Voxelwise meta-analysis of gray matter reduction in major depressive disorder

Background

Voxel-based morphometry (VBM) has been widely used in studies of major depressive disorder (MDD) and has provided cumulative evidence of gray matter abnormalities in patients relative to controls. Thus we performed a meta-analysis to integrate the reported studies to determine the consistent gray matter alterations in MDD.

Methods

A systematic search was conducted to identify VBM studies which contrasted MDD patients against a comparison group. The coordinates of gray matter change across studies were meta-analyzed using the activation likelihood estimation (ALE) method hybridized with the rank-based Genome Scan Meta-Analysis (GSMA) to quantitatively estimate regional gray matter reductions in MDD.

Results

A total of 20 VBM studies comparing 543 major depressive patients with 750 healthy control subjects were included. Consistent gray matter reductions in all MDD patients relative to healthy controls were identified in the bilateral anterior cingulate cortex (ACC), right middle and inferior frontal gyrus, right hippocampus and left thalamus.

Conclusions

Meta-analysis of all primary VBM studies indicates that significant gray matter reductions in MDD are localized in a distributed neural network which includes frontal, limbic and thalamic regions. Future studies will benefit from the use of a longitudinal approach to examine anatomical and functional abnormalities within this network and their relationship to clinical profile, particularly in first-episode and drug-naive MDD patients.     

Reduced amygdalar gray matter volume in familial pediatric bipolar disorder

OBJECTIVE: Subcortical limbic structures have been proposed to be involved in the pathophysiology of adult and pediatric bipolar disorder (BD). We sought to study morphometric characteristics of these structures in pediatric subjects with familial BD compared with healthy controls. METHOD: Twenty children and adolescents with BD I (mean age = 4.6 years, four females) and 20 healthy age, gender, and IQ-matched controls underwent high-resolution magnetic resonance imaging at 3 T. Patients were mostly euthymic and most were taking medications. Amygdala, hippocampus, thalamus, and caudate volumes were determined by manual tracings from researchers blinded to diagnosis. Analyses of covariance were performed, with total brain volume, age, and gender as covariates. RESULTS:No differences were found in the volumes of hippocampus, caudate, and thalamus between subjects with BD and controls. Subjects with BD had smaller volumes in the left and right amygdala, driven by reductions in gray matter volume. Exploratory analyses revealed that subjects with BD with past lithium or valproate exposure tended to have greater amygdalar gray matter volume than subjects with BD without such exposure. CONCLUSIONS: Children and adolescents with early-onset BD may have reduced amygdalar volumes, consistent with other studies in this population. Prolonged medication exposure to lithium or valproate may account for findings in adults with BD of increased amygdalar volume relative to controls.     

Association of depression duration with reduction of global cerebral gray matter volume in female patients with recurrent major depressive disorder

OBJECTIVE: The authors investigated the relationship between depression duration and cerebral gray matter volume in female patients with recurrent major depressive disorder. METHOD: Magnetic resonance imaging was used to measure intracranial and total brain volumes as well as gray matter and white matter volumes of the cerebrum; frontal, temporal, parietal, and occipital lobes; cerebellum; and the lateral and third ventricles in 23 female patients with DSM-IV major depression. RESULTS: Correlation and regression analyses showed a significant relationship between total illness duration and cerebral gray matter (including cortical lobe) volume after correction for intracranial volume and age. CONCLUSIONS: Depressive states may lead to changes in global cerebral gray matter volume.     

Reduced gray matter volume in schizophrenia.

