ANNUAL REPORT MHeNS School for Mental Health and Neuroscience

Transcription

1 MHeNS School for Mental Health and Neuroscience ANNUAL REPORT 2011 School for Mental Health and Neuroscience Faculty of Health, Medicine and Life Sciences

2 Content Preface Professor Dr. Harry Steinbusch 5 1. From MHeNS EURON towards Neuroscience Campus Maastricht 9 2. Organizational structure Divisions Goals & Results 3.1 Division I: Cognitive Neuropsychiatry & Clinical Neuroscience Division I: Research lines Division II: Mental Health Division II: Expert groups Division III: Neuroscience Division III: Research lines Facts and Figures 4.1 Earning Power Research Staff Output results 5.1 Aggregated results of the School Output Best publications PhD theses Master and PhD Educational Activities Master Programme PhD Programme 55 Annexes: I MHeNS / EURON PhD Educational Programme II Current PhD theses (2012) 62 III List of Abbreviations 78

3 Preface 4 harry steinbusch scientific director I am pleased to provide you with our Annual Report 2011 for the School for Mental Health and Neuroscience (MHeNS), situated within the Faculty of Health, Medicine and Life Sciences (FHML). The report presents an overview and full information concerning the fields of research output, earning power, staff members and master and postdoctoral teaching activities. The School has continued to grow not only regarding the number of publications, e.g., 452 papers during the reporting period, but also in the quality of the papers as indicated by an increase in the average journal impact factors, even though there was no increase in non-tenured staff members since in 2011 and we were confronted with a substantial budget cut of 10%. We were, however, able to maintain our high level of the number of PhD theses with 31in2009, 22 in 2010 and 23 in At the present time, we expect to award 30 theses in In this respect, it is important is to compare this output to the number of tenured scientific staff. Thus, the figures are than even better for 2011: 23/23 = 1.0 and for /23 = 1.3. Because the performance contract states the number of 0.5 theses per fte, we have exceeded the expectation considerably. Our School hosts about 46 regular PhD students. Most of the PhD students produce their theses within the required or expected time of 4 years. It is our goal to reduce this time further since we would like to incorporate the last year of the master as the first year of a PhD trajectory. The guidance of these students is a significant challenge that requires an enormous and coordinated effort of staff members. In accordance with the performance contract with the Faculty of Health, Medicine and Life Sciences we have focused on establishing more funding from peer-reviewed NWO (Dutch Medical Research Council) and FP7- EU grants, which has resulted in us being less dependent on grants obtained from other agencies. Grants obtained from industrial contract research now represent a more limited component of our funding. As stated in chapter 4.1 Earning Power, it is important to note that a total of euro 1.3 million peer reviewed and euro 1.1 million non-peer reviewed or industrial projects were received. Consequently, we can state that during this period we fully achieved all the goals of our performance contract with FHML and the Maastricht University Medical Centre + (MUMC+). In 2011 a discussion was continued concerning the appropriate size for an Institute. In accordance with its achievements, MHeNS has been regarded as sufficiently large to act as an independent School within FHML and university. However, with respect to the near future, it is worth noting that neuroscience research is more fragmented in the capital area than is desirable. This speaks to the need for closer cooperation among the different units. To this end, we have engaged in some reorganization of our clinical groups and divisions, although we will still have three divisions. Thus, one division will be clearly focused on Cognitive Neuropsychiatry & Clinical Neuroscience, one division will be on gene-environment research in mental health and illness, and the third one will focus on Neurodegeneration and Plasticity. In line with this, educational activities of the Master s programs correspond to these subdivisions. The strength of MHeNS is its translational approach. For example, division 1 focuses on neuroepidemiology and brain imaging, division 2 focuses on gene-environmental changes/interactions related to psychiatric disturbances such as psychoses, and division 3 uses animal and cellular models related to systems-level neuroscience research. These lines of research at MHeNS will continue to find much synergy within collaborative projects and research networks and our future plans towards a Neuroscience Campus Maastricht. 5

4 In conclusion, I would like to thank all members of MHeNS for contributing their knowledge and expertise to the School and students in the past years. Importantly, these changes and improvements that have been made will cre ate new opportunities for the upcoming years. I look forward to new directions and challenges in the restructured academic environment in the coming year. Prof. Harry W.M. Steinbusch Scientific Director School for Mental Health and Neuroscience 6 chapter 1 From MHeNS - EURON towards Neuroscience Campus Maastricht

5 From MHeNS - EURON towards Neuroscience Campus Maastricht The mission of the School for Mental Health & Neuroscience (MHeNS) at Maastricht University and the European Graduate School for Neuroscience (EURON) at the Euregional level is three fold: 1. focusing on a basic understanding of brain function and disease mechanisms, 2. understanding the function of genes and proteins, cellular processes and neuronal networks in relation to human health, 3. establishing reciprocal translational links between bed to bench and reverse, especially with starting points in translational integrative projects as a next step in elucidating the complex interplay between multiple genetic and environmental factors which will enable them to reveal how this interplay translates into normal brain function and/or disease. European Graduate School of Neuroscience (EURON) EURON has been re-accredited by the Royal Dutch Academy of Arts and Sciences (KNAW) for the period 2010 to The external review committee (ERC) of MHeNS (2009) has made some clear observations concerning MHeNS in relation 8 based on clinical questions investigated in animal to EURON. The report of the ERC identifies MHeNS as 9 models and their implications for treatment strategies in patient care. This mission can be made only possible by building on multidisciplinary approaches. Significantly, because we are a School we have integrated our research with strategic educational activities. These are related both towards Master and PhD as well as Postdoctoral training. Therefore, as a foundation for future new scientists we will educate and train Master and PhD students to become independent researchers who are able to plan and execute cutting edge science and to function well in multidisciplinary research programs in academia, hospital and/or industry. This will be achieved by sharing expertise and knowledge and by stimulating mobility of Master and PhD students. For EU- RON, we aim for uniformity and standardization for PhD degrees among the four participating countries, i.e., the Netherlands, Belgium, France and Germany. Indisputably, the training of young competent PhD s in the Neurosciences is crucial to maintaining the competitiveness of the European community in Neuroscience-based research. The new generation of our (neuro)scientists should be capable of integrating information across different levels of research. Similarly, they should be competent to participate the prime coordinator of EURON and states that MHeNS is in a favourable position to continue to develop as a centre of excellence in Europe. The shared expertise, knowledge and infrastructure of EURON will facilitate this goal. The ERC emphasizes that current leadership of MHeNS has developed an excellent research training program, making optimal use of the geographical Euregional location and opportunities for EU funded programs. The committee stated that the PhD program and the supervision is very good and of importance for PhD students on many levels, e.g., sharing expertise, knowledge transfer, mobility opportunities and opportunities for learning new techniques. In addition, EURON aims to produce uniform PhD degrees of the highest quality and to execute the Bologna process. The translational research focus of MHeNS to perform high impact translational neuroscience research fits very well with the mission of EURON to address research topics in a multidisciplinary approach. Strategic Goals for MHeNS The School will be facing in the immediate forthcoming period some important challenges. However, we believe the effects of these changes will also create major opportuni-

