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.     

The (Eigen)value of diffusion tensor imaging to investigate depression after traumatic brain injury

Background: Many people with a traumatic brain injury (TBI), even mild to moderate, will develop major depression (MD). Recent studies of patients with MD suggest reduced fractional anisotropy (FA) in dorsolateral prefrontal cortex (DLPFC), temporal lobe tracts, midline, and capsule regions. Some of these pathways have also been found to have reduced FA in patients with TBI. It is unknown whether the pathways implicated in MD after TBI are similar to those with MD without TBI. This study sought to investigate whether there were specific pathways unique to TBI patients who develop MD. Methods: A sample of TBI‐MD subjects (N = 14), TBI‐no‐MD subjects (N = 12), MD‐no‐TBI (N = 26), and control subjects (no TBI or MD, N = 23), using a strict measurement protocol underwent psychiatric assessments and diffusion tensor brain Magnetic Resonance Imaging (MRI). Results: The findings of this study indicate that (1) TBI patients who develop MD have reduced axial diffusivity in DLPFC, corpus callosum (CC), and nucleus accumbens white matter tracts compared to TBI patients who do not develop MD and (2) MD patients without a history of TBI have reduced FA along the CC. We also found that more severe MD relates to altered radial diffusivity. Conclusions: These findings suggest that compromise to specific white matter pathways, including both axonal and myelination aspects, after a mild TBI underlie the susceptibility of these patients developing MD. Hum Brain Mapp 35:227–237, 2014. © 2012 Wiley Periodicals, Inc.     

Altered white matter integrity of forebrain in treatment-resistant depression: a diffusion tensor imaging study with tract-based spatial statistics

Background

The association between alterations of the white matter (WM) integrity in brain regions and mood dysregulation has been reported in major depressive disorder (MDD). However, there has never been a neuroimaging study in patients who have treatment-resistant depression (TRD) and are in a current treatment-resistant state. In the present study, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) method to investigate the WM integrity of different brain regions in patients who had TRD and were in a current treatment-resistant state.

Methods

Twenty-three patients with TRD and Hamilton Rating Scale total score of ≥ 18 and 19 healthy controls matched with age, gender, and education level to patients were scanned with DTI. Thirty 4 mm thick, no gap, contiguous axial slices were acquired and fractional anisotropy (FA) images were generated for each participant. An automated TBSS approach was used to analyze the data.

Results

Voxel-wise statistics revealed that patients with TRD had lower FA values in the right anterior limb of internal capsule, the body of corpus callosum, and bilateral external capsule compared to healthy subjects. Patients with TRD did not have increased FA values in any brain regions compared to healthy subjects. There was no correlation between the FA values in any brain region and patients' demographics and the severity of illness.

Conclusions

Our findings suggest the abnormalities of the WM integrity of neuronal tracts connecting cortical and subcortical nuclei and two brain hemispheres may play a key role in the pathogenesis of TRD.     

Effect of scanner in longitudinal diffusion tensor imaging studies

The purpose of this study was to evaluate the effects of longitudinal drift in scanner hardware, inter-scanner variability (bias), and scanner upgrade on longitudinal changes in global and regional diffusion properties using longitudinal data obtained on two scanners of the exact same model at one institution. A total of 224 normal subjects were scanned twice, at an interval of about 1 year, using two 3.0-T scanners of the exact same model. Both scanners were simultaneously upgraded during the study period. The subjects were divided into four groups according to the combination of scanners used. With use of tract-based spatial statistics, we evaluated the effects of scanner drift and inter-scanner variability (bias) on global and regional fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) changes of the white matter. Even with scanners of the exact same model, inter-scanner variability (bias) significantly affected longitudinal results. FA, AD, and RD of the white matter were relatively stable within the same scanner. We also investigated the effect of scanner upgrade on longitudinal FA, AD, and RD changes. The scanner upgrade included only software upgrade, not hardware upgrade; however, there was a significant effect of scanner upgrade on longitudinal results. These results indicate that inter-scanner variability and scanner upgrade can significantly affect the results of longitudinal diffusion tensor imaging studies.     

