Microstructural brain abnormalities in medication-free patients with major depressive disorder: a systematic review and meta-analysis of diffusion tensor imaging.

BACKGROUND: Multiple meta-analyses of diffusion tensor imaging (DTI) studies have reported impaired white matter integrity in patients with major depressive disorder (MDD). However, owing to inclusion of medicated patients in these studies, it is difficult to conclude whether these reported alterations are associated with MDD or confounded by medication effects. A meta-analysis of DTI studies on medication-free (medication-naive and medication washout) patients with MDD would therefore be necessary to disentangle MDD-specific effects. METHODS: We analyzed white matter alterations between medication-free patients with MDD and healthy controls using anisotropic effect size-signed differential mapping (AES-SDM). We used DTI query software for fibre tracking. RESULTS: Both pooled and subgroup meta-analyses in medication washout patients showed robust fractional anisotropy (FA) reductions in white matter of the right cerebellum hemispheric lobule, body of the corpus callosum (CC) and bilateral superior longitudinal fasciculus III (SLF III), whereas FA reductions in the genu of the CC and right anterior thalamic projections were seen in only medication-naive patients. Fibre tracking showed that the main tracts with observed FA reductions included the right cerebellar tracts, body of the CC, bilateral SLF III and arcuate fascicle. LIMITATIONS: The analytic techniques, patient characteristics and clinical variables of the included studies were heterogeneous; we could not exclude the effects of nondrug therapies owing to a lack of data. CONCLUSION: By excluding the confounding influences of current medication status, findings from the present study may provide a better understanding of the underlying neuropathology of MDD.

Voxel-wise meta-analyses of brain blood flow and local synchrony abnormalities in medication-free patients with major depressive disorder.

BACKGROUND: Published meta-analyses of resting-state regional cerebral blood flow (rCBF) studies of major depressive disorder (MDD) have included patients receiving antidepressants, which might affect brain activity and thus bias the results. To our knowledge, no meta-analysis has investigated regional homogeneity changes in medication-free patients with MDD. Moreover, an association between regional homogeneity and rCBF has been demonstrated in some brain regions in healthy controls. We sought to explore to what extent resting-state rCBF and regional homogeneity changes co-occur in the depressed brain without the potential confound of medication. METHODS: Using the effect-size signed differential mapping method, we conducted 2 meta-analyses of rCBF and regional homogeneity studies of medication-free patients with MDD. RESULTS: Our systematic search identified 14 rCBF studies and 9 regional homogeneity studies. We identified conjoint decreases in resting-state rCBF and regional homogeneity in the insula and superior temporal gyrus in medication-free patients with MDD compared with controls. Other changes included altered resting-state rCBF in the precuneus and in the frontal-limbic-thalamic-striatal neural circuit as well as altered regional homogeneity in the uncus and parahippocampal gyrus. Meta-regression revealed that the percentage of female patients with MDD was negatively associated with resting-state rCBF in the right anterior cingulate cortex and that the age of patients with MDD was negatively associated with rCBF in the left insula and with regional homogeneity in the left uncus. LIMITATIONS: The analysis techniques, patient characteristics and clinical variables of the included studies were heterogeneous. CONCLUSION: The conjoint alterations of rCBF and regional homogeneity in the insula and superior temporal gyrus may be core neuropathological changes in medication-free patients with MDD and serve as a specific region of interest for further studies on MDD.

Brain grey matter volume alterations in late-life depression.

BACKGROUND: Voxel-based morphometry (VBM) studies have demonstrated that grey matter abnormalities are involved in the pathophysiology of late-life depression (LLD), but the findings are inconsistent and have not been quantitatively reviewed. The aim of the present study was to conduct a meta-analysis that integrated the reported VBM studies, to determine consistent grey matter alterations in individuals with LLD. METHODS: A systematic search was conducted to identify VBM studies that compared patients with LLD and healthy controls. We performed a meta-analysis using the effect size signed differential mapping method to quantitatively estimate regional grey matter abnormalities in patients with LLD. RESULTS: We included 9 studies with 11 data sets comprising 292 patients with LLD and 278 healthy controls in our meta-analysis. The pooled and subgroup meta-analyses showed robust grey matter reductions in the right lentiform nucleus extending into the parahippocampus, the hippocampus and the amygdala, the bilateral medial frontal gyrus and the right subcallosal gyrus as well as a grey matter increase in the right lingual gyrus. Meta-regression analyses showed that mean age and the percentage of female patients with LLD were not significantly related to grey matter changes. LIMITATIONS: The analysis techniques, patient characteristics and clinical variables of the studies included were heterogeneous, and most participants were medicated. CONCLUSION: The present meta-analysis is, to our knowledge, the first to overcome previous inconsistencies in the VBM studies of LLD and provide robust evidence for grey matter alterations within fronto-striatal-limbic networks, thereby implicating them in the pathophysiology of LLD. The mean age and the percentage of female patients with LLD did not appear to have a measurable impact on grey matter changes, although we cannot rule out the contributory effects of medication.

Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD.

BACKGROUND: Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI. METHOD: A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms "DTI" or "diffusion tensor;" "whole brain" or "voxel-based;" and "depress*." Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region. RESULTS: We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum. LIMITATIONS: The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences. CONCLUSION: Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This isstrong evidence for the involvement of these neural circuits in the pathology of MDD.

Enhancing the bioaccessibility of puerarin through the collaboration of high internal phase Pickering emulsions with ß-carotene.

Puerarin, a bioactive flavonoid found in the root of Pueraria lobata, is claimed to possess various medicinal properties. However, application of puerarin in functional foods is currently limited by its poor bioaccessibility. Existing delivery systems that guarantee puerarin bioaccessibility involve complex preparation steps and safety issues. Therefore, this study aimed to use meat protein and olive oil to efficiently and economically fabricate a food grade high internal phase Pickering emulsion (HIPPE) with co-encapsulated puerarin and ß-carotene to improve the bioaccessibility of puerarin. Moreover, the impact on lipid digestibility and puerarin bioaccessibility was verified using a simulated in vitro gastrointestinal tract. Co-encapsulating puerarin and ß-carotene in HIPPE increased puerarin bioaccessibility (85.17%) compared to that achieved with only puerarin in HIPPE (62.66%). This increased bioaccessibility may have been due to the personalized formulation and the exceptional structure of the HIPPE, which slowed down lipid digestion and inhibited puerarin degradation. A synergistic interaction occurred between ß-carotene and HIPPE to improve puerarin bioaccessibility. Our results have important implications for the design of effective delivery systems for encapsulation of puerarin and other bioactive components.

Chemotherapy-induced grey matter abnormalities in cancer survivors: a voxel-wise neuroimaging meta-analysis.

BACKGROUND: Findings regarding chemotherapy-induced grey matter abnormalities are heterogeneous, and no meta-analysis has quantitatively assessed brain structural alterations in cancer survivors treated with chemotherapy. PURPOSE: To investigate the grey matter abnormalities in non-CNS (central nervous system) cancer survivors treated with chemotherapy using Anisotropic Effect Size Signed Differential Mapping (AES-SDM) software. METHOD: We identified studies published up to Sep 2018 that compared grey matter in non-CNS cancer survivors treated with chemotherapy (CT+, 10 data sets including 433 individuals) and cancer survivors not treated with chemotherapy (CT-, 7 data sets including 210 individuals) or healthy controls (HC, 3 data sets including 407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. RESULTS: Compared with both CT- and HC, the CT + groups exhibited a reduced grey matter volume (GMV), mainly in the prefrontal and anterior cingulate cortex (ACC) and right fusiform gyrus (FG). A smaller GMV in the FG and prefrontal cortex were found in the CT + compared with the CT-groups and in the CT + groups with impaired cognition. GMV in two areas was positively associated with the time since chemotherapy. CONCLUSIONS: The present results suggest that non-CNS cancer survivors treated with chemotherapy exhibit grey matter abnormalities in the brain, especially in the prefrontal and ACC cortex. Grey matter volume changes after chemotherapy may contribute to cognitive impairments in cancer survivors that can be observed after chemotherapy.

