Appendix 2 Research programs

2.1 Brain Imaging Inventory of the 2016-2021 period:

• The essence of our research program is the development and clinical application of advanced brain imaging techniques focused on multi-modal imaging, precision medicine and minimally invasive brain imaging. • In 2016-2021 we adhered to the goals set out in the ‘Project plan Amsterdam Neuroscience’ (2015), namely to focus on fully translational (from bench to bedside via micro EEG/PET/SPECT/

MRI) via institutional funding, multimodal imaging technologies, with minimally invasive programs suitable for ‘personalized medicine’ and drug-targeting strategies (via defining new physiological parameters such as pharmacoMRI, dynamic fMRI-MRS, MEG, amyloid and tau PET, and other innovative receptor imaging strategies, like synaptic vesicle glycoprotein (SV2A) imaging and EEG/neuropsychological data). • More recently, with the advent of big data approaches and AI methods such as radiomics and machine learning, we added the organization of core facilities and engagement in data processing and analysis initiatives to our agenda via intensified integration with physics and mathematics (via PoC and Amsterdam Neuroscience funding), as well as institutional funding for building a basic neuroimaging infrastructure and AI databases. • We impact patient well-being by providing potential prognostic and diagnostic neuroimaging biomarkers that can be used for precision medicine in patients with MS, AD, depression, ADHD, OCD, movement disorders, post-anoxic coma, etc. For example, machine learning analysis of clinical and neuroimaging data enabled early confirmation of the diagnosis of frontotemporal dementia (J Alzheimer’s Dis 2019).

Also, with machine learning of EEG data we obtained faster and more accurate predictions of good and poor outcome in patients in coma after a cardiac arrest (Ann Neurology 2019). For more information see Amsterdam Neuroscience - Brain Imaging.

Strengths:

• The Brain Imaging program has a strong distinctive profile, which is the application of advanced imaging tools and techniques primarily to advance drug-targeting strategies. This is where the available expertise of the Principal Investigators lies and where we can make a difference. • We are a medium sized program with respect to budget and full-time equivalent (FTE). With relatively little funding, our program was highly productive over the past six years: on average 2.99 publications/PI/year were published, whereas this was 2.29 for other technical programs.

These publications were also of high quality (average no. of impact papers between IF 5-10 was 0.52 /PI/year, whereas 0.44 for other technical programs). Nevertheless, we lack real high impact (IF >10) papers: this was only 0.12 paper/PI/year versus 0.33 for the rest, likely reflecting the lack of really high impact brain imaging journals.

Our thesis production was on average for the technical programs; namely 0.15 PhD thesis/PI/year. In sum, a highly efficient and productive program. Several prestigious grants have been obtained, including Veni, Vidi (2), Memorable, TOP, Abipat, DATA2PERSON,

ENBIT, Eurostars (4), COVID-19 (2), Alzheimer Nederland, STW (NWO),

NWA-ORC and an ERC Consolidator grant. • Over the past period, we have been working on improving our weak points, such as getting preclinical studies going as well as studies at 7T, in addition to building a basic research infrastructure. • Another strength is the enormous amount of talent and expertise that is available within our program. We engage in big data approach, for instance, by setting up an Amsterdam Neuroscience Neuroimaging database and analysis pipeline. D. Veltman is a driving force behind several ENIGMA programs. We also have a decent amount of AI knowledge within our program, which is strengthened with the close collaboration of the department of Biomedical Engineering and Physics. Since brain imaging is a fast-evolving field, we want to

put young enthusiastic researchers in the spotlight more; they have organized the TN2 meeting on Brain Imaging in the fall of 2019 as well as 2022. Of note, several young talents (Vriend, Mutsaerts, Schrantee, Golla) were appointed fixed positions. Interestingly, their postgraduate careers took a fly after receiving a proof-of-concept (PoC) or regular grant from Amsterdam Neuroscience, illustrating the success of this program.

Weaknesses:

• The enormous amount of talent and expertise is at the same time a weakness of our program, because the available expertise is scattered on small islands all over Amsterdam Neuroscience. There is still (too) little collaboration with other departments (e.g., Mathematics and

Computer Science, and Biomedical Engineering and Physics / Medical

Physics). • We do not have the infrastructure to host all these AI and big data approaches. We are currently working on expanding the existing research infrastructure with existing initiatives (AI infrastructure,

ADORE, as well as the Imaging Core Facility of the departments of

Radiology and Nuclear Medicine). For this purpose, we need to embed the newly established neuroimaging infrastructure. In addition, the available technical knowledge on both sides of the Amstel (physicists, engineers, ICT specialists, etc.) will have to become more involved in the Brain Imaging program. Another weakness is that for transparency regarding pricing of PET and MRI scans, we are relying on the Imaging

Core Facility.

Opportunities:

• The strong AI focus, by appointing four professors in AI at the UvA (of which one on AI and Medical Image Analysis at the departments of

Radiology and Nuclear Medicine and Medical Physics location AMC), the huge amounts of imaging data that are already available, which is like a goldmine for AI, as well a number of initiatives that are taking place for building a large infrastructure, such as the RICC/Imaging

Core Facility, ADORE, AI infrastructure, and the enormous amount

of talent and expertise that is available within our program are all opportunities we need to grasp. • Quick wins: research with large international patient cohorts (e.g.,

ENIGMA, human connectome project, MS imaging data), joining the

AI course that has been started, and joining in / further developing research infrastructure within Informatieplan Onderzoek 2019-2022, as well as the HPC facility, Imaging Core Facility, and the newly build

Imaging Center at location VUmc. The Imaging Center at location

VUmc is a unique building where MRI, PET including whole body

PET-CT, CT, optical imaging, radionuclide synthesis facilities and cyclotrons are united, making it highly suitable for true multimodal imaging.

Threats:

• Currently, the technical input in the Brain Imaging program is still limited, as it is too scattered and present on several islands within

Amsterdam Neuroscience. We will strengthen this by the activities indicated above. • Staff positions are scarce, which makes it extremely difficult to keep highly talented PhD and post docs. We need more structural support in the form of fixed positions for young talent. • Costs of dynamic PET scans, tracer production, arterial sampling and data analysis are (very) high. • Availability of PET and MRI slots for brain research.

