Miao Chang

Neurobiological Commonalities and Distinctions Among Three Major Psychiatric Diagnostic Categories: A Structural MRI Study

BACKGROUND Schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) are distinct diagnostic categories in current psychiatric nosology, yet there is increasing evidence for shared clinical and biological features in these disorders. No previous studies have examined brain structural features concurrently in these 3 disorders. The aim of this study was to identify the extent of shared and distinct brain alterations in SZ, BD, and MDD. We examined gray matter (GM) volume and white matter (WM) integrity in a total of 485 individuals (135 with SZ, 86 with BD, 108 with MDD, and 156 healthy controls [HC]) who underwent high-resolution structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) at a single site. RESULTS Significant 4-group (SZ, BD, MDD, and HC groups) differences (P < .05, corrected) in GM volumes were found primarily in the paralimbic and heteromodal corticies. Post hoc analyses showed that the SZ, BD, and MDD groups shared GM volume decreases in 87.9% of the total regional volume with significant 4-group differences. Significant 4-group differences in WM integrity (P < .05 corrected) were found in callosal, limbic-paralimbic-hetermodal, cortico-cortical, thalamocortical and cerebellar WM. Post hoc analyses revealed that the SZ and BD groups shared WM alterations in all regions, while WM alterations were not observed with MDD. CONCLUSIONS Our findings of common alterations in SZ, BD, and MDD support the presence of core neurobiological disruptions in these disorders and suggest that neural structural distinctions between these disorders may be less prominent than initially postulated, particularly between SZ and BD.

Sexual dimorphism of the cerebellar vermis in schizophrenia.

Converging lines of evidence implicate structural and functional abnormalities in the cerebellum in schizophrenia (SCZ). The cerebellar vermis is of particular interest given its association with clinical symptoms and cognitive deficits in SCZ and its known connections with cortical regions such as the prefrontal cortex. Prior neuroimaging studies have shown structural and functional abnormalities in the vermis in SCZ. In this study, we examined the cerebellar vermis in 50 individuals with SCZ and 54 healthy controls (HC) using a quantitative volumetric approach. All participants underwent high-resolution structural magnetic resonance imaging (MRI). The vermis was manually traced for each participant, and vermis volumes were computed using semiautomated methods. Volumes for total vermis and vermis subregions (anterior and posterior vermis) were analyzed in the SCZ and HC groups. Significant diagnosis-by-sex interaction effects were found in total vermis and vermis subregion analyses. These effects appeared to be driven by significantly decreased posterior vermis volumes in males with SCZ. Exploratory analyses did not reveal significant effects of clinical variables (FEP status, illness duration, and BPRS total score and subscores) on vermis volumes. The findings herein highlight the presence of neural sex differences in SCZ and the need for considering sex-related factors in studying the disorder.

Disrupted structural and functional connectivity in prefrontal-hippocampus circuitry in first-episode medication-naïve adolescent depression

Background Evidence implicates abnormalities in prefrontal-hippocampus neural circuitry in major depressive disorder (MDD). This study investigates the potential disruptions in prefrontal-hippocampus structural and functional connectivity, as well as their relationship in first-episode medication-naïve adolescents with MDD in order to investigate the early stage of the illness without confounds of illness course and medication exposure. Methods Diffusion tensor imaging and resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 26 first-episode medication-naïve MDD adolescents and 31 healthy controls (HC). Fractional anisotropy (FA) values of the fornix and the prefrontal-hippocampus functional connectivity was compared between MDD and HC groups. The correlation between the FA value of fornix and the strength of the functional connectivity in the prefrontal cortex (PFC) region showing significant differences between the two groups was identified. Results Compared with the HC group, adolescent MDD group had significant lower FA values in the fornix, as well as decreased functional connectivity in four PFC regions. Significant negative correlations were observed between fornix FA values and functional connectivity from hippocampus to PFC within the HC group. There was no significant correlation between the fornix FA and the strength of functional connectivity within the adolescent MDD group. Conclusions First-episode medication-naïve adolescent MDD showed decreased structural and functional connectivity as well as deficits of the association between structural and functional connectivity shown in HC in the PFC-hippocampus neural circuitry. These findings suggest that abnormal PFC-hippocampus neural circuitry may present in the early onset of MDD and play an important role in the neuropathophysiology of MDD.

Trait-Related Cortical-Subcortical Dissociation in Bipolar Disorder: Analysis of Network Degree Centrality.

