1. Table of Contents Preface Word from the Scientific Advisory Board - Word from the director. 3. Description Research Institute...

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1 Annual Report 2011

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5 Table of contents 1. Table of Contents Preface Word from the Scientific Advisory Board - Word from the director 3. Description Research Institute Structure Research Institute SWOT Analysis News & Highlights International Collaboration Input Research Institute a) Funding b) Fte per type of funding c) Number of newly started PhD projects Output Research Institute a) Scientific Output b) Scientific Quality c) Indicators of Esteem d) Societal Impact Per Research Program a) Description - Advanced Technology Programs Genes & the Brain Brain Disease Mechanisms b) Input (per program) c) Output (per program) Scientific Research Committees Education & Training Appendices

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7 2. Preface Word from the Scientific Advisory Board * The state of the Neuroscience Campus Amsterdam shows a high potential top neuroscience institute on the steep part of its growth curve. The major programs and the high technology programs outperform expectations: after three years of integrative functioning in Neuroscience Campus Amsterdam, there is a high volume and especially high-to-top-level scientific quality of publications and PhD theses, placing the Neuroscience Campus Amsterdam between the leading institutes in their field, as evidenced by all performance indicators. All major research program-leaders at Neuroscience Campus Amsterdam expressively stated the positive effects of integration. Moreover, as the Human Genome Project neared the completion of its first goal (i.e. mapping of genes), the Neuroscience Campus Amsterdam departments successfully participated in the search of genes for common diseases - the most complex to identify - and for genes related to synapse function, neurodevelopmental disorders and neurodegeneration. The clinical departments continued their prominence among the world leaders in neuroinflammatory diseases like Multiple sclerosis, in neurodegenerative diseases like Alzheimer's and Parkinson's Disease and in neuropsychiatric disorders like depression. The impressive clinical problems intensify active translational approaches into new basic research areas, from intraoperative functional microscopy - including imaging and electrophysiologic recording - to searching new inroads across the blood-brain barrier and using stem cells derived from patients as a model for deciphering and treating his disease. Program- and team-leaders of the Neuroscience Campus successfully obtained a number of big international and national individual-, program- or technology grants, based upon their scientific track record and the added value of robust interdisciplinary cooperation and available enabling technology. Especially in the actual period of shrinking funds, the Neuroscience Campus Amsterdam may cherish their earning power. The Neuroscience Campus Amsterdam has developed a high quality reporting on a complex organization, giving evidence of its scientific and financial health in terms of fundraising power, bibliometric performance and societal impact monitoring. Prof. dr. Martinus F. Niermeijer Chair of the Scientific Advisory Board * Quote from a report written by the Scientific Advisory Board on the occasion of the Midterm Review of the Neuroscience Campus Amsterdam and the progress made during

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9 Word from the director On behalf of all partners of the Neuroscience Campus Amsterdam staff, coworkers and graduate students - we present the year-report of It was the year in which a Midterm Review took place (see previous page for a summary) and also the year in which two major other initiatives were started. First, in order to be able to continue to invest in scientific excellence and the translational potential of our brain disease-oriented research and graduate training, the Neuroscience Campus Amsterdam needs to generate new funding. This ambition was reiterated recently with the official start of the Translational Neuroscience Network Netherlands (TN3), a national community of brain disease-oriented neuroscientists, neurologists and psychiatrists and started by the Neuroscience Campus Amsterdam during the fall of TN3 operates under the auspices of the National Initiative Brain and Cognition (NIBC, a task force of the National Research Council (NWO). The NIBC promotes excellent brain and cognition research, as well as societal innovations deriving from it. We will use the TN3 community and organization to gain better access to opinion-leading gremia at the national level and to be able shift gears and form strong interuniversity consortia that are aimed at major national funding opportunities. Second, we need to better organize our knowledge utilization, and provide a professional infrastructure that can facilitate public-private partnerships of the Neuroscience Campus Amsterdam with external industrial partners. To this end, we have decided - and found support from Board of the Deans - to start a socalled Industry Alliance Office. The unit of the Neuroscience Campus Amsterdam will function as a front desk directed toward the pharma and biotech industry. In doing so, during 2012 and later, we foresee a major shift towards a more market-oriented position of our institute, but without losing our main focus on scientific excellence and integrity. Prof. dr. Arjen B. Brussaard Director 7

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11 3. Description Research Institute Neuroscience Campus Amsterdam Neuroscience research is a high profile knowledge industry and aims at making seminal contributions to the understanding of the human brain and the fight against brain disease. Our current insight coming from recent studies of Neuroscience Campus investigations into the human genome and networks of genes, interacting proteins, neuron-glia interactions, and synaptic transmission embedded in neuronal networks has paved the way towards the understanding the molecular and cellular basis of higher brain functions and its pathology. In parallel, on our campus, numerous brain imaging, neurological studies and psychiatric research of large cohorts of patients have created valuable assets that are unique worldwide. We have transcended the boundaries of various disciplines including biomedical, biophysical, biopsychological and clinical neurosciences. The ongoing research strategy, and output of the collaborative research programs of the Neuroscience Campus Amsterdam, thereby focusing on the most important and pioneering areas of neuroscience, have been described in the annual report. The Neuroscience Campus Amsterdam houses more than 520 professionals on one campus and they all collaborate in the field of Translational Neurosciences to an extent that is unique in the Netherlands. The partners in this network organization are the investigators and graduate students, gathered in interdisciplinary research teams and executing our research programs. All our research activities are essentially interdisciplinary and incorporate the newest theoretical, methodological and application paradigms currently available. Our strongholds and international reputation builds both on previous work in molecular biology and biology and genetics of the brain, synapse function and neuronal networks, as well as on our clinical studies of the major brain diseases. We study the brain and its disease mechanisms through an integrative approach from molecule-to-bedside and back. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Through this collaboration we aim at delivering proof-of-concept for radically new approaches in the early diagnosis of brain disease, the elucidation of its underlying mechanisms, and thus providing new perspectives on therapy. 9

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13 4. Structure Research Institute Mission The mission of the Neuroscience Campus Amsterdam is to study the brain and its disease mechanisms through an integrative approach running from molecule-tobedside. We apply a systems biology approach of the brain where clinicians and clinical researchers are working side-by-side with neuroscientists, geneticists, psychologists, biophysicists and statisticians. Aims & Objectives The Neuroscience Campus Amsterdam currently the largest neuroscience research community gathered on one campus in the Netherlands. We are strongly focusing on molecular neurobiology, going all the way from biophysics, genetics, genomics and systems biology of the synapse, to heritability and genetic basis of brain function. Research Activities The Neuroscience Campus Amsterdam teams focus on three areas of research supported by Support Facilities: Advanced technology Programs, Genes & the Brain and Brain Disease Mechanisms. Advanced Technology Programs Brain Disease Mechanisms Research Support Facilities Genes & the Brain Figure 1. Mainstream research areas of the Neuroscience Campus Amsterdam 11

14 Figure 2. Research Programs. As shown in Figure 2, each research activity area is further subdivided in a focused number of research programs and facilities. These have been further described in section 10 of this annual report. 12

15 Advanced Technology Programs The Neuroscience Campus Amsterdam puts much effort in Advanced Technology Programs, thereby securing a strong translational link between those groups providing for instance tailor-made Photonics technology and laboratories where these methods can be successfully applied (i.e. human health and life sciences). In additional there is an established translational link between the Brain Imaging experts and those involved in any of our Brain Disease Programs, including our so-called imaging genetics initiatives. Statistical geneticists, biostatisticians and bioinformatics experts provide state-of-the-art Integrated Analysis and Modeling methodology; (neuro)psychologists and clinicians apply this methodology when screening patients, their genes and their endophenotypes. Further novel insight is being generated through reconstruction of synaptic gene networks in the Systems Biology of the Synapse program. Finally, there is potentially a strong link between the Drugs screening and Therapy Design program and clinical activities of the Brain Disease Mechanisms teams Genes and the Brain The words molecules, genes, synapses, connectivity and brain function are the buzzwords of all our initiatives. This interest provides a strong translational potential between genetics, molecular neurobiology, functional genomics, neurophysiology, psycho-pharmacology and behavioral neuroscience within the area 'genes and the brain' but also between the latter and the 'brain disease mechanism' programs. There is strong collaboration between labs providing research support and investigators that largely depend on such activities including the clinicians and the statistical geneticists. Brain Disease Mechanisms All research in the Brain Disease Mechanisms programs is aimed and integrated with our in-house patient clinics, notably the VUmc Alzheimer Center, the Multiple Sclerosis Center Amsterdam and the treatment of Depression in the GGZ ingeest-clinic. In addition, given the fact that we have a growing number of Parkinson's disease patients, the Neurodegeneration research program also includes research on patient-material from these patients. Moreover, also nicotine- and alcohol-abuse data of our depressed patients is being analyzed in the Addictive Behavior Program. The link between attentive traits in human twins and those being observed in ADHD patients continues to provide a further strong translational program towards the understanding of attentive behavior, impulsivity and cognition in general. Support Facilities Support Facilities are aimed at one-way research support, thereby serving as core facilities to generate data and provide tissue- or sample-analysis, or generate models (including transgenic mice and cell lines) in relation to specific research-project questions. The research project questions are generated, prioritized and argued (in relation to the overall research program) by the program committee and/or the program leaders. 13

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17 5. SWOT Analysis Strength Since the start of this campus-wide collaboration we have been forming new expertise-teams and have invested in more than 80 new translational projects. In addition to the 147 PhD projects currently running on campus, the European Neuroscience Campus Network (ENC-Network) was set up, to formalize the international setting of our graduate training program, both of the Master of Neurosciences and of the Joint PhD in Neurosciences. This has brought the Neuroscience Campus Amsterdam in connection with a selection of major and opinion leading institutes in Europe. The acquisition of National Research Council and coming from European agencies is currently funding around 75% of our ongoing concern (current acquisition ~ 28 M /year). New infrastructures including an automated cellomics facility, photonics setups and a stem cell laboratory were installed in previous years and are currently up and running. Major prizes and research grants were awarded including two new ERC Starting Grants and two VICI grants and major funding for in particular the MS research program. Our translational strength is further exemplified by our in-depth knowledge of the genetics of the brain, and our enabling technologies and our access to large patient cohorts, biobanks, mutant mouse models and state of the art genomics, proteomics, brain imaging infrastructures. However, the real strength of our institute is the collaborative attitude and excellence of our scientists, graduates and coworkers. NCA can be characterized by its strong coherence and common strategy towards the future. Weaknesses To make the efforts of the collaborations within the Neuroscience Campus endurable initiatives, we need to design alternative strategies that would give rise to new funding for innovation initiatives on campus. Thus in addition to dedicating tenured staff - and collaborating - on conditional national and European funding, we need to invest in endurable collaboration research programs with industry (see below). Opportunities The industrial market and putative sponsors are often oriented towards thematically organized knowledge-domains and innovation - and not towards mono-disciplinary Research & Design (R&D). The Neuroscience Campus Amsterdam is an ideal party to collaborate with industry since it has organized its R&D by building on the trans-disciplinary strengths of our collaborations. The international reputation of our publications is strong, and of high impact. The expertise and infrastructure is excellent. Therefore now is the right time to start creating industrial-academic partnerships on campus, and start building on collaborations that are characterized by open innovation and where creating new funding for the academic sector is an integral part of the business model. 15

18 Our unique selling point is that clinical trials performed on campus can be directly coupled to explorative biological research aimed at generating mechanistic insights into the disease etiology. To this end, during the fall of 2011, the Board of Deans gave consent to start a pilot project aimed at implementing the infrastructure and make available the manpower to organize a so-called Industry Alliance Office, aimed at facilitating knowledge utilization and focused on organizing more investments from the pharma/biotech industry in collaborative research programs being executed on our campus. Threats The adagium of 2011 for the Neuroscience Campus Amsterdam was to make choices and to take consequences of these choices. Although we remain optimistic, the current economic crisis worldwide poses serious threats both for acquiring (un)condition funding for basic research and for knowledge utilization initiatives. Therefore firm initiatives are necessary to solidify our position based on scientific excellence. This includes a continued focus on national opportunities (such as the recent published gravitation call from NWO) and a focus on public-private partnership (such as proposed in the Innovation Contract) but, in particular, also a forward ambition of the partners of NCA to participate in international initiatives and opportunities within the context of FP7 and Horizon 2020 (Joint Programming, Flagship, etc.). 16

19 6. News & Highlights of the year 2011 Major external funding acquired in 2011 ERC starting grants for Huibert Mansvelder (CNCR) and for Jacqueline Vink (Biological Psychology, FPP) VICI grants for Brenda Penninx (GGZ ingeest) and Erwin Peterman (also LaserLaB, FEW) Major Stichting MS Research funding of 2.5 M for research under coordination of Jeroen Geurts and Elga de Vries (VUmc) FP7 grant for Adriaan Lammertsma (VUmc) Private investor/donations to MS Center of Chris Polman (VUmc) Additional 1.1 M donation to Polman & Geurts for MS research Newly appointed professors Prof. John van Swieten newly appointed as research professor at VUmc Prof. Danielle Posthuma appointed as Fenna Diemer Lindeboom Professor at the VU Prof. Ronald Boellaard appointed as research professor at VUmc Prof. Elga de Vries appointed as research professor at VUmc Prof. Henk Berendse appointed as research professor at VUmc Prof. Henry Weinstein appointed as research professor at VUmc Major Publication Output The Neuroscience Campus Amsterdam research groups published hundreds of peer reviewed papers in 2011, of which 44% in the top-10 journals worldwide, whereas 72 papers were published in high impact journals (i.e. IF ~ 9-10 or higher). For an overview, a subselection of 28 publication highlights is outlined below. In section 10, these and other highlights are discussed in more detail. Neuropsychiatry: Demirkan et al. & Middeldorp, C.M. (2011). Genetic risk profiles for depression and anxiety in adult and elderly cohorts. Molecular Psychiatry, 16(7), (IF = 15.5) Liu et al. (2011). Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Molecular Psychiatry, 16(1), 2-4. (groups of Penninx and Boomsma) Middeldorp et al. (2011). The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data. Translational Psychiatry, 1, e50. (groups of Penninx and Boomsma) (IF = 15.5) Lips et al. (2011) Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Molecular Psychiatry. doi: /mp [Epub ahead of print]. (group of Posthuma) (IF = 15.5) 17

