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March 15, 2026

Unravelling Structural and Metabolic Alterations in the Hippocampus and Anterior Cingulate Cortex Using Integrated MRI and MRS in Major Depressive Disorder

Key Points

The study aims to investigate structural and metabolic alterations in the hippocampus and anterior cingulate cortex in major depressive disorder (MDD).
Participants included patients with MDD (n = 64) and healthy controls (n = 47) assessed via MRI and MRS.
Structural imaging used three-dimensional T1-weighted MRI at 3.0 T, analyzed with Freesurfer 7.2.0.
Metabolite concentrations were quantified using Osprey software and correlated with depression severity (HDRS, MDRS).
False discovery rate was used for statistical adjustment of multiple comparisons.
Significant reduction in total NAA, myoinositol, total choline, and total creatine in the hippocampus of MDD patients.
Increased levels of tNAA and tCr in the ACC; ACC volume was significantly larger in MDD patients.
Weak positive correlation between tCho levels and hippocampal/mid-ACC volumes, while glutamate levels negatively correlated with depression severity.

Abstract

The present study investigated structural and metabolic changes in the two brain regions of the limbic system, right hippocampus and anterior cingulate cortex (ACC), implicated in the pathophysiology of major depressive disorder (MDD). Three-dimensional-T1-weighted magnetic resonance imaging (MRI) and single-voxel in vivo magnetic resonance spectroscopy (MRS) were performed on a 3.0 T MRI in patients with MDD (n = 64) and healthy controls (HC, n = 47). The severity of depression was assessed using clinical scales (Hamilton Depression Rating Score HDRS and Montgomery-Åsberg Depression Rating Score MDRS). The automated volumetric segmentation of the T1-weighted MR images was performed using Freesurfer 7.2.0. The tissue-corrected concentration of neurochemicals was quantified using Osprey software. The relationship between hippocampal and ACC metabolite levels was examined with their volumes. Additionally, the levels of neurochemicals and volumes were correlated with the severity of depression. After adjusting for multiple comparisons using the false discovery rate (FDR), the concentration of total NAA (t-NAA, N-acetyl aspartate+ N-acetyl-aspartyl-glutamate NAAG), myoinositol (mI), total choline (tCho) and total creatine (tCr) were significantly reduced (pFDR FDR < 0.05). Further, the volume of ACC was significantly increased in patients with MDD. Although hippocampal volume was not different between the two groups, a weak positive correlation was observed between the tCho levels and the volumes of the hippocampus and mid-ACC. Hippocampal glutamate + glutamine (Glx) levels showed a weak negative correlation with the MDRS score, whereas ACC tCho showed a negative correlation with the HDRS score. Our observations suggested that the pathophysiology of MDD is not only associated with hippocampal neurodegeneration but may also involve glial proliferation, leading to increased ACC volume. These changes might alter neurotransmission in the limbic system, contributing to the pathophysiology of depression.

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Unravelling Structural and Metabolic Alterations in the Hippocampus and Anterior Cingulate Cortex Using Integrated MRI and MRS in Major Depressive Disorder

Key Points

Abstract

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