Premenstrual Dysphoric Disorder Subjects Research Articles

Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids

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 and the Brain

Premenstrual Dysphoric Disorder and the Brain

Abnormalities of Dorsolateral Prefrontal Function in Women With Premenstrual Dysphoric Disorder: A Multimodal Neuroimaging Study

To investigate the neural substrate of premenstrual dysphoric disorder (PMDD), the authors used [15O]H2O positron emission tomography (PET) regional cerebral blood flow (rCBF) and blood-oxygen-level-dependent (BOLD) functional MRI (fMRI) signal measurements during working memory in conjunction with a 6-month hormone manipulation protocol. PET and fMRI scans were obtained from women with prospectively confirmed PMDD and asymptomatic comparison subjects while they completed the n-back task during three hormone conditions: ovarian suppression induced by the gonadotropin-releasing hormone agonist leuprolide acetate, leuprolide plus estradiol, and leuprolide plus progesterone. Fifteen patients and 15 matched comparison subjects underwent PET imaging. Fourteen patients and 14 comparison subjects underwent fMRI. For each hormone condition, rCBF was measured with [15O]H2O PET, and BOLD signal was measured with fMRI, both during an n-back working memory paradigm. Global Assessment of Functioning Scale (GAF) scores and clinical characteristics were obtained for each patient before hormone manipulation, and symptoms were measured before and during the protocol. In both the PET and fMRI studies, a main effect of diagnosis was observed, with PMDD patients showing greater prefrontal activation than comparison subjects. In the patient group, the degree to which dorsolateral prefrontal cortex activation was abnormally increased correlated with several dimensions of disease: disability as indicated by GAF scores, age at symptom onset, duration of PMDD, and differences in pre- and postmenses PMDD symptoms. Abnormal working memory activation in PMDD, specifically in the dorsolateral prefrontal cortex, is related to PMDD severity, symptoms, age at onset, and disease burden. These results support the clinical relevance of the findings and the proposal that dorsolateral prefrontal cortex dysfunction represents a substrate of risk for PMDD. The concordance of the fMRI and PET data attests to the neurobiological validity of the results.

Survey of premenstrual symptom severity and impairment in Korean adolescents: Premenstrual dysphoric disorder, subthreshold premenstrual dysphoric disorder and premenstrual syndrome

The aims of the study were to examine the prevalence of premenstrual dysphoric disorder (PMDD), subthreshold PMDD and premenstrual syndrome (PMS) among adolescents, and to assess the nature of symptoms and the impact on daily life functions, especially for PMDD and subthreshold PMDD. A cross-sectional survey was conducted among adolescents from an urban area. Participants included 984 girls divided into the following four groups, using a premenstrual symptoms screening tool: PMDD, subthreshold PMDD, moderate/severe PMS and no/mild PMS. An Adolescent Mental Problem Questionnaire, Center for Epidemiological Studies-Depression Scale, revised Children's Manifest Anxiety Scale, and a menstrual information questionnaire were also used. Sixty-three (6.76%) of the subjects met the criteria for PMDD and 58 (6.2%) were subthreshold PMDD. The subthreshold PMDD group included 79.3% who met the symptom criteria for PMDD, but their impairment was moderate, and 21.7% who were falling short by the number of symptoms for PMDD diagnosis, though reporting severe impairment. The symptom intensity and frequency of the subthreshold PMDD subjects were similar to those in subjects with PMDD. In these two groups, 69% had moderate to severe physical symptoms. Psychiatric problems, including depression and anxiety, were higher in the PMDD and subthreshold PMDD groups than in the moderate/severe PMS and no/mild PMS group. In total, 20% of adolescents reported suffering from distressing premenstrual symptoms, and girls with PMDD and subthreshold PMDD were very similar in their symptom severity and characteristics. Prospective daily charting is needed to confirm the accurate diagnosis and management of PMDD.