20 Ripke et al. (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 43(10), (group of Posthuma) (IF = 36.4) Neurodegeneration: Cordonnier, C. & Flier, W.M. van der (2011). Brain microbleeds and Alzheimer's disease: innocent observation or key player? Brain, 134, (IF = 9.23) Flier, W.M. van der, Pijnenburg, Y.A.L., Fox, N.C. & Scheltens, P. (2011). Early-onset versus late-onset Alzheimer's disease: the case of the missing APOE epsilon 4 allele. Lancet Neurology, 10(3), (IF = 33.6) Plagnol et al. and Heutink, P. & Wood, N.W. (2011). A Two-Stage Meta- Analysis Identifies Several New Loci for Parkinson's Disease. PLoS Genetics, 7(6). (IF = 9.5) Neuroinflammation: Alvarez, J.I., Dodelet-Devillers, A., Kebir, H., Ifergan, I, Fabre, P.J., Terouz, S., Sabbagh, M., Wosik, K., Bourbonniere, L., Bernard, M., Horssen, J. van, Vries, H.E. de, Charron, F. & Prat, A. (2011). The Hedgehog Pathway Promotes Blood-Brain Barrier Integrity and CNS Immune Quiescence. Science, 334(6063), (IF = 31.4) Kooij et al. and Valk, P. van der & Vries, H.E. de (2011). Adenosine triphosphate-binding cassette transporters mediate chemokine (C-C motif) ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis. Brain, 134, (IF = 9.23) Kappos, L., Li, D., Calabresi, P.A., O'Connor, P., Bar-Or, A., Barkhof, F., Yin, M., Leppert, D., Glanzman, R., Tinbergen, J. & Hauser, S.L. (2011). Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet, 378(9805), (IF = 33.6) Killestein, J. & Polman, C.H. (2011). Determinants of interferon beta efficacy in patients with multiple sclerosis. Nature Reviews Neurology, 7(4), (IF = 29.5) - review Killestein, J., Rudick, R.A. & Polman, C.H. (2011). Oral treatment for multiple sclerosis. Lancet Neurology, 10(11), (IF = 21.7) Patsopoulos, N.A., Bakker, P.I.W. & Polman, C.H. (2011). Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. Annals of Neurology, 70(6), (IF = 10.7) Polman, C.H. et al. (2011). Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Annals of Neurology, 69(2), (IF = 10.7) - review 18

21 Child Neurology: López-Hernández, T., Ridder, M.C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G.C., Martinez, A, Estevez, R. & Knaap, M.S. van der (2011). Mutant GlialCAM Causes Megalencephalic Leukoence-phalopathy with Subcortical Cysts, Benign Familial Macrocephaly, and Macrocephaly with Retardation and Autism. American Journal of Human Genetics, 88(4), (IF = 11.7) Ridder, M.C., Boor, I., Lodder, J.C., Postma, N.L., Capdevila-Nortes, X., Duarri, A., Brussaard, A.B., Estévez, R., Scheper, G.C., Mansvelder, H.D. & Knaap, M.S. van der (2011). Megalencephalic leucoencephalopathy with cysts: defect in chloride currents and cell volume regulation. Brain, 134(11), (IF = 9.23) Steenweg, M.E., Pouwels, P.J.W., Wolf, N.I., Wieringen, W.N. van, Barkhof, F. & Knaap, M.S. van der (2011). Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging. Brain, 134(11), (IF = 9.23) Synaptic Transmission: Rao-Ruiz, P., Rotaru, D.C., Loo, R.J., Mansvelder, H.D., Stiedl, O., Smit, A.B. & Spijker, S. (2011). Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear. Nature Neuroscience, 14(10), (IF = 14.2) Guillem, K., Bloem, B., Poorthuis, R.B., Loos, M., Smit, A.B., Maskos, U., Spijker, S. & Mansvelder, H.D. (2011). Nicotinic acetylcholine receptor β2- subunits in the medial prefrontal cortex control attention. Science, 333, (IF = 31.4) Oberlaender, M., Boudewijns, Z.S.R.M., Kleele, T., Mansvelder, H.D., Sakmann, B. & Kock, C.P.J. de (2011). Three-dimensional axon morphologies of individual layer 5 neurons indicate cell type-specific intracortical pathways for whisker motion and touch. PNAS, 108(10), (IF = 9.8) Vinkhuyzen, A.A.E., Sluis, S. van der & Posthuma, D. (2011). Life events moderate variation in cognitive ability (g) in adults. Molecular Psychiatry, 16(1), 4-6. (IF = 15.5) Counotte, D.S., Goriounova, N.A., Li, K.W., Loos, M., Schors, R.C. van der, Schetters, D., Schoffelmeer, A.N.M., Smit, A.B., Mansvelder, H.D., Pattij, T. & Spijker, S. (2011). Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nature Neuroscience, 14(4), (IF = 14.2) Toonen, R.F. & Verhage, M. (2011). Crashpilot Underachieves due to Acetylation at the Nerve Terminal. Neuron, 72(5), (IF = 14.0) - review Walter, A.M., Groffen, A.J., Sorensen, J.B. & Verhage, M. (2011). Multiple Ca(2+) sensors in secretion: teammates, competitors or autocrats? Trends in Neurosciences, 34(9), (IF = 13.3) - review 19

22 Advanced Technology: Witte, S.M., Negrean, A., Lodder, J.C., Kock, C.P.J. de, Testa-Silva, G., Mansvelder, H.D. & Groot, M.L. (2011). Label-free live brain imaging and targeted patching with third-harmonic generation microscopy. PNAS, 108(15), (IF = 9.8) Braber, A. den, Ent, D. van t, Boomsma, D.I., Cath, D.C., Veltman, D.J., Thompson, P.M. & Geus, E.J.C. de (2011). White matter differences in monozygotic twins discordant or concordant for obsessive-compulsive symptoms: a combined diffusion tensor imaging/voxel-based morphometry study. Biological Psychiatry, 70(10), (group of De Geus) (IF = 8.9) Khatri, B., Barkhof, F., Comi, G., Hartung, H.P., Kappos, L., Montalban, X., Pelletier, J., Stites, T., Wu, S., Holdbrook, F., Zhang-Auberson, L., Francis, G. & Cohen, J.A. (2011). Comparison of fingolimod with interferon beta-1a in relapsing remitting multiple sclerosis: a randomized extension of the TRANSFORMS study. Lancet Neurology, 10(6), (IF = 18.2) Kilsdonk, I.D., Barkhof, F. & Wattjes, M.P. (2011) Revisions to McDonald Criteria for Diagnosis of Multiple Sclerosis: Impact of 3-Tesla Magnetic Resonance Imaging. Annals of Neurology, 70(1), (IF = 10.7) - review 20

23 7. International Collaboration Overview of major newly - and previously - established collaborations Prof. Adriaan Lammertsma participates in INMIND (FP7 consortium) Dr. Jeroen Geurts participates in Program grant: Pathobiology of MS: complex interplay between degeneration, inflammation and repair, of the Canadian MS Society. Prof. Philip Scheltens, representing the Alzheimer Center VUmc and the Neuroscience Campus Amsterdam, acts as national coordinator Joint Programming Neurodegeneration (FP7 collaboration) CNCR and Synaptologics continue to participate in major FP7 collaboration called SynSys - coordinator Prof. Guus Smit ( CNCR and Synaptologics continue to participate in FES consortium called NeuroBasic PharmaPhenomics - managing director Prof. Arjen Brussaard (see Neuroscience Campus Amsterdam coordinates the European Neuroscience Campus Network (ENC-Network), an Erasmus Mundus Joint Master Programme and Joint Doctorate Programme, aimed at funding > 125 new MSc students, in addition to > 50 new PhD projects. The estimate is that of around thirty of the newly appointed PhD students will graduate at VU/VUmc - director Prof. Arjen Brussaard (see 21

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25 8. Input Research Institute 8a) Funding External income The collective and aggregate acquisition of external funding during 2011 amounted to a consolidation of the number and amount of awarded grants, including the number of personalized grants(see section 6) and a cumulative sum of more than 28 M of external grant support in External Funding - Neuroscience Campus Amsterdam gs 2 gs 3 gs 4 (mix) Total Total Total Total Total Table 1 Acquisition of grants by collaborative efforts of the Neuroscience Campus Amsterdam - started in 2011 and compared to acquisitions. For further information, on acquisition per research program, see section 10b. In this overview, gs 2 is NWO funded research, gs 3 is project funding from non-profit, ministries, FES & EU and gs 4 is based on a mix of contract-research (for profit/industry) and donations/philanthropy. 23

26 8b) Fte per type of funding (research time) Total fte research (including PhD students) Type of funding gs 1 gs 2 gs 3 gs 4 mixed Total Total n.a Total n.a Total n.a Total Total fte research PhD students Type of funding gs 1 gs 2 gs 3 gs 4 mixed Total Total n.a Total n.a Total n.a Total Table 2 Total of research appointments. A total of > 400 scientists even excluding support and technical staff - contribute to this total. The research time per research program is split in section 10b. In this overview, gs2 is NWO funded research, gs3 is project funding from non-profit, ministries, FES & EU and gs4 is based on a mix of contract-research (for profit/industry) and donations/philanthropy. For a full list of all coworkers see appendix 1. 24

27 8c) New PhD projects started 2011 In 2010, 32 new PhD projects were started. For a full list of all newly started projects and PhD students, see appendix 2. We are confident about the future perspectives of Neuroscience Campus Amsterdam, given the acquisition of the Erasmus Mundus Joint Doctorate (with in total 50 additional PhD projects to be appointed up to 2014, of which ~ 25 projects are primarily or in collaboration with the Neuroscience Campus Amsterdam). PhD projects Newly started Table 3 Newly started PhD project in recent years. The boost in 2009 is explained by the start of BrainTrain. Currently around 50% of the projects is funded by European grants. 25

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29 9. Output Research Institute 9a) Scientific Output Theses Scientific papers Rest DissA DissB DissC DissD Wp WpREF WpNR VP Total Books Chptrs Total Total Total Total Table 4 Aggregate of the output of Neuroscience Campus Amsterdam. The numbers of refereed papers (WpRef) has increased compared to , the number of books and book-chapters and non-sci contributions was deliberately lowered since then. A full list of publications published is outlined in appendix 3. Abbreviations: Theses A: Promotion VU/VUmc PhD-student at VU Theses B: Promotion external PhD-student at VU Theses C: Promotion VU/VUmc PhD-student at other university Theses D: Promotion external PhD-student at other university (promotor, co-promotor) Wp: Books/monographs/book chapters/proceedings WpRef: Scientific Papers refereed WpNR: Scientific Papers non-refereed WB: Books/monographs WBC: - Book chapters/proceedings VP: Professional publication 27

30 9b) Scientific Output Program leaders and Support Coordinators The number of articles published per year and the total number of citations each year to the aggregate of these papers published by the current program leaders of the Neuroscience Campus Amsterdam has shown a solid growth in output and relevance of their output in previous years. At the onset of the new era in which the Neuroscience Campus Amsterdam became operational (i.e. during 2008) the yearly output amounted to ~ 400 research papers per year. In 2011 this number has increased to > 500 papers, with 75% being published in a top 25% journal and 44% being in the top-10 (see Figure 3 and Table 5). In 2008 > 9600 citations were collected to the accumulation of these research papers. Currently the aggregate citation scores of papers by our opinion leaders have increased to citations in The sum of all citations to publications published by our program leaders over the last ten year accumulates to > to a total of 3200 papers, being published as primary or corresponding author and an average of ~ 30 citations per published article. If also 'coauthor' papers are included, the currently active program leaders together have published ~ 4500 peer reviewed publications and have collected > citations thus far Relative Impact Factor Scores in 2011 SCI journal Impact Factor > 4 Figure 3: Relative distribution of 2011 SCI publications (508 in total) categorized according to Relative Impact Factor. A major proportion of the current output belongs to the category of highest impact papers (i.e. top 10%). And 7 out 10 papers belong to the top quarter of SCI journal publications and thus have a journal Impact Factor of 4 or higher. See also Table 5 for comparison with the 2008, 2009 and 2010 scores

31 To be able to make a comparison to the research output of previous years we have also included data and percentile scores from 2008, 2009 and 2010 respectively (see Table 5). Table 5 Comparison of Relative Impact Factors scores in 2011 compared to 2010, 2009 and

