Diagnostic value of structural, functional and effective connectivity in bipolar disorder.

INTRODUCTION: The aim of this systematic review is to assess the functional magnetic resonance imaging (fMRI) studies of bipolar disorder (BD) patients that characterize differences in terms of structural, functional, and effective connectivity between the patients with BD, patients with other psychiatric disorders and healthy controls as possible biomarkers for diagnosing the disorder using neuroimaging. METHODS: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), guidelines a systematic search for recent (since 2015) original studies on connectivity in bipolar disorder was conducted in PUBMED and SCOPUS. RESULTS: A total of 60 studies were included in this systematic review: 20 of the structural connectivity, 33 of the functional connectivity, and only 7 of the studies focused on effective connectivity complied with the inclusion and exclusion criteria. DISCUSSION: Despite the great heterogeneity in the findings, there are several trends that emerge. In structural connectivity studies, the main abnormalities in bipolar disorder patients were in the frontal gyrus, anterior, as well as posterior cingulate cortex and differences in emotion and reward-related networks. Cerebellum (vermis) to cerebrum functional connectivity was found to be the most common finding in BD. Moreover, prefrontal cortex and amygdala connectivity as part of the rich-club hubs were often reported to be disrupted. The most common findings based on effective connectivity were alterations in salience network, default mode network and executive control network. Although more studies with larger sample sizes are needed to ascertain altered brain connectivity as diagnostic biomarker, there is a perspective that the method could be used as a single marker of diagnosis in the future, and the process of adoption could be accelerated by using approaches such as semiunsupervised machine learning.

Common Environmental Factors May Underpin the Comorbidity Between Generalized Anxiety Disorder and Mood Disorders Via Activated Nitro-oxidative Pathways.

Generalized Anxiety Disorder (GAD) commonly co-occurs with mood disorders, especially Major Depressive Disorder (MDD) and bipolar disorder (BD), which are accompanied by activated neuro-immune and neuro-oxidative pathways. The aim of this narrative review is to review the phenomenological similarities and dissimilarities and the shared pathways between GAD and mood disorders. We searched PubMed, Scopus, and Google Scholar for articles published in English from 1980 to present. GAD and mood disorders, either MDD or BD, show some phenomenological overlaps and a high degree of comorbidity, especially between GAD and MDD. Both GAD and mood disorders are also frequently comorbid with other anxiety disorders, substance use disorders and medical conditions, including cardio- vascular disorder (CVD). Mood disorders have a worse prognosis when GAD is present. GAD and mood disorders are associated with female sex and may partly share genetic variants of risk. Moreover, both GAD and mood disorders frequently share similar environmental risks factors including Early Life Time Trauma (ELT) and Psychological Stressors in Adulthood (PSA). Increased nitro-oxidative stress and lipid peroxidation coupled to lowered lipid-associated antioxidant defenses are evident in GAD, MDD and type I bipolar patients. Patients with comorbid GAD and MDD show significantly higher nitro- oxidative biomarkers as compared with patients presenting with either GAD or MDD as well as patients with BD with or without co-occurring GAD. Activated immune-inflammatory processes characterized by increased levels of CRP and pro-inflammatory cytokines are other shared pathways that underpin GAD and mood disorders. Moreover, these pathways may explain comorbidities with medical disorders including CVD. Aberrations in HPA-axis, GABA and glutamate neurotransmission, NMDA and mu opioid-receptors and neuroimaging fields have yielded more inconsistent findings. In conclusion, here we propose a new model explaining GAD and the comorbidity between GAD and mood disorders. Common triggers such as ELT/PSA may underpin GAD and its comorbidity with mood disorders via activated neuro-oxidative, neuro-nitrosative and neuro-immune pathways.

Response to Pharmacological Treatment in Major Depression Predicted by Electroencephalographic Alpha Power - a Pilot Naturalistic Study.

BACKGROUND: Pharmacological treatment of depression is currently led by the trial and error principle mainly because of lack of reliable biomarkers. Earlier findings suggest that baseline alpha power and asymmetry could differentiate between responders and non-responders to specific antidepressants. AIM: The current study investigated quantitative electroencephalographic (QEEG) measures before and early in treatment as potential response predictors to various antidepressants in a naturalistic sample of depressed patients. We were aiming at developing markers for early prediction of treatment response based on different QEEG measures. MATERIALS AND METHODS: EEG data from 25 depressed subjects were acquired at baseline and after one week of treatment. Mean and total alpha powers were calculated at eight electrode sites F3, F4, C3, C4, P3, P4, O1, O2. Response to treatment was defined as 50% decrease in MADRS score at week 4. RESULTS: Mean P3 alpha predicted response with sensitivity and specificity of 80%, positive and negative predictive values of 92.31% and 71.43%, respectively. The combined model of response prediction using mean baseline P3 alpha and mean week 1 C4 alpha values correctly identified 80% of the cases with sensitivity of 84.62%, and specificity of 71.43%. CONCLUSIONS: Simple QEEG measures (alpha power) acquired before initiation of antidepressant treatment could be useful in outcome prediction with an overall accuracy of about 80%. These findings add to the growing body of evidence that alpha power might be developed as a reliable biomarker for the prediction of antidepressant response.

Whole-genome-wide association study in the Bulgarian population reveals HHAT as schizophrenia susceptibility gene.

OBJECTIVE: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49×10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus.

The endophenotype project and the validation theory: integration of neurobiology and psychiatry.

In this paper we set forth the major meta-empirical concepts for mental disorders determination. We especially focus on the methodological prerequisites and particular compounds and the endophenotype construct in a case study of bipolar disorders. It is discussed as a mediating level between the genetic causation and the environmental influences in the mental disorder causation. This epigenetic area includes such constructs as cognitive neuropsychological markers, neurotrophic proteins impairment, instability of circadian rhythms (other chronobiological disturbances as well), deregulation of the motivation and reward mechanisms, changes in the GABA metabolism, symptom provocation with "psychotomymetic" agents, etc. Eventually the core ideas of the original validation theory in comparison with the endophenotype concept are shown as milestones of the novel integration of neurobiology and psychiatry. The major issue posed in the endophenotype debate concerns "the independence from the state". According to the formulation of Hassler and Drevets this notion indicates the presentation of the endophenotype regardless of the activity of the disorder, i.e., its presence even in the pre-morbid and remission periods. In the present study we argue that there is another dimension of "state independence" to be assessed. The validation theory in particular defines the entire space-and-time sequence disposition of the endophenotype indicators, e.g. cognitive-psychological and neuroimaging. It is well known that mental states, whether normal or pathological, are very dynamical, just as their neurophysiological correlates are. By this reason it is necessary to explore their relationships simultaneously.