Subjective sleep problems in young women suffering from premenstrual dysphoric disorder

Subjective sleep problems in young women suffering from premenstrual dysphoric disorder

Late, but not early, wake therapy reduces morning plasma melatonin: Relationship to mood in Premenstrual Dysphoric Disorder

Wake therapy improves mood in Premenstrual Dysphoric Disorder (PMDD), a depressive disorder in DSM-IV. We tested the hypothesis that the therapeutic effect of wake therapy in PMDD is mediated by altering sleep phase with melatonin secretion. We measured plasma melatonin every 30 min (18:00–09:00 h) in 19 PMDD and 18 normal control (NC) women during mid-follicular (MF) and late luteal (LL) menstrual cycle phases, and during LL interventions with early wake therapy (EWT) (sleep 03:00–07:00 h)(control condition) vs. late wake therapy (LWT) (sleep 21:00–01:00 h)(active condition). Melatonin offset was delayed and duration was longer in the symptomatic LL vs. asymptomatic MF phase in both NC and PMDD subjects. LWT, but not EWT, advanced offset and shortened duration vs. the LL baseline, although they improved mood equally. Later baseline LL morning melatonin offset was associated with more depressed mood in PMDD patients, and longer melatonin duration in the MF phase predicted greater mood improvement following LWT. That LWT, but not EWT, advanced melatonin offset and shortened duration while they were equally effective in improving mood suggests that decreasing morning melatonin secretion is not necessary for the therapeutic effects of wake therapy in PMDD.

Proton Magnetic Resonance Spectroscopy Measurement of Brain Glutamate Levels in Premenstrual Dysphoric Disorder

Women who suffer from premenstrual dysphoric disorder (PMDD) classically display depressive and anxiety symptoms in the premenstrum. Preclinical and clinical studies have suggested a role of glutamate in anxiety and depression. This investigation aims at demonstrating fluctuations of glutamate across the menstrual cycle in the medial prefrontal cortex of women who suffer from PMDD and healthy control subjects (HCs). Twelve PMDD women and 13 HCs were randomized to two single-voxel 3 Tesla proton magnetic resonance spectroscopy examinations of the medial prefrontal cortex during the follicular phase and the luteal phase. A phase effect was observed; the levels of glutamate/creatine plus phosphocreatine (Cr) were significantly lower during the luteal phase compared with the follicular phase. However, no statistically significant diagnosis or phase x diagnosis effects were found. The optimized stimulated echo acquisition mode (STEAM) pulse timings selected in this study (echo time [TE], mixing time [TM] = 240, 27 msec) allow us to interpret our results as the first report of alterations of brain glutamate levels across the menstrual cycle. Hormonal fluctuations associated with the menstrual cycle likely contribute to these glutamate level variations. Although PMDD women undergo a similar decrease in glutamate during the luteal phase as the HCs, PMDD women may display an increased behavioral sensitivity to those phase-related alterations. These menstrual cycle-related variations of glutamate levels may also contribute to the influence of the phases of the menstrual cycle in other neuropsychiatric disorders.

Toward a functional neuroanatomy of premenstrual dysphoric disorder

Background Premenstrual dysphoric disorder (PMDD) is a prevalent disorder in the spectrum of affective illness, and is associated with significant morbidity. The neurobiology of this underdiagnosed and undertreated illness is poorly understood. A functional magnetic resonance imaging (fMRI) probe of fronto-limbic function was used to advance understanding of PMDD pathophysiology. Methods We applied BOLD fMRI and Statistical Parametric Mapping to study neural response to emotional words in the context of an emotional Go/NoGo inhibitory control task. We examined alterations in this response across the menstrual cycle, in the premenstrual (late luteal) phase and the postmenstrual (late follicular) phase. Results In the premenstrual ( vs. postmenstrual) phase, PMDD subjects, compared with asymptomatic subjects, showed an increased amygdala response to negative vs. neutral stimuli, and a decreased ventral striatum response to positive vs. neutral stimuli. PMDD subjects failed to show the asymptomatic subjects' patterns of increased medial and decreased lateral orbitofrontal cortex (OFC) response to negative vs. neutral stimuli in the premenstrual vs. postmenstrual phase. This decreased premenstrual medial OFC response to negative stimuli in PMDD subjects was further enhanced in the context of behavioral inhibition. Limitations Further studies with larger numbers of subjects are needed. Conclusions The results support a neurobiological model of enhanced negative emotional processing, diminished positive emotional processing, and diminished top-down control of limbic activity in PMDD during the premenstrual phase. These findings provide a basis for a neurocircuitry model of PMDD, and have implications for studies of mood/emotional regulation across the human menstrual cycle in health and disease.

