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.

RNFL thickness is lower in BD participants compared to the MDD and controls.GCC thickness were lower in BD participants compared to the controls.HAM-D scores are negatively correlated with RNFL temporal and, GCC inferotemporal and superotemporal thickness.

Neuroretinal Alterations in Schizophrenia and Bipolar Disorder: An Updated Meta-analysis.

Schizophrenia (SZ) and bipolar disorder (BD) are characterized by major symptomatic, cognitive, and neuroanatomical changes. Recent studies have used optical coherence tomography (OCT) to investigate retinal changes in SZ and BD, but their unique and shared changes require further evaluation. Articles were identified using PubMed and Google Scholar. 39 studies met the inclusion criteria. Diagnostic groups were proband (SZ/BD combined), SZ, BD, and healthy control (HC) eyes. Meta-analyses utilized fixed and random effects models when appropriate, and publication bias was corrected using trim-and-fill analysis ("meta" package in R). Results are reported as standardized mean differences with 95% CIs. Data from 3145 patient eyes (1956 SZ, 1189 BD) and 3135 HC eyes were included. Studies identified thinning of the peripapillary retinal nerve fiber layer (pRNFL, overall and in 2 subregions), m-Retina (overall and all subregions), mGCL-IPL, mIPL, and mRPE in SZ patients. BD showed thinning of the pRNFL (overall and in each subregion), pGCC, and macular Retina (in 5 subregions), but no changes in thickness or volume for the total retina. Neither SZ nor BD patients demonstrated significant changes in the fovea, mRNFL, mGCL, mGCC, mINL, mOPL, mONL, or choroid thicknesses. Moderating effects of age, illness duration, and smoking on retinal structures were identified. This meta-analysis builds upon previous literature in this field by incorporating recent OCT studies and examining both peripapillary and macular retinal regions with respect to psychotic disorders. Overall, this meta-analysis demonstrated both peripapillary and macular structural retinal abnormalities in people with SZ or BD compared with HCs.

Subcortical Volume Changes in Schizophrenia and Bipolar Disorder: A Quantitative MRI Study

SUMMARY: Volume abnormalities in subcortical structures, including the hippocampus, amygdala, thalamus, caudate, putamen, and globus pallidus have been observed in schizophrenia (SZ) and bipolar disorder (BD), not all individuals with these disorders exhibit such changes. In addition, the specific patterns and severity of volume changes may vary between individuals and at different stages of the disease. The study aims to compare the volumes of these subcortical structures between healthy subjects and individuals diagnosed with SZ or BD. Volumetric measurements of lateral ventricle, globus palllidus, caudate, putamen, hippocampus, and amygdale were made by MRI in 52 healthy subjects (HS), 33 patients with SZ, and 46 patients with BD. Automatic segmentation methods were used to analyze the MR images with VolBrain and MRICloud. Hippocampus, amygdala and lateral ventricle increased in schizophrenia and bipolar disorder patients in comparison with control subjects using MRIcloud. Globus pallidus and caudate volume increased in patients with schizophrenia and bipolar disorder compared control subjects using Volbrain. We suggested that our results will contribute in schizophrenia and bipolar disorder patients that assessment of the sub-cortical progression, pathology, and anomalies of subcortical brain compositions. In patients with psychiatric disorders, VolBrain and MRICloud can detect subtle structural differences in the brain.

Se han observado anomalías de volumen en las estructuras subcorticales, incluidos el hipocampo, la amígdala, el tálamo, el núcleo caudado, el putamen y el globo pálido, en la esquizofrenia (SZ) y el trastorno bipolar (BD); no todos los individuos con estos trastornos presentan tales cambios. Además, los patrones específicos y la gravedad de los cambios de volumen pueden variar entre individuos y en diferentes etapas de la enfermedad. El estudio tuvo como objetivo comparar los volúmenes de estas estructuras subcorticales entre sujetos sanos e individuos diagnosticados con SZ o BD. Se realizaron mediciones volumétricas del ventrículo lateral, globo pálido, núcleo caudado, putamen, hipocampo y amígdala mediante resonancia magnética en 52 sujetos sanos (HS), 33 pacientes con SZ y 46 pacientes con BD. Se utilizaron métodos de segmentación automática para analizar las imágenes de resonancia magnética con VolBrain y MRICloud. El hipocampo, la amígdala y el ventrículo lateral aumentaron en pacientes con esquizofrenia y trastorno bipolar en comparación con sujetos de control que utilizaron MRIcloud. El globo pálido y el núcleo caudado aumentaron en pacientes con esquizofrenia y trastorno bipolar en comparación con los sujetos control que utilizaron Volbrain. Sugerimos que en pacientes con esquizofrenia y trastorno bipolar, nuestros resultados contribuirán a la evaluación de la progresión subcortical, la patología y las anomalías de las composiciones cerebrales subcorticales. En pacientes con trastornos psiquiátricos, VolBrain y MRICloud pueden detectar diferencias estructurales sutiles en el cerebro.