32 9c) Indicators of esteem A shortlist of awards, more details on grants awarded, and listing of other indicators of esteem are outlined in appendix 4. 9d) Societal Impact In general the Neuroscience Campus Amsterdam investigator focus on the biological mechanisms underlying common mental health and neurological brain diseases, applying the latest technology and thereby providing new perspectives on therapy. Finding the 'cause' of brain diseases, design its 'cure' and implement this to the level of 'patient care' are all at the core of our research ambition. Many of our research projects are directly (or indirectly) related to 'brain diseases' programs. This includes the activities of the VUmc Alzheimer Center, the MS Center Amsterdam, the Center for Children with White Matter Disorders and the GGZ ingeest-clinic affiliated patient research-programs for Anxiety and Depression disorders (NESDA) of the GGZ ingeest-clinic. In doing so, we also provide community services in relation to patient care (advise and information to care takers). Notably are two initiatives, one being the so-called MS-supportal (a virtual reception and internet-portal for MS patients) and one being the Memory Clinic of the Alzheimer Center that was launched in the fall of Moreover many of our senior investigators publish in national professional journals, give layman-lectures by invitation and/or participate in education projects. 30

33 10. Per Research Program 10a) Description Advanced Technology Programs Research Programs in short: Figure 4 Advanced Technology Research Programs. Innovation and development of the latest techniques are embedded in independent research programs that provide 'translational potential' (as indicated by the arrows) for newly developed project in 'adjacent' research programs where this new technology is being applied in a (pre)clinical settling. 31

34 ADVANCED TECHNOLOGY PROGRAMS Brain Imaging Research Program Committee: Adriaan Lammertsma (program leader) Dick Veltman (program leader) Frederik Barkhof Eco de Geus Ruud Verdaasdonk Modern neuroscience increasingly depends on advanced, state-of-the-art brain imaging techniques to characterize brain function and morphology in healthy subjects and in patients with neurological and psychiatric disorders. In addition, brain imaging is increasingly being used in animal models of disease. The VU/VUmc is unique in that it is the only academic center in the Netherlands that houses all major imaging technologies: o positron/single photon emission tomography (PET/SPECT) o magnetic resonance imaging (MRI), including a 3 Tesla functional MRI (fmri) and MR spectroscopy (MRS) o magneto-encephalography (MEG) and EEG, including MRI-compatible EEG o repetitive transcranial magnetic stimulation (rtms) o optical imaging with combined PET/3T MRI becoming available in Since state of the art applied research requires similarly advanced methodological expertise, the Brain Imaging program encompasses all methodological developments needed for pursuing advanced research goals in applied (clinical and preclinical) projects. The aims of the Brain Imaging research program in recent years were twofold. The first aim was to make optimal use of the extensive imaging facilities at the VU/VUmc campus, and to integrate these techniques with each other, wherever possible. The program instigates and performs methodological imaging research, in particular with regard to functional and structural connectivity, and molecular imaging. Second, the program aimed to function as a center of expertise, providing advice and if necessary assistance to scientists from other programs. Expertise in the field of imaging and imaging-analysis are two strongholds of the VUmc, and as such provide clinicians and neuroscientists in other research programs with a unique set of tools for non-invasive, in vivo investigations of the brain, both in humans and in animal models of disease. Neuroimaging is likely to be used not only for characterizing neural substrate of various neuropsychiatric disorders, but also for assessment of psychopathological traits cutting across diagnostic categories and for identification of endophenotypes, which may aid in understanding the genetic basis of these disorders. 32

35 In 2011, two projects (by Bob van Dijk and Dennis van t Ent) were finished aiming at providing access to grid computing using multiple nodes to enable computationally intensive analyses, and creating easy-to-use pipelines for voxel based morphometry (SPM8/VBM) and cortical thickness measurements (Freesurfer). Together with advances in imaging genetics, this allowed the research groups associated with the NEtherlands Study on Depression and Anxiety (NESDA, PI Prof. B. Penninx) and the Netherlands Twin Registry (NTR, led by Prof. D. Boomsma and Prof. E. de Geus) to participate in the worldwide ENIGMA study. Also in 2011, the Brain Imaging group has commenced implementing methodology for advanced multivariate data analysis including graph analysis and support vector machine learning (AM Wink). Key Publications - Brain Imaging Braber, A. den, Ent, D. van t, Boomsma, D.I., Cath, D.C., Veltman, D.J., Thompson, P.M. & Geus, E.J.C. de (2011). White matter differences in monozygotic twins discordant or concordant for obsessive-compulsive symptoms: a combined diffusion tensor imaging/voxel-based morphometry study. Biological Psychiatry, 70(10), Folkersma, H., Boellaard, R., Yaqub, M.M., Kloet, R.W., Windhorst, A.D., Lammertsma, A.A., Vandertop, W.P. & Berckel, B.N.M. van (2011). Widespread and Prolonged Increase in (R)-(11)C- PK11195 Binding After Traumatic Brain Injury. Journal of Nuclear Medicine, 52(8), Schoonheim, M.M., Geurts, J.J., Landi, D., Douw, L., Meer, M.L. van der, Vrenken, H., Polman, C.H., Barkhof & F., Stam, C.J. (2011). Functional connectivity changes in multiple sclerosis patients: A graph analytical study of MEG resting state data. Human Brain Mapping, Nov 11. doi: /hbm [Epub ahead of print]. Steenweg, M.E., Pouwels, P.J.W., Wolf, N.I., Wieringen, W.N. van, Barkhof, F. & Knaap, M.S. van der (2011). Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging. Brain, 134(11), Heuvel, O.A. van den, Gorsel, H.C. van, Veltman, D.J. & Werf, Y.D. van der (2011). Impairment of executive performance after transcranial magnetic modulation of the left dorsal frontalstriatal circuit. Hum Brain Mapping, Sep 23. doi: /hbm [Epub ahead of print]. 33

36 ADVANCED TECHNOLOGY PROGRAMS Drugs Screening and Therapy Design Research Program Committee: Peter Heutink (program leader) Guus Smit (program leader) Marjo van der Knaap Adriaan Lammertsma Huibert Mansvelder Matthijs Verhage The aims of this advanced technology program are twofold: The first aim is to make optimal use of our growing potential in cellomics facilities, which currently include cell culture robots and automated fluorescence time lapse microscopy tools that allow for medium throughput screening of genetically modified celllines. The unique asset of this technology is that the Neuroscience Campus can offer new bioassays by taking gene polymorphisms or haplotypes selected in for instance Genome Wide Analyses (GWA) and model these directly at the cellular level to test the effect of genetic variation or mutations on for instance neuronal outgrowth or cell survival. Since this technology is automated and executed in multiwell plates, it allows for the focused testing of (small molecule) shrna libraries or compound libraries (in collaboration with for instance partners from TI- Pharma. The second aim is to set up a so-called stem-cell facility, and to implement and further investigate to potential of stem-cell therapy (first in mutant mouse models of Childhood White Matter Disorders and in the long run in human patients). The program s collaborative research projects concern screening of potential therapeutic compounds in view of neurodegenerative disease (grey matter) as well as while matter disorders. In particular through bundling of the newest insights into the genetic vulnerability toward grey or white matter disorders in cellular assays and combining these with drug (design) screening, will help us to achieve a number of truly translated objectives. Second, in particular for the devastating (and Mendelian genetic) child neurology disorders (but potentially in the long run also for more common diseases including MS) stem-cell therapy may be a serious option when it comes to curing the diseases. Highlights - Drugs Screening & Therapy Design Sushant Jain in the group of Heutink published another methodology paper, see Jain, S., Sondervan, D., Rizzu, P., Bochdanovits, Z., Caminada, D. & Heutink, P. (2011). The Complete Automation of Cell Culture: Improvements for High-Throughput and High-Content Screening. Journal of Biomolecular Screening, 16(8), Key Publication - Drugs Screening & Therapy Design Brams, M., Pandya, A., Kuzmin, D., Elk, R. van, Krijnen, L., Yakel, J.L., Tsetlin, V., Smit, A.B. & Ulens, C. (2011). A Structural and Mutagenic Blueprint for Molecular Recognition of Strychnine and d- Tubocurarine by Different Cys-Loop Receptors. PloS Biology, 9(3) (IF = 12.5) 34

37 ADVANCED TECHNOLOGY PROGRAMS Integrative Analysis & Modeling Research Program Committee: Danielle Posthuma (program leader) Mathisca de Gunst (program leader) Niels Cornelisse Jaap Heringa Klaus Linkenkaer-Hansen Pim van Nierop Arjen van Ooyen Sophie van der Sluis Aad van der Vaart The Integrative Analysis and Modeling program provides the essential expertise on modeling and data analysis for the Neuroscience Campus systems biology approach of the brain. It develops and assesses statistical methods and computational tools for the analysis of large, complex data sets. It also builds biology-based mathematical and computational models and designs modelbased statistical tools for model systems with a limited number of components that are used to unravel generic principles of the involved biological networks. The program has three aims: to develop novel research methodology for integrative research concerning large and complex data sets (Methods for Large Data Sets); to perform research aimed at developing innovative tools for dedicated mathematical and computational modeling and statistical analysis (Biologybased Modeling and Methods); to perform integrative analysis of data obtained from different disciplines and levels of data (Integrative Data Analysis) The program s collaborative research projects concern modeling and analysis of data in the areas of genetic epidemiology, gene expression analysis and gene network modeling, phenomics, and neuronal networks. The research will result in mathematical and computational models, statistical methods and data analysis tools for biological networks, as well as high-level bioinformatics algorithms, including the integration and collaborative annotation of -omic data, and optimization of statistical analyses in a cluster environment. It will also be instrumental in the transfer of technology and skills into -omic bioinformatics, and in design of experiments and predictive biology. The IAM platform also directs the internationally renowned Genetic Cluster Computer (geneticcluster.org), which plays a central role in large scaled collaborative GWAS efforts. Highlights - Integrative Analysis & Modeling Wessel van Wieringen, together with Saskia Wilting and Renske Steenbergen, received a CCA- VICI grant to produce multivariate statistical models that describe the development of HPVinduced cervical cancer in vitro from a longitudinal experiment in which multiple molecular levels (DNA copy number, methylation, gene expression, and microrna expression) of 35

38 consecutive stages of a cell line model have been characterized in high-throughput fashion. The high-dimensionality of the information on and the dependency between the molecular levels make the inference of the molecular mechanisms underlying cervical cancer development a statistical challenge, which is to be tackled within this project. A EU-grant in the FP7-framework was awarded to Wessel van Wieringen and Mark van de Wiel. In a case-control study involving radiation-induced thyroid cancer patients and healthy controls, multiple molecular levels (DNA copy number, methylation, gene expression, and microrna expression) of the samples have been characterized in high-throughput fashion. From these data, the project aims to develop multivariate statistical models that describe the mechanisms at the molecular level of the cell. This should enhance the understanding of what distinguishes the cases from the controls. The high-dimensionality of the information on and the dependency between the molecular levels make the inference of the molecular mechanisms underlying the distinction between cases and control a statistical challenge, which is to be tackled within this project. Danielle Posthuma played a central role in the largest GWAS study to date on schizophrenia, which was published in Nature Genetics. The Genetic Cluster Computer accommodated all analyses carried out for this study. A grant from the Mathematics cluster STAR was awarded to Mathisca de Gunst for a project entitled "Modeling gene regulatory networks: an integrative Bayesian approach". The project will focus on the development and application of statistical tools for the simultaneous inference of sub-network structure and sub-network dependent transcriptional regulators. The Neurophysiological Biomarker Toolbox (NBT), which has previously received funding from IAM (Phase 1), is now supported with its own Wiki ( and used extensively by 100+ students at the VU. The NBT is expected to be introduced in a paper currently under revision in Frontiers in Neuroscience. Danielle Posthuma participated in the MAGIC consortium which resulted in two major papers in Nature Genetics and Cell on metabolic traits Novel software to conduct gene-set analysis has been developed and successfully applied to schizophrenia by Esther Lips, a PhD student partly funded by NCA-IAM. Her results were published in the number one journal of psychiatry (Molecular Psychiatry) and have led to more insight into the etiology of schizophrenia. Key Publication - Integrative Analysis & Modeling (In bold: members program committee IAM and persons financed through NCA-IAM) Bosker, F.J., Hartman, C.A., Nolte, I.M., Prins, B.P., Terpstra, P., Posthuma, D., Veen, T. van, Willemsen, G., DeRijk, R.H., Geus, E.J.C. de, Hoogendijk, W.J.G., Sullivan, P.F., Penninx, B.W.J.H., Boomsma, D.I., Snieder, H. & Nolen, W.A. (2011). Poor replication of candidate genes for major depressive disorder using genome-wide association data. Molecular Psychiatry, 16(5), [IF=15] Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC) (incl D Posthuma), and others (2011). Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genetics, 43(11), (IF = 34.3) Geeven, G., MacGillavry, H.D., Eggers, R., Sassen, M.M., Verhaagen, J., Smit, A.B., Gunst, M.C.M. de & Kesteren, R.E. van (2011). LLM3D: a log-linear modeling-based method to predict functional gene regulatory interactions from genome-wide expression data. Nucleic Acids Research, 39(13), Jansen, R., Timmerman, J., Loos, M., Spijker, S., Ooijen, A. van, Brussaard, A.B., Mansvelder, H.D., Smit, A.B., Gunst, M.C.M. de & Linkenkaer-Hansen, K. (2011). Novel Candidate Genes Associated with Hippocampal Oscillations. PLoS ONE, 6(10), e (IF = 4.41 ) Lips, E.S., Cornelisse, L.N., Toonen, R.F., Min, J.L., Hultman, C.M.; the International Schizophrenia Consortium, Holmans, P.A., O'Donovan, M.C., Purcell, S.M., Smit, A.B., Verhage, M., Sullivan, P.F., Visscher, P.M., Posthuma, D. (2011)/ Functional gene group analysis identifies synaptic gene groups as risk factor for schizophrenia. Molecular Psychiatry. doi: /mp [Epub ahead of print]. [IF=15.0] Liu, Y., Blackwood, D.H., Caesar, S., Geus, E.J.C. de, Farmer, A., Ferreira, M.A.R., Ferrier, I.N., Fraser, C., Gordon-Smith, K., Green, E.K., Grozeva, D., Gurling, H.M., Hamshere, M.L., Heutink, P., Holmans, P.A., Hoogendijk, W.J.G., Hottenga, J.J., Jones, L., Jones, I.R., Kirov, G., Lin, D., McGuffin, P., Moskvina, V., Nolen, W.A., Perlis, R.H., Posthuma, D., Scolnick, E.M., Smit, A.B., Smit, J.H., Smoller, J.W., St Clair, D., Dyck, R. van, Verhage, M., Willemsen, G., Young, A.H., Zandbelt, 36

