This study was the first to report the relationships between brain iron deposition and multiple factors associated with depression (treatment, symptom severity-HRDS, relapse frequency, mean duration of single episode, and total course of disease onset). Our study discovered widespread increased susceptibility across the basal ganglia and cortex in depression, which could not be reversed by treatment. More important was the finding that susceptibility across the putamen, hippocampus, and thalamus were strongly correlated with the total course of disease onset, but not the severity of depressive status-HRDS. It is suggested that brain iron deposition may be a cumulative marker of brain damage in depression, but not an immediate indicator of symptoms.
Before the QSM method was successful developed[25, 26], there were two types of methods to detect iron in the brain, i.e., qualitative MRI methods (T2, T2*, R2*, SWI (susceptibility weighted imaging)), and semi-quantitative MRI methods (magnetic field correlation (MFC) imaging, phase imaging). However, all the above-mentioned methods are essentially based on the characteristics of the magnetic field, which may cause blooming artifacts[33, 34], so the traditional MRI quantification methods do not provide an absolute quantification and are under the effect of non-local influences. Compared to the traditional techniques, QSM is believed to be able to give a more accurate and specific measurement on tissue magnetic susceptibility[36, 37]. This susceptibility can be calculated using a map of the resonance frequency in each voxel, which traditionally utilizes the MR phase signal from GRE imaging and has been shown to correlate well with tissue iron concentration in most gray matter regions in the brain.
As iron deposition in the brain is spatially selective (significant brain iron deposition was found in the basal ganglia and other deep-brain nuclei), these ROIs are usually subjectively chosen, artificially outlined, extracted, and analyzed directly in most previous MRI researches. In fact, there are two major deficiencies with this strategy. First, it usually ignores the changes in the most important structure of the brain (the cortex). Abnormal deposition of iron in the cerebral cortex has been proved in vitro by other established methods, such as histochemical analysis, staining or transcranial sonography. Second, the extraction of artificially outlined ROIs is subject to two definite limitations: i) results are generally prone to inaccuracies in ROI definition due to the intricate anatomical substructures and weak contrast of anatomical boundaries on QSM; and ii) the poor consistency of repeated measurements depending on subjective outlining might cause a group-dependent study bias. In need of special is that, although ROIs extracted according to the MNI-template in FSL could overcome the above deficiencies, there was still limitation of the method adopted in this study that the registration might be not perfect because of lost or mixed image information.
In our study, consistent results from both a whole-brain and regional QSM study showed that brain regions with abnormal susceptibility in patients with depression included the frontal lobes, temporal lobes, occipital lobes, hippocampal regions, putamen, thalamus, cingulum, and cerebellum. We found it interesting that increased brain iron deposition occurred not only in two iron-rich areas (not all iron-rich brain areas were involved), but also in areas with minimal iron content (cortex, hippocampus and cerebellum). This phenomenon was also reported in previous QSM whole-brain studies of iron deposition in PD and MS patients[19, 24]. Although its intrinsic mechanism remains unclear, this distribution pattern of aberrant brain iron deposition is enough to draw our attention and strongly suggest that studies on iron in the brain should not be focused merely on DGM. So far, direct evidence of the relations between iron deposition patterns in the brain and depression has been exhibited in this study. In fact, regions of aberrant brain iron deposition we reported here were consistent with those reported by structural and fMRI studies of depression[39, 40]. That is, in a state of stress or depression, brain iron deposition may be one of physiological and pathological changes, with synergistic effects on the structure and function of the sensitive brain regions.
In subsequent analysis, we found the susceptibility in the involved brain regions could not be reversed by treatment, and was not correlated with the severity of depressive status-HRDS. The results were slightly different from the previous reports, which might be explained by two reasons: (i) different sample populations and (ii) different methods of brain iron deposition analysis. Our further results found that not only the susceptibility in the putamen, thalamus and hippocampus presented a nearly statistically significant association with the relapse frequency and mean duration of single episode, but also a strongly correlated with the total course of disease onset. In fact, the relapse frequency and mean duration of single episode were the two determinations of the total course of disease onset. We believed that these three factors should be all closely related to the brain iron deposition in the above brain regions, and “a nearly statistically significant” might be attributed to the limited sample size in this study. Besides, it was not surprising to find that these regions of brain iron deposition were associated with the depression-related conditions, as previous studies had revealed that the putamen (part of the striatum) is related to motor and cognitive functions, and its dysfunction is known to be associated with loss of dopaminergic neurons within the cortical-striatum-thalamocortical circuit. The thalamus is thought to be involved in the pathophysiology of depressive disorders and is currently drawing sustaining attention, and a recent research has reported that abnormal thalamocortical connectivity was found in depression. Another brain region involved was the well-studied hippocampus, which has always been regarded as a targeted area in depression research because of its important role in emotion, cognition and memory. In general, brain iron deposition in the specific brain regions may be a cumulative marker of brain damage in depression, but not an immediate indicator of symptom.
We sincerely apologize for the shortcomings of the paper. 1) A limited sample size in this study could lead to statistical errors of type I and II. 2) We had not adopted a finer scale for the selection of cortical interest areas. 3) This study did not have sufficient follow-up to understand the further evolution of brain iron deposition in depression.
In conclusions, brain iron deposition is related to the total course of disease onset, but not the severity of depression, which suggest that brain iron deposition may be a sign of brain damage in multiple recurrent depression.