Major Depressive Disorder Brain Research Articles

The use of diffusional kurtosis imaging and neurite orientation dispersion and density imaging of the brain in major depressive disorder

Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) are new diffusional magnetic resonance imaging (dMRI) techniques for the characterization of neural tissues in human brain. In this study, we used these dMRI techniques to evaluate the whole-brain microstructural changes in patients with major depressive disorder (MDD). Twenty-three patients with MDD and 26 healthy subjects underwent dMRI. We compared the dMRI metrics between the 2 groups and examined the relationships between the metrics and the clinical symptoms of MDD. The MDD patients showed significant fractional anisotropy reduction in the bilateral parietal, right parieto-occipital, and right superior temporal corti, compared with the controls. Mean kurtosis values were significantly reduced in MDD patients in the right superior temporal cortex and bilateral posterior thalamic radiation. Neurite density index reductions were found in the right superior temporal cortex, bilateral insulae, right inferior frontal cortex, left parahippocampal region, left middle cerebellar peduncle, and right cerebellum. Regarding the orientation dispersion index (ODI), we detected significant decreases in the left thalamus and left occipital cortex, and significant increases in the bilateral superior longitudinal fasciculi and left posterior thalamic radiation tract. Further, there were significant positive correlations between the total Hamilton Depression Rating scale-21 scores and the ODI values in the right frontal gyri. These results suggest that the DKI and NODDI methods may provide more information about microstructural abnormalities in patients with MDD than the DTI method. It is thus expected that these techniques will be adopted as the informative methods for neuroimaging study.

Multimodal Investigation of Network Level Effects Using Intrinsic Functional Connectivity, Anatomical Covariance, and Structure-to-Function Correlations in Unmedicated Major Depressive Disorder

Converging evidence suggests that major depressive disorder (MDD) affects multiple large-scale brain networks. Analyses of the correlation or covariance of regional brain structure and function applied to structural and functional MRI data may provide insights into systems-level organization and structure-to-function correlations in the brain in MDD. This study applied tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and intrinsic functional connectivity in data from unmedicated individuals with MDD (n=17) and healthy comparison participants (HC, n=20). These regions were then used as seeds for exploratory anatomical covariance and connectivity analyses. Reduction in volume in the anterior cingulate cortex (ACC) and lower structural covariance between the ACC and the cerebellum were observed in the MDD group. Additionally, individuals with MDD had significantly lower whole-brain intrinsic functional connectivity in the medial prefrontal cortex (mPFC). This mPFC region showed altered connectivity to the ventral lateral PFC (vlPFC) and local circuitry in MDD. Global connectivity in the ACC was negatively correlated with reported depressive symptomatology. The mPFC–vlPFC connectivity was positively correlated with depressive symptoms. Finally, we observed increased structure-to-function correlation in the PFC/ACC in the MDD group. Although across all analysis methods and modalities alterations in the PFC/ACC were a common finding, each modality and method detected alterations in subregions belonging to distinct large-scale brain networks. These exploratory results support the hypothesis that MDD is a systems level disorder affecting multiple brain networks located in the PFC and provide new insights into the pathophysiology of this disorder.

Myelination of the brain in Major Depressive Disorder: An in vivo quantitative magnetic resonance imaging study

Evidence from post-mortem, genetic, neuroimaging, and non-human animal research suggests that Major Depressive Disorder (MDD) is associated with abnormalities in brain myelin content. Brain regions implicated in this research, and in MDD more generally, include the nucleus accumbens (NAcc), lateral prefrontal cortex (LPFC), insula, subgenual anterior cingulate cortex (sgACC), and medial prefrontal cortex (mPFC). We examined whether MDD is characterized by reduced myelin at the whole-brain level and in NAcc, LPFC, insula, sgACC, and mPFC. Quantitative magnetic resonance imaging (qMRI) permits the assessment of myelin content, in vivo, in the human brain through the measure of R1. In this study we used qMRI to measure R1 in 40 MDD and 40 healthy control (CTL) participants. We found that the MDD participants had lower levels of myelin than did the CTL participants at the whole-brain level and in the NAcc, and that myelin in the LPFC was reduced in MDD participants who had experienced a greater number of depressive episodes. Although further research is needed to elucidate the role of myelin in affecting emotional, cognitive, behavioral, and clinical aspects of MDD, the current study provides important new evidence that a fundamental property of brain composition, myelin, is altered in this disorder.

