobulin and prothrombin fragments 1.2. Ultrasound showed normal ovarian architecture with no evidence of polycystic ovarian changes in any patients in the T-treated group. No patient experienced adverse symptoms while on T treatment, in particular, there were no complaints of hirsutism or acne and no one requested termination of treatment. CONCLUSION: Low-dose testosterome administration to women for over two years did not induce changes in ovarian architecture but had small, potentially atherogenic effects on some parameters of lipid and lipoprotein metabolism. However, no differences were detected in markers of activation of the clotting system to indicate an actual increase in the risk of thrombosis. Overall, this study provides largely reassuring data about the safety of low-dose androgen treatment in women. However, caution should be exercised in women with existing or a familial predisposition to lipid abnormalities, because of the small but significant changes found in HDL-C, apo-A1 and VLDL-C.

[Real time ultrasound in routine breast diagnosis]. / Real-time-Sonographie in der Mammaroutinediagnostik.

Ultrasound examination of the breast is used in three indications: the premenstrual syndrome, the examination of cyst and the short-time control of high-risk patients. The differential main point is the diagnosis of cysts, which may save the patient from "blind" puncture. In this field, ultrasound is more competent than mammography; furthermore, the oedematous changes occurring before the onset of menstruation can be easily seen with sonography. For the early detection of cancer of the breast, ultrasound is merely additional but its diagnostic value is bound to rise with progressing development.