UNIVERSITY OF FACULTY OF HEALTH AND MEDICAL SCIENCES

BRIDGE- TRANSLATIONAL EXCELLENCE PROGRAMME

PROJECT SYNOPSIS TEMPLATE 1

Project title The Neurophysiological Basis of Ultrafast Magnetic Resonance Encephalography

Mentor 1 Gitte Moos Knudsen, Prof. Dr. Med., Neurobiology Research Unit, Rigshospitalet ([email protected]) Mentor 2 Maiken Nedergaard, Prof. Dr. Med., Center for Translational Neuromedicine, ([email protected])

Framework This project will be performed in a unique translational environment that will bridge applied and basic medical across two of forefront units, The Section for Translational Neuroscience (STN) at the University of Copenhagen, and The Neurobiology Research Unit (NRU) at Copenhagen University Hospital, Rigshospitalet. This exclusive setting allows the selected candidate to collaborate with a committed NRU data-analysis and biostatisticians team while also granting access to dedicated data analysis server facilities, MR infrastructure and preliminary Magnetic Resonance Encephalography (MREG) data. Regular lab meetings in NRU and STN provides synergy and feedback both from neuroimaging and data-analysis as well as glymphatics experts, ensuring the projects continued progress. The collaboration with the world leading STN lab investigating the glymphatic system, will help guide the projects scientific relevance. Moreover, both STN and NRU have a strong scientific network for MREG data analysis, including collaborations with Prof. Kiviniemi who developed state-of-the-art MREG fluid dynamic imaging. Alongside personal mentoring by Prof. Knudsen and Nedergaard, the project setup ensures an excellent scientific environment for advanced MREG imaging analysis.

Project Ultrafast Magnetic Resonance Encephalography (MREG), is a novel MR technique synopsis that enables image acquisition of the entire brain at 10 Hz, roughly 30 times faster than standard BOLD fMRI. This allows non-aliased imaging of cardiac and respiratory pulsations, hypothesized to be the driving force of intracranial pressure (ICP) fluctuations that propel cerebrospinal fluid (CSF) through the brain. MREG may have

1 The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme.

wide-spread applications in basic and clinical research investigating CSF PAGEfluctuations 2 OF 2 , yet its underlying biological signal is not yet well understood. This project aims to characterize underlying properties of MREG. Data from different cognitive and neurophysiological states will be recorded in healthy subjects to investigate how changes in ICP and neuronal activity affects the MREG signal. These data will be collected as part of already ongoing studies. The BRIDGE-postdoc will be able to influence and assist in data collection, but his/her main responsibility will be to critically develop an MREG image-processing pipeline to accurately quantify CSF movements.

Profile of Please outline the desired background and scientific qualifications of a potential potential fellow/mentee fellow  Excellent MR data processing skills (e.g. FSL, SPM or Freesurfer)  Preferably high quality first author publications in state-of-the-art MR imaging  PhD in neuroscience  Background in computer science, physics, or biomedical engineering

UNIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES

BRIDGE- TRANSLATIONAL EXCELLENCE PROGRAMME

MENTOR CV TEMPLATE 1

Name Gitte Moos Knudsen

Title Professor, overlæge, dr.med.

Current Neurobiology Research Unit (NRU) & NeuroPharm (The Center for department(s) Experimental Medicine Neuropharmacology), Dept of , The Neuroscience Center, Rigshospitalet

Current position(s) Professor, overlæge, dr.med., Head of NRU and NeuroPharm

Education/training MD from University of Copenhagen (UCPH), 24.1.1984. Board certified user of radioisotopes 1986. FMGEMS exam (US) 1989. Board certified in neurology January 1995. DMSc (dr.med.) from UCPH, 16.12.1994.

Scientific career I am a translational neurobiologist and clinical neurologist with interest in profile advanced methodological developments that I subsequently apply in my research to address pertinent neurobiological and clinical issues. My scientific interests include blood-brain barrier transport, neurobiology of cerebral blood flow and metabolism and the neurobiology of cerebral neurotransmission with particular emphasis on molecular brain imaging. I have a particular focus on multimodality neuroimaging of neuro-transmission in healthy individuals and in patients with neurological or psychiatric disorders. NRU encompasses around 50 staff members and has an annual budget of roughly €3.5 million. NRU has extensive experience in organization and governance of large scale research collaborative projects, e.g., the Lundbeck Foundation Center for Integrated Molecular Brain Imaging (Cimbi) and Center for Experimental Medicine Neuropharmacology (NeuroPharm) and has participated in many European collaborations most recently INMiND supported by EU FP7. NRU collaborate nationally and internationally and has expertise in molecular, functional and structural brain imaging in brain disorders. The NRU preclinical laboratory includes standard wet laboratory facilities and NRU also has two psychological/physiological test rooms equipped with all the required facilities. As of 2019, NRU will apart from a SPECT-scanner have its own brain research dedicated 3T MR-scanner and mock-up MR scanner installed in the North Wing at Rigshospitalet. Bibliometric Published 351 Medline indexed scientific papers and reviews as well as 28 summary books/book chapters. No. citations >13,500. H-index: 56 (Web of Science). ResearcherID: C-1368-2013, ORCID-ID: orcid.org/0000-0003-1508-6866

1 Do not exceed two pages. The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme

Hansen HD, Mandeville JB et al. Functional characterization of 5-HT1B receptorPAGE 2 OFdrugs 2 in non-human primates using simultaneous PET-MR. J Neurosci. 2017 Nov 1;37(44):10671-10678 da Cunha-Bang S, Hjordt LV et al. Serotonin 1B receptor binding is associated with trait anger and level of psychopathy in violent offenders. Biol Psychiatry. 2017 Aug 15;82(4):267-274 Beliveau V, Ganz M et al. A High-Resolution In Vivo Atlas of the Human Brain's Serotonin System. J Neurosci. 2017 Jan 4;37(1):120-128 Mc Mahon B, Andersen SB et al. Seasonal difference in brain serotonin transporter binding predicts symptom severity in patients with seasonal affective disorder. Brain. 2016 May;139(Pt 5):1605-14 Knudsen GM, Jensen PS et al. The Center for Integrated Molecular Brain Imaging (Cimbi) Database. NeuroImage. 2016 Jan 1;124(Pt B):1213-1219 Frokjaer VG, Pinborg A et al. Role of Serotonin Transporter Changes in Depressive Responses to Sex-Steroid Hormone Manipulation: A Positron Emission Tomography Study. Biol Psychiatry. 2015 Oct 15;78(8):534-43 Haahr ME, Hansen DL et al. Central 5-HT neurotransmission modulates weight loss following gastric bypass surgery in obese individuals. J Neurosci. 2015 Apr 8;35(14):5884-9 Fisher PM, Haahr ME et al. Fluctuations in [11C]SB207145 PET binding associated with change in threat-related amygdala reactivity in humans. Neuropsychopharmacology. 2015 May;40(6):1510-8 Haahr ME, Fisher PM et al. Central 5-HT4 receptor binding as biomarker of serotonergic tonus in humans: a [11C]SB207145 PET study. Mol Psychiatry. 2014 Apr;19(4):427-32 Fisher PM, Madsen MK et al. Three-week bright-light intervention has dose-related effects on threat-related corticolimbic reactivity and functional coupling. Biol Psych. 2014 Aug 15;76(4):332-9 Contributions to My mentoring philosophy is that each student is unique and is entitled to be mentoring, mentored according to his/her skills, wishes, and personal ambitions. As the training, main supervisor of a substantial number of PhD-students and postdocs it supervision becomes natural and necessary to have a collaborative learning environment, where PhD-students have a daily supervisor in terms of either a more experienced PhD-student and/or a postdoc. PhD-students often get assistance from pregraduate students which means that at virtually every level of training, you get to teach and train people. In my view, this supports a vibrant collaborative team-work spirit. Since 1999, I have supervised a total of 24 PhD-students (hereof 14 females) who have defended their PhD degrees. After earning their PhD degree, they were recruited as post docs by different foreign institutions: Childrens Hospital Harvard Medical School (Cecilie Licht), Stanford University (Birgitte Kornum; Mikael Palner), Imperial College London (David Erritzøe), and Charité Berlin (Jan Kalbitzer). Of the remaining, eight became either senior researchers or post docs in Danish academic institutions, four went on to clinical training for specialization, and two became employed in drug companies in Denmark and Sweden. Currently, I am supervising 9 PhD students and mentoring 10 post docs. My laboratory supervises about 20 national and international pregraduate and PhD students every year. Regular teaching of pregraduate medical, pharmaceutical and human biology students and organizer of 1-2 PhD courses per year. Regularly teaching at international courses: annually at the PET Pharmacokinetic course (80 students) and at summer courses.

UNIVERSITY OF COPENHAGEN FACULTY OF HEALTH AND MEDICAL SCIENCES

BRIDGE- TRANSLATIONAL EXCELLENCE PROGRAMME

MENTOR CV TEMPLATE 1

Name Maiken Nedergaard

Title Professor, Co-Director, dr.med.

Current Center for Translationel Neuromedicine, University of Copenhagen department(s) University of Rochester Medical Center, Rochester, NY USA

Current position(s) Co-Director, Center for Translational Neuromedicine (Rochester and UCPH), Professor of , Neuroscience and Neurology Professor of Glial Cell Biology

Education/training MD from University of Copenhagen (UCPH), 1983. MDSc (dr. med.) from UCPH, 1988. Resident at Rigshospitalet/UCPH, 1983-1984. Postdoc at UCPH, 1984-1987. Postdoc at Cornell Univ. Med. School, 1987-1988.

Scientific career I am a glial cell biologist. My goal is to discover new aspects of glial cells that profile are useful for diagnostics and therapeutic efforts across multiple neurological diseases. We are specifically focused on the glymphatic system – a brain-wide highly polarized fluid transport system that clear potential neurotoxic metabolic products out of the brain, such as amyloidMy lab utilize primarily optical techniques, but we are collaborating with several groups on MR and PET imaging. Gitte Moos Knudsen group is our closest collaborator in Denmark. The Center for Translational Neuromedicine (CTN) at the University of Copenhagen was established in 2015, with the aim of developing Copenhagen into one of the world’s major hotspots for neuroscience research. The focus of the Center is to develop new approaches for investigating and treating neurological diseases. The Nedergaard lab’s focus is on defining interstitial ion homeostasis, fluid transport and glymphatic flow in the adult brain, with special emphasis on the mechanisms of CSF fluid dynamics and protein clearance, and its dysregulation in proteinopathic neurodegenerative disorders, including Alzheimer’s disease. We are also engaged in defining the contribution of to brain ion homeostasis, and the latter’s role in arousal and its disorders. This work has advanced the field significantly, and as such, been internationally recognized through many prestigious awards, including the AAAS Newcomb Cleveland Prize for the most influential paper

1 Do not exceed two pages. The CV’s and project synopsis of each mentor team will be posted on the programme webpage in advance of the admissions process to the programme

published in 2013. Professor Nedergaard’s lab at CTN (UCPH) comprisesPAGE 2 OF35 3 members, from Associate Professors to Postdocs, PhD students and MSc/BSc students. The Nedergaard laboratory includes standard wet laboratory facilities and is responsible for a 9.4T rodent MRI Core Facility. The Nedergaard lab is funded by 40 million DKK grants from the Novo Nordisk Foundation and the Lundbeck Foundation. The goal is to accelerate the process of bringing the newest research from the lab and into the treatment of patients. In total the center is/has participated in 42 projects funded by e.g. EU H2020 and ERC

Bibliometric 1. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gunderson GA, Benveniste H, Vates GE, Deane summary R, Goldman SA, Nagelhus EA, Nedergaard M. (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science Translational Medicne 4:147ra111. 2. Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. (2013) Sleep Drives Metabolite Clearance from the Adult Brain. Science 342:373-7. 3. Rangroo Thrane V, Thrane AS, Wang F, Cotrina ML, Smith NA, Chen M, Xu Q, Kang N, Fujita T, Nagelhus EA, Nedergaard M, et al. (2013) Ammonia triggers neuronal disinhibition and seizures by impairing potassium buffering. Nature Medicine 19, 1643-1648. 4. Nedergaard M. (2013) Neuroscience. Garbage truck of the brain. Science 340(6140):1529- 30. 5. Ding F, O'Donnell J, Xu Q, Kang N, Goldman N, Nedergaard M. (2016) Changes in the composition of brain interstitial ions control the sleep-wake cycle. Science 352:550-5. 6. Nedergaard M, Goldman SA. (2016) Brain Drain: An internal plumbing system rids the brain of toxic wastes. Sleep is when this cleanup ritual occurs. Scientific American. 44-49. 7. Wei HS, Kang H, Rasheed ID, Zhou S, Lou N, Gershteyn A, McConnell ED, Wang Y, Richardson KE, Palmer AF, Xu C, Wan J, Nedergaard M. (2016) Erythrocytes Are Oxygen- Sensing Regulators of the Cerebral Microcirculation. . 91(4): 851-62. 17citations 8. Verkhratsky A, Nedergaard M (2018) Physiology of Astroglia. Physiol Rev 98: 239–389, 2018 9. Plog BA, Mestre H, Olveda GE, Sweeney AM, Kenney HM, Cove A, Dholakia KY, Tithof J, Nevins TD, Lundgaard I, et al. (2018). Transcranial optical imaging reveals a pathway for optimizing the delivery of immunotherapeutics to the brain. JCI insight 3. 10.1172/jci.insight.120922 10. Rasmussen MK, Mestre H, Nedergaard M (2018) The glymphatic pathway in neurological disorders. Lancet Neurol 17 (11): 1016-1024 Published 241 Medline indexed scientific papers and reviews as well as 21 books/book chapters. Publications cited > 25,736, H-index 90, Web of Science, March 2018

Contributions to My mentoring philosophy is to provide a platform on which talented students mentoring, can blossom. I will advise and critique ongoing experiments, discuss overall training, goals and encourage creativity. However, I will not provide experimental supervision plans. I expect students to work relatively independent and be highly motivated.

Since 1994, I have supervised a total of 32 PhD-students who have defended their PhD degrees. Currently, I am supervising 5 PhD students and mentoring 10 post docs. My student and postdocs have succeeded in both research, medicine, and industry. Several are faculty members at institutions such as UCSF, Albert Einstein, Children’s Hospital Washington, Strong Hospital, Rochester, Rutger University, Portland, Oregon, NYU, Shenyang and Shanghai Universities.