[FG] de Quervain DominiqueHead of Research Unit Prof. Dr. med.Dominique de QuervainOverviewMembersPublicationsProjects & CollaborationsProjects & Collaborations OverviewMembersPublicationsProjects & Collaborations Projects & Collaborations 24 foundShow per page10 10 20 50 Feasibility study on the use of Ze 91019 on day-time cognition and quality of life in people with occasional sleep problems Research Project | 2 Project MembersIt is well known that cognitive performance and quality of life can be impaired after nights of little or no sleep (Hudson, 2020) (Roth, 2007). Therefore, people with occasional sleep problems, i.e. with 1-2 nights per week with impaired sleep, can suffer from impaired cognition the following day. Moreover, occasional sleep problems may lead to reduced overall quality of life (Buysse, 2007). Many people with insomnia do not wish to use conventional hypnotic drugs because of concerns about side effects and the risks of tolerance and dependence, and others do not want to spend the time and efforts required with behavioral therapies (Vincent, 2001). Thus, there is an increasing interest in the use of complementary and alternative medicines, such as herbal and dietary supplements, partly because of their natural properties and perceived relative absence of residual effects. Valerian and hop have both been an integral part of traditional medicine for Centuries. Pharmacological and clinical studies are available demonstrating the applicability of Redormin ® 500, a 45% methanolic extract from valerian root and from hop strobiles, in sleep disorders (Abourashed, 2004), (Dimpfel, 2006), (Morin, 2005), (Koetter, 2007). Not only could the effect be visualized through EEG measurements, but also new ideas regarding the mechanism of action were brought forth (Koetter, 2007)). Currently an agonistic effect on central adenosine receptors, and thus a counteracting effect on caffeine induced sleeplessness through the lignans in hydrophilic valerian root extracts is discussed as a potential mechanism of action for valerian root extract (Schumacher, 2002). The studies available mainly focused on the improvement of sleep quality rather than on improvements of cognitive performance and day performance. Therefore, the aim of this feasibility study is to determine the effect of Redormin® 500 on day-time cognition and quality of life in people with occasional sleep problems. Simulation Hallucinations Using Mixed Reality Research Project | 2 Project MembersBackground: Reality discrimination (RD), the ability to discriminate between perception and imagination, is central to the assessment of psychiatric health, especially in the context of psychotic disorders. Impairments in RD are associated with auditory and visual hallucination proneness in patients with psychotic disorders as well as the general population. However, there are currently no instruments available that allow for the combined assessment of auditory and visual RD performance. Furthermore, RD paradigms are limited in their ability to account for the complex phenomenology of natural hallucinations. More sensitive assessment methods are crucial to improve patient care, diagnosis, and treatment. Objectives: The overall goal of the proposed research is to develop a dual-modality RD paradigm to investigate the cognitive mechanisms underlying visual and auditory hallucinations and their relation to psychotic disorders. The first objective is to simulate hallucinatory perceptual experiences using a novel immersive technology method to manipulate the visual and auditory perception of natural environments. The second objective is to extend this simulation into a dual-modality RD paradigm based on the signal detection framework. Thereafter, the RD paradigm will be applied in healthy adults from the general population (Objective 3) and patients diagnosed with psychotic disorder (Objective 4). Methods: A first study will test the hypothesis that visual and auditory RD performance is associated with hallucination proneness in the general population (N=100). A second study will evaluate visual and auditory RD performance in a sample of patients with psychotic disorders (N=30) and will test the hypothesis that these patients are impaired in RD relative to matched controls from Study 1. In both studies, participants will complete the newly-designed RD paradigm as well as assessments of hallucination proneness and predisposition to psychosis (Study 1) or psychosis severity (Study 2). Expected Value of the Proposed Project: This research will contribute to the understanding of visual and auditory hallucinations and their shared cognitive mechanisms in the general population and patients with psychotic disorders. The novel RD paradigm may provide an improved measure of psychosis proneness that is more objective and behaviorally sensitive to hallucinatory experiences. This research may have important implications for the assessment, treatment, and early detection of psychotic disorders and will provide an ecologically valid framework from which innovative psychological interventions can be developed. Genome-guided drug identification: A randomized placebo-controlled trial on the influence of fampridine on working memory Research Project | 2 Project MembersBackground: The discrepancy between the urgent need for improved therapeutic compounds and the lack of significant development of novel drugs illustrates the importance of pursuing new strategies aimed at identifying druggable targets related to psychiatric disease. Recent advances in large-scale genetic studies suggest that human genetic discoveries have the potential of translating into novel treatment targets for psychiatric conditions. Aim: To implement a drug repurposing strategy and perform a proof-of-concept clinical trial on the influence of a potassium channel blocker (fampridine) on working memory performance, an intermediate trait of psychiatric disorders. Methods: Guided by recent genetic findings in schizophrenia, we focus on those loci that point to genes targeted by currently approved drugs. As starting point serves the large schizophrenia genome-wide association study that provided genes robustly linked to the risk for the disorder. As intermediate filtering layer serves working memory performance, which is a well-established intermediate phenotype for schizophrenia. Finally, one repurposing candidate, fampridine, is selected and tested for its putative influence on working memory performance in the framework of a randomized placebo-controlled trial in healthy subjects. Expected value: We anticipate that the exponentially increased genetic knowledge of psychiatric disorders together with the use of biologically-informed phenotypes and appropriate data-mining methodology will be a starting point for the identification of novel drug targets and treatments, i.e. the very goal of the present proposal. Should the current randomized control trial turn out positive, it might open new avenues for the treatment of cognitive symptoms in psychiatric disorders with known and hopefully also new and specific potassium channel blockers. Effects of an exercise and sport intervention among refugees living in a Greek refugee camp: A randomized controlled trial Research Project | 10 Project MembersDue to ongoing political and social conflicts, the number of international refugees has been increasing. Refugees are exposed to severe mental