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Differential grey matter structure in women with premenstrual dysphoric disorder: evidence from brain morphometry and data-driven classification
Department of Women’s and Children’s Health, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology.
Department of Surgical Sciences, Radiology, Uppsala University, Uppsala, Sweden.
Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria.
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2022 (English)In: Translational Psychiatry, E-ISSN 2158-3188, Vol. 12, no 1, article id 250Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Springer Nature, 2022. Vol. 12, no 1, article id 250
National Category
Psychiatry
Identifiers
URN: urn:nbn:se:umu:diva-203604DOI: 10.1038/s41398-022-02017-6ISI: 000811739600001PubMedID: 35705554Scopus ID: 2-s2.0-85132071288OAI: oai:DiVA.org:umu-203604DiVA, id: diva2:1728822
Available from: 2023-01-19 Created: 2023-01-19 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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