BACKGROUND Bipolar disorder is a systemic brain disorder. Accumulated evidence suggested that cortical-subcortical imbalance could be a trait-related pathogenic factor of bipolar disorder. Degree centrality, a robust index of focal connectivity in which the number of direct connections from one node to all nodes is counted, has not previously been studied in bipolar disorder as a whole. METHODS Resting state functional magnetic resonance imaging was performed on 52 patients with DSM-IV bipolar I disorder and 70 healthy controls recruited between September 2009 and July 2014. Degree centrality was calculated within cerebral gray matter for each subject and compared between patients with bipolar disorder and healthy controls. Hub distributions of both groups were explored. Effects of medication exposure and mood state on degree centrality, as well as cortical-subcortical degree centrality correlations, were explored. RESULTS Compared to healthy controls, patients with bipolar disorder exhibited significant decrease in degree centrality in cortical regions, including the middle temporal pole, inferior temporal gyrus, and ventral prefrontal cortex, but showed significant increase in degree centrality mainly in subcortical regions, including caudate, thalamus, parahippocampal gyrus, hippocampi, anterior cingulate, insula, and amygdala, and a small portion of cortical regions, such as superior and middle frontal gyrus (P < .05, corrected). Spatial distributions of the 2 groups were very similar. No significant effects of medication exposure or mood state on degree centrality were found. Patients with bipolar disorder also showed significant decrease in cortical-subcortical degree centrality correlation (P = .003). CONCLUSIONS These findings further contribute to the mounting evidence of cortical-subcortical dissociation in bipolar disorder pathophysiology. In addition, this study supports the continued development and implementation of graph-based techniques to enhance our understanding of the underlying neural mechanisms in mental disorders such as bipolar disorder, which are increasingly viewed as systemic brain disorders rather than disorders arising from disruption within a single structure or a limited number of structures. Due to the heterogeneity of our sample, as well as the small sample size of each medication and mood state subgroups, further investigation is needed to support our findings.

Amygdala-Prefrontal Cortex Resting-State Functional Connectivity Varies with First Depressive or Manic Episode in Bipolar Disorder.

BACKGROUND Bipolar disorder (BD) is one of the most complex mental illnesses, characterized by interactive depressive and manic states that are 2 contrary symptoms of disease states. The bilateral amygdala and prefrontal cortex (PFC) appear to play critical roles in BD; however, abnormalities seem to manifest differently in the 2 states and may provide further insight into underlying mechanisms. METHODS Sixteen participants with first-episode depressive and 13 participants with first-episode manic states of bipolar disorder as well as 30 healthy control (HC) participants underwent resting-state functional magnetic resonance imaging (fMRI). Resting-state functional connectivity (rsFC) between the bilateral amygdala and PFC was compared among the 3 groups. RESULTS Compared with depressive state participants of the BD group, manic state participants of the BD group showed a significant decrease in rsFC between the amygdala and right orbital frontal cortex (p<0.05, corrected). In addition, rsFC between the amygdala and left middle frontal cortex was significantly decreased in depressive and manic state participants of the BD group when compared with the HC group (p<0.05, corrected). CONCLUSIONS Our findings suggest that mood state during the first episodes of BD may be related to abnormality in hemispheric lateralization. The abnormalities in amygdala- left PFC functional connectivity might present the trait feature for BD, while deficits in amygdala- right PFC functional connectivity might be specific to manic episode, compared to depressive episode.

Voxel-Based Morphometry in Individuals at Genetic High Risk for Schizophrenia and Patients with Schizophrenia during Their First Episode of Psychosis

Background Understanding morphologic changes in vulnerable and early disease state of schizophrenia (SZ) may provide further insight into the development of psychosis. Method Whole brain voxel-based morphometry was performed to identify gray matter (GM) regional differences in 60 individuals with SZ during their first psychotic episode (FE-SZ), 31 individuals at genetic high risk for SZ (GHR-SZ) individuals, and 71 healthy controls. Results Significant differences were found in several regions including the prefrontal cortex, parietal lobe, temporal lobe, hippocampus, occipital lobe, and cerebellum among the three groups (p<0.05, corrected). Compared to the HC group, the FE-SZ group had significantly decreased GM volumes in several regions including the cerebellum, hippocampus, fusiform gyrus, lingual gyrus, supramarginal gyrus, and superior, middle, and inferior temporal gyri and significantly increased GM volumes in the middle frontal gyrus and inferior operculum frontal gyrus (p<0.05). The GHR-SZ group had significant decreases in GM volumes in the supramaginal gyrus, precentral gyrus, and rolandic operculum and significant increases in GM volumes in the cerebellum, fusiform gyrus, middle frontal gyrus, inferior operculum frontal gyrus, and superior, middle, and inferior temporal gyri when compared to the HC group (p<0.05). Compared to the GHR-SZ group, the FE-SZ group had significant decreases in GM volumes in several regions including the cerebellum, fusiform gyrus, supramarginal gyrus, and superior, middle, and inferior temporal gyri (p<0.05). Conclusions The findings herein implicate the involvement of multisensory integration in SZ development and pathophysiology. Additionally, the patterns of observed differences suggest possible indicators of disease, vulnerability, and resiliency in SZ.

