Pathogenesis Of Bipolar Disorder Research Articles

The neural correlates of guilt highlight preclinical manifestations between bipolar and major depressive disorders.

Over 25% of bipolar disorder (BD) patients are misdiagnosed with major depressive disorder (MDD). An urgent need exists for a biomarker to differentiate BD from MDD. Various manifestations and intensities of maladaptive guilt processing might uniquely contribute to the pathogenesis of BD compared to MDD. This study adopted a first-person perspective guilt-provoking functional magnetic resonance imaging (fMRI) task, respectively induced by painful and ambiguous scenarios in 111 individuals: 35 with remitted MDD, 38 with remitted bipolar I disorder (BD-I), and 38 matched controls. A significant interaction between group and sense of agency in predicting guilt ratings for ambiguous, rather than painful, scenarios. The association between sense of agency and guilt was significant in MDD but not in BD-I patients or controls. Activation in the dorsomedial prefrontal cortex (dmPFC), pregenual anterior cingulate cortex (pgACC), and right inferior parietal lobule (IPL) was higher in BD-I than MDD subjects in response to ambiguous scenarios, whereas these were comparable to painful ones. The correlation between guilt ratings and activation in the dorsal anterior cingulate cortex (dACC) to ambiguous scenarios was significant in MDD, but not in BD-I or controls. The results of the multivariate pattern classification analysis showed that in the ambiguous scenarios, the accuracy of using brain activation patterns in the dmPFC, pgACC, and IPL to distinguish between participants with MDD and BD-I was 70.0%, 71.5%, and 68.7%, respectively. An additional test of the classification model, employing a combined mask of the three ROIs to distinguish between the two mood disorders in ambiguous scenarios, achieved an accuracy of 78.6% and an AUC value of 0.84. Subjective reports and neural correlates of guilt in ambiguous social situations, as well as a sense of agency, could provide to be a potential biomarker to help distinguish between BD-I and MDD even in the remitted stage.

Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.

Bipolar disorder (BD) is a common psychiatric disorder characterized by alterations between manic/hypomanic and depressive states. Rare pathogenic copy number variations (CNVs) that overlap with exons of synaptic genes have been associated with BD. However, no study has comprehensively explored CNVs in synaptic genes associated with BD. Here, we evaluated the relationship between BD and rare CNVs that overlap with synaptic genes, not limited to exons, in the Japanese population. Using array comparative genome hybridization, we detected CNVs in 1839 patients with BD and 2760 controls. We used the Synaptic Gene Ontology database to identify rare CNVs that overlap with synaptic genes. Using gene-based analysis, we compared their frequencies between the BD and control groups. We also searched for synaptic gene sets related to BD. The significance level was set to a false discovery rate of 10%. The RNF216 gene was significantly associated with BD (odds ratio, 4.51 [95% confidence interval, 1.66-14.89], false discovery rate < 10%). The BD-associated CNV that corresponded with RNF216 also partially overlapped with the minimal critical region of the 7p22.1 microduplication syndrome. The integral component of the postsynaptic membrane (Gene Ontology:0099055) was significantly associated with BD. The CNV overlapping with the intron region of GRM5 in this gene set showed a nominal significant association between cases and controls (P < 0.05). We provide evidence that CNVs in RNF216 and postsynaptic membrane-related genes confer a risk of BD, contributing to a better understanding of the pathogenesis of BD.

