Neuropsychopharmacology : official publication of the American College of NeuropsychopharmacologyJan 13, 2024

Resting brain network activity differs between men and women with major depression

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 29, 2026

Abstract

Resting-state fMRI data from 138 unmedicated patients with first-episode Major Depressive Disorder (MDD) indicate significant sex differences in neural network dynamics.

MDD patients showed greater persistence in a neural network pattern involving activation of the default mode network (DMN) and deactivation of the frontoparietal network (FPN) compared to healthy controls.
Male MDD patients spent more time in two neural patterns involving the salience network (SN) and DMN than male healthy controls.
Male MDD patients transitioned more frequently from the DMN + FPN- pattern to the DMN + SN- pattern compared to male healthy controls.
Female MDD patients exhibited less persistence in the DMN + SN- pattern compared to female healthy controls.
The findings suggest that the imbalance between the SN and DMN may serve as a neurobiological marker for sex differences in MDD.

Simplified

Sex-specific neurobiological changes have been implicated in Major Depressive Disorder (MDD). Dysfunctions of the default mode network (DMN), salience network (SN) and frontoparietal network (FPN) are critical neural characteristics of MDD, however, the potential moderating role of sex on resting-state network dynamics in MDD has not been sufficiently evaluated. Thus, resting-state functional magnetic resonance imaging (fMRI) data were collected from 138 unmedicated patients with first-episode MDD (55 males) and 243 healthy controls (HCs; 106 males). Recurring functional network co-activation patterns (CAPs) were extracted, and time spent in each CAP (the total amount of volumes associated to a CAP), persistence (the average number of consecutive volumes linked to a CAP), and transitions across CAPs involving the SN, DMN and FPN were quantified. Relative to HCs, MDD patients exhibited greater persistence in a CAP involving activation of the DMN and deactivation of the FPN (DMN + FPN-). In addition, relative to the sex-matched HCs, the male MDD group spent more time in two CAPs involving the SN and DMN (i.e., DMN + SN- and DMN-SN + ) and transitioned more frequently from the DMN + FPN- CAP to the DMN + SN- CAP relative to the male HC group. Conversely, the female MDD group showed less persistence in the DMN + SN- CAP relative to the female HC group. Our findings highlight that the imbalance between SN and DMN could be a neurobiological marker supporting sex differences in MDD. Moreover, the dominance of the DMN accompanied by the deactivation of the FPN could be a sex-independent neurobiological correlate related to depression.

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Funding

Competing interests

Over the past three years, Dr. Pizzagalli has received consulting fees from Albright Stonebridge Group, Boehringer Ingelheim, Compass Pathways, Engrail Therapeutics, Neumora Therapeutics (formerly BlackThorn Therapeutics), Neurocrine Biosciences, Neuroscience Software, Otsuka, Sunovion, and Takeda; he has received honoraria from the Psychonomic Society and American Psychological Association (for editorial work) and from Alkermes; he has received research funding from the Brain and Behavior Research Foundation, Dana Foundation, Millennium Pharmaceuticals, and Wellcome Leap; he has received stock options from Compass Pathways, Engrail Therapeutics, Neumora Therapeutics, and Neuroscience Software. There are no conflicts of interest with the work conducted in this study. No funding from these entities was used to support the current work, and all views expressed are solely those of the authors. The other authors report no financial relationships with commercial interests.

PubMed

Resting brain network activity differs between men and women with major depression

Abstract

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Competing interests

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