Further Evidence of Emotional Allodynia in Unmedicated Young Adults with Major Depressive Disorder

Background

Recent evidence suggests that sensitivity to the emotional sequela of experimental thermal pain(measured by emotional unpleasantness) is heightened in individuals with major depressive disorder(MDD), a phenomenon we termed “emotional allodynia”. The aim of this study was to examine whether acute happy and sad mood induction alters emotional allodynia in MDD. We hypothesized that emotional allodynia will be a robust characteristic of individuals with MDD compared to healthy controls. Thus, it would remain following acute mood induction, independent of valence.

Methods

Twenty-one subjects with current MDD and 21 well-matched healthy subjects(HC) received graded brief temperature stimuli following happy and sad mood inductions procedures(MIP). All subjects rated the intensity and affect(pleasantness/unpleasantness) of each stimulus. Sensory(pain intensity) and affective(pain unpleasantness) thresholds were determined by methods of constant stimuli.

Results

The MIPs reliably induced happy and sad mood and the resulting induced mood and subjective arousal were not different between the groups at the time of temperature stimulation. Compared to HC, MDD individuals demonstrated emotional allodynia. We found significantly decreased affective pain thresholds whereby significantly lower temperatures became unpleasant in the MDD compared to the HC group. This was not observed for the sensory pain thresholds. Within the MDD, the affective pain thresholds were significantly lower than the corresponding pain intensity thresholds, whereby non-painful temperatures were already unpleasant for the MDD irrespective of the induced mood. This was not observed for the HC groups where the affective and pain intensity thresholds were comparable.

Conclusions

These findings suggest that emotional allodynia may be a chronic characteristic of current MDD. Future studies should determine if emotional allodynia persists after psychological or pharmacological interventions. Finally, longitudinal work should examine whether emotional allodynia is a result of or vulnerability for depression and the role it plays in the increased susceptibility for pain complaints in this disorder.     

磁休克治疗对重度抑郁症患者脑功能网络的影响

目的 磁休克治疗(MST)是一种新兴的神经调节干预技术,在重度抑郁症(MDD)治疗中得到广泛应用,然而其抗抑郁机制尚不清楚。探索MST对不同疗效MDD患者脑功能网络的调控作用,对MST治疗的抗抑郁作用机制研究具有重要意义。方法 本文对18例MDD患者MST作用前后的静息态脑电进行记录,基于皮尔逊相关方法构建脑功能网络;应用复杂网络理论对比分析脑功能网络拓扑结构的改变;根据HDRS-17评分变化率进一步区分治疗有效组和无效组,对网络特征进行二次比较。结果 MST后,MDD患者的脑功能网络平均节点度、平均聚类系数和平均全局效率值均比治疗前显著升高,平均路径长度值显著降低,小世界属性显著增大;相比于治疗无效组,治疗有效组的脑功能网络特征参数变化量更大。结论 MST显著改变了MDD患者脑功能网络拓扑结构,对患者的脑功能网络具有一定的调制作用,这些结果为MST治疗的抗抑郁机制研究提供了实验支持和理论依据。     

Metabolomics in Schizophrenia and Major Depressive Disorder

Defining pathophenotype, a systems level consequence of a disease genotype, together with environmental and stochastic influences, is an arduous task in psychiatry. It is also an appealing goal, given growing need for appreciation of brain disorders biological complexity, aspiration for diagnostic tests development and ambition to identify novel drug targets. Here, we focus on the Schizophrenia and Major Depressive Disorder and highlight recent advances in metabolomics research. As a systems biology tool, metabolomics holds a promise to take part in elucidating interactions between genes and environment, in complex behavioral traits and psychopathology risk translational research.     