6 ties. The first opportunity is related to the establishment of the Maastricht University Medical Center (MUMC+). Within this framework new Centers of Excellence (CoE) will be established in which the starting point is care-related research issues. In addition these CoE should go beyond the existing borders and mandates of the 5 established Schools and Faculties. Recently, an analysis of the five Schools by the MUMC+ Governing Board has been conducted. As a result, it was decided that the criteria for carrying the certificate of Centre of Excellence include that a School should have sufficient critical mass to guarantee sufficient PhD-output and demonstrate the ability of staff to obtain VENI, VIDI and VICI awards, as well as grants from major organizations such as the Netherlands Foundation for Scientific Research (NWO). Cognitive and Clinical Neuroscience with 4 tracks. We would like to build further and even strengthen our partnership with other groups in FPN and thus within NCM, such as the Cognitive Neuroimaging group of Prof.dr. R. Goebels, the Neuroplasticity group of Prof.dr. P. De Weerd and the Psychopharmacology group of Prof.dr. J. Ramaekers. NCM should be seen as comparable to the Neuroscience Campus Amsterdam in Amsterdam, the F.C. Donders Institute in Nijmegen or the Rudolf Magnus Institute and Hubrecht Laboratory in Utrecht. All the ingredients are available. all these criteria. As a result MHeNS considered themselves as a Centre of Excellence. We will need, however, more tenure-track positions to support and recruit excellent career-oriented staff members from within or beyond to achieve our formal recognition. Another consideration regarding Strategic Goals for the next 3 years is the implementation of a ZKO, a Care Clinical Research Unit, headed by Prof. Dr. J. van Os. The MUMC+ is a fusion of the FHML with the Academic Hospital Maastricht which will take effect in This ZKO Mental Health and Neuroscience initiative started in 2009 and will continue to deal with all aspects of mental health related issues related to research, patient care and education in the MUMC+. The plan is that this ZKO will further expand into a Centre of Excellence in Contextual Neuroscience. The School of MHeNS and the CoE will jointly work together. The focus of EURON is towards the MHeNS, since no in depth patient care-related issues are dealt with. As mentioned the CoE can greatly facilitate direct opportunities for translational research from bed to bench and viceversa. Finally, we would like to provide some additional thoughts with respect to EURON. We have mentioned before that MHeNS is a fully integrated partner in EURON. However, EURON comprises ten other universities in the broader Euregio as well. MHeNS has the lead in all organizational aspects (as noted by the KNAW external review committee). Because it already provides an excellent opportunity for networking, further Euregional activities and introduction of our European Master in Neuroscience (EMiN) will be established. Just a few words about EMiN. Why do we need another master, since there are already several masters available, e.g.,. Cognitive and Clinical Neuroscience a combined effort from FPN and FHML, the master in Biomedical Sciences within FHML and the AKO-master, also within FHML? EMiN is different in various ways; it combines the expertises from 7 universities in the field of fundamental new master students the best possible training and, thereby, attract the best students. Our internal rotation system enables our students to work at various laboratories and we will have a chance to adapt and choose the best students for further training in the PhD trajectory. Thus, there is a clear win-win situation for students, teachers and partners involved in the programme. The EURON programme will slightly expand beyond our current partners with new associated partners outside the Euregio. In addition, a clear link will be made towards new partners in China, South Korea and Brazil. A specific point deserving of attention is our partnership with the Faculty of Psychology and Neuroscience (FPN). It is essential that in the coming years we should have a full integrative programme of all Neuroscience activities within Maastricht University. These partnerships are important for research and educational exchanges and could be a basis for a further growth towards a Neuroscience Campus Maastricht (NCM). An NCM would not only comprise all activities within FPN and MHeNS (MUMC+) but would also include FBE. NCM should reach a high national and international visibility. It has already a well-established master programme The foundation of our future plans is that the research within MHeNS is divided into the three reorganized divisions. The choice for three divisions is based upon methodsrelated considerations: division 1 on patient care-related cognitive neuropsychiatry & clinical neuroscience; division 10 An analysis by the Board has revealed that MHeNS meets and translational neuroscience. Therefore, we can offer our 2 on patient care - related gene environment investiga- point of view of health services research. In addition, a 11 tions, and division 3 on animal models for neurodegenerative and neuropsychiatric disorders. More specifically, the common line is towards two translational themes: 1: Gene- Environmental Changes in Neuropsychiatric Diseases and 2: Neurodegeneration and Plasticity as outlined below. In this way, critical mass is created and MHeNS CoE so that research and patient care will acquire additional visibility within MUMC+. The specific focus on translational themes is in line with 1) the wish of MUMC+ to have a specific translational research focus in comparison with the other UMCs in the Netherlands, and 2) the wish that patients in both the short and long term should benefit from research. MHeNS also recognizes this need for a translational approach. Theme 1: Gene-Environmental Changes in Neuropsychiatric Diseases In this research line participating groups are identifying interactions between genes and environment, neuroimaging (i.e., identifying cerebral phenotypes for the study of ecogenetics) and experimental psychology and psychopharmacology (i.e., identifying experimental psychological and psychopharmacological phenotypes for the study of ecogenetics). This will facilitate the early recognition and treatment of psychiatric disorders, in particular psychosis and depression, leading ultimately to mental health services research. Theme 2: Neurodegeneration and Plasticity In this research line there is a direct link between clinical applied human research towards mechanistic approaches using transgenic mouse and rat models for neurodegeneration. Thus, participating fields within this translational line include quantitative neuromorphology, molecular neurobiology, behavioural neuroscience, neuroimmunology, neuroimaging and psychopharmacology. These involve clinical services for adult neurodegenerative disorders and developmental cognitive disorders, both from the point of view of early detection and intervention and from the large number of molecular neurobiological questions can be addressed. To summarize, MHeNS clearly wants to move forward and has established its Center of Excellence level. However, most importantly we need further increases in critical mass. To a certain extent this is beyond our control and, therefore, will need to be encouraged/facilitated by the MUMC+ in the form of concrete rewards (financial support) as successive, specified goals are achieved. We have already increased a variety of funding opportunities and we will continue to do so thereby increasing both the number of Ph.D. students as well as postdocs. However, to increase critical mass at the tenure-track level we need full cooperation and support by the MUMC+ and UM. We intend to gain international recognition of each of the two research lines, showing this consistently on a translational level. In this way we clearly will distinguish ourselves within the national competition. Thus, to summarize, the focus of MHeNS will be on various levels: 1. Research: three divisions work on translational research themes related to cognitive, motor and anxiety disorders.

7 2. Education: further expanding and strengthening Research Master, Ph.D. and postdoctoral activities, 3. Collaboration: further exploring the possibilities for a three faculty based Neuroscience Campus Maastricht. 12 chapter 2 Organizational structure

8 Organizational structure MHeNS is managed by the Board of MHeNS. The board is the body where strategis issues are discussed and effectuated. It consists of five members: the scientific director, the managing director and the three division leaders. Dean of the Faculty Health, Medicine and Life Sciences Prof. Dr. Martin Paul Prof. Dr. Albert Scherpbier since May 1 st, 2011 Managing Director Laurent Louwies Scientific Director Prof. Dr. Harry Steinbusch 14 Cognitive Neuropsychiatry and Mental Health Neuroscience 15 Clinical Neuroscience Prof. Dr. Frans Verhey Deputies Dr. Martin van Boxtel Dr. Caroline van Heugten Psychiatry & Neuropsychology (section Neuropsychology) Movement Sciences General Practice Radiology Othorhinolaryngology Neurology Prof. Dr. Inez Myin-Germeys Deputy Dr. Koen Schruers Psychiatry & Neuropsychology (section Psychiatry) Prof. Dr. Marc de Baets Deputies Prof. Dr. Martin van Kleef Dr. Yasin Temel Psychiatry & Neuropsychology (section Neuroscience) Neurosurgery Anesthesiology Urology Ophthalmology Neurology (2009) Pediatrics Figure 2.1 Organogram of MHeNS: the contribution of the different Departments of FHML to the current three Divisions of MHeNS.