Genes Linked to Mood Symptoms of Premenstrual Dysphoric Disorder

Genes Linked to Mood Symptoms of Premenstrual Dysphoric Disorder

Fluctuating serotonergic function in premenstrual dysphoric disorder and premenstrual syndrome: findings from neuroendocrine challenge tests

Premenstrual dysphoric disorder (PMDD) has been assumed to be a subtype of premenstrual syndrome (PMS) with depressive symptoms, such as depressive mood, tension, anxiety, and mood liability during luteal phase. At present, no conclusion has been established about serotonergic function in PMDD. The purpose of this study was to investigate the serotonergic function of PMDD subjects in comparison to PMS without PMDD subjects and normal controls via neuroendocrine challenge tests. Twenty-four women (seven with PMDD, eight with PMS without PMDD, and nine normal controls) were tested on three occasions (follicular phase, early luteal phase, and late luteal phase) receiving paroxetine 20 mg orally as a serotonergic probe at 8:00 A: .M: . Plasma ACTH and cortisol were measured prior to the administration and every hour for 6 h thereafter. As a whole, there were significant differences in serotonergic function measured by ACTH and cortisol responses to paroxetine challenge across these three groups. PMDD subjects showed higher serotonergic function in follicular phase but lower serotonergic function in luteal phase, compared with women with PMS without PMDD and normal controls. The present findings suggest that PMDD women have fluctuating serotonergic function across their menstrual cycles and that the pattern may be different from PMS without PMDD.

Investigation of transcription factor AP-2beta genotype in women with premenstrual dysphoric disorder

It has repeatedly been shown that the serotonergic system is involved in the symptomatology of premenstrual dysphoric disorder (PMDD). Women with PMDD are reported to differ from symptom-free controls with regard to serotonin-related biological markers. Evidence from family and twin studies suggests a genetic contribution to the aetiology of PMDD. The expression of human transcription factor AP-2β in neural crest cell lineages and neuroectodermal cells suggests that this protein may be of importance for functional characteristics of neurons by regulating the expression of target genes. Within the monoaminergic systems, several genes have binding sites for AP-2β in regulatory regions, suggesting an involvement of AP-2β in these systems. The gene encoding AP-2β is located on chromosome 6p12–p21.1 and includes a polymorphic region consisting of a variable number of [CAAA] repeats located in the second intron. We have earlier shown that AP-2β genotype is associated with serotonergic phenotypes and that brainstem levels of AP-2β correlate positively to serotonin metabolism in rat frontal cortex. The aim of this study was to investigate the relationship between PMDD and transcription factor AP-2β genotype. The participants included 176 women with PMDD and 91 healthy controls. Genotyping was performed by polymerase chain reactions. We did not observe any differences in AP-2β genotype frequencies between PMDD subjects and controls. Our results suggest that AP-2β genotype is not a risk factor for PMDD. To our knowledge, this is the first study investigating transcription factor AP-2β genotype in women with PMDD. Hence, these results should be considered preliminary until replicated.

Heart rate variability in premenstrual dysphoric disorder

Measuring heart rate variability (HRV) is a way to assess the autonomic regulation of the heart. Decreased HRV, indicating reduced parasympathetic tone, has previously been found in depression and anxiety disorders. The objective of this study was to assess HRV in women with premenstrual dysphoric disorder (PMDD). To this end, time domain variables and frequency domain variables were assessed in 28 women with PMDD and in 11 symptom-free controls during both the symptomatic luteal phase and the non-symptomatic follicular phase of the menstrual cycle. Two variables reflecting vagal activity in the time domain, the root mean square of differences of successive normal RR intervals (rMSSD) and standard deviation of normal RR intervals (SDNN) were lower in PMDD patients, but this difference was statistically significant in the follicular phase only. The most important vagal measure in the frequency domain, supine high frequency (HF), also appeared lower in PMDD subjects during the follicular phase. It is suggested that PMDD may be associated with reduced vagal tone compared to controls and that this difference is most apparent in the non-symptomatic follicular phase of the menstrual cycle.

Menstrual cycle-related brain metabolite changes using 1H magnetic resonance spectroscopy in premenopausal women: a pilot study

Proton magnetic resonance spectroscopy ( 1H-MRS) was used to assess neurochemical brain changes across the menstrual cycle in five women with premenstrual dysphoric disorder (PMDD) and six control subjects. Women with PMDD and control subjects were scanned on days 8 and 26 within one menstrual cycle (i.e. at times of complete absence and height of PMDD symptoms, respectively). The point resolved spectroscopic sequence (PRESS) was used to localize a voxel of 8 ml in the medial frontal gray matter and in the occipito-parietal white matter. The ratio of N-acetyl-aspartate to creatine in the region of the medial prefrontal cortex and the cingulate gyrus declined significantly from the follicular to the luteal phase in both groups of subjects. The menstrual phase-dependent significant increase in the ratio of choline to creatine was observed in the parietal white matter. The myo-inositol/creatine ratio exhibited a trend toward higher levels in the PMDD patients in the luteal phase of the menstrual cycle. Differences between PMDD and control subjects were not statistically significant. Menstrual cycle phase-dependent changes in ovarian hormonal concentrations may influence the neurochemistry of brain activity in premenopausal women.