Influence of FKBP5 polymorphism and DNA methylation on structural changes of the brain in major depressive disorder

A single nucleotide polymorphism of rs1360780 in the FKBP5 gene is associated with a predisposition to developing major depressive disorder (MDD). We investigated the interactive effects of FKBP5 rs1360780 allelic variants, DNA methylation, and the diagnosis of MDD on structural changes of the entire brain. One hundred and fourteen patients with MDD and eighty-eight healthy controls underwent T1-weighted structural magnetic resonance imaging and FKBP5 rs1360780 genotyping, including DNA methylation of intron 7. We analyzed the volume of cortical and subcortical regions and cortical thickness using FreeSurfer. Significant genotype-by-diagnosis interactions were observed for volumes of the left pars triangularis, supramarginal gyrus, superior parietal lobule, right frontomarginal, and posterior midcingulate gyrus. The T allele was associated with significant volume reductions in these brain regions only in the MDD group except for the right posterior midcingulate gyrus. FKBP5 DNA methylation showed a positive correlation with the thickness of the right transverse frontopolar gyrus in the C allele homozygote group. Our findings suggest that the FKBP5 gene and its epigenetic changes could have influence on morphologic changes of several brain regions involved in emotion regulation, and that this process may be associated with the development of MDD.

Evaluation of molecular brain changes associated with environmental stress in rodent models compared to human major depressive disorder: A proteomic systems approach

Objectives: Rodent models of major depressive disorder (MDD) are indispensable when screening for novel treatments, but assessing their translational relevance with human brain pathology has proved difficult.Methods: Using a novel systems approach, proteomics data obtained from post-mortem MDD anterior prefrontal cortex tissue (n = 12) and matched controls (n = 23) were compared with equivalent data from three commonly used preclinical models exposed to environmental stressors (chronic mild stress, prenatal stress and social defeat). Functional pathophysiological features associated with depression-like behaviour were identified in these models through enrichment of protein–protein interaction networks. A cross-species comparison evaluated which model(s) represent human MDD pathology most closely.Results: Seven functional domains associated with MDD and represented across at least two models such as “carbohydrate metabolism and cellular respiration” were identified. Through statistical evaluation using kernel-based machine learning techniques, the social defeat model was found to represent MDD brain changes most closely for four of the seven domains.Conclusions: This is the first study to apply a method for directly evaluating the relevance of the molecular pathology of multiple animal models to human MDD on the functional level. The methodology and findings outlined here could help to overcome translational obstacles of preclinical psychiatric research.

Inverse changes in L1 retrotransposons between blood and brain in major depressive disorder.

Long interspersed nuclear element-1 (LINE-1 or L1) is a type of retrotransposons comprising 17% of the human and mouse genome, and has been found to be associated with several types of neurological disorders. Previous post-mortem brain studies reveal increased L1 copy number in the prefrontal cortex from schizophrenia patients. However, whether L1 retrotransposition occurs similarly in major depressive disorder (MDD) is unknown. Here, L1 copy number was measured by quantitative PCR analysis in peripheral blood of MDD patients (n = 105) and healthy controls (n = 105). The results showed that L1 copy number was increased in MDD patients possibly due to its hypomethylation. Furthermore, L1 copy number in peripheral blood and five brain regions (prefrontal cortex, hippocampus, amygdala, nucleus accumbens and paraventricular hypothalamic nucleus) was measured in the chronic unpredictable mild stress (CUMS) model of depression in mice. Intriguingly, increased L1 copy number in blood and the decreased L1 copy number in the prefrontal cortex were observed in stressed mice, while no change was found in other brain regions. Our results suggest that the changes of L1 may be associated with the pathophysiology of MDD, but the biological mechanism behind dysfunction of L1 retrotransposition in MDD remains to be further investigated.

