Depression and the prefrontal-hippocampal pathway - A multimodal neuroimaging study in transgender women

Abstract

This study aims to investigate functional and neurotransmitter signaling in the prefrontal-hippocampal pathway in relation to depression in a cohort of Thai transgender women. Twenty participants completed mental health surveys and imaging between January and March 2024. Depression severity was measured by Patient Health Questionnaire-9 (PHQ-9) scores. Higher PHQ-9 scores were associated with lower GABA levels in the hippocampus, and with lower fractional amplitude of low-frequency fluctuations (fALFF) in the dorsolateral prefrontal cortex. However, removal of the hippocampal GABA outlier resulted in a non-significant relationship with PHQ-9. Therefore, future studies with larger datasets should further investigate the association between GABA and depression in a transgender cohort. These findings revealed interactions between neurotransmitter signaling and functional brain activity of the hippocampal-prefrontal circuit in depression.

Keywords: Depression; Neuroimaging; Spectroscopy; Transgender women; fMRI.

Fig. 1

Neurotransmitter and functional MRI associations with depression. Scatter plots illustrate the relationship of patient health questionnaire (PHQ-9) scores with gamma-aminobutyric acid (GABA) in the hippocampal (A) and fractional amplitude of low frequency fluctuation (fALFF) in the dorsolateral prefrontal cortex (DLPFC) (B) after controlling for the confounder. 95 % Confidence intervals and marginal histograms are also displayed. GABA/Cr indicates GABA concentrations normalized to the creatinine reference.

Fig. 2

DLPFC fALFF partially mediated the association between depression scores and hippocampal GABA. The right diagram displays separate linear models, while the left diagram illustrates the mediation analysis model. A) Direct associations between gamma-aminobutyric acid (GABA) in the hippocampus and patient health questionnaire (PHQ-9) scores, and between fractional amplitude of low frequency fluctuations (fALFF) in the dorsolateral prefrontal cortex (DLPFC) and PHQ-9 were estimated. B) The mediation analysis revealed a trend-level mediation effect of DLPFC fALFF on the relationship between hippocampal GABA and PHQ-9. The arrows indicate regression coefficients, and asterisks denote significance association (p < 0.05). L indicates the left hemisphere, and R indicates the right hemisphere.