and physical strain, as well as traumatic experiences during their flight. As a consequence, the risk of psychiatric disorders is markedly increased among international refugees with particularities based on gender. International organizations have criticized the lack of early interventions as a key problem, because untreated mental disorders are often difficult to cure at a later stage. Today, exercise and sport have been successfully employed to treat a wide range of psychiatric disorders. With PTSD patients, however, very limited empirical evidence exists, and studies carried out with international refugees are nearly non-existent. In 2017, we have implemented a first pilot one-group pre-test/post-test study in a Greek refugee camp, corroborating the potential benefits of exercise and sport on refugees' mental health and fitness. The proposed study will take place in the Koutsochero refugee camp, located close to the city of Larissa (Greece). The randomized controlled trial will include an exercise and sport intervention group (n=68) and a wait-list control group (n=68). Participants (50% men/women, 16-59 years) will be assessed three times at baseline, immediately post-intervention (after 3 months), and follow-up (after 6 months). In the second year of study, the program will be opened to all camp residents. Exercise and sport will be offered five times per week (60 min/session) for three months. Participants will participate in at least two sessions per week. The program is developed according to the participants' needs and preferences and they will be able to choose between a range of activities. PTSD symptoms will serve as primary outcome. Several secondary outcomes will be assessed, and the project will identify potential gender issues. A strategy will be developed how the exercise and sport program can be continued after the SNIS funding comes to an end, and how the program can be scaled up beyond the borders of the Koutsochero camp. Learning from the extraordinary: The molecular underpinnings of extreme memorizers Research Project | 2 Project MembersStellen Sie sich vor, Sie könnten sich für jedes Datum seit Jahrzehnten an den Wochentag erinnern und sich wüssten noch, was Sie an jedem dieser Tage getan haben. Was unmöglich klingt, existiert tatsächlich als extrem seltener Befund, genannt Highly Superior Autobiographical Memory (HSAM). Derzeit sind weltweit rund 60 Personen mit HSAM bekannt. Wir werden eine eingehende genetische Analyse von HSAM Individuen durchführen, um den molekularen Mechanismus zu suchen, der diesem extrem stabilen Gedächtnis zugrunde liegt. Bei Erfolg könnten die Ergebnisse unser Verständnis des Gedächtnisses verändern und neue Wege zur Behandlung von Gedächtnisstörungen eröffnen. Population-wide screens of the immune repertoire: a reverse personalized-medicine approach Research Project | 2 Project MembersAntibodies are crucial for the intact function of the human immune system. For example, they are responsible for the body's defense against bacteria and cancer cells, but are also implicated in a variety of neuropsychiatric disorders. The present driver-project aims at identifying rare antibodies that will help elucidating mechanisms of disease and help identifying suitable targets for drug discovery. This will be achieved by an unprecedented high-throughput search for auto-antibodies in blood samples of thousands of participants. The Transfaculty Research Platform Molecular and Cognitive Neurosciences represents Basel's involvement in this Zurich-Basel alliance project. The Platform contributes with a unique combination of functional and structural brain imaging, genetic, behavioral, and biological data from thousands of healthy young participants who underwent detailed neuropsychological assessments. The intelligent interconnection of this database information with the data arising from the large, unselected patient cohort of the University Hospital Zurich will be crucial for the informed decisions that will result in the prioritization of novel drug targets. Exercise, Arterial Cross-Talk Modulation and Inflammation in an Ageing Population: miRNA substudy Research Project | 4 Project MembersWe have previously validated a multidisciplinary research perspective encompassing epigenetic pathways embedded in vascular and exercise medicine. Exercise can improve microvascular phenotype leading to healthier ageing and better cardiovascular (CV) outcome. Cardiorespiratory fitness has been identified as a sixth vital sign and a valid surrogate marker for cardiovascular and all-cause mortality. Regular intensive exercise has previously been shown to induce reprogramming of DNA methylation of p66 Shc gene promoter, thereby inhibiting p66 Shc gene expression and reducing systemic oxidative stress. This molecular pathway was associated with improvements of retinal microvascular health and may represent a mechanistic link whereby exercise protects against age-related oxidative stress and microvascular damage. Retinal vessel analysis is a new diagnostic approach to quantify microvascular remodeling and stratify CV risk. The retinal phenotype has been associated with incidence CV disease and mortality. Circulating microRNAs (miRNAs) are small non-coding nucleotides that regulate cell function. Upstream of the vascular phenotype, miRNAs are post-transcriptional regulators of inflammation, oxidative stress and lipid metabolism, which contribute to the progression of atherosclerosis. Analyzing circulating miRNAs has the potential to improve CV risk stratification and better understand the underlying gene expression in cardiovascular disease. Previous studies have highlighted the potential of single target miRNAs as a biomarker-guided CV therapy and novel tool in personalized medicine. The investigation of specific single miRNA expressions after acute or long-term exercise interventions have illustrated new insights in vascular regeneration processes. However, the next step, to identify new pathways from upstream gene regulation to the downstream manifest phenotype, is to use an untargeted circulating miRNA approach in combination with sensitive vascular phenotyping. In our approach, exercise is used as a treatment concept to identify miRNAs that may be targeted in future treatment strategies, such as development of gene-specific inhibitors or mimetics of miRNA expression. In this study, we will assess untargeted circulating miRNAs by next generation sequencing (NGS) in 38 healthy older active (HOA), 36 healthy older sedentary (HOS) as well as 84 older sedentary CV risk patients (OSR) aged 50 to 80 years. Our first aim is to determine the association of long-term physical activity with retinal endothelial function and circulating miRNA profile in HOA and HOS as well as OSR. Our second aim is to examine the effects of a high-intensity interval training (HIIT) on retinal endothelial function and circulating miRNA profile in OSR. Data acquisition of retinal endothelial function and blood sampling have been performed between 2016 and 2018. The proposed one-year grant will enable NGS from available blood samples to analyze miRNA expression and associations with retinal microvascular phenotype in active and sedentary older adults. The study will allow for an innovative approach to define new pathways from genotype to phenotype in order to disentangle molecular interactions in the process of microvascular ageing associated