Research strategy for the coming 6 years:

• Although our strategy for 2019-2021 was to (1) fully embed the newly established research infrastructure within the goals set out by the Brain Imaging program)(see above) and (2) provide centralized support, especially optimize opportunities in the field of AI and big data analysis, we only partly achieved this goal, partly also due to COVID related issues, as well as the fact that the Imaging

Core Facility (within the department of Radiology and Nuclear

Medicine) is still under construction. For the coming 3 years, we want to finalize these goals by executing the following: (1) the basic research neuroimaging infrastructure that has been set up should be

embedded within Amsterdam Neuroscience via a grant(s), possibly sponsored via the Amsterdam Biocomputation Center (ACB) and/or ADORE fund, in addition to the Imaging Core Facility (that is still under construction). And (2) our strategy for centralized support is to involve technical experts (e.g., Hugo Vrenken, Alle Meije Wink, Matthan Caan, Henk Marquering, Ivana Išgum, Paul Groot, Ronald van Schijndel, Martijn Steenwijk, Ronald Boellaard, Maqsood Yaqub, Sandeep Golla and others) more in our program; although this has been actualized, we want to involve a technical expert(s) also in steering committee of the Brain Imaging program. In addition, we want to organize several method-specific subgroups within the Brain Imaging program. For instance, through Amsterdam Neuroscience calls for grants with a specific topic like we did in 2020 on AI, which was a huge success. Moreover, we want to organize regular methodspecific meetings within our program. In conclusion, in the coming years, the Brain Imaging program will focus on infrastructure, gluing the islands together and joining forces!

For the Top 5 publications, see Appendix 3 – Output (p. 59).

2.2 Systems & Network Neurosciences

Inventory of period 2019-2021 (outcomes, process and integration):

• The goal of the research program Systems & Network Neuroscience is to understand how networks of neurons and brain areas give rise to brain function and behavior. In addition, studying the interaction of the central nervous system with peripheral organs offers new avenues to improve health. The research program of Systems & Network

Neuroscience brings together research groups using invasive and non-invasive approaches in the living brain to study and manipulate brain networks in health and disease. • This research program relates to the fundamental as well as the clinical themes in Amsterdam Neuroscience, with good connections with the industry, facilitating novel technological developments.

Applying these technologies to study and manipulate neuronal and brain networks in the living brain and actively apply it to the treatment of pathological conditions will not only increase understanding of how brain networks give rise to function, but also have direct impact on health prospects of patients.

Strengths:

• The program promotes the implementation of technological advances in neuroscience such as: MEG, EEG, deep brain stimulation (DBS),

TMS/TDCS, brain surgery, in vivo nerve stimulation, in vivo neuronal and network recordings, opto-and chemogenetic manipulations,

Optical Coherence Tomography (OCT) of the human retina, miniscope and 2P imaging, functional magnetic resonance imaging (fMRI), PET scans, computational approaches and others. • A major focus of the program is on understanding brain networks for sensory processing, motor control, cognition, mood, reward and harnessing collaborations on cross-discipline functional studies of brain function in relation to health.

Weaknesses:

• The fact that research groups are scattered in different locations limits the ability to share facilities and resources, and the opportunity for interactions among researchers. • Lack of an efficient communication platform to share progress with participating Principal Investigators.

Opportunities:

• Key indicators of the program: ◦ Study of network function and pathophysiological mechanisms of disease at the systems level. ◦ A mechanistic understanding of how networks of neurons give rise to brain function and behavior. ◦ Use of cell-type and network specific manipulations of brain function in health and disease ◦ Examine how neural activity in the central nervous system coordinates the activity between the brain and body. ◦ Design and engineering of electrophysiological or mechanical systems that control sensory feedback and information processing in the brain. ◦ Improvement of clinical applications of technologies developed within and outside Neuroscience Amsterdam. • Excellent research groups with top publications. • Strong complementary expertise at both universities and Amsterdam

UMC on neurotechnology. • Strong ties with clinical departments with large patient cohorts for current and future applications of technologies. • Strong links with industry to facilitate technological developments.

Threats:

• Lack of opportunities for research funding (particularly for individual grants). • Excessive demand for valorization and collaborations with non-academic sectors. • Excessive teaching load. • Time-consuming bureaucracy for obtaining ethical permits for animal and human. • Pandemics.

Research strategy for the coming 3 years:

• Our goal is to understand how networks of neurons and brain areas give rise to brain function and behavior. In addition, studying the interaction of the central nervous system with peripheral organs offers new avenues to improve health. The research program of

Systems & Network Neuroscience will continue to bring together research groups using invasive and non-invasive approaches in the living brain to study and manipulate brain networks in health and disease. The program will keep on promoting the implementation of technological advances in the neuroscience field such as described in the strengths above.

For the Top 5 publications, see Appendix 3 – Output (p. 59).

2.3 Cellular & Molecular Mechanisms

Strengths:

• Strong link with Amsterdam Neuroscience clinical programs, strong translational profile. • Coordination of SYNGO consortium (CNCR leads international consortium of expert labs, Koopmans et al. Neuron, top 5% best cited papers, excellent funding by Broad, SFARI). • Key opinion leaders in monogenic neurodevelopmental disorders of the synapse (SNAREopathies, white paper in Neuron 2019, coordinate international consortium, organize patient family days) and technology to tag, isolate, sort, harvest and probe cell-type/circuitspecific synaptic populations at a molecular level. • New assays for functional analysis of disease mutations in neurodevelopmental disorders, novel cellular model to quantitatively assess synaptic parameters in iPSC-derived human neurons at a single-cell level (Meijer et al., 2019). • Expertise in iPSC derived neural cells: a biobank to store cells for the generation of patient iPSC, expertise on generating neural cell structures from patient cells to answer research questions in disease-relevant tissue, optimizing culture for iPSC derived inhibitory neurons to create E/I balanced human networks in vitro. • Key expertise and infrastructure for functional imaging in neuronal cells and organoids, screening platforms, advanced data management and

AI-driven data analysis (coordination NWO Roadmap NL-BioImaging). • Unique expertise in molecular pathways in neurodegenerative diseases (proteostasis, stress, protein misfolding (e.g., Alzheimer’s,

Parkinson’s, Huntington’s Disease). • Expertise groups on alterations in proteomics and metabolomics in neurodegenerative diseases. • Expertise on the blood-retinal and blood-brain barrier (BBB) and the neurovascular unit (NVU), based on human retinal and brain tissue and animal models. • Expertise in analysis and targeting of metabolic processes in the brain (mitochondria, microglia-neuron interactions, lipid droplets, circadian clock machinery, gene and protein profiling with postmortem human brain tissues) and link this to behavior and peripheral metabolism. • PoC funding has strengthened the collaboration between the collaborating CMM teams.

Weaknesses:

• Diversity of topics, expertise and lab locations. • Bioinformatic support/expertise is limited (especially for analysis and integration of -omics datasets). • While collaborations between CMM members at the CNCR of the Vrije

Universiteit Amsterdam are established, collaborations with CMM members outside this campus are more difficult. • Throughput of our analysis is rate limiting. • Limited access to genomic profiles of patients with neurodegenerative disease in Amsterdam and the Netherlands limits the establishment of cohorts. • Progress is currently slowed by the labor-intensive nature of patch-clamp electrophysiology. A more high-throughput technology to assess synapse function, such as cutting-edge optical methods, could be beneficial if proper resolution can be obtained. • • Individual approaches to use (patient-derived) iPSC cell lines for validation.

