Feng Bi

Early-Course Unmedicated Schizophrenia Patients Exhibit Elevated Prefrontal Connectivity Associated with Longitudinal Change

Strong evidence implicates prefrontal cortex (PFC) as a major source of functional impairment in severe mental illness such as schizophrenia. Numerous schizophrenia studies report deficits in PFC structure, activation, and functional connectivity in patients with chronic illness, suggesting that deficient PFC functional connectivity occurs in this disorder. However, the PFC functional connectivity patterns during illness onset and its longitudinal progression remain uncharacterized. Emerging evidence suggests that early-course schizophrenia involves increased PFC glutamate, which might elevate PFC functional connectivity. To test this hypothesis, we examined 129 non-medicated, human subjects diagnosed with early-course schizophrenia and 106 matched healthy human subjects using both whole-brain data-driven and hypothesis-driven PFC analyses of resting-state fMRI. We identified increased PFC connectivity in early-course patients, predictive of symptoms and diagnostic classification, but less evidence for “hypoconnectivity.” At the whole-brain level, we observed “hyperconnectivity” around areas centered on the default system, with modest overlap with PFC-specific effects. The PFC hyperconnectivity normalized for a subset of the sample followed longitudinally (n = 25), which also predicted immediate symptom improvement. Biologically informed computational modeling implicates altered overall connection strength in schizophrenia. The initial hyperconnectivity, which may decrease longitudinally, could have prognostic and therapeutic implications.

Altered Cortical Thickness Related to Clinical Severity But Not the Untreated Disease Duration in Schizophrenia

Although previous studies have reported deficits in the gray matter volume of schizophrenic patients, it remains unclear whether these deficits occur at the onset of the disease, before treatment, and whether they are progressive over the duration of untreated disease. Furthermore, the gray matter volume represents the combinations of cortical thickness and surface area; these features are believed to be influenced by different genetic factors. However, cortical thickness and surface area in antipsychotic-naive first-episode schizophrenic patients have seldom been investigated. Here, the cortical thicknesses and surface areas of 128 antipsychotic-naive first-episode schizophrenic patients were compared with 128 healthy controls. The patients exhibited significantly lower cortical thickness, primarily in the bilateral prefrontal and parietal cortex, and increased thickness in the bilateral anterior temporal lobes, left medial orbitofrontal cortex, and left cuneus. Furthermore, decreased cortical thickness was related to positive schizophrenia symptoms but not to the severity of negative symptoms and the untreated disease duration. No significant difference of surface area was observed between the 2 groups. Thus, without the confounding factors of medication and illness progression, this study provides further evidence to support anatomical deficits in the prefrontal and parietal cortex early in course of the illness. The increased thicknesses of the bilateral anterior temporal lobes may represent a compensatory factor or may be an early-course neuronal pathology caused by preapoptotic osmotic changes or hypertrophy. Furthermore, these anatomical deficits are crucial to the pathogenesis of positive symptoms and relatively stable instead of progressing during the early stages of the disease.

Two Patterns of White Matter Abnormalities in Medication-Naive Patients With First-Episode Schizophrenia Revealed by Diffusion Tensor Imaging and Cluster Analysis.