基于内在功能连接推定抑郁症脑网络效率的改变

本文研究了在保留最大化内在功能连接条件下抑郁症患者脑网络效率的改变,并探索了改变的拓扑效率和抑郁症病理学之间的关系.为此,我们收集了20例抑郁症患者和20例在年龄、性别和教育水平相匹配的健康被试的静息态功能磁共振图像数据.图论分析显示,与健康对照组比较,抑郁症患者的节点效率减少在左海马旁回、右杏仁核,左颞横回和左颞极(颞中回)减少.减少的节点效率表明,在抑郁症患者脑网络中这些区域传送信息到其他区域的能力减弱.此外,发现局部效率降低在左内侧额上回、左眶部额上回、右回直肌、左杏仁核、右顶上回、左丘脑和左颞极(颞中回).并且发现左内侧额上回、左杏仁核、左丘脑与PHQ-9得分呈负相关.降低的局部效率表明抑郁症患者脑网络中这些区域的局部网络信息传送能力受到抑制.这些结果进一步确认在抑郁症患者中涉及情感信息处理的前额-丘脑-边缘区域被破坏.我们的发现为抑郁症病人的辅助诊断提供了新的潜在生物学标记物.     

Smoking and Major Depressive Disorder in Chinese Women

Objective

To investigate the risk factors that contribute to smoking in female patients with major depressive disorder (MDD) and the clinical features in depressed smokers.

Methods

We examined the smoking status and clinical features in 6120 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and smoking status and between risk factors for MDD and smoking status.

Results

Among the recurrent MDD patients there were 216(3.6%) current smokers, 117 (2.0%) former smokers and 333(5.6%) lifetime smokers. Lifetime smokers had a slightly more severe illness, characterized by more episodes, longer duration, more comorbid illness (panic and phobias), with more DSM-IV A criteria and reported more symptoms of fatigue and suicidal ideation or attempts than never smokers. Some known risk factors for MDD were also differentially represented among smokers compared to non-smokers. Smokers reported more stressful life events, were more likely to report childhood sexual abuse, had higher levels of neuroticism and an increased rate of familial MDD. Only neuroticism was significantly related to nicotine dependence.

Conclusions

Although depressed women smokers experience more severe illness, smoking rates remain low in MDD patients. Family history of MDD and environmental factors contribute to lifetime smoking in Chinese women, consistent with the hypothesis that the association of smoking and depression may be caused by common underlying factors.     

Genetic Association of Butyrylcholinesterase with Major Depressive Disorder

Biochemical Genetics - Major depressive disorder (MDD) is characterized as clinical depression, which primarily affects the mood and behaviour of an individual. In the present study...     

MRI-guided dmPFC-rTMS as a Treatment for Treatment-resistant Major Depressive Disorder

Here we outline the protocol for magnetic resonance imaging (MRI) guided repetitive transcranial magnetic stimulation (rTMS) to the dorsal medial prefrontal cortex (dmPFC) in patients with major depressive disorder (MDD). Technicians used a neuronavigation system to process patient MRIs to generate a 3-dimensional head model. The head model was subsequently used to identify patient-specific stimulatory targets. The dmPFC was stimulated daily for 20 sessions. Stimulation intensity was titrated to address scalp pain associated with rTMS. Weekly assessments were conducted on the patients using the Hamilton Rating Scale for Depression (HamD₁₇) and Beck Depression Index II (BDI-II). Treatment-resistant MDD patients achieved significant improvements on both HAMD and BDI-II. Of note, angled, double-cone coil rTMS at 120% resting motor threshold allows for optimal stimulation of deeper midline prefrontal regions, which results in a possible therapeutic application for MDD. One major limitation of the rTMS field is the heterogeneity of treatment parameters across studies, including duty cycle, number of pulses per session and intensity. Further work should be done to clarify the effect of stimulation parameters on outcome. Future dmPFC-rTMS work should include sham-controlled studies to confirm its clinical efficacy in MDD.     

Identification and Validation of Urinary Metabolite Biomarkers for Major Depressive Disorder

