Weihong Kuang

Disrupted Brain Connectivity Networks in Drug-Naive, First-Episode Major Depressive Disorder

BACKGROUND Neuroimaging studies have shown that major depressive disorder (MDD) is accompanied by structural and functional abnormalities in specific brain regions and connections; yet, little is known about alterations of the topological organization of whole-brain networks in MDD patients. METHODS Thirty drug-naive, first-episode MDD patients and 63 healthy control subjects underwent a resting-state functional magnetic resonance imaging scan. The whole-brain functional networks were constructed by thresholding partial correlation matrices of 90 brain regions, and their topological properties (e.g., small-world, efficiency, and nodal centrality) were analyzed using graph theory-based approaches. Nonparametric permutation tests were further used for group comparisons of topological metrics. RESULTS Both the MDD and control groups showed small-world architecture in brain functional networks, suggesting a balance between functional segregation and integration. However, compared with control subjects, the MDD patients showed altered quantitative values in the global properties, characterized by lower path length and higher global efficiency, implying a shift toward randomization in their brain networks. The MDD patients exhibited increased nodal centralities, predominately in the caudate nucleus and default-mode regions, including the hippocampus, inferior parietal, medial frontal, and parietal regions, and reduced nodal centralities in the occipital, frontal (orbital part), and temporal regions. The altered nodal centralities in the left hippocampus and the left caudate nucleus were correlated with disease duration and severity. CONCLUSIONS These results suggest that depressive disorder is associated with disruptions in the topological organization of functional brain networks and that this disruption may contribute to disturbances in mood and cognition in MDD patients.

Resting-State Functional Connectivity in treatment-Resistant Depression

OBJECTIVE The authors used resting-state functional connectivity MRI to evaluate brain networks in patients with refractory and nonrefractory major depressive disorder. METHOD In a cross-sectional study, 28 patients with refractory major depression, 32 patients with nonrefractory major depression, and 48 healthy comparison subjects underwent scanning using a gradient-echo echo-planar imaging sequence on a 3-T MR system. Thirteen regions of interest that have been identified in the literature as relevant to mood regulation were selected as seed areas. A reference time series was extracted for each seed and used for voxel-wise correlation analysis with the rest of the brain. Voxel-based comparisons of z-value maps among the three groups were performed using one-way analysis of variance followed by post hoc t tests with age and duration of illness as covariates of no interest. RESULTS Relative to healthy comparison subjects, both patient groups showed significantly reduced connectivity in prefrontal-limbic-thalamic areas bilaterally. However, the nonrefractory group showed a more distributed decrease in connectivity than the refractory group, especially in the anterior cingulate cortex and in the amygdala, hippocampus, and insula bilaterally; in contrast, the refractory group showed disrupted functional connectivity mainly in prefrontal areas and in thalamus areas bilaterally. CONCLUSIONS Refractory depression is associated with disrupted functional connectivity mainly in thalamo-cortical circuits, while nonrefractory depression is associated with more distributed decreased connectivity in the limbic-striatal-pallidal-thalamic circuit. These results suggest that nonrefractory and refractory depression are characterized by distinct functional deficits in distributed brain networks.

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.

Abnormal regional spontaneous neural activity in treatment-refractory depression revealed by resting-state fMRI

Treatment‐refractory depression (TRD) represents a large proportion of the depressive population, yet has seldom been investigated using advanced imaging techniques. To characterize brain dysfunction in TRD, we performed resting‐state functional MRI (rs‐fMRI) on 22 TRD patients, along with 26 matched healthy subjects and 22 patients who were depressed but not treatment‐refractory (NDD) as comparison groups. Results were analyzed using a data‐driven approach known as Regional Homogeneity (ReHo) analysis which measures the synchronization of spontaneous fMRI signal oscillations within spatially neighboring voxels. Relative to healthy controls, both depressed groups showed high ReHo primarily within temporo‐limbic structures, and more widespread low ReHo in frontal, parietal, posterior fusiform cortices, and caudate. TRD patients showed more cerebral regions with altered ReHo than did NDD. Moderate but significant correlations between the altered regional ReHo and measures of clinical severity were observed in some identified clusters. These findings shed light on the pathophysiological mechanisms underlying TRD and demonstrate the feasibility of using ReHo as a research and clinical tool to monitor persistent cerebral dysfunction in depression, although further work is necessary to compare different measures of brain function to elucidate the neural substrates of these ReHo abnormalities. Hum Brain Mapp, 2011.