A quantitative meta-analysis of fMRI studies in bipolar disorder

Chen C‐H, Suckling J, Lennox BR, Ooi C, Bullmore ET. A quantitative meta‐analysis of fMRI studies in bipolar disorder.
Bipolar Disord 2011: 13: 1–15. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Functional magnetic resonance imaging (fMRI) has been widely used to identify state and trait markers of brain abnormalities associated with bipolar disorder (BD). However, the primary literature is composed of small‐to‐medium‐sized studies, using diverse activation paradigms on variously characterized patient groups, which can be difficult to synthesize into a coherent account. This review aimed to synthesize current evidence from fMRI studies in midlife adults with BD and to investigate whether there is support for the theoretical models of the disorder. Methods: We used voxel‐based quantitative meta‐analytic methods to combine primary data on anatomical coordinates of activation from 65 fMRI studies comparing normal volunteers (n = 1,074) and patients with BD (n = 1,040). Results: Compared to normal volunteers, patients with BD underactivated the inferior frontal cortex (IFG) and putamen and overactivated limbic areas, including medial temporal structures (parahippocampal gyrus, hippocampus, and amygdala) and basal ganglia. Dividing studies into those using emotional and cognitive paradigms demonstrated that the IFG abnormalities were manifest during both cognitive and emotional processing, while increased limbic activation was mainly related to emotional processing. In further separate comparisons between healthy volunteers and patient subgroups in each clinical state, the IFG was underactive in manic but not in euthymic and depressed states. Limbic structures were not overactive in association with mood states, with the exception of increased amygdala activation in euthymic states when including region‐of‐interest studies. Conclusions: In summary, our results showed abnormal frontal‐limbic activation in BD. There was attenuated activation of the IFG or ventrolateral prefrontal cortex, which was consistent across emotional and cognitive tasks and particularly related to the state of mania, and enhanced limbic activation, which was elicited by emotional and not cognitive tasks, and not clearly related to mood states.     

White matter reduction in patients with schizophrenia as revealed by voxel-based morphometry: An activation likelihood estimation meta-analysis

Schizophrenia is thought to be a mental disorder caused by the disconnection of brain regions. Cumulative evidence of white matter deficit in patients with schizophrenia has been reported using voxel-based morphometry (VBM), but these studies have not been quantitatively reviewed. In the study reported herein, we used activation likelihood estimation (ALE) analysis to quantitatively estimate focal white matter abnormalities in patients with schizophrenia. Seventeen studies that compared the white matter deficit of patients with schizophrenia and healthy controls were ascertained. The frontal white matter regions and internal capsule revealed consistent white matter reduction in patient groups relative to healthy controls, suggesting a clear focal white matter deficit in patients with schizophrenia. These results support the macro-circuit theory of white matter change in schizophrenia.     

Voxel based morphometric and diffusion tensor imaging analysis in male bipolar patients with first-episode mania

Objectives

Structural abnormality of both gray and white matter has been detected in patients with bipolar disorder (BD). But results were greatly inconsistent across studies which were most likely attributed to heterogeneous populations as well as processing techniques. The present study aimed to investigate brain structural and microstructural alterations in a relative homogenous sample of bipolar mania.

Methods

3D T1-weighted magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were conducted in 18 patients with BD and 27 healthy volunteers. Gray matter (GM) and white matter (WM) differences were evaluated using voxel-based morphometry (VBM) and voxel-based analysis of fractional anisotropy (FA) maps derived from DTI, respectively.

Results

Patients with BD had a larger volume of GM in the left thalamus and bilateral basal ganglia, including the bilateral putamen and extending to the left claustrum, as well as reduced FA values in the left posterior corona radiata.