Major depressive disorder (MDD) is a widespread and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. In this study, a nuclear magnetic resonance spectroscopy–based metabonomic approach was employed to profile urine samples from 82 first-episode drug-naïve depressed subjects and 82 healthy controls (the training set) in order to identify urinary metabolite biomarkers for MDD. Then, 44 unselected depressed subjects and 52 healthy controls (the test set) were used to independently validate the diagnostic generalizability of these biomarkers. A panel of five urinary metabolite biomarkers—malonate, formate, N-methylnicotinamide, m-hydroxyphenylacetate, and alanine—was identified. This panel was capable of distinguishing depressed subjects from healthy controls with an area under the receiver operating characteristic curve (AUC) of 0.81 in the training set. Moreover, this panel could classify blinded samples from the test set with an AUC of 0.89. These findings demonstrate that this urinary metabolite biomarker panel can aid in the future development of a urine-based diagnostic test for MDD.Major depressive disorder (MDD)¹ is a debilitating mental disorder affecting up to 15% of the general population and accounting for 12.3% of the global burden of disease (1, 2). Currently, the diagnosis of MDD still relies on the subjective identification of symptom clusters rather than empirical laboratory tests. The current diagnostic modality results in a considerable error rate (3), as the clinical presentation of MDD is highly heterogeneous and the current symptom-based method is not capable of adequately characterizing this heterogeneity (4). An approach that can be used to circumvent these limitations is to identify disease biomarkers to support objective diagnostic laboratory tests for MDD.Metabonomics, which can measure the small molecules in given biosamples such as plasma and urine without bias (5), has been extensively used to characterize the metabolic changes of diseases and thus facilitate the identification of novel disease-specific signatures as putative biomarkers (6–10). Nuclear magnetic resonance (NMR) spectroscopy–based metabonomic approaches characterized by sensitive, high-throughput molecular screening have been employed previously in identifying novel biomarkers for a variety of neuropsychiatric disorders, including stroke, bipolar disorder, and schizophrenia (11–13).Specifically with regard to MDD, several animal studies have already characterized the metabolic changes in the blood and urine (14–19). These studies provide valuable clues as to the pathophysiological mechanism of MDD. However, no study has been designed with the aim of diagnosing this disease. Recently, using an NMR-based metabonomic approach, this research group identified a unique plasma metabolic signature that enables the discrimination of MDD from healthy controls with both high sensitivity and specificity (20). These findings motivated further study on urinary diagnostic metabolite biomarkers for MDD, which would be more valuable from a clinical applicability standpoint, as urine can be more non-invasively collected. Moreover, previous studies have also demonstrated the feasibility of identifying diagnostic metabolite biomarkers of psychiatric disorders in the urine. For example, using an NMR-based metabonomics approach, Yap et al. (21) identified a unique urinary metabolite signature that clearly discriminated autism patients from healthy controls. As systemic metabolic disturbances have been observed in the urine of a depressed animal model, it is likely that diagnostic metabolite markers for MDD can be detected in human urine.Therefore, in this study, NMR spectroscopy combined with multivariate pattern recognition techniques were used to profile 82 first-episode drug-naïve MDD subjects and 82 healthy controls (the training set) in order to identify potential metabolite biomarkers for MDD. Furthermore, 44 unselected MDD subjects and 52 healthy controls (the test set) were employed to independently validate the diagnostic performance of these urinary metabolite biomarkers.     

Changes of Functional Brain Networks in Major Depressive Disorder: A Graph Theoretical Analysis of Resting-State fMRI

Recent developments in graph theory have heightened the need for investigating the disruptions in the topological structure of functional brain network in major depressive disorder (MDD). In this study, we employed resting-state functional magnetic resonance imaging (fMRI) and graph theory to examine the whole-brain functional networks among 42 MDD patients and 42 healthy controls. Our results showed that compared with healthy controls, MDD patients showed higher local efficiency and modularity. Furthermore, MDD patients showed altered nodal centralities of many brain regions, including hippocampus, temporal cortex, anterior cingulate gyrus and dorsolateral prefrontal gyrus, mainly located in default mode network and cognitive control network. Together, our results suggested that MDD was associated with disruptions in the topological structure of functional brain networks, and provided new insights concerning the pathophysiological mechanisms of MDD.     