with physical activity behavior. The role of epigenetic modification of glucocorticoid-related genes in aversive memory and post-traumatic stress disorder Research Project | 2 Project MembersPost-traumatic stress disorder (PTSD) is a chronic pathological response to a traumatic event. Aversive memories of such an event are thought to play an important role in the pathogenesis and symptomatology of the disorder. We have previously shown that glucocorticoids play a critical role in regulating aversive memories with potentially important implications for PTSD. Furthermore, we have shown that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to aversive memories and PTSD risk in survivors of the Rwandan genocide. In the current application we propose to extend our previous work by studying epigenetic modifications in genes related to glucocorticoid signalling using gene-set based methods on whole-genome methylation data in survivors of the Rwandan genocide. In addition, we will have the possibility to further explore the findings, in a healthy population with existing genome-wide methylation data regarding aversive memory processing and its underlying neural correlates. The findings of the proposed study will add to the understanding of the mechanisms related to increased PTSD risk after traumatic events. IMAging GEnetics for MENtal Disorders (IMAGEMEND) Research Project | 3 Project MembersMental disorders are leading causes of disability, absence from work and premature retirement in Europe. While magnetic resonance imaging (MRI) facilities are broadly available and a vast research literature exists, few neuroimaging applications have reached clinical practice in psychiatry. A major problem is that mental illnesses are currently diagnosed as discrete entities defined clinically. Instead, recent results show that mental disorders are best understood as quantitative alterations in neural systems relevant across traditional diagnostic boundaries that reflect individual, genetic and environmental risk factors. In the IMAGEMEND consortium, we aim to discover these systems to identify the patient characteristics most relevant for treatment, derive biomarkers and decision rules from this systems-level dimensional account, and systematically validate biomarker panels in patient, high-risk and epidemiological samples to produce automated imaging-based diagnostic and predictive tests tailored for wide distribution throughout Europe in standard clinical settings. Focusing on schizophrenia, bipolar disorder and attention deficit-hyperactivity disorder, we have assembled Europe's largest dataset combining neuroimaging, genetic, environmental, cognitive and clinical information on approximately 13000 participants, and have recruited international replication datasets of more than 30000 people. This unique resource will be processed using a new generation of multivariate statistical analysis to optimize existing imaging technology for the benefit of patients. We will also develop new imaging technology to enable the direct imaging-based therapeutic modification of neural circuits through rapid real-time MRI. Our deliverables will promote personalized treatment through more accurate patient stratification, allow diagnoses at the pre-symptomatic stage for early intervention and prevention, and improve prediction of treatment response and disease progression. Gene-environment interactions in the etiology, symptomatology and treatment of Posttraumatic Stress Disorder Research Project | 2 Project MembersGenetic risk factors contribute to the susceptibility of developing Posttraumatic Stress Disorder (PTSD) after exposure to traumatic events. A comprehensive characterization of the genetics of PTSD could contribute to a better understanding of the underlying molecular mechanisms and provide important insights for the development of drugs to prevent and treat PTSD. Furthermore, PTSD is uniquely suited for the study of gene × environment interactions since trauma exposure constitutes a necessary factor for the disorder to manifest. Likewise, in contrast to other disorders, the relevant environmental risk factor can be quantified and included in the analyses, which makes PTSD uniquely suited for etiological research on individual vulnerability factors. The recent development of cost-effective genotyping platforms allows high-resolution genome-wide association studies for the unbiased identification of novel genes related to PTSD. This project aims at systematically investigating the genetics of PTSD, by using genome-wide scans in a large sample of individuals from conflict regions in Africa. More specifically, we plan to investigate gene × environment interactions in the etiology and symptomatology of PTSD. The identified genetic risk factors will be validated in an independent sample and their influence on the response to trauma-focused therapeutic treatment will be analyzed. The results of this project will contribute to a deeper understanding of genetic risk factors involved in PTSD etiology and their role in trauma-focused therapy. 123 123 OverviewMembersPublicationsProjects & Collaborations
Projects & Collaborations 24 foundShow per page10 10 20 50 Feasibility study on the use of Ze 91019 on day-time cognition and quality of life in people with occasional sleep problems Research Project | 2 Project MembersIt is well known that cognitive performance and quality of life can be impaired after nights of little or no sleep (Hudson, 2020) (Roth, 2007). Therefore, people with occasional sleep problems, i.e. with 1-2 nights per week with impaired sleep, can suffer from impaired cognition the following day. Moreover, occasional sleep problems may lead to reduced overall quality of life (Buysse, 2007). Many people with insomnia do not wish to use conventional hypnotic drugs because of concerns about side effects and the risks of tolerance and dependence, and others do not want to spend the time and efforts required with behavioral therapies (Vincent, 2001). Thus, there is an increasing interest in the use of complementary and alternative medicines, such as herbal and dietary supplements, partly because of their natural properties and perceived relative absence of residual effects. Valerian and hop have both been an integral part of traditional medicine for Centuries. Pharmacological and clinical studies are available demonstrating the applicability of Redormin ® 500, a 45% methanolic extract from valerian root and from hop strobiles, in sleep disorders (Abourashed, 2004), (Dimpfel, 2006), (Morin, 2005), (Koetter, 2007). Not only could the effect be visualized through EEG measurements, but also new ideas regarding the mechanism of action were brought forth (Koetter, 2007)). Currently an agonistic effect on central adenosine receptors, and thus a counteracting effect on caffeine induced sleeplessness through the lignans in hydrophilic valerian root extracts is discussed as a potential mechanism of action for valerian root extract (Schumacher, 2002). The studies available mainly focused on the improvement of sleep quality rather than on improvements of cognitive performance and day performance. Therefore, the aim of this feasibility study is to determine the effect of Redormin® 500 on day-time cognition and quality of life in people with occasional sleep problems. Simulation Hallucinations Using Mixed Reality Research Project | 2 Project MembersBackground: Reality discrimination (RD), the ability to discriminate between perception and imagination, is central to the assessment of psychiatric health, especially in the context of psychotic disorders. Impairments in RD are associated with auditory and visual hallucination proneness in patients with psychotic disorders as well as the general population. However, there are currently no instruments available that allow for the combined assessment of auditory and visual RD performance. Furthermore, RD paradigms are limited in their ability to account for the complex phenomenology of natural hallucinations. More sensitive assessment methods are crucial to improve patient care, diagnosis, and treatment. Objectives: The overall goal of the proposed research is to develop a dual-modality RD paradigm to investigate the cognitive mechanisms underlying visual and auditory hallucinations and their relation to psychotic disorders. The first objective is to simulate hallucinatory perceptual experiences using a novel immersive technology method to manipulate the visual and auditory perception of natural environments. The second objective is to extend this simulation into a dual-modality RD paradigm based on the signal detection framework. Thereafter, the RD paradigm will be applied in healthy adults from the general population (Objective 3) and patients diagnosed with psychotic disorder (Objective 4). Methods: A first study will test the hypothesis that visual and auditory RD performance is associated with hallucination proneness in the general population (N=100). A second study will evaluate visual and auditory RD performance in a sample of patients with psychotic disorders (N=30) and will test the hypothesis that these patients are impaired in RD relative to matched controls from Study 1. In both studies, participants will complete the newly-designed RD paradigm as well as assessments of hallucination proneness and predisposition to psychosis (Study 1) or psychosis severity (Study 2). Expected Value of the Proposed Project: This research will contribute to the understanding of visual and auditory hallucinations and their shared cognitive mechanisms in the general population and patients with psychotic disorders. The novel RD paradigm may provide an improved measure of psychosis proneness that is more objective and behaviorally sensitive to hallucinatory experiences. This research may have important implications for the assessment, treatment, and early detection of psychotic disorders and will provide an ecologically valid framework from which innovative psychological interventions can be developed. Genome-guided drug identification: A randomized placebo-controlled trial on the influence of fampridine on working memory Research Project | 2 Project MembersBackground: The discrepancy between the urgent need for improved therapeutic compounds and the lack of significant development of novel drugs illustrates the importance of pursuing new strategies aimed at identifying druggable targets related to psychiatric disease. Recent advances in large-scale genetic studies suggest that human genetic discoveries have the potential of translating into novel treatment targets for psychiatric conditions. Aim: To implement a drug repurposing strategy and perform a proof-of-concept clinical trial on the influence of a potassium channel blocker (fampridine) on working memory performance, an intermediate trait of psychiatric disorders. Methods: Guided by recent genetic findings in schizophrenia, we focus on those loci that point to genes targeted by currently approved drugs. As starting point serves the large schizophrenia genome-wide association study that provided genes robustly linked to the risk for the disorder. As intermediate filtering layer serves working memory performance, which is a well-established intermediate phenotype for schizophrenia. Finally, one repurposing candidate, fampridine, is selected and tested for its putative influence on working memory performance in the framework of a randomized placebo-controlled trial in healthy subjects. Expected value: We anticipate that the exponentially increased genetic knowledge of psychiatric disorders together with the use of biologically-informed phenotypes and appropriate data-mining methodology will be a starting point for the identification of novel drug targets and treatments, i.e. the very goal of the present proposal. Should the current randomized control trial turn out positive, it might open new avenues for the treatment of cognitive symptoms in psychiatric disorders with known and hopefully also new and specific potassium channel blockers. Effects of an exercise and sport intervention among refugees living in a Greek refugee camp: A randomized controlled trial Research Project | 10 Project MembersDue to ongoing political and social conflicts, the number of international refugees has been increasing. Refugees are exposed to severe mental and physical strain, as well as traumatic experiences during their flight. As a consequence, the risk of psychiatric disorders is markedly increased among international refugees with particularities based on gender. International organizations have criticized the lack of early interventions as a key problem, because untreated mental disorders are often difficult to cure at a later stage. Today, exercise and sport have been successfully employed to treat a wide range of psychiatric disorders. With PTSD patients, however, very limited empirical evidence exists, and studies carried out with international refugees are nearly non-existent. In 2017, we have implemented a first pilot one-group pre-test/post-test study in a Greek refugee camp, corroborating the potential benefits of exercise and sport on refugees' mental health and fitness. The proposed study will take place in the Koutsochero refugee camp, located close to the city of Larissa (Greece). The randomized controlled trial will include an exercise and sport intervention group (n=68) and a wait-list control group (n=68). Participants (50% men/women, 16-59 years) will be assessed three times at baseline, immediately post-intervention (after 3 months), and follow-up (after 6 months). In the second year of study, the program will be opened to all camp residents. Exercise and sport will be offered five times per week (60 min/session) for three months. Participants will participate in at least two sessions per week. The program is developed according to the participants' needs and preferences and they will be able to choose between a range of activities. PTSD symptoms will serve as primary outcome. Several secondary outcomes will be assessed, and the project will identify potential gender issues. A strategy will be developed how the exercise and sport program can be continued after the SNIS funding comes to an end, and how the program can be scaled up beyond the borders of the Koutsochero camp. Learning from the extraordinary: The molecular underpinnings of extreme memorizers Research Project | 2 Project MembersStellen Sie sich vor, Sie könnten sich für jedes Datum seit Jahrzehnten an den Wochentag erinnern und sich wüssten noch, was Sie an jedem dieser Tage getan haben. Was unmöglich klingt, existiert tatsächlich als extrem seltener Befund, genannt Highly Superior Autobiographical Memory (HSAM). Derzeit sind weltweit rund 60 Personen mit HSAM bekannt. Wir werden eine eingehende genetische Analyse von HSAM Individuen