39 T., Boomsma, D.I., Craddock, N., O Donovan, M.C., Owen, M.J., Penninx, B.W.J.H., Purcell, S., Sklar, P. & Sullivan, P.F. (2011). Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder. Molecular Psychiatry, 16(1), 2-4. [IF=15.0] Ripke, S., Sanders, A.R., Kendler, K.S., Levinson, D.F., Sklar, P., Holmans, P.A., Lin, D.Y., Duan, J., Ophoff, R.A., Andreassen, O.A., Scolnick, E., Cichon, S., St Clair, D., Corvin, A., Gurling, H., Werge, T., Rujescu, D., Blackwood, D.H., Pato, C.N., Malhotra, A.K., Purcell, S., Dudbridge, F., Neale, B.M., Rossin, L., Visscher, P.M., Posthuma, D., and several other in the Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium (2011). Genome-wide association study identifies five new schizophrenia loci. Nature Genetics, 43(10), (IF = 34.3) Steenweg, M.E., Pouwels, P.J.W., Wolf, N.I., Wieringen, W.N. van, Barkhof, F. & Knaap, M.S. van der (2011). Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging. Brain, 134(11), Van Ooyen, A. (2011). Using theoretical models to analyse neural development. Nature Reviews Neuroscience, 12 (6), (invited review) Vinkhuyzen, A.A.E., Sluis, S. van der & Posthuma, D. (2011). Life events moderate variation in cognitive ability (g) in adults. Molecular Psychiatry, 16(1), 4-6. [IF=15] Wiel, M.A. van de, Picard, F., Wieringen, W.N. van & Ylstra, B. (2011). Preprocessing and downstream analysis of microarray DNA copy number profiles. Briefings in bioinformatics, 12(1), Zhu, H., Shyh-Chang, N., Segre, A.V., Shinoda, G., Shah, S.P., Einhorn, W.S., Takeuchi, A., Engreitz, J.M., Hagan, J.P., Kharas, M.G., Urbach, A., Thornton, J.E., Triboulet, R., Gregory, R.I., Hottenga, J.J., Geus, E.J.C. de, Posthuma, D., Willemsen, G.; DIAGRAM Consortium; MAGIC Investigators (incl D Posthuma), Altshuler, D. & Daley, G.Q. (2011). The Lin28/let-7 axis regulates glucose metabolism. Cell, 147(1), [IF=32.40] 37

40 ADVANCED TECHNOLOGY PROGRAMS Photonics and Life Cell Imaging Research Program Committee: Marloes Groot (program leader) Huibert Mansvelder (program leader) Johannes de Boer Davide Iannuzzi George Kraal Erwin Peterman Ruud Toonen Gijs Wuite In this research, the investigators develop integrated non-linear optical imaging systems consisting of an in vitro imaging platform and in vivo, whole animal, imaging platforms that make optimal use of shared versatile laser systems. Advancement in neuroscience research requires the development of techniques that enable in vivo visualization of individual neurons, neuronal networks, and synaptic contacts, with high spatial and temporal resolution and penetration depth, while these circuits are processing information. The development of new optical in vivo imaging modalities that have sub-cellular resolution will allow identification of novel biomarkers for early detection of brain disease. New optical tools can, in addition to identification of new biomarkers, also be developed to perturb and interfere with the progression of disease at very early (pre-clinical) stages. The ability to visualize neurons inside living brain tissue is a fundamental requirement in neuroscience and neurosurgery. Especially the development of a noninvasive probe of brain morphology with micrometer-scale resolution is highly desirable, as it would provide a noninvasive approach to optical biopsies in diagnostic medicine. Two-photon laser-scanning microscopy (2PLSM) is a powerful tool in this regard, and has become the standard for minimally invasive high-resolution imaging of living biological samples. However, while 2PLSM-based optical methods provide sufficient resolution, they have been hampered by the requirement for fluorescent dyes to provide image contrast. Here we demonstrate high-contrast imaging of live brain tissue at cellular resolution, without the need for fluorescent probes, using optical third-harmonic generation (THG). We exploit the specific geometry and lipid content of brain tissue at the cellular level to achieve partial phase matching of THG, providing an alternative contrast mechanism to fluorescence. We find that THG brain imaging allows rapid, noninvasive label-free imaging of neurons, white-matter structures, and blood vessels simultaneously. Furthermore, we exploit THG-based imaging to guide micropipettes towards designated neurons inside live tissue. This work is a major step towards label-free microscopic live brain imaging, and opens up possibilities for the development of laserguided microsurgery techniques in the living brain. In the coming years, this research program aims to bring this technique into the clinic. Based on the state of the art microscope technology described above, a prototype system will be developed that will be tested on laboratory animals at first and ultimately in the operating theatre during brain surgery. 38

41 Highlights - Photonics & Life Cell Imaging The groups of Marloes Groot, Ruud Toonen & Huibert Mansvelder have setup two major highend Laser Scanning Microscopy setups with funding in part provided by the Neuroscience Campus Amsterdam. Huibert Mansvelder was award an ERC Starting Grant in 2011 by the European Research Council, entitled: Optical dissection of circuits underlying fast cholinergic signalling during cognitive behaviour. Key Publications - Photonics & Life Cell Imaging Guillem, K., Bloem, B., Poorthuis, R.B., Loos, M., Smit, A.B., Maskos, U., Spijker, S, & Mansvelder, H.D. (2011). Nicotinic acetylcholine receptor β2-subunits in the medial prefrontal cortex control attention. Science, 333, (Impact factor: 31.4) Testa-Silva, G., Loebel, A., Giugliano, M., Kock, C.P.J. de, Meredith, R.M.* & Mansvelder, H.D.* (2011). Hyperconnectivity and slow synapses during early development of medial prefrontal cortex in a mouse model for mental retardation and autism. Cerebral Cortex, doi: /cercor/bhr224. [Epub ahead of print.] (Impact factor: 6.9) Poorthuis, R.B., Bloem, B., Schak, B., Wester, J., Kock, C.P. de & Mansvelder, H.D. (2012). Layer- Specific Modulation of the Prefrontal Cortex by Nicotinic Acetylcholine Receptors. Cerebral Cortex, 2012 Jan 30. [Epub ahead of print.] (Impact factor: 6.9) Witte, S., Negrean, A., Lodder, J.C., Kock, C.P.J. de, Testa Silva, G., Mansvelder, H.D.* & Groot, M.L.* (2011). Label-free live brain imaging and targeted patching with third-harmonic generation microscopy. Proceedings of the National Academy of Sciences of the United States of America, 108(15), (*Shared senior authors) (IF = 9.43) Jansen, R., Timmerman, J., Loos, M., Spijker, S., Ooijen, A. van, Brussaard, A.B., Mansvelder, H.D., Smit, A.B., Gunst, M.C.M. de & Linkenkaer-Hansen, K. (2011). Novel Candidate Genes Associated with Hippocampal Oscillations. PLoS ONE, 6(10) 39

42 Genes & the Brain Research Programs in short: Figure 5 Genes & the Brain Research Programs. We have three mainstream research programs in this area where mechanistic models based on the genetic makeup of the brain is the common denominator theme. The arrows indicate that the three research programs have strong translational links and in part shared expertise. 40

43 GENES & THE BRAIN Attention & Cognition Research Program Committee: Dorret Boomsma (program leader) Matthijs Verhage (program leader) Meike Bartels Niels Cornelisse Peter Heutink Jelle Jolles Huibert Mansvelder Hanne Meijers Rhiannon Meredith Tonny Mulder Pim van Nierop Tommy Pattij Brenda Penninx Danielle Posthuma Guus Smit Attention and cognition research is probably one of the most intensively studied topics in Neuroscience Research. A total of eight departments of three faculties have joined in the Attention & Cognition program. Researchers with different backgrounds, ranging from molecular genetics and biology to genetic epidemiology, psychology and clinical applications, contribute to this multidisciplinary program. This intense collaboration and the availability of unique resources, such as a large collection of twin families, well phenotyped longitudinal cohorts recruited from clinics throughout the Netherlands, novel animal models for attention and mental retardation and state of the art research facilities concentrated at one city campus, generates unique potential. Highlights - Attention & Cognition The resting-state questionnaire (RSQ): A paradigm shift in resting-state neuroimaging, under coordination of Klaus Linkenkaer-Hansen. The human brain generates complex patterns of activity and cognition during wakeful rest, but their relationship has remained largely unexplored. The team of Linkenkaer-Hansen has developed a self-report Resting-State Questionnaire (RSQ) of 50 five-point Likert items for rating feelings and thoughts during the classical eyes-closed rest condition. In the past year ( ) the RSQ was used in functional magnetic resonance imaging (fmri) to investigate links between cognition and brain activity during the resting state (RS). The RSQ data revealed large inter-individual differences in thoughts and feelings experienced by the participants during RS-fMRI imaging. As our instructions were 'typical' such differences are likely to occur in most RS measurements. PCA identified factors that were related to emotions ("I felt happy") or cognitive control ("I had difficulty holding on to my thoughts"). Independent component analysis identified distinct group-averaged networks of brain regions with temporally correlated BOLD signals, including RS networks such as the default mode and the executive networks. Importantly, the investigators observed that individual variation in resting-state cognition meaningfully explains individual variation within the fmri-derived functional brain networks. Thus, the RSQ could prove useful for shedding light on functional implications of genetic or disease-related variation in RS brain activity. 41

44 Mouse model for Fragile X mental retardation: Over the last 12 months, the team of Rhiannon Meredith has continued to work on a research line using the transgenic mouse model for Fragile X mental retardation. This mouse has been shown to have mild spatial learning and memory impairments. Two PhD students in this team, Julia Dawitz and Ioannis Kramvis have been investigating synaptic activity in the hippocampal and entorhinal cortex regions necessary for spatial learning. Using multiphoton calcium imaging and electrophysiology, their work focuses on early developmental stages of postnatal brain development. Their projects are integrated within the EC FP7 BrainTrain consortium, coordinated by the CNCR and the VU University Amsterdam. In a related study, Meredith et al. published their results testing the effects of glutamatergic antagonists upon synaptic function in developing hippocampus of Fragile X model mice. They found these drugs could correct small changes in excitatory synaptic function but were restricted to a specific developmental stage, supporting their recent article that sensitive time-windows for susceptibility occur in neurodevelopmental disorders (Meredith et al., 2012). Hoekstra RA, Vinkhuyzen AAE, Wheelwright S, Bartels M, Boomsma DI, Baron-Cohen S, Posthuma D, van der Sluis S. Brief report: the construction and validation of an abridged version of the Autism-spectrum quotient (AQ-short), J Autism Dev Disord May;41(5): This study reports on the development and validation of an abridged version of the 50-item Autism-Spectrum Quotient (AQ), a self-report measure of autistic traits. We aimed to reduce the number of items whilst retaining high validity and a meaningful factor structure. The item reduction procedure was performed on data from 1,263 Dutch students and general population adults. The resulting 28-item AQ-Short was subsequently validated in 3 independent samples, both clinical and controls, from the Netherlands and the UK. The AQ-Short comprises two higher-order factors assessing 'social behavioral difficulties' and 'a fascination for numbers/patterns'. The clear factor structure of the AQ-Short and its high sensitivity and specificity make the AQ-Short a useful alternative to the full 50-item version. Rizzi T, Arias-Vasquez A, Rommelse N, Kuntsi J, Asherson P, Banaschewski T,. and Posthuma D. The ATXN1 and TRIM31 genes are related to intelligence but only in an ADHD background: Evidence from a large collaborative study totaling 4963 subjects AJMG-B, 156(2): Intelligence is a highly heritable trait for which it has proven difficult to identify the actual genes. In the past decade, five whole-genome linkage scans have suggested genomic regions important to human intelligence; however, so far none of the responsible genes or variants in those regions have been identified. Apart from these regions, a handful of candidate genes have been identified, although most of these are in need of replication. The recent growth in publicly available data sets that contain both whole genome association data and a wealth of phenotypic data, serves as an excellent resource for fine mapping and candidate gene replication. We used the publicly available data of 947 families participating in the International Multi-Centre ADHD Genetics (IMAGE) study to conduct an in silico fine mapping study of previously associated genomic locations, and to attempt replication of previously reported candidate genes for intelligence. Although this sample was ascertained for attention deficit/hyperactivity disorder (ADHD), intelligence quotient (IQ) scores were distributed normally. We tested 667 single nucleotide polymorphisms (SNPs) within 15 previously reported candidate genes for intelligence and SNPs in five genomic loci previously identified through whole genome linkage and association analyses. Significant SNPs were tested in four independent samples (4,357 subjects), one ascertained for ADHD, and three population-based samples. Associations between intelligence and SNPs in the ATXN1 and TRIM31 genes and in three genomic locations showed replicated association, but only in the samples ascertained for ADHD, suggesting that these genetic variants become particularly relevant to IQ on the background of a psychiatric disorder. Vinkhuyzen AAE, van der Sluis S, Posthuma D Life Events Moderate Variation in General IQ in Adults, Mol Psychiat, 2011 Jan;16(1):4-6. The heritability of general cognitive ability (g) in adults is estimated to lie approximately between 75 and 85%. Despite this overwhelming indirect evidence of genes for g, only a handful of genes have been identified so far, together explaining <~5% of the genetic variation. Several reasons have been suggested for this missing heritability, including the presence of gene environment interactions (GEI). We have investigated the presence of GEI for measured Life Events and g, in a population-based sample of adult twins and their siblings (N=560). Results demonstrated modest negative moderation of genetic factors by several Life Events and considerable moderation of these Life Events on the overall environmental influence, with direction depending on the specific Life Event. 42

