Alterations In Cerebral Structure,Function And Iron Deposition In Patients With Major Depressive Disorder:A Multiparameter MRI Study

Part 1 Structural asymmetry in patients with major depressive disorderBackground and purposeStructural and functional asymmetry are a fundamental biological trait of human brain.Each cerebral hemisphere has its own distinct strategy for multifarious perceptual and cognitive processing,such as handedness,language,and visuospatial functions.Moreover,the modulation of emotions is also lateralized within the cerebral hemispheres.As a severe mental disease,major depressive disorder?MDD?is featured with emotional dysregulation that typically presents as excessive sadness,anhedonia and suicidality.Right hemisphere hyperactivity and/or left hemisphere hypoactivity often appears to be a characteristic in neuroimaging studies of depression.To date,however,few studies have evaluated abnormalities in structural asymmetry in untreated patients with MDD.Subjects and methodsThree-dimensional high-resolution structural magnetic resonance images were acquired from 35 treatment-na?ve patients with MDD and 35 normal controls?NCs?.The inclusion criteria for patients were meeting the Diagnostic and Statistical Manual of Mental Disorders IV diagnostic criteria for MDD,and were currently depressed but not receiving any drug treatments,and had a total 24-item Hamilton Depression Scale(HAM-D₂₄)score>20?moderate severity?.The asymmetry index in cortical thickness and subcortical volume were calculated based on an automated surface-based technique.Differences in the asymmetry index between the patients with MDD and the NCs for vertex-wise cortical thickness were evaluated using the general linear model,for region-of-interest-wise?ROI-wise?cortical thickness and for the subcortical volume were assessed using the Mann-Whitney U test.Correlations between asymmetry index and the HAM-D₂₄ scores,the Self-Rating Depression Scale?SDS?scores,and the Self-Rating Anxiety Scale?SAS?scores were analysed in patients with MDD.ResultsAbnormalities in structural asymmetry in patients with MDD were mainly located in the prefrontal-striatal-pallidal-thalamic circuit,including the superior frontal cortex,rostral middle frontal cortex,caudal middle frontal cortex,nucleus accumbens,pallidum and thalamus.No significant correlation was observed between symptom severity and asymmetric measurements.ConclusionsThis part of study utilized an automated surface-based approach and provide further evidence for the altered morphological interhemispheric imbalances in depression.These alterations were independent of depressive symptom severity,suggesting that cerebral asymmetry could be an appropriate indicator of morphological variations in mental disease.Part 2 Structural connectivity in patients with major depressive disorderBackground and purposeMany previous anatomical studies have focused on decreases in grey matter volume in patients with MDD.The abnormal regions reported in these studies,which are collectively known as cortical-limbic areas such as the dorsolateral prefrontal cortex,orbitofrontal cortex,posterior cingulate cortex,amygdala,putamen,and thalamus.Patients with depression in resting-state functional studies often showed altered functional connectivity?FC?within cognitive/emotional networks.However,the structural connectivity in patients with MDD has not been comprehensively examined.Otherwise,some patients with MDD endure the disease for many years and experience multiple episodes before seeking treatment because of stigma and shame associated with depression in traditional Chinese culture.Without treatment,the episodes may continue and may be characterized by increasingly serious symptoms.However,patients with multiple depressive episodes are receiving insufficient attention.Whether anatomical patterns are further damaged or compensated in untreated multiple-episode?ME?MDD compared to those in first-episode?FE?MDD is unclear.Subjects and methodsStructural magnetic resonance imaging was performed in 35 patients with MDD and35 age-,sex-,and education-matched controls.The cortical thickness and subcortical volume were calculated using FreeSurfer software.Differences between the patients with MDD and NCs in vertex-wise cortical thickness were evaluated using the general linear model,and in ROI-wise cortical thickness were assessed using the independent samples t-test,and in subcortical volume were analyzed using the Mann-Whitney U test.Abnormal structural/functional changes in the dorsolateral prefrontal cortex and orbitofrontal cortex in patients with MDD have been extensively reported.Therefore,the average cortical thickness of bilateral dorsolateral prefrontal cortex and orbitofrontal cortex were calculated using the ROI method and compared between patients with MDD and NCs.Furthermore,patients with MDD were divided into two subgroups based on the previous number of episodes,i.e.,FE group and ME group.The differences in average cortical thickness and subcortical volume in all regions observed between the MDD and NC groups in the previous statistical comparison were examined in the FE and ME groups using the independent sample t-test.Correlation analyses were performed to explore the relationships among brain structures and HAM-D₂₄ scores,SDS scores,and SAS scores in patients with MDD.Particularly,structural covariance was examined with the Pearson correlation analysis to determine the structural relationships within brain structures.ResultsA comparison of the cortical thickness between the MDD and NC groups showed relatively symmetrical changes in sixteen clusters,with both significant increases and decreases in cortical thickness observed.The largest and most significant increases