9 Members of EURON MHeNS is the coordinator of the European Graduate School of Neuroscience (EURON). EURON is a research and training network of 11 universities in four countries i.e. Belgium, Germany, France and the Netherlands. 16 EURON MHeNS Belgium Université Libre de Bruxelles Universiteit Hasselt Katholieke Universiteit Leuven Université de Liège Université catholique de Louvain Germany RWTH Aachen University University of Bonn University of Cologne Saarland University, Homburg France Université Lille 1 Figure 2.2 EURON in relation to MHeNS. The Netherlands Maastricht University (MHeNS) chapter 3 Divisions Goals & Results

10 Divisions Goals & Results 3.1 Division I: Cognitive Neuropsychiatry & Clinical Neuroscience Division Leader: Prof. Dr. Frans Verhey Deputies: Dr. Martin van Boxtel Prof.Dr. Caroline van Heugten Prof.Dr. Robert van Oostenbrugge Staff: Dr. Paulien Aalten Dr. Jos Adam Dr. Marjan van den Akker Prof. Dr. Bert Aldenkamp Dr. Lucien Anteunis Dr. Walter Backes Dr. Saartje Burgmans Prof. Dr. Jan Willen Cohen Ter Vaart Dr. Jeanette Dijkstra Dr. Annelien Duits Dr. Carin Faber Dr. Ellen Gerrits Dr. Ed. Gronenschild Prof. Dr. Fred Hendrikse Dr. Paul Hofman Prof. Dr. Raymond Hupperts Dr. Sebastiaan Koehler Dr. Vivian Kranen van Mastenbroek Prof. Dr. Herman Kingma Prof. Dr. Bernd Kremer Dr. Marc de Krom Dr. Abraham Kroon Dr. Albert Leentjens Prof. Dr. Peter de Leeuw Prof. Dr. Werner Mess Prof. Dr. Job Metsemakers Dr. Rudolf Ponds Dr. Sascha Rasquin Prof. Dr. Harry Uylings Dr. Wim van der Elst Dr. Pieter - Jelle Visser Prof. Dr. Hans Vles 18 Dr. Marjolein de Vugt Dr. Wim E.J. Weber Prof. Dr. Joachim Wildberger Dr. Ieke Winkens Dr. Claire Wolfs 19 Goals & Results CNP&CNS performs fundamental and applied research on brain-cognition relationships. CNP&CNS mission is to generate new insights into neurocognitive and neurobehavioural mechanisms in order to improve treatment and care for people with cognitive disorders, and other neurological disorders. Since 2009, clinical neuroscience researchers have been assigned to the Division 1 and the new name became Cognitive Neuropsychiatry & Clinical Neuroscience (CNP&CNS), covering the translational nature of the Division 1 research program. With respect to the medical conditions, the focus is upon neurodegeneration in relation to neurodegenerative diseases of the central nervous system, such as Alzheimer s disease and its prodromal phases, Parkinson s disease, peripheral nervous system disease such as small fiber neuropathy, acquired brain damage such as stroke, traumatic brain injuries, and epilepsy. The general goal of the division is to develop new insights into the neurocognitive and neuro-behavioral mechanisms in order to improve treatment and care for people with such conditions. We investigate the contribution of biological, neuropsychological and psychosocial factors, single and in combination, and the effect of ageing on the development of normal neurocognition and mild to severe cognitive dysfunction. Research in Division 1 is conducted in a multi-disciplinary way, with contributions of researchers from neuropsychology, cognitive neuroscience, neuropsychiatry, clinical neurology, neuroradiology and neuro-epidemiology. In 2011 we continued to investigate normal, successful and pathological ageing, but with a greater emphasis on the translational focus. In addition, new projects started on neuropsychological Interventions, both in healthy older persons and in patients with brain Injury as part of the NWO/FES program on Brain and Cognition. Six PhD students successfully defended their thesis of whom 2 students received a Cum Laude judgment. E-health is one the new developments in health care which Is Increasingly explored in this division. In 2011 the Alzheimer Center Limburg celebrated its 10th birthday and as part of the festivities a successful fund raising campaign was conducted. This resulted in the start of a new PhD study directed towards the development and evaluation of self-management strategies for caregivers of Alzheimer patients.

11 3.1.1 Division I Research lines Research-Line: P.I.: Neurodegenerative disorders: mechanisms, early diagnosis and biomarkers Prof. Dr. F. Verhey, Dr. P-J Visser, Dr. P. Aalten, Dr. R. van Oostenbrugge, Dr. A. Leentjens, Dr. M. van Boxtel, Dr. S. Koehler, Dr. A. Duits, Research-Line: P.I.: Neuropsychological interventions and cognitive rehabilitation Dr. C. van Heugten, Dr. M. de Vugt, Dr. R. Ponds, Dr. M. van Boxtel, Dr. I. Winkens, Prof. Dr. F. Verhey T. van Berenschot Post doc/ Drs. K. Beerhorst, Drs. R. Besseling, PhD students: Drs. A. Colon, Drs. F. van Dooren, PhD students: Drs. I. Brands, Drs. M. van Eeden, Drs. R. Binie, Drs. H. Braakman, Dr. S. Burgmans, Dr. H. Jacobs Drs. O. Schiepers, Drs. P. Spauwen, Drs. M. Fens, Drs. E. de Joode, Drs. M. Hermans, Drs. S. van der Kruijs, PhD students: Drs. S. Aarts, Drs. L. Clerx, Drs. W. van Zwam Drs. B. ter Mors, Drs. V. Moulaert, Drs. S. Stappenberg -Klinkenberg, Drs. B. Dandachi-Fitzgerald, Focus of research: Insight into the prevention, etiology and Drs. S. Smeets, Drs. N. Tielemans, Drs. E. Vanhoutte, Drs. M. Vaessen, Drs. R. Drijgers, Drs. L. Elias, treatment of type 2 diabetes and other Drs. D. van Vliet, Drs. L. Willemstein, Drs. M. Vlooswijk Drs. R. Handels, Drs. M. Huijts, chronic diseases and mental health Drs. G. Wolters Focus of research: Chronic epilepsy 20 Drs. M. Legra, Drs. N. Vermunt, Drs. S. Vos Focus of research: Cognitive rehabilitation and health 21 Focus of research: Translational research into the early diagnosis of pathological ageing A large scale national biobank, coordinated by MUMC and the VU-MC, formed the infrastructure for translational research into the early diagnosis of pathological ageing (Parelsnoer Neurodegeneratief). Novel diagnostic technology for the early detection of Alzheimer s disease will be examined and evaluated in terms of Health Technology Assessment, i.e., with respect to its added value to existing diagnostic procedures (LeARN, CTMM). A project funded by VSB was started on the prediction of individual trajectories in cognitive disorders. Collaboration with the Department of Neurology and Radiology was intensified, which has led to a new study on neurovascular mechanisms of cognitive disorders, and the interaction between vascular and neurodegenerative mechanisms. In 2011 dr. Robert van Oostenbrugge was appointed professor in vascular neurology. Research-Line: P.I.: Determinants of normal, successful and pathological cognitive ageing Dr. M. van Boxtel, Prof. Dr. F. Verhey, Prof.Dr. R. van Oostenbrugge, Dr. S. Koehler, Dr. P. Hofman, Dr. W. Backes, Dr. Division staff members supported the initiation of the Maastricht Study (MS), a study to provide more insight into the prevention, etiology and treatment of type 2 diabetes and other chronic diseases and mental health. The MS is a good example of the integrative approach we are aiming at, with input from the departments of Psychiatry & Psychology, Neurology, Neuroradiology, and Neuro-ophtalmology). The central theme of the input from our division is the relation between cognitive function and (silent) cerebrovascular disease in type 2 diabetes, and the application of novel brain imaging methods for the early detection of cognitive dysfunction as well as cerebrovascular disease. The NWO/FES program (0,9Me) aims to develop internetbased low-level intervention strategies to support the development of the cognitive ageing process in middle-aged and older adults continued in service evaluation research. Interventions in cognitive and acquired brain disorders A stronger focus was put on evidence based neuropsychological interventions, psychosocial interventions, caregiver interventions, cognitive rehabilitation and health service evaluation research. Interventions are investigated in cognitive and acquired brain disorders. The VSB fonds/zonmw for a research programme on successful psychosocial reintegration of patients and caregivers after stroke continued in In this programme 4 PhD students (Maastricht, Nijmegen and Utrecht) investigate the course and predictors of psychosocial functioning, costs of psychosocial care and effectiveness of two new psychosocial interventions for patients and caregivers aimed at self-management and cognitive behavioural therapy for post-stroke depression and anxiety. The NWO/FES Brain & Cognition programme (0.9 Me) continued in 2011 studying the effectiveness of cognitive rehabilitation and factors influencing the success of cognitive rehabilitation will be examined. Research-Line: P.I.: Post doc/ PhD students: Epilepsy/ neuropathy and myotonic dystrophy Prof. Dr. B. Aldenkamp, Dr. M. de Krom, Prof. Dr. H. Vles, Dr. C. Faber The central theme within the research topic Epilepsy is Chronic Epilepsy. This topic is studied in a translational design by means of animal studies, genetic studies (drug resistance), and studies in humans focussed on the impact on cognitive function in chronic epilepsy including brain imaging studies into the early detection of cognitive deterioration. A substantial grant from the National Epilepsy Fund (NEF) was obtained for this programme (led by Prof. Dr. B. Aldenkamp). Research into neuromuscular disorders (led by Dr. C. Faber) targets myotonic dystrophy and neuropathy, with a focus on small fibre neuropathy. In 2010, a formal international cooperation within this later field was established with Prof S. Waxman (Yale University). Furthermore, a PhD funded by the GBS CIDP Foundation International and a grant from a Baxter PNS Fellowship started a study on clinimetric aspects (outcome measures) in Small Fibre Neuropathy (SFN) within a large multi-dimensional international multi-centre collaboration project, captured under the umbrella PeriNomS Inflammatory Peripheral Neuropathy Outcome Measures Standardisation PeriNomS study, small fibre neuropathy (SFN) PeriNomS study). Furthermore, additional funding was obtained from the Talecris Talents programme.