durchführen, um den molekularen Mechanismus zu suchen, der diesem extrem stabilen Gedächtnis zugrunde liegt. Bei Erfolg könnten die Ergebnisse unser Verständnis des Gedächtnisses verändern und neue Wege zur Behandlung von Gedächtnisstörungen eröffnen. Population-wide screens of the immune repertoire: a reverse personalized-medicine approach Research Project | 2 Project MembersAntibodies are crucial for the intact function of the human immune system. For example, they are responsible for the body's defense against bacteria and cancer cells, but are also implicated in a variety of neuropsychiatric disorders. The present driver-project aims at identifying rare antibodies that will help elucidating mechanisms of disease and help identifying suitable targets for drug discovery. This will be achieved by an unprecedented high-throughput search for auto-antibodies in blood samples of thousands of participants. The Transfaculty Research Platform Molecular and Cognitive Neurosciences represents Basel's involvement in this Zurich-Basel alliance project. The Platform contributes with a unique combination of functional and structural brain imaging, genetic, behavioral, and biological data from thousands of healthy young participants who underwent detailed neuropsychological assessments. The intelligent interconnection of this database information with the data arising from the large, unselected patient cohort of the University Hospital Zurich will be crucial for the informed decisions that will result in the prioritization of novel drug targets. Exercise, Arterial Cross-Talk Modulation and Inflammation in an Ageing Population: miRNA substudy Research Project | 4 Project MembersWe have previously validated a multidisciplinary research perspective encompassing epigenetic pathways embedded in vascular and exercise medicine. Exercise can improve microvascular phenotype leading to healthier ageing and better cardiovascular (CV) outcome. Cardiorespiratory fitness has been identified as a sixth vital sign and a valid surrogate marker for cardiovascular and all-cause mortality. Regular intensive exercise has previously been shown to induce reprogramming of DNA methylation of p66 Shc gene promoter, thereby inhibiting p66 Shc gene expression and reducing systemic oxidative stress. This molecular pathway was associated with improvements of retinal microvascular health and may represent a mechanistic link whereby exercise protects against age-related oxidative stress and microvascular damage. Retinal vessel analysis is a new diagnostic approach to quantify microvascular remodeling and stratify CV risk. The retinal phenotype has been associated with incidence CV disease and mortality. Circulating microRNAs (miRNAs) are small non-coding nucleotides that regulate cell function. Upstream of the vascular phenotype, miRNAs are post-transcriptional regulators of inflammation, oxidative stress and lipid metabolism, which contribute to the progression of atherosclerosis. Analyzing circulating miRNAs has the potential to improve CV risk stratification and better understand the underlying gene expression in cardiovascular disease. Previous studies have highlighted the potential of single target miRNAs as a biomarker-guided CV therapy and novel tool in personalized medicine. The investigation of specific single miRNA expressions after acute or long-term exercise interventions have illustrated new insights in vascular regeneration processes. However, the next step, to identify new pathways from upstream gene regulation to the downstream manifest phenotype, is to use an untargeted circulating miRNA approach in combination with sensitive vascular phenotyping. In our approach, exercise is used as a treatment concept to identify miRNAs that may be targeted in future treatment strategies, such as development of gene-specific inhibitors or mimetics of miRNA expression. In this study, we will assess untargeted circulating miRNAs by next generation sequencing (NGS) in 38 healthy older active (HOA), 36 healthy older sedentary (HOS) as well as 84 older sedentary CV risk patients (OSR) aged 50 to 80 years. Our first aim is to determine the association of long-term physical activity with retinal endothelial function and circulating miRNA profile in HOA and HOS as well as OSR. Our second aim is to examine the effects of a high-intensity interval training (HIIT) on retinal endothelial function and circulating miRNA profile in OSR. Data acquisition of retinal endothelial function and blood sampling have been performed between 2016 and 2018. The proposed one-year grant will enable NGS from available blood samples to analyze miRNA expression and associations with retinal microvascular phenotype in active and sedentary older adults. The study will allow for an innovative approach to define new pathways from genotype to phenotype in order to disentangle molecular interactions in the process of microvascular ageing associated with physical activity behavior. The role of epigenetic modification of glucocorticoid-related genes in aversive memory and post-traumatic stress disorder Research Project | 2 Project MembersPost-traumatic stress disorder (PTSD) is a chronic pathological response to a traumatic event. Aversive memories of such an event are thought to play an important role in the pathogenesis and symptomatology of the disorder. We have previously shown that glucocorticoids play a critical role in regulating aversive memories with potentially important implications for PTSD. Furthermore, we have shown that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to aversive memories and PTSD risk in survivors of the Rwandan genocide. In the current application we propose to extend our previous work by studying epigenetic modifications in genes related to glucocorticoid signalling using gene-set based methods on whole-genome methylation data in survivors of the Rwandan genocide. In addition, we will have the possibility to further explore the findings, in a healthy population with existing genome-wide methylation data regarding aversive memory processing and its underlying neural correlates. The findings of the proposed study will add to the understanding of the mechanisms related to increased PTSD risk after traumatic events. IMAging GEnetics for MENtal Disorders (IMAGEMEND) Research Project | 3 Project MembersMental disorders are leading causes of disability, absence from work and premature retirement in Europe. While magnetic resonance imaging (MRI) facilities are broadly available and a vast research literature exists, few neuroimaging applications have reached clinical practice in psychiatry. A major problem is that mental illnesses are currently diagnosed as discrete entities defined clinically. Instead, recent results show that mental disorders are best understood as quantitative alterations in neural systems relevant across traditional diagnostic boundaries that reflect individual, genetic and environmental risk factors. In the IMAGEMEND consortium, we aim to discover these systems to identify the patient characteristics most relevant for treatment, derive biomarkers and decision rules from this systems-level dimensional account, and systematically validate biomarker panels in patient, high-risk and epidemiological samples to produce automated imaging-based diagnostic and predictive tests tailored for wide distribution throughout Europe in standard clinical settings. Focusing on