Aberrations in the Ventral Tegmental Area predict depression severity in the general population

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Abstract Submission 

Sarah Khalife¹, Lena Oestreich¹, Steffen Bollmann¹, Andrew Zalesky²

¹University of Queensland, Brisbane, Queensland, ²The University of Melbourne, Melbourne, Victoria

Sarah Khalife  
University of Queensland
Brisbane, Queensland

Lena Oestreich  
University of Queensland
Brisbane, Queensland

Steffen Bollmann  
University of Queensland
Brisbane, Queensland

Andrew ZALESKY, PhD  
The University of Melbourne
Melbourne, Victoria

Approximately 300 million individuals are affected by major depression worldwide, making it one of the leading causes of disability (WHO, 2017). A growing body of literature indicates that many depression symptoms, such as loss of motivation and anhedonia may be attributed to the influence of inflammatory cytokines on mesolimbic dopamine signaling (Felger et al., 2017). Midbrain dopaminergic neurons originating from the ventral tegmental area (VTA) are among the areas most susceptible to these negative consequences of inflammatory cytokines. As such, it is conceivable that depression may be caused by dopaminergic neuron depletion and/or dysfunction in the VTA, possibly as a sequelae of inflammation. Here we set out to test whether diffusion MRI and Quantitative Susceptibility Mapping (QSM) markers sensitive transient processes, together with microstructural markers, can predict depression severity across the general population.

We included 8,249 participants with varying degrees of depression severity from the UK biobank (Sudlow et al., 2015). Diffusion weighted imaging (DWI), QSM and T1-weighted images were included in the analyses. Pre-processing of DWI and QSM data was performed by the UK biobank (Alfaro-Almagro et al., 2018). Free-water correction was applied to the pre-processed DWI data (Pasternak et al., 2009). The VTA was delineated with the Levinson-Bari Limbic Brainstem Atlas (Levinson et al., 2023) and co-registered to DWI subject space. Estimates of the DWI metrics free-water (FW), isotropic volume fraction (ISOVF), Intra-cellular volume fraction (ICVF) and orientation dispersion index (ODI), as well as magnetic susceptibility derived from QSM were extracted from the VTA. Depression symptomatology was evaluated using the Recent Depressive Symptoms questionnaire, assessing the severity of depressed mood, disinterest, restlessness, and tiredness on a 4-point Likert scale within the past two weeks (Dutt et al., 2022). Multiple linear regression analysis was conducted to estimate associations between the MRI-derived metrics in the VTA and depression severity while controlling for age, age squared and sex.

Participants ranged in age from 46 to 82 years (M=64.1, SD=7.7). The variance inflation factor (VIF) for FW (VIF=28) and ISOVF (VIF=28), indicated the presence of multicollinearity. Due to ease of interpretation in the context of the other neurite orientation and dispersion density imaging (NODDI) metrics ICVF and ODI, FW was removed from the regression model while ISOVF was kept in the model. The overall model was significant (F(7,8248)=41.53, p<0.001) and explained 3.32% of the variance in depression severity. The predictors ODI and magnetic susceptibility independently contributed to depression severity (β=1.17, p=0.002 and β=0.42, p=0.002, respectively), such that depression severity increased with increasing ODI and magnetic susceptibility. ISOVF contributed negatively to depression severity (β= -0.48, p=0.027), such that depression severity increased with decreasing ISOVF.

ISOVF, which estimates the amount of extracellular volume, was negatively associated with depression severity. In gray matter, glial cells in the extracellular space transport nutrients and energy to neurons and may influence how well neurons function and communicate. A decrease in ISOVF could therefore suggest functional aberrations of dopaminergic neurons originating from VTA with increasing depression severity. The positive association between magnetic susceptibility and depression severity is suggestive of increased iron content in the VTA, which may reflect neurodegeneration in this area as depressive symptoms worsen. In conclusion, transient markers sensitive to extracellular processes derived from diffusion MRI and QSM in the VTA are predictive of depression severity across the general population. Future studies may wish to examine whether these estimates can be utilized for diagnostic classification of major depression.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Subcortical Structures

Diffusion MRI ²

ADULTS

Psychiatric

Psychiatric Disorders

STRUCTURAL MRI

Sub-Cortical

Other - Ventral Tegmental Area