Relationship between the LHPP Gene Polymorphism and Resting-State Brain Activity in Major Depressive Disorder

A single-nucleotide polymorphism at the LHPP gene (rs35936514) has been reported in genome-wide association studies to be associated with major depressive disorder (MDD). However, the neural system effects of rs35936514 that mediate the association are unknown. The present work explores whether the LHPP rs35936514 polymorphism moderates brain regional activity in MDD. A total of 160 subjects were studied: a CC group homozygous for the C allele (23 individuals with MDD and 57 controls) and a T-carrier group carrying the high risk T allele (CT/TT genotypes; 22 MDD and 58 controls). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Brain activity was assessed using the amplitudes of low-frequency fluctuations (ALFF). MDD patients showed a significant increased ALFF in the left middle temporal gyrus and occipital cortex. The T-carrier group showed increased ALFF in the left superior temporal gyrus. Significant diagnosis × genotype interaction was noted in the bilateral lingual gyri, bilateral dorsal lateral prefrontal cortex (dlPFC), and left medial prefrontal cortex (mPFC) (P < 0.05, corrected). Results demonstrated that MDD patients with LHPP rs35936514 CT/TT genotype may influence the regional brain activity. These findings implicate the effects of the rs35936514 variation on the neural system in MDD.

Alteration of cortico-limbic-striatal neural system in major depressive disorder and bipolar disorder

BACKGROUND It is often difficult to differentiate major depressive disorder (MDD) and bipolar disorder (BD) merely according to clinical symptoms. Similarities and differences in neural activity between the two disorders remain unclear. In current study, we use amplitude of low-frequency fluctuations (ALFF) to compare neural activation changes between MDD and BD patients. METHODS One hundred and eighty-three adolescents and young adults (57 MDD, 46 BD and 80 healthy controls, HC) were scanned during resting state. The ALFF for each participant was calculated, and were then compared among all groups using voxel-based analysis. RESULTS There was a significant effect of diagnosis in the core regions of cortico-limbic-striatal neural system. Furthermore, MDD showed left-sided abnormal neural activity while BD showed a bilateral abnormality in this neural system. LIMITATIONS This study was underpowered to consider medications, mood states and neural developmental effects on the neural activation. CONCLUSIONS Differences in lateralization of ALFF alterations were found. Alterations predominated in the left hemisphere for MDD, whereas alterations were bilateral for BD.

Similarities and differences of functional connectivity in drug-naïve, first-episode adolescent and young adult with major depressive disorder and schizophrenia

Major depressive disorder (MDD) and schizophrenia (SZ) are considered two distinct psychiatric disorders. Yet, they have considerable overlap in symptomatology and clinical features, particularly in the initial phases of illness. The amygdala and prefrontal cortex (PFC) appear to have critical roles in these disorders; however, abnormalities appear to manifest differently. In our study forty-nine drug-naïve, first-episode MDD, 45 drug-naïve, first-episode SZ, and 50 healthy control (HC) participants from 13 to 30 years old underwent resting-state functional magnetic resonance imaging. Functional connectivity (FC) between the amygdala and PFC was compared among the three groups. Significant differences in FC were observed between the amygdala and ventral PFC (VPFC), dorsolateral PFC (DLPFC), and dorsal anterior cingulated cortex (dACC) among the three groups. Further analyses demonstrated that MDD showed decreased amygdala-VPFC FC and SZ had reductions in amygdala-dACC FC. Both the diagnostic groups had significantly decreased amygdala-DLPFC FC. These indicate abnormalities in amygdala-PFC FC and further support the importance of the interaction between the amygdala and PFC in adolescents and young adults with these disorders. Additionally, the alterations in amygdala-PFC FC may underlie the initial similarities observed between MDD and SZ and suggest potential markers of differentiation between the disorders at first onset.

Comparing abnormalities of amplitude of low-frequency fluctuations in multiple system atrophy and idiopathic Parkinson's disease measured with resting-state fMRI

Multiple system atrophy (MSA) and Idiopathic Parkinsons disease (IPD) show overlapping clinical manifestations with different treatment and prognosis. However, the shared and distinct underlying neural substrates are not yet understood, which needs to be explored between MSA and IPD. Resting-state functional magnetic resonance imaging data were collected from 29 MSA patients, 17 IPD patients and 25 healthy controls (HC) and the Amplitude of Low-Frequency Fluctuations (ALFF) was compared. Lower ALFF in bilateral basal ganglion, bilateral ventrolateral prefrontal cortex and right amygdala, as well as higher ALFF in parieto-temporo-occipital cortex and right cerebellum was shared between both patient groups to compare with HC. In contrast to IPD, decreased or increased ALFF in different regions of visual associative cortices and decreased ALFF in right cerebellum were found in MSA group. Our findings suggested shared and distinct spontaneous brain activity abnormalities in striato-thalamo-cortical (STC) loop, default mood network, visual associative cortices and cerebellum were present in MSA and IPD, which may help to explain similar clinical symptoms in both disorders but a more severe illness prognosis in MSA. Further research is needed to better describe the functional role of the cerebellum and visual associative cortices in early stages of MSA and IPD.