Frontostriatal circuitry and the tryptophan kynurenine pathway in major psychiatric disorders.

RATIONALE: An imbalance of the tryptophan kynurenine pathway (KP) commonly occurs in psychiatric disorders, though the neurocognitive and network-level effects of this aberration are unclear. OBJECTIVES: In this study, we examined the connection between dysfunction in the frontostriatal brain circuits, imbalances in the tryptophan kynurenine pathway (KP), and neurocognition in major psychiatric disorders. METHODS: Forty first-episode medication-naive patients with schizophrenia (SCZ), fifty patients with bipolar disorder (BD), fifty patients with major depressive disorder (MDD), and forty-two healthy controls underwent resting-state functional magnetic resonance imaging. Plasma levels of KP metabolites were measured, and neurocognitive function was evaluated. Frontostriatal connectivity and KP metabolites were compared between groups while controlling for demographic and clinical characteristics. Canonical correlation analyses were conducted to explore multidimensional relationships between frontostriatal circuits-KP and KP-cognitive features. RESULTS: Patient groups shared hypoconnectivity between bilateral ventrolateral prefrontal cortex (vlPFC) and left insula, with disorder-specific dysconnectivity in SCZ related to PFC, left dorsal striatum hypoconnectivity. The BD group had higher anthranilic acid and lower xanthurenic acid levels than the other groups. KP metabolites and ratios related to disrupted frontostriatal dysconnectivity in a transdiagnostic manner. The SCZ group and MDD group separately had high-dimensional associations between KP metabolites and cognitive measures. CONCLUSIONS: The findings suggest that KP may influence cognitive performance across psychiatric conditions via frontostriatal dysfunction.

The Role of Total White Blood Cell Count in Antipsychotic Treatment for Patients with Schizophrenia.

BACKGROUND: Total white blood cell count (TWBCc), an index of chronic and low-grade inflammation, is associated with clinical symptoms and metabolic alterations in patients with schizophrenia. The effect of antipsychotics on TWBCc, predictive values of TWBCc for drug response, and role of metabolic alterations require further study. METHODS: Patients with schizophrenia were randomized to monotherapy with risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, perphenazine or haloperidol in a 6-week pharmacological trial. We repeatedly measured clinical symptoms, TWBCc, and metabolic measures (body mass index, blood pressure, waist circumference, fasting blood lipids and glucose). We used mixed-effect linear regression models to test whether TWBCc can predict drug response. Mediation analysis to investigate metabolic alteration effects on drug response. RESULTS: At baseline, TWBCc was higher among patients previously medicated. After treatment with risperidone, olanzapine, quetiapine, perphenazine, and haloperidol, TWBCc decreased significantly (p < 0.05). Lower baseline TWBCc predicted greater reductions in Positive and Negative Syndrome Scale (PANSS) total and negative scores over time (p < 0.05). We found significant mediation of TWBCc for effects of waist circumference, fasting low-density lipoprotein cholesterol, and glucose on reductions in PANSS total scores and PANSS negative subscale scores (p < 0.05). CONCLUSION: TWBCc is affected by certain antipsychotics among patients with schizophrenia, with decreases observed following short-term, but increases following long-term treatment. TWBCc is predictive of drug response, with lower TWBCc predicting better responses to antipsychotics. It also mediates the effects of certain metabolic measures on improvement of negative symptoms. This indicates that the metabolic state may affect clinical manifestations through inflammation.

Multivariate classification based on large-scale brain networks during early abstinence predicted lapse among male detoxified alcohol-dependent patients.

Identifying biomarkers to predict lapse of alcohol-dependence (AD) is essential for treatment and prevention strategies, but remains remarkably challenging. With an aim to identify neuroimaging features for predicting AD lapse, 66 male AD patients during early-abstinence (baseline) after hospitalized detoxification underwent resting-state functional magnetic resonance imaging and were then followed-up for 6 months. The relevance-vector-machine (RVM) analysis on baseline large-scale brain networks yielded an elegant model for differentiating relapsing patients (n = 38) from abstainers, with the area under the curve of 0.912 and the accuracy by leave-one-out cross-validation of 0.833. This model captured key information about neuro-connectome biomarkers for predicting AD lapse.

The interactions between host genome and gut microbiome increase the risk of psychiatric disorders: Mendelian randomization and biological annotation.