Association of plasma arachidonic acid levels with a bipolar disorder and the effects of a FADS gene variant

Recent genome-wide association studies (GWASs) have identified fatty acid desaturase (FADS) genes, which code key enzymes involved in polyunsaturated fatty acid (PUFA) desaturation as susceptibility genes for bipolar disorder (BD). Several quantitative changes in PUFAs suggest their involvement in BD pathogenesis. Therefore, this study aimed to clarify the relationship between BD and PUFAs by conducting lipidomics covariating with the FADS gene variant (rs174550), which is associated with PUFA levels and BD susceptibility. The concentrations of 23 fatty acids were measured using plasma samples from the BD group (n = 535) and the control group (n = 107). Differences in each PUFA concentration ratio were compared between the two groups. Also, differences in each PUFA concentration ratio were compared for each genotype in rs174550. Our results showed that the BD group had significantly lower concentrations of linoleic acid (LA) (β = −0.36, p = 0.023) and arachidonic acid (AA) (β = −0.18, p = 0.013) than the control group. Concerning the effect of FADS on the PUFA concentration ratio, carriers of C-allele at rs174550 had significantly decreased γ-linolenic acid and AA concentration ratios. A previous GWAS reported that the presence of a C-allele at rs174550 increased the BD risk. This direction is consistent with the lipidomic results of the present study. In conclusion, both the FADS and BD were considered to regulate the AA concentration. Thus, as the FADS gene variant is crucial for conducting lipidomics of BD we believe that the allele frequency of FADS must be analyzed.

Serum Zonulin Level in Patients with Bipolar Disorder

Abstract Background Bipolar disorder is a chronic and recurrent condition, associated with significantly impaired functioning and reduced quality of life. Given the importance of immune system in the etiology of bipolar disorder, studies on the gut, the largest immune system in the body, represent an important area for research. A change in intestinal permeability may be considered biomarker of local or even distant immune-mediated disorders. Increased gut permeability allows the passage, through the intestinal epithelial layer, of macromolecules, toxins, and bacterial species (both pathogenic and commensal) that may trigger immune-mediated diseases in different systems. Zonulin is regarded as a non-invasive biomarker for intestinal permeability. This study aimed at assessment of the serum zonulin level in patients with bipolar disorder I and its relation with the severity of the symptoms of the disorder, the age of onset of the disorder, the frequency of relapses and response to therapeutic trials. Methods two hundred patients with bipolar I disorder, divided into one hundred patients in acute manic or depressive episode and one hundred patients in full remission were compared to one hundred age and sex matched healthy controls. The patients were administered Young Mania Rating Scale (YMRS) and Hamilton Depression Rating Scale (HDRS) to determine the severity of manic and depressive symptoms, respectively. Venous blood samples were collected, and serum zonulin was measured. Results The mean serum zonulin in patients was significantly higher than healthy controls. Serum zonulin levels was significantly higher in patients with acute episodes than patients in remission. Conclusion The current research indicates that zonulin is increased in patients with bipolar disorder and this finding may contribute to the role of intestinal permeability or BBB in the pathogenesis of bipolar disorder.

Single-cell multiomics analysis reveals cell/tissue-specific associations in bipolar disorder

This study investigates the cellular origin and tissue heterogeneity in bipolar disorder (BD) by integrating multiomics data. Four distinct datasets were employed, including single-cell RNA sequencing (scRNA-seq) data (embryonic and fetal brain, n = 8, 1,266 cells), BD Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) data (adult brain, n = 210), BD bulk RNA-seq data (adult brain, n = 314), and BD genome-wide association study (GWAS) summary data (n = 413,466). The integration of scRNA-seq data with multiomics data relevant to BD was accomplished using the single-cell disease relevance score (scDRS) algorithm. We have identified a novel brain cell cluster named ADCY1, which exhibits distinct genetic characteristics. From a high-resolution genetic perspective, glial cells emerge as the primary cytopathology associated with BD. Specifically, astrocytes were significantly related to BD at the RNA-seq level, while microglia showed a strong association with BD across multiple panels, including the transcriptome-wide association study (TWAS), ATAC-seq, and RNA-seq. Additionally, oligodendrocyte precursor cells displayed a significant association with BD in both ATAC-seq and RNA-seq panel. Notably, our investigation of brain regions affected by BD revealed significant associations between BD and all three types of glial cells in the dorsolateral prefrontal cortex (DLPFC). Through comprehensive analyses, we identified several BD-associated genes, including CRMP1, SYT4, UCHL1, and ZBTB18. In conclusion, our findings suggest that glial cells, particularly in specific brain regions such as the DLPFC, may play a significant role in the pathogenesis of BD. The integration of multiomics data has provided valuable insights into the etiology of BD, shedding light on potential mechanisms underlying this complex psychiatric disorder.

