Evidence map›Paper›PMID 40251694›Full record

ArticleBiology of sex differences2025

Differential brainstem connectivity according to sex and menopausal status in healthy male and female individuals.

Lisa A Kilpatrick, Arpana Church, David Meriwether, Swapna Mahurkar-Joshi, Vince W Li, Jessica Sohn, Juliana Reist, Jennifer S Labus, Tien Dong, Jonathan P Jacobs and 3 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biology of sex differences, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Sex differences in neuromodulatory subcortical systems and their implications for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Review
  3. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

13 authors.

Lisa A KilpatrickVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Arpana ChurchVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
David MeriwetherVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Swapna Mahurkar-JoshiVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Vince W LiVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jessica SohnVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Juliana ReistVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jennifer S LabusVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Tien DongVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Jonathan P JacobsVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Bruce D NaliboffVatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Lin Chang *Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. LinChang@mednet.ucla.edu.
Emeran A Mayer *Vatche and Tamar Manoukian Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. EMayer@mednet.ucla.edu.

Funding

The role of brain-gut microbiome interactions in mediating IBS and constipation symptoms during menses and menopauseU54DK123755 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Elaine Hsiao · 2020 to 2026
$10.5M
Dysregulation of inflammation resolution as therapeutic target for IBDK01DK133666 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI David Meriwether · 2023 to 2026
$648k
NIDDK NIH HHS K01 DK133666NIDDK NIH HHS U54 DK123755NIDDK NIH HHS U54DK123755
6 · The paper itself

Abstract

backgroundBrainstem nuclei play a critical role in both ascending monoaminergic modulation of cortical function and arousal, and in descending bulbospinal pain modulation. Even though sex-related differences in the function of both systems have been reported in animal models, a complete understanding of sex differences, as well as menopausal effects, in brainstem connectivity in humans is lacking. This study evaluated resting-state connectivity of the dorsal raphe nucleus, right and left locus coeruleus complex (LCC), and periaqueductal gray (PAG) according to sex and menopausal status in healthy individuals. In addition, relationships between systemic estrogen levels and brainstem-network connectivity were examined in a subset of participants.

methodsResting-state fMRI was performed in 47 healthy male (age, 31.2 ± 8.0 years), 53 healthy premenopausal female (age, 24.7 ± 7.3 years; 22 in the follicular phase, 31 in the luteal phase), and 20 postmenopausal female participants (age, 54.6 ± 7.2 years). Permutation Analysis of Linear Models (5000 permutations) was used to evaluate differences in brainstem-network connectivity according to sex and menopausal status, controlling for age. In 10 males and 17 females (9 premenopausal; 8 postmenopausal), estrogen and estrogen metabolite levels in plasma and stool were determined by liquid chromatography-mass spectrometry/mass spectrometry. Relationships between estrogen levels and brainstem-network connectivity were evaluated by partial least squares analysis.

resultsLeft LCC-executive control network connectivity showed an overall sex difference (p = 0.02), with higher connectivity in females than in males; however, this was mainly due to differences between males and premenopausal females (p = 0.008). Additional sex differences were dependent on menopausal status: PAG-default mode network (DMN) connectivity was higher in postmenopausal females than in males (p = 0.04), and PAG-sensorimotor network (SMN) connectivity was higher in premenopausal females than in males (p = 0.03) and postmenopausal females (p = 0.007). Notably, higher free 2-hydroxyestrone levels in stool were reliably associated with higher PAG-SMN and PAG-DMN connectivity in premenopausal females (p < 0.01).

conclusionsHealthy females show higher brainstem-network connectivity involved in cognitive control, sensorimotor function, and self-relevant processes than males, dependent on their menopausal status. Further, 2-hydroxyestrone, implicated in pain, may modulate PAG connectivity in premenopausal females. These findings may relate to differential vulnerabilities to chronic stress-sensitive disorders at different life stages.

Indexed as

Brain StemMenopauseSex CharacteristicsAdultEstrogensFemaleHumansMagnetic Resonance ImagingMaleMiddle AgedYoung AdultEstrogensBrainstem nucleiEstrogenNeuroimagingSex differences

Identifiers

PMID40251694
PMCPMC12007138

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.