BACKGROUND: The correlation between human gut microbiota and psychiatric diseases has long been recognized. Based on the heritability of the microbiome, genome-wide association studies on human genome and gut microbiome (mbGWAS) have revealed important host-microbiome interactions. However, establishing causal relationships between specific gut microbiome features and psychological conditions remains challenging due to insufficient sample sizes of previous studies of mbGWAS. METHODS: Cross-cohort meta-analysis (via METAL) and multi-trait analysis (via MTAG) were used to enhance the statistical power of mbGWAS for identifying genetic variants and genes. Using two large mbGWAS studies (7,738 and 5,959 participants respectively) and12 disease-specific studies from the Psychiatric Genomics Consortium (PGC), we performed bidirectional two-sample mendelian randomization (MR) analyses between microbial features and psychiatric diseases (up to 500,199 individuals). Additionally, we conducted downstream gene- and gene-set-based analyses to investigate the shared biology linking gut microbiota and psychiatric diseases. RESULTS: METAL and MTAG conducted in mbGWAS could boost power for gene prioritization and MR analysis. Increases in the number of lead SNPs and mapped genes were witnessed in 13/15 species and 5/10 genera after using METAL, and MTAG analysis gained an increase in sample size equivalent to expanding the original samples from 7% to 63%. Following METAL use, we identified a positive association between Bacteroides faecis and ADHD (OR, 1.09; 95 %CI, 1.02-1.16; P = 0.008). Bacteroides eggerthii and Bacteroides thetaiotaomicron were observed to be positively associated with PTSD (OR, 1.11; 95 %CI, 1.03-1.20; P = 0.007; OR, 1.11; 95 %CI, 1.01-1.23; P = 0.03). These findings remained stable across statistical models and sensitivity analyses. No genetic liabilities to psychiatric diseases may alter the abundance of gut microorganisms.Using biological annotation, we identified that those genes contributing to microbiomes (e.g., GRIN2A and RBFOX1) are expressed and enriched in human brain tissues. CONCLUSIONS: Our statistical genetics strategy helps to enhance the power of mbGWAS, and our genetic findings offer new insights into biological pleiotropy and causal relationship between microbiota and psychiatric diseases.

[Hippocampal Development Deviation and Its Relationship With Cognition in Major Psychiatric Disorders].

Objective: To investigate hippocampal development deviation and its association with cognition in patients with major psychiatric disorders (MPDs), including schizophrenia, bipolar disorder and major depressive disorder. Methods: The T1-weighted MRI data of 174 first-episode drug-naïve schizophrenia (FES) atients, 169 bipolar disorder (BD) patients, 184 major depressive disorder (MDD) patients, and 321 healthy controls were collected and their hippocampal volume was extracted after preprocessing with Freesurfer 5.3. A normative neurodevelopment model was applied to calculate the hippocampal deviation scores. Data on cognitive functions, including visual memory, attention, spatial working memory, were collected. Comparison by different sexes was made to identify difference between the hippocampal development deviation scores of the control group and those of the disease groups. We also investigated the moderating effect of age on the deviation score and explored the association between the deviation score and cognitive function. Results: The hippocampal development deviation scores of patients with MPDs were significantly lower than those of the healthy controls (false discovery rate [FDR]-P<0.05). Analysis of the moderating effect of age revealed lower deviation scores in young patients (<[25.83-28.56] yr.) and higher deviation scores in old patients (>[35.87-54.35] yr.) in comparison with those of the healthy controls. The right hippocampal deviation scores in male FES patients were positively correlated with the number of errors for tasks concerning spatial working memory ( r=0.32, FDR-P=0.04). Conclusion: Our findings suggest abnormal hippocampal development in MPDs patients and its different distribution in MPDs patients of different age groups. The hippocampal development deviation score may provide a new perspective for further understanding of etiology in MPDs.

Identifying transdiagnostic biological subtypes across schizophrenia, bipolar disorder, and major depressive disorder based on lipidomics profiles.

Emerging evidence has demonstrated overlapping biological abnormalities underlying schizophrenia (SCZ), bipolar disorder (BP), and major depressive disorder (MDD); these overlapping abnormalities help explain the high heterogeneity and the similarity of patients within and among diagnostic categories. This study aimed to identify transdiagnostic subtypes of these psychiatric disorders based on lipidomics abnormalities. We performed discriminant analysis to identify lipids that classified patients (N = 349, 112 with SCZ, 132 with BP, and 105 with MDD) and healthy controls (N = 198). Ten lipids that mainly regulate energy metabolism, inflammation, oxidative stress, and fatty acylation of proteins were identified. We found two subtypes (named Cluster 1 and Cluster 2 subtypes) across patients with SCZ, BP, and MDD by consensus clustering analysis based on the above 10 lipids. The distribution of clinical diagnosis, functional impairment measured by Global Assessment of Functioning (GAF) scales, and brain white matter abnormalities measured by fractional anisotropy (FA) and radial diffusivity (RD) differed in the two subtypes. Patients within the Cluster 2 subtype were mainly SCZ and BP patients and featured significantly elevated RD along the genu of corpus callosum (GCC) region and lower GAF scores than patients within the Cluster 1 subtype. The SCZ and BP patients within the Cluster 2 subtype shared similar biological patterns; that is, these patients had comparable brain white matter abnormalities and functional impairment, which is consistent with previous studies. Our findings indicate that peripheral lipid abnormalities might help identify homogeneous transdiagnostic subtypes across psychiatric disorders.