BACKGROUND: There is emerging evidence that gray matter (GM) is reduced in patients with schizophrenia. Information on the extent of global differences in the 3 principal supertentorial compartments is necessary for interpretation of regional effects. The relation of GM reduction to clinical status and neurocognition also requires examination. METHODS: Magnetic resonance imaging, neurocognitive measures, and clinical assessment of symptoms and functioning were obtained for 130 patients (51 neuroleptic naive, 79 previously treated) and 130 healthy controls (75 men, 55 women in each group). RESULTS: Overall GM volume was reduced in patients compared with controls. This was evident in men (6% reduction) and women (2% reduction) and was already evident at the first presentation of neuroleptic-naive patients. The reduction sustained correction for age and total intracranial volume. Compartmental volumes did not correlate with the severity of positive (r, -0.08 to 0.23) or negative (r, -0.01 to -0.07) symptoms, but GM volume was associated with better premorbid functioning in women (r, 0.36-0.51). Small but significant correlations (r, 0.19-0.44) were observed between GM volume and performance in 6 neurocognitive domains. These correlations varied by diagnosis, most higher in patients, and were moderated by sex. CONCLUSIONS: Gray matter volume reduction in schizophrenia is already evident in men and women at first presentation. While this reduction is not correlated with symptom severity, it is associated with cognitive performance. Since GM development accelerates in the later part of gestation, while white matter growth is primarily postnatal, the results may support the hypothesis that neurodevelopmental processes relate to GM deficit.     

Reduced gray matter volume in psychotic disorder patients with a history of childhood sexual abuse

Childhood trauma is associated with smaller gray matter volume, similar to the pattern seen in psychotic disorders. We explored the relationship between childhood abuse, psychosis, and brain volume in a group of 60 individuals with a psychotic disorder and 26 healthy control subjects. We used voxel-based morphometry (VBM) to quantify gray and white matter volume and the Childhood Trauma Questionnaire (CTQ) to measure childhood abuse. Within the psychotic disorder group, total gray matter volume was inversely correlated with the severity of childhood sexual abuse (r = ? .34, p = .008), but not the other types of abuse. When the 24 patients with sexual abuse were compared with demographically matched samples of 23 patients without sexual abuse and 26 control subjects, only patients with a history of sexual abuse had reduced total gray matter volume (t(48) = 2.3, p = .03; Cohen's d = .63). Voxel-based analysis revealed a cluster in the prefrontal cortex where volume was negatively correlated with sexual abuse severity. Voxel based comparison of the three matched groups revealed a similar pattern of results, with widespread reductions in psychosis patients with sexual abuse relative to controls that were not found in psychosis patients without sexual abuse. These findings indicate that some of the variance of gray matter volume in psychotic disorders can be explained by a history of sexual abuse.     

Reduced volume of gray matter in patients with trigeminal neuralgia

Accumulating evidence from brain structural imaging studies has supported that chronic pain could induce changes in brain gray matter volume. However, few studies have focused on the gray matter alterations of Trigeminal neuralgia (TN). In this study, twenty-eight TN patients (thirteen females; mean age, 45.86 years ±11.17) and 28 healthy controls (HC; thirteen females; mean age, 44.89 years ±7.67) were included. Using voxel-based morphometry (VBM), we detected abnormalities in gray matter volume in the TN patients. Based on a voxel-wise analysis, the TN group showed significantly decreased gray matter volume in the bilateral superior/middle temporal gyrus (STG/MTG), bilateral parahippocampus, left anterior cingulate cortex (ACC), caudate nucleus, right fusiform gyrus, and right cerebellum compared with the HC. In addition, we found that the gray matter volume in the bilateral STG/MTG was negatively correlated with the duration of TN. These results provide compelling evidence for gray matter abnormalities in TN and suggest that the duration of TN may be a critical factor associated with brain alterations.     

基于形变的形态学测量对首次发病未服药抑郁症患者大脑灰质异常的研究

目的:探讨首次发病未服药抑郁症患者（major depressive disorder）大脑灰质结构改变以及抑郁症早期诊断的影像学指标。方法:对38例抑郁症患者（抑郁症组）和65名年龄、性别相匹配的健康对照（对照组）进行3D T 1加权结构像磁共振成像扫描,采用基于形变的形态学测量（deformation-...     