Can retinal nerve fiber layer (RNFL) thickness be a marker for distinguishing bipolar depression from unipolar depression?

Objective We aimed to compare retinal nerve fiber layer (RNFL) thickness and ganglion cell complex (GCC) thickness in bipolar disorder (BD) and major depressive disorder (MDD). Method The study included thirty MDD, thirty-two BD participants in depressive episode, and thirty-seven controls matched according to age, gender, body mass index (BMI), and smoking status. Optic coherence tomography (OCT) measurements were performed for both participants and controls. The RNFL and GCC thickness were measured and recorded automatically by a spectral OCT device. Participants were also subjected to Hamilton Depression Rating Scale (HAM-D). Results RNFL superior thickness was significantly lower in BD participants, compared to the MDD participants and controls (p = 0.001). GCC inferior (p = 0.022) and inferonasal (p = 0.005) thickness were detected lower in BD group, compared to the control groups. In the BD group, HAM-D scores were negatively correlated with RNFL-temporal (p = 0.049, r= −0.357), GCC inferotemporal (p = 0.02, r= −0.416) and superotemporal thickness (p = 0.002, r= −0.546). Conclusions RNFL thickness were lower in BD participants compared to the MDD and controls and, GCC thickness were lower in BD participants compared to the controls. Our findings support the hypothesis that neurodegeneration is part of the pathogenesis of BD. Future research are needed to confirm the lack of RNFL thickness in MDD, which could have immediate therapeutic consequences as well as implications for distinguishing BD from MDD.

Improving Quality of Life in Bipolar Disorders with an Immersive Virtual Reality Remediation Training Randomized Controlled Trial (RCT).

Background: Health-related quality of life (H-QoL) is a critical measure in bipolar disorder (BD). Recent trials using virtual reality (VR) have shown potential in improving H-QoL. However, VR's effect on the H-QoL of people with BD needs to be further explored. Methods: This study involved a secondary analysis of a feasibility randomized controlled trial, focusing on "quality of life". Participants (aged 18-75) diagnosed with bipolar disorder were randomized into two groups. The experimental group used the CEREBRUM VR app, while the control group received the usual care. Quality of life was assessed using the Short-Form Health Survey (SF-12). Results: A total of 39 individuals in the experimental group and 25 in the control group represent the final samples. The results showed a greater improvement in the SF-12 total score in the experimental group (8.7%) compared to the control group (F = 66.851 p < 0.0001), specifically in the dimension of physical activity limitation, emotional impact, concentration, pain, calmness, energy levels, discouragement, and social activities. Conclusions: This study demonstrated an improvement in QoL for individuals with BD following a VR intervention. As a feasibility study, this secondary outcome needs to be confirmed by further phase III studies. If confirmed, VR could offer valuable rehabilitation tools and insights into the pathogenesis and treatment of BD.

Concentration of HSPA1A and transthyretin proteins in the blood serum of patients with bipolar disorder