Opportunities:

• Increasing interest from industry for our assays, tools and expertise. • Opportunities to combine different life science & enabling technologies e.g., visual omics by combining microscopy and omics data of the same sample will translate next-generation life science technologies to applications and scientific breakthroughs. • Share CMM expertise in different biomedical technologies, methodologies and analysis to connect single molecule research to their analysis in intact organisms in different (disease) models. • Team science: CMM members lead or are part of many leading consortia worldwide (Human Brain Project, SYNGO, ESCO, Brainmodel,

Brainscapes).

• Mathematical modeling to describe/understand how cellular phenotypes translate to network/disease phenotypes and to predict druggable targets. • Data management/data access mechanisms for sensitive data to organize stem cell research. • Cellular Imaging (LCAM-AMC) and O2Flow facility MCBI at the UMC location VUmc have state-of-the-art techniques available for (correlative light and) electron microscopy, functional imaging of cells, organoids and tissues, light sheet and super resolution imaging, and flow cytometry. • The research line on the molecular mechanisms of synaptic inhibition could be better integrated at the biophysical level to strengthen the mechanistic interpretation, as well as at a higher systems level. • Better integration, collaboration and exchange of techniques between

CNCR at Vrije Universiteit Amsterdam and SILS and AMC location. • Accelerate development of innovative medicines by understanding the relation between (disease-related) proteins, molecular pathways, neuronal cell phenotypes and small animal models. • Established infrastructure and expertise will be used for a more prominent role in national consortia including NWO Roadmap GWI,

NWA and Gravitation.

Threats:

• The locations: Vrije Universiteit Amsterdam / Amsterdam UMC location VUmc will move to new building which result in a discontinuation of animal research. • PhD candidates that encountered delays due to COVID lab closing are reaching the end of their contracts in 2022-2024 but failed to catch up experimentally. • Reduction in the acceptance of animal experimentation (yet partly covered by proposed patient-derived iPSC activities). • Comparatively less funding opportunities for non-disease related, fundamental neuroscience research. • Excessive bureaucracy and delays for obtaining ethical permits for animal and human experiments. • Increasing costs for lab reagents. • Reagents are on back order causing delays for PhD candidates.

Strategy for 2022-2027:

• Develop new dimensions for the SYNGO knowledgebase (proteinprotein interactions, causality modeling). • Promote international collaboration on monogenic neurodevelopmental disorders of the synapse (SNAREopathies) and promote trial readiness. • Identify cellular mechanisms which regulate synaptic strength and explore the physiological relevance on synaptic computation and brain function. • Team up with computational neuroscientists for modelling our in vitro human networks. • Continue developing technology to probe the molecular framework of sparsely distributed memory encoding ensembles, including cell-state dependent proteomics (e.g., protein turnover in the face of neuronal activity). This technology will be available for others within CMM who would like to apply it to their own research. • Further development of proteomics / imaging methods to study glia-synapse interaction, which may be of interest / compatible to the research of many in the CMM program. • Continue developing models (BBB, NVU, iPSC, neuron-glia co-culture) to understand the correlation between metabolic disease and brain function and pathology (i.e., dementia, depression, diabetes, obesity). • Development of a zebrafish model for studying pathophysiological effects on the BBB.

For the Top 5 publications, see Appendix 3 – Output (p. 60).

2.4 Complex Trait Genetics

The CTG program investigates the genetic, epigenetic and environmental causes of individual differences in brain function and dysfunction related to cognitive, mental and physical health. CTG has approximately 30 members, from several departments of the Vrije Universiteit Amsterdam, Amsterdam UMC (location VUmc & AMC) and University of Amsterdam.

Strengths:

• Establishment of a biobank to store cells for the generation of patient iPSC (VU Amsterdam). • Establishments of platforms for generating neural (UvA, VU

Amsterdam) and retinal (Amsterdam UMC) cell structures from patient cells, including 3D organoid structures, to address research questions in disease-relevant tissues. • Development of a 3D-bioprinting platform for analyzing genetically modified stem cell lines for studying age-related macular degeneration (Amsterdam UMC). • Establishment of a (pre-)clinical translational genetics AUMC pipeline for gene therapy, small molecule therapy, and stem cell replacement therapy of genetic retinal disorders (Amsterdam UMC). • Deepening links between psychiatry and complex trait genetics and vice versa (GGZ inGeest AUMC/VUmc). • Newly established collaborations with national and international consortia, such as between AMC and NESDA, between UvA and the

‘Collaborative Center for XDP (CCXDP) @ Massachusetts General

Hospital, NWA-consortia, NWO Zwaartekracht, etc. • Founding of new expertise centers: Eye and Brain Platform, Emma

Precision Medicine Center (Amsterdam UMC). • Funding and completion of six successful research programs through the Amsterdam Neuroscience PoC /Alliance grant system. • Many prestigious grants and awards, including ERC starting/advanced,

NWO ZonMw TOP, Vidi, Vici. • High quality and quantity of research output.

Weaknesses:

• There is not yet enough connection and collaboration between different

CTG research groups regarding shared research disciplines and shared technical expertise, such as the iPSC labs at the VU Amsterdam/UvA/

Amsterdam UMC, methodology, strategies and knowledge on complex genetics analysis (VU Amsterdam/UvA/Amsterdam UMC). • There is not yet enough connection and collaboration between different CTG research groups regarding unique research disciplines and research-group-specific expertise: such as integrating knowledge on complex genetic loci/repetitive DNA with GWAS-associated studies (UvA/VU Amsterdam), linking genetics with neuro-psychiatric and neurological disease phenotypes (UvA/VU Amsterdam/Amsterdam

UMC), 3D bioprinting technologies (Amsterdam UMC/UvA/VU

Amsterdam), Genetics and the penetrance of neurological disease associated phenotypes (Amsterdam UMC/UvA/VU Amsterdam). • Growing need for expertise to perform multi-modal analysis (e.g., multi-omics). • Continuing and growing need for funds to support research projects to connect the different research groups and share expertise within

CTG.

Opportunities:

• We should have regular meetings within CTG, focusing on knowledge exchange and stimulating collaborations between different groups. • Increased knowledge exchange can lead individual CTG members to write new grant proposals on projects that bridge different research programs. • Improvement of data management and data access mechanisms for patient-derived sensitive data. • Communicate and share expertise and knowledge regarding computational modeling and specific technical expertise that could be applied to other research questions (3D organoid model-systems, 3D bioprinting, etc.).

Threats:

• A continuing threat to the CTG program is how to fund research that would strengthen the collaborations between individual researchers, research programs and institutes, which is the main goal of Amsterdam

Neuroscience. In times when most researchers are hired on specific projects with little time to explore additional research interests, great ideas and ambitions for collaborations within CTG can only be realized if there are funds available. • There are significant worries about the continued availability and cost increases of certain specialized lab reagents as a result of

COVID-related shortages and recent geopolitical issues.

