Examinations of pathomechanisms in schizophrenic and bipolar disorders – results from two functional magnetic resonance imaging studies

Psychiatric disorders, in particular schizophrenia and bipolar disorder, affect the patients’ lives deeply on many levels and place a heavy burden on the healthcare system. The treatment of these diseases is often complicated and marked by many setbacks. Symptoms that have the strongest consequences for coping with everyday life are the impairments of cognitive performance, for example memory or attention deficits. Therefore, it is of great interest to better understand the underlying pathomechanisms to eventually improve treatment options for those patients. In this thesis two different fMRI studies were used to investigate the functional correlates of patients suffering from schizophrenia or bipolar disorder while performing a combined oddball-incongruence task and a reward associated task. Study A conducted a categorical comparison between bipolar and schizophrenia patients of the brain activation during an oddball and incongruence task. The results showed pathophysiological differences in the activation intensities between bipolar and schizophrenia patients as well as between the patient groups and healthy individuals. Overall it seems as if the brain activation severely depended on the task difficulty leading to compensatory hyperactivations in frontal brain areas of bipolar patients during the oddball task. Schizophrenia patients demonstrated low threshold hyperactivations in the intraparietal cortex compared to healthy controls. In the cognitively more demanding incongruence condition these compensatory mechanisms seemed to fail leading to hypoactivations in various brain regions such as the middle frontal gyrus or ventral pathway. Pilot study B searched retrospectively for functional markers which enable support vector machine algorithms predicting specific treatment response to typical and atypical antipsychotics as well as aripiprazole in a transnosological sample consisting of bipolar and schizophrenia patients. Consequently, (de-)activation differences between responders and non-responders in their respective treatment arm resulting from the desire-reason-dilemma paradigm were applied to support vector machine algorithms. The implementation of parameter estimates from deactivations of aripiprazole non-responders in brain regions partially associated with the default mode network, led to a successful treatment response prediction of patients receiving aripiprazole. Even though in future studies the sample sizes should be increased and monotherapeutical treatment ensured, this thesis already provides important insights on the pathomechanisms of bipolar disorder and schizophrenia patients or more specifically within the spectrum of both diseases. Prospectively, further studies can help to specify potential functional biomarkers which also might be able to predict treatment response and consequently approach personalized precision treatment in psychiatric disorders

Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells

Glioblastomas are highly malignant brain tumors that derive from brain-tumor-initiating cells (BTICs) and can be subdivided into several molecular subtypes. Metformin is an antidiabetic drug currently under investigation as a potential antineoplastic agent. The effects of metformin on glucose metabolism have been extensively studied, but there are only few data on amino acid metabolism. We investigated the basic amino acid profiles of proneural and mesenchymal BTICs to explore a potential distinct utilization and biosynthesis in these subgroups. We further measured extracellular amino acid concentrations of different BTICs at baseline and after treatment with metformin. Effects of metformin on apoptosis and autophagy were determined using Western Blot, annexin V/7-AAD FACS-analyses and a vector containing the human LC3B gene fused to green fluorescent protein. The effects of metformin on BTICs were challenged in an orthotopic BTIC model. The investigated proneural BTICs showed increased activity of the serine and glycine pathway, whereas mesenchymal BTICs in our study preferably metabolized aspartate and glutamate. Metformin treatment led to increased autophagy and strong inhibition of carbon flux from glucose to amino acids in all subtypes. However, oral treatment with metformin at tolerable doses did not significantly inhibit tumor growth in vivo. In conclusion, we found distinct amino acid profiles of proneural and mesenchymal BTICs, and inhibitory effects of metformin on BTICs in vitro. However, further studies are warranted to better understand potential resistance mechanisms against metformin in vivo

Geophysical and atmospheric evolution of habitable planets

The evolution of Earth-like habitable planets is a complex process that depends on the geodynamical and geophysical environments. In particular, it is necessary that plate tectonics remain active over billions of years. These geophysically active environments are strongly coupled to a planet's host star parameters, such as mass, luminosity and activity, orbit location of the habitable zone, and the planet's initial water inventory. Depending on the host star's radiation and particle flux evolution, the composition in the thermosphere, and the availability of an active magnetic dynamo, the atmospheres of Earth-like planets within their habitable zones are differently affected due to thermal and nonthermal escape processes. For some planets, strong atmospheric escape could even effect the stability of the atmosphere

In vivo hippocampal subfield volumes in bipolar disorder—A mega-analysis from The Enhancing Neuro Imaging Genetics through Meta-Analysis Bipolar Disorder Working Group

The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans from 4,698 individuals (BD = 1,472, healthy controls [HC] = 3,226) from 23 sites worldwide were processed with FreeSurfer. We used linear mixed‐effects models and mega‐analysis to investigate differences in hippocampal subfield volumes between BD and HC, followed by analyses of clinical characteristics and medication use. BD showed significantly smaller volumes of the whole hippocampus (Cohen's d = −0.20), cornu ammonis (CA)1 (d = −0.18), CA2/3 (d = −0.11), CA4 (d = −0.19), molecular layer (d = −0.21), granule cell layer of dentate gyrus (d = −0.21), hippocampal tail (d = −0.10), subiculum (d = −0.15), presubiculum (d = −0.18), and hippocampal amygdala transition area (d = −0.17) compared to HC. Lithium users did not show volume differences compared to HC, while non‐users did. Antipsychotics or antiepileptic use was associated with smaller volumes. In this largest study of hippocampal subfields in BD to date, we show widespread reductions in nine of 12 subfields studied. The associations were modulated by medication use and specifically the lack of differences between lithium users and HC supports a possible protective role of lithium in BD