in thickness were observed in the bilateral insula,superior frontal cortex,middle temporal gyrus,and left posterior cingulate cortex,caudal middle frontal cortex,precuneus,precentral gyrus,and right entorhinal cortex.The regions with significantly decreased thickness were the bilateral rostral middle frontal cortex,left lingual gyrus,medial orbitofrontal cortex,and right pericalcarine cortex.The analysis of ROI-wised cortical thickness showed that compared with NCs,MDD group had significantly thicker left caudal middle frontal cortex,isthmus of the cingulate cortex,precentral cortex,superior frontal cortex,and right posterior cingulate cortex,a nd bilateral paracentral cortex,and significantly thinner left lingual cortex and medial orbitofrontal cortex.Furthermore,the bilateral dorsolateral prefrontal cortex was thicker in patients with MDD than in NCs,and the right orbitofrontal cortex OFC was thinner in patients with MDD than in NCs.The MDD group showed a nearly significant trend towards alterations in subcortical volumes in the left pallidum and the bilateral amygdala.In the hippocampal subfields analysis,the MDD group also showed a nearly significant trend towards decreases in volumes in the left presubiculum and bilateral hippocampal fissure.The subgroup comparison of FE and ME MDD patients showed that the left posterior cingulate cortex,isthmus of the cingulate cortex,and the right orbitofrontal cortex were thicker in the ME group than in the FE group.In comparison with NCs,the structural connectivity in patients with MDD between left caudal middle frontal cortex and left precentral cortex,left caudal middle frontal cortex and left superior frontal cortex were decreased,and between left superior middle frontal cortex and right posterior cingulate cortex,left paracentral cortex and left precentral cortex,left paracentral cortex and right paracentral cortex were increased.Furthermore,the strong structural connectivity between left dorsolateral prefrontal cortex and right dorsolateral prefrontal cortex,left dorsolateral prefrontal cortex and left amygdala were shown in the NC group,but were not seen in the MDD group.Among the structural measurements and clinical features in patients with MDD,only cortical thickness of left isthmus of the cingulate cortex showed a significant correlation with depressive duration.ConclusionsThis part of study complements and extends previous anatomical studies of patients with MDD and shows that structural alterations in untreated patients with MDD are primarily located in the frontal-basal ganglia circuits.The altered structural covariance may provide structural evidence for deficits in functional networks in MDD.The finding of a lack of correlation within dorsolateral prefrontal cortex and amygdala in patients with MDD supports an underlying structural mechanism for dysregulation of top-down or bottom-up processes.Morphological abnormalities in the left posterior cingulate cortex and the right orbitofrontal cortex may be critical for the pathophysiological progression of multiple-episode MDD.Moreover,dynamic changes in morphology were observed during the progression of MDD,which may be a more reliable measure than traditional clinical variables.Part 3 Functional connectivity and functional asymmetry in patients with major depressive disorderBackground and purposeBased on event-related functional studies,MDD has been hypothesized to result from enhanced processing of negative information in the limbic system accompanied by attenuated information transfer from limbic areas to prefrontal areas,which causes insufficient inhibitory control from prefrontal areas.However,this model only expl ains an impaired,unilateral information transfer circuit and ignores the potential involvement of an inter-hemispheric communication impairment in MDD.Otherwise,increased metabolic imbalance with the left hemisphere being hypoactive and the right hemisphere being hyperactive might be the key pathogenic mechanisms underlying MDD.Further research on abnormalities in functional asymmetry may provide more information about pathways underlying altered hemispheric interactions in MDD.Subjects and methodsStructural magnetic resonance imaging and resting-state functional magnetic resonance imaging were performed in 33 patients with MDD and 33 healthy controls.The functional images were processed using the toolbox for Data Processing&Analysis for Brain Imaging software.Intra-and inter-hemispheric FC strength of the default mode network areas,including bilateral medial superior frontal gyrus,middle frontal gyrus,orbital part middle frontal gyrus,medial orbitofrontal gyrus,anterior cingulate gyrus,posterior cingulate gyrus,hippocampus,parahippocampal gyrus,inferior parietal lobule,supramarginal gyrus,angular gyrus,precuneus,middle temporal gyrus,and middle temporal pole,were calculated.To quantify the FC differences between the left and right hemispheres,the asymmetry index was computed for each ROI.Otherwise,the corpus callosum is the largest of the intra-and inter-hemispheric myelinated axonal tracts that connect and integrate neural activity in the human brain,which might play an important role in functional asymmetry.Evidence from diffusion tensor imaging studies suggested that impaired white matter integrity in the white matter fascicles in patients with MDD were associated with the corpus callosum.Therefore,we further analyzed the volumetric changes in corpus callosum in patients with MDD.The corpus callosum was segmented to five subregions included the genu of corpus callosum,anterior midbody of corpus callosum,posterior midbody of corpus callosum,isthmus of corpus callosum and splenium of corpus callosum.The independent two-sample t-test was used to