Patterns of Convergence and Divergence Between Bipolar Disorder Type I and Type II: Evidence From Integrative Genomic Analyses.

Aim: Genome-wide association studies (GWAS) analyses have revealed genetic evidence of bipolar disorder (BD), but little is known about the genetic structure of BD subtypes. We aimed to investigate the genetic overlap and distinction of bipolar type I (BD I) & type II (BD II) by conducting integrative post-GWAS analyses. Methods: We utilized single nucleotide polymorphism (SNP)-level approaches to uncover correlated and distinct genetic loci. Transcriptome-wide association analyses (TWAS) were then approached to pinpoint functional genes expressed in specific brain tissues and blood. Next, we performed cross-phenotype analysis, including exploring the potential causal associations between two BD subtypes and lithium responses and comparing the difference in genetic structures among four different psychiatric traits. Results: SNP-level evidence revealed three genomic loci, SLC25A17, ZNF184, and RPL10AP3, shared by BD I and II, and one locus (MAD1L1) and significant gene sets involved in calcium channel activity, neural and synapsed signals that distinguished two subtypes. TWAS data implicated different genes affecting BD I and II through expression in specific brain regions (nucleus accumbens for BD I). Cross-phenotype analyses indicated that BD I and II share continuous genetic structures with schizophrenia and major depressive disorder, which help fill the gaps left by the dichotomy of mental disorders. Conclusion: These combined evidences illustrate genetic convergence and divergence between BD I and II and provide an underlying biological and trans-diagnostic insight into major psychiatric disorders.

Serotonin 2A receptor polymorphism rs3803189 mediated by dynamics of default mode network: a potential biomarker for antidepressant early response.

BACKGROUND: Serotonin 2A receptors (HTR2A) play a crucial role in the therapeutic response to antidepressant. The activity of serotonergic system could modulate the connectivity of the default mode network (DMN) in human brain. Our research investigated the influence of the single nucleotide polymorphism (SNP) of HTR2A on the early treatment response of antidepressant and their relation to dynamic changes of DMN for the first time. METHODS: A total of 134 major depressive disorder patients and 95 healthy controls from two independent datasets were enrolled. All subjects have genotyped candidate HTR2A polymorphisms, dynamic brain parameters flexibility and integration were calculated according to the resting-state functional magnetic resonance imaging (rs-fMRI) at baseline. Patients received selective serotonin reuptake inhibitors (SSRIs) treatment with conventional dose in the next two weeks. RESULTS: We found the correlation of the risk-associated variant belonged to HTR2A polymorphism rs3803189 with the achievements of antidepressant early response, and also with the stronger dynamic changes of DMN. Further mediation analysis indicated that the bond between rs3803189 and antidepressant early response was mediated by the integration between the right angular gyrus (AG.R) and the subcortical network (SCN), which were validated over both the main and replication datasets. LIMITATIONS: Except the AG.R-SCN circuit, other factors which influence the relationship between rs3803189 and antidepressant therapy deserve to be explored further. Besides, heterogeneity of samples limited the power of the current result. CONCLUSIONS: Our findings provided a potential biomarker for individual treatment sensitivity and produced positive effects on revealing the complicated gene-brain-disorder relationship.

Aberrant functional connectivity between the suprachiasmatic nucleus and the superior temporal gyrus: Bridging RORA gene polymorphism with diurnal mood variation in major depressive disorder.