Differentiation between Luminal A and B Molecular Subtypes of Breast Cancer Using Pharmacokinetic Quantitative Parameters with Histogram and Texture Features on Preoperative Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

OBJECTIVE: The aim of the present study was to use pharmacokinetic quantitative parameters with histogram and texture features on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to differentiate between the luminal A and luminal B molecular subtypes of breast cancer. METHODS: We retrospectively reviewed the data of 94 patients with histopathologically proven breast cancer. The pharmacokinetic quantitative parameters (Ktrans, Kep, and Ve) with their corresponding histogram and texture features based on preoperative DCE-MRI were obtained. The parameters were compared using the Mann-Whitney U-test between the luminal A and luminal B groups, the human epidermal growth factor receptor-2 (HER2)-positive luminal B and HER2-negative luminal B groups, and the lymph node metastasis (LNM)-positive and LNM-negative groups. Receiver operating characteristic curves were generated for parameters that presented significant between-group differences. RESULTS: The maximum values of Ktrans, Kep, and Ve, and the mean and 90th percentile values of Ve were significantly higher in the luminal B group than in the luminal A group. Among the texture features, only skewness of Ktrans significantly differed between the luminal A and B groups. All histogram features of Ktrans were higher in the HER2-positive luminal B group than in the HER2-negative luminal B group. However, no parameter differed between the LNM-positive and LNM-negative groups. CONCLUSION: Pharmacokinetic quantitative parameters with histogram and texture features obtained from DCE-MRI are associated with the molecular subtypes of breast cancer, and may serve as potential imaging biomarkers to differentiate between the luminal A and luminal B molecular subtypes.

Meta-analytic investigations of common and distinct grey matter alterations in youths and adults with obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is a disabling illness with onset generally in childhood. OCD-youths differ from OCD-adults with regard to gender distribution, comorbidity patterns and treatment options. However, little is known about the neural correlate differences underpin those two populations. The current meta-analysis summarizes voxel based morphometry findings to elucidate whether differences of neural correlates exist between these two populations. Both OCD-youths and OCD-adults demonstrated greater striatal volume and smaller prefrontal grey matter volume (GMV). However, smaller GMV in left visual cortex was observed in OCD-youths only, while smaller GMV in anterior cingulate gyrus and greater GMV in cerebellum were demonstrated only in OCD-adults. Meta-regression showed greater GMV in left putamen was most prominent in samples with higher percentages of medicated OCD-adults. Our findings confirmed the most consistent GMV alterations in OCD were in prefrontal-striatal circuitry. Besides, other regions may involve at different developmental stages including deficits of visual cortex in OCD-youths and abnormalities of limbic-cerebellar circuit in OCD-adults. Medication effect may be more pronounced in the striatum, especially the putamen.

Functional MRI reveals different response inhibition between adults and children with ADHD.

OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) has been recognized as a disorder of executive function, and a number of functional MRI (fMRI) studies have been conducted to investigate the altered brain activation patterns between ADHD patients and healthy controls. However, the findings across different studies have been inconsistent, and the different neural mechanisms between adults and children with ADHD remain unclear. The aim of this study was to perform a meta-analysis of fMRI studies to further investigate and compare the abnormalities in adults and children with ADHD during motor response inhibition. METHOD: Activation likelihood estimation (ALE) was used to investigate brain activation differences between ADHD patients and controls, and a subtraction meta-analysis was performed to compare adult and child patients. RESULTS: Twenty-three studies met the inclusion criteria. Meta-analysis using ALE detected significantly decreased activation during response inhibition in ADHD in the supplementary motor area, insula, caudate, and precentral gyrus, as well as increased activation in the postcentral gyrus, inferior frontal gyrus, and precuneus. The activation decreases in the right caudate were greater in child ADHD patients than adult ADHD patients. CONCLUSIONS: This meta-analysis identified dysfunction in several areas of the motor inhibition network that may play a role in the abnormal neural mechanisms of response inhibition in ADHD. The comparison of child and adult subgroups raises the possibility that the persistence of functional abnormalities of the caudate may be an important factor in whether ADHD persists.

Altered functional connectivity in the brain default-mode network of earthquake survivors persists after 2 years despite recovery from anxiety symptoms.

Although acute impact of traumatic experiences on brain function in disaster survivors is similar to that observed in post-traumatic stress disorders (PTSD), little is known about the long-term impact of this experience. We have used structural and functional magnetic resonance imaging to investigate resting-state functional connectivity and gray and white matter (WM) changes occurring in the brains of healthy Wenchuan earthquake survivors both 3 weeks and 2 years after the disaster. Results show that while functional connectivity changes 3 weeks after the disaster involved both frontal-limbic-striatal and default-mode networks (DMN), at the 2-year follow-up only changes in the latter persisted, despite complete recovery from high initial levels of anxiety. No gray or WM volume changes were found at either time point. Taken together, our findings provide important new evidence that while altered functional connectivity in the frontal-limbic-striatal network may underlie the post-trauma anxiety experienced by survivors, parallel changes in the DMN persist despite the apparent absence of anxiety symptoms. This suggests that long-term changes occur in neural networks involved in core aspects of self-processing, cognitive and emotional functioning in disaster survivors which are independent of anxiety symptoms and which may also confer increased risk of subsequent development of PTSD.