45 The broad heritability of g ranged from only 9% to above 90% across levels of positive, negative, and neutral Life Events, suggesting that the extent to which genetic and environmental influences affect individual differences in g in adults is not equal across the entire population, but varies with exposure to Life Events. Polderman TJ, Huizink AC, Verhulst FC, van Beijsterveldt CE, Boomsma DI, Bartels M. A genetic study on attention problems and academic skills: results of a longitudinal study in twins. J Can Acad Child Adolesc Psychiatry Feb;20(1): Several studies reported a negative association between ADHD symptoms and academic achievement. We investigated the etiology of the association between Attention Problems (AP, one of the core symptoms in ADHD) in early childhood and four academic skills across childhood in a genetically informative design. Academic skills (mathematics, spelling, reading and comprehension) were measured with standardized tests performed at school in grade 2, 4, and 6. AP were measured with mother ratings of the Devereux Child Behavior Rating Scale at age 5 and the Child Behavior Checklist at age 7. Subjects were 767 Dutch twins from 445 families. AP were negatively associated with most academic skills in each grade, and this association was stable over time. Correlations of AP with mathematics and comprehension were around , and with spelling around Correlations with reading were not significant. A significant genetic correlation (-0.40) between AP and mathematics across time indicated that shared genes play a role for these measures. The genetic correlations of AP with spelling and comprehension (both -0.28, p= 0.09) were non-significant. More complex academic skills, requiring higher cognitive processes, like mathematics and comprehension, are especially negatively associated with attention problems. The association between AP and mathematics is partly due to shared genes, while the association with comprehension, and spelling was driven by unique environmental factors. Polderman TJ, van Dongen J, Boomsma DI. The relation between ADHD symptoms and fine motor control: a genetic study. Child Neuropsychol. 2011;17(2): Previous research has shown that fine motor control (MC) performance, measured with a computerized task, was less accurate in children with ADHD and in their unaffected siblings, compared to healthy children. This might indicate a shared genetic etiology between MC and ADHD; it was therefore suggested that MC could serve as endophenotype for ADHD. We examined the association between ADHD symptoms (AS) and MC in a genetically informative design that can distinguish between a genetic and a nongenetic familial etiology for the association. Participants were 12-year-old twins and their siblings (N = 409). AS were rated on a continuous scale with the Strengths and Weaknesses of ADHD and Normal behavior scale (SWAN). MC accuracy and stability was measured with the computerized pursuit task of the Amsterdam Neuropsychological Tasks (ANT). Analyses were performed with Structural Equation Modelling. AS were weakly associated with MC accuracy of the left and right hand (r = -.10/-.10). No association with MC stability was found (r = -.01/-.03). AS were highly heritable (75%), while MC accuracy of the right hand and MC stability showed no genetic influences. For MC accuracy of the left hand, variance was explained by genetic (10%), common environmental (23%), and unique environmental variances. The association between MC accuracy of the left hand and AS was explained by a shared genetic influence but the genetic correlation was low (r = -.14). The phenotypic and genetic associations between AS and computerized MC were weak, suggesting that fine MC is not a proper endophenotype for ADHD. Resting-State Questionnaire data reveal seven dimensions of cognition during rest. B. Alexander Diaz *1, Sophie van der Sluis 2, Jeroen S. Benjamins 3, Sarah Moens 3, Eus J.W. Van Someren 1,3, Huibert D. Mansvelder 1, Klaus Linkenkaer-Hansen 1 Background: Almost half of the waking day, the human mind wanders off from the sensory environment, devoting consciousness to reflection on past experiences and imagination [1-3]. To allow for systematic measurement and characterization of resting-state cognition, we developed the Resting-State Questionnaire (RSQ), a 50-item survey rated on a five-point Likert-scale depending on the level of agreement [4]. Here, we describe a factor model of RSQ data obtained as part of an online test battery implemented in the Netherlands Sleep Registry (NSR). Methods: Participants (n = 922 [75% female], mean age years) were instructed to create a quiet environment around their computer, and follow the procedures presented on-screen. After five minutes of eyesclosed rest participants were notified through headphones and instructed to fill out the online RSQ. The data were preprocessed in MATLAB to screen for outliers, e.g., extremely high or low (sum-)scores on the RSQ. Additionally, participants were asked to indicate whether they were disturbed during the experiment, in which case they were removed from further analysis. We performed exploratory (Oblimin rotation) and confirmatory factor analyses on the screened data (n = 601) in Mplus 5.1. Criteria for the selection of factors in the exploratory factor analysis 43

46 were 1) eigenvalues of the R-matrix >1 and explaining >=3% of the total variance, 2) factor loadings >.32 and 3) an item should not load on more than 2 factors. The thus obtained factors were then used as a template to build a confirmatory factor model. Results: Based on the RSQ items associated with the seven-factor solution, we labeled the factors: Comfort, Self, Theory of Mind, Planning, Discontinuity of Mind, Somatic Awareness, and Sleepiness. This model may be used to relate neurophysiological measures of the resting state, e.g., EEG and fmri, to cognition. In addition, the model could prove beneficial in investigating the impact of braindisorders on mind wandering and other aspects of resting-state cognition. Low birth weight (LBW) is associated with attention problems (AP) and attentiondeficit/hyperactivity disorder (ADHD). The etiology of this association is unclear. We investigated whether there is a causal influence of birth weight (BW) on AP in a longitudinal dataset from >29,000 twins registered with the Netherlands Twin Register with BW 1,500 g and gestational age (GA) 32 weeks. Hyperactivity and AP were assessed at ages 3, 7, 10, and 12 years; weight was assessed at birth and age 2 years. Children in the lowest BW category of 1,500 to 2,000 g scored 0.18 to 0.37 standard deviations (SD) higher on AP than children in the reference category of 3,000 to 3,500 g. This effect was present in term-born and preterm-born children. Importantly, in BW discordant monozygotic (MZ), dizygotic (DZ), and unrelated (UR) pairs, the child with the lower BW scored higher on hyperactivity and AP than the child with the higher BW and within-pair differences were similar for MZ, DZ, and UR pairs. This pattern is consistent with a causal effect of BW on AP. These results strongly indicate that the association of birth weight and AP represents a causal relationship. (See: Groen-Blokhuis MM, Middeldorp CM, van Beijsterveldt CE, Boomsma DI. Evidence for a causal association of low birth weight and attention problems. J Am Acad Child Adolesc Psychiatry ;50(12): e2) Key Publications - Attention & Cognition Meredith, R.M., Jong, R.E. de & Mansvelder, H.D. (2011). Functional rescue of excitatory synaptic transmission in the developing hippocampus in Fmr1-KO mouse. Neurobiology of Disease, 41(1), (IF=4.625). Meredith, R.M., Dawitz, J. & Kramvis, I. (2012) Sensitive time windows for susceptibility in neurodevelopmental disorders. TINS /j.tins [E-pub ahead of print.] (IF 13.3). Smit, D.J.A., Geus, E.J.C. de, Nieuwenhuijzen, M.E. van de, Beijsterveldt, C.E.M. van, Baal, G.C.M. van, Mansvelder, H.D., Boomsma, D.I., Linkenkaer-Hansen, K. (2011). Scale-free modulation of resting-state neuronal oscillations reflects prolonged brain maturation in humans. Journal of Neuroscience. 31(37), Saviouk, V., Hottenga, J.J., Slagboom, E.P., Distel, M.A., Geus, E.J. de, Willemsen, G. & Boomsma, D.I. (2011). ADHD in Dutch adults: Heritability and linkage study. American Journal of Medical Genetics B Neuropsychiatric Genetics, 156(3), (IF = 3.48) Vinkhuyzen, A.A.E., Sluis, S. van der & Posthuma, D. (2011). Life events moderate variation in cognitive ability (g) in adults. Molecular Psychiatry, 16(1), 4-6 (IF = 15.5) 44

47 GENES & THE BRAIN Addictive Behavior Research Program Committee: Guus Smit (program leader) Ton Schoffelmeer (program leader) Huibert Mansvelder Brenda Penninx Sabine Spijker Dick Veltman Jacqueline Vink Taco De Vries This program addresses the development of drug and alcohol addiction as well as relapse to compulsive drug- and alcohol-seeking behavior during abstinence in both laboratory animals (rodents) and humans. The availability of operant animal models to study the motivational and cognitive aspects of addiction, the availability of advanced in vitro and in vivo neurophysiological techniques and that of state-of-the-art genomics/proteomics expertise in this program is unique. Moreover, the availability of genome-wide data in NESDA as well as the Dutch Twin Register allows us to identify genetic risk factors, whereas the application of brain imaging enables us to examine the motivational and cognitive aspects and pharmacotherapy of relapse behavior in humans. The investigators examine how individual differences in cognition (such as attention and impulsivity) and emotion (anxiety), primarily addressed in other research programs of the institute, determine the individual susceptibility to develop addictive behavior and the individual s risk to relapse to drug- and alcohol-seeking behavior during abstinence. In this respect, animal and human studies aimed to identify the genetic basis of addiction proneness (identification of vulnerability genes, including studies in twins), will be initiated. Animal studies address the psychopharmacology and neurobiology of cue-induced relapse to drug- and food-seeking behavior as well as that of extinction of drug/foodrelated memories during abstinence. Clinical studies are being performed in drug addicts, employing brain imaging (fmri) and pharmacotherapy, in order to examine the functional anatomy and pharmacotherapy of relapse behavior (predicted by animal studies). Major deliverables of this research are: Identification of genetic risk factors (polymorphisms) for the acquisition of nicotine, heroin and alcohol addiction. Identification of novel targets (e.g. synaptic proteins) for pharmacotherapeutical intervention of relapse to drug and/or alcohol consumption during abstinence. Identification of distinct impulsivity traits as treatable risk factors for the development of compulsive nicotine- and alcohol-seeking behavior. Synthesis and in vivo application of compounds targeting nicotine and glutamate receptors as putative future medicines. 45

48 Recent milestones reached include: We discovered that repeated exposure to nicotine during adolescence in rats causes neurocognitive dysfunctioning in adults. Endocannabinoids were found to regulate reward-seeking by altering the patterns of dopamine release in the nucleus accumbens. Evidence was obtained that alcohol dependence in humans is a risk factor for an unfavorable course of depression and/or anxiety. Moreover, the motivation for alcohol was found to be enhanced in rats that suffer from long-term depressive symptoms following social defeat. Combining progressive ratio schedules of reinforcement with a behavioral economics approach of analysis, poor impulse control was identified as a trait factor associated with a compulsive nature of nicotine seeking in rats. Impulsive choice appeared to be a risk factor for impaired extinction of cocaine seeking and enhanced relapse to drug seeking during abstinence in rats. Key Publications - Addictive Behavior Counotte D, Goriounova N, Li KW, Loos M, van der Schors R, Schetters D, Schoffelmeer ANM, Smit AB, Mansvelder HD, Pattij T (2011) Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nature Neuroscience, 14(4), (IF = 14.2) Counotte, D.S., Smit, A.B., Pattij, T. & Spijker, S. (2011). Development of the motivational system during adolescence, and its sensitivity to disruption by nicotine. Developmental Cognitive Neuroscience, 1(4), Pergadia, M.L., Glowinski, A.L., Wray, N.R., Agrawal, A., Saccone, S.F., Loukola, A., Broms, U., Korhonen, T., Penninx, B.W.J.H., Grant, J.D., Nelson, E.C., Henders, A.K., Schrage, A.J., Chou, Y.- L., Keskitalo-Vuokko, K., Zhu, Q., Gordon, S.D., Vink, J.M., Geus, E.J.C. de, Macgregor, S., Liu, J.Z., Willemsen, G., Medland, S.E., Boomsma, D.I., Montgomery, GW, Rice, J.P., Goate, A.M., Heath, A.C., Kaprio, J., Martin, N.G. & Madden, P.A.F. (2011). A 3p26-3p25 Genetic Linkage Finding for DSM-IV Major Depression in Heavy Smoking Families. American Journal of Psychiatry, 168(8), (IF = 12.8) Boschloo L, Vogelzangs N, Van den Brink W, Smit JH, Veltman DJ, Beekman AT, Penninx BW (2012) Alcohol use disorders and the course of depressive and anxiety disorders. British Journal pf Psychiatry, in press. (IF = 6.0) Diergaarde L, van Mourik Y, Pattij T, Schoffelmeer ANM, De Vries TJ (2011) Poor impulse control predicts inelastic demand for nicotine but not alcohol in rats. Addiction Biology, in press. doi: /j x. (IF = 4.2) Broos N, Diergaarde L, Schoffelmeer ANM, Pattij T, De Vries TJ (2012) Trait impulsivity predicts resistance to extinction and propensity to relapse to cocaine seeking: a bidirectional approach. Neuropsychopharmacology, in press. doi: /npp (IF = 6.7) Oleson EB, Beckert MV, Morra JT, Lansink CS, Cachope R, Abdullah RA, Loriaux AL, Schetters D, Pattij T, Roitman MF, Lichtman AH, Cheer JF (2012) Endocannabinoids shape accumbal encoding of cue-motivated behavior via CB1 receptor activation in the ventral tegmentum. Neuron 73, (IF = 14.0) Van den Oever MC, Spijker S, Smit AB. The synaptic pathology of drug addiction. Adv Exp Med Biol. 2012; 970: PubMed PMID: Counotte DS, Goriounova NA, Moretti M, Smoluch MT, Irth H, Clementi F, Schoffelmeer AN, Mansvelder HD, Smit AB, Gotti C, Spijker S. Adolescent nicotine exposure transiently increases high-affinity nicotinic receptors and modulates inhibitory synaptic transmission in rat medial prefrontal cortex. FASEB J Feb 3. [Epub ahead of print] PubMed PMID:

49 GENES & THE BRAIN Systems Biology of the Synapse Research Program Committee: Matthijs Verhage (program leader) Guus Smit (program leader) Niels Cornelisse Sander Groffen Marloes Groot Ronald van Kesteren Ka Wan Li Huibert Mansvelder Rhiannon Meredith Pim van Nierop Danielle Posthuma Sabine Spijker Oliver Stiedl Ruud Toonen Heidi de Wit The overall aim of this program is to understand molecular function and plasticity of the synapse in health and disease. In order to do so, the collaborating investigators aim at constructing protein interaction models (interactome) of the synapse that will be based on different conditions of synaptic function and on mouse knockouts of synaptic proteins. The synaptic interactome models are based on quantitative experimental data, which ultimately explain how a complex protein network drives synaptic functions in the brain and predicts its adaptive capacities in response to environmental cues, such as behavioral challenges and pharmacological interventions. Finally, knowledge about synaptic function is being integrated to study synaptic networks in vitro and in vivo. Specific objectives are to provide targets for synaptic modulation and to dissect disease phenotypes by identifying crucial nodes and connectivity of the network. In order to generate quantitative experimental data on proteins and protein states and to reveal crucial nodes of the complete synaptic system, the research apply genetic, behavioral and pharmacological intervention and analyze the perturbation outcome using synapse-wide proteomics, synapse physiology, life cell imaging techniques and electron microscopy. Between over twenty new projects were realized in which various technical approaches have been applied, ranging from whole synapse screens (itraq (quantitative) high-throughput MALDI-TOF) and subsynaptic protein complex analysis (immunoprecipitations and pull-down of tagged proteins) to biocore interaction analysis to derive kinetic parameters for proteins of interest, synaptic localization of proteins using confocal and electron microscopy. In 2011, the research teams started to harvest from their research investments The loop between computational science and experimental neuroscience is being 'closed' by using several perturbation approaches, involving gene knockdown, over-expression, pharmacological agents, and the use of peptide 47

50 mimetics to test model robustness and refine parameters. Modeling the synapse will allow us to predict and test synapse function and the physiology of neuronal circuitry. This information is crucially needed to design future therapeutic strategies addressing the many brain disorders for which synaptic dysfunction is a central aspect. Hence a truly integrated experimental and theoretical systems approach is applied to reach the objectives. Highlight - Systems Biology of the Synapse In 2011 the team of Ronald van Kesteren and Prof. Guus Smit made more modifications to their setups in automated confocal cellular imaging and screening instrumentation. High-resolution confocal imaging, together with automated image acquisition and advanced online image analysis algorithms will be used for the systematic functional analysis genes and proteins that mediate synapse formation and synaptic plasticity in vitro. Key Publications - Systems Biology of the Synapse Rao-Ruiz, P., Rotaru, D.C., Loo, R.J., Mansvelder, H.D., Stiedl, O., Smit, A.B. & Spijker, S. (2011). Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear. Nature Neuroscience, 14(10), (IF = 14.2) Guillem, K., Bloem, B., Poorthuis, R.B., Loos, M., Smit, A.B., Maskos, U., Spijker, S. & Mansvelder, H.D. (2011). Nicotinic acetylcholine receptor β2-subunits in the medial prefrontal cortex control attention. Science, 333, (IF = 31.4) Oberlaender, M., Boudewijns, Z.S.R.M., Kleele, T., Mansvelder, H.D., Sakmann, B. & Kock, C.P.J. de (2011). Three-dimensional axon morphologies of individual layer 5 neurons indicate cell type-specific intracortical pathways for whisker motion and touch. Proceedings of the National Academy of Sciences of the United States of America, 108(10), (IF = 9.8) Counotte, D.S., Goriounova, N.A., Li, K.W., Loos, M., Schors, R.C. van der, Schetters, D., Schoffelmeer, A.N.M., Smit, A.B., Mansvelder, H.D., Pattij, T. & Spijker, S. (2011). Lasting synaptic changes underlie attention deficits caused by nicotine exposure during adolescence. Nature Neuroscience, 14(4), (IF = 14.2, also reported in Res Prog Attention & Cognition) Toonen, R.F. & Verhage, M. (2011). Crashpilot Underachieves due to Acetylation at the Nerve Terminal. Neuron, 72(5), (IF = 14.0) Walter, A.M., Groffen, A.J., Sorensen, J.B. & Verhage, M. (2011). Multiple Ca(2+) sensors in secretion: teammates, competitors or autocrats? Trends in Neurosciences, 34(9), (IF = 13.3) Lips ES, Cornelisse LN, Toonen RF, Min JL, Hultman CM; the International Schizophrenia Consortium, Holmans PA, O'Donovan MC, Purcell SM, Smit AB, Verhage M, Sullivan PF, Visscher PM, Posthuma D. Functional gene group analysis Identifies synaptic gene groups as risk factor for schizophrenia. Mol Psychiatry Sep 20. doi: /mp [Epub ahead of print] PubMed PMID: Végh MJ, de Waard MC, van der Pluijm I, Ridwan Y, Sassen MJ, van Nierop P, van der Schors RC, Li KW, Hoeijmakers JH, Smit AB, van Kesteren RE. Synaptic proteome changes in a DNA repair deficient ercc1 mouse model of accelerated aging. J Proteome Res Mar 2;11(3): Epub 2012 Feb 13. Klemmer P, Meredith RM, Holmgren CD, Klychnikov OI, Stahl-Zeng J, Loos M, van der Schors RC, Wortel J, de Wit H, Spijker S, Rotaru DC, Mansvelder HD, Smit AB, Li KW. Proteomics, ultrastructure, and physiology of hippocampal synapses in a fragile X syndrome mouse model reveal presynaptic phenotype. J Biol Chem Jul 22;286(29): Epub 2011 May 19. PubMed PMID: Dahlhaus M, Li KW, van der Schors RC, Saiepour MH, van Nierop P, Heimel JA, Hermans JM, Loos M, Smit AB, Levelt CN. The synaptic proteome during development and plasticity of the mouse visual cortex. Mol Cell Proteomics May;10(5):M Epub 2011 Mar

51 Brain Disease Mechanisms Research Programs in short: Figure 6 Brain Disease Mechanisms Research Programs. Three main types of brain disorders are currently being investigated. Each of these research programs is based upon large groups of patient cohort and patient clinical activities. Transdisciplinary dialogue is guaranteed because most programs are being supervised by both clinical and preclinical research leaders. The aim of the Neuroscience Campus is further to provide strong translational links between the Genes & the Brain programs and expertise being developed and the patient diagnosis and therapy oriented programs. 49

52 BRAIN DISEASE MECHANISMS Anxiety & Depression Research Program Committee: Brenda Penninx (program leader) Eco de Geus (program leader) Zoltán Bochdanovits Dorret Boomsma Peter Heutink Odile van den Heuvel Adriaan Lammertsma Christel Middeldorp Guus Smit Jan Smit Oliver Stiedl Dick Veltman Matthijs Verhage The overall aim of the anxiety and depression program is to identify genomic regions and gene variants that mediate vulnerability to these affective disorders; to understand this vulnerability at the synaptic and brain systems level; to determine their interaction with age, sex and environmental challenges; and to use this understanding to explain the observed patterns of brain activity of behaving humans. Ongoing research has already linked clinical outcomes to neuroanatomy of postmortem tissue, autonomic nervous system and Hypothalamus-Pituitary-Axis function, serum markers such as vitamin D, inflammation, and (f)mri traits, as well as receptor characteristics obtained from GABA-ergic (flumazenil), dopaminergic (raclopride), and serotonergic PET ligands. By cross-linking these, and other novel endophenotypes to newly detected genetic variants for anxiety and depression the program will uncover part of the actual pathways from molecule to mind for these afflictions. Translational targets are improved diagnostics and prognostics, and stronger evidence-based and personalized therapeutic intervention. The program will provide new insights into pathophysiology of depression and anxiety and suggest previously unsuspected etiologic pathways for these diseases. This will translate into better care for patients by improving early detection of individuals at risk, which is a critical concern for clinicians identifying new therapeutic targets developing targeted interventions based on genetically defined risk. Highlight - Anxiety & Depression NOCDA, worldwide the largest comprehensive prospective study of the naturalistic course of obsessive-compulsive disorder (OCD), established a firm collaboration with Boston University group on OCD research and The Brown Longitudinal Obsessive Compulsive Study (after NOCDA the second largest OCD study worldwide). Two very large genotyping projects in the NESDA and NTR cohorts that were funded by the Grant Opportunity (GO) awards in the USA were completed, and genome-wide SNP and CNV data are now available in ~15,000 subjects. First results from the combined projects were 50

53 presented at a symposium that we organized at the World Psychiatric Genetics meeting in Washington DC. CNCR researchers contributed to the long-awaited consensus paper in Neuroscience Biobehavioral Reviews on conceptual issues in stress research to address the issue of the inflated and inappropriate use of the term 'stress', amongst others in psychiatric research. A new project on Light Therapy for depression and sleep disorders in Parkinson s patients was fully funded. Brenda Penninx got awarded the prestigious VICI personal career grant, which allows her to continue her research in the area of metabolic stress and cellular aging in depression. As part of this, she will start a randomized trial examining and comparing the psychiatric and metabolic consequences of antidepressant and running therapies. Dorret Boomsma received the prestigious Royal Dutch Academy of Sciences (KNAW) Merian award for scientific excellence in an inspiring female role model. Christel Middeldorp was awarded the Research Prize of the European Psychiatric Association for the best article of 2011 by an early career psychiatrist for this paper. Key Publications - Anxiety & Depression Lieverse, R., Someren, E.J.W. van, Nielen, M.M.A., Uitdehaag, B.M., Smit, J.H. & Hoogendijk, W.J.G. (2011). Bright Light Treatment in Elderly Patients With Nonseasonal Major Depressive Disorder A Randomized Placebo-Controlled Trial. Archives of General Psychiatry, 68(1), Heuvel, O.A. van den, Mataix-Cols, D., Zwitser, G., Cath, D.C., Werf, Y.D. van der, Groenewegen, H.J., Balkom, A.J.L.M. van & Veltman, D.J. (2011). Common limbic and frontalstriatal disturbances in patients with obsessive compulsive disorder, panic disorder and hypochondriasis. Psychological Medicine, 41(11), Middeldorp, C.M., Moor, M.H.M. de, McGrath, L.M., Gordon, S.D., Blackwood, D.H., Costa, P.T., Terracciano, A., Krueger, R.F., Geus, E.J.C. de, Nyholt, DR, Tanaka, T., Esko, T., Madden, P.A.F., Derringer, J., Amin, N., Willemsen, G., Hottenga, J.J., Distel, M.A., Uda, M., Sanna, S., Spinhoven, P., Hartman, C.A., Ripke, S., Sullivan, P.F., Realo, A., Allik, J., Heath, A.C., Pergadia, M.L., Agrawal, A., Lin, P., Grucza, R.A., Widen, E., Cousminer, D.L., Eriksson, J.G., Palotie, A., Barnett, J.H., Lee, P.H., Luciano, M, Tenesa, A., Davies, G., Lopez, L.M., Hansell, N.K., Medland, S.E., Ferrucci, L., Schlessinger, D., Montgomery, GW, Wright, M.J., Aulchenko, Y.S., Janssens, A.C.J.W., Oostra, B.A., Metspalu, A., Abecasis, G.R., Deary, I.J., Räikkönen, K., Bierut, L.J., Martin, N.G., Wray, N.R., Duijn, C.M. van, Smoller, J.W., Penninx, B.W.J.H. & Boomsma, D.I. (2011). The genetic association between personality and major depression or bipolar disorder. A polygenic score analysis using genome-wide association data. Translational Psychiatry, 1, e50. Koolhaas, J.M., Bartolomucci, A., Buwalda, B., Boer, S.F. de, Flügge, G., Korte, S.M., Meerloo, P., Murison, R., Olivier, B., Palanza, P., Richter-Levin, G., Sgoifo, A., Steimer, T., Stiedl, O., Dijk, G. van, Wöhr, M. & Fuchs, E. (2011). Stress revisited: A critical evaluation of the stress concept. Neuroscience and Biobehavioral Reviews, 35(5), Demirkan, A., Penninx, B.W.J.H., Hek, K., Wray, N.R., Amin, N., Aulchenko, Y.S., Dyck, R. van, Geus, E.J.C. de, Hofman, A., Uitterlinden, A.G., Hottenga, J.J., Nolen, W.A., Oostra, B.A., Sullivan, P.F., Willemsen, G., Zitman, F.G., Tiemeier, H., Janssens, A.C.J.W., Boomsma, D.I., Duijn, C.M. van & Middeldorp, C.M. (2011). Genetic risk profiles for depression and anxiety in adult and elderly cohorts. Molecular Psychiatry, 16(7),