Diurnal mood variation (DMV), a common symptom of major depressive disorder (MDD), is associated with circadian related genes and dysregulation of the suprachiasmatic nucleus (SCN). Previous research confirmed that the RORA gene is involved in the regulation of circadian rhythms. In this study, we hypothesized that polymorphisms of RORA may affect DMV symptoms of MDD through functional changes in the SCN. A total of 208 patients diagnosed with depression and 120 control subjects were enrolled and underwent a resting-state functional magnetic resonance imaging (rs-fMRI). Blood samples were collected and genotyping of 9 RORA gene SNPs were performed using next-generation sequencing technology. Patients were categorized as an AA genotype or C allele carriers based on RORA rs72752802 polymorphism. SCN-seed functional connectivity (FC) was compared between the two groups and correlation with severity of DMV was analyzed. Finally, a mediation analysis was performed to further determine FC intermediary effects. We observed that rs72752802 was significantly associated with patients' DMV symptoms. C allele carriers of rs72752802 showed significantly decreased FC between the right SCN and right superior temporal gyrus (rSTG). This was also correlated with DMV symptoms. In addition, the rs72752802 SNP influenced DMV symptoms through intermediary effects of SCN-rSTG connectivity. The study presented here provides a neurological and genetic basis for understanding depressed patients experiencing DMV.

Discriminating Suicide Attempters and Predicting Suicide Risk Using Altered Frontolimbic Resting-State Functional Connectivity in Patients With Bipolar II Disorder.

Bipolar II disorder (BD-II) major depression episode is highly associated with suicidality, and objective neural biomarkers could be key elements to assist in early prevention and intervention. This study aimed to integrate altered brain functionality in the frontolimbic system and machine learning techniques to classify suicidal BD-II patients and predict suicidality risk at the individual level. A cohort of 169 participants were enrolled, including 43 BD-II depression patients with at least one suicide attempt during a current depressive episode (SA), 62 BD-II depression patients without a history of attempted suicide (NSA), and 64 demographically matched healthy controls (HCs). We compared resting-state functional connectivity (rsFC) in the frontolimbic system among the three groups and explored the correlation between abnormal rsFCs and the level of suicide risk (assessed using the Nurses' Global Assessment of Suicide Risk, NGASR) in SA patients. Then, we applied support vector machines (SVMs) to classify SA vs. NSA in BD-II patients and predicted the risk of suicidality. SA patients showed significantly decreased frontolimbic rsFCs compared to NSA patients. The left amygdala-right middle frontal gyrus (orbital part) rsFC was negatively correlated with NGASR in the SA group, but not the severity of depressive or anxiety symptoms. Using frontolimbic rsFCs as features, the SVMs obtained an overall 84% classification accuracy in distinguishing SA and NSA. A significant correlation was observed between the SVMs-predicted NGASR and clinical assessed NGASR (r = 0.51, p = 0.001). Our results demonstrated that decreased rsFCs in the frontolimbic system might be critical objective features of suicidality in BD-II patients, and could be useful for objective prediction of suicidality risk in individuals.

Brain functional abnormalities in the amygdala subregions is associated with anxious depression.

BACKGROUND: Functional neuroimaging studies have provided strong support for the critical role the amygdala plays in emotional processing. The amygdala is composed of three primary distinct nuclei that have different functions in emotional regulation. Anxious depression (AD) was considered as a common dimensional symptom of Major Depressive Disorder (MDD). However, the neuroimaging basis of this special MDD subtype remains largely unknown. Therefore, it is necessary to study the functional connectivity of the amygdala's subregions in AD patients. METHODS: Eighty-three patients with AD, 70 non-anxious depression (NAD) patients, and 62 healthy controls were collected. Age and gender were well-matched. The functional connectivity of three amygdala subregions, including centromedial (CM), laterobasal (LB), and superficial (SF), were compared among the AD, NAD, and HC groups. The correlation between functional connectivity in the amygdala subregions and the HAMD factor scores were further analyzed. RESULTS: Patients with AD showed decreased functional connectivity between the right CM/LB and the right middle frontal gyrus relative to the NAD group. The NAD patients showed decreased functional connectivity between the right precentral gyrus and the right CM/SF compared to the HC group. The functional connectivity between the right CM and the right middle frontal gyrus was negatively correlated with the anxiety/somatization factor. CONCLUSION: The functional connectivity between the right CM/LB and the right middle frontal gyrus might be the neurobiological mechanism of anxious depression. The FC between the right CM and the right middle frontal gyrus may help to explain the special clinical feature of the AD patients.

Early identification of bipolar from unipolar depression before manic episode: Evidence from dynamic rfMRI.