IntroductionInsufficient knowledge about the pathophysiological processes in bipolar disorder (BD) leads to difficulties in differentiating this disorder from other affective disorders. Quantitative analysis of serum protein profiles in BD expands our understanding of the pathophysiology of the disease and may aid in subsequent diagnosis. As a result of a previously conducted comparative mass spectrometric study of serum proteins in patients with depression, bipolar disorder and healthy donors, increased expression of Heat Shock 70kDa Protein1A (HSPA1A) and transthyretin was identified.ObjectivesDetermination of HSPA1A and transthyretin concentrations in the blood serum of patients with mental disorders.MethodsBlood serum of 28 patients with bipolar disorder aged 49 years [33;52], 30 patients with recurrent depressive disorder aged 40 years [31; 51] and 130 patients with schizophrenia aged 38 years [31;49], as well as 20 mentally and somatically healthy individuals aged 35 years [31;40] was studied. The amount of Heat shock protein 1A (HSPA1A) and Transthyretin (thyroxine and retinol transport protein) was determined using a Enzyme-linked Immunosorbent Assay Kit from Homo sapiens (Cloud-Clone Corp). Statistical data processing was carried out in the Statistica 12.0 program.ResultsA statistically significant (p = 0.016) increase in the level of HSPA1A was found in patients with BD (0.84 [0.59; 1.09] ng/ml), compared with healthy individuals (0.61 [0.51; 0.77] ng/ml). HSPA1A plays a pivotal role in the protein quality control system, ensuring the correct folding of proteins. It is known that this protein is involved in the embryonic development of the central nervous system, as well as in neuroprotection by preventing the death of neurons due to its anti-apoptotic properties. A statistically significant (p = 0.047) increase in the level of transthyretin was found in patients with BD 21.8 рg/ml, compared with healthy individuals 19.4 pg/ml. Transthyretin plays an important role in ensuring the normal state of the central nervous system and is involved in cognitive processes.ConclusionsThus, the HSPA1A and transthyretin are probably involved in the pathogenesis of BD and can be proposed as be proposed as an additional paraclinical criterion for differential diagnosis.Support by RSF №23-75-00023.Disclosure of InterestNone Declared

TAAR1 as a new target for the treatment of bipolar disorder: Anti-manic and anti-depressant activity of the novel agonist PCC0105004

Background: Bipolar disorder (BD) is a deleterious psychiatric disorder, and the available pharmacotherapies have limited efficacy with significant side effects. Trace amine-associated receptor 1 (TAAR1) is an emerging drug target for neuropsychiatric disorders such as schizophrenia and substance user disorders. However, it is unknown whether TAAR1 is involved in the pathogenesis of BD. This study examined the effects and underlying mechanisms of a novel TAAR1 agonist, PCC0105004, in a rat model of ouabain (OUA)-induced BD.Methods: Intracerebroventricular (ICV) administration of OUA-induced BD model was established. The in vitro cell-based cAMP assay was used to examine TAAR1 agonism of PCC0105004. The receptor specificity of PCC0105004 was determined by an off-target panel assay that included radioligand binding and enzymatic assays. The effects of PCC0105004 on manic-like and depressive-like behaviors were evaluated in the rat BD model. TAAR1-mediated signaling and oxidative stress parameters were biochemically determined in the prefrontal cortex and the hippocampus of rats.Results: Western blotting revealed reduced TAAR1 expression level in the prefrontal cortex but unchanged in the hippocampus in model rats. PCC0105004, a TAAR1 agonist with the agonism EC50 value of 0.06182 μM, attenuated the manic-like behaviors on the 7th day and the depressive-like behaviors on the 14th day at doses that did not affect locomotor activity in the BD rats. Mechanistically, PCC0105004 exerted its behavioral effects via the reduction of ROS damage through the phosphorylation activation of the TAAR1/Akt/GSK3β/BDNF signaling pathway.Conclusion: These results demonstrated the potential antimanic-like and antidepressant-like efficacy of a novel TAAR1 agonist PCC0105004 in rats and revealed its underlying molecular basis, which supports the possibility of TAAR1 agonists as candidate pharmacotherapeutics for BD.