Brain-derived subgroups of bipolar II depression associate with inflammation and choroid plexus morphology.

AIM: Elevated inflammation and larger choroid plexus (ChP) volume has been previously identified in mood disorders. Connections between inflammation, ChP, and clinical symptoms in bipolar II depression (BDII-D) are unclear. Data-driven clustering based on neuroanatomical phenotypes may help to elucidate neurobiological associations in BDII-D. METHODS: Inflammatory cytokines, clinical symptoms, and neuroanatomical features were assessed in 150 BDII-D patients. Sixty-eight cortical surface area (SA) and 19 subcortical volumes were extracted using FreeSurfer. The ChP volume was segmented manually using 3D Slicer. Regularized canonical correlation analysis was used to identify significantly correlated components between cortical SA and subcortical volumes (excluding the ChP), followed by k-means clustering to define brain-derived subgroups of BDII-D. Low-grade inflammation was derived by averaging the standardized z scores of interleukin (IL)-6, IL-1ß, and tumor necrosis factor-α (TNF-α), which were computed to create a composite z-value score. Partial Pearson correlations followed by multiple comparison correction were conducted to explore associations between inflammation, clinical symptoms, and ChP volume. RESULTS: Subgroup I demonstrated smaller subcortical volume and cortical SA, higher inflammation, and larger ChP volume compared with subgroup II. Greater ChP volume was associated with a higher low-grade inflammation (mean r = 0.289, q = 0.003), CRP (mean r = 0.249, q = 0.007), IL-6 (left r = 0.200, q = 0.03), and TNF-α (right r = 0.226, q = 0.01), while greater IL-1ß was significantly associated with severe depressive symptoms in BDII-D (r = 0.218, q = 0.045). CONCLUSIONS: Neuroanatomically-derived subgroups of BDII-D differed in their inflammation levels and ChP volume. These findings suggest an important role of elevated peripheral inflammation and larger ChP in BDII-D.

Social cognitive deficit is associated with visuomotor coordination impairment and dopamine transporter availability in euthymic bipolar disorder.

BACKGROUND: Extensive evidence has suggested functional connections between co-occurring visuomotor and social cognitive deficits in neuropsychiatric disorders; however, such association has not been studied in bipolar disorder (BD). We aimed to investigate the relationship between visuomotor coordination and social cognition in the euthymic stage of BD (euBD). Given the shared neurobiological underpinnings involving the dopaminergic system and corticostriatal circuitry, we hypothesized a positive correlation between social cognition and visuomotor coordination in euBD patients. METHODS: 40 euBD patients and 59 healthy control (HC) participants underwent evaluation of social (Diagnostic Analysis of Nonverbal Accuracy 2-Taiwan version (DANVA-2-TW)), non-social cognitive function and visuomotor coordination. A subgroup of participants completed single-photon emission computed tomography for striatal dopamine transporter (DAT) availability assessment. RESULTS: EuBD patients showed impaired nonverbal emotion recognition (ps ≤ 0.033) and poorer visuomotor coordination (ps < 0.003) compared to HC, with a positive correlation between these two abilities (r = 0.55, p < 0.01). However, after considering potential confounding factors, instead of visuomotor coordination, striatal DAT availability was a unique predictor of emotion recognition accuracy in euBD (beta = 0.33, p = 0.001). CONCLUSION: Our study result supported a functional association between social cognition and visuomotor coordination in euBD, with striatal dopaminergic dysfunction emerged as a crucial contributing factor in their interrelation.

Multi-study evaluation of neuroimaging-based prediction of medication class in mood disorders.