Future perspectives for the next 6 years:

• The ambition for the next six years is for CTG to invest more in translational genetics: Studying genetic disorders and specific sub-phenotypes of psychiatric disorders using CRISPR/Cas9 genetic engineering, multi-omics approaches, 3D organoid modeling and 3D bioprinting. • We further aim to develop and apply novel statistical tools for the analyses of genetic data, and increasingly apply bioinformatics tools to integrate the outcomes from genetic studies into neurobiological and functional follow-up studies.

For the Top 5 publications, see Appendix 3 – Output (p. 60).

2.5 Neurodegeneration

Strengths:

• Within the program the main focus is Alzheimer’s disease (AD),

Parkinson’s disease (PD), Frontotemporal dementia (FTD), and

Dementia with Lewy bodies (DLB). Amsterdam Neuroscience holds strong expertise in clinical phenotyping, neuroanatomy/ neuropathology and molecular profiling of neurodegenerative disorders and conduct of clinical trials. In the past year, translational research and team science was stimulated by various local (i.e., seminars, PoCs, TKI-PPP) and national (e.g., ZonMw Memorabel

PAGE-AD, NWA BioClock application SILS-NIN, Parkinson Alliance

Netherlands) initiatives. This has led to novel collaborations between basic and clinical researchers on campus and initiatives to integrate patient care and research. • For AD, the main focus in the past years was to study the origin of disease using biological markers and genetics, to improve diagnosis and prognosis by identifying and applying robust and disease-specific biomarkers (Teunissen, Lancet Neurol 2021) and identify meaningful subtypes to improve patient stratification (Tijms, Brain 2020) e.g., in clinical trials. Substantial advances have been made in PET, MRI and biofluid biomarker measurements for AD early diagnosis and predicting progression (van Maurik, Lancet Neurol 2019). A major strength of the

Alzheimer program has been the large Amsterdam Dementia Biobank infrastructure with biofluids combined with large datasets of the

Amsterdam Dementia cohort (n>6000 patients; e.g., Verberk Ann,

Neurol 2018). Expertise in genetic, molecular, pathological, high-end microscopy and (in vivo and postmortem) MRI has contributed to novel insights into disease mechanisms underlying early age-at-onset and/ or atypical (non-amnestic) AD and FTD. Amsterdam took the lead in large consortia (e.g., Netherlands Consortium of Dementia Cohorts,

NCDC; A Personalized Medicine Approach for Alzheimer’s Disease,

ABOARD; www.aboard-project.nl) to move toward a personalized approach in patient care and treatment strategies. • The main focus in Parkinson’s research is to improve the treatment of PD by (1) identifying tissue, biofluid and imaging biomarkers for diagnosis and prediction of disease progression, (2) understanding

psychiatric and cognitive symptoms, and (3) advancing treatments of motor symptoms. Preclinical PD research focused on unraveling disease mechanisms showed that disturbed lipid metabolism plays a central role in Lewy body formation (Shahmoradian et al. Nature Neurosci 2019). To guide the development of novel biomarkers, a multicenter longitudinal cohort study named ‘Profiling Parkinson’s’ (ProPark), has been formed in close collaboration with academic, private and industry partners. After showing that deep brain stimulation (DBS) surgery is equally efficacious when performed under general anesthesia as opposed to awake surgery for PD (Holewijn et al. JAMA 2021), the focus is now on the development of adaptive DBS and automated DBS programming. In 2017, Professor Marten Smidt and dr. Lars van der Heide founded Macrobian Biotech to work towards novel treatments for PD (macrobianbiotech.com).

Weaknesses:

• It has been difficult to obtain funding for research across diseases. It has been difficult to recruit or hold onto postdocs/young researchers willing to dedicate their time to basic or clinical research. Talent policy in general is hampered by a CAO that makes it difficult to keep personnel on temporary contracts. The lack of legal support in Amsterdam UMC is an important weakness. Compute, clusters, infrastructural support for large datasets, particularly imaging is insufficiently accounted for. Neuroscience cluster is down, but access to surfSARA is not yet organized. Also, with growing datasets and an increasing emphasis on making data available, an increasing demand is made on the time of research personnel that is in fact not hired to prepare, query and archive data sets.

Opportunities:

• The search for biomarker panels (tissue, CSF and blood) can be continued using the biological samples in combination with the comprehensive and uniformly acquired longitudinal clinical data, imaging data of the clinical cohorts. For AD, we will further strengthen our position for clinical trials by a firm link with IAO, ACRU in the

context of ADORE, and knowledge that can be applied to improve trial design (e.g., outcome measures, particularly Amsterdam IADL-Q, proteomics-based subtypes, genetic or molecular profiles, responder analyses). • In 2022, the Amsterdam UMC Parkinson and Movement Disorders

Center will be launched, and programs will be developed to further integrate care and research, develop a PD and movement disorders biobank and stimulate team science. We will also stimulate research across parkinsonian disorders to identify common and disease-specific pathogenetic mechanisms.

Threats:

• The research is financed largely by external funding which makes the program vulnerable. To secure successful continuation of the important research lines of Alzheimer Center Amsterdam and Parkinson and Movement Disorders center, it is of the utmost importance that the external funding is matched, and a mature infrastructure of senior research staff can be accommodated within the first cash flow.

Continuity of external funding is crucial because a considerable part of the research team depends on these funds. Constant and high-quality staff and services in all departments are essential for our multidisciplinary research (e.g., imaging infrastructure/pipelines; genetics/ genomics/clinical research and bioinformatics facilities).

Research strategy, research process and innovation - 2022- 2027:

We will continue to grow as an attractive partner for basic research and clinical trials, via recruitment, stratification of participants for next clinical phase 1 to phase 4 trials (in collaboration with the Industry Alliance Office and Brain Research Center). With hersenonderzoek.nl we facilitate recruitment of participants for brain research. To achieve a future of individualized prevention of neurodegenerative diseases, we will further optimize (molecular) diagnosis and identify (poly)genic risk factors that contribute to early age-at-onset, more severe disease progression or resilience in well-defined AD/PD/FTD/DLB cohorts. In addition to our clinical cohorts, we will continue to build cohorts of cognitively normal

individuals (e.g., twins, 100+). To overcome the heterogeneity dilemma that hampers drug development and to identify molecular profiles and (novel) drug targets for personalized treatment strategies, we will set up an induced pluripotent stem cells (iPSC) biobank of the brain donors (TKI-PPP TKI CONCERT, Van de Berg/Pijnenburg). We will continue to search for novel tissue, blood and PET biomarkers for improving early diagnosis and predicting disease progression for AD, PD and related disorders. For PD, we will embark on clinical personalized and pharmacogenomics research, amongst others via the Levodopa in early Parkinson’s disease cohort (Leap study), the Parkinson Personalized Therapeutics Initiative www.proparkinson.nl), adaptive DBS and automated DBS programming.