assess significant differences in volumes of callosal subregions,intra-hemispheric FC,inter-hemispheric FC,asymmetry index of intra-hemispheric FC and asymmetry index of inter-hemispheric FC between the patients with MDD and the NCs.Correlation analysis was performed to explore the relationships between structural and functional parameters with statistically significant differences and the clinical features in patients with MDD.ResultsIntra-hemispheric FC strength in the bilateral posterior cingulate gyrus,and left medial superior frontal gyrus,medial orbitofrontal gyrus,angular gyrus,and precuneus were significantly lower in the MDD group than in the NC group.Inter-hemispheric FC strength in the bilateral posterior cingulate gyrus were significantly lower in the MDD group than in the NC group.Intra-hemispheric FC strength of the precuneus,inter-hemispheric FC strength of the middle frontal gyrus,orbital part middle frontal gyrus,and anterior cingulate gyrus in patients with MDD showed right-lateralized asymmetry,which were reverse to asymmetry patterns of controls.Compared with NC group,the MDD group showed significantly smaller volumes in the genu of corpus callosum.No significant differences in the volumes of the anterior midbody of corpus callosum,posterior midbody of corpus callosum,isthmus of corpus callosum and splenium of corpus callosum were found between the MDD and NC groups.Significantly positive correlation between volume of the genu of corpus callosum and asymmetry index of inter-hemispheric FC strength of anterior cingulate gyrus,negative correlation between HAM-D₂₄ scores and asymmetry index of inter-hemispheric FC strength of medial orbitofrontal gyrus,and negative correlation between disease duration and asymmetry index of inter-hemispheric FC strength of anterior cingulate gyrus were found in patients with MDD.ConclusionsReductions in information exchange within intra-hemispheric and between inter-hemispheric default mode network were found in middle-aged patients with MDD.Furthermore,this study provides important new evidence for the potential contributions of altered functional asymmetry to MDD,and suggests that functional asymmetry can be a promising biomarker of condition assessment and even treatment surveillance for MDD.Particularly,the reduced functional asymmetry of anterior cingulate gyrus was related to volumetric decreases in the genu of corpus callosum and disease duration,indicating that aberrant inter-hemispheric connections may contribute to anatomical deficits in corpus callosum in MDD.Part 4 Iron deposition in patients with major depressive disorderBackground and purposeMany molecular mechanisms and pathways,including neurotransmitter systems activity,oxidative and nitrosative stress,inflammation,neurotrophins activity and the regulation of neurogenesis,have been recently elucidated as having relationships with depression.These pathogeneses all involve iron metabolism.Iron plays key roles in brain growth and development,neurotransmitter systems,myelination and mitochondrial respiration.The aim of this study was to investigate brain iron states and to examine their relationships with depressive severity and gray matter volume in untreated patients with MDD using the quantitative susceptibility mapping?QSM?approach.Subjects and methodsTwenty-five patients with MDD and 25 age and sex-matched NCs underwent MRI scans.Post-processing of the susceptibility-weighted imaging was performed using the Susceptibility Mapping and phase Artefacts Removal Toolbox software and was used to generated QSM images.For each participant,the average susceptibility values of the selected regions,including the bilateral dorsal lateral prefrontal cortex,orbitofrontal cortex,anterior cingulate cortex,putamen,pallidum,and amygdala,were manually calculated using the QSM images with MRIcron software by 2 experienced radiologists who were blinded to participant allocation.The volumes of the selected regions were extracted by FreeSurfer.The differences in gray matter volume and average susceptibility values of the12 brain regions between the MDD and NC groups were assessed using independent two-sample t-tests.Correlational analyses were performed to explore the relationships between gray matter volume,average susceptibility value and the clinical features of patients with MDD.ResultsIn comparison to the NCs,the patients with MDD showed greater susceptibility values in the left dorsal lateral prefrontal cortex and left putamen.No brain regions showed decreased susceptibility values in the MDD group.Compared with the NCs,the patients with MDD exhibited significantly lower gray matter volumes of the left amygdala,right amygdala and left dorsolateral prefrontal cortex.No cerebral regions showed larger gray matter volume in patients with MDD compared to the NCs.In the patients with MDD,no significant correlation between susceptibility value/gray matter volume and disease severity/duration was detected.A negative association was observed between susceptibility value and gray matter volume of the left dorsal lateral prefrontal cortex in patients with MDD.ConclusionsBrain iron homeostasis in patients with MDD was changed.Although iron concentration did not correlate with any clinical factor,the average susceptibility value and gray matter volume of the left dorsal lateral prefrontal cortex were significantly negatively correlated.This result suggests that bran iron dyshomeostasis may play important roles in MDD,especially for in gray matter loss.Combined assessment of brain iron content and gray matter volume may reveal promising biomarkers for understanding the underlying pathological changes of MDD and for monitoring clinical progression and therapeutic effects in MDD patients.