Neural correlates during working memory processing in major depressive disorder.

BACKGROUND: Functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD) have revealed cortical-limbic-subcortical dysfunctions during working memory (WM) processing, but the results are inconsistent and it is unclear to what extent these findings are influenced by demographic, clinical characteristics and task performance of patients. The present study conducted a quantitative coordinate-based meta-analysis of fMRI data to investigate the hypothesized dysfunction in the neural correlates during WM processing in MDD. METHODS: A systematic research was conducted for fMRI studies during WM processing comparing MDD patients with healthy controls (HC). Meta-analysis was performed using effect size signed differential mapping (ES-SDM). Meta-regression analyses with age, sex and medication as factors were performed in MDD group. RESULTS: Functional MRI data of 160 MDD patients and 203 HC from 13 WM experiments across 11 studies were included in this meta-analysis. In the pooled meta-analysis of all included studies, significant increased activation during WM in the left lateral prefrontal cortex, left precentral gyrus, left insula, right superior temporal and right supramarginal areas, and significant decreased activity in the right precentral gyrus, right precuneus and right insula were observed in MDD compared with controls. In the subgroup analysis of the studies with matched task performance, MDD subgroup showed hyperactivation only in the left prefrontal cortex and hypoactivation in the regions similar to the pooled analysis. The meta-regression with age, sex and medication showed no significance in MDD group. CONCLUSIONS: Regardless of differences in task performance between groups, patients with MDD showed consistent functional abnormalities in the cortical-limbic-subcortical circuitry during WM processing. Distinct patterns of neural engagement may reflect compensatory neural strategies to potential dysfunction in MDD.

Magnetization transfer imaging of suicidal patients with major depressive disorder.

Magnetization transfer imaging (MTI) provides a quantitative measure of the macromolecular structural integrity of brain tissue, as represented by magnetization transfer ratio (MTR). In this study, we utilized MTI to identify biophysical alterations in MDD patients with a history of suicide attempts relative to MDD patients without such history. The participants were 36 medication-free MDD patients, with (N = 17) and without (N = 19) a history of a suicide attempt, and 28 healthy controls matched for age and gender. Whole brain voxel-based analysis was used to compare MTR across three groups and to analyze correlations with symptom severity and illness duration. We identified decreased MTR in left inferior parietal lobule and right superior parietal lobule in suicide attempters relative to both non-attempters and controls. Non-attempters also showed significantly reduced MTR in left inferior parietal lobule relative to controls, as well as an MTR reduction in left cerebellum. These abnormalities were not correlated with symptom severity or illness duration. Depressed patients with a history of suicide attempt showed bilateral abnormalities in parietal cortex compared to nonsuicidal depressed patients and healthy controls. Parietal lobe abnormalities might cause attentional dysfunction and impaired decision making to increase risk for suicidal behavior in MDD.

The common traits of the ACC and PFC in anxiety disorders in the DSM-5: meta-analysis of voxel-based morphometry studies.

BACKGROUND: The core domains of social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD) with and without agoraphobia (GA), and specific phobia (SP) are cognitive and physical symptoms that are related to the experience of fear and anxiety. It remains unclear whether these highly comorbid conditions that constitute the anxiety disorder subgroups of the Diagnostic and Statistical Manual for Mental Disorders--Fifth Edition (DSM-5) represent distinct disorders or alternative presentations of a single underlying pathology. METHODS: A systematic search of voxel-based morphometry (VBM) studies of SAD, GAD, PD, GA, and SP was performed with an effect-size signed differential mapping (ES-SDM) meta-analysis to estimate the clusters of significant gray matter differences between patients and controls. RESULTS: Twenty-four studies were eligible for inclusion in the meta-analysis. Reductions in the right anterior cingulate gyrus and the left inferior frontal gyrus gray matter volumes (GMVs) were noted in patients with anxiety disorders when potential confounders, such as comorbid major depressive disorder (MDD), age, and antidepressant use were controlled for. We also demonstrated increased GMVs in the right dorsolateral prefrontal cortex (DLPFC) in comorbid depression-anxiety (CDA), drug-naïve and adult patients. Furthermore, we identified a reduced left middle temporal gyrus and right precentral gyrus in anxiety patients without comorbid MDD. CONCLUSION: Our findings indicate that a reduced volume of the right ventral anterior cingulate gyrus and left inferior frontal gyrus is common in anxiety disorders and is independent of comorbid depression, medication use, and age. This generic effect supports the notion that the four types of anxiety disorders have a clear degree of overlap that may reflect shared etiological mechanisms. The results are consistent with neuroanatomical DLPFC models of physiological responses, such as worry and fear, and the importance of the ventral anterior cingulate (ACC)/medial prefrontal cortex (mPFC) in mediating anxiety symptoms.

