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

Abstract

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 GABA_A-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 GABA_A-active neurosteroids.

Fig. 1. Emotional task performance in subjects with PMDD (N = 29) and controls (N = 27).

Subjects with PMDD showed lower accuracy and reaction times in the face-matching condition compared with controls during the late-luteal phase. *p < 0.05. Error bars indicate 1 standard error of the mean. PMDD, premenstrual dysphoric disorder.

Fig. 2. Whole-brain group comparison between subjects with PMDD (N = 29) and controls (N = 27) of emotion-induced brain activity during the late-luteal phase of the menstrual cycle (p_FWE < 0.05, TFCE).

Surface representation of significant clusters showing increased brain activity during task [Faces>Shapes contrast] in subjects with PMDD, compared with controls, during the late-luteal phase across the whole brain (p_FWE < 0.05, TFCE). ACC Anterior Cingulate Cortex, FWE Family Wise Error correction, Ins Insula, MFG Medial Frontal Gyrus, PCC Posterior Cingulate Cortex, PCun Precuneus, PoG Postcentral Gyrus, PMDD Premenstrual Dysphoric Disorder, SFG Superior Frontal Gyrus, SMA Supplementary Motor Area, TFCE Threshold-Free Cluster Enhancement.

Fig. 3. Group differences in associations between emotion-induced brain activity and log(ISO/ALLO) serum levels in subjects with PMDD (N = 29) and controls (N = 24) during the late-luteal phase of the menstrual cycle (p_FWE < 0.10, TFCE).

Upper: Brain slices depicting clusters in which the interaction between brain activity during task [Faces>Shapes contrast] and log(ISO/ALLO) serum levels differed between groups (p_FWE < 0.10, TFCE). The cluster in the parahippocampal gyrus/amygdala region was significant at the p_FWE < 0.05 level, while the cluster in the fusiform gyrus was marginally significant with p_FWE = 0.06. The analysis was conducted voxel-wise within a mask combining brain regions showing increased task-related activation for both PMDD and controls. Lower: Corresponding scatter plots illustrating the relationships between mean parameter estimates extracted from significant clusters and serum ISO/ALLO levels. Simple regression lines were added for visualization. Subjects with PMDD exhibited positive associations between log(ISO/ALLO) levels and brain activity in the right parahippocampal gyrus/amygdala and right fusiform gyrus. Control subjects, on the other hand, showed significant negative associations between log(ISO/ALLO) and brain activity in both clusters. ALLO Allopregnanolone, FWE Family Wise Error correction, ISO isoallopregnanolone, PMDD Premenstrual Dysphoric Disorder, TFCE Threshold-Free Cluster Enhancement.

Fig. 4. Associations between emotion-induced brain activity and anxiety scores in subjects with PMDD (N = 29) during the late-luteal phase of the menstrual cycle (p_FWE < 0.05, TFCE).

Upper: Brain slice depicting clusters in which there was a significant linear relationship between brain activity during task [Faces>Shapes contrast] and anxiety scores (p_FWE < 0.05, TFCE). The analysis was conducted voxel-wise within a mask combining brain regions showing increased task-related activation in subjects with PMDD during the late-luteal phase. Lower: Corresponding scatter plots illustrating relationships between mean parameter estimates extracted from significant clusters and anxiety scores. Simple regression lines were added for visualization. DRSP Daily Record of Severity of Problems, FWE Family Wise Error correction, PMDD Premenstrual Dysphoric Disorder, TFCE Threshold-Free Cluster Enhancement.