Surface Vulnerability of Cerebral Cortex to Major Depressive Disorder

Major depressive disorder (MDD) is accompanied by atypical brain structure. This study first presents the alterations in the cortical surface of patients with MDD using multidimensional structural patterns that reflect different neurodevelopment. Sixteen first-episode, untreated patients with MDD and 16 matched healthy controls underwent a magnetic resonance imaging (MRI) scan. The cortical maps of thickness, surface area, and gyrification were examined using the surface-based morphometry (SBM) approach. Increase of cortical thickness was observed in the right posterior cingulate region and the parietal cortex involving the bilateral inferior, left superior parietal and right paracentral regions, while decreased thickness was noted in the parietal cortex including bilateral pars opercularis and left precentral region, as well as the left rostral-middle frontal regions in patients with MDD. Likewise, increased or decreased surface area was found in five sub-regions of the cingulate gyrus, parietal and frontal cortices (e.g., bilateral inferior parietal and superior frontal regions). In addition, MDD patients exhibited a significant hypergyrification in the right precentral and supramarginal region. This integrated structural assessment of cortical surface suggests that MDD patients have cortical alterations of the frontal, parietal and cingulate regions, indicating a vulnerability to MDD during earlier neurodevelopmental process.     

Resequencing Three Candidate Genes for Major Depressive Disorder in a Dutch Cohort

Major depressive disorder (MDD) is a psychiatric disorder, characterized by periods of low mood of more than two weeks, loss of interest in normally enjoyable activities and behavioral changes. MDD is a complex disorder and does not have a single genetic cause. In 2009 a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. Many of the top signals of this GWAS mapped to a region spanning the gene PCLO, and the non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became genome wide significant after post-hoc analysis. We performed resequencing of PCLO, GRM7, and SLC6A4 in 50 control samples from the GAIN-MDD cohort, to detect new genomic variants. Subsequently, we genotyped these variants in the entire GAIN-MDD cohort and performed association analysis to investigate if rs2522833 is the causal variant or simply in linkage disequilibrium with a more associated variant. GRM7 and SLC6A4 are both candidate genes for MDD from literature. We aimed to gather more evidence that rs2522833 is indeed the causal variant in the GAIN-MDD cohort or to find a previously undetected common variant in either PCLO, GRM7, or SLC6A4 with a higher association in this cohort. After next generation sequencing and association analysis we excluded the possibility of an undetected common variant to be more associated. For neither PCLO nor GRM7 we found a more associated variant. For SLC6A4, we found a new SNP that showed a lower P-value (P = 0.07) than in the GAIN-MDD GWAS (P = 0.09). However, no evidence for genome-wide significance was found. Although we did not take into account rare variants, we conclude that our results provide further support for the hypothesis that the non-synonymous coding SNP rs2522833 in the PCLO gene is indeed likely to be the causal variant in the GAIN-MDD cohort.     

Fear Extinction as a Model for Synaptic Plasticity in Major Depressive Disorder

Background

The neuroplasticity hypothesis of major depressive disorder proposes that a dysfunction of synaptic plasticity represents a basic pathomechanism of the disorder. Animal models of depression indicate enhanced plasticity in a ventral emotional network, comprising the amygdala. Here, we investigated fear extinction learning as a non-invasive probe for amygdala-dependent synaptic plasticity in patients with major depressive disorder and healthy controls.

Methods

Differential fear conditioning was measured in 37 inpatients with severe unipolar depression (International Classification of Diseases, 10^th revision, criteria) and 40 healthy controls. The eye-blink startle response, a subcortical output signal that is modulated by local synaptic plasticity in the amygdala in fear acquisition and extinction learning, was recorded as the primary outcome parameter.

Results

After robust and similar fear acquisition in both groups, patients with major depressive disorder showed significantly enhanced fear extinction learning in comparison to healthy controls, as indicated by startle responses to conditioned stimuli. The strength of extinction learning was positively correlated with the total illness duration.

Conclusions

The finding of enhanced fear extinction learning in major depressive disorder is consistent with the concept that the disorder is characterized by enhanced synaptic plasticity in the amygdala and the ventral emotional network. Clinically, the observation emphasizes the potential of successful extinction learning, the basis of exposure therapy, in anxiety-related disorders despite the frequent comorbidity of major depressive disorder.     

Personality,Attentional Biases towards Emotional Faces and Symptoms of Mental Disorders in an Adolescent Sample

Objective

To investigate the role of personality factors and attentional biases towards emotional faces, in establishing concurrent and prospective risk for mental disorder diagnosis in adolescence.

