Xiaoqi Huang

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.

Short-term Effects of Antipsychotic Treatment on Cerebral Function in Drug-Naive First-Episode Schizophrenia Revealed by “Resting State” Functional Magnetic Resonance Imaging

CONTEXT Most of what we know about antipsychotic drug effects is at the receptor level, distal from the neural system effects that mediate their clinical efficacy. Studying cerebral function in antipsychotic-naive patients with schizophrenia before and after pharmacotherapy can enhance understanding of the therapeutic mechanisms of these clinically effective treatments. OBJECTIVE To examine alterations of regional and neural network function in antipsychotic-naive patients with first-episode schizophrenia before and after treatment with second-generation antipsychotic medication. DESIGN Case-control study. SETTING Huaxi MR Research Center and Mental Health Centre of the West China Hospital. PARTICIPANTS Thirty-four antipsychotic-naive patients with first-episode schizophrenia were scanned using gradient-echo echo-planar imaging while in a resting state. After 6 weeks of antipsychotic treatment, patients were rescanned. Thirty-four matched healthy control subjects were studied at baseline for comparison purposes. MAIN OUTCOME MEASURES The amplitude of low-frequency fluctuations (ALFF) of blood oxygen level-dependent signals, believed to reflect spontaneous neural activity, was used to characterize regional cerebral function. Functional connectivity across brain regions was evaluated using a seed voxel correlation approach and an independent component analysis. Changes in these measures after treatment were examined to characterize effects of antipsychotic drugs on regional function and functional integration. RESULTS After short-term treatment with second-generation antipsychotic medications, patients showed increased ALFF, particularly in the bilateral prefrontal and parietal cortex, left superior temporal cortex, and right caudate nucleus. Increased regional ALFF was associated with a reduction of clinical symptoms, and a widespread attenuation in functional connectivity was observed that was correlated with increased regional ALFF. CONCLUSIONS We demonstrate for the first time, to our knowledge, that widespread increased regional synchronous neural activity occurs after antipsychotic therapy, accompanied by decreased integration of function across widely distributed neural networks. These findings contribute to the understanding of the complex systems-level effects of antipsychotic drugs.

Association of Cerebral Deficits With Clinical Symptoms in Antipsychotic-Naive First-Episode Schizophrenia: An Optimized Voxel-Based Morphometry and Resting State Functional Connectivity Study

OBJECTIVE The purpose of the present study was to characterize the association between clinical symptoms and anatomical and functional cerebral deficits in a relatively large sample of antipsychotic-naive first-episode schizophrenia patients using optimized voxel-based morphometry and resting state functional connectivity analysis. METHOD Participants were 68 antipsychotic-naive first-episode schizophrenia patients and 68 matched healthy comparison subjects. Both patients and healthy comparison subjects were scanned using a volumetric three-dimensional spoiled gradient recall sequence and a gradient-echo echo-planar imaging sequence. Psychopathology of first-episode schizophrenia patients was evaluated using the Positive and Negative Syndrome Scale (PANSS). Optimized voxel-based morphometry was used to characterize gray matter deficits in schizophrenia patients. The clinical significance of regional volume reduction was investigated by examining its association with symptoms in patients with first-episode schizophrenia and with alterations in resting state functional connectivity when brain regions with gray matter volume reduction were used as seed areas. RESULTS Significantly decreased gray matter volume was observed in schizophrenia patients in the right superior temporal gyrus (Brodmanns area 41), right middle temporal gyrus (Brodmanns area 21), and right anterior cingulate gyrus (Brodmanns area 32). Decreased gray matter volume in these brain regions was related to greater disturbance as shown on PANSS scores for positive symptoms, general psychopathology symptoms, thought disturbance, activation, paranoia, and impulsive aggression as well as total PANSS scores. A positive correlation was observed between PANSS scores for thought disturbance and temporo-putamen connectivity, and negative correlations were found between temporo-precuneus connectivity and total PANSS scores as well as scores for negative symptoms and anergia. CONCLUSIONS The findings revealed volume loss in the right superior temporal gyrus, right middle temporal gyrus, and right anterior cingulate gyrus among antipsychotic-naive first-episode schizophrenia patients. In addition, the functional networks involving the right superior temporal gyrus and middle temporal gyrus were associated with clinical symptom severity. No abnormalities were observed in resting state connectivity with regions of identified gray matter deficits.

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.