Moonraker — Enceladus Multiple Flyby Mission

Enceladus, an icy moon of Saturn, possesses an internal water ocean and jets expelling ocean material into space. Cassini investigations indicated that the subsurface ocean could be a habitable environment having a complex interaction with the rocky core. Further investigation of the composition of the plume formed by the jets is necessary to fully understand the ocean, its potential habitability, and what it tells us about Enceladus's origin. Moonraker has been proposed as an ESA M-class mission designed to orbit Saturn and perform multiple flybys of Enceladus, focusing on traversals of the plume. The proposed Moonraker mission consists of an ESA-provided platform with strong heritage from JUICE and Mars Sample Return and carrying a suite of instruments dedicated to plume and surface analysis. The nominal Moonraker mission has a duration of ∼13.5 yr. It includes a 23-flyby segment with 189 days allocated for the science phase and can be expanded with additional segments if resources allow. The mission concept consists of investigating (i) the habitability conditions of present-day Enceladus and its internal ocean, (ii) the mechanisms at play for the communication between the internal ocean and the surface of the South Polar Terrain, and (iii) the formation conditions of the moon. Moonraker, thanks to state-of-the-art instruments representing a significant improvement over Cassini's payload, would quantify the abundance of key species in the plume, isotopic ratios, and the physical parameters of the plume and the surface. Such a mission would pave the way for a possible future landed mission

Cortical activation abnormalities in bipolar and schizophrenia patients in a combined oddball–incongruence paradigm

Patients with bipolar disorder and schizophrenia often suffer from severe cognitive impairment even during times of remission. This study investigated the pathomechanisms underlying their deficits in cognitive control. A combined oddball-incongruence fMRI task was applied to examine similarities and differences of neural activation patterns between patients and healthy controls. Bipolar and schizophrenia patients demonstrated hyperactivations in the intraparietal cortex during the oddball condition. Furthermore, bipolar patients revealed diagnosis-specific hyperactivation in the left middle frontal gyrus, precentral gyrus, anteroventral prefrontal cortex and orbitofrontal cortex regions compared to schizophrenia patients and healthy individuals. In comparison to healthy controls the patients showed hypoactivations in the inferior frontal junction and ventral pathway during the cognitively more demanding incongruence. Taken together, bipolar patients seem to recruit frontal and parietal areas during the oddball condition to compensate for potential deficits in their attentional network. During more challenging tasks, i.e., the incongruence condition, their compensatory mechanisms seem to collapse leading to hypoactivations in the same frontal areas as well as the ventral pathway

Stattic and metformin inhibit brain tumor initiating cells by reducing STAT3-phosphorylation

Glioblastoma (GBM) is the most common and malignant type of primary brain tumor and associated with a devastating prognosis. Signal transducer and activator of transcription number 3 (STAT3) is an important pathogenic factor in GBM and can be specifically inhibited with Stattic. Metformin inhibits GBM cell proliferation and migration. Evidence from other tumor models suggests that metformin inhibits STAT3, but there is no specific data on brain tumor initiating cells (BTICs). We explored proliferation and migration of 7 BTICs and their differentiated counterparts (TCs) after treatment with Stattic, metformin or the combination thereof. Invasion was measured in situ on organotypic brain slice cultures. Protein expression of phosphorylated and total STAT3, as well as AMPK and mTOR signaling were explored using Western blot. To determine functional relevance of STAT3 inhibition by Stattic and metformin, we performed a stable knock-in of STAT3 in selected BTICs. Inhibition of STAT3 with Stattic reduced proliferation in all BTICs, but only in 4 out of 7 TCs. Migration and invasion were equally inhibited in BTICs and TCs. Treatment with metformin reduced STAT3-phosphorylation in all investigated BTICs and TCs. Combined treatment with Stattic and metformin led to significant additive effects on BTIC proliferation, but not migration or invasion. No additive effects on TCs could be detected. Stable STAT3 knock-in partly attenuated the effects of Stattic and metformin on BTICs. In conclusion, metformin was found to inhibit STAT3-phosphorylation in BTICs and TCs. Combined specific and unspecific inhibition of STAT3 might represent a promising new strategy in the treatment of glioblastoma

Heterogeneity of Amino Acid Profiles of Proneural and Mesenchymal Brain-Tumor Initiating Cells

Glioblastomas are highly malignant brain tumors that derive from brain-tumor-initiating cells (BTICs) and can be subdivided into several molecular subtypes. Metformin is an antidiabetic drug currently under investigation as a potential antineoplastic agent. The effects of metformin on glucose metabolism have been extensively studied, but there are only few data on amino acid metabolism. We investigated the basic amino acid profiles of proneural and mesenchymal BTICs to explore a potential distinct utilization and biosynthesis in these subgroups. We further measured extracellular amino acid concentrations of different BTICs at baseline and after treatment with metformin. Effects of metformin on apoptosis and autophagy were determined using Western Blot, annexin V/7-AAD FACS-analyses and a vector containing the human LC3B gene fused to green fluorescent protein. The effects of metformin on BTICs were challenged in an orthotopic BTIC model. The investigated proneural BTICs showed increased activity of the serine and glycine pathway, whereas mesenchymal BTICs in our study preferably metabolized aspartate and glutamate. Metformin treatment led to increased autophagy and strong inhibition of carbon flux from glucose to amino acids in all subtypes. However, oral treatment with metformin at tolerable doses did not significantly inhibit tumor growth in vivo. In conclusion, we found distinct amino acid profiles of proneural and mesenchymal BTICs, and inhibitory effects of metformin on BTICs in vitro. However, further studies are warranted to better understand potential resistance mechanisms against metformin in vivo