12 3.2 Division II: Mental Health Division Leader: Prof. Dr. Inez Myin-Germeys Deputies: Dr. Marieke Wichers Dr. Ruud van Winkel Staff: Dr. Maarten Bak Dr. Philippe Delespaul Dr. Rob van Diest Dr. Marjan Drukker Prof. Dr. Eric Griez Dr. Ed Goenenschild Prof. Dr. Peter van Harten Dr. Gunter Kenis Prof. Dr. Andries Korebrits Dr. Tineke Lataster Dr. Ritsaert Lieverse Dr. Richel Lousberg Dr. Machteld Marcelis Dr. Nancy Nicolson Prof. Dr. Jim van Os Dr. Frenk Peeters Dr. Bart Rutten Dr. Jan Schieveld Dr. Jean-Paul Selten Dr. Ruud Severijns Dr. Jacqueline Strik Dr. Wolfgang Viechtbauer Prof. Dr. Marten de Vries Dr. Marieke Wichers Dr. Ruud van Winkel Dr. Franz Wojciechowski Goals & Results psychosis, 1000 relatives and 1000 parents and 500 controls As outlined in the SEP protocol, division II Mental Health is over a period of 10 years. The last wave of data-collec- focusing on gene-environment research in mental health tion has been started in 2011 and is expected to be finished 22 and illness, within a translational context, bringing togeth- in Finally, the large data-set of real-life ESM data com- 23 er human and animal components of gene-environment interaction research as well as translating these findings to the clinic. The ultimate goal is to identify interactive determinants of reactive phenotypes at the level of lived experience relevant to mental health and resilience. In 2011, we worked on the following goals: 1) In order to improve G*E studies searching for the causes of complex diseases such as severe mental disorders, increasingly large sample sizes are urgently required. The EU- GEI study with 28 European partners, funded by a large FP7 grant, is half-way. The last consortium meting in London in November 2011 demonstrated that the study is going well, with all centers being actively involved in data collection. Secondly, a large general-population study has been set up together with the Trimbos Institute. The NEMESIS II study is collecting genetic data as well as data on mental health in 7000 participants from the general population. Division II was specifically involved in collecting data on psychosis. The second wave of this study will be finished in Third, the third wave of data-collection in the national (Amsterdam, Utrecht, Groningen, Maastricht) GROUP study has been set up. This study is following up 1000 patients with bined with genetic information has been finalized. First papers on real-time gene-environment interactions using reactive phenotypes are expected to come out in ) A second approach to progress G*E studies, is to improve the assessment strategy of environmental exposures in relation to lived experience (reactive phenotytpes), relevant for mental health and resilience. In 2011, the PsyMate has further been developed to investigate neuro- and social cognition in real-life. Apart from the PsyMate as a dedicated device, we started developing a PsyMate App for IPod and Android. This App will become available in ) Division II is actively involved in forming international networks to accelerate psychiatry research. The EURON Psychiatry Institute has been formed to formalize the intensive collaboration between the University of Leuven (UPC Kortenberg) and Division II of Maastricht University. This formal collaboration will also strengthen the clinical neuroscience within EURON. Second, members of division II are active partners in the European ROAMER project, aiming to set up a European Roadmap to Mental Health Research.