Quantitative prediction of individual psychopathology in trauma survivors using resting-state FMRI.

Neuroimaging techniques hold the promise that they may one day aid the clinical assessment of individual psychiatric patients. However, the vast majority of studies published so far have been based on average differences between groups. This study employed a multivariate approach to examine the potential of resting-state functional magnetic resonance imaging (MRI) data for making accurate predictions about psychopathology in survivors of the 2008 Sichuan earthquake at an individual level. Resting-state functional MRI data was acquired for 121 survivors of the 2008 Sichuan earthquake each of whom was assessed for symptoms of post-traumatic stress disorder (PTSD) using the 17-item PTSD Checklist (PCL). Using a multivariate analytical method known as relevance vector regression (RVR), we examined the relationship between resting-state functional MRI data and symptom scores. We found that the use of RVR allowed quantitative prediction of clinical scores with statistically significant accuracy (correlation=0.32, P=0.006; mean squared error=176.88, P=0.001). Accurate prediction was based on functional activation in a number of prefrontal, parietal, and occipital regions. This is the first evidence that neuroimaging techniques may inform the clinical assessment of trauma-exposed individuals by providing an accurate and objective quantitative estimation of psychopathology. Furthermore, the significant contribution of parietal and occipital regions to such estimation challenges the traditional view of PTSD as a disorder specific to the fronto-limbic network.

Grey matter reduction associated with posttraumatic stress disorder and traumatic stress.

In recent decades, many imaging studies have reported brain structural alterations in posttraumatic stress disorder (PTSD). However, due to differences in the selection of control subjects, it is difficult to conclude whether the observed alterations were related to disease or traumatic stress. The present study was to provide a quantitative voxelwise meta-analysis of grey matter (GM) changes in PTSD relative to either trauma-exposed controls without PTSD (TEC) or non-traumatised healthy controls (HC) separately and to conduct a systematic review of voxel-based morphometry (VBM) studies that compared trauma-exposed individuals with HC to explore the effect of traumatic stress. GM reduction was identified in the medial prefrontal cortex in PTSD compared to both TEC and HC. Additional GM reduction was also observed in PTSD in the left hippocampus, left middle temporal gyrus and right superior frontal gyrus compared with TEC. Additionally, GM decreased in the left occipital cortex in PTSD compared with HC. The present study delimited the significant differences among VBM results in PTSD research when different control groups were chosen.

White matter deficits in first episode schizophrenia: an activation likelihood estimation meta-analysis.

BACKGROUND: Diffusion tensor imaging (DTI) has been widely used in psychiatric research and has provided evidence of white matter abnormalities in first episode schizophrenia (FES). The goal of the present meta-analysis was to identify white matter deficits by DTI in FES. METHODS: A systematic search was conducted to collect DTI studies with voxel-wised analysis of the fractional anisotropy (FA) in FES. The coordinates of regions with FA changes were meta-analyzed using the activation likelihood estimation (ALE) method which weighs each study on the basis of its sample size. RESULTS: A total of 8 primary studies were selected, including 271 FES patients and 297 healthy controls. Among these studies, 52 regions showed reductions in the FA in FES while 2 regions had increased FA. Consistent FA reductions in the white matter of the right deep frontal and left deep temporal lobes were identified in all FES patients relative to healthy controls. Fiber tracking showed that the main tracts involved were the cingulum bundle, the left inferior longitudinal fasciculus, the left inferior fronto-occipital fasciculus and the interhemispheric fibers running through the corpus callosum. CONCLUSIONS: The current findings provide evidence confirming the lack of connection in the fronto-limbic circuitry at the early stages of the schizophrenia. Because the coordinates reported in the primary literature were highly variable, future investigations with large samples would be required to support the identified white matter changes in FES.

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.