Method

Data were obtained as part of the IMAGEN study, conducted across 8 European sites, with a community sample of 2257 adolescents. At 14 years, participants completed an emotional variant of the dot-probe task, as well two personality measures, namely the Substance Use Risk Profile Scale and the revised NEO Personality Inventory. At 14 and 16 years, participants and their parents were interviewed to determine symptoms of mental disorders.

Results

Personality traits were general and specific risk indicators for mental disorders at 14 years. Increased specificity was obtained when investigating the likelihood of mental disorders over a 2-year period, with the Substance Use Risk Profile Scale showing incremental validity over the NEO Personality Inventory. Attentional biases to emotional faces did not characterise or predict mental disorders examined in the current sample.

Discussion

Personality traits can indicate concurrent and prospective risk for mental disorders in a community youth sample, and identify at-risk youth beyond the impact of baseline symptoms. This study does not support the hypothesis that attentional biases mediate the relationship between personality and psychopathology in a community sample. Task and sample characteristics that contribute to differing results among studies are discussed.     

Increased Amygdala Response to Shame in Remitted Major Depressive Disorder

Proneness to self-blaming moral emotions such as shame and guilt is increased in major depressive disorder (MDD), and may play an important role in vulnerability even after symptoms have subsided. Social psychologists have argued that shame-proneness is relevant for depression vulnerability and is distinct from guilt. Shame depends on the imagined critical perception of others, whereas guilt results from one’s own judgement. The neuroanatomy of shame in MDD is unknown. Using fMRI, we compared 21 participants with MDD remitted from symptoms with no current co-morbid axis-I disorders, and 18 control participants with no personal or family history of MDD. The MDD group exhibited higher activation of the right amygdala and posterior insula for shame relative to guilt (SPM8). This neural difference was observed despite equal levels of rated negative emotional valence and frequencies of induced shame and guilt experience across groups. These same results were found in the medication-free MDD subgroup (N = 15). Increased amygdala and posterior insula activations, known to be related to sensory perception of emotional stimuli, distinguish shame from guilt responses in remitted MDD. People with MDD thus exhibit changes in the neural response to shame after symptoms have subsided. This supports the hypothesis that shame and guilt play at least partly distinct roles in vulnerability to MDD. Shame-induction may be a more sensitive probe of residual amygdala hypersensitivity in MDD compared with facial emotion-evoked responses previously found to normalize on remission.

Whoever blushes confesses guilt, true innocence never feels shame.

JJ Rousseau     

Study of the Serum Copper Levels in Patients with Major Depressive Disorder

Copper may be involved in the pathophysiology of depression. Clinical data on this issue are very limited and not conclusive. The purpose of the study was to determine the copper concentration in the serum of patients with major depressive disorder and to discuss its potential clinical usefulness as a biomarker of the disease. A case–control clinical study included 69 patients with current depressive episode, 45 patients in remission and 50 healthy volunteers. Cu concentration was measured by electrothermal atomic absorption spectrometry (ETAAS). The mean serum copper level in depressed patients was slightly lower (by 11 %; not statistically significant) than in the control group. Furthermore, there was no significant difference in Cu²⁺ concentration between depressive episode and remission, nor between remission and control group. In the remission group were observed significant correlations between copper levels and the average number of relapses over the past years or time of remission. There was no correlation between serum copper and severity of depression, as measured by HDRS and MADRS. The obtained results showed no significant differences between the copper concentration in the blood serum of patients (both with current depressive episode and in remission) and healthy volunteers, as well as the lack of correlations between the copper level in the active stage of the disease and clinical features of the population. Our study is the first conducted on such a large population of patients, so the results may be particularly important and reliable source of knowledge about the potential role of copper in depression.     

Interhemispheric Functional Connectivity and Its Relationships with Clinical Characteristics in Major Depressive Disorder: A Resting State fMRI Study

Background

Abnormalities in large-scale, structural and functional brain connectivity have been increasingly reported in patients with major depressive disorder (MDD). However, MDD-related alterations in functional interaction between the cerebral hemispheres are still not well understood. Resting state fMRI, which reveals spontaneous neural fluctuations in blood oxygen level dependent signals, provides a means to detect interhemispheric functional coherence. We examined the resting state functional connectivity (RSFC) between the two hemispheres and its relationships with clinical characteristics in MDD patients using a recently proposed measurement named “voxel-mirrored homotopic connectivity (VMHC)”.