High-field MRI reveals an acute impact on brain function in survivors of the magnitude 8.0 earthquake in China

Besides the enormous medical and economic consequences, national disasters, such as the Wenchuan 8.0 earthquake, also pose a risk to the mental health of survivors. In this context, a better understanding is needed of how functional brain systems adapt to severe emotional stress. Previous animal studies have demonstrated the importance of limbic, paralimbic, striatal, and prefrontal structures in stress and fear responses. Human studies, which have focused primarily on patients with clinically established posttraumatic stress disorders, have reported abnormalities in similar brain structures. At present, little is known about potential alterations of brain function in trauma survivors shortly after traumatic events. Here, we show alteration of brain function in a cohort of healthy survivors within 25 days after the Wenchuan earthquake by a recently discovered method known as “resting-state” functional MRI. The current investigation demonstrates that regional activity in frontolimbic and striatal areas increased significantly and connectivity among limbic and striatal networks was attenuated in our participants who had recently experienced severe emotional trauma. Trauma victims also had a reduced temporal synchronization within the “default mode” of resting-state brain function, which has been characterized in humans and other species. Taken together, our findings provide evidence that significant alterations in brain function, similar in many ways to those observed in posttraumatic stress disorders, can be seen shortly after major traumatic experiences, highlighting the need for early evaluation and intervention for trauma survivors.

High-Field Magnetic Resonance Imaging of Suicidality in Patients With Major Depressive Disorder

OBJECTIVE Suicide is a major social and public health problem, but its neurobiology in major depressive disorder is poorly understood. The purpose of this study was to use magnetic resonance diffusion tensor imaging to characterize abnormalities of white matter integrity in major depressive disorder patients with and without a history of suicide attempts. METHOD Participants were 52 patients with major depressive disorder, with (N=16) and without (N=36) a history of suicide attempts, and 52 healthy comparison subjects matched for age, gender, education, and ethnicity. Diffusion tensor imaging in a 3.0 Tesla magnetic resonance scanner was performed. Whole-brain voxel-based analysis was used to compare fractional anisotropy across the three groups and analyze the correlation with symptom severity. A region-of-interest analysis was applied to the bilateral hippocampus, thalamus, and lentiform nucleus RESULTS Fractional anisotropy was decreased in the left anterior limb of the internal capsule in suicide attempters relative to both nonattempters and healthy comparison subjects, in the right frontal lobe relative to comparison subjects only, and in the right lentiform nucleus relative to nonattempters only. There was no significant correlation with symptom severity. CONCLUSIONS Decreased fractional anisotropy in the left anterior limb of the internal capsule appears to characterize patients with major depressive disorder who have a history of attempting suicide. Longitudinal studies are required to validate this as a potential marker that may inform the development of strategies for reducing suicide.

Regional increases of cortical thickness in untreated, first-episode major depressive disorder

The large majority of structural MRI studies of major depressive disorder (MDD) investigated volumetric changes in chronic medicated patients in whom course of illness and treatment effects may impact anatomic measurements. Further, in few studies, separate measurements of cortical thickness and surface area have been performed that reflect different neurobiological processes regulated by different genetic mechanisms. In the present study, we investigated both cortical thickness and surface area in first-episode, treatment-naïve, mid-life MDD to elucidate the core pathophysiology of this disease and its early impact on the brain. We observed increased cortical thickness in the right hemisphere, including medial orbitofrontal gyrus, pars opercularis, rostral middle frontal gyrus and supramarginal gyrus. Increased thickness of rostral middle frontal gyrus was negatively related with depression severity on the Hamilton Depression Rating Scale. Furthermore, MDD patients showed significantly increased associations in cortical thickness measurements among areas where increased cortical thickness was observed. Analysis of pial area revealed a trend toward increased surface area in the left parahippocampal gyrus in MDD. To permit comparison of our data with those of previous gray matter volume studies, voxel-based morphometry was performed. That analysis revealed significantly increased gray matter volume in left paracentral lobule, left superior frontal gyrus, bilateral cuneus and thalamus which form limbic-cortico–striato–pallido–thalamic loops. These changes in first-episode, treatment-naïve, mid-life MDD patients may reflect an active illness-related cortical change close to illness onset, and thus potentially provide important new insight into the early neurobiology of the disorder.