Conclusions

By combined analysis, alterations in subcortical GM areas and part of the corresponding association fiber area were detected. Compared with observations in homogeneous samples, our findings indicate that disruption of the limbic network may be intrinsic to BD.     

A diffusion tensor imaging study of white matter in obsessive-compulsive disorder

Our objective was to test for differences between subjects with obsessive-compulsive disorder (OCD) and healthy controls with respect to white matter architecture within the cingulum bundle (CB) and anterior limb of the internal capsule (ALIC). We studied eight subjects with active OCD and 10 matched healthy controls using diffusion tensor magnetic resonance imaging (DT-MRI) at 1.5 T (Tesla). Fractional anisotropy (FA) was evaluated in both CB and ALIC. Both voxelwise and region-of-interest methods of analysis were employed. Within both the left CB and the left ALIC, subjects with OCD exhibited significantly greater FA than healthy controls. In the right CB, subjects with OCD exhibited significantly decreased FA versus healthy control subjects. Additionally, the OCD group exhibited abnormal asymmetry (left > right) of FA in the CB. These results provide preliminary evidence for abnormal architecture within the CB and ALIC in OCD. FA differences in these areas are consistent with the presence of abnormal connections between the nodes linked by these tracts. This could explain why surgically severing these tracts is therapeutic. Additional studies are needed to replicate these findings and to clarify their pathological and clinical significance.     

Alteration of fractional anisotropy and apparent diffusion coefficient in obsessive-compulsive disorder: a diffusion tensor imaging study

BACKGROUND: Abnormalities of fractional anisotropy (FA) have been reported in previous diffusion tensor imaging (DTI) studies in patients with obsessive-compulsive disorder (OCD). However, there are some inconsistencies in the results and the apparent diffusion coefficient (ADC) has not been investigated. The goal of this study was to investigate white matter abnormalities and water diffusivity, as reflected by FA and ADC, using DTI in patients with OCD. METHODS: Fifteen patients with OCD and 15 healthy volunteers underwent DTI. Voxelwise analysis was used to compare FA in white matter and ADC in gray matter/white matter of the two groups. RESULTS: Compared with healthy volunteers, the patients had higher FA in the bilateral semioval center extending to the subinsular white matter; and a higher ADC in the left medial frontal cortex. There were no areas with a significantly lower FA or ADC in patients compared with healthy volunteers. CONCLUSIONS: A significantly higher FA was found in regions associated with the emotion of disgust and a trend for a higher ADC was found in a region associated with the regulation of emotions. These findings suggest that neurocircuits involved in disgust processing may play an important role in the pathophysiology of OCD.     

磁共振扩散张量成像在鉴别胶质瘤不同成分中的应用

目的 评价扩散张量成像(DTI)在区分胶质瘤不同成分方面的价值.方法 对经手术证实的30例颅内胶质瘤行MRI常规序列及DTI扫描,其中低级别胶质瘤16例,高级别14例.并根据扫描结果,计算胶质瘤强化区、非强化区、囊变坏死区、瘤周异常区及对侧正常区的DTI各向异性分数(FA值)和相对各向异性(RA值).结果 低级别胶质瘤中,未强化区与对侧正常区之间的FA值及RA值均有显著性差异(P＜0.05);高级别胶质瘤中,FA值和RA值由高到低的顺序均为:对侧正常区、瘤周异常区、强化区、囊变坏死区;且任2个区域的FA值及RA值差异均有统计学意义(P＜0.05).结论 DTI可为鉴别胶质瘤不同成分提供一定信息,对制定手术计划和放疗方案具有一定的指导作用.     

Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder.