Methodology/Principal Findings

We compared the interhemispheric RSFC, computed using the VMHC approach, of seventeen first-episode drug-naive patients with MDD and seventeen healthy controls. Compared to the controls, MDD patients showed significant VMHC decreases in the medial orbitofrontal gyrus, parahippocampal gyrus, fusiform gyrus, and occipital regions including the middle occipital gyrus and cuneus. In MDD patients, a negative correlation was found between VMHC of the fusiform gyrus and illness duration. Moreover, there were several regions whose VMHC showed significant negative correlations with the severity of cognitive disturbance, including the prefrontal regions, such as middle and inferior frontal gyri, and two regions in the cereballar crus.

Conclusions/Significance

These findings suggest that the functional coordination between homotopic brain regions is impaired in MDD patients, thereby providing new evidence supporting the interhemispheric connectivity deficits of MDD. The significant correlations between the VMHC and clinical characteristics in MDD patients suggest potential clinical implication of VMHC measures for MDD. Interhemispheric RSFC may serve as a useful screening method for evaluating MDD where neural connectivity is implicated in the pathophysiology.     

Epidemiology of Major Depressive Disorder in Mainland China: A Systematic Review

Background

Major depressive disorder (MDD) is one of the important causes of disease burden in the general population. Given the experiencing rapid economic and social changes since the early 1990s and the internationally recognized diagnostic criteria and interview instruments across the surveys during 2001–2010 in china, the epidemiological studies on MDD got varied results. We performed this meta-analysis to investigate current, 12-month and lifetime prevalence rates of MDD in mainland China.

Methods

PubMed, Embase, Chinese Biological Medical Literature database (CBM), Chinese National Knowledge Infrastructure database (CNKI), and the Chinese Wanfang and Chongqing VIP database were searched for associated studies. We estimated the overall prevalence of MDD using meta-analysis.

Conclusions

Seventeen eligible studies were included. Our study showed that the overall estimation of current, 12-month and lifetime prevalence of MDD was 1.6, 2.3, 3.3%, respectively. The current prevalence was 2.0 and 1.7% in rural and urban areas, respectively; between female and male, it was 2.1 and 1.3%, respectively. In addition, the current prevalence of MDD diagnosed with SCID (Structured Clinical Interview for DSM-IV) was 1.8% and that diagnosed with CIDI (Composite International Diagnostic Interview) was 1.1%. In conclusion, our study revealed a relatively high prevalence rate in the lifetime prevalence of MDD. For current prevalence, MDD diagnosed with SCID had a higher prevalence rate than with CIDI; males showed a lower rate than females, rural residents seemed to have a greater risk of MDD than urban residents.     

Tractography of the Brainstem in Major Depressive Disorder Using Diffusion Tensor Imaging

Background

The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem’s role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls.

Methods

MDD patients (n = 95) and age- and gender-matched controls (n = 34) were assessed using probabilistic tractography of DTI to delineate three distinct brainstem tracts: the nigrostriatal tract (connecting brainstem to striatum), solitary tract (connecting brainstem to amygdala) and corticospinal tract (connecting brainstem to precentral cortex). Fractional anisotropy (FA) was used to measure the white matter integrity of these tracts, and measures were compared between MDD and control participants.

Results

MDD participants were characterized by a significant and specific decrease in white matter integrity of the right solitary tract (p<0.009 using independent t-test), which is a “bottom up” afferent pathway that connects the brainstem to the amygdala. This decrease was not related to symptom severity.

Conclusions

The results provide new evidence to suggest that structural connectivity between the brainstem and the amygdala is altered in MDD. These results are interesting in light of predominant theories regarding amygdala-mediated emotional reactivity observed in functional imaging studies of MDD. The characterization of altered white matter integrity in the solitary tract in MDD supports the possibility of dysfunctional brainstem-amygdala connectivity impacting vulnerable circuits in MDD.