Ketamine Treatment and Global Brain Connectivity in Major Depression.

Capitalizing on recent advances in resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) and the distinctive paradigm of rapid mood normalization following ketamine treatment, the current study investigated intrinsic brain networks in major depressive disorder (MDD) during a depressive episode and following treatment with ketamine. Medication-free patients with MDD and healthy control subjects (HC) completed baseline rs-fcMRI. MDD patients received a single infusion of ketamine and underwent repeated rs-fcMRI at 24 h posttreatment. Global brain connectivity with global signal regression (GBCr) values were computed as the average of correlations of each voxel with all other gray matter voxels in the brain. MDD group showed reduced GBCr in the prefrontal cortex (PFC) but increased GBCr in the posterior cingulate, precuneus, lingual gyrus, and cerebellum. Ketamine significantly increased GBCr in the PFC and reduced GBCr in the cerebellum. At baseline, 2174 voxels of altered GBCr were identified, but only 310 voxels significantly differed relative to controls following treatment (corrected α<0.05). Responders to ketamine showed increased GBCr in the lateral PFC, caudate, and insula. Follow-up seed-based analyses illustrated a pattern of dysconnectivity between the PFC/subcortex and the rest of the brain in MDD, which appeared to normalize postketamine. The extent of the functional dysconnectivity identified in MDD and the swift and robust normalization following treatment suggest that GBCr may serve as a treatment response biomarker for the development of rapid acting antidepressants. The data also identified unique prefrontal and striatal circuitry as a putative marker of successful treatment and a target for antidepressants' development.

Shortened telomere length in white matter oligodendrocytes in major depression: potential role of oxidative stress.

Telomere shortening is observed in peripheral mononuclear cells from patients with major depressive disorder (MDD). Whether this finding and its biological causes impact the health of the brain in MDD is unknown. Brain cells have differing vulnerabilities to biological mechanisms known to play a role in accelerating telomere shortening. Here, two glia cell populations (oligodendrocytes and astrocytes) known to have different vulnerabilities to a key mediator of telomere shortening, oxidative stress, were studied. The two cell populations were separately collected by laser capture micro-dissection of two white matter regions shown previously to demonstrate pathology in MDD patients. Cells were collected from brain donors with MDD at the time of death and age-matched psychiatrically normal control donors (N=12 donor pairs). Relative telomere lengths in white matter oligodendrocytes, but not astrocytes, from both brain regions were significantly shorter for MDD donors as compared to matched control donors. Gene expression levels of telomerase reverse transcriptase were significantly lower in white matter oligodendrocytes from MDD as compared to control donors. Likewise, the gene expression of oxidative defence enzymes superoxide dismutases (SOD1 and SOD2), catalase (CAT) and glutathione peroxidase (GPX1) were significantly lower in oligodendrocytes from MDD as compared to control donors. No such gene expression changes were observed in astrocytes from MDD donors. These findings suggest that attenuated oxidative stress defence and deficient telomerase contribute to telomere shortening in oligodendrocytes in MDD, and suggest an aetiological link between telomere shortening and white matter abnormalities previously described in MDD.

The neural correlates of reward-related processing in major depressive disorder: A meta-analysis of functional magnetic resonance imaging studies