schizophrenia, bipolar disorder and attention deficit-hyperactivity disorder, we have assembled Europe's largest dataset combining neuroimaging, genetic, environmental, cognitive and clinical information on approximately 13000 participants, and have recruited international replication datasets of more than 30000 people. This unique resource will be processed using a new generation of multivariate statistical analysis to optimize existing imaging technology for the benefit of patients. We will also develop new imaging technology to enable the direct imaging-based therapeutic modification of neural circuits through rapid real-time MRI. Our deliverables will promote personalized treatment through more accurate patient stratification, allow diagnoses at the pre-symptomatic stage for early intervention and prevention, and improve prediction of treatment response and disease progression. Gene-environment interactions in the etiology, symptomatology and treatment of Posttraumatic Stress Disorder Research Project | 2 Project MembersGenetic risk factors contribute to the susceptibility of developing Posttraumatic Stress Disorder (PTSD) after exposure to traumatic events. A comprehensive characterization of the genetics of PTSD could contribute to a better understanding of the underlying molecular mechanisms and provide important insights for the development of drugs to prevent and treat PTSD. Furthermore, PTSD is uniquely suited for the study of gene × environment interactions since trauma exposure constitutes a necessary factor for the disorder to manifest. Likewise, in contrast to other disorders, the relevant environmental risk factor can be quantified and included in the analyses, which makes PTSD uniquely suited for etiological research on individual vulnerability factors. The recent development of cost-effective genotyping platforms allows high-resolution genome-wide association studies for the unbiased identification of novel genes related to PTSD. This project aims at systematically investigating the genetics of PTSD, by using genome-wide scans in a large sample of individuals from conflict regions in Africa. More specifically, we plan to investigate gene × environment interactions in the etiology and symptomatology of PTSD. The identified genetic risk factors will be validated in an independent sample and their influence on the response to trauma-focused therapeutic treatment will be analyzed. The results of this project will contribute to a deeper understanding of genetic risk factors involved in PTSD etiology and their role in trauma-focused therapy. 123 123
Feasibility study on the use of Ze 91019 on day-time cognition and quality of life in people with occasional sleep problems Research Project | 2 Project MembersIt is well known that cognitive performance and quality of life can be impaired after nights of little or no sleep (Hudson, 2020) (Roth, 2007). Therefore, people with occasional sleep problems, i.e. with 1-2 nights per week with impaired sleep, can suffer from impaired cognition the following day. Moreover, occasional sleep problems may lead to reduced overall quality of life (Buysse, 2007). Many people with insomnia do not wish to use conventional hypnotic drugs because of concerns about side effects and the risks of tolerance and dependence, and others do not want to spend the time and efforts required with behavioral therapies (Vincent, 2001). Thus, there is an increasing interest in the use of complementary and alternative medicines, such as herbal and dietary supplements, partly because of their natural properties and perceived relative absence of residual effects. Valerian and hop have both been an integral part of traditional medicine for Centuries. Pharmacological and clinical studies are available demonstrating the applicability of Redormin ® 500, a 45% methanolic extract from valerian root and from hop strobiles, in sleep disorders (Abourashed, 2004), (Dimpfel, 2006), (Morin, 2005), (Koetter, 2007). Not only could the effect be visualized through EEG measurements, but also new ideas regarding the mechanism of action were brought forth (Koetter, 2007)). Currently an agonistic effect on central adenosine receptors, and thus a counteracting effect on caffeine induced sleeplessness through the lignans in hydrophilic valerian root extracts is discussed as a potential mechanism of action for valerian root extract (Schumacher, 2002). The studies available mainly focused on the improvement of sleep quality rather than on improvements of cognitive performance and day performance. Therefore, the aim of this feasibility study is to determine the effect of Redormin® 500 on day-time cognition and quality of life in people with occasional sleep problems.
Simulation Hallucinations Using Mixed Reality Research Project | 2 Project MembersBackground: Reality discrimination (RD), the ability to discriminate between perception and imagination, is central to the assessment of psychiatric health, especially in the context of psychotic disorders. Impairments in RD are associated with auditory and visual hallucination proneness in patients with psychotic disorders as well as the general population. However, there are currently no instruments available that allow for the combined assessment of auditory and visual RD performance. Furthermore, RD paradigms are limited in their ability to account for the complex phenomenology of natural hallucinations. More sensitive assessment methods are crucial to improve patient care, diagnosis, and treatment. Objectives: The overall goal of the proposed research is to develop a dual-modality RD paradigm to investigate the cognitive mechanisms underlying visual and auditory hallucinations and their relation to psychotic disorders. The first objective is to simulate hallucinatory perceptual experiences using a novel immersive technology method to manipulate the visual and auditory perception of natural environments. The second objective is to extend this simulation into a dual-modality RD paradigm based on the signal detection framework. Thereafter, the RD paradigm will be applied in healthy adults from the general population (Objective 3) and patients diagnosed with psychotic disorder (Objective 4). Methods: A first study will test the hypothesis that visual and auditory RD performance is associated with hallucination proneness in the general population (N=100). A second study will evaluate visual and auditory RD performance in a sample of patients with psychotic disorders (N=30) and will test the hypothesis that these patients are impaired in RD relative to matched controls from Study 1. In both studies, participants will complete the newly-designed RD paradigm as well as assessments of hallucination proneness and predisposition to psychosis (Study 1) or psychosis severity (Study 2). Expected Value of the Proposed Project: This research will contribute to the understanding of visual and auditory hallucinations and their shared cognitive mechanisms in the general population and patients with psychotic disorders. The novel RD paradigm may provide an improved measure of psychosis proneness that is more objective and behaviorally sensitive to hallucinatory experiences. This research may have important implications for the assessment, treatment, and early detection of psychotic disorders and will provide an ecologically valid framework from which innovative psychological interventions can be developed.