IMPORTANCE Accumulating evidence supports the hypothesis that cerebral white matter abnormalities are involved in the pathophysiology of schizophrenia; however, findings from in vivo neuroimaging studies have been inconsistent. Besides confounding factors, including age, illness duration, and medication effects, an additional cause for the inconsistent results may be heterogeneity in the nature of white matter alterations associated with the disorder. OBJECTIVE To investigate whether different patterns of white matter abnormalities exist in a large cohort of medication-naive patients with first-episode schizophrenia and the relationship between such patterns and clinical parameters. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional diffusion tensor imaging study of 113 medication-naive patients with first-episode schizophrenia and 110 demographically matched healthy control individuals. The study was conducted in the mental health center of West China Hospital, Sichuan University, Chengdu, China, from January 2006 to June 2014. MAIN OUTCOMES AND MEASURES The patterns of white matter abnormalities revealed by tract-specific analysis in conjunction with hierarchical clustering. RESULTS With diffusion features extracted from 18 fiber tracts, cluster analysis revealed 2 patterns of abnormalities. One pattern (42.5% of patient sample) showed widespread white matter abnormalities compared with matched healthy control individuals, while another pattern (57.5% of patient sample) only showed circumscribed regional white matter abnormalities, mainly in the left superior longitudinal fasciculus. Patients in these subgroups did not differ in demographic features; however, negative symptoms were more severe in patients with widespread white matter abnormalities. CONCLUSIONS AND RELEVANCE Two distinct patterns of white matter abnormalities exist at the early phase of schizophrenia, with those having global abnormalities experiencing more severe negative symptoms. The finding that distinct subgroups of patients with schizophrenia have different forms of white matter pathology may reflect qualitatively distinct genetic influences or neurodevelopmental alterations and thus represents a promising strategy for resolving neurobiological heterogeneity in the schizophrenia syndrome.

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.

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.

White Matter Abnormalities in Post-traumatic Stress Disorder Following a Specific Traumatic Event

Studies of posttraumatic stress disorder (PTSD) are complicated by wide variability in the intensity and duration of prior stressors in patient participants, secondary effects of chronic psychiatric illness, and a variable history of treatment with psychiatric medications. In magnetic resonance imaging (MRI) studies, patient samples have often been small, and they were not often compared to similarly stressed patients without PTSD in order to control for general stress effects. Findings from these studies have been inconsistent. The present study investigated whole-brain microstructural alterations of white matter in a large drug-naive population who survived a specific, severe traumatic event (a major 8.0-magnitude earthquake). Using diffusion tensor imaging (DTI), we explored group differences between 88 PTSD patients and 91 matched traumatized non-PTSD controls in fractional anisotropy (FA), as well as its component elements axial diffusivity (AD) and radial diffusivity (RD), and examined these findings in relation to findings from deterministic DTI tractography. Relations between white matter alterations and psychiatric symptom severity were examined. PTSD patients, relative to similarly stressed controls, showed an FA increase as well as AD and RD changes in the white matter beneath left dorsolateral prefrontal cortex and forceps major. The observation of increased FA in the PTSD group suggests that the pathophysiology of PTSD after a specific acute traumatic event is distinct from what has been reported in patients with several years duration of illness. Alterations in dorsolateral prefrontal cortex may be an important aspect of illness pathophysiology, possibly via the regions established role in fear extinction circuitry. Use-dependent myelination or other secondary compensatory changes in response to heightened demands for threat appraisal and emotion regulation may be involved.

Intrinsic disruption of white matter microarchitecture in first-episode, drug-naive major depressive disorder: A voxel-based meta-analysis of diffusion tensor imaging.

&NA; Previous studies have demonstrated the influences of episodes and antidepressant drugs on white matter (WM) in patients with major depressive disorder (MDD). However, most diffusion tensor imaging (DTI) studies included highly heterogeneous individuals with different numbers of depressive episodes or medication status. To exclude the confounding effects of multiple episodes or medication, we conducted a quantitative voxel‐based meta‐analysis of fractional anisotropy (FA) in patients with first‐episode, drug‐naive MDD to identify the intrinsic WM alterations involved in the pathogenesis of MDD. The pooled meta‐analysis revealed significant FA reductions in the body of the corpus callosum (CC), bilateral anterior limb of the internal capsule (ALIC), right inferior temporal gyrus (ITG) and right superior frontal gyrus (SFG) in MDD patients relative to healthy controls. Meta‐regression analyses revealed that FA reduction in the right ALIC and right SFG was negatively correlated with symptom severity and duration of depression, respectively. Our findings provide robust evidence that the WM impairments in the interhemispheric connections and frontal‐subcortical neuronal circuits may play an important role in MDD pathogenesis.