Clinicians often face a dilemma in diagnosing bipolar disorder patients with complex symptoms who spend more time in a depressive state than a manic state. The current gold standard for such diagnosis, the Diagnostic and Statistical Manual (DSM), is not objectively grounded in pathophysiology. In such complex cases, relying solely on the DSM may result in misdiagnosis as major depressive disorder (MDD). A biologically-based classification algorithm that can accurately predict treatment response may help patients suffering from mood disorders. Here we used an algorithm to do so using neuroimaging data. We used the neuromark framework to learn a kernel function for support vector machine (SVM) on multiple feature subspaces. The neuromark framework achieves up to 95.45% accuracy, 0.90 sensitivity, and 0.92 specificity in predicting antidepressant (AD) vs. mood stabilizer (MS) response in patients. We incorporated two additional datasets to evaluate the generalizability of our approach. The trained algorithm achieved up to 89% accuracy, 0.88 sensitivity, and 0.89 specificity in predicting the DSM-based diagnosis on these datasets. We also translated the model to distinguish responders to treatment from nonresponders with up to 70% accuracy. This approach reveals multiple salient biomarkers of medication-class of response within mood disorders.

Aberrant dynamic functional connectivity in corticostriatal circuitry in depressed bipolar II disorder with recent suicide attempt.

BACKGROUND: The underlying neurobiological mechanisms on suicidal behavior in bipolar disorder remain unclear. We aim to explore the mechanisms of suicide by detecting dynamic functional connectivity (dFC) of corticostriatal circuitry and cognition in depressed bipolar II disorder (BD II) with recent suicide attempt (SA). METHODS: We analyzed resting-state functional magnetic resonance imaging (fMRI) data from 68 depressed patients with BD-II (30 with SA and 38 without SA) and 35 healthy controls (HCs). The whole-brain dFC variability of corticostriatal circuitry was calculated using a sliding-window analysis. Their correlations with cognitive dysfunction were further detected. Support vector machine (SVM) classification tested the potential of dFC to differentiate BD-II with SA from HCs. RESULTS: Increased dFC variability between the right vCa and the right insula was found in SA compared to non-SA and HCs, and negatively correlated with speed of processing. Decreased dFC variability between the left dlPu and the right postcentral gyrus was found in non-SA compared to SA and HCs, and positively correlated with reasoning problem-solving. Both SA and non-SA exhibited decreased dFC variability between the right dCa and the left MTG, and between the right dlPu and the right calcarine when compared to HCs. SVM classification achieved an accuracy of 75.24 % and AUC of 0.835 to differentiate SA from non-SA, while combining the abnormal dFC features between SA and non-SA. CONCLUSIONS: Aberrant dFC variability of corticostriatal circuitry may serve as potential neuromarker for SA in BD-II, which might help to discriminate suicidal BD-II patients from non-suicidal patients and HCs.

Default mode network dynamic functional network connectivity predicts psychotic symptom severity.

Neuropsychiatric disorders affect millions of people worldwide every year. Recent studies showed that the symptomatic overlaps across neuropsychiatric disorders mislead schizophrenia and bipolar disorder diagnosis. Additionally, recent studies claimed that schizoaffective disorder as a condition overlapped with both schizophrenia and bipolar disorder. Since symptomatic overlap among these disorders causes misdiagnosis, a need for neuroimaging biomarkers differentiating these disorders for a more accurate diagnosis is crucial. This study investigates dynamics functional network connectivity (dFNC) in the default mode network (DMN) of schizophrenia, bipolar, and schizoaffective disorder patients and compares them with their relative and healthy control. Additionally, it explored whether DMN dFNC features can predict the symptom severity of these neuropsychiatric disorders. Here, we found that dFNC features can differentiate schizophrenia from bipolar disorder. At the same time, we did not see a significant difference between schizoaffective with other conditions. Additionally, we found dFNC features can predict symptom severity of these three conditions.

Cross-Disorder Analysis of Shared Genetic Components Between Cortical Structures and Major Psychiatric Disorders.