A novel role of NK3 receptor signaling in bipolar disorder

Objective: Bipolar disorder (BD) affects more than 1% of the global population with limited therapeutic options. The neurokinin B (NKB)-neurokinin B receptor (NK3R) is involved in a variety of emotional activities. This study explored the role of NK3 receptor signaling in bipolar disorder.Materials and methods: In this study, a model of intracerebroventricular (ICV) administration of OUA-induced BD was used to investigate the possible role of NK3R signaling in BD. The involvement of NK3R in the expression of OUA-induced BD was assessed by genetically knocking down the NK3R-encoding TACR3 gene with shRNA approach in the hippocampus and systemic administration of a NK3R antagonist ESN364,. Biochemical techniques were used to examine the NK3R-associated signaling changes and the oxidative stress parameters in the hippocampus of BD rats.Result: The NK3R expression level was elevated in the hippocampus BD rats. Both TACR3 knockdown in the hippocampus and ESN364 treatment reversed the manic-like and depression-like behaviors in BD rats Inhibition of the NK3R signaling reversed oxidative stress-induced damage via upregulating the BDNF signaling pathway in the hippocampus.Conclusion: These results demonstrated that NK3R signaling plays a key role in the pathogenesis of BD and that pharmacological antagonist of NK3R such as ESN364 could represent a novel therapeutic strategy for the management of BD.

Functional Alterations in Patients with Bipolar Disorder and Their Unaffected First-Degree Relatives: Insight from Genetic, Epidemiological, and Neuroimaging Data.

Bipolar disorder (BD) profoundly affects cognitive and psychosocial functioning, leading to a significant illness burden on patients and their families. Genetic factors are predominant in the onset of bipolar disorder and functional impairments. This disorder exhibits a strong family aggregation, with heritability estimates reaching up to 80%. Individuals with BD often experience impaired functioning, especially in significant areas such as physical performance, sleep, cognition, interpersonal interactions, socioeconomic status, family and marital relationships, work and school performance, well-being, and life expectancy. However, patients with different subtypes exhibit significant heterogeneity in social functioning, cognition, and creativity levels. There are notable differences in psychosocial and cognitive function in their unaffected first-degree relatives (UFR) who do not suffer but may carry susceptibility genes compared to healthy control (HC) without a family history. The observations indicate common genetic structures between BD patients and their UFR, which results in varying degrees of functional abnormalities. Therefore, this article mainly provides evidence on cognition, creativity, and psychosocial functioning in patients with BD and their UFR to provide a more comprehensive understanding of this critical topic in the field of BD. By integrating various findings, including clinical data and neuroimaging studies, our article aims to provide insights and valuable information for a deeper exploration of the pathogenesis of BD and the development of more targeted therapeutic strategies in the future.

Enhanced Dynamic Laterality Based on Functional Subnetworks in Patients with Bipolar Disorder.

An ocean of studies have pointed to abnormal brain laterality changes in patients with bipolar disorder (BD). Determining the altered brain lateralization will help us to explore the pathogenesis of BD. Our study will fill the gap in the study of the dynamic changes of brain laterality in BD patients and thus provide new insights into BD research. In this work, we used fMRI data from 48 BD patients and 48 normal controls (NC). We constructed the dynamic laterality time series by extracting the dynamic laterality index (DLI) at each sliding window. We then used k-means clustering to partition the laterality states and the Arenas-Fernandez-Gomez (AFG) community detection algorithm to determine the number of states. We characterized subjects' laterality characteristics using the mean laterality index (MLI) and laterality fluctuation (LF). Compared with NC, in all windows and state 1, BD patients showed higher MLI in the attention network (AN) of the right hemisphere, and AN in the left hemisphere showed more frequent laterality fluctuations. AN in the left hemisphere of BD patients showed higher MLI in all windows and state 3 compared to NC. In addition, in the AN of the right hemisphere in state 1, higher MLI in BD patients was significantly associated with patient symptoms. Our study provides new insights into the understanding of BD neuropathology in terms of brain dynamic laterality.

The Cerebellum's Role in Affective Disorders: The Onset of Its Social Dimension.

