high da: stable prefrontal cortex dopamine: cognitive stability

low da: distractible functional and neurochemical reciprocity

low da: inflexible striatum dopamine: cognitive flexibility high da: flexible

A balancing act with dopamine

Human beings are extremely capable of adapting to their constantly aim to provide more insight into this proc- changing environment. But often we need to ignore those changes, ess, with the ultimate aim of understanding stay as we are, and continue acting as normal. So how do we know the neurobiological basis of neuropsychiat- when it’s appropriate to change our behaviour and how do we balance ric disorders such as ADHD and Parkinson’s fl exibility and stability? Roshan Cools is working on the hypothesis disease. One characteristic of these disorders that this is mediated by the brain substance dopamine, which regu- is a neurochemical imbalance, leading to in- lates the dynamic interaction between two regions of the brain. flexibility, impulsivity and/or compulsivity. We hope that our approach will eventually lead to individualized treatment strategies that target the complex cognitive deficits ‘Things developed so quickly’, Cools associated with these conditions. ’ observes, referring to her position as Prin- cipal Investigator at the Donders Institute, Two interacting regions where she started only two years ago, ‘We appear to need both cognitive flexibility soon after which she obtained a NWO and stability. If we’re too flexible, we tend Vidi grant. ‘There are fourteen people in to be distracted and our behaviour becomes my group if I include my affiliated and unstable and, if we’re too stable, we become Master’s students,’ she says. Thanks to a inflexible. A pure form of reciprocity would flourishing research programme, initial imply that we need only a single mechanism results are already coming in. that can be adjusted dynamically, depending on the task at hand. However, we often need With a command of English language that to be both flexible and stable at the same reflects the time she’s spent in the Anglo- time. That is, while we should be flexible Saxon world – Cools was a PhD student in response to relevant changes, we should at St. John’s College in Cambridge (UK) remain stable when there are irrelevant with Trevor W Robbins and a postdoc in changes. To resolve this apparent paradox, Berkeley California with Mark D’Esposito it’s plausible to postulate two separate – and a pace that reflects her quick mind, mechanisms that work together. We think she explains the main hypothesis of her the prefrontal cortex – commonly associated research project: ‘It’s not only the abnor- with complex cognitive requirements – and mal mind that has difficulty adapting. the striatum, a deep brain subcortical struc- Prolonged or severe periods of stress and ture traditionally associated only with move- fatigue also make the usually healthy mind ment control, work together. Dopamine inflexible or unfocused. In our research we balances this interaction.

2 Donders Institute for Brain, Cognition and Behaviour Roshan Cools

Baseline levels sensitive brain areas in rats. Roshan, York University) for a multidisciplinary ‘The assumption that two separate mecha- trained as a psychologist, advocates new project on serotonin and dopamine. One nisms are involved in the balancing act is behavioural studies with rodents, if only third of the $1 million plus grant will not enough to account for the paradox- to reduce the hassle involved with using go to research at the Donders Institute. ical effects of dopaminergic drugs,’ Cools human subjects. ‘Imagine one of my PhD Serotonin is a brain substance that, like explains. ‘How can drugs that enhance students is doing an fMRI study on the dopamine, has long been seen as cru- dopamine improve cognitive flexibility in effect of dopamine on a simple reward cial to processes that control behaviour, some individuals (e.g. those with Parkin- and punishment learning task,’ she says. including decision making and reinforce- son’s) while improving cognitive stability Her subjects have to come in four times: ment learning. However, compared to in others (e.g. those with ADHD)? And as for a trial with a dopamine enhancer, one dopamine, there’s much less known well as influencing the brain region that with a dopamine blocker, one with both about the mechanisms through which the dopaminergic drug innervates, its ef- drugs to control for placebo effects, and serotonin affects behaviour. Cools and her fects will also depend on the baseline lev- one control study with no drugs at all. ‘It colleagues will address this issue by using els of dopamine in that region. The drug takes 18 months to organize this and it’s existing understanding of dopamine and will remedy brain functioning in regions very expensive.’ a constellation of methods that have shed with low baseline levels of dopamine, much light on the role of dopamine, in- while detrimentally overdosing function Roshan is about to return to Berkeley tegrating functional magnetic resonance in brain regions in which the baseline – not to accept the job they offered her imaging, psychopharmacology and neur- levels of dopamine are already optimal.’ (she intends to stay at Donders), but to onal recordings in monkeys and humans spend a month on ‘contemplative’ writing – all guided by computational theory. Move or freeze? alongside old colleagues and to enjoy the − Iris Roggema An intriguing question is how do we know American can-do attitude. It’s pretty ad- when it’s appropriate to change? What dictive she admits and, suddenly putting kinds of clues are considered relevant? on a Californian accent, she says: Oh, we To understand this issue in the normal just love what you’re doing. It’s so incred- brain a lot of work is needed on patients ibly fantastic, we love you!’ with neurochemical disorders, hopefully leading to a model for cognitive flexibility. Explorative steps with serotonin List of publications: ‘We also shouldn’t ignore all the rodent This year, one of the highly prestigious www.ru.nl/neuroimaging/staff/cognitive_control/ work that’s been done,’ Cools says with Human Frontiers Science Program (HFSP) roshan_cools/ a smile, referring to the fact that she is grants was awarded to Roshan Cools, in the daughter of Professor Lex Cools, the collaboration with Kae Nakamura (Kansai neuropharmacologist from Nijmegen Medical University, School of Medicine, who did so much work on dopamine- Osaka Japan) and Nathaniel Daw (New

Newsletter 15 October 2009 3 Exploring Brain Computer Interfacing

Finding true motivation lies in bridging the gap between scientifi c that picks up a specific brain signal and trans- specialisations, university and society, says Peter Desain, the director of lates it into a computer signal, be it a cursor, a BrainGain – a special project set up to investigate potential applications mouse or a spelling programme. of neuroscientifi c research fi ndings. He’s just been celebrating the sub- mission of a new patent application. Deciphering the neural code might Patent on Noise be considered the holy grail of cognitive neuroscience, but this ultimate ‘The best ideas arise when applying technology goal is not yet within reach. Many interesting detours have been identi- from one field of knowledge to another, says fi ed en route, so why wait to explore them or perhaps even exploit them? Desain states. ‘For example, broadband mobile phone signals are labelled with an individual random bit pattern that makes it possible to identify your personal call from the blurred, Bridge builder mixed signal of all the phones in an area.’ It’s At the Donders Institute at Radboud University exactly this idea that Desain and his colleague Nijmegen it’s Professor Peter Desain – head of the Farquhar apply in a newly patented BCI system. Artificial Intelligence department – who plays a key role in developing tools for inferring the state of ‘We watermark the stimuli with a characteris- cognitive processes directly from measurements of tic, possibly subliminal, noise, which you can brain activity. Trained as both a technical mathema- then trace back to a brain signal in the subject. tician and a psychologist, and now working as a fun- So, if we present two stimuli, for example a damental researcher and inventor, he really enjoying sound on the left side and one on the right side, bringing people together; he’s the incarnation of a we can distinguish the one that the subject is bridge builder. paying attention to. With visual stimulation it works even better. And selective attention is BrainGain – a consortium of 23 research groups often an easier and more natural task than the and companies both large and small led by Desain classic BCI task of imaged movement. Systems – translates insights from neuroscience into applica- like this are still quite cumbersome and hard to tions that benefit both healthy users and people train, both for the user and the machine’. suffering from autism, ADHD and ALS. The latter are progressively locked in their mind due to loss of Another idea Desain’s team is currently testing muscle control. The communication by eye blinks