For the Top 5 publications, see Appendix 3 – Output (p. 61).

2.6 Neuroinfection & -Inflammation

The neuroinfection & -inflammation program has a strong track record in preclinical models, cohort studies and clinical randomized controlled trials leading to high profile output. The theme’s clinical research addresses burning clinical questions with direct relevance to patient care resulting in high societal impact.

Period 2019-2022

The neuroinfection & -immunity program has focused on two disease areas: multiple sclerosis (MS; location VUmc) and neurological infections (location AMC), but also includes research on the blood-brain barrier and immune-mediated neuromuscular disorders.

Strengths:

• Several prestigious research grants have been obtained including ERC

Consolidator, ZonMw Vidi, ZonMw Vici, Topconsortia for Knowledge and Innovation (TKI), Prinses Beatrix Spierfonds (PBF), Marie Curie

International Trainings network (ITN) and MS Research Foundation

Center Grant. • Twenty-six PhD theses have been successfully defended and the number of publications was >450. • Nationwide MS projects have been initiated on extended dosing of natalizumab (NEXT-MS trial, Dutch Brain Foundation and MS Research

Foundation), on feasibility of stopping immunomodulatory therapy in stable patients (DOT-MS trial, funded by ZonMw and MS Research

Foundation) and extended dosing of Ocrelizumab, BLOOMS-trail, funded by ZonMw and Treatmeds). • Two investigator initiated randomized controlled trials in chronic inflammatory demyelinating polyneuropathy (CIDP) and myositis have started (funded by ZonMw and PBF). • A multicenter study has been initiated aimed at improving prognosis by using innovative methods to diagnose causes of encephalitis (the

IPACE study funded by ZonMw Vidi and ERC Consolidator grant).

• An institutional PoC grant started a nationwide cohort study and biobank of neonatal bacterial meningitis has been established.

Recent grants from the European and Developing Countries Clinical

Trials Partnership (Horizon 2020) and Gates Foundation sustained this project. • TN2 meetings were transformed into a successful webinar series including sessions on neuroinfection &-inflammation. • During the COVID pandemics the investigators from the neuroinfection & -inflammation program initiated several high profile COVID19 related projects: ◦ The Amsterdam UMC COVID19 biobank was set up by Diederik van de Beek and Matthijs Brouwer and resulted in a biobank with over 5,000 patients and >80,000 samples. These samples could be used for multiple local, national and international projects that have been published in Nature, Science (3), Science immunology, PNAS and many other journals. Funding was acquired from the Amsterdam UMC COVID19 fund (150k€) to perform a baseline set of measurements that could be used by all Amsterdam UMC researchers. 2) As member of the ‘Target to B consortium’ for B-cell mediated autoimmune disease Filip Eftimov acquired ZonMw funding (3.5M€) to assess the efficacy of COVID19 vaccination in patients using immunosuppressive medication so far resulting in publications in Lancet Rheumatology, BMC Medicine, MS Related Disorders and several others submitted papers. The COVID-related national infrastructure that was set up for this study will be used for the ImmuneHealth XL, a developing collaboration between the different consortia on autoimmunity (including CIDP and MS). ◦ After prior cooperation between the neuro-infections research group (Diederik van de Beek) and InflaRx, a pharmaceutical company producing a C5a complement inhibitor (Vilobelimab), a phase II RCT in severe COVID-19 patients was set up in early 2020 in a collaboration of InflaRX and the departments of Internal medicine, Neurology and ICU of Amsterdam UMC. The phase II RCT showed potential benefit of the drug (publication Lancet Rheumatology) after which a phase III RCT with 360 patients was performed, of which the results are expected in April 2022.

Weaknesses:

• Interaction between NII members is suboptimal because of different lab locations, expertise and topics. No routinely scheduled meetings have been set up to improve interaction. However, the balance between having more meetings and keeping time for research is challenging. • Continuity of external funding remains important to consolidate the successes of the past. • Dependence on external funding for core research structures such as biobanking.

Opportunities:

• Sharing of new diagnostic methods to speed up diagnostics or monitor disease activities through biomarkers research. To optimize innovative developments within Amsterdam Neuroscience, increased interaction between research groups is paramount. So far, this has mostly been done at the research institute level, whereas cooperation on the research program level has not been optimally explored. • Regular meetings (e.g., biannual) with the research program leaders and task force members to identify opportunities for cooperation, and shared scientific presentations. An example of successful interaction has been the MS/CIDP joint research project, enabled by an Amsterdam Neuroscience seeding grant. • Learning from each other’s research strategies, which already resulted in a shift in focus from industry driven to investigator-initiated research in MS research and a reciprocal shift towards industry projects in the neuro-infection research. • There is a sense of urgency to create a clinical trial unit, which will be incorporated in the ADORE Concept. This unit will be elemental for future multicenter studies, using a hubs and spokes model with

Amsterdam UMC and regional hospitals. • Both locations of Amsterdam UMC are well known tertiary referral centers in the Netherlands for autoimmune neurological diseases, including multiple sclerosis, immune-mediated neuropathies and myopathies and neurosarcoidosis, and neurologic infections such as bacterial meningitis and neuroborreliosis, both for diagnosis and (advanced) treatments.

• The close interaction between clinicians and basic researchers stimulates research to solve major clinical problems. Clinicians and researchers take part in several national and international bodies (e.g., guideline committees, advisory boards of patient and government organizations), write for the lay-press and are active in national media. Researchers are involved in active dissemination e.g., website, Twitter, Facebook and organization patient/participant days. • We actively seek collaboration with the industry, both for diagnostics, disease monitoring and treatment. • The national RIVM booster vaccination program affecting hundreds of thousands of patients with auto-immune diseases in the Netherlands was tailored based on results of the Target to B-COVID study emphasizing the societal impact of our studies. • The vitality of the research program is high. Two MS fellow neurologists and one MS research fellow have been appointed for at least another two years, who were involved in recent successful grant applications. A recent 2021 ERC Consolidator grant has further boosted the neuro-infections research line. Combined with 2019

Vici grant, there is substantial room to invest in new research opportunities. Structural funding has been acquired to consolidate the neuro-sarcoidosis research. A nationwide research network has been established for a neonatal meningitis and sepsis cohort (NO-GBS study). Furthermore, a worldwide database (INCbase) for

CIDP has been set up which will put us at the front of inflammatory neuropathies research. At this moment, alternative trial designs such as Trials within Cohorts (TwiCs) is being explored within

INCbase as funding for investigator-initiated trails in rare disease remains cumbersome. Renewal of leadership and acknowledgment of talent is an important theme in Neuroinfection & -inflammation.