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are the most frequent mental disorders whose indeterminate etiopathogenesis spurs to explore new aetiologic scenarios. In light of the neuropsychiatric symptoms characterizing Cerebellar Cognitive Affective Syndrome (CCAS), the objective of this narrative review is to analyze the involvement of the cerebellum (Cbm) in the onset of these conditions. It aims at detecting the repercussions of the Cbm activities on mood disorders based on its functional subdivision in vestibulocerebellum (vCbm), pontocerebellum (pCbm) and spinocerebellum (sCbm). Despite the Cbm having been, for decades, associated with somato-motor functions, the described intercellular pathways, without forgiving the molecular impairment and the alteration in the volumetric relationships, make the Cbm a new important therapeutic target for MDD and BD. Given that numerous studies have showed its activation during mnestic activities and socio-emotional events, this review highlights in the Cbm, in which the altered external space perception (vCbm) is strictly linked to the cognitive-limbic Cbm (pCbm and sCbm), a crucial role in the MDD and BD pathogenesis. Finally, by the analysis of the cerebellar activity, this study aims at underlying not only the Cbm involvement in affective disorders, but also its role in social relationship building.

Differential Expression of Proteins Associated with Bipolar Disorder as Identified Using the PeptideShaker Software.

The prevalence of bipolar disorder (BD) in modern society is growing rapidly, but due to the lack of paraclinical criteria, its differential diagnosis with other mental disorders is somewhat challenging. In this regard, the relevance of proteomic studies is increasing due to the development of methods for processing large data arrays; this contributes to the discovery of protein patterns of pathological processes and the creation of new methods of diagnosis and treatment. It seems promising to search for proteins involved in the pathogenesis of BD in an easily accessible material-blood serum. Sera from BD patients and healthy individuals were purified via affinity chromatography to isolate 14 major proteins and separated using 1D SDS-PAGE. After trypsinolysis, the proteins in the samples were identified via HPLC/mass spectrometry. Mass spectrometric data were processed using the OMSSA and X!Tandem search algorithms using the UniProtKB database, and the results were analyzed using PeptideShaker. Differences in proteomes were assessed via an unlabeled NSAF-based analysis using a two-tailed Bonferroni-adjusted t-test. When comparing the blood serum proteomes of BD patients and healthy individuals, 10 proteins showed significant differences in NSAF values. Of these, four proteins were predominantly present in BD patients with the maximum NSAF value: 14-3-3 protein zeta/delta; ectonucleoside triphosphate diphosphohydrolase 7; transforming growth factor-beta-induced protein ig-h3; and B-cell CLL/lymphoma 9 protein. Further exploration of the role of these proteins in BD is warranted; conducting such studies will help develop new paraclinical criteria and discover new targets for BD drug therapy.

Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder.

Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

Aberrant functional connectivity within and between brain networks in patients with early-onset bipolar disorder

ObjectiveThis study used independent component analysis (ICA) to investigate the connectivity patterns of resting-state functional large-scale brain networks in patients with early-onset bipolar disorder (BD). MethodsICA was used to extract brain functional network components from 43 early-onset BD patients and 21 healthy controls (HCs). Then, the functional connectivity (FC) and functional network connectivity (FNC) within and between the independent brain networks was calculated, and the correlation between the connectivity changes and neuropsychological scale was evaluated. ResultsCompared with HCs, FC increased in the right hippocampus and inferior temporal gyrus, and left triangular inferior frontal gyrus of the anterior default mode network (aDMN); right median cingulate and paracingulate gyri, and inferior parietal lobule of the posterior DMN (pDMN); and right precentral and postcentral gyrus of the sensorimotor network (SMN) in early-onset BD patients. However, FC decreased in the left superior frontal gyrus of the aDMN, left paracentral lobule of the SMN, and left lingual gyrus and calcarine of the visual network in early-onset BD patients. There was no significant correlation between FC values of differential brain regions within resting-state networks (RSNs) and neuropsychological scores (uncorrected p > 0.05). In addition, the FNC among the pDMN-auditory network, pDMN-visual network, left frontoparietal network (lFPN)-visual network, lFPN-aDMN and dorsal attention network-ventral attention network (DAN-VAN) were increased in early-onset BD patients. The zFNC of the pDMN-visual network was positively correlated with the anxiety/somatization score (r = 0.5833, p < 0.0001) and sleep disorders (r = 0.6150, p < 0.0001). The zFNC of the lFPN-aDMN was positively correlated with despair (r = 0.4505, p = 0.004 × 10 < 0.05 after Bonferroni correction). The zFNC of the DAN-VAN was positively correlated with cognitive impairment (r = 0.4598, p = 0.0032 × 10 < 0.05 after Bonferroni correction). The zFNC of the DAN-VAN showed a positive correlation trend with the Hamilton Depression Scale (HAMD) total score (r = 0.4404, p = 0.005 × 10 = 0.05 after Bonferroni correction). ConclusionsPatients with early-onset BD showed changes in a wide range of neural functional networks, involving changes in executive control, attention, perceptual regulation, cognition and other neural networks, which may provide new imaging evidence for understanding the pathogenesis of early-onset BD and for therapeutic intervention targets.