BACKGROUND AND HYPOTHESIS: Although large-scale neuroimaging studies have demonstrated similar patterns of structural brain abnormalities across major psychiatric disorders, the underlying genetic etiology behind these similar cross-disorder patterns is not well understood. STUDY DESIGN: We quantified the extent of shared genetic components between cortical structures and major psychiatric disorders (CS-MPD) by using genome-wide association study (GWAS) summary statistics of 70 cortical structures (surface area and thickness of the whole cortex and 34 cortical regions) and five major psychiatric disorders, consisting of attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Cross-disorder analyses were then conducted to estimate the degree of similarity in CS-MPD shared genetic components among these disorders. STUDY RESULTS: The CS-MPD shared genetic components have medium-to-strong positive correlations in ADHD, BD, MDD, and SCZ (r = 0.415 to r = 0.806) while ASD was significantly correlated with ADHD, BD, and SCZ (r = 0.388 to r = 0.403). These pairwise correlations of CS-MPD shared genetic components among disorders were significantly associated with corresponding cross-disorder similarities in cortical structural abnormalities (r = 0.668), accounting for 44% variance. In addition, one latent shared factor consisted primarily of BD, MDD, and SCZ, explaining 62.47% of the total variance in CS-MPD shared genetic components of all disorders. CONCLUSIONS: The current results bridge the gap between shared cross-disorder heritability and shared structural brain abnormalities in major psychiatric disorders, providing important implications for a shared genetic basis of cortical structures in these disorders.

Common brain cortical abnormality in smoking behavior and bipolar disorder: discriminant analysis using cortical thickness and surface area.

Cigarette smoking is highly prevalent among patients with bipolar disorder (BD). Structural brain abnormalities related to smoking behavior and BD risk are indicated by magnetic resonance imaging (MRI) studies. However, cortical alterations common to smoking behavior and BD remain unclear. Our purpose was to identify common cortical alterations between smoking behavior and BD. 3T MRI-based indices of cortical thickness and surface area using FreeSurfer were acquired from 166 healthy control (HC) nonsmokers, 39 HC smokers, 33 BD nonsmokers, and 18 BD smokers. A stepwise discriminant-function analysis (DFA) with cortical structures as predictors was performed to classify BD patients into nonsmokers and smokers. Next, DFAs with the selected structures as predictors were performed to discriminate smoking status or diagnostic status. Differences in the selected features among the four groups were examined. The first DFA showed that six brain features discriminated between nonsmokers and smokers among BD patients. The six brain features related to BD smoking status also discriminated between HCs and BD patients and HC nonsmokers and BD smokers. Among the six features, left insular thickness showed a negative additive effect of smoking status and BD diagnosis. Our findings suggest the common neurobiological involvement of insular thickness in smoking behavior and BDrisk.

Fish oil supplementation alters emotion-generated corticolimbic functional connectivity in depressed adolescents at high-risk for bipolar I disorder: A 12-week placebo-controlled fMRI trial.

OBJECTIVE: To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder. METHODS: Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained. RESULTS: Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p < 0.0001). In the FO group, but not placebo group, the decrease in AMY-ITG functional connectivity correlated with decreases in Childhood Depression Rating Scale-Revised and Clinical Global Impression-Severity Scale scores. CONCLUSIONS: In depressed high-risk youth FO supplementation alters emotion-generated corticolimbic functional connectivity which correlates with changes in symptom severity ratings.

Emotion-Related Network Reorganization Following Fish Oil Supplementation in Depressed Bipolar Offspring: An fMRI Graph-Based Connectome Analysis.

INTRODUCTION: Mood disorders are associated with fronto-limbic structural and functional abnormalities and deficits in omega-3 polyunsaturated fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Emerging evidence also suggests that n-3 PUFA, which are enriched in fish oil, promote cortical plasticity and connectivity. The present study performed a graph-based connectome analysis to investigate the role of n-3 PUFA in emotion-related network organization in medication-free depressed adolescent bipolar offspring. METHODS: At baseline patients (n = 53) were compared with healthy controls (n = 53), and patients were then randomized to 12-week double-blind treatment with placebo or fish oil. At baseline and endpoint, erythrocyte EPA+DHA levels were measured and fMRI scans (4 Tesla) were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Graph-based analysis was used to characterize topological properties of large-scale brain network organization. RESULTS: Compared with healthy controls, patients exhibited lower erythrocyte EPA+DHA levels (p = 0.0001), lower network clustering coefficients (p = 0.029), global efficiency (p = 0.042), and lower node centrality and connectivity strengths in frontal-limbic regions (p<0.05). Compared with placebo, 12-week fish oil supplementation increased erythrocyte EPA+DHA levels (p<0.001), network clustering coefficient (p = 0.005), global (p = 0.047) and local (p = 0.023) efficiency, and node centralities mainly in temporal regions (p<0.05). LIMITATIONS: The duration of fish oil supplementation was relatively short and the sample size was relatively small. CONCLUSIONS: These findings provide preliminary evidence that abnormalities in emotion-related network organization observed in depressed high-risk youth may be amenable to modification through fish oil supplementation.