BACKGROUND: Several studies assessing volumetric measurements of regional brain structure in bipolar disorder have been published in recent years, but their results have been inconsistent. Our aim was to complete a meta-analysis of regional morphometry in bipolar disorder as assessed using magnetic resonance imaging (MRI). METHODS: We conducted a systematic literature search of MRI studies of bipolar disorder and identified studies which reported volume measurements in a selected number of regions. Twenty-six studies comprising volumetric measurements on up to 404 independent patients with bipolar disorder were included. A meta-analysis was carried out comparing the volumes of regions in bipolar disorder to comparison subjects using a random effects model. RESULTS: Patients with bipolar disorder had enlargement of the right lateral ventricle, but no other regional volumetric deviations which reached significance. Strong heterogeneity existed for several regions, including the third ventricle, left subgenual prefrontal cortex, bilateral amygdala and thalamus. CONCLUSIONS: Regional volume of most structures we studied is preserved in bipolar disorder as a whole, which was significantly associated only with right-sided ventricular enlargement. However the extensive heterogeneity detected indicates the need for further studies to establish if consistent regional brain volume deviation exists in bipolar disorder or in specific clinical subsets of the illness.     

Verifying the hypothesis of disconnection syndrome in patients with conduction aphasia using diffusion tensor imaging

BACKGROUND: It is thought in disconnection theory that connection of anterior and posterior language function areas, i.e. the lesion of arcuate fasciculus causes conduction aphasia. OBJECTIVE: To verify the theory of disconnection elicited by repetition disorder in patients with conduction aphasia by comparing the characteristics of diffusion tensor imaging between healthy persons and patients with conduction aphasia. DESIGN: Case-control observation. SETTING: Department of Neurology, Hongqi Hospital Affiliated to Mudanjiang Medical College. PARTICIPANTS: Five male patients with cerebral infarction-involved arcuate fasciculus conduction aphasia, averaged （43±2）years, who hospitalized in the Department of Neurology, Hongqi Hospital Affiliated to Mudanjiang Medical College from February 2004 to February 2005 were involved in this experiment. The involved patients were all confirmed as cerebral infarction by skull CT and MRI, and met the diagnosis criteria revised in 1995 4th Cerebrovascular Conference. They were examined by the method of Aphasia Battery of Chinese (ABC) edited by Surong Gao. The results were poorer than auditory comprehension disproportionately, and consistented with the mode of conduction aphasia. Another 5 male healthy persons, averaged （43±1）years, who were physicians receiving further training in the Department of Neurology, Beijing Tiantan Hospital were also involved in this experiment. Informed consents of detected items were obtained from all the subjects. METHODS: All the subjects were performed handedness assessment with assessment criteria of handedness formulated by Department of Neurology, First Hospital Affiliated to Beijing Medical University. Arcuate fasciculus of involved patients and health controls were analyzed with diffusion tensor imaging (DTI) and divided into 3 parts (anterior, middle and posterior segments) for determining FA value (mean value was obtained after three times of measurements), and a comparison of FA value was made between two sides. MAIN OUTCOME MEASURES: Analysis results of arcuate fasciculus DTI of healthy controls and patients with conduction aphasia. RESULTS: Five patients with conduction aphasia and 5 healthy controls participated in the final analysis. ①All the subjects were right-handedness. ② The left FA value of anterior, middle and posterior segments of arcuate fasciculus was larger than the right one in most normal volunteers, i.e. arcuate fasciculus with normal function on the left side was more than that on the right side. Because the amount of healthy controls was small, so positive conclusion has not been obtained, and only above-mentioned tendency was demonstrated. Healthy controls had good bilateral arcuate fasciculus; Three patients with conduction aphasia presented left FA value of anterior segment of arcuate fasciculus smaller than the right one, and two patients presented the left FA value larger than the right one. Four patients presented the left FA value of middle segment of arcuate fasciculus smaller than the right one, and one patient presented the left FA value larger than the right one, i.e. middle segment of arcuate fasciculus of 5 patients with conduction aphasia was all involved in at different degrees. Four patients with conduction aphasia presented the left FA value of posterior segment of arcuate fasciculus smaller than the right one, and one patient presented the left FA value larger than the right one, i.e. posterior segment of arcuate fasciculus of 5 patients was all injured at different degrees. CONCLUSION: Arcuate fasciculus of patients with conduction aphasia all is involved in at different degrees, which verifies the theory of disconnection of repetition disorder in patients with conduction aphasia.     