Posttraumatic Stress Disorder: Structural Characterization with 3-T MR Imaging

Purpose To explore cerebral alterations related to the emergence of posttraumatic stress disorder (PTSD) by using three-dimensional T1-weighted imaging and also to explore the relationship of gray and white matter abnormalities and the anatomic changes with clinical severity and duration of time since the trauma. Materials and Methods Informed consent was provided, and the prospective study was approved by the ethics committee of the West China Hospital. Recruited were 67 patients with PTSD and 78 adult survivors without PTSD 7-15 months after a devastating earthquake in western China. All participants underwent magnetic resonance (MR) imaging with a 3-T imager to obtain anatomic images. Cortical thickness and volumes of 14 subcortical gray matter structures and five subregions of the corpus callosum were analyzed with software. Statistical differences between patients with PTSD and healthy survivors were evaluated with a general linear model. Averaged data from the regions with volumetric or cortical thickness differences between groups were extracted in each individual to examine correlations between morphometric measures and clinical profiles. Results Patients with PTSD showed greater cortical thickness in the right superior temporal gyrus, inferior parietal lobule, and left precuneus (P < .05; Monte Carlo null-z simulation corrected) and showed reduced volume in the posterior portion of the corpus callosum (F = 6.167; P = .014) compared with healthy survivors of the earthquake. PTSD severity was positively correlated with cortical thickness in the left precuneus (r = 0.332; P = .008). The volumes of posterior corpus callosum were negatively correlated with PTSD ratings in all survivors (r = -0.210; P = .013) and with cortical thickness of the left precuneus in patients with PTSD (r = -0.302; P = .017). Conclusion Results indicate that patients with PTSD had alterations in both cerebral gray matter and white matter compared with individuals who experienced similar psychologic trauma from the same stressor. Importantly, early in the course of PTSD, gray matter changes were in the form of increased, not decreased, cortical thickness, which may have resulted from neuroinflammatory or other trophic process related to endocrine changes or functional compensation. (©) RSNA, 2016.

Sex differences in intrinsic brain functional connectivity underlying human shyness

Shyness is a fundamental trait associated with social-emotional maladaptive behaviors, including many forms of psychopathology. Neuroimaging studies have demonstrated that hyper-responsivity to social and emotional stimuli occurs in the frontal cortex and limbic system in shy individuals, but the relationship between shyness and brain-wide functional connectivity remains incompletely understood. Using resting-state functional magnetic resonance imaging, we addressed this issue by exploring the relationship between regional functional connectivity strength (rFCS) and scores of shyness in a cohort of 61 healthy young adults and controlling for the effects of social and trait anxiety scores. We observed that the rFCS of the insula positively correlated with shyness scores regardless of sex. Furthermore, we found that there were significant sex-by-shyness interactions in the dorsal anterior cingulate cortex and insula (two core nodes of the salience network) as well as the subgenual anterior cingulate cortex: the rFCS values of these regions positively correlated with shyness scores in females but negatively correlated in males. Taken together, we provide evidence for intrinsic functional connectivity differences in individuals with different degrees of shyness and that these differences are sex-dependent. These findings might have important implications on the understanding of biological mechanisms underlying emotional and cognitive processing associated with shyness.

Microstructural Abnormalities in Children with Post-traumatic Stress Disorder: A Diffusion Tensor Imaging Study at 3.0T

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder characterized by re-experiencing, avoidance and hyperarousal. Brain microstructure abnormalities in PTSD, especially in children, are not yet well characterized. The aim of this study was to use MR diffusion tensor imaging (DTI) to identify brain microstructure alterations in children with PTSD compared to non-PTSD controls who experienced the same time-limited trauma. We studied 27 children with PTSD and 24 age- and gender-matched traumatized controls without PTSD, who all experienced the 2008 Sichuan major earthquake. DTI data were acquired and analyzed in terms of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD). Children with PTSD showed an abnormal pattern, not only of FA, but also of the diffusivity measures MD, AD and RD. Most of the abnormal brain regions belonged to two important networks: the default-mode network, including precuneus and angular gyrus, and the salience network, including insula, putamen and thalamus. This DTI study identifies microstructural abnormalities of children with PTSD after a major earthquake, our results are consistent with the suggestion that pediatric PTSD is accompanied by a connectivity disequilibrium between the salience and default-mode networks, a finding of potential pathophysiological significance.