13 4) Division II has further invested in combined ESM neuroimaging approaches (either PET, MRI or fmri). Combining imaging data with real-time and real-world person-environment interaction patterns is extremely powerful, since it provides ecological validity for the neuroimaging data, correlating real life behaviour with alterations in specific brain regions, and vice-versa, improves the understanding the neural mechanisms underlying real-life behaviour. Division II is setting up a large cross-diagnosis study focusing on underlying mechanisms of reward, stress and aberrant salience, studied with experimental fmri paradigms as well as real-life ESM assessment. 5) Translational studies bringing together basic animal research and patient studies remain a core research line within division II. The translational expert-group has initiated 24 a number of studies, translating human findings to Drs. M. van Winkel, Drs. T. Batink. Drs. N. Leibold, Drs. D. Hernaus animal models and vice versa. 25 6) Division II is continuously working to develop the Psy- Mate as a therapeutic tool for mental illness, such as depression and psychosis. The first, ZON-MW supported trial on depression will be finished in Preliminary data suggest that behavioural activation using active feedback through PsyMate is beneficial for patients with severe depression, improving real-life positive affect, activities and decreasing symptoms of depression. Prof. Inez Myin-Germeys is still division leader of Division II. Marieke Wichers and Ruud van Winkel have been appointed as deputies in The methodological expert groups withing the division focus on 1) genetics, 2) Experience Sampling, 3) Neuroimaging, 4) Experimental approaches, 5) Epidemiology and Mental Health Services Research, and 6) Translational approaches Division II: Expert groups Expert-group: Genetics Coordinator: Dr. R. van Winkel P.I.: Prof. Dr. J. van Os, Dr. B. Rutten, Dr. G. Kenis, Dr. W. Vichtbauer, Dr. M. Drukker, Dr. M. Wichers, Dr. C. Simons PhD students: Dr. D. Collip, Drs. C. Hamels, Drs. M. Van Nierop, Drs. J. Decoster, Drs. N. Geschwind, Drs. C. Lothmann Focus of research: The design of genetic studies in the field of psychiatry as well as investi-gating the role of genetic variances and geneenvironment interactions in the etiology, severity and course of psychopathology The genetics expert group coordinates the design of genetic studies in the field of psychiatry as well as the choice of various genetic methodologies, choice of SNPs and genes of interest for the different research lines. Furthermore, it offers a platform for bringing together several disciplines in order to conduct adequately designed, multi-disciplinary and translational research to establish the role of genetic variances and gene-environment interactions in the etiology, severity and course of psychopathology and dimensions of psychological and psychiatric traits. Expert-group: Coordinator: P.I.: Post doc/ PhD students: Experience Sampling Dr. M. Wichers Prof. Dr. I. Myin-Germeys, Dr. T. Lataster, Dr. R. van Winkel, Dr. Ph. Delespaul, Dr. N. Nicolson, Dr. W. Viechtbauer, Dr. N. Jacobs Dr. C. Simons, Drs. M. Oorschot, Drs. N. Geschwind, Dr. D. Collip, Dr. R. Kuepper, Dr. J. Lataster, Drs. C. Lothmann, Drs. J. Decoster, Drs. C. van Zelst, Drs. F. Smeets, Drs. I. Kramer, Drs. J. Hartmann, Drs. M. Janssens, Drs. M. Gevonden, Focus of research: To guard and increase the quality of ESM data collections and analyses, as well as to increase statistical expertise and analytic possibilities The aim of the EXM expertgroup is to guard and increase the quality of ESM data collections and analyses, to examine the validity of the method and the items used in ESM and report on this in international peer-reviewed journals, as well as to increase statistical expertise and analytic possibilities, such as time-series analysis in ESM. Expert-group: Coordinator: P.I.: Collaborators: Post doc/ PhD students: Neuro-imaging Dr. M. Marcelis (psychiatrist) Dr. K. Schruers, Prof. Dr. I. Myin-Germeys, Dr. E. Gronenschild, Prof. Dr. J. van Os, Dr. L. Ritsaert, Dr. M. Wichers Dr. A. Roebroeck, Dr. V. van de, Dr. M. van Kroonenburgh, Dr. P. Hofman Prof. Dr. R. Goebel, Prof. Dr. K. van Laere, Prof. Dr. F. Mottaghy, Dr. J. Suckling Dr. P. Habets, Drs. P. Domen, Drs. C. van der Leeuw, Drs. S. Peeters, Dr. L. Goossens, Dr. D. Collip, Dr. J. Lataster, Drs. R. Kuepper, Focus of research: To combine expertise on various neuroimaging modalities (eg. smri, DTI, fmri, PET, MRS) and analysing techniques to examine brain structure and function in psychiatric disorders The expert group Neuro-imaging is a group of researchers that are using various neuroimaging modalities (e.g. smri, DTI, fmri, PET, MRS) and analysing techniques to examine brain structure and function in psychiatric disorders, such as psychotic and anxiety disorder. Our main goals are to examine i) neurobiological pathways influencing psychopathology, ii) genetic and environmental determinants of brain phenotypes, and iii) neural mechanisms underlying therapeutic interventions.

14 Expert-group: Coordinator: P.I.: Post doc/ PhD students: Experimental Psychopathology Dr. T. Lataster Dr. K. Schruers, Prof. Dr. E. Griez Dr. C. Simons, Dr. L. Goossens, Drs. F. Smeets, Drs. M. Janssens, Drs. A. Shazad, Drs. K. de Cort, Drs. I. Knuts, Drs. D. Collip, Drs. J. Lataster Focus of research: To design novel experimental tasks assessing underlying (neuro)psychological and biological mechanisms that are implicated in the development, course and outcome of psychiatric disorders Expert-group: Epidemiology and mental health services research Coordinator: Dr. M. Drukker P.I Methodology: Dr. W. Viechtbauer, Prof. Dr. J. van Os, Dr. R. Lousberg, Dr. M. Drukker PI Health Services Research: Dr. M. Bak, Dr. Ph. Delespaul, Drs. G. Driessen, Dr. F. van Dael, Dr. M. Drukker Focus of research: To discuss the correct use of research methods (epidemiology) and metaanalyses as well as to work on data of patient registers and monitors This expert group provides support to those researchers This expert group aims to analyse and develop in correct 26 designing novel experimental tasks assessing underlying use of research methods (epidemiology) and meta-analyses. Furthermore, this expert group works on the data of tions? approach mechanisms involving gene-environment interac- (neuro)psychological and biological mechanisms that are 27 implicated in the development, course and outcome of one register (Psychiatric Case Register) and two monitors - What is the role of epigenetic mechanisms in mediating psychiatric disorders. The focus is on psychotic and affective (Cumulative Needs for Care Monitor and Medication Moni- long term effects of environmental exposures and disorders. Our goal is to combine these experimental tor), as well as on data of healthy children, collected by the gene-environment interactions? designs with the observational methods (for example the youth health care division (YHCD) of the Public Health Service Experience Sampling Method) that have been developed South-Limburg and the Infant Welfare Centre register. within our department in order to improve validity of our studies. Expert-group: Coordinator: P.I.: Post doc/ PhD students: Translational and Cross-species Research Dr. B. Rutten Dr. G. Kenis, Dr. D. van den Hove, Prof. Dr. H. Steinbusch, Prof. Dr. J. van Os, Prof. Dr. K-P. Lesch, Prof. Dr. F. Verhey, Dr. K. Schruers, Dr. P-J. Visser Dr. B.e Machiels, Drs. E. Lambrichts, Dr. O. Peerbooms, Drs. L. Chouliaras, Drs. N. Leibold, Drs. S. Mafi Rad, Drs. C. Hammels, Drs. E. Pischva Focus of research: To support and stimulate innovative projects on translational research questions that require a cross-species The mission of this expert group / team is to support and stimulate innovative projects on translational research questions that require a cross-species approach. The research of its members aims to decipher molecular and cellular pathways that underlie sensitivity and resilience to environmental exposures, and gene-environment interactions in (neuro)psychiatric phenotypes. The ultimate goal is to identify molecular and cellular pathways that are causally involved in the etiologies of psychiatric disorders, to identify biologic markers that predict disease onset and course, to establish the reversibility of neurobiological changes, and to find novel preventive and therapeutic strategies. To this end, the team brings together multidisciplinary expertise ranging from epidemiology, genetics, molecular biology, biochemistry, experimental neuroscience, quantitative neuroanatomy, behavioral ecogenetics and clinical psychiatry. The bundling of expertise enables innovative, translational research projects on specific research questions in a variety of study group such as patients with a certain (neuro)psychiatric disorder, controls without psychiatric disorders, certain animal species, and cell cultures. Extrapolation of research findings from certain animal species to the human situation, and vice versa, is associated with numerous promises, challenges and pitfalls. The main tasks of the Expert Group are therefore i) to intensify sharing of knowledge, ii) to develop state-of-the-art methodologies, using cross-species approaches, and iii) to maximize success of such collaborative research efforts within our Research School. The team focuses on the following two main research questions: - What are the neurobiological underpinnings of neuropsychiatric phenotypes; with a particular focus on These research questions are applied preferentially to the following themes which cut across the School of Mental Health and Neuroscience: i) affect regulation, ii) cognition, iii) psychosis, iv) resilience.