Threats:

• The merge of AMC and VUmc may lead to increased management tasks and meeting frequencies, which inevitably leads to reduced time for research. • Increasing use of healthcare by an aging population will increase clinical tasks whereas educational tasks are not expected to decrease. • The high workload for partners in MSCA due to either increased bureaucracy, clinical tasks and/or teaching duties limiting time investment into research (and grant writing). • A cutting-edge genetic core facility and biocomputational support will be vital for the near future. At this moment it remains difficult to attract knowledgeable biocomputational experts. • Continuity of external funding remains important to consolidate the successes of the past. • Availability of neuroimaging is currently an important threat in the field of MS research, both in the clinical setting and for research. • Finally, legal support is too often an important delaying factor in setting up research collaborations, multicenter studies and randomized clinical trials.

Strategy 2022-2024:

We will continue with clinical and translational research by combining large nationwide prospective cohorts and randomized controlled clinical trials with extensive bio-banking to facilitate patient stratification and basic and translational research. Innovative research methods that have recently been implemented in Amsterdam Neuroscience such as single cell sequencing, single cell immune profiling, single molecule arrays, platelet sequencing, multiparameter flow cytometry, lipidomics, high-end microscopical imaging (Nikon center of excellence) and pathogen discovery sequencing will spark further high-resolution studies using our human samples. Biomarker research will be one of the more directly clinically applicable techniques that can change clinical practice in the next 5-10 years. With the unique cohorts, we will remain an attractive partner for industrial partners for development of new diagnostic tools, but also for randomized controlled trials.

For the op 5 publications, see Appendix 3 – Output (p. 62).

2.7 Neurovascular Disorders

Strengths:

• Translational research/AI: several research groups seek to improve treatment of acute stroke. ◦ RADISH: platelet RNA as biomarker for delayed cerebral ischemia in subarachnoid hemorrhage. ◦ INSIST (In Silico Trials for treatment of Acute Ischemic Stroke) consortium. ◦ The role of pericyte contraction and specialized pro-resolving lipid mediators in microvascular reperfusion after acute ischemic stroke. ◦ AI-STROKE, ELECTRA-STROKE: EEG for the detection and triage of acute stroke patients, using in-depth signal analysis and AI. • Improvement of treatment for acute stroke, both ischemic and hemorrhagic, cerebral venous thrombosis and subdural hematomas (CONTRAST collaboration: MR CLEAN NO-IV, published in NEJM; MR

CLEAN MED, published in Lancet; MR CLEAN LATE, final analysis ongoing; MR ASAP, final analysis ongoing]; ULTRA, published in Lancet;

ISCHEMIA, inclusion ongoing; DIST, submitted for publication; TORCH, inclusion ongoing; ELIMINATE, pilot study ongoing; TO-ACT, published in JAMA Neurology). • Chair of Stroke Recovery and Rehabilitation Task force aimed to achieve consensus on outcomes and improve trials in neurorehabilitation. • Research strategy:

Maintaining leading role in prospective registries and clinical trials

Maximum focus on following research lines: ◦ Diagnosis and acute treatment of acute ischemic stroke including prehospital triage and early rehabilitation. ◦ Subarachnoid and intracerebral hemorrhage. ◦ Cerebral venous thrombosis. ◦ Subdural hematoma.

All research lines collaborate on (inter)national basis. • Societal impact:

Endovascular treatment (MR CLEAN) has become the standard of care worldwide for patients with acute ischemic stroke. The department of neurorehabilitation has been recognized as center of excellence in the field worldwide.

Weaknesses:

• For some conditions: small population of patients, usually with severe deficits. • Collaboration on a national basis can be challenging because there are many partners involved. • Increasing bureaucracy, both internally and externally, delays research and increases costs. • Insufficient collaboration with neurologists in acute stroke care settings with respect to research.

Opportunities:

• Proof-of-Concepts/Collaborations: ◦ CINTICS trial: Circulating Nanotraces to Identify the Cause of Stroke. This is a collaboration with LUMC, to improve pre-hospital triage of stroke patients. ◦ CONTRAST-2 consortium: New funding opportunities for stroke research Dutch Heart Foundation, Dutch Brain Foundation and industry. Aimed for 2023. In collaboration with Erasmus MC and Maastricht UMC. Studies focused on acute stroke treatment, pre-hospital triage and intracerebral hemorrhage. ◦ CLEOPATRA: Cost-Effectiveness of CT Perfusion for Patients suffering from Acute ischemic stroke. ◦ PROFITS: Identifying biomarkers of spontaneous neurological recovery and improving patient-specific prognostic modeling of outcome at 3 months post-stroke. ◦ Vaccine induced immune thrombotic thrombocytopenia (VITT): International collaboration. ◦ IRIS: Improving Reperfusion Strategies In acute Stroke: international collaboration.

◦ IRIS-pooling: Initiated pooling of six trials comparing EVT alone versus IV alteplase and EVT. ◦ DSHR/iCORIC: Dutch chronic Subdural Hematoma Research group/The international COllaborative Research Initiative on Chronic subdural hematoma. • ‘Quick wins’/sense of urgency/societal impact: ◦ For ischemic stroke: Impact by improving pre-hospital triage (CINTICS, ELECTRA-STROKE, AI-STROKE). ◦ For hemorrhagic stroke: the DIST-RCT study (CONTRAST consortium) will show whether minimally-invasive endoscopy-guided surgery will be effective. ISCHEMIA aims at paradigm shift in treatment of DCI in SAH. National and international collaboration in the field of cSDH will hopefully lead to treatment guidelines. • External stakeholders:

Funding has been received from several industry partners such as

Stryker, Medtronic, Penumbra, Bayer, etc. Need for nationwide funding, especially for translational research in stroke recovery and rehabilitation. • Vitality/worldwide trends/funding highlights: ◦ MR CLEAN Registry (national database for endovascular treatment for patients with acute ischemic stroke). ◦ Supervision of MRCLEAN NO-IV replica trial in China (DIRECT-MT), data-pooling. ◦ International cerebral venous thrombosis consortium. ◦ Nationwide Quality Registration Neurological Surgery for subarachnoid hemorrhage. ◦ Dutch Chronic subdural hematoma registry. ◦ IRIS • Program leaders include new, young and ambitious research leaders.

Threats:

• Capacity of Amsterdam UMC to admit patients. • General Data Protection Regulation. • Lack of structural research funding. • Lack of core facilities that support research. • Focus on outcomes such as mRS limits understanding of stroke recovery in terms of behavioral restitution.

Strategy for the coming years:

The overarching aim of our research theme for the coming 6 years is on improving diagnosis and treatment of acute stroke. Within this context, we have a special focus on clinical research (clinical trials), phenotyping and translational research (including AI). To attain our goals, we need to consolidate and strengthen our (inter)national collaboration. Funding must come from NWO/ZonMw and ERC grants, charity organizations and industry. We need to attract new young talent, both physicians (investigator-clinicians) and researchers.

For the Top 5 publications, see Appendix 3 – Output (p. 62).