Magnetization transfer imaging reveals the brain deficit in patients with treatment-refractory depression

BACKGROUND Studies on treatment resistant depression (TRD) using advanced magnetic resonance imaging techniques are very limited. METHODS A group of 15 patients with clinically defined TRD and 15 matched healthy controls underwent magnetization transfer imaging (MTI) and T1-weighted (T1W) imaging. MTI data were processed and analyzed voxel-wised in SPM2. A voxel based morphometric (VBM) analysis was performed using T1W images. RESULTS Reduced magnetization transfer ratio was observed in the TRD group relative to normal controls in the anterior cingulate, insula, caudate tail and amygdala-parahippocampal areas. All these regions were identified within the right hemisphere. VBM revealed no morphological abnormalities in the TRD group compared to the control group. Negative correlations were found between MRI and clinical measures in the inferior temporal gyrus. LIMITATIONS The cross-sectional design and small sample size. CONCLUSIONS The findings suggest that MTI is capable of identifying subtle brain abnormalities which underlie TRD and in general more sensitive than morphological measures.

Disorganization of white matter architecture in major depressive disorder: a meta-analysis of diffusion tensor imaging with tract-based spatial statistics

White matter (WM) abnormalities have long been suspected in major depressive disorder (MDD). Tract-based spatial statistics (TBSS) studies have detected abnormalities in fractional anisotropy (FA) in MDD, but the available evidence has been inconsistent. We performed a quantitative meta-analysis of TBSS studies contrasting MDD patients with healthy control subjects (HCS). A total of 17 studies with 18 datasets that included 641 MDD patients and 581 HCS were identified. Anisotropic effect size-signed differential mapping (AES-SDM) meta-analysis was performed to assess FA alterations in MDD patients compared to HCS. FA reductions were identified in the genu of the corpus callosum (CC) extending to the body of the CC and left anterior limb of the internal capsule (ALIC) in MDD patients relative to HCS. Descriptive analysis of quartiles, sensitivity analysis and subgroup analysis further confirmed these findings. Meta-regression analysis revealed that individuals with more severe MDD were significantly more likely to have FA reductions in the genu of the CC. This study provides a thorough profile of WM abnormalities in MDD and evidence that interhemispheric connections and frontal-striatal-thalamic pathways are the most convergent circuits affected in MDD.

Impact of acute stress on human brain microstructure: An MR diffusion study of earthquake survivors

A characterization of the impact of natural disasters on the brain of survivors is critical for a better understanding of posttraumatic responses and may inform the development of more effective early interventions. Here we report alterations in white matter microstructure in survivors soon after Wenchuan earthquake in China in 2008. Within 25 days after the Wenchuan earthquake, 44 healthy survivors were recruited and scanned on a 3T MR imaging system. The survivors were divided into two groups according to their self‐rating anxiety scale (SAS) score, including the SAS(+) (SAS > 55 after correction) group and “SAS(−)” (SAS < 55 after correction) group. Thrity‐two healthy volunteers were also recruited as control group before earthquake. Individual maps of fractional anisotropy (FA) were calculated and voxel‐based analysis (VBA) was performed to allow the comparison between survivors and controls using ANCOVAs in SPM2. In addition, a correlation between SAS score and regional FA value was examined using Pearsons correlation analysis in SPSS 11.5. Compared with the healthy cohort, the whole group of 44 survivors showed significantly decreased FA values in the right prefrontal lobe, the parietal lobe, the basal ganglia, and the right parahippocampus. These effects did not appear to depend on self‐rating anxiety. For the first time we provide evidence that acute trauma altered cerebral microstructure within the limbic system; furthermore, these alterations are evident shortly after the traumatic event, highlighting the need for early evaluation and intervention for trauma survivors. Hum Brain Mapp, 2013.