Prognostic prediction of therapeutic response in depression using high-field MR imaging

Despite significant advances in the treatment of major depression, there is a high degree of variability in how patients respond to treatment. Approximately 70% of patients show some improvement following standard antidepressant treatment and are classified as having non-refractory depressive disorder (NDD), while the remaining 30% of patients do not respond to treatment and are classified as having refractory depressive disorder (RDD). At present, there are no objective, neurological markers which can be used to identify individuals with depression and predict clinical outcome. We therefore examined the diagnostic and prognostic potential of pre-treatment structural neuroanatomy using support vector machine (SVM). Sixty-one drug-naïve adults suffering from depression and 42 healthy volunteers were scanned using structural magnetic resonance imaging (sMRI). Patients then received standard antidepressant medication (either tricyclic, typical serotonin-norepinephrine reuptake inhibitor or typical selective serotonin reuptake inhibitor). Based on clinical outcome, we selected two groups of RDD (n=23) and NDD (n=23) patients matched for age, sex and pre-treatment severity of depression. Diagnostic accuracy of gray matter was 67.39% for RDD (p=0.01) and 76.09% for NDD (p<0.001), while diagnostic accuracy of white matter was 58.70% for RDD (p=0.13) and 84.65% for NDD (p<0.001). SVM applied to gray matter correctly distinguished between RDD and NDD patients with an accuracy of 69.57% (p=0.006); in contrast, SVM applied to white matter predicted clinical outcome with an accuracy of 65.22% (p=0.02). These results indicate that both gray and white matter have diagnostic and prognostic potential in major depression and may provide an initial step towards the use of biological markers to inform clinical treatment. Future studies will benefit from the integration of structural neuroimaging with other imaging modalities as well as genetic, clinical and cognitive information.

Localization of cerebral functional deficits in treatment-naive, first-episode schizophrenia using resting-state fMRI

BACKGROUND Spontaneous low-frequency fluctuations (LFF) in the blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal have been shown to reflect cerebral spontaneous neural activity, and the present study attempts to explore the functional changes in the regional brain in patients with schizophrenia using the amplitude of the BOLD signals. METHODS A total of 66 treatment-naïve, first-episode schizophrenia (FES) patients and 66 normal age- and sex-matched controls were recruited. Resting-state fMRIs were obtained using a gradient-echo echo-planar imaging sequence. The amplitude of LFF (ALFF) was calculated using REST software. Voxel-based analysis of the ALFF maps between control and patient groups was performed with twos-sample t-tests using SPM2. RESULTS Compared to the controls, the FES group showed significantly decreased ALFF in the medial prefrontal lobe (MPFC) and significant increases in the ALFF in the left and right putamen. Significant positive correlations were observed between ALFF values in the bilateral putamen in both the patient and control groups. CONCLUSIONS Alterations of the ALFF in the MPFC and putamen in FES observed in the present study suggest that the functional abnormalities of those areas are at an early stage of the disease.

Abnormal small-world architecture of top–down control networks in obsessive–compulsive disorder

BACKGROUND Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disorder that is characterized by recurrent intrusive thoughts, ideas or images and repetitive ritualistic behaviours. Although focal structural and functional abnormalities in specific brain regions have been widely studied in populations with OCD, changes in the functional relations among them remain poorly understood. This study examined OCD-related alterations in functional connectivity patterns in the brains top-down control network. METHODS We applied resting-state functional magnetic resonance imaging to investigate the correlation patterns of intrinsic or spontaneous blood oxygen level-dependent signal fluctuations in 18 patients with OCD and 16 healthy controls. The brain control networks were first constructed by thresholding temporal correlation matrices of 39 brain regions associated with top-down control and then analyzed using graph theory-based approaches. RESULTS Compared with healthy controls, the patients with OCD showed decreased functional connectivity in the posterior temporal regions and increased connectivity in various control regions such as the cingulate, precuneus, thalamus and cerebellum. Furthermore, the brains control networks in the healthy controls showed small-world architecture (high clustering coefficients and short path lengths), suggesting an optimal balance between modularized and distributed information processing. In contrast, the patients with OCD showed significantly higher local clustering, implying abnormal functional organization in the control network. Further analysis revealed that the changes in network properties occurred in regions of increased functional connectivity strength in patients with OCD. LIMITATIONS The patient group in the present study was heterogeneous in terms of symptom clusters, and most of the patients with OCD were medicated. CONCLUSION Our preliminary results suggest that the organizational patterns of intrinsic brain activity in the control networks are altered in patients with OCD and thus provide empirical evidence for aberrant functional connectivity in the large-scale brain systems in people with this disorder.