2.8 Compulsivity, Impulsivity & Attention

Strengths:

• Strong in experimental and translational research. • Strong group of mid-career scientists (with huge grants). • CIA is well organized. • CIA meetings were attractive to multiple Principal Investigators from different fields of expertise, leading to multiple collaborative projects led by Principal Investigators from the various institutes.

Due to COVID-19 the meetings disappeared from the agenda. At this moment it is possible again to re-introduce these regular brainstorm meetings. • Functional analysis of disease mutations involved in neurodevelopment disorders. Development of IPSC derived networks of inhibitory and excitatory neurons to study E/I balance in neurodevelopment disorders in vitro.

Summary: The CIA has continuously been an active program with a high level of Principal Investigator participation and others, regularly attending meetings and actively seeking collaborations across the institutions (although we were severely hindered by COVID in this respect). Because of the representation across many levels of science (animal work, in vitro work, clinical work, neuroscience, and genetics) this has led to cross-fertilization and links across the scientific levels from basic/fundamental to applied. The program is still on par for obtaining funding (but see below at threats). The high level of funding and functioning has resulted in an ability to attract and keep high quality students and PhD candidates who become talented early career postdocs.

Weaknesses:

• We need to increase throughput of our analysis and better access to genomic profiles of patients with neurodevelopmental disorders in

Amsterdam and the Netherlands to create cohorts. • No solid longitudinal cohorts, apart from pre-post treatment study designs. • We should try bringing together more closely the pre-clinical and clinical research. • We should benefit more from the multidisciplinary collaborations (as initiated by institute seed money) in getting external funding for these translational projects.

Summary: The lack of cohort studies may be seen as a hiatus in the consolidation of the CIA work across institutes. This includes the lack of longitudinal assessments of patients and systematic assessment of genetics/neuroscience, in patient cohorts as well as population-based ones. Collaborative projects (i.e., across Amsterdam UMC/UvA/VU Amsterdam) for translational research, bench to bedside, may have lacked external funding.

Opportunities:

• Translation between preclinical and clinical research. • Studying disease phenotypes at different scales in the brain in the same patient. Collaboration between neuroscientists and clinicians. • Expected merge of the 2 departments of Psychiatry in 2022/2023. • Group funding. • More collaboration with industrial parties in valorization projects, by building new consortia with help of the Industry Alliance Office.

Summary: Some of the novel opportunities for CIA may arise with the upcoming integration of the Psychiatry departments of the VUmc and AMC (both strong on OCD/compulsivity research), providing new opportunities in integrating the research performed at different levels, in-depth at the neuronal level (depth recordings, mouse models, and in vitro IPSC recordings) or systems level (EEG, fMRI) and their translation into the clinic (neuromodulatory techniques such as DBS and TMS). There are opportunities for creating grant proposals across the participating institutions.

Threats:

• Slow merging process departments of Psychiatry. • Interdisciplinary and preclinical research in psychiatry is hard to get funded. • COVID-19. • Temporary closure of the animal lab facilities at the campus of the

Vrije Universiteit Amsterdam, delaying projects and hampering the attraction of young talent.

Summary: Funding is perceived as one of the major threats to continuing our CIA program successfully. Although our relatively small program has proven to be able to attract grants, soft money is never guaranteed in the competitive scientific world and therefore a continuously present threat. COVID has been disruptive for some (not all) research, especially animal and patient research. This may re-emerge in the fall of 2022.

Strategy for the coming years:

• A continuation of the translational neuroscientific work. CIA is at the forefront of deepening our knowledge of deep-brain stimulation research (OCD) with direct usability of that knowledge for optimizing treatment. CIA is also at the forefront in studies of non-invasive neuromodulation (rTMS) in OCD, using personalized (task-)fMRI-based targeting. These topics in DBS/TMS will be expanded for optimal treatment outcome, prediction of response and the study of the short- and long-term neuroplastic effects. • A continuation of research into treatment prediction models, by integrative modeling of neuroscience and genetics data. Future continuation of this work will focus on multi-omics by integrating the various levels of genetic variants, transcriptomics and imaging genetics (at meso- and systems level). • Continuation and strengthening of consortium work that is making

Amsterdam a hub for large-scale international neuroscience and genetics. Our aim is to obtain and/or maintain prominent positions in the ENIGMA consortium, and in the Psychiatric Genomics Consortium. • The merger of Psychiatry departments of Amsterdam UMC will give the opportunity to integrate research work for topics in which there

is little collaboration presently. OCD and OCD spectrum disorders are strongly represented across both sides of Amsterdam UMC. Likewise, the merger may also be an opportunity for research in the impulsive disorders. • We seek to strengthen computational modeling in various forms in our research programs. We seek an expansion of Artificial Intelligence approaches (Artificial Neural Networks) to a wider range of fields, such as (Psychiatric) Genetics. A further integration of departments will aid. There are further opportunities for the integration of neuronal modeling (as performed in various labs: UvA Human Brain Project and

VU Neural Biomarker Toolbox). We will continue these approaches to inform clinical treatment of OCD (TMS and DBS) and Autism/sensory sensitivity. • We have the ambition to integrate research topics across ages (child and adult), especially for typical childhood neuropsychiatric disorders of CIA (OCD, ASD, ADHD) a lifespan perspective is consistent with the early onset and recognizes the protracted course these disorders often take. • Recent developments in genetic methodology–including the availability of large scale genetically informative datasets, mouse and human brain transcriptome datasets, and more–allows the integration of human psychiatric genetics research with animal research. Results from genetic studies are increasingly powerful and consistently point to specific neurotransmitters and/or brain structures involved in disease etiology, as well as neuroinflammatory involvement.

This knowledge can be used to inform mouse studies (e.g., with chemogenetic drivers), which in turn may inform the localization of neural circuits that can be targeted in TMS or DBS approaches.

Our aim is to start leveraging the integration of the large available genetic datasets and translate them into treatment, thus integrating the many specialized CIA groups. • Disorders investigated in CIA show prevalence differences in the sexes, as well as qualitative differences in disease expression. We aim to consequently investigate these sex differences.

For the Top 5 publications, see Appendix 3 – Output (p. 62).

2.9 Mood, Anxiety, Psychosis, Stress & Sleep

Depression, anxiety, and psychosis constitute the majority of the most prevalent mental disorders, accounting for two-thirds of all affected people. These disorders share several risk factors with, and hence the biological underpinning of less prevalent, but possibly even more burdening– chronic psychiatric disorders like psychotic disorders and post-traumatic stress disorder. Our research program therefore aims for a transdiagnostic understanding of these disorders. We take a life span perspective (from early vulnerability to late disease chronicity) and integrate cross-disorder translational, preclinical and clinical studies to improve treatment and prevention possibilities for these disorders in an evidence-based way.