15 3.3 Division III: Neuroscience Division Leader: Prof. Dr. Marc De Baets Deputies: Prof. Dr. Maarten van Kleef Dr. Yasin Temel Staff: Dr. Ronald Deumens Dr. Daniel van den Hove Dr. Danilo Gavilanes Dr. Govert Hoogland Dr. Bert Joosten Prof. Dr. Philip van Kerrebroeck Dr. Gommert van Koeveringe Dr. Boris Kramer Dr. Ellen La Heij (uit dienst) Dr. Fred van Leeuwen Dr. Mario Losen Dr. Marco Marcus Dr. Piluca Martinez Prof. Dr. Koo van Overbeeke Dr. Jos Prickaerts Prof. Dr. Harry Steinbusch Prof. Dr. Veerle Visser-Vandewalle Prof. Dr. Hans Vles Dr. Lim Lee Wei Goals & Results The Division Neuroscience performs translational research The results of the research efforts in division 3 are described with a strong emphasis on fundamental research. The by the different Principal investigators and exper- translational research area can be subdivided into two tise groups. 28 parts: neurodegeneration and neuroplasticity. 29 Its mission is to uncover the underlying mechanisms of neurodegenerative and regenerative processes for neurological and psychiatric diseases to improve early diagnosis, health and treatment strategies. Thus, we aim to gain knowledge of physiological and pathophysiological mechanisms underlying affective, cognitive and motor disorders. Within this context, the role of neuroinflammation and pain is also studied as well as their link to developmental disturbances and neuro-urogenital control. Main research topics include cell signalling, brain plasticity, neurodegeneration, regeneration,genetics and epigenetics. Eventually, its aim is to translate relevant scientific findings into new neurotherapies including pharmacotherapy, antibodies or deep brain stimulation. The multidisciplinary staff consists of professionals from relevant disciplines within research and clinic. There are collaborations within world-wide international networks of research offering a strong environment to come up with new neurotherapeutical approaches.

16 3.3.1 Division III: Research Lines Research line: Signal Transduction P.I.: Dr. J. Prickaerts, Prof. Dr. H. Steinbusch Post doc: Dr. T. Vanmierlo, Dr. M. van Duinen Signal Translation / Signal Transduction Neuroplasticity PhD students: Drs. O. Reneerkens, Drs. E. Bollen, Drs. A Sierksma, Drs. J. De Vry, Drs. S. Akkerman Environment Epigenetics Experimental Neurosurgery Pain: Transition from acute to chronic pain Modulation of chronic pain Associated Researchers: Dr. Y. Temel, Dr A. Blokland (FPN), Prof. Dr. F. Verhey, Prof. Dr. M. De Baets Focus of research: Cellular signal transduction in affective and cognitive processes in health and disease. Chronic pain is associated with an enormous socio-economic burden and can result from a plethora of clinical conditions. In our research, we focus primarily on traumainduced neuropathies in the peripheral and/or central nervous system, which are a common cause of chronic pain. The initial pathological events at the site of nerve damage form the drive of pathological events higher up in the neuraxis, and are considered to be fundamental to the estab- Urology The major aim is to unravel the mechanism of action of signaling pathways both in health and disease while at the same time exploring the therapeutic potential of key 30 Neuroinflammation Translational neuro- factors in the affected signaling pathway. The focus in this Drs. A. Swijsen, Drs. H. Vlamings, lishment of chronic of pain. We aim at understanding the 31 inflammation Central Nervous System neuroinflammation Neonatology Epilepsy Alzheimer disease respect is on the growth factor Brain Derived Neurotropic Factor (BDNF) and the second messengers camp and cgmp. In the field of signal transduction in cognitive processes/ disorders we have shown that phosphodiesterase (PDE) inhibitors, which inhibit the degradation of camp and/or cgmp by PDEs, improve memory in rats independently of cerebrovascular effects. This is of major importance since this indicates that the second messengers can be targets for new drugs to improve memory function directly. Therefore, the biological mechanism of action of specific PDE inhibitors to improve memory is investigated in depth in collaboration with international academic partners (eg. University of Genoa) and pharmaceutical companies. A proof of concept study funded by a grant from ZonMW is ongoing to investigate the memory improving potential of a specific PDE type 4 inhibitor in healthy subjects as well as in age-related memory impaired subjects. This is done in collaboration with Division 1 of MHeNS and the Faculty of Psychology and Neuroscience (FPN). Finally, we have started to apply our in house developed innovative method of microelectroporation as a non-viral approach for targeted gene delivery in specific brain areas of rodents. This approach has been used to directly influence the expression of BDNF receptors implicated in signal transduction in either affective or cognitive processes. This line of research is funded by the Internationale Stichting Alzheimer Onderzoek (ISAO). The results of these studies will help us to find new therapeutic targets for affective and cognitive disorders. Research line: P.I.: Post doc: PhD students: Experimental Neurosurgery Dr. Y. Temel, Dr. G. Hoogland, Prof. Dr. V. Visser-Vandewalle and Prof. Dr. H.Steinbusch Dr. LW. Lim Drs. M. Aalbers, Drs. P. Andrade, Drs. A. Jahanshahi, Drs. S. Hescham, Drs. M. Janssen, Drs. S. Tan, Drs. M. Raijmakers, Drs. N. Gosens, Drs. Y. Yakkioui, Drs. D. Zeef Focus of research: Movement disorders and related psychiatric symptoms, Epilepsy, biology of skull base tumours Our group is continuing to perform both clinical and experimental studies. In this respect, we have conducted studies to improve the surgical therapy for Parkinson s disease patients, by developing novel evaluation methods (saccadometry). In our experimental studies, we mainly focused on developing novel therapies in experimental models of Parkinson s disease (tailored neurostimulation), epilepsy (how do neonatal seizures imprint on neurodevelopment and role of neuroinflammation in epileptogenesis), pain (role of neuroinflammation in generating pain), and Huntington s disease (neurostimulation and gene therapy). These lines of research are supported by grants from the NWO- Veni, Cure Huntington s Disease Intitiative (CHDI, New York, USA), transnational University Limburg, and Hersenstichting Nederland. Research-Line: Transition from acute to chronic pain P.I.: Dr. B. Joosten, Prof M.Marcus PhD students: Drs. S. van Gorp, Drs. L. Knaepen, Drs. M. Theunissen Focus of research: Identification of predictors of chronic pain and investigating approaches aimed at prevention of chronic pain processes of neurodegeneration and regeneration in relation to neuropathic pain. In a recently completed Ph.D. project we found that injury to peripheral nerves induces structural plasticity in the wiring of the spinal nociceptive network, a phenomenon which is likely long-lasting. In a collaboration with UMC Utrecht, we reported on immune-related molecular requirements for chronic pain in animal models of peripheral tissue inflammation and peripheral neuropathy. In two ongoing Ph.D. projects we are investigating predictors of neuropathic pain after spinal cord injury. As a strategy to prevent pain chronification after nerve injury, we aim to provide (1) repair of nerve injuries / damage, (2) immuno-modulatory therapies (Prof. Dr. M. De Baets, Dr. M. Losen, Dr. P. Martinez) and (3) functional training paradigms (e.g. enriched environment). Moreover, we are interested in understanding the pathological events by which pain-related insults during the neonatal period can have long-lasting effects on pain in adulthood (Dr. J. Pawluski, Prof. Dr. H. Steinbusch).

