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Emotion-induced brain activation across the menstrual cycle in individuals with premenstrual dysphoric disorder and associations to serum levels of progesterone-derived neurosteroids
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
Department of Women's and Children's Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Women's and Children's Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
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2023 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 13, no 1, article id 124Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2023. Vol. 13, no 1, article id 124
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-206958DOI: 10.1038/s41398-023-02424-3ISI: 000968319200001PubMedID: 37055419Scopus ID: 2-s2.0-85152386545OAI: oai:DiVA.org:umu-206958DiVA, id: diva2:1753359
Available from: 2023-04-26 Created: 2023-04-26 Last updated: 2024-05-17Bibliographically approved
In thesis
1. Premenstrual dysphoric disorder: brain structure and function, GABAA-active neurosteroids and GABAA receptor plasticity
Open this publication in new window or tab >>Premenstrual dysphoric disorder: brain structure and function, GABAA-active neurosteroids and GABAA receptor plasticity
2024 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2024. p. 128
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2310
Keywords
Premenstrual dysphoric disorder, GABAA receptor, neurosteroids, allopregnanolone, isoallopregnanolone, functional magnetic brain imaging, salience network
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:umu:diva-224452 (URN)978-91-8070-420-5 (ISBN)978-91-8070-419-9 (ISBN)
Public defence
2024-08-23, Bergasalen, Byggnad 27, Norrlands Universitetssjukhus, Umeå, 13:00 (English)
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Available from: 2024-05-24 Created: 2024-05-17 Last updated: 2024-05-20Bibliographically approved

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Stiernman, LouiseBoraxbekk, Carl-JohanJohansson, Inga-MajBixo, Marie

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