Strengths:

Amsterdam Neuroscience has been a leader in research on depression, anxiety disorders, and psychosis for decades, and recently acquired international leadership in insomnia research. Hitherto, the MAPSS program has been very successful with regard to grant acquisition, and publication- and societal output as generated by outstanding scientists and science teams.

• Strong collaboration and integration of our scientific research program with Mental Health Care Organizations (MHCO) in the area of Amsterdam (e.g., GGZ inGeest and Arkin). There are collaborative academic workplaces in the areas of depression, anxiety, bipolar disorder, PTSD and psychosis in these MHCOs. • There are long-term observational cohorts such as the Netherlands

Study of Depression and Anxiety (NESDA) and the Netherlands Sleep

Registry that provide new knowledge. • There are many innovative clinical trials within depression, anxiety, and psychosis that focus on topics as childhood trauma, inflammation, suicidality, and sleep. These include large randomized clinical trials aiming to reverse childhood trauma (RESET trial), anti-inflammatory treatment for immunometabolic depression (INFLAMED trial), antidepressant discontinuation, adulthood trauma and trials

using rTMS for bipolar depression. These examples illustrate the innovative approach to look beyond ‘classical’ psychiatric diagnoses and to develop approaches that are more transdiagnostic. Single cell proteomics and transcriptomics in animal models (at risk) for psychiatric disorders can be used to find pathways used for hypothesis-driven interventions. Stress and sleep are modifiable risk factors for the onset and a poorer course across mood and anxiety and psychotic disorders that can be disentangled. • The key role of insomnia in the risk, severity, treatment resistance and relapse of mood and anxiety disorders has been demonstrated across our studies using epidemiology, GWAS, experimental EEG and brain imaging, and intervention and prevention RCTs. MAPSS currently runs a worldwide unique study on the value of integrating insomnia intervention in the treatment of anxiety- and stress-related disorders. • MAPSS is involved in many EU projects, such as EarlyCause and

A-Tuition, the IMI-project PRISM2 and personal ERC grants. • MAPSS-based researchers lead several multi-center RCTs on antidepressant discontinuation (TEMPO and OPERA) that involve psychiatrists, GPs, pharmacists across five Dutch university medical centers (next to Amsterdam, also Groningen, Nijmegen, Rotterdam and Leiden). • The MARIO project (Mood And Resilience In Offspring) is an

Amsterdam-based multicenter study to understand intergenerational transmission of MDD. • New collaborations formed over the last two years, with roots in several funded PoC grants– in terms of a large Gravitation application (submitted 2022) on sleep and memory processing led by Eus van

Someren, under the name ‘Nightwatch’, and an NWA grant on stress and burn-out by Christiaan Vinkers under the name ‘DESTRESS’ (submitted 2022).

Weaknesses:

• The breadth of activities of individual researchers within MAPSS spans the entire fundamental-translational chain from molecule to patient. This makes it difficult to integrate all research activities.

Yet, this might not be necessary, as small-scale collaborative efforts have proven worthwhile as well. • The different locations make it challenging to convene regularly.

A future merger of the Departments of Psychiatry at the locations

VUmc and AMC could be a facilitator of more integration, with better exchange between departments and specializations within the MAPSS program.

Opportunities:

• The multidisciplinary research infrastructure within MAPSS opens up possibilities for national and international collaborations as well as providing opportunities for young talent. EU-based funding is generally well geared for this, and individual research teams have been successful with this in the past. For example, stress researchers from molecule to patient from over all of the Netherlands have united in the STRESS-NL consortium to foster new translational collaborations (www.stress-nl.nl) and have now expanded into Europe with the STRESS-EU database that combines and unites existing data and researchers (www.stressdatabase.eu). • When it comes to uniting all these research activities within MAPSS, knowledge centers could overcome fragmentation to a certain extent by integrating facilitating research themes centered around depression, anxiety disorders, and psychosis, covering the entire chain from fundamental to translational research; from molecular biology to applied clinical research, with tracking of patient cohorts and clinical trials. • As the research within MAPSS integrates both fundamental research (animal models, molecular and cellular level), as well as innovative treatments for patients, another opportunity for MAPSS is to be an important regional partner for innovative research activities, building and consolidating network structures with top clinical university

hospitals, universities (VU Amsterdam and UvA), and mental health institutions in the Amsterdam/North Holland region. Within large mental health institutions such as Arkin and GGZ inGeest, scientists and clinicians can come together to create innovative scientific patient-related outcomes. • Being active in the full breadth of the scientific field of mood, anxiety, and psychosis, MAPSS can be clearly recognizable to the general public, other Dutch and international scientists, and funding agencies to shape and implement innovative patient-related research. • Another relatively quick win is that several existing large databases can be used to augment the transdiagnostic and translational

MAPSS strategy. We have ongoing collaborations for this with e.g., innovative small-scaled companies (e.g., Metabolon) as well as with large pharma companies (Jansen, Boehringer Ingelheim), which can be further exploited for future studies.

Threats:

We identified several general and some MAPSS-specific threats: • A major threat for MAPSS and research in general is the increased bureaucracy with respect to preclinical research that depends on animals (CCD, DEC, IvD), and clinical research with respect to patients (extensive legal contracts required for even relatively elementary collaborations, ethical approval, data storage, monitoring, particularly for investigator-initiated studies) which impedes progress related to innovative approaches and team science, and makes research more costly than it should be, and which is not reflected in the project duration and budgets of national and international funding agencies. • Another major threat for (MAPSS-related) fundamental research is the sentiment of research without animals as articulated by our own minister, as discussed in the media roughly a year ago. In addition, costs of rebuilding and exploitation of a new animal facility are left for individual researchers to pay, as prices have increased >40%, whereas grant money is not sufficient. Lastly, the move to a new building and facility while our current building/facility is partially shut down impact current research lines.

• It is more and more difficult to share some of our MAPSS cohort/study data and biosamples with (academic) partners within and outside of

Europe through stricter laws. Contracts for this take more and more energy and time, which limits adequate collaboration. • Financial support for large-scale studies (infrastructure) from funding agencies and within the institute is limited which makes it hard to maintain such useful infrastructures for the future and further build on them. • Overhead rates within the Amsterdam UMC, Vrije Universiteit

Amsterdam and UvA are such that it makes it rather unattractive for private entities to collaborate. • Mental Health research is embedded in two research institutes: next to Amsterdam Neuroscience, there is also participation in Amsterdam

Public Health. This requires division of attention of clinical researchers involved, but also limits visibility of the entire range of research activities. Establishing integrative research centers around certain strong and central themes (e.g., through an Amsterdam Center of

Depression and Anxiety, ADA) could help reduce this threat.

Future Strategy:

Priority on: • Integration of fundamental and clinical research. • Expanding on transdiagnostic approaches. • Unite for external funding. • Prevention research for mood, anxiety and psychotic disorders.

For the Top 5 publications, see Appendix 3 – Output (p. 63).