17 Research-Line: Modulation of chronic pain P.I.: Dr. B. Joosten PhD students: Drs. W. Pluijms, Drs. K. van Boxem, Drs. R. Slangen Focus of research: The understanding and application of neuromodulatory techniques, in particular spinal cord stimulation and pulsed radiofrequency, in order to minimize chronic (neuropathic) pain Today Spinal Cord Stimulation (SCS) is used in the treatment of intractable neuropathic pain (NPP). Despite the The research focus is directed towards fundamental understanding existence of SCS as a pain therapy for over 40 years, up till of bladder physiology, pharmacology and now only two randomized clinical trials (RCT s) have been the origins of bladder dysfunction. Three project lines are performed: one in patients with CRPS-1(Chronic Regional ongoing in order to study different levels of bladder dysfunction Pain Syndrome) and the other one in patients with Failed in a translational research program based in the 32 Back Surgery Syndrome (FBSS), both of which provide lim- Research School for Mental health and Neuroscience and romodulation treatments by means of determination of 3413 also revealed changes in spontaneous breathing pat- 33 ited clinical evidence that SCS relieves neuropathic pain. We extend implementation of SCS in other NPP syndromes and designed and completed a pilot study on the clinical effect of SCS in painful diabetic polyneuropathy (PDP). As a follow-up, an RCT (Rachelle Slangen) on the effect of SCS in PDP is currently ongoing. In order to understand the underlying mechanism of action of SCS in PDP a rat model for PDP was developed in the laboratory and the effect of various stimulation parameters was analyzed. It is our intention to study the role of SCS in small fiber neuropathies experimentally as well as clinically in collaboration with Dr. C. Faber (Department of Neurology). From a basic scientific point of view the role of glial cells (as immune-regulatory cells) in the modulation of chronic pain (or plasticity of the nervous system) has our prime interest. Pulsed Radiofrequency as a minimally invasive therapy for treatment of chronic lumbar radicular pain (low back pain) is being studied based on an RCT (Koen van Boxem). In a rat model of lumbar radicular pain, the mechanism of action PRF is being studied. Research Line: Urology P.I.: Dr. G. Van Koeveringe Co investigators: Dr. S.W. de Wachter, Prof. Dr. Ph. E.BV. van Kerrebroeck, Prof. Dr. J.I. Gillespie. Post doc: Dr. L. Herfst until May 2011 PhD students: Drs. V. Vennemann, Drs. M. Smits, Drs A. Schueth Master student: R. Hohnen Focus of research: Neurourology: bladder signalling, control mechanisms and neuromodulation in close collaboration with the clinical urology department and the Pelvic Care Centre Maastricht. Line 1, Characterisation, analysis and physiological and structural mapping of control pathways within the urinary bladder wall and their connections with the central nervous system. In this basic research line, multiple pathways such as for example cholinergic, the NO-cyclicGMP pathway and the prostaglandin pathway have been shown to play a role in the intrinsic control mechanism inside the bladder wall, involving the network of interstitial cells and autonomous bladder activity. The way by which this mechanism is efferently modulated or afferently used by the central nervous system is subject to future electrophysiological recording and tracer studies. Furthermore the assessment of the control pathways, by means of for example analysis of the non-voiding detrusor activity is expanded to animal models representing different mechanisms of diseases affecting bladder control such as a subvesical obstruction guinea pig model, an Alzheimer transgenic mouse model and a decerebrated rat model. The determination of the respective contribution of either bladder or brain/nerve dysfunction to these diseases will contribute to a better understanding of the clinical problems and (patho)physiological mechanisms. (Herfst, Schueth, van Koeveringe, funded by an EU FP7-ITN Marie Curie grant). Line 2: The bladder control system in humans in the normal and the diseased state. The perception of bladder sensations in humans and the relationship to voiding behaviour is investigated. A relationship of an existing overactive bladder syndrome with non-voiding activity is studied using high-resolution urodynamic measurements. A relationship is sought between psychological profile and the degree of bladder fullness perception. (Vennemann, de Wachter, van Koeveringe, funded by the Astellas exploratory non-voiding activity study). Line 3: Neuromodulation in humans for complaints of overactive bladder and voiding dysfunction (over- and underactivity of both bladder and bladder outlet). In this research line both working mechanisms (using techniques and models described above) and an optimisation of the current neu- predictive factors and optimisation of techniques are the main subjects to be studied. (Smits, de Wachter, van Kerrebroeck, funded by a grant from Medtronic). Research Line: Alzheimer disease; neurodegeneration and posttranslational modifications of proteins P.I.: Dr. F. Van Leeuwen, Prof. Dr. H. Steinbusch Post doc: Dr. N. Kholod, Dr. J.-J. Cheng PhD students: Drs. F. Dennissen, Drs. R. Gentier Focus of research: Protein quality control in Alzheimer s disease Efficient neuronal function depends on cellular homeostasis. Posttranslational modifications (e.g., ubiquitination) contribute to many functions such as control of short-lived proteins, transcription factors and degradation of aberrant proteins. These homeostatic control mechanisms are often flawed during aging and disease. Our research focuses on quality control mechanisms such as the ubiquitin-proteasome system (UPS). We have discovered that mutant ubiquitin (UBB+1) accumulates in the hallmarks of Alzheimer s disease (AD), suggesting that it has a function in this multifactorial disease. Indeed, UBB+1 inhibits the UPS and results in neuronal dysfunction. In the past year we have fully characterized the enzyme Ubiquitin-C-terminal hydrolase L3 that is able to hydrolyse UBB+1 (in collaboration with Prof. Dantuma, Karolinska Institute, Stockholm, Sweden). In addition, we developed tools (e.g., transgenic animals) to study the effects of UBB+1 in vivo (Fischer et al., 2009, Dennissen et al., 2011). We are currently investigating anatomical (light and immunoelectron microscopy) and behavioral aspects (e.g., Morris water maze and fear conditioning) in these UBB+1mice (line#3413) as well as genetic crosses with the Alzheimer mouse model line (APP-Swe/PSEN1, exon9).significantly, interactions between UBB+1 and Aβ plaque formation have already been shown, e.g., plaque load changes. A comprehensive phenotype analysis of line terns and altered hypoxic response, suggesting a central dysfunction of respiratory regulation. Accordingly, brainstem regions involved in the control of respiration, such as the nuclei of the tractus solitarius (NTS) and the parabrachial nuclei strongly expressed UBB+1. Interestingly, this expression pattern matches the distribution of UBB+1 in autonomic regulatory centres in the brainstem (oral pons and NTS) of AD patients, but not in age matched controls. These data demonstrate that UBB+1 is a primary factor in breathing dysfunction in line 3413 and are consistent with the contribution of bronchopneumonia as a cause of death in AD patients. Research Line: Translational neuroinflammation P.I.: Prof. Dr. M. De Baets, Dr. P. Martinez, Dr. M. Losen and Dr. P. Molenaar PhD students: Drs. A. Gomez Focus of research: Defining antigen-specific approaches to treatments in neurodegenerative and neuroimmunological diseases We are working with a broad range of diseases from Myasthenia gravis to, Alzheimer s disease to Schizophrenia.