A framework for the analysis of phantom data in multicenter diffusion tensor imaging studies

Diffusion tensor imaging (DTI) is commonly used for studies of the human brain due to its inherent sensitivity to the microstructural architecture of white matter. To increase sampling diversity, it is often desirable to perform multicenter studies. However, it is likely that the variability of acquired data will be greater in multicenter studies than in single‐center studies due to the added confound of differences between sites. Therefore, careful characterization of the contributions to variance in a multicenter study is extremely important for meaningful pooling of data from multiple sites. We propose a two‐step analysis framework for first identifying outlier datasets, followed by a parametric variance analysis for identification of intersite and intrasite contributions to total variance. This framework is then applied to phantom data from the NIH MRI study of normal brain development (PedsMRI). Our results suggest that initial outlier identification is extremely important for accurate assessment of intersite and intrasite variability, as well as for early identification of problems with data acquisition. We recommend the use of the presented framework at frequent intervals during the data acquisition phase of multicenter DTI studies, which will allow investigators to identify and solve problems as they occur. Hum Brain Mapp 34:2439–2454, 2013. © 2012 Wiley Periodicals, Inc.     

Traumatic axonal injury: Relationships between lesions in the early phase and diffusion tensor imaging parameters in the chronic phase of traumatic brain injury

This prospective study of traumatic brain injury (TBI) patients investigates fractional anisotropy (FA) from chronic diffusion tensor imaging (DTI) in areas corresponding to persistent and transient traumatic axonal injury (TAI) lesions detected in clinical MRI from the early phase. Thirty‐eight patients (mean 24.7 [range 13–63] years of age) with moderate‐to‐severe TBI and 42 age‐ and sex‐matched healthy controls were included. Patients underwent 1.5‐T clinical MRI in the early phase (median 7 days), including fluid‐attenuated inversion recovery (FLAIR) and T2* gradient echo (T2*GRE) sequences. TAI lesions from the early phase were characterized as nonhemorrhagic or microhemorrhagic. In the chronic phase (median 3 years), patients and controls were imaged at 3 T with FLAIR, T2*GRE, T1, and DTI sequences. TAI lesions were classified as transient or persistent. The FLAIR/T2*GRE images from the early phase were linearly registered to the FA images from the chronic phase and lesions manually segmented on the FA‐registered FLAIR/T2*GRE images. For regions of interest (ROIs) from both nonhemorrhagic and microhemorrhagic lesion, we found a significant linear trend of lower mean FA from ROIs in healthy controls to ROIs in patients without either nonhemorrhagic or microhemorrhagic lesions and further to transient and finally persistent lesion ROIs (P < 0.001). Histogram analyses showed lower FA in persistent compared with transient nonhemorrhagic lesion ROIs (P < 0.001), but this was not found in microhemorrhagic lesion ROIs (P = 0.08–0.55). The demonstrated linear trend of lower FA values from healthy controls to persistent lesion ROIs was found in both nonhemorrhagic and microhemorrhagic lesions and indicates a gradual increasing disruption of the microstructure. Lower FA values in persistent compared with transient lesions were found only in nonhemorrhagic lesions. Thus, clinical MRI techniques are able to depict important aspects of white matter pathology across the stages of TBI. © 2016 Wiley Periodicals, Inc.     

