Neurobiological Analyses Within the FORESEE III Study

Study Overview
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Brief Summary
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In this observational, non-invasive clinical study different neurobiological analyses will be performed in a group of patients with severe treatment resistant major depression participating in an efficacy study of deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB) - FORESEE III.

Detailed Description
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This study is a sub-project of the FORESEE III study (Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression). The FORESEE III study itself is a randomized, sham-controlled, double blind (patient and observer blinded) clinical trial to assess the antidepressant effect of DBS compared to sham. The aim of this sub-project is to analyze the time-course of biological correlates of treatment resistant major depression as well as neurobiological markers of treatment response to treatment with DBS in a well-characterized patient population during 12 month of DBS. Specific neurobiological analyses include testing of epigenetic markers (DNA methylation in candidate genes of depression and epigenome-wide association studies, EWAS) markers of neuroinflammation (cytokines, neuropeptides and other immune factors) micro RNAs and transcriptome signatures markers of neurodegeneration (neurofilament light protein) metabolomic analyses and endocrinological parameters including glucose tolerance. All markers will be tested in blood samples (and urine samples for metaboloic profiling) before neurosurgery as well as at several time points during DBS and sham condition intervals. Additionally hemodynamic parameters will be analysed at test stimulation of the slMFB during neurosurgery. The results will be correlated with clinical and other biological response parameters of the FORESEE III study and are hypothesized to indicate treatment response as well as allowing prediction of response to DBS. All neurobiological analyses will be linked in a tightly integrated and comprehensive translational approach. Further, a volunteer group of healthy controls will be recruited and tested for blood-markers of neurodegeneration (neurofilament light protein, 4.) as well as metabolomic analyses in blood and urine (5.).

Official Title
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Neurobiological Analyses Within the FORESEE III Study

Conditions
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Treatment Resistant Depression

Participation Criteria
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Eligibility Criteria
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DBS Patients: Inclusion Criteria: All enrolled subjects of the Controlled Randomized Clinical Trial to assess Efficacy of Deep Brain Stimulation (DBS) of the slMFB in Patients with Treatment Resistant Major Depression (FORESEE III) may participate in this study. Exclusion Criteria: Non-Caucasian (because of requirements for genetic/epigenetic analyses) Somatic diseases like diabetes, cancer and severe liver- and kidney-diseases Healthy Controls: Inclusion Criteria: All healthy volunteers without any clinically significant psychiatric or somatic symptoms are eligible. Exclusion Criteria: Any clinically significant psychiatric symptoms Conditions like diabetes, cancer or severe liver- and kidney diseases Drug or alcohol abuse