18 Our goal is to define fine antigen-specificities of individual immunization trials have shown some adverse effects. Because cerebellar changes due to chorioamnionitis in the preterm reversibility of neurobiological changes, and to find novel patients antibodies and their mechanisms of action and/ antibodies can also exert inflammatory responses, lamb that might account for the motor and non-motor def- preventive and therapeutic strategies. or individualised treatments based on this new knowledge. the effector mechanisms of a therapeutic antibody need icits seen in neonates born after antenatal inflammation. Environmental Epigenetics focuses on two main research The project includes studies of inter-patient heterogeneity to be carefully controlled we are studying the contribution themes/questions. First, what are the neurobiological underpinnings in the target autoantigens the autoantibodies and their of these mechanisms to the therapeutic effect (plaque Research Line: Environmental Epigenetics of neuropsychiatric phenotypes, with a par- pathogenic actions and immunological and tissue-specific clearing and improvement of memory function) and possible P.I.: Dr. D. Van den Hove, Prof. Dr. K.P. Lesch, ticular focus on mechanisms involving gene-environment factors that influence clinical presentation and severity. side effects using pro-inflammatory mouse IgG2a and Prof. Dr. H. Steinbusch interactions? Second, what is the role of epigenetic mecha- State of the art technology is used: mature (CD22+) B lymphocytes anti-inflammatory mouse IgG1 antibodies in an AD mouse PhD students: Drs. L. Chouliaras, Drs. F. Boulle, nisms in mediating gene-environment interactions in and are isolated from peripheral blood or tissue and model Drs. E. Pishva, Drs. C. Hammels, long term consequences of (developmental) environmen- immortalized with EBV and the polyclonal B cell activator Drs. N. Leibold, Drs. R. Opstelten, tal perturbations? These research themes/questions are CpG After immortalization, B cell clones produce Research Line: Neonatology, Developmental Neuroscience Drs. S. Jabob, Drs. K. Schraut applied to Alzheimer s disease, depression and anxiety monoclonal antibodies. The screening of the antibodies is Associated disorders, schizophrenia and epilepsy. State-of-the-art performed by immunohistochemistry or radioimmunoassay. P.I.: Dr. A. Gavilanes, Prof. Dr. B. Kramer, Researchers: Dr. B. Rutten, Dr. G. Kenis, technologies are being employed to analyze the epigenetic We also test new approaches to explore the possibili- Prof. Dr. H. Steinbusch, Dr. B.E. Machiels, Prof. Dr. J. van Os, changes in single genes, signaling pathways or the entire ties for treatment: We have demonstrated that Bortezomib Prof. Dr. L. Zimmermann, Prof. Dr. J. Vles Dr. K. Schruers, Prof. Dr. F. Verhey, genome in response to variations in environmental exposure. can improve MG symptoms and, therefore, proteasome Postdoc: Dr. E Strackx Dr. P-J. Visser, Dr. G. Hoogland Research involves various innovative, translational 34 inhibition is a promising therapeutic strategy to target PhD students: Drs.E. Vlassaks, Drs. K. Cox, Focus of research: Understanding gene-environment projects using in vitro cell cultures, in vivo animal models, plasma cells in antibody mediated autoimmune diseases. 35 Research Line: Central Nervous System neuroinflammation P.I.: Dr. P. Martinez, Dr. M. Losen, Prof. Dr. H. Steinbusch, Prof. Dr. M. De Baets PhD students: Drs. J. Stevens, Drs. G. Bode Focus of research: Understanding neuroinflammation in neurodegenerative diseases We are studying the role of innate immunity in the pathogenic mechanism involved in neurodegenerative diseases and the involvement of lipids in the early inflammatory process. We are studying the function/dysfunction of danger signal molecules e.g., Serum amyloid P component and the ceramide transporter in the neurodegenerative process. Moreover we also study the role of these proteins in ER and mitochondrial dysfunction, early pathogenic mechanisms in the neurodegenerative process. Passive immunization with human anti-abeta antibodies is a new therapeutic approach. However recent passive Drs. Michelle Sparnaaij, Drs. R. Jellema, Drs. M. Seehaase, Drs. M. Gantert Associated Researchers: Dr. P. Martínez, Dr. D. van den Hove, Prof. Dr. M. De Baets Focus of research: Asphyxia and inflammation We focused on the study of the impact of asphyxia and inflammation during fetal and neonatal CNS development. The topics were: 1) Fetal asphyxia (FA): our data support the concept that severe FA has a critical role in neurodegeneration and aging in the rat. M. Seehase and R. Jellema tested new therapeutic approaches to neuroprotection in preterm lambs. Perinatal treatment with propofol reduced brain injury and intrauterine treatment with mesenchymal stem cells showed neuroprotection and preserved brain function. 2) Fetal asphyctic preconditioning: E. Vlassaks and M. Sparnaaij characterized the basic mechanisms of brain and placental inflammatory response, and K. Cox showed the fetal brain genomic reprogramming in this model of endogenous neuroprotection due to sub-lethal FA in the rat. 3) Fetal (LPS) inflammation: E. Strackx documented cortical (GxE) interactions, and their underlying epigenetic mechanisms, in the pathophysiology of psychiatric disorders The organization of DNA into chromatin enables the cell to use powerful regulatory mechanisms broadly defined as epigenetics. Epigenetic changes are reversible and responsive to environmental influences, unlike genetic mutations, which represent rare events with permanent consequences on genes. Research on Environmental Epigenetics aims to characterize the molecular basis that underlies sensitivity to environmental exposures and associated gene-environment interactions in (neuro)psychiatric phenotypes and disorders, with a particular interest in epigenetics. This program examines several aspects of epigenetic regulation, such as DNA methylation at promoter sites, chromatin modifications, gene silencing induced by mirnas, and other novel epigenetic mechanisms, for their roles in disease and dysfunction consequent to environmental conditions. The ultimate goal of this program is to identify molecular and cellular pathways that are causally involved in the etiologies of psychiatric disorders, to identify biologic markers that predict disease onset and course, to determine the and human tissues and/or biologic samples to examine (epi)genetic modifications and to determine the precise mechanism responsible for these changes. Of note, the Environmental Epigenetics group is part of a broader initiative at Maastricht University, which is referred to as Translational Neuropsychiatry (TNP), bringing together all divisions within MHeNS in a collaborate approach to further investigate the neurobiology of psychiatric disorders in a translational setting. As such, these lines of research are supported by grants from the Internationale Stichting Alzheimer Onderzoek (ISAO), NWO-Veni and Hersenstichting Nederland.

19 36 chapter 4 Facts and Figures

20 Facts and Figures 4.1 Earning Power In this section, we present information concerning resources and funding. Direct funding is provided mainly by the MUMC+ and comes indirectly from the Dutch Ministry of Education, Culture and Science. Research Funding: funds received in competition from national and international science foundations. Contracts: funds from third parties. Direct Funding at Division level Div. Year Granted organisation Project Amount in e Acquired by Maastricht University Kootstra Talent Fellowship* (postdoc) D. Collip Maastricht University Kootstra Talent Fellowship (PhD-student) N. Leibold Maastricht University Kootstra Talent Fellowship (postdoc) H. Wigman SUBTOTAL MENTAL HEALTH Maastricht University Kootstra Talent Fellowship (PhD-student) N. van Goethem SUBTOTAL NEUROSCIENCE TOTAL MHeNS * Kootstra Talent Fellowships: Awarded by the Faculty Health, Medicine and Life Sciences. Talented future PhD students: The fellowship is meant to bridge the time between graduation of a talented student in Medicine, Health or Life Sciences and the start of an official contract as a PhD-student. Talented future postdocs: The fellowship is meant to bridge the time between graduation of the PhD-student and the start of an official contract as a postdoc.