Meta-analysis of magnetic resonance imaging studies of the corpus callosum in bipolar disorder

Objective: The corpus callosum (CC) plays a pivotal role in inter‐hemispheric transfer and integration of information and is a relatively understudied structure in bipolar disorder (BD). Magnetic resonance imaging (MRI) studies have reported callosal abnormalities in this condition but findings have been inconsistent. Structural changes affecting the CC may underlie functional abnormalities in BD and could contribute to, or explain the pathophysiology of, the condition. Method: A systematic review was carried out to identify, appraise and summarize MRI studies which compared callosal areas in BD with an unrelated control group. The findings were then synthesized using random effects meta‐analysis. Consideration was given to a number of variables to explain heterogeneity. Results: Five case–control studies were identified. Bipolar patients showed reduced callosal areas in comparison with healthy volunteers with no evidence of heterogeneity or publication bias. Conclusion: Findings from this study indicate that callosal areas are reduced in BD and suggest that a failure to integrate information across the hemispheres may contribute to the pathophysiology of the disorder. Further research is necessary to clarify the underlying cellular changes leading to these morphometric differences.     

Volume reduction of ventromedial prefrontal cortex in bipolar II patients with rapid cycling: a voxel-based morphometric study

Although rapid cycling (RC), a course specifier of bipolar I or II disorder, is particularly common among bipolar II patients compared with bipolar I patients, the pathophysiological lines of evidence regarding bipolar II with RC are still limited. In this preliminary study with a cross-sectional design, we examined the regional gray matter (GM) volume in 14 bipolar II patients with RC, 17 patients without RC and 84 healthy controls by whole-brain and region-of-interest (ROI) analysis methods, using magnetic resonance imaging with voxel-based morphometry. Whole-brain analysis in this study revealed that the bipolar II patients with RC showed GM volume reductions in the bilateral hemispheres of the medial orbital prefrontal cortex, ventromedial prefrontal cortex, anterior cingulate, insula and parahippocampus, in the left hemisphere of the inferior temporal cortex and cerebellum, and in the brainstem, compared with the healthy controls. Moreover, ROI analysis focusing on the ventral prefrontal cortex, i.e., Brodmann areas 10, 11 and 47, revealed that the bipolar II patients with RC showed GM volume reduction in the ventromedial prefrontal cortex, compared with the patients without RC. The findings of our pilot study suggest that the ventromedial prefrontal cortex is associated with the generation of RC in bipolar II disorder.     

皮质下缺血性血管性认知损害扩散张量成像研究

目的通过扩散张量成像(DTI)探讨皮质下缺血性血管性认知损害患者白质微结构变化及其与认知功能之间的相关性。方法采集49例皮质下缺血性脑血管病患者[轻度血管性痴呆(VaD)10例、非痴呆型血管性认知损害(VCIND)20例、认知功能正常19例]DTI数据并观察皮质下白质微结构改变,分析VaD组患者DTI参数与认知功能间的相关性。结果与对照组相比,VaD组内侧前额叶、前扣带回、胼胝体干、双侧顶叶、右侧颞叶、双侧眶额叶,以及VCIND组右侧额下回、右侧海马、双侧楔前叶FA值减低(均P=0.000);与VCIND组比较,VaD组内侧前额叶、前扣带回、胼胝体、双侧顶叶、右侧颞叶FA值减低(P=0.000)。与对照组相比,VaD组内侧前额叶、胼胝体、双侧顶叶、双侧颞叶、前扣带回,以及VCIND组双侧楔前叶、右侧海马MD值升高(均P=0.000);与VCIND组相比,VaD组右侧内侧前额叶、前扣带回、胼胝体干、双侧顶叶、双侧颞叶MD值升高(均P=0.000)。VaD组内侧前额叶FA值与数字连线测验A时呈显著负相关(r=-0.782,P=0.007),双侧额下回MD值与数字连线试验A时程呈显著正相关(r=0.877,P=0.001)。结论 DTI对皮质下缺血性认知损害患者白质微结构改变更敏感,能够反映患者认知功能早期异常改变;内侧前额叶白质微结构的改变是影响患者执行能力的重要因素。