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| DBS patients<br>Patients with treatment resistant major depression participating in the FORESEE III study. | |
| Healthy controls<br>Age- and sex-matched healthy controls undergoing analyses of neurodegenerative markers (neurofilament light protein) in blood and metabolomic analyses in blood and urine. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in DNA methylation patterns in plasma at 1 month of deep brain stimulation (DBS) | Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression. | At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B) | 
| Change from baseline in DNA methylation patterns in plasma at 4 month of deep brain stimulation (DBS) | Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression. | At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B) | 
| Change from baseline in DNA methylation patterns in plasma at 12 month of deep brain stimulation (DBS) | Epigenetic mechanisms such as DNA methylation crucially govern gene function and have been shown to be temporally dynamic and responsive to environmental stress. Epigenetic patterns in blood, saliva or other peripheral material have been suggested to partly reflect central epigenetic processes. DNA will by isolated and undergo bisulfite conversion. Using pyro- and direct sequencing, samples will be analyzed for DNA methylation in candidate genes of depression. | At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups) | 
| Change from baseline in neuroinflammatory and neuropeptide patterns at 1 month of deep brain stimulation (DBS) | A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors. | At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B) | 
| Change from baseline in neuroinflammatory and neuropeptide patterns at 4 month of deep brain stimulation (DBS) | A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors. | At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B) | 
| Change from baseline in neuroinflammatory and neuropeptide patterns at 12 month of deep brain stimulation (DBS) | A new method of analysis (Proseek® Multiplex Inflammation, Olink Bioscience, Uppsala, Sweden) will be used to determine any change in patterns of relevant neuropeptides and inflammatory markers. This multiplex proximity extension assay (PEA) will simultaneously analyze 92 different proteins, including cytokines, neuropeptides and other immune factors. | At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups) | 
| Change from baseline in transcriptome profiles at 1 month of deep brain stimulation (DBS) | A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles. | At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B) | 
| Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 4 month of deep brain stimulation (DBS) | A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles. | At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B) | 
| Change from baseline in exosomal Micro-RNA (miR) expression levels and transcriptome profiles at 12 month of deep brain stimulation (DBS) | A massive parallel next generation deep sequencing (NGS) technology will be used followed by bioinformatic network analysis to determine intraindividual changes in exosomal miR ( (miRs, 19-22 nt long non-coding RNAs) and transcriptome profiles. | At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups) | 
| Change from baseline in plasma levels of Neurofilament light protein at 2 days before surgical device implantation | Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays. | At baseline (up to 10 to 7 weeks before surgical device implantation) and at 2 days before surgical device implantation | 
| Change from baseline in plasma levels of Neurofilament light protein at 1 month of deep brain stimulation (DBS) | Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays. | At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B) | 
| Change from baseline in plasma levels of Neurofilament light protein at 4 month of deep brain stimulation (DBS) | Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays. | At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B) | 
| Change from baseline in plasma levels of Neurofilament light protein at 12 month of deep brain stimulation (DBS) | Neurofilament light protein is part of the neuroaxonal cytoskeleton and can be released into plasma following neuroaxonal damage. In plasma it will be measured by single-molecule array (SiMoA) assays. | At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups) | 
| Change from baseline in metabolite profiles in plasma and urine at 1 month of deep brain stimulation (DBS) | Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis. | At baseline (up to 10 weeks before surgical device implantation) and at 1 month of DBS (week 5 group A, week 21 group B) | 
| Change from baseline in metabolite profiles in plasma and urine at 4 month of deep brain stimulation (DBS) | Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis. | At baseline (up to 10 weeks before surgical device implantation) and at 4 month of DBS (week 17 group A, week 33 group B) | 
| Change from baseline in metabolite profiles in plasma and urine at 12 month of deep brain stimulation (DBS) | Metabolite profiles of plasma and urine samples will be analysed by chromatographic separation techniques, different mass spectrometric ionization modes and mass analyzers in order to assess molecular changes in the metabolome. The metabolomic methodologies may include fingerprinting, nontargeted, and targeted approaches, metabolic profiling and metabolic flux analysis. | At baseline (up to 10 weeks before surgical device implantation) and at 12 month of DBS (end of study both groups) | 
| Change from baseline in insuline resistance at week 41 | An oral glucose tolerance test with blood measures of glucose, insulin and c-peptide at several time points during a period of 3 hours after oral intake of 75g glucose will be performed. | At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups) | 
| Change from baseline in systemic metabolic parameters at week 41 | Different systemic metabolic parameters will be measured in blood. | At baseline (up to 10 weeks before surgical device implantation) and at week 41 (both groups) | 
| Cardiac stroke volume (ml) | Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring). | At test stimulation of the slMFB during neurosurgery | 
| Non-invasive blood pressure (mmHG) | Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring). | At test stimulation of the slMFB during neurosurgery | 
| Cardiac stroke volume variation (%) | Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring) | At teststimulation of the slMFB during neurosurgery | 
| Systemic vascular resistance (mmHg⋅min⋅mL-1) | Measured with ClearSight System, Edwards Lifesciences (allowing non-invasive and real-time continuous hemodynamic monitoring). | At test stimulation of the slMFB during neurosurgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Treatment Resistant Depression, Neurobiological correlates of treatment resistant depression, Predictors of treatment response in DBS