Genome-guided drug identification: A randomized placebo-controlled trial on the influence of fampridine on working memory Research Project | 2 Project MembersBackground: The discrepancy between the urgent need for improved therapeutic compounds and the lack of significant development of novel drugs illustrates the importance of pursuing new strategies aimed at identifying druggable targets related to psychiatric disease. Recent advances in large-scale genetic studies suggest that human genetic discoveries have the potential of translating into novel treatment targets for psychiatric conditions. Aim: To implement a drug repurposing strategy and perform a proof-of-concept clinical trial on the influence of a potassium channel blocker (fampridine) on working memory performance, an intermediate trait of psychiatric disorders. Methods: Guided by recent genetic findings in schizophrenia, we focus on those loci that point to genes targeted by currently approved drugs. As starting point serves the large schizophrenia genome-wide association study that provided genes robustly linked to the risk for the disorder. As intermediate filtering layer serves working memory performance, which is a well-established intermediate phenotype for schizophrenia. Finally, one repurposing candidate, fampridine, is selected and tested for its putative influence on working memory performance in the framework of a randomized placebo-controlled trial in healthy subjects. Expected value: We anticipate that the exponentially increased genetic knowledge of psychiatric disorders together with the use of biologically-informed phenotypes and appropriate data-mining methodology will be a starting point for the identification of novel drug targets and treatments, i.e. the very goal of the present proposal. Should the current randomized control trial turn out positive, it might open new avenues for the treatment of cognitive symptoms in psychiatric disorders with known and hopefully also new and specific potassium channel blockers.
Effects of an exercise and sport intervention among refugees living in a Greek refugee camp: A randomized controlled trial Research Project | 10 Project MembersDue to ongoing political and social conflicts, the number of international refugees has been increasing. Refugees are exposed to severe mental and physical strain, as well as traumatic experiences during their flight. As a consequence, the risk of psychiatric disorders is markedly increased among international refugees with particularities based on gender. International organizations have criticized the lack of early interventions as a key problem, because untreated mental disorders are often difficult to cure at a later stage. Today, exercise and sport have been successfully employed to treat a wide range of psychiatric disorders. With PTSD patients, however, very limited empirical evidence exists, and studies carried out with international refugees are nearly non-existent. In 2017, we have implemented a first pilot one-group pre-test/post-test study in a Greek refugee camp, corroborating the potential benefits of exercise and sport on refugees' mental health and fitness. The proposed study will take place in the Koutsochero refugee camp, located close to the city of Larissa (Greece). The randomized controlled trial will include an exercise and sport intervention group (n=68) and a wait-list control group (n=68). Participants (50% men/women, 16-59 years) will be assessed three times at baseline, immediately post-intervention (after 3 months), and follow-up (after 6 months). In the second year of study, the program will be opened to all camp residents. Exercise and sport will be offered five times per week (60 min/session) for three months. Participants will participate in at least two sessions per week. The program is developed according to the participants' needs and preferences and they will be able to choose between a range of activities. PTSD symptoms will serve as primary outcome. Several secondary outcomes will be assessed, and the project will identify potential gender issues. A strategy will be developed how the exercise and sport program can be continued after the SNIS funding comes to an end, and how the program can be scaled up beyond the borders of the Koutsochero camp.
Learning from the extraordinary: The molecular underpinnings of extreme memorizers Research Project | 2 Project MembersStellen Sie sich vor, Sie könnten sich für jedes Datum seit Jahrzehnten an den Wochentag erinnern und sich wüssten noch, was Sie an jedem dieser Tage getan haben. Was unmöglich klingt, existiert tatsächlich als extrem seltener Befund, genannt Highly Superior Autobiographical Memory (HSAM). Derzeit sind weltweit rund 60 Personen mit HSAM bekannt. Wir werden eine eingehende genetische Analyse von HSAM Individuen durchführen, um den molekularen Mechanismus zu suchen, der diesem extrem stabilen Gedächtnis zugrunde liegt. Bei Erfolg könnten die Ergebnisse unser Verständnis des Gedächtnisses verändern und neue Wege zur Behandlung von Gedächtnisstörungen eröffnen.
Population-wide screens of the immune repertoire: a reverse personalized-medicine approach Research Project | 2 Project MembersAntibodies are crucial for the intact function of the human immune system. For example, they are responsible for the body's defense against bacteria and cancer cells, but are also implicated in a variety of neuropsychiatric disorders. The present driver-project aims at identifying rare antibodies that will help elucidating mechanisms of disease and help identifying suitable targets for drug discovery. This will be achieved by an unprecedented high-throughput search for auto-antibodies in blood samples of thousands of participants. The Transfaculty Research Platform Molecular and Cognitive Neurosciences represents Basel's involvement in this Zurich-Basel alliance project. The Platform contributes with a unique combination of functional and structural brain imaging, genetic, behavioral, and biological data from thousands of healthy young participants who underwent detailed neuropsychological assessments. The intelligent interconnection of this database information with the data arising from the large, unselected patient cohort of the University Hospital Zurich will be crucial for the informed decisions that will result in the prioritization of novel drug targets.
