Browsing by Subject "depression"

Major Depressive Disorder (MDD) is a prevalent health issue worldwide, yet one third of patients are unresponsive to first-line treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) is a promising alternative treatment and better understanding of the neural network impairments associated with MDD could significantly improve its efficacy. Recent research has identified a ‘depression network’ involving key brain regions, suggesting that MDD symptoms arise from functional connectivity impairments within this network. This thesis aims to map the activity and functional connectivity of six bilateral regions of interest (ROIs) implicated in MDD: dorsolateral prefrontal cortex (dlPFC), dorsomedial prefrontal cortex (dmPFC), ventromedial prefrontal cortex (vmPFC), inferior frontal gyrus (IFG), intraparietal sulci (IPS) and pre-supplementary motor area (pre-SMA). The intention is to describe biomarkers of depression and map the depression network to identify connectivity impairments between these cortical sites. Literature on these ROIs was reviewed and rsEEG data from 24 MDD patients and 9 healthy controls was collected to analyze the activity and functional connectivity of selected ROIs. Our results suggest that MDD involves widespread connectivity impairment including in regions that have not previously been included in the research on depression, such as IFG and IPS. Most ROIs showed trends of reduced activity in delta, theta, alpha and beta bands. The effects were most noticeable in the theta band, especially in the IFG, dmPFC, and dlPFC. However, the functional connectivity impairments were more prominent and significant, particularly in the beta and alpha bands. Notably, the IPS and vmPFC stood out as key nodes with the most dysfunctional connections in MDD. These findings support the idea of a depression network characterized by connectivity abnormalities rather than localized activity impairments. This study emphasizes the importance of a network-based approach in understanding MDD. The search for biomarkers as well as novel stimulation targets should consider regions beyond the traditional dlPFC or the frontal cortex, to include regions such as IPS, IFG and vmPFC.

Tiivistelmä – Referat – Abstract Mental disorders are among the leading causes of global disease burden and years lived with disability. Their pathogenesis is poorly understood and there are enormous challenges in the development of biomarkers to aid in diagnosis and more effective therapeutic options. It has been documented that the microbiota-gut-brain axis shows alterations in mental disorders such as anxiety, depression, autism spectrum disorders, bipolar disorder and schizophrenia. Here we study the gut microbiota of individuals with axis I mental disorders and their unaffected siblings by 16S RNA gene amplicon sequencing. In the Central Valley of Costa Rica, a total of 37 participants were recruited and diagnosed using a Best Estimate Diagnosis protocol. For each of the individuals diagnosed with a mental disorder a healthy sibling was selected after matching by age and gender. A total of 13 pairs of 26 siblings, affected and unaffected, was used for the analysis. In a subsequent analysis, individuals were also divided into the three categories of “unaffected” (UA), “affected without psychosis” (AA) and “affected with psychosis” (AP). They underwent clinical assessments about their habits and diet and about resilience (Connor-Davidson Resilience Scale), current status (SADS-C) and disability (WHODAS 2.0). Their fecal samples were collected freshly and stored at -80°C. DNA was extracted, libraries constructed by PCR and subjected for Illumina MiSeq 300 paired-end 16S RNA amplicon sequencing for analysis of the gut microbiota. The sequencing data were analyzed using the R packages mare and vegan for gut microbiota composition, diversity and richness, taking into account the identified confounders. All participants were of Hispanic ethnicity, residents of the San José Greater Metropolitan Area, adults and 69% of them were women. Affected individuals had major depression, bipolar affective disorder, psychosis non-otherwise specified or schizoaffective disorder. Based on beta-diversity analysis as a measure of the community-level microbiota variation, it was found that the use of levothyroxine (R2=0.08, p=0.005) and of irbesartan (R2=0.068 ,p=0.001) had a significant impact on the microbiota composition and hence the use of these drugs was included as confounder in further analyses. Several statistically significant differences in the relative abundance of intestinal bacteria were identified: Differences were found in the relative abundance of bacterial families Peptostreptococcaceae, Ruminococcaceae, Porphyromonadaceae, and in bacterial genera Pseudomonas, Barnesiella, Odoribacter, Paludibacter, Lactococcus, Clostridium, Acidaminococcus and Haemophilus. Our results indicate that affected individuals have more pro-inflammatory Proteobacteria (Pseudomonas) and less bacteria associated to healthy phenotype, such as Barnesiella and Ruminococcaceae, the former being dose-dependently depleted in AP and AA compared to UA. Furthermore, we documented decreased bacterial richness among affected participants while no significant differences were detected in alpha diversity. Our study identified significant differences in the microbiota of individuals affected by mental illness when comparing to their healthy siblings. The results may have important implications for the holistic understanding of mental health and its diagnosis and therapeutics. Larger studies to confirm these findings would be justified.