Prevalence of white matter hyperintensities is not elevated in a large sample of adolescents and young adults with bipolar disorder

Objective: The increased prevalence rate of white matter hyperintensities is one of the most consistently reported brain abnormalities in adults with bipolar disorder. However, findings in children and adolescents with bipolar disorder are less consistent. Prior studies have been constrained by small sample sizes and/or poor age- and sex-matching of healthy controls. We examined this topic in the largest sample of adolescents with bipolar disorder to date. Methods: T2-weighted 3-Tesla magnetic resonance imaging data were acquired for 83 adolescents with bipolar disorder diagnosed via the Kiddie Schedule for Affective Disorders and the Schizophrenia, Present and Lifetime version semi-structured interview and 64 age- and sex-matched healthy controls. All acquired scans were examined by neuroradiologists and the presence or absence of white matter hyperintensities was determined for each participant. Results: The prevalence of white matter hyperintensities did not differ between adolescents with bipolar disorder (13.3%) and controls (21.9%; χ2 = 1.90; p = 0.168). Conclusion: In contrast to the study hypothesis, the prevalence of white matter hyperintensities was not higher in adolescents with bipolar disorder than controls. The large sample size and good matching for age and sex bolster the reliability of this negative finding. Future studies are warranted to evaluate the prevalence, incidence, and predictors of white matter hyperintensities in early-onset bipolar disorder prospectively.

Temporal dynamics alterations of spontaneous neuronal activity in anterior cingulate cortex predict suicidal risk in bipolar II patients.

Bipolar disorder type II (BD-II) is linked to an increased suicidal risk. Since a prior suicide attempt (SA) is the single most important risk factor for sequent suicide, the elucidation of involved neural substrates is critical for its prevention. Therefore, we examined the spontaneous brain activity and its temporal variabilities in suicide attempters with bipolar II during a major depressive episode. In this cross-sectional study, 101 patients with BD-II, including 44 suicidal attempters and 57 non-attempters, and 60 non-psychiatric controls underwent a resting-state functional magnetic resonance imaging (fMRI). Participants were assessed with Hamilton Rating Scale for Depression (HAMD) and Nurses, Global Assessment of Suicide Risk (NGASR). The dynamics of low-frequency fluctuation (dALFF) was measured using sliding-window analysis and its correlation with suicidal risk was conducted using Pearson correlation. Compared to non-attempters, suicidal attempters showed an increase in brain activity and temporal dynamics in the anterior cingulate cortex (ACC). In addition, the temporal variabilities of ACC activity positively correlated with suicidal risk (R = 0.45, p = 0.004), while static ACC activity failed to (R = 0.08, p > 0.05). Our findings showed that an aberrant static ALFF and temporal variability could affect suicidal behavior in BD-II patients. However, temporal variability of neuronal activity was more sensitive than static amplitude in reflecting diathesis for suicide in BD-II. Dynamics of brain activity could be considered in developing neuromarkers for suicide prevention.

Novel 18F-Labeled Isonicotinamide-Based Radioligands for Positron Emission Tomography Imaging of Glycogen Synthase Kinase-3ß.

Glycogen synthase kinase-3ß (GSK-3ß), a cytoplasmic serine/threonine protein kinase, is involved in several human pathologies including Alzheimer's disease, bipolar disorder, diabetes, and cancer. Positron emission tomography (PET) imaging of GSK-3ß could aid in investigating GSK-3ß levels under normal and pathological conditions. In this study, we designed and synthesized fluorinated PET radioligands starting with recently identified isonicotinamide derivatives that showed potent affinity to GSK-3ß. After extensive in vitro inhibitory activity assays and analyzing U87 cell uptake, we identified [18F]10a-d as potential tracers with good specificity and high affinity. They were then subjected to further in vivo evaluation in rodent brain comprising PET imaging and metabolism studies. The radioligands [18F]10b-d penetrated the blood-brain barrier and accumulated in GSK-3ß-rich regions, including amygdala, cerebellum, and hippocampus. Also, it could be specifically blocked using the corresponding standard compounds. With these results, this work sets the basis for further development of novel 18F-labeled GSK-3ß PET probes.

Systemic inflammation and grey matter volume in schizophrenia and bipolar disorder: Moderation by childhood trauma severity.

BACKGROUND: Elevated levels of systemic inflammation are consistently reported in both schizophrenia (SZ) and bipolar-I disorder (BD), and are associated with childhood trauma exposure. We tested whether childhood trauma exposure moderates associations between systemic inflammation and brain morphology in people with these diagnoses. METHODS: Participants were 55 SZ cases, 52 BD cases and 59 healthy controls (HC) who underwent magnetic resonance imaging. Systemic inflammation was measured using a composite z-score derived from serum concentrations of interleukin 6, tumor necrosis factor alpha and C-reactive protein. Indices of grey matter volume covariation (GMC) were derived from independent component analysis. Childhood trauma was measured using the Childhood Trauma Questionnaire (CTQ Total score). RESULTS: A series of moderated moderation analyses indicated that increased systemic inflammation were associated with increased GMC in the striatum and cerebellum among all participants. Severity of childhood trauma exposure moderated the relationship between systemic inflammation and GMC in one component, differently among the groups. Specifically, decreased GMC in the PCC/precuneus, parietal lobule and postcentral gyrus, and increased GMC in the left middle temporal gyrus was associated with increased systemic inflammation in HC individuals exposed to high (but not low or average) levels of trauma and in SZ cases exposed to low (but not average or high) levels of trauma, but not in BD cases. CONCLUSIONS: Increased systemic inflammation is associated with grey matter changes in people with psychosis, and these relationships may be partially and differentially moderated by childhood trauma exposure according to diagnosis.

Exploring brain insulin resistance in adults with bipolar depression using extracellular vesicles of neuronal origin.

Accumulating evidence suggests that disrupted insulin signaling is involved in bipolar disorder (BD) pathogenesis. Herein, we aimed to directly explore the potential role of neuronal insulin signaling using an innovative technique based on biomarkers derived from plasma extracellular vesicles enriched for neuronal origin (NEVs). We leveraged plasma samples from a randomized, double-blind, placebo-controlled, 12-week clinical trial evaluating infliximab as a treatment of bipolar depression. We isolated NEVs using immunoprecipitation against neuronal marker L1CAM from samples collected at baseline and weeks 2, 6 and 12 (endpoint) and measured NEV biomarkers using immunoassays. We assessed neuronal insulin signaling at its first node (IRS-1) and along the canonical (Akt, GSK-3ß, p70S6K) and alternative (ERK1/2, JNK and p38-MAPK) pathways. A subset of participants (n = 27) also underwent whole-brain magnetic resonance imaging (MRI) at baseline and endpoint. Pre-treatment, NEV biomarkers of insulin signaling were independently associated with cognitive function and MRI measures (i.e. hippocampal and ventromedial prefrontal cortex [vmPFC] volumes). In fact, the association between IRS-1 phosphorylation at serine site 312 (pS312-IRS-1), an indicator of insulin resistance, and cognitive dysfunction was mediated by vmPFC volume. In the longitudinal analysis, patients treated with infliximab, a tumor necrosis factor-alpha antagonist with known insulin sensitizing properties, compared to those treated with placebo, had augmented phosphorylation of proteins from the alternative pathway. Infliximab responders had significant increases in phosphorylated JNK levels, relative to infliximab non-responders and placebo responders. In addition, treatment with infliximab resulted in increase in MRI measures of brain volume; treatment-related changes in the dorsolateral prefrontal cortex volume were mediated by changes in biomarkers from the insulin alternative pathway. In conclusion, our findings support the idea that brain insulin signaling is a target for further mechanistic and therapeutic investigations.

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

Bipolar disorder (BD) is a chronic mental illness characterized by changes in mood that alternate between mania and hypomania or between depression and mixed states, often associated with functional impairment. Although effective pharmacological and non-pharmacological treatments are available, several patients with BD remain symptomatic. The advance in the understanding of the neurobiology underlying BD could help in the identification of new therapeutic targets as well as biomarkers for early detection, prognosis, and response to treatment in BD. In this review, we discuss genetic, epigenetic, molecular, physiological and neuroimaging findings associated with the neurobiology of BD. Despite the advances in the pathophysiological knowledge of BD, the diagnosis and management of the disease are still essentially clinical. Given the complexity of the brain and the close relationship between environmental exposure and brain function, initiatives that incorporate genetic, epigenetic, molecular, physiological, clinical, environmental data, and brain imaging are necessary to produce information that can be translated into prevention and better outcomes for patients with BD.

Increased Proinflammatory Cytokines, Executive Dysfunction, and Reduced Gray Matter Volumes In First-Episode Bipolar Disorder and Major Depressive Disorder.

BACKGROUNDS: The association between systemic inflammation, executive dysfunction, and gray matter (GM) volume difference in first-episode affective disorders, including bipolar and major depressive disorders, is unclear. METHODS: Twenty-two patients with first-episode bipolar disorder, 22 age- and sex-matched patients with first-episode major depressive disorder, and 22 matched controls were enrolled in our study; all patients underwent comprehensive assessments, including clinical assessment, executive function examination (Wisconsin card sorting test [WCST]), proinflammatory cytokine receptors (soluble interleukin-6 receptor and tumor necrosis factor-α receptor 1 [TNFR1]), and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze the GM volume difference between bipolar and major depressive disorders. RESULTS: Patients with bipolar disorder were more likely to exhibit higher levels of TNFR1 (P = .038), more number of deficits in WCST (P < .05), and smaller GM volume in the middle frontal cortex (uncorrected voxel level P < .001) compared with those with major depressive disorder and healthy controls. Positive associations were observed between the middle frontal cortex volume, executive function, and the TNFR1 level. DISCUSSION: GM volume reduction in the middle frontal cortex, a greater level of systemic inflammation, and executive dysfunction were observed in first-episode affective disorders, especially bipolar disorder. A positive correlation between middle frontal cortex volume, executive function, and the TNFR1 level may indicate a divergent effect of brain and systemic inflammation functioning in the early phase (first episode) of affective disorder.

Brain perfusion during manic episode and at 6-month follow-up period in bipolar disorder patients: Correlation with cognitive functions.

BACKGROUND: Patterns of altered cerebral perfusion and cognitive dysfunction have been described in Bipolar Disorder (BD) acute episodes and euthymia. Knowledge of the relationship between cognitive function and perfusion in a manic state and status when followed up is still limited. OBJECTIVE: To describe brain perfusion alterations and its relationship with cognitive impairment in patients with BD during manic episodes and after 6 months. METHODS: Observational-prospective study in 10 type I BD adults during moderate-severe manic episodes. We assessed sociodemographic data and clinical variables as well as cognitive function through Screening for Cognitive Impairment in Psychiatry (SCIP-S). Finally, we performed a Brain Perfusion SPECT using a Tc99m-ethyl cysteine dimer. RESULTS: During manic episodes, patients showed cognitive impairment with a mean SCIP-S score of 63.8 ± 17.16. This was positively correlated with perfusion measured as relative reuptake index (RRI) at the right temporal pole (ρ = 0.65 p = .0435) and negatively correlated with right the orbitofrontal cortex (ρ = -0.70 p = .0077) and the right subgenual cingulate cortex (ρ = -0.70 p = .0256). Episode severity measured by the Young Mania Rating Scale (YMRS) positively correlated with RRI at the right temporal pole (ρ = 0.75, p = .01). At follow-up, six patients were taking treatment and were euthymic, we found a negative correlation with the YMRS and RRI at the bilateral orbitofrontal cortex (ρ = -0.8827, p = .019). They did not show significant improvement in cognitive performance at SCIP-S, and there was negative correlation with the following of the SCIP-S subscales; processing speed with the bilateral dorsolateral prefrontal, the bilateral medial prefrontal, the left temporal pole cortex RRI, and verbal fluency with the bilateral anterior cingulate cortex RRI. CONCLUSION: Cognitive impairment was correlated with brain perfusion patterns at baseline and follow-up. Large sample size studies with longer follow-up are needed to describe the changes in perfusion and cognitive functions in BD.