Beclomethasone-induced vasoconstriction in women with major depressive disorder

OBJECTIVE: It has been hypothesized that abnormal negative feedback of cortisol release in major depressive disorder (MDD) may involve impaired central glucocorticoid receptor (GR) function. Beclomethasone-induced vasoconstriction (BIV) was recently used to test the hypothesis that impaired GR function generalizes to peripheral tissues, and it was reported that BIV was decreased in medicated patients with MDD. The objective was to test the hypothesis that BIV would be reduced in unmedicated women with MDD compared with healthy controls. DESIGN: Case-control. SETTING: A university womens' mental health research unit. PARTICIPANTS: Women aged 18-65 years (n=19) diagnosed, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, with MDD after a structured interview and clinical assessment. Healthy women pair-matched for age, reproductive and smoking status. PROCEDURES: BIV was tested using a range of beclomethasone dipropionate concentrations (1-100 microg/mL) applied to the forearm, with vasoconstriction scored visually after 15-18 hours by raters blinded to diagnosis and the randomization of the application sites. OUTCOME MEASURE: Visual scores for BIV at each beclomethasone concentration. RESULTS: No significant differences between patients with MDD and controls were found. Postmenopausal women showed less of a response than premenopausal women or women taking sex-hormone preparations. CONCLUSION: The study did not concur with the previous finding that BIV is decreased in MDD. Further research is needed to determine whether the difference in findings is due to medication or to other factors that may have distinguished the samples, including sex, age, reproductive status, illness severity, treatment resistance and setting.     

Reduced white matter volume of the caudate nucleus in patients with schizophrenia

To examine volumetric abnormality, the caudate nucleus was measured in patients with schizophrenia and healthy subjects using magnetic resonance imaging. The absolute and relative volumes of white matter in the caudate nucleus were found to be significantly smaller in patients with schizophrenia compared to those in healthy subjects. There were significant correlations between dosages of neuroleptics during the previous year and absolute gray matter volumes of the caudate nucleus as well as relative white matter volumes in patients with schizophrenia. These findings suggest that reduced white matter volume of the caudate nucleus may be a factor affecting the abnormal connectivity of the corticostriatal loop, and that neuroleptic medication would be related to white matter alteration in patients with schizophrenia. Our result replicates a previous study reporting that there is a lack of negative correlation between age and caudate nucleus volume. We also suggest that the disease process of schizophrenia might interfere with normal aging.     

抑郁症首次发病患者脑白质的弥散张量成像研究

目的 探讨抑郁症首次发病（以下简称首发）患者全脑白质纤维的完整性是否受到损害。方法 对14例未接受过治疗的首发抑郁症患者（抑郁症组）和14名与抑郁症组按性别、年龄匹配的正常人（正常人组）进行全脑弥散张量成像扫描，使用以像素为基础的分析方法比较两组各向异性分数（FA）。结果 抑郁症组的右侧额中回（x=36，y=49．x=10；t=4．89，像素集合=258）、左侧枕颞外侧回（x=-42，y=-56，z=-1；t=5．00，像素集合=96）、右侧顶叶的角回（x=24，y=-47，z=41；t=5．23，像素集合=120）和深部（x=42，y=-65，z=27；t=4．56，像素集合=76）白质FA值低于正常人（未校正，P〈0．001），上述FA值差异有统计学意义的区域与抑郁症组的症状严重程度（BDI和HAMD评分）以及病程之间无显著相关性。未发现抑郁症组比正常人组FA值高的脑区。结论 白质病变在抑郁症发病早期即已存在，其完整性的损害可能破坏了调节心境的神经环路。     

Changes in gray matter volume in patients with bipolar disorder.