Cortisol circadian rhythms during the menstrual cycle and with sleep deprivation in premenstrual dysphoric disorder and normal control subjects

Background: In this study we extended previous work by examining whether disturbances in the circadian rhythms of cortisol during the menstrual cycle distinguish patients with premenstrual dysphoric disorder (PMDD) from normal control (NC) subjects. In addition, we tested the differential response to the effects of early and late partial sleep deprivation on cortisol rhythms. Methods: In 15 PMDD and 15 NC subjects we measured cortisol levels every 30 min from 6:00 pm to 9:00 am during midfollicular (MF) and late luteal (LL) menstrual cycle phases and also during a randomized crossover trial of early (sleep 3:00 am–7:00 am) versus late (sleep 9:00 pm–1:00 am) partial sleep deprivation administered in two subsequent and separate luteal phases. Results: In follicular versus luteal menstrual cycle phases we observed altered timing but not quantitative measures of cortisol secretion in PMDD subjects, compared with NC subjects: in the LL versus MF phase the cortisol acrophase was a mean of 1 hour earlier in NC subjects, but not in PMDD subjects. The effect of sleep deprivation on cortisol timing measures also differed for PMDD versus NC subjects: during late partial sleep deprivation (when subjects’ sleep was earlier), the cortisol acrophase was almost 2 hours earlier in PMDD subjects. Conclusions: Timing rather than quantitative measures of cortisol secretion differentiated PMDD subjects from NC subjects both during the menstrual cycle and in response to early versus late sleep deprivation interventions.

Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects

In this study of 23 patients with premenstrual dysphoric disorder (PMDD) and 18 normal comparison (NC) subjects, we examined sleep EEG measures during baseline midfollicular (MF) and late luteal (LL) menstrual cycle phases and after early sleep deprivation (ESD), in which subjects slept from 03.00 to 07.00 h, and late sleep deprivation (LSD), in which subjects slept from 21.00 to 01.00 h. Each sleep deprivation night was followed by a night of recovery sleep (ESD-R, LSD-R) (sleep 22.30–06.30 h) and was administered in the late luteal phase of separate menstrual cycles. During baseline studies, sleep EEG measures differed significantly by menstrual cycle phase, but not group. Both PMDD and NC groups showed longer REM latencies and less REM sleep (minutes and percent) during the luteal compared with the follicular menstrual cycle phase. PMDD subjects, however, did not show sleep architecture changes similar to those of patients with major depressive disorders. Sleep quality was better during recovery nights of sleep in PMDD compared with NC subjects. REM sleep measures changed in association with clinical improvement in responders to sleep deprivation. Both early and late sleep deprivation may help to correct underlying circadian rhythm disturbances during sleep in PMDD, although differential sleep changes during ESD vs. LSD did not correlate with clinical response. Further sleep studies addressing additional circadian variables may serve to elucidate mechanisms mediating the therapeutic effects of sleep deprivation in PMDD.

Pain Sensitivity in Women with Premenstrual Dysphoric Disorder: A Preliminary Report

Objective: An impairment in endogenous opioid and/or serotonergic activity during the luteal phase may play a role in the etiology of premenstrual dysphoric disorder (PDD). This study tested the hypothesis that because of these alterations, PDD patients would exhibit greater pain sensitivity than non-PDD controls when tested during the luteal phase of their menstrual cycles. Participants: Seven subjects prospectively diagnosed with PDD and 11 healthy controls participated in the experiment. Design: After completing the Prospective Report of the Impact and Severity of Menstrual Symptoms (PRISM) calendar for 2 months for diagnostic purposes, all subjects underwent thermal and ischemic pain testing during the luteal phase of their menstrual cycles. Results: PDD subjects were significantly more sensitive to ischemic pain than were controls, with PDD subjects exhibiting lower ischemic pain onset and ischemic pain tolerance. PDD subjects also described their ischemic pain as more intense than did controls. No differences in thermal pain perception emerged. Conclusions: These results support the hypothesis that women suffering from PDD exhibit greater ischemic pain sensitivity compared with non-PDD controls. Several mechanisms may underlie this difference.