Exercise, Arterial Cross-Talk Modulation and Inflammation in an Ageing Population: miRNA substudy Research Project | 4 Project MembersWe have previously validated a multidisciplinary research perspective encompassing epigenetic pathways embedded in vascular and exercise medicine. Exercise can improve microvascular phenotype leading to healthier ageing and better cardiovascular (CV) outcome. Cardiorespiratory fitness has been identified as a sixth vital sign and a valid surrogate marker for cardiovascular and all-cause mortality. Regular intensive exercise has previously been shown to induce reprogramming of DNA methylation of p66 Shc gene promoter, thereby inhibiting p66 Shc gene expression and reducing systemic oxidative stress. This molecular pathway was associated with improvements of retinal microvascular health and may represent a mechanistic link whereby exercise protects against age-related oxidative stress and microvascular damage. Retinal vessel analysis is a new diagnostic approach to quantify microvascular remodeling and stratify CV risk. The retinal phenotype has been associated with incidence CV disease and mortality. Circulating microRNAs (miRNAs) are small non-coding nucleotides that regulate cell function. Upstream of the vascular phenotype, miRNAs are post-transcriptional regulators of inflammation, oxidative stress and lipid metabolism, which contribute to the progression of atherosclerosis. Analyzing circulating miRNAs has the potential to improve CV risk stratification and better understand the underlying gene expression in cardiovascular disease. Previous studies have highlighted the potential of single target miRNAs as a biomarker-guided CV therapy and novel tool in personalized medicine. The investigation of specific single miRNA expressions after acute or long-term exercise interventions have illustrated new insights in vascular regeneration processes. However, the next step, to identify new pathways from upstream gene regulation to the downstream manifest phenotype, is to use an untargeted circulating miRNA approach in combination with sensitive vascular phenotyping. In our approach, exercise is used as a treatment concept to identify miRNAs that may be targeted in future treatment strategies, such as development of gene-specific inhibitors or mimetics of miRNA expression. In this study, we will assess untargeted circulating miRNAs by next generation sequencing (NGS) in 38 healthy older active (HOA), 36 healthy older sedentary (HOS) as well as 84 older sedentary CV risk patients (OSR) aged 50 to 80 years. Our first aim is to determine the association of long-term physical activity with retinal endothelial function and circulating miRNA profile in HOA and HOS as well as OSR. Our second aim is to examine the effects of a high-intensity interval training (HIIT) on retinal endothelial function and circulating miRNA profile in OSR. Data acquisition of retinal endothelial function and blood sampling have been performed between 2016 and 2018. The proposed one-year grant will enable NGS from available blood samples to analyze miRNA expression and associations with retinal microvascular phenotype in active and sedentary older adults. The study will allow for an innovative approach to define new pathways from genotype to phenotype in order to disentangle molecular interactions in the process of microvascular ageing associated with physical activity behavior.
The role of epigenetic modification of glucocorticoid-related genes in aversive memory and post-traumatic stress disorder Research Project | 2 Project MembersPost-traumatic stress disorder (PTSD) is a chronic pathological response to a traumatic event. Aversive memories of such an event are thought to play an important role in the pathogenesis and symptomatology of the disorder. We have previously shown that glucocorticoids play a critical role in regulating aversive memories with potentially important implications for PTSD. Furthermore, we have shown that an epigenetic modification of the glucocorticoid receptor gene promoter is linked to aversive memories and PTSD risk in survivors of the Rwandan genocide. In the current application we propose to extend our previous work by studying epigenetic modifications in genes related to glucocorticoid signalling using gene-set based methods on whole-genome methylation data in survivors of the Rwandan genocide. In addition, we will have the possibility to further explore the findings, in a healthy population with existing genome-wide methylation data regarding aversive memory processing and its underlying neural correlates. The findings of the proposed study will add to the understanding of the mechanisms related to increased PTSD risk after traumatic events.
IMAging GEnetics for MENtal Disorders (IMAGEMEND) Research Project | 3 Project MembersMental disorders are leading causes of disability, absence from work and premature retirement in Europe. While magnetic resonance imaging (MRI) facilities are broadly available and a vast research literature exists, few neuroimaging applications have reached clinical practice in psychiatry. A major problem is that mental illnesses are currently diagnosed as discrete entities defined clinically. Instead, recent results show that mental disorders are best understood as quantitative alterations in neural systems relevant across traditional diagnostic boundaries that reflect individual, genetic and environmental risk factors. In the IMAGEMEND consortium, we aim to discover these systems to identify the patient characteristics most relevant for treatment, derive biomarkers and decision rules from this systems-level dimensional account, and systematically validate biomarker panels in patient, high-risk and epidemiological samples to produce automated imaging-based diagnostic and predictive tests tailored for wide distribution throughout Europe in standard clinical settings. Focusing on schizophrenia, bipolar disorder and attention deficit-hyperactivity disorder, we have assembled Europe's largest dataset combining neuroimaging, genetic, environmental, cognitive and clinical information on approximately 13000 participants, and have recruited international replication datasets of more than 30000 people. This unique resource will be processed using a new generation of multivariate statistical analysis to optimize existing imaging technology for the benefit of patients. We will also develop new imaging technology to enable the direct imaging-based therapeutic modification of neural circuits through rapid real-time MRI. Our deliverables will promote personalized treatment through more accurate patient stratification, allow diagnoses at the pre-symptomatic stage for early intervention and prevention, and improve prediction of treatment response and disease progression.
Gene-environment interactions in the etiology, symptomatology and treatment of Posttraumatic Stress Disorder Research Project | 2 Project MembersGenetic risk factors contribute to the susceptibility of developing Posttraumatic Stress Disorder (PTSD) after exposure to traumatic events. A comprehensive characterization of the genetics of PTSD could contribute to a better understanding of the underlying molecular mechanisms and provide important insights for the development of drugs to prevent and treat PTSD. Furthermore, PTSD is uniquely suited for the study of gene × environment interactions since trauma exposure constitutes a necessary factor for the disorder to manifest. Likewise, in contrast to other disorders, the relevant environmental risk factor can be quantified and included in the analyses, which makes PTSD uniquely suited for etiological research on individual vulnerability factors. The recent development of cost-effective genotyping platforms allows high-resolution genome-wide association studies for the unbiased identification of novel genes related to PTSD. This project aims at systematically investigating the genetics of PTSD, by using genome-wide scans in a large sample of individuals from conflict regions in Africa. More specifically, we plan to investigate gene × environment interactions in the etiology and symptomatology of PTSD. The identified genetic risk factors will be validated in an independent sample and their influence on the response to trauma-focused therapeutic treatment will be analyzed. The results of this project will contribute to a deeper understanding of genetic risk factors involved in PTSD etiology and their role in trauma-focused therapy.