BACKGROUND: Several lines of evidence suggest the presence of neurofunctional abnormalities in patients with bipolar disorder. These functional abnormalities may stem from structural pathology in these or connected brain regions. Previous studies have generally used a region of interest (ROI) approach to study morphologic changes in bipolar disorder with inconsistent findings among research groups, which may reflect differences in how ROIs are defined. Voxel based morphometry (VBM) allows a more exploratory analysis without the necessity for predefined anatomic boundaries. In this study we utilized VBM to compare gray matter volume between groups of bipolar and healthy subjects. METHODS: Thirty-two patients with bipolar disorder and 27 healthy subjects participated in structural magnetic resonance imaging (MRI) scans. MRI images were segmented, normalized to a standard stereotactic space, and compared on a voxel-by-voxel basis using statistical parametric mapping. RESULTS: Bipolar subjects showed increased gray matter in several regions including portions of anterior cingulate, ventral prefrontal cortex, fusiform gyrus and parts of the primary and supplementary motor cortex. Bipolar subjects showed decreased gray matter volume in superior parietal lobule. CONCLUSIONS: These data support suggestions that neurofunctional deficits are related to structural brain abnormalities in patients with bipolar disorder. The increased gray matter observed in several regions suggests that some affected areas may demonstrate volumetric expansion, at least in some patient populations.     

Gray matter volume in major depressive disorder: A meta-analysis of voxel-based morphometry studies

We designed this study to perform a meta-analysis of gray matter (GM) findings in major depressive disorder (MDD) by using the signed differential mapping (SDM) toolbox. The Pubmed, ScienceDirect and Scopus databases were searched, and only studies published or published online before November 2010 have been included. Twenty voxel-based morphometry (VBM) studies of adult MDD patients were entered in the meta-analysis by SDM toolbox with threshold criteria set as error probability less than 0.00005 and cluster more than 50 voxels. Onset age, numbers of patients and controls, gender ratio of both groups, ratio of medicated patients, depression rating scores, illness duration, co-morbidity and existence of corrected p value were also meta-regressed as covariates to exclude confounding biases. Voxel-wise meta-analytic results of these 20 VBM studies in MDD patients revealed that GM deficits were observed in the right anterior cingulate cortex and left anterior cingulate cortex when patients were compared with controls. The findings remained mostly unchanged in jackknife sensitivity analyses. The potential confounding factors had little impact on the results. This meta-analysis suggested GM deficits of the anterior cingulate cortex might be important in the etiology of MDD.     

Reduced gray matter volume of dorsal cingulate cortex in patients with obsessive-compulsive disorder: a voxel-based morphometric study

Aims: Previous morphometric studies using magnetic resonance imaging (MRI) have revealed structural brain abnormalities in obsessive–compulsive disorder (OCD). The aim of the present study was to investigate the alterations in brain structure of patients with OCD using a voxel‐based morphometry (VBM) method. Methods: Sixteen patients with OCD free of comorbid major depression, and 32 sex‐ and age‐matched healthy subjects underwent MRI using a 1.5‐T MR scanner. OCD severity was assessed with the Yale–Brown Obsessive–Compulsive Scale (mean ± SD: 22 ± 7.6; range: 7–32). MR images were spatially normalized and segmented using the VBM5 package ( http://dbm.neuro.uni‐jena.de/vbm/ ). Statistical analysis was performed using statistical parametric mapping software. Results: Significant reductions in regional gray matter volume were detected in the left caudal anterior cingulate cortex and right dorsal posterior cingulate cortex in the patients with OCD as compared to healthy controls (uncorrected, P < 0.001). No significant differences in white matter volumes were observed in any brain regions of the patients. No significant correlation between Yale–Brown Obsessive–Compulsive Scale score and regional gray matter or white matter volume was observed. Conclusions: Regional gray matter alteration in the dorsal cingulate cortex, which is suggested to play a role in non‐emotional cognitive processes, may be related to the pathophysiology in OCD.     