BackgroundA growing number of functional magnetic resonance imaging (fMRI) studies have been conducted in major depressive disorder (MDD) to elucidate reward-related brain functions. The aim of this meta-analysis was to examine the common reward network in the MDD brain and to further distinguish the brain activation patterns between positive stimuli and monetary rewards as well as reward anticipation and outcome. MethodsA series of activation likelihood estimation (ALE) meta-analyses were performed across 22 fMRI studies that examined reward-related processing, with a total of 341 MDD patients and 367 healthy controls. ResultsWe observed several frontostriatal regions that participated in reward processing in MDD. The common reward network in MDD was characterized by decreased subcortical and limbic areas activity and an increased cortical response. In addition, the cerebellum, lingual gyrus, parahippocampal gyrus and fusiform gyrus preferentially responded to positive stimuli in MDD, while the insula, precuneus, cuneus, PFC and inferior parietal lobule selectively responded to monetary rewards. Our results indicated a reduced caudate response during both monetary anticipation and outcome stages as well as increased activation in the middle frontal gyrus and dorsal anterior cingulate during reward anticipation in MDD. LimitationsThe reward-related tasks and mood states of patients included in our analysis were heterogeneous. ConclusionsOur current findings suggest that there exist emotional or motivational pathway dysfunctions in MDD during reward-related processing. Future studies may be strengthened by paying careful attention to the types of reward used as well as the different components of reward processing examined.

Fractality analysis of frontal brain in major depressive disorder

EEGs of the frontal brain of patients diagnosed with major depressive disorder (MDD) have been investigated in recent years using linear methods but not based on nonlinear methods. This paper presents an investigation of the frontal brain of MDD patients using the wavelet-chaos methodology and Katz's and Higuchi's fractal dimensions (KFD and HFD) as measures of nonlinearity and complexity. EEGs of the frontal brain of healthy adults and MDD patients are decomposed into 5 EEG sub-bands employing a wavelet filter bank, and the FDs of the band-limited as well as those of their 5 sub-bands are computed. Then, using the ANOVA statistical test, HFDs and KFDs of the left and right frontal lobes in EEG full-band and sub-bands of MDD and healthy groups are compared in order to discover the FDs showing the most meaningful differences between the two groups. Finally, the discovered FDs are used as input to a classifier, enhanced probabilistic neural network (EPNN), to discriminate the MDD from healthy EEGs. The results of HFD show higher complexity of left, right and overall frontal lobes of the brain of MDD compared with non-MDD in beta and gamma sub-bands. Moreover, it is observed that HFD of the beta band is more discriminative than HFD of the gamma band for discriminating MDD and non-MDD participants, while the KFD did not show any meaningful difference. A high accuracy of 91.3% is achieved for classification of MDD and non-MDD EEGs based on HFDs of left, right, and overall frontal brain beta sub-band. The findings of this research, however, should be considered tentative because of limited data available to the authors.

Genome-Wide DNA Methylation Scan in Major Depressive Disorder

While genome-wide association studies are ongoing to identify sequence variation influencing susceptibility to major depressive disorder (MDD), epigenetic marks, such as DNA methylation, which can be influenced by environment, might also play a role. Here we present the first genome-wide DNA methylation (DNAm) scan in MDD. We compared 39 postmortem frontal cortex MDD samples to 26 controls. DNA was hybridized to our Comprehensive High-throughput Arrays for Relative Methylation (CHARM) platform, covering 3.5 million CpGs. CHARM identified 224 candidate regions with DNAm differences >10%. These regions are highly enriched for neuronal growth and development genes. Ten of 17 regions for which validation was attempted showed true DNAm differences; the greatest were in PRIMA1, with 12–15% increased DNAm in MDD (p = 0.0002–0.0003), and a concomitant decrease in gene expression. These results must be considered pilot data, however, as we could only test replication in a small number of additional brain samples (n = 16), which showed no significant difference in PRIMA1. Because PRIMA1 anchors acetylcholinesterase in neuronal membranes, decreased expression could result in decreased enzyme function and increased cholinergic transmission, consistent with a role in MDD. We observed decreased immunoreactivity for acetylcholinesterase in MDD brain with increased PRIMA1 DNAm, non-significant at p = 0.08.While we cannot draw firm conclusions about PRIMA1 DNAm in MDD, the involvement of neuronal development genes across the set showing differential methylation suggests a role for epigenetics in the illness. Further studies using limbic system brain regions might shed additional light on this role.

Human White Matter Atlas

Human White Matter Atlas