The molecular and neurochemical basis of altered intrinsic neural timescales in major depressive disorder: a multimodal imaging-transcriptomic investigation of esketamine and sertraline treatment.
7 affiliations
- 1Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, Department of Radiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
- 2Queen Mary School, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China.
- 3The School of Medical Imaging, Changsha Medical University, Changsha, 410000, China.
- 4Department of Psychosomatic Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China.
- 5Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK. [email protected].
- 6Department of Psychosomatic Medicine, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Jiangxi, 330006, China. [email protected].
- 7Jiangxi Provincial Key Laboratory for Precision Pathology and Intelligent Diagnosis, Department of Radiology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, 330006, China. [email protected].
Abstract
Introduction
Major depressive disorder (MDD) is characterized by dysfunction in higher-order cortical regions involved in emotional and cognitive processes; however, its neurobiological basis remains unclear. Pharmacological treatments, including esketamine and sertraline, produce rapid antidepressant effects. We investigated the local intrinsic neural dynamics underlying these antidepressant effects using intrinsic neural timescales (INT), which measure the duration and capacity of information integration in localized brain regions.Methods
A total of 57 healthy controls and 41 patients with MDD were included. All patients with MDD received six intravenous infusions of esketamine (0.25 mg/kg) and two weeks of sertraline treatment. All participants underwent resting-state fMRI to quantify INT alterations at the voxel and brain network levels, followed by spatial correlation analyses linking autocorrelation metrics of INT signals to transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. The spatial correlation between PLS2 scores and case-control t-statistic maps did not pass rigorous spin permutation testing (r = 0.484, p = 0.068) and did not meet the conventional significance threshold of 0.05. Accordingly, all subsequent enrichment analyses based on PLS2 results are presented as exploratory preliminary observations for hypothesis generation.Results
Compared with healthy controls, patients with MDD exhibited significantly elevated INT levels in the left and right precuneus. Following treatment, patients with MDD showed significantly increased INT in the left occipital midline region and left calcarine cortex. At the brain network level, INT levels were significantly reduced in the default mode network (DMN) in patients with MDD compared with healthy controls. Compared with the pre-treatment state, the cerebellar network (CN) showed significantly elevated INT levels after treatment. Partial least squares regression analysis suggested potential associations between INT alterations and spatial gene expression gradients particularly those associated with immune responses, hormonal regulation, neutrophils, regulatory T cells, and glutamatergic synapses. Cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Alterations in INT also correlated with cortical 5-HT1b and NAT receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits.Conclusion
This study advances understanding of treatment-related brain abnormalities in patients with MDD from the perspective of local neural dynamics. These findings support a multiscale pathophysiological framework involving brain connectivity dynamics, molecular architecture, and neurochemical regulation in MDD.
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BibTeX
@article{liu2026molecular,
title = {{The molecular and neurochemical basis of altered intrinsic neural timescales in major depressive disorder: a multimodal imaging-transcriptomic investigation of esketamine and sertraline treatment.}},
author = {Xiang Liu and Yuanzhi He and Lifeng Li and Zhanxiang Hu and Haijun Li and Lihao Wu and Liping Zhang and Zihao Su and HengRui Liu and Guojiang Wu and Dechang Peng},
journal = {BMC psychiatry},
year = {2026},
month = aug,
doi = {10.1186/s12888-026-08477-0},
url = {https://europepmc.org/article/MED/42972310},
note = {CC BY},
}
RIS
TY - JOUR
TI - The molecular and neurochemical basis of altered intrinsic neural timescales in major depressive disorder: a multimodal imaging-transcriptomic investigation of esketamine and sertraline treatment.
AU - Xiang Liu
AU - Yuanzhi He
AU - Lifeng Li
AU - Zhanxiang Hu
AU - Haijun Li
AU - Lihao Wu
AU - Liping Zhang
AU - Zihao Su
AU - HengRui Liu
AU - Guojiang Wu
AU - Dechang Peng
PY - 2026
DA - 2026/08/05
JO - BMC psychiatry
DO - 10.1186/s12888-026-08477-0
UR - https://europepmc.org/article/MED/42972310
AB - Introduction Major depressive disorder (MDD) is characterized by dysfunction in higher-order cortical regions involved in emotional and cognitive processes; however, its neurobiological basis remains unclear. Pharmacological treatments, including esketamine and sertraline, produce rapid antidepressant effects. We investigated the local intrinsic neural dynamics underlying these antidepressant effects using intrinsic neural timescales (INT), which measure the duration and capacity of information integration in localized brain regions.Methods A total of 57 healthy controls and 41 patients with MDD were included. All patients with MDD received six intravenous infusions of esketamine (0.25 mg/kg) and two weeks of sertraline treatment. All participants underwent resting-state fMRI to quantify INT alterations at the voxel and brain network levels, followed by spatial correlation analyses linking autocorrelation metrics of INT signals to transcriptomic data from the Allen Human Brain Atlas and PET-derived neurotransmitter receptor maps. The spatial correlation between PLS2 scores and case-control t-statistic maps did not pass rigorous spin permutation testing (r = 0.484, p = 0.068) and did not meet the conventional significance threshold of 0.05. Accordingly, all subsequent enrichment analyses based on PLS2 results are presented as exploratory preliminary observations for hypothesis generation.Results Compared with healthy controls, patients with MDD exhibited significantly elevated INT levels in the left and right precuneus. Following treatment, patients with MDD showed significantly increased INT in the left occipital midline region and left calcarine cortex. At the brain network level, INT levels were significantly reduced in the default mode network (DMN) in patients with MDD compared with healthy controls. Compared with the pre-treatment state, the cerebellar network (CN) showed significantly elevated INT levels after treatment. Partial least squares regression analysis suggested potential associations between INT alterations and spatial gene expression gradients particularly those associated with immune responses, hormonal regulation, neutrophils, regulatory T cells, and glutamatergic synapses. Cell-type enrichment analysis identified excitatory and inhibitory neurons as key cellular contributors. Alterations in INT also correlated with cortical 5-HT1b and NAT receptor density, suggesting a role for inhibitory neurotransmission in temporal integration deficits.Conclusion This study advances understanding of treatment-related brain abnormalities in patients with MDD from the perspective of local neural dynamics. These findings support a multiscale pathophysiological framework involving brain connectivity dynamics, molecular architecture, and neurochemical regulation in MDD.
SN - 1471-244X
ER -