Localized gray matter volume abnormalities in generalized anxiety disorder

Generalized anxiety disorder (GAD) is characterized by excessive and persistent worrying. Neural substrates of this disorder are insufficiently understood, which relates to functional as well as to structural brain abnormalities. Especially, findings on the neuroanatomy of GAD have been inconsistent and were predominantly derived from pediatric samples. Therefore, we studied adult patients. Thirty-one women (16 patients with GAD and 15 healthy control participants) underwent structural MRI scanning. Gray matter volumes for specific brain regions involved in worrying, anticipatory anxiety, and emotion regulation were analyzed by means of voxel-based morphometry. Relative to controls, patients with GAD had larger volumes of the amygdala and the dorsomedial prefrontal cortex (DMPFC). Moreover, patients’ self-reports on symptom severity were positively correlated with volumes of the DMPFC and the anterior cingulate cortex. Patients with GAD show localized gray matter volume differences in brain regions associated with anticipatory anxiety and emotion regulation. This abnormality may represent either a predisposition for GAD or a consequence of disorder-specific behavior, such as chronic worrying. This issue should be addressed in future MRI studies.     

Prospective study of major depressive disorder with white matter hyperintensity

Objective To investigate clinical characteristics, outcome, and risk factor for cerebrovascular disease in patients who had major depressive disorder and white matter hyperintensity (WMHI). Method A total of 123 new patients diagnosed with major depressive disorder by semi-structured interview underwent magnetic resonance imaging (MRI) and were placed into one of three groups based on results. Patients with no abnormal findings (NF), patients with WMHI and no lacunar infarction (WMHI), and patients with lacunar infarction (LI). Results In the WMHI group, age at initial onset of depression and age at time of interview were both higher than in the NF group, as was severity of depression. Hamilton Rating Scale for Depression (HRSD) scores were significantly higher in the WMHI group than in the NF group. Total WMHI was significantly correlated only with age at initial onset of depression and age at time of interview. In the WMHI group, age at interview was lower than in the LI group and systolic and diastolic blood pressures were lower. Survival analysis regarding the clinical outcome of remission was conducted, but no significant differences were discovered among the three groups, WMHI, LI, and NF. However, the suicide rate was significantly higher in the LI group than in the other two groups. Conclusions The origin and clinical characteristics of depression accompanied by WMHI may be specific; additional stringent study in comparison with individuals with LI is needed.     

Bone mineral density in premenopausal women with major depressive disorder

This cross-sectional study investigated whether a group of unmedicated patients with major depressive disorder, single episode, had decreased bone mineral density (BMD). The BMD at the lumbar spine and proximal femur in 25 premenopausal women with major depressive disorder and 15 normal women was measured by dual-energy X-ray absorptiometry. Bone turnover markers and serum cortisol levels were also evaluated for each subject. As compared with values in the normal women, the mean BMD in the depressed women was significantly lower at the lumbar spine and at all sites of the proximal femur. There was no statistically significant difference between serum cortisol levels and bone turnover markers except for significantly higher urinary excretion of deoxypyridinoline cross-links in the patients compared with the controls. In conclusion, depressed women may have decreased BMD even at the very early stages of the illness, and this possibility should be taken into consideration in treatment.     

Reduced electrocortical response to threatening faces in major depressive disorder

Background: There is growing support for the emotion context insensitivity hypothesis, which states that major depressive disorder (MDD) is associated with a deficit in emotional reactivity. Under this hypothesis, depressed individuals exhibit reduced behavioral and physiological responses to both appetitive and aversive stimuli. We sought to examine this possibility using the late positive potential, a neural response sensitive to aversive and threatening stimuli. Methods: Forty‐seven individuals participated in the study, 22 of whom met criteria for current MDD and 25 with no history of depression or other Axis I disorders. All individuals passively viewed emotional faces while event‐related potentials were recorded. Results: The vertex positive potential was significantly increased in response to fearful and angry faces across the entire sample. The late positive potential was also increased in response to threatening faces, but only among never‐depressed individuals. In the MDD group, this electrocortical response to emotional faces was absent. Conclusions: This study provides neural evidence in support of the view that MDD is associated with blunted emotional reactivity to negative stimuli, which until now has been examined primarily with measures of behavior, self‐report, and peripheral physiology. These results are also consistent with two prior studies showing reduced amygdala activation in response to fearful faces among depressed individuals. It remains to be determined whether abnormal activity in response to emotional stimuli is associated with trait risk for MDD or results from MDD. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.