Diffusion MRI and MR spectroscopy reveal microstructural and metabolic brain alterations in chronic mild stress exposed rats: A CMS recovery study

Abstract

Chronic mild stress (CMS) induced depression elicits several debilitating symptoms and causes a significant economic burden on society. High variability in the symptomatology of depression poses substantial impediment to accurate diagnosis and therapy outcome. CMS exposure induces significant metabolic and microstructural alterations in the hippocampus (HP), prefrontal cortex (PFC), caudate-putamen (CP) and amygdala (AM), however, recovery from these maladaptive changes are limited and this may provide negative effects on the therapeutic treatment and management of depression. The present study utilized anhedonic rats from the unpredictable CMS model of depression to study metabolic recovery in the ventral hippocampus (vHP) and microstructural recovery in the HP, AM, CP, and PFC. The study employed H MR spectroscopy (H MRS) and in-vivo diffusion MRI (d-MRI) at the age of week 18 (week 1 post CMS exposure) week 20 (week 3 post CMS) and week 25 (week 8 post CMS exposure) in the anhedonic group, and at the age of week 18 and week 22 in the control group. The d-MRI data have provided an array of diffusion tensor metrics (FA, MD, AD, and RD), and fast kurtosis metrics (MKT, W and W). CMS exposure induced a significant metabolic alteration in vHP, and significant microstructural alterations were observed in the HP, AM, and PFC in comparison to the age match control and within the anhedonic group. A significantly high level of N-acetylaspartate (NAA) was observed in vHP at the age of week 18 in comparison to age match control and week 20 and week 25 of the anhedonic group. HP and AM showed significant microstructural alterations up to the age of week 22 in the anhedonic group. PFC showed significant microstructural alterations only at the age of week 18, however, most of the metrics showed significantly higher value at the age of week 20 in the anhedonic group. The significantly increased NAA concentration may indicate impaired catabolism due to astrogliosis or oxidative stress. The significantly increased W in the AM and HP may indicate hypertrophy of AM and reduced volume of HP. Such metabolic and microstructural alterations could be useful in disease diagnosis and follow-up treatment intervention in depression and similar disorders.

Neurite atrophy in dorsal hippocampus of rat indicates incomplete recovery of chronic mild stress induced depression

“…Recently, we have reported significant metabolic and microstructural alterations in the HP and in the AM of anhedonic rats until five weeks after CMS exposure in a longitudinal MRI study. Importantly, an apparent normalization was observed at eight weeks after stress exposures . However, one limitation of this study was the lack of matching controls at Week 8 post‐CMS paradigms.…”

“…These directions were therefore removed from all data sets to ensure a homogeneous data foundation for the study. Before parameter estimation, diffusion images were registered using the b = 0 images as a target, followed by de‐noising and Gibbs ringing correction as described previously . After post‐processing, dMRI data were again inspected visually for any misalignment or any other artifacts.…”

“…Five ROIs were evaluated, namely AM, CP, dHP, vHP, and PFC (Figure ). Due to limitations in dMRI image resolution, we have not been able to delineate further sub‐regions in dHP or vHP …”

“…This model has shown the pertinent face, predictive, and construct validity, and is therefore regarded as a realistic model of depression. The unpredictable CMS model of depression has consistently shown microstructural alterations in stress‐sensitive brain regions, namely hippocampus (HP), prefrontal cortex (PFC), caudate putamen (CP), and amygdala (AM) …”

“…DKI has been shown to possess microstructural sensitivity in clinical as well as in preclinical studies, not only in the brain but also in other vital organs, such as kidney . Here we report on ex vivo findings of microstructural alterations in stress‐sensitive brain regions in animals that were included in a longitudinal in vivo investigation of CMS recovery . The in vivo data were recently made available for researchers interested in the comparison and reanalysis of the data.…”