54 BRAIN DISEASE MECHANISMS Neurodegeneration Research Program Committee Philip Scheltens (program leader) Peter Heutink (program leader) Common clinical cohorts: Henk Berendse Wiesje van der Flier Research theme 1: Neuropathology and biomarker studies Wilma van de Berg Annemieke Rozemuller Research theme 2: Neurogenetics and pathogenetic mechanisms Guus Smit Pieter Voorn Research theme 3: NeuroImaging Adriaan Lammertsma Cees Stam Research theme 4: New therapeutic approaches Eric van Exel Erik Scherder This is a clinically oriented translational program. The main focus is to unravel the underlying often overlapping pathophysiologic substrates of the common neurodegenerative disorders with AD and PD as their most well known representatives. The classical forms of AD and PD are considered distinct diseases, but many patients show a large overlap in symptoms, pathology and genetic findings. To enable targeted drug therapies, an adequate characterization of the underlying pathology at protein level is needed. It has become clear that at a molecular level there are common denominators and that an integrated joint approach on neurodegenerative disease holds the best promise for unraveling the pathogenesis of these disorders. The translational component will be evidenced in a bidirectional approach by using biomarkers and clinical information from patients to guide the preclinical program and findings from cellular and genetic research can immediately be tested and validated in clinical samples. Common goals of this program are: o to further unravel the, possibly in part common, neuronal substrates, as well as neuropathological and pathogenetic mechanisms of the above mentioned disorders; o to develop early, preferably even presymptomatic, diagnostic markers; o to develop novel therapeutic approaches. Among the current available resources, there is extensive expertise from clinic, patient cohorts (also collaborative with other centers), phenotyping (including imaging), biomarkers, (early)diagnostic markers, neuroanatomy, 52

55 neuropathology, transcriptomics, proteomics, gene finding, functional characterization, cellular, animal models and therapeutic approaches. A translational research plan has been constructed according to four major disease lines in this program: Alzheimer (and related forms of dementia) Parkinson FrontoTemporal Lobar Degeneration Normal Aging Highlights - Neurodegeneration Newly appointed professors at VUmc: J.C. van Swieten, H. Weinstein, and H.W. Berendse. Appointed as member of Royal Dutch Academy of Sciences: Prof. dr. Ph Scheltens. Key Publications - Neurodegeneration Berge, S.A. van den, Strien, M.E. van, Korecka, J.A., Dijkstra, A.A., Sluijs, J.A, Kooijman, L., Eggers, R., Filippis, L. De, Vescovi, A.L., Verhaagen, J., Berg, W.D.J. van de & Hol, E.M. (2011). The proliferative capacity of the subventricular zone is maintained in the parkinsonian brain. Brain, 134, Wouterlood FG, Härtig W, Groenewegen HJ, Voorn P. (2011). Density of gradients of vesicular glutamate- and GABA transporter immunoreactive boutons in calbindin- and μ-opiod receptor defined compartments in the rat striatum. The Journal of Comparative Neurology 2011 Dec 15. doi: /cne [Epub ahead of print] Cordonnier, C. & Flier, W.M. van der (2011). Brain microbleeds and Alzheimer's disease: innocent observation or key player? Brain, 134, Flier, W.M. van der, Pijnenburg, Y.A.L., Fox, N.C. & Scheltens, P. (2011). Early-onset versus lateonset Alzheimer's disease: the case of the missing APOE epsilon 4 allele. Lancet Neurology, 10(3), Kamphuis, P.J.G.H., Verhey, F.R., Olde Rikkert, M.G., Twisk, J.W., Swinkels, S.H. & Scheltens, P. (2011). Efficacy of a medical food on cognition in Alzheimer's disease: results from secondary analyses of a randomized, controlled trial. Journal of Nutrition Health and Aging, 15(8), Kesteren, R.E. van, Mason, M.R.J., Macgillavry, H.D., Smit, A.B. & Verhaagen, J. (2011). A gene network perspective on axonal regeneration. Frontiers in Molecular Neuroscience, 4, 46. Nejatbakhsh, N., Guo, C.H., Lu, T.Z., Pei, L., Smit, A.B., Sun, H.S., Kesteren, R.E. van & Feng, Z.P. (2011). Caltubin, a Novel Molluscan Tubulin-Interacting Protein, Promotes Axonal Growth and Attenuates Axonal Degeneration of Rodent Neurons. Journal of Neuroscience, 31(43), Renton, A.E., Majounie, E., Waite, A., Simon-Sanchez, J., Rollinson, S., Gibbs, J.R., Schymick, J.C., Laaksovirta, H., Swieten, J.C. van, Myllykangas, L., Kalimo, H., Paetau, A., Abramzon, Y., Remes, A.M., Kaganovich, A., Scholz, S.W., Duckworth, J., Ding, J.H., Harmer, D.W., Hernandez, D.G., Johnson, J.O., Mok, K., Ryten, M., Trabzuni, D., Guerreiro, R.J., Orrell, R.W., Neal, J., Murray, A., Pearson, J., Jansen, I.E., Sondervan, D., Seelaar, H., Blake, D., Young, K., Halliwell, N., Callister, J.B., Toulson, G., Richardson, A., Gerhard, A., Snowden, J., Mann, D., Neary, D., Nalls, M.A., Peuralinna, T., Jansson, L., Isoviita, V.M., Kaivorinne, A.L., Holtta-Vuori, M., Ikonen, E., Sulkava, R., Benatar, M., Wuu, J., Chio, A., Restagno, G., Borghero, G., Sabatelli, M., Heckerman, D., Rogaeva, E., Zinman, L., Rothstein, J.D., Sendtner, M., Drepper, C., Eichler, E.E., Alkan, C., Abdullaev, Z., Pack, S.D., Dutra, A., Pak, E., Hardy, J., Singleton, A., Williams, N. M., Heutink, P., Pickering-Brown, S., Morris, H.R., Tienari, P.J. & Traynor, B.J. (2011). A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron, 72(2), Baillie, J.K., Barnett, M.W., Upton, K.R., Gerhardt, D.J., Richmond, T.A., Sapio, F. De, Brennan, P., Rizzu, P., Smith, S., Fell, M., Talbot, R.T., Gustincich, S., Freeman, T.C., Mattick, J.S., Hume, D.A., Heutink, P., Carninci, P., Jeddeloh, J.A. & Faulkner, G.J. (2011). Somatic retrotransposition alters the genetic landscape of the human brain. Nature, 479(7374),

56 BRAIN DISEASE MECHANISMS White Matter Diseases Research Program Committee: Theme 1: Multiple sclerosis and other neuroinflammatory diseases Chris Polman (program leader and theme leader) Christien Dijkstra (theme leader) Frederik Barkhof (theme leader) Bernard Uitdehaag (vice theme leader) Elga de Vries Paul van der Valk Annette van der Goes (program coordinator) Theme 2: Childhood white matter diseases Marjo van der Knaap (program leader and theme leader) Gert Scheper (vice program leader) Cornelis Jakobs (theme leader) Gajja Salomons Jeroen Vermeulen (theme leader) Theme 1: Multiple Sclerosis (MS) The primary goal of the VUmc MS Center Amsterdam is to perform internationally distinctive MS research that allows better understanding and treatment of MS. The center has an excellent international reputation and is one of the top five MS research groups in the world. The MS Center Amsterdam is a multidisciplinary research center in which more than 100 experts of different disciplines within the VU university medical center (VUmc) cooperate to work on questions regarding the cause, cure and care of MS. The combination of fundamental and clinical research allows us to quickly apply new research developments in diagnosis and treatment of MS. Likewise, questions concerning the pathogenesis of the disease that arise in the clinic can be answered vice versa in collaboration with basic scientists. This MS Center is unique because it unites a comprehensive array of disciplines ranging from experimental laboratory research to clinical research. The researchers of the VUmc MS Center Amsterdam have more recently decided to join forces to devote their expertise and focus to understanding neurodegeneration in MS and to work towards identifying novel targets for future neuroprotective treatment. The leading hypothesis is that neurodegeneration is causal to clinical progression and cognitive decline in MS, and we propose that the development of neuroprotective strategies is a crucial next step in the treatment of the disease. Theme 2: Childhood white matter diseases The primary goal of the Center for Childhood White Matter Disorders (CWMDs) is to improve the diagnosis and understanding of CWMDs in order to develop better treatment. CWMDs comprise a group of disorders that can be divided into acquired damage and genetic disorders. The genetic CWMDs can be divided in metabolic and non-metabolic. 54

57 The Center for CWMDs combines diagnosis, care, research on disease mechanisms and development of novel therapies, both specific and symptomatic. The center is multidisciplinary with clinicians, clinical and basic researchers with a broad range of expertise. This set-up allows easy interaction of specialists in different fields. The work of the center is greatly facilitated by a large database of information on patients from all over the world, their MRIs, DNA, body fluids, tissues and cell lines. This database is conditional for research on the etiology and pathophysiology of rare to extremely rare disorders. For the development of curative treatment, new strategies are applied, including compound screening and stem cell technology. Optimization of symptomatic treatment is an important target, especially treatment of spasticity and loss of communication. The focus on CWMDs is unique world-wide. We participate in educational courses on MRI interpretation & pattern recognition, neuropathology of CWMDs and treatment for spasticity around the world. We offer training of fellows and young specialists in metabolic research, MRI interpretation and neuropathology of CWMDs. For our studies on treatment, we aim at patients within The Netherlands, within Europe and potentially outside. Highlights - White Matter Disease, theme 1 In 2011 MS researchers of VUmc again have published articles in high impact journals like: Science, Lancet, Lancet Neurology, Brain and Neurology. In October 2011 the international world congress of MS (ECTRIMS&ACTRIMS) took place in the RAI in Amsterdam. More than scientists visited this ECTRIMS&ACTRIMS. It was the biggest ECTRIMS congress ever. During ECTRIMS&ACTRIMS congress a large number MS researchers of VUmc were selected for presentations and posters: 4 invited reviews, 2 oral presentations and 9 posters. Our excellent international position is also expressed by the fact that MS researchers of VUmc received both the price for best presentation (Menno Schoonheim dep. Radiology) and best poster (Veronica Popescu dep. Radiology) at the ECTRIMS&ACTRIMS congress. Furthermore Maarten Witte (dep. Pathology) received the MSIF Young Researchers Award given for the best presentation of a translational project by a young researcher at ECTRIMS&ACTRIMS. The research program of 2.4 M that the MS center has received in 2010 from the Netherlands MS Research Foundation has started. A team of 20 researchers from different disciplines work together to further understand neurodegeneration in MS and investigate possibilities for neuroprotection in MS. As a test, together with the Dutch MS Research Foundation, a fundraising campaign has been enrolled in Amsterdam donors of the foundation in the region of Amsterdam have been written to. We have asked a donation to perform research on neurodegeneration in MS. The letter was supported with television and radio advertisement on the local stations. The test was a success and will be expanded in In 2011 MS researchers of VUmc have obtained several projects for MS research. Some large projects are: o Together with his Canadian colleagues Jeroen Geurts (Dept. of Anatomy & Neuroscience, VUmc) has received a large grant of 3.5 million CAD (ca. 2.5 million Euro) for the program grant, entitled Pathobiology of MS: complex interplay between degeneration and inflammation. o A joint European effort between academia and industry has been awarded with a Marie Curie ITN grant (4M ) focusing on the pathological role and therapeutic targeting of Transglutaminase in various diseases. Anne-Marie van Dam, Benjamin Drukarch and Micha Wilhelmus (Dept. Anatomy & Neurosciences) jointly work on this grant with nine other European teams. 55

