Major depressive disorder (MDD) and schizophrenia are common mental illnesses that have a considerable negative impact on patients’ lives. For these disorders, brain magnetic resonance imaging (MRI) studies indicated common and disease-specific alterations in brain structure and/or function [1–6]. In fact, previous studies reported altered subcortical volumes in various psychiatric disorders, including MDD and schizophrenia (7–12). Subcortical regions, including the caudate [7, 8], thalamus, and hippocampus [8], are found to be smaller in MDD patients compared to healthy controls (HCs); however, the study conducted using MRI of 8,590 samples from the UK Biobank did not observe any statistically significant differences between individuals with depressive symptoms and HCs in any of the subcortical volumes [9]. In contrast, in schizophrenia several consistent changes in subcortical volume have been reported [10, 11]. The Enhancing Neuroimaging Genetics through Mega-Analysis (ENIGMA) Consortium Schizophrenia Working Group conducted a multicenter meta-analysis and found that patients with schizophrenia had smaller volumes in the hippocampus, amygdala, thalamus, and accumbens and larger volumes in the pallidum compared to HCs [12].
Subcortical brain regions are involved in various neural networks and are rich projection sites for neurons related to important neuromodulators such as dopamine, serotonin, and norepinephrine, as well as target sites for psychotropic drugs [13]. Positron emission tomography (PET) imaging provides evidence for the dysregulation of the dopamine system in patients with schizophrenia and loss of monoamine variability in patients with MDD [14], corresponding to the therapeutic targets. Since dopamine synthesis and metabolism depend on brain iron, basal nuclei have high quantities of iron [15]. Quantitative susceptibility mapping (QSM) is an MRI technique that can be used to measure the magnetic susceptibility of different brain tissue types [16, 17]. This technique can be used to identify various contrasts in the brain, including high-contrast paramagnetic substances such as ferritin and iron in the cortex and deep gray matter; hemorrhage; and microbleeds containing deoxyhemoglobin, methemoglobin, and hemosiderin [18]. Further, QSM can be used to identify low-contrast diamagnetic substances, such as myelin in white matter and calcification in the brain [18]. Therefore, QSM can potentially be used to examine the degrees of iron deposition and myelination, which are important considerations in brain evaluation. Additionally, QSM image contrasts, particularly in subcortical structures, may provide a detailed atlas [19–21]. For example, QSM clearly delineates the nucleus accumbens, internal and external globus pallidus, red nucleus, and substantia nigra, for which contrast on T1-weighted images (T1WI) is difficult to obtain [20].
A significant increase in susceptibility values was observed in the bilateral putamen of severely depressed patients compared to mildly and moderately depressed patients or HCs [22]. In addition, there was a significant increase in local magnetic susceptibility in the subcortical structure, including hippocampus, pituitary, and thalamus in the depressed group compared to the HCs [23]. Furthermore, the magnetic susceptibility of the globus pallidus, putamen, and thalamus was increased in patients with first-episode schizophrenia compared to HCs [24]. Therefore, subcortical volume analysis combined with QSM can be used to evaluate microstructural changes and iron deposition and to provide a biologically specific subcortical measure to reveal pathological subcortical changes caused by psychiatric disorders.
In addition, only a few studies on psychiatric disorders examine the relationship between structural subcortical volume changes and magnetic susceptibility; however, research indicates a negative correlation between volume and magnetic susceptibility in the hippocampus in schizophrenia patients [25]. In neurological studies using amyloid-beta (Aβ) PET, subcortical Aβ is associated with changes in the surface morphology of specific brain regions, and a high Aβ is associated with poor cognitive function and small hippocampal volume in cognitively normal individuals [26]. Moreover, the distinctive mediating effects of Aβ and subcortical volume changes on cognitive function in patients with mild cognitive impairment suggest a relationship between neurodegenerative markers and volume [27]. Therefore, to clarify the relationship between volume and magnetic susceptibility by QSM, we conducted an analysis in which the original multi-echo T2*-weighted images (T2*WIs) were co-registered with T1WIs to improve consistency between QSM analysis and volume analysis by T1WI [28].
We hypothesized that the insufficiency of magnetic susceptibility, which reflects an increase and/or decrease in iron deposition and myelination, is related to changes in subcortical structures. Accordingly, we perform a MRI volumetry analysis combined with QSM atlas to examine whether there are specific differences in subcortical brain volumes and magnetic susceptibility among patients with MDD, patients with schizophrenia, and HCs. Finally, we investigated whether there is any relationship between subcortical volume and magnetic susceptibility in individuals with these psychiatric disorders.