Quantitative MRI at 7-Tesla reveals novel frontocortical myeloarchitecture anomalies in major depressive disorder

Major depressive disorder (MDD) is increasingly associated with brain abnormalities, particularly in prefrontal and anterior cingulate cortices. Previous studies using conventional MRI have shown cortical thinning in these areas, but the underlying microstructural processes remain unclear. Meta-analyses, such as those by the ENIGMA MDD Consortium, highlight orbitofrontal and rostral anterior cingulate cortex thinning as robust correlates of MDD. However, these measures only reflect shape changes at the cortical boundaries and do not provide insights into the internal microstructure. This study aimed to address this gap by using ultra-high field (7.0 Tesla) MRI and quantitative imaging to map intracortical myelin and iron concentration, crucial microstructural components, in these regions among individuals with MDD and healthy controls. Intracortical myelination is crucial for neural circuit integrity and plasticity, and both myelination and iron concentration are implicated in the development and maintenance of cortical structure. Preliminary evidence suggests a potential role for intracortical demyelination in the prefrontal regions in MDD, but more research is needed using advanced MRI techniques. Therefore, this study utilized a unique approach to gain finer-grained insights into the microstructural underpinnings of cortical abnormalities observed in MDD.

The literature review extensively cites studies supporting the association between MDD and prefrontal/anterior cingulate cortex abnormalities. Meta-analyses, specifically those from the ENIGMA MDD Consortium, are highlighted, showing consistent cortical thinning in MDD. However, the authors emphasize that these macroscopic measures don't capture underlying microstructural changes. The review then focuses on the importance of intracortical myelination and iron concentration as potential microstructural contributors to MDD. It cites studies suggesting a link between intracortical demyelination, particularly in prefrontal regions, and the etiology of depression. The role of iron in myelin synthesis and the potential consequences of iron imbalance (oxidative stress, neural cell death) are also discussed. The review sets the stage for the study's hypothesis: that alterations in intracortical myelination and iron concentration may underlie the macroscopic cortical changes observed in MDD.

This study recruited 73 individuals, resulting in a final sample of 48 MDD patients and 10 healthy controls (HC) after exclusion criteria were applied. The MDD diagnosis was confirmed using the Composite International Diagnostic Interview (CIDI). HC participants had no history of depression or other psychopathology. The Inventory of Depressive Symptomology (IDS) and Childhood Trauma Questionnaire (CTQ) were used to assess symptom severity and childhood trauma. MRI data acquisition was performed using a Philips Achieva 7T MRI scanner with a 32-channel head coil. A multi-echo magnetization-prepared rapid gradient echo (MP2RAGE) sequence was used to acquire T1 and T2* maps simultaneously. T1 maps were calculated using a lookup table based on the sequence parameters, serving as a proxy for intracortical myelin. T2* maps served as a proxy for iron concentration. Regions of interest (ROIs) were defined using the Desikan-Killiany atlas: rostral anterior cingulate cortex (RACC), medial orbitofrontal cortex (MOFC), and lateral orbitofrontal cortex (LOFC). Quantitative relaxation time values were sampled from 10 cortical depths within each ROI. Data analysis was performed using JASP, including ANCOVA to compare MDD and HC groups on various metrics (average T1/T2*, area under the curve (AUC) of T1/T2* profiles, and T1/T2* at the WM/GM transitional zone) while controlling for age and sex. Exploratory analyses investigated the relationships between clinical characteristics and microstructural measures within the MDD group.

The key finding was a significant association between MDD diagnosis and decreased intracortical myelination (higher T1 values) in the lateral orbitofrontal cortex (LOFC). This effect was observed across cortical depths (average T1), in the depth-dependent distribution of T1 (AUC), and at the WM/GM transition zone. The effect size was moderate to large (Cohen's d = 0.55-0.66). Importantly, this effect was specific to the LOFC; no significant differences were found in other ROIs (RACC, MOFC) or in a control region (primary somatosensory cortex). Furthermore, MDD symptom severity (IDS score) was positively correlated with increased average T1, T1 AUC, and T1 offset in the LOFC, indicating a stronger association between higher symptom severity and decreased myelination. No significant relationships were found between microstructural measures and antidepressant use, comorbid anxiety disorders, or childhood trauma. No significant differences were found in T2* values (iron concentration) between MDD patients and healthy controls in any region.

The study's findings provide novel, fine-grained insights into the microstructural alterations in the frontocortical regions of individuals with MDD. The specific association of decreased intracortical myelination with MDD diagnosis and severity in the LOFC supports the hypothesis that intracortical demyelination contributes to MDD pathophysiology. The LOFC's role in processing negative affect makes this finding particularly relevant. The lack of significant findings regarding iron concentration suggests that myelin abnormalities might be the primary microstructural driver in this context, although further investigation is needed. The results also highlight the importance of using advanced neuroimaging techniques like 7.0 Tesla MRI to uncover subtle microstructural changes that conventional MRI may miss. The study's findings align with previous research suggesting a role for intracortical myelination in depression, but this is the first study to use high-resolution quantitative MRI to demonstrate a direct link between reduced myelination and MDD symptoms.

This study demonstrates, for the first time using ultra-high field quantitative MRI, that decreased intracortical myelination in the lateral orbitofrontal cortex is associated with MDD diagnosis and symptom severity. These findings suggest intracortical demyelination as a potential driver of cortical abnormalities in MDD. Future longitudinal studies with larger samples are needed to establish causality and investigate the relationship between intracortical myelination, treatment response, and relapse in MDD. Further research could also explore the underlying biological mechanisms driving these changes.

The relatively small sample size, particularly the small number of healthy controls, and the cross-sectional design are limitations. The cross-sectional nature prevents causal inferences and limits the ability to assess the impact of illness duration. The study also lacked the statistical power to fully examine the relationship between microstructure and macrostructure in MDD. Future research should address these limitations by using larger, longitudinal samples and investigating the interplay between microstructural and macrostructural changes in MDD.