58 Highlights - White Matter Disease, theme 2 We have organized the 11th International Congress of the European Society of Magnetic Resonance in Neuropediatrics, Amsterdam, March We have organized special sessions on MRI of white matter disorders, including teaching sessions. The meeting had a high number of attendees and was a great success. We organized an international farewell symposium for Prof Cornelis Jakobs with excellent speakers and an international audience of approximately 300 attendants. This event was adjacent to the SSIEM Academy, a 2 day postdoctoral metabolic training course for biochemist and clinicians organized in collaboration with the education and training advisory committee of Society for the Study of Inborn Errors of Metabolism (SSIEM). The course attracted many students from all over the world. Prof Jakobs received the Cornelia de Lange penning from the Dutch Society of Child Neurology in honor of his contributions in the diagnostics and research of neurometabolic disorders. The Metabolic Laboratory received the Science award of the Dutch Society of Clinical Chemistry for the best paper published by members of the society in 2010 (Kranendijk et al, IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 2010; 330: 336 (IF 29.7) For the third time we received a ZonMw TOP grant for our studies on CWMD. The two mutant mouse models for vanishing white matter we made prove to have a clinical and histopathologic phenotype that is similar to the human disease. This is a major step for the studies on the pathophysiology and stem cell treatment of the disease. We started an entirely new project on vanishing white matter (VWM) to get a better understanding of the disease mechanisms. The genetic defect in VWM is known for a decade and we do not understand how this defect leads to a brain white matter disease. So far, the research has been hypothesis driven. The study that started in 2011 with a new molecular scientist, Dr. T. Abbink, will largely be an open screen. Major progress was made in the area of megalencephalic leukoencephalopathy with subcortical cysts (MLC): the second gene associated with the disease was found and the first evidence for the function of the MLC1 protein was provided. For the innovation in the DNA diagnostics and research using next generation sequence technologies, we hired a post-doc with experience in genomics. This rapidly resulted in a breakthrough in 2-hydroxyglutaric aciduria research, complementary to previous findings reported in 2010 (Science). Key Publications - White Matter Diseases, theme 1 Alvarez, J.I., Dodelet-Devillers, A., Kebir, H., Ifergan, I, Fabre, P.J., Terouz, S., Sabbagh, M., Wosik, K., Bourbonniere, L., Bernard, M., Horssen, J. van, Vries, H.E. de, Charron, F. & Prat, A. (2011). The Hedgehog Pathway Promotes Blood-Brain Barrier Integrity and CNS Immune Quiescence. Science, 334(6063), Geurts, J.J.G., Roosendaal, S.D., Calabrese, M., Ciccarelli, O., Agosta, F., Chard, D.T., Gass, A., Huerga, E., Moraal, B., Pareto, D., Rocca, M.A., Wattjes, M.P., Yousry, T.A., Uitdehaag, B.M.J. & Barkhof, F. (2011). Consensus recommendations for MS cortical lesion scoring using double inversion recovery MRI. Neurology, 76(5), Kappos, L., Li, D., Calabresi, P.A., O'Connor, P., Bar-Or, A., Barkhof, F., Yin, M., Leppert, D., Glanzman, R., Tinbergen, J. & Hauser, S.L. (2011). Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet, 378(9805), Khatri, B., Barkhof, F., Comi, G., Hartung, H.P., Kappos, L., Montalban, X., Pelletier, J., Stites, T., Wu, S., Holdbrook, F., Zhang-Auberson, L., Francis, G. & Cohen, J.A. (2011). Comparison of fingolimod with interferon beta-1a in relapsing-remitting multiple sclerosis: a randomised extension of the TRANSFORMS study. Lancet Neurology, 10(6), Killestein, J., Rudick, R.A. & Polman, C.H. (2011). Oral treatment for multiple sclerosis. Lancet Neurology, 10(11), Kooij, G., Mizee, M.R., Horssen, J. van, Reijerkerk, A., Witte, M.E., Drexhage, J.A.R., Pol, SM van der, Hof, B Van Het, Scheffer, G.L., Scheper, R.J., Dijkstra, C.D., Valk, P. van der & Vries, H.E. de (2011). Adenosine triphosphate-binding cassette transporters mediate chemokine (C-C motif) 56

59 ligand 2 secretion from reactive astrocytes: relevance to multiple sclerosis pathogenesis. Brain, 134 (pt2), Lassmann, H., Niedobitek, G., Aloisi, G.,Middeldorp, J.M., Amor, S., Bennett, J., Bauer, J., Bradl, M., Bruck, W., Coccia, E., Gattenlohner, S., Hoftberger, R., Junker, A., Khan, G., Meier, U., O Connor, K., Owens, G., Reynolds, R., Serafini, B., Stadelmann, C., Tzartos, J., Valk. P. van der (2011). Epstein Barr virus in the multiple sclerosis brain: a controversial issue report on a focused workshop held in the Centre for Brain Research of the Medical University of Vienna, Austria. Brain, 134(9), Linker, R.A., Lee, DH, Ryan, S., Dam, A.M.W. van, Conrad, R., Bista, P., Zeng, W., Hronowsky, X., Buko, A., Chollate, S., Ellrichmann, G., Bruck, W., Dawson, K., Goelz, S., Wiese, S., Scannevin, R.H., Lukashev, M. & Gold, R. (2011). Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain, 134, Polman, C.H., Reingold, S.C., Banwell, B., Clanet, M., Cohen, J.A., Filippi, M., Fujihara, K., Havrdova, E., Hutchinson, M., Kappos, L., Lublin, F.D., Montalban, X., O'Connor, P., Sandberg- Wollheim, M., Thompson, A.J., Waubant, E., Weinshenker, B. & Wolinsky, J.S. (2011). Diagnostic Criteria for Multiple Sclerosis: 2010 Revisions to the McDonald Criteria. Annals of Neurology, 69(2), Seewann, A.M., Vrenken, H., Kooi, E.J., Valk, P. van der, Knol, D.L., Polman, C.H., Pouwels, P.J.W., Barkhof, F. & Geurts, J.J.G. (2011). Imaging the tip of the iceberg: visualization of cortical lesions in multiple sclerosis. Multiple Sclerosis, 17(10), Sombekke, M.H., Jafari, N., Bendfeldt, K., Mueller-Lenke, N., Radue, E.W., Naegelin, Y., Kappos, L., Matthews, P.M., Polman, C.H., Barkhof, F., Hintzen, R. & Geurts, J.J.G. (2011). No Influence of Kif1B on Neurodegenerative Markers in Multiple Sclerosis. Neurology, 76(21), Wiebenga, O.T., Hulst, H.E., Kooi, E.J., Killestein, J. & Geurts, J.J.G. (2011). Multicenter Randomized Clinical Trial of Donepezil for Memory Impairment in Multiple Sclerosis. Neurology, 77(22), Key Publications - White Matter Diseases, theme 2 López-Hernández, T., Ridder, M.C., Montolio, M., Capdevila-Nortes, X., Polder, E., Sirisi, S., Duarri, A., Schulte, U., Fakler, B., Nunes, V., Scheper, G.C., Martinez, A, Estevez, R. & Knaap, M.S. van der (2011). Mutant GlialCAM Causes Megalencephalic Leukoencephalopathy with Subcortical Cysts, Benign Familial Macrocephaly, and Macrocephaly with Retardation and Autism. American Journal of Human Genetics, 88(4), [IF: 11,680] Ridder, M.C., Boor, I., Lodder, J.C., Postma, N.L., Capdevila-Nortes, X., Duarri, A., Brussaard, A.B., Estévez, R., Scheper, G.C., Mansvelder, H.D. & Knaap, M.S. van der (2011). Megalencephalic leucoencephalopathy with cysts: defect in chloride currents and cell volume regulation. Brain, 134(11), [IF: 9,230] López-Hernández, T., Sirisi, S., Capdevila-Nortes, X., Montolio, M., Fernandez-Duenas, V., Scheper, G.C., Knaap, M.S. van der, Casquero, P., Ciruela, F., Ferrer, I., Nunes, V. & Estevez, R. (2011). Molecular mechanisms of MLC1 and GLIALCAM mutations in megalencephalic leukoencephalopathy with subcortical cysts. Human Molecular Genetics, 20(16), [IF: 8,058] Duarri, A., Heredia, M.L. de, Capdevila-Nortes, X., Ridder, M.C., Montolio, M., Lopez-Hernandez, T., Boor, P.K.I., Lien, C.F., Hagemann, T., Messing, A., Gorecki, D.C., Scheper, G.C., Martinez, A, Nunes, V., Knaap, M.S. van der & Estevez, R. (2011). Knockdown of MLC1 in primary astrocytes causes cell vacuolation: A MLC disease cell model. Neurobiology of Disease, 43(1), [IF: 5,121] Steenweg, M.E., Pouwels, P.J.W., Wolf, N.I., Wieringen, W.N. van, Barkhof, F. & Knaap, M.S. van der (2011). Leucoencephalopathy with brainstem and spinal cord involvement and high lactate: quantitative magnetic resonance imaging. Brain, 134(11), [IF: 9,230] Biancheri, R., Zara, F., Rossi, A., Mathot, M., Nassonge, M.G., Yalcinkaya, C., Erturk, O., Tuysus, B., Di Rocco, M., Gazzerro, E., Bugiani, M., Spaendonck, R. van, Sistermans, E.A., Minetti, C., Knaap, M.S. van der & Wolf, N.I. (2011). Hypomyelination and congenital cataract: broadening the clinical phenotype. Archives of Neurology, 68(9), [IF: 7,108] Bralten, L.B.C., Kloosterhof, N.K., Balvers, R., Sacchetti, A., Lapre, L., Lamfers, M., Leenstra, S., Jonge, H. de, Kros, J.M., Jansen, E.E.W., Struys, E.A., Jakobs, C.A.J.M., Salomons, G.S., Diks, S.H., Peppelenbosch, M., Kremer, A., Hoogenraad, C.C., Smitt, P.A.E.S. & French, P.J. (2011). IDH1 R132H Decreases Proliferation of Glioma Cell Lines In Vitro and In Vivo. Annals of Neurology, 69(3), [IF: 10,746] 57

60 10b) Input per program fte per type of funding (incl PhD students) gs 1 gs 2 gs 3 gs 4 Total Total Total Total Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synaps Brain Disease Mechanisms Anxiety and Depression Neurodegeneration White Matter Disease Affiliated research n.a. Total fte PhD students per type of funding gs 1 gs 2 gs 3 gs 4 Total Total Total Total Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synaps Brain Disease Mechanisms Anxiety and Depression Neurodegeneration White Matter Disease Affiliated research n.a. Total Table 6 - Input in fte per Research Program. A full list of coworkers is outlined in appendix 1. 58

61 10b) Input per program (continued) External Funding gs 2 gs 3 gs 4 Total Total Total Advanced Technology Brain Imaging Drugs Screening & Therapy Design Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synapse Brain Disease Mechanisms Anxiety & Depression Neurodegeneration White Matter Disease Affiliated Research Table 7 Grant acquisition per Research Program of 2011 compared to 2010 and Acquisition is split in types of funding. A full list of acquired external funding is outlined in appendix 6. In this overview, gs2 is NWO-funded research, gs3 is project funding from non-profit, ministries, FES & EU and gs4 is based on a mix of contract-research (for profit/industry) and donations/philanthropy. 59

62 10c) Output per program Scientific Output Theses Scientific papers Rest DissA DissC DissB DissD Wp WpREF WpNR VP Total Total Total Books Chapters Advanced Technology Brain Imaging Drugs Screening & Therapy Des Integrative Analysis & Modeling Photonics & Life Cell Imaging Genes & the Brain Attention & Cognition Addictive Behavior Systems Biology of the Synaps Brain Disease Mechanisms Anxiety and Depression Neurodegeneration White Matter Disease Affiliated research Table 8 - Output in 2011 per Research Program of the Neuroscience Campus Amsterdam, compared to previous years. A full list of publications is outlined in appendix 3. Also listed are the total output numbers (primarily determined by the WpREF) of previous year. Abbreviations: Theses A: Promotion VU/VUmc PhD-student at VU Theses B: Promotion external PhD-student at VU Theses C: Promotion VU/VUmc PhD-student at other university Theses D: Promotion external PhD-student at other university (promotor, co-promotor) WP: Books/monographs/book chapters/proceedings WP Ref: Scientific Papers refereed WP NR: Scientific Papers non-refereed VP: Professional publication 60

63 10c) Output per program (continued) % of papers in 2010 with RIF* of 5 % of papers in 2010 with RIF of 4 % of papers in 2010 with RIF of 3 % of papers in 2010 with RIF of 2 % of papers in 2010 with RIF of 1 Advanced Technology Brain Imaging 31% 34% 23% 9% 3% Drugs Screening & Therapy Design 71% 0% 29% 0% 0% Integrative Analysis & Modeling 55% 25% 15% 0% 5% Photonics & Life Cell Imaging 50% 50% 0% 0% 0% Genes & the Brain Attention & Cognition 46% 21% 18% 13% 3% Addictive Behavior 41% 47% 12% 0% 0% Systems Biology of the Synapse 53% 27% 13% 7% 0% Brain Disease Mechanisms Anxiety & Depression 72% 25% 3% 0% 0% Neurodegeneration 56% 24% 17% 2% 0% White Matter Disease 36% 38% 15% 10% 1% Affiliated Research 25% 32% 25% 15% 4% * RIF = Relative Impact Factor Quartile Category: 5: top 10% 4: 11-25% 3: 26-50% 2: 51-75% 1: % Table 9 - Quality of the Program Committee per Research Program. Shown are per research program the percentile of 2011 papers categorized according to the RIF, i.e. Relative Impact Factor. 61

64 62 Annual Report 2011

65 11. Scientific Research Committees Quality control at the Neuroscience Campus Amsterdam is done by three internal committees, one for Biomedical Research (CWO-FALW), one for Psychology Research (CWO-FPP), and one for Medical Research (CWO-VUmc) and an external Scientific Advisory Board (chaired by Prof. Martinus Niermeijer - for more information, see our website). The chairs of the different committees meet twice a year with Management Team and moreover are involved in screening internal projects. We follow the VSNU accredited academic evaluation cycle with a recent Self-Evaluation (i.e. the so-called Midterm) Review during the summer of 2011 and an upcoming External Audit in the summer of

66 Exchange Honours students of Master of Neurosciences Amsterdam-Rotterdam (director Gerard Borst & Huibert Mansvelder) Graduate School Neurosciences Amsterdam Rotterdam (director August Smit) PhD training in Europe - ITN (coordinator Heidi de Wit) MSc & PhD training in Europe - Erasmus Mundus funded programs (director - Arjen Brussaard) 64