OBJECTIVE: Misdiagnosis of bipolar disorder (BD) as unipolar disorder (UD) may cause improper treatment strategy to be chosen, especially in the early stages of disease. The aim of this study was to characterize alterations in specific brain networks for depressed patients who transformed into BD (tBD) from UD. METHOD: The module allegiance from resting-fMRI by applying a multilayer modular method was estimated in 99 patients (33 tBD, 33 BD, 33 UD) and 33 healthy controls (HC). A classification model was trained on tBD and UD patients. HC was used to explore the functional declination patterns of BD, tBD, and UD. RESULTS: Based on our classification model, difference mainly reflected in default-mode network (DMN). Compared with HC, both BD and tBD focused on the difference of somatomotor network (SMN), while UD on the abnormity of DMN. The patterns of brain network between patients with BD and tBD were well-overlapped, except for cognitive control network (CCN). CONCLUSION: The functional declination of internal interaction in DMN was suggested to be useful for the identification of BD from UD in the early stage. The higher recruitment of DMN may predispose patients to depressive states, while higher recruitment of SMN makes them more sensitive to external stimuli and prone to mania. Furthermore, CCN may be a critical network for identifying different stages of BD, suggesting that the onset of mania in depressed patients is accompanied by CCN related cognitive impairments.

Abnormal Alterations of Regional Spontaneous Neuronal Activity in Inferior Frontal Orbital Gyrus and Corresponding Brain Circuit Alterations: A Resting-State fMRI Study in Somatic Depression.

Background: Major depressive disorders often involve somatic symptoms and have been found to have fundamental differences from non-somatic depression (NSD). However, the neural basis of this type of somatic depression (SD) is unclear. The aim of this study is to use the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses to examine the abnormal, regional, spontaneous, neuronal activity and the corresponding brain circuits in SD patients. Methods: 35 SD patients, 25 NSD patients, and 27 matched healthy controls were selected to complete this study. The ALFF and seed-based FC analyses were employed, and the Pearson correlation was determined to observe possible clinical relevance. Results: Compared with NSD, the SD group showed a significant ALFF increase in the right inferior temporal gyrus; a significant ALFF decrease in left hippocampus, right inferior frontal orbital gyrus and left thalamus; and a significant decrease in the FC value between the right inferior frontal orbital gyrus and the left inferior parietal cortex (p < 0.05, corrected). Within the SD group, the mean ALFF value of the right inferior frontal orbital gyrus was associated with the anxiety factor scores (r = -0.431, p = 0.010, corrected). Conclusions: Our findings suggest that abnormal differences in the regional spontaneous neuronal activity of the right inferior frontal orbital gyrus were associated with dysfunction patterns of the corresponding brain circuits during rest in SD patients, including the limbic-cortical systems and the default mode network. This may be an important aspect of the underlying mechanisms for pathogenesis of SD at the neural level.

TPH-2 Gene Polymorphism in Major Depressive Disorder Patients With Early-Wakening Symptom.

Background: Sleep disturbances, such as early wakening, are frequently observed in patients with major depressive disorder (MDD). The suprachiasmatic nuclei (SCN), which controls circadian rhythm, is innervated by the raphe nucleus, a region where Tryptophan hydroxylase-2 (TPH-2) gene is primarily expressed. Although TPH-2 is often implicated in the pathophysiology of depression, few studies have applied a genetic and imaging technique to investigate the mechanism of early wakening symptom in MDD. We hypothesized that TPH-2 variants could influence the function of SCN in MDD patients with early wakening symptom. Methods: One hundred and eighty five MDD patients (62 patients without early wakening and 123 patients with early wakening) and 64 healthy controls participated in this study. Blood samples were collected and genotyping of rs4290270, rs4570625, rs11178998, rs7305115, rs41317118, and rs17110747 were performed by next-generation sequencing (NGS) technology. Logistic regression model was employed for genetic data analysis using the PLINK software. Based on the allele type, rs4290270, which was significant in the early wakening MDD group, participants were categorized into two groups (A allele and T carrier). All patients underwent whole brain resting-state functional magnetic resonance imaging (rs-fMRI) scanning and a voxel-wise functional connectivity comparison was performed between the groups. Results: rs4290270 was significantly linked to MDD patients who exhibited early wakening symptom. The functional connectivities of the right SCN with the right fusiform gyrus and right middle frontal gyrus were increased in the T carrier group compared to the A allele group. In addition, the functional connectivities of the left SCN with the right lingual gyrus and left calcarine sulcus were decreased in the T carrier group compared to the A allele group. Conclusion: These findings suggested that the TPH-2 gene variant, rs4290270, affected the circadian regulating function of SCN. The altered functional connectivities, observed between the SCN and right fusiform gyrus, right middle frontal gyrus, the right lingual gyrus and left calcarine sulcus, could highlight the neural mechanism by which SCN induces sleep-related circadian disruption in T carrier MDD patients. Hence, rs4290270 could potentially serve as a reliable biomarker to identify MDD patients with early wakening symptom.