MRI-Derived Markers of Acute & Chronic Inflammatory Processes in the VTA Associated with Depression
Poster No:
397
Submission Type:
Abstract Submission
Authors:
Sarah Khalife1, Steffen Bollmann2, Andrew Zalesky3,4, Lena Oestreich1,5
Institutions:
1School of Psychology, The University of Queensland, Brisbane, QLD, Australia, 2School of Electrical Engineering and Computer Science, The University of Queensland, Brisbane, QLD, Australia, 3Melbourne Health, The University of Melbourne, Carlton South, VIC, Australia, 4Department of Biomedical Engineering, The University of Melbourne,, Parkville, VIC, Australia, 5Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia
First Author:
Co-Author(s):
Steffen Bollmann
School of Electrical Engineering and Computer Science, The University of Queensland
Brisbane, QLD, Australia
School of Electrical Engineering and Computer Science, The University of Queensland
Brisbane, QLD, Australia
Andrew Zalesky, PhD
Melbourne Health, The University of Melbourne|Department of Biomedical Engineering, The University of Melbourne,
Carlton South, VIC, Australia|Parkville, VIC, Australia
Melbourne Health, The University of Melbourne|Department of Biomedical Engineering, The University of Melbourne,
Carlton South, VIC, Australia|Parkville, VIC, Australia
Lena Oestreich, PhD
School of Psychology, The University of Queensland|Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
Brisbane, QLD, Australia|Brisbane, QLD, Australia
School of Psychology, The University of Queensland|Australian Institute for Bioengineering and Nanotechnology, The University of Queensland
Brisbane, QLD, Australia|Brisbane, QLD, Australia
Introduction:
Depression is a leading cause of disability worldwide, with inflammation implicated in its aetiology. Acute inflammation induces transient changes in the extracellular space (Yi et al., 2019), while chronic inflammation can lead to neurodegeneration (Somani et al., 2022) (Fig. 1). Inflammatory cytokines disrupt dopamine signalling in the brain's reward system, particularly affecting dopaminergic neurons originating in the ventral tegmental area (VTA), contributing to depressive symptoms such as anhedonia and reduced motivation (Felger & Treadway, 2017). Depression may partly stem from dopaminergic neuron dysfunction or depletion in the VTA as a secondary result of inflammation. This study investigates whether diffusion MRI and Quantitative Susceptibility Mapping (QSM) markers, sensitive to neuroinflammation and microstructural processes in the VTA, are associated with depression history and acute depressive symptoms.
Methods:
Data from 32,495 UK Biobank participants were analyzed using minimally preprocessed diffusion-weighted imaging (DWI), QSM, and T1-weighted MRI scans. The VTA was delineated using the Levinson-Bari Limbic Brainstem Atlas (Levinson et al., 2023), transformed from MNI space to participant-native space (ICBM 152 Nonlinear Atlases, 2009). Metrics sensitive to inflammatory processes (free water [FW], isotropic volume fraction [ISOVF], magnetic susceptibility) and microstructure (intracellular volume fraction [ICVF], orientation dispersion index [ODI], and volume) were extracted from the VTA. We compared 3,807 participants with major depressive disorder (MDD) to matched controls using ANOVAs. Linear regression assessed VTA metrics as predictors of symptom severity in 1,151 pseudo-randomly selected participants, balancing Recent Depressive Symptoms questionnaire scores and controlling for age, sex, and BMI.
Results:
Individuals with a history of MDD had significantly increased FW and ISOVF (FW: F(1, 7612)=12.29, p<0.001; ISOVF: F(1, 7612)=10.26, p=0.001), suggesting increased extracellular volume processes. ICVF and ODI were elevated but not significant after Bonferroni correction (Fig. 2). High multicollinearity between FW and ISOVF (r= 0.96, p<0.001; FW VIF=34.12; ISOVF VIF=33.08) indicated that both likely reflect similar processes. ISOVF was retained to reduce multicollinearity. The regression model (F(9, 1141)= 9.673, p<0.001) explained 6.35% of the variance in acute depressive symptom severity. Higher ICVF (β=4.57, p=0.007) and ODI (β=6.36, p=0.004) were positively associated with greater symptom severity, indicating microstructural changes with increasing depression severity. ISOVF was negatively associated with symptom severity (β=-2.83, p=0.017), suggesting elevated extracellular water content links to acute inflammation. Sex (β= -0.93, p< 0.001) and BMI (β=0.11, p<0.001) were also significant predictors, with males exhibiting lower symptom severity and higher BMI with increased symptom severity. Age and age squared were not significantly associated. Volume and magnetic susceptibility were not associated with depression history or symptom severity.
Conclusions:
Individuals with a depression history exhibit increased markers of extracellular water in the VTA, indicated by elevated FW and ISOVF, suggesting neuroinflammatory processes linked to chronic inflammation. Lower ISOVF, coupled with increased ICVF and ODI, associated with higher acute depressive symptom severity, may reflect microstructural changes as a secondary consequence of inflammation. These patterns align with findings that acute neuroinflammation is characterized by increased hindered diffusion due to microglial activation, whereas chronic inflammation shows reduced hindered diffusion. The absence of significant changes in magnetic susceptibility suggests that chronic processes like iron deposition or demyelination may not significantly impact the VTA in depression. These findings highlight neuroinflammation's role in depression and its potential as a therapeutic target.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Subcortical Structures 2
Keywords:
Affective Disorders
Astrocyte
Dopamine
Glia
Myelin
Psychiatric
Psychiatric Disorders
STRUCTURAL MRI
Sub-Cortical
Other - VTA, Depression, UK biobank, ventral tegmental area (VTA), Inflammation,
1|2Indicates the priority used for review
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ICBM 152 Nonlinear atlases (2009) – NIST. (n.d.). Retrieved December 1, 2023, from https://nist.mni.mcgill.ca/icbm-152-nonlinear-atlases-2009/
Levinson, S. (2023). A structural connectivity atlas of limbic brainstem nuclei. Frontiers in Neuroimaging, 1, 1009399. https://doi.org/10.3389/fnimg.2022.1009399
Somani, A. (2022). Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study. Brain Sciences, 12(2), 144. https://doi.org/10.3390/brainsci12020144
Yi, S. Y. (2019). Detecting Microglial Density With Quantitative Multi-Compartment Diffusion MRI. Frontiers in Neuroscience, 13. https://doi.org/10.3389/fnins.2019.00081