Evaluation of Serum Zonulin and Occludin Levels in Bipolar Disorder.

The etiology of bipolar disorder (BD) is still not fully understood. Little is currently known about the relationship between the interaction the gastrointestinal system and brain function and BD. Zonulin is the only known physiological modulator of tight junctions and is a biomarker for intestinal permeability (IP). Occludin is an integral transmembrane tight junction protein involved in the maintenance and assembly of such junctions. The current study aims to determine whether zonulin and occludin levels are altered in BD and whether they can serve as clinical biomarkers of disease. Forty-four patients with BD and 44 healthy controls were included in this study. The Young Mania Rating Scale (YMRS) was used to determine the severity of manic symptoms, while the Hamilton Depression Rating Scale (HDRS) was used to determine the severity of depressive symptoms, and the Brief Functioning Rating Scale (FAST) to assess functionality. Venous blood samples were taken from all participants and serum zonulin and occludin levels were measured. The mean serum zonulin and occludin levels of the patients were significantly higher compared to the healthy control group. There was no difference between manic, depressive, and euthymic patients in terms of zonulin and occludin levels. There was no correlation between the total number of attacks, duration of disease, YMRS, HDRS, FAST scores, and zonulin and occludin levels in the patient group. The groups were divided into three according to body mass index as normal, overweight, and obese. Zonulin and occludin levels increased as body mass index increased and were highest in the obese group. The study shows that zonulin and occludin levels in BD increase independently of the disease stage. Consideration of the role of IP in the pathogenesis of BD may be helpful in determining the appropriate treatment modality.

Multi-omics analysis of a drug-induced model of bipolar disorder in zebrafish

Emerging studies demonstrate that inflammation plays a crucial role in the pathogenesis of bipolar disorder (BD), but the underlying mechanism remains largely unclear. Given the complexity of BD pathogenesis, we performed high-throughput multi-omic profiling (metabolomics, lipidomics, and transcriptomics) of the BD zebrafish brain to comprehensively unravel the molecular mechanism. Our research proved that in BD zebrafish, JNK-mediated neuroinflammation altered metabolic pathways involved in neurotransmission. On one hand, disturbed metabolism of tryptophan and tyrosine limited the participation of the monoamine neurotransmitters serotonin and dopamine in synaptic vesicle recycling. On the other hand, dysregulated metabolism of the membrane lipids sphingomyelin and glycerophospholipids altered the synaptic membrane structure and neurotransmitter receptors (chrnα7, htr1b, drd5b, and gabra1) activity. Our findings revealed that disturbance of serotonergic and dopaminergic synaptic transmission mediated by the JNK inflammatory cascade was the key pathogenic mechanism in a zebrafish model of BD, provides critical biological insights into the pathogenesis of BD.

A pilot investigation of differential hydroxymethylation levels in patient-derived neural stem cells implicates altered cortical development in bipolar disorder.

Bipolar disorder (BD) is a chronic mental illness characterized by recurrent episodes of mania and depression and associated with social and cognitive disturbances. Environmental factors, such as maternal smoking and childhood trauma, are believed to modulate risk genotypes and contribute to the pathogenesis of BD, suggesting a key role in epigenetic regulation during neurodevelopment. 5-hydroxymethylcytosine (5hmC) is an epigenetic variant of particular interest, as it is highly expressed in the brain and is implicated in neurodevelopment, and psychiatric and neurological disorders. Induced pluripotent stem cells (iPSCs) were generated from the white blood cells of two adolescent patients with bipolar disorder and their same-sex age-matched unaffected siblings (n = 4). Further, iPSCs were differentiated into neuronal stem cells (NSCs) and characterized for purity using immuno-fluorescence. We used reduced representation hydroxymethylation profiling (RRHP) to perform genome-wide 5hmC profiling of iPSCs and NSCs, to model 5hmC changes during neuronal differentiation and assess their impact on BD risk. Functional annotation and enrichment testing of genes harboring differentiated 5hmC loci were performed with the online tool DAVID. Approximately 2 million sites were mapped and quantified, with the majority (68.8%) located in genic regions, with elevated 5hmC levels per site observed for 3' UTRs, exons, and 2-kb shorelines of CpG islands. Paired t-tests of normalized 5hmC counts between iPSC and NSC cell lines revealed global hypo-hydroxymethylation in NSCs and enrichment of differentially hydroxymethylated sites within genes associated with plasma membrane (FDR = 9.1 × 10-12) and axon guidance (FDR = 2.1 × 10-6), among other neuronal processes. The most significant difference was observed for a transcription factor binding site for the KCNK9 gene (p = 8.8 × 10-6), encoding a potassium channel protein involved in neuronal activity and migration. Protein-protein-interaction (PPI) networking showed significant connectivity (p = 3.2 × 10-10) between proteins encoded by genes harboring highly differentiated 5hmC sites, with genes involved in axon guidance and ion transmembrane transport forming distinct sub-clusters. Comparison of NSCs of BD cases and unaffected siblings revealed additional patterns of differentiation in hydroxymethylation levels, including sites in genes with functions related to synapse formation and regulation, such as CUX2 (p = 2.4 × 10-5) and DOK-7 (p = 3.6 × 10-3), as well as an enrichment of genes involved in the extracellular matrix (FDR = 1.0 × 10-8). Together, these preliminary results lend evidence toward a potential role for 5hmC in both early neuronal differentiation and BD risk, with validation and more comprehensive characterization to be achieved through follow-up study.

Magnesium and Zinc in Bipolar Disorders

Bipolar disorder ( BD ) is a severe and recurrent mood disorder. The influence of magnesium and zinc on animal behavior is certain and this has been experimentally demonstrated repeatedly. However, some clinical studies have positively correlated the decrease in the concentration of the two cations with a more severe symptomatology of BD, but in other cases no modified values ​​of the concentration of magnesium and zinc were found or no relationship was identified between these concentrations and the clinical manifestations of the disease. This diversity of results has various causes but the most important of these are: problems regarding the diagnosis of BP and the diagnostic criteria used; the phases of the disease in which the cationic concentrations were determined were different; determination of intracellular magnesium was rarely done; the different ages of the patients and different associated diseases influenced the interpretation of the results. In some studies, the administration of some mood modulators (sodium valproate, carbamazepine or quetiapine) in BD type I hospitalized adult patients during the maniacal episode has increased plasma zinc and erythrocyte magnesium concentration . Missing correlations between how long is the evolution of the disease and the levels of these cations. Existing date support the idea that a low level of magnesium and zinc play a role in pathogenesis of BD. The assertion of a definite beneficial role of the association of magnesium and zinc with mood modulators in BD therapy requires more clinical studies.