Depression and anxiety are the two most common mental disorders worldwide, and especially common among women of reproductive age. Hence, they are also common problems among pregnant women. Maternal depression and anxiety not only compromise the mother’s quality of life during pregnancy but increase the risk of perinatal complications and poor child neurodevelopment. The biological mechanisms that underpin this transmission remain largely unknown. The placenta, a transient fetal organ functioning as an interface between the mother and the fetus, plays a pivotal role, as the placenta transmits all environmental cues to the fetus. This thesis aims to investigate differential gene expression in the first-trimester chorionic villi and birth placenta samples from women with depression and/or anxiety and healthy controls. Samples are collected and processed as a part of the InTraUterine sampling in early pregnancy (ITU) study and both chorionic villus samples (CVS) collected during the early pregnancy and delivery placenta samples were studied. I defined three different phenotypes based on (i) maternal depression and anxiety disorder diagnosis, (ii) antidepressant and anxiolytic medication purchases, or (iii) self-reported depressive and anxiety symptoms during pregnancy. Genome-wide analysis of differential gene expression was conducted with DESeq2 R-package and further gene set enrichment analysis was performed with a web-based platform FUMA. When comparing mothers with depressive and anxiety symptoms to asymptotic controls, but not those with or without diagnoses or medication purchases, I found 478 genes differentially expressed. In the enrichment analysis these genes related to immune response and inflammation, such as leukocyte and T cell activation, defense response, and cytokine production. Together these results indicate that maternal depressive and anxiety symptoms during pregnancy change the immune system functions in the placenta which may partly explain the adverse effects of maternal depression and anxiety on the developing fetus. These findings may afford a target for timely targeted interventions to prevent perinatal complications and the transmission of maternal depression and anxiety to the next generation.

While weeks of continuous treatment is required for conventional antidepressant drugs (e.g. fluoxetine) to bring their full therapeutic effects, a subanesthetic dose of ketamine alleviates the core symptoms of depression (anhedonia, depressed mood) and suicidal thinking within just few hours and the effects may last for days. Nitrous oxide (N2O, “laughing gas”), another NMDAR antagonist, has recently been shown to have similar rapid antidepressant effects in treatment-resistant depressed patients (Nagele et al. 2015). We previously found using naïve mice ketamine and N2O treatment to upregulate five mRNAs related to the MAPK pathway and synaptic plasticity, both implicated as being important in the action of rapid-acting antidepressants. In the current study, these shared mechanisms were further investigated in C57BL/6JHsd mice, using behavioral test batteries to study depressive-like behaviour and RT-qPCR for biochemical analyses. We first aimed to demonstrate behavioral differences between naïve mice and a chronic corticosterone-induced animal model of depression, and to use this model to investigate antidepressant-like effects of ketamine and N2O. According to the results, chronic corticosterone produced some behaviors typical of a depressive-like phenotype, namely significant worsening of coat state and decreased saccharin consumption in the saccharin preference test. Both ketamine and N2O exhibited antidepressant-like effects by reverting decreased saccharin preference. We then aimed to elucidate the effects of ketamine and N2O on five previously found shared mRNAs: Arc, Dusp1, Dusp5, Dusp6 and Nr4a1. N2O significantly upregulated all targets in the vmPFC, except Dusp5, two hours after beginning of N2O treatment. Neither ketamine nor sole chronic corticosterone produced any significant changes. The results of this study suggest that N2O is a potential candidate for rapid alleviation of depressive symptoms. We suggest that the action of rapid-acting antidepressants, more specifically N2O, is based on a homeostatic response of the brain to a presented challenge. Here this challenge would be cortical excitation previously been shown to be caused by N2O, which leads to activation of pathways such as MAPK and subsequent Arc, Dusp and Nr4a1 signaling. The level of expression of these markers would then depend on which phase this response is in and hence, the differences in time between treatment and brain sample dissection could be a reason for conflicting results to previous research. Future studies would benefit from detailed investigation of the chronic corticosterone-induced model due to its potential in controlling for behavioral variability, thus reducing the number of animals needed for preclinical research. Overall the preliminary findings of this study could be one of the first steps in the search for the mechanisms underlying the potential antidepressant effect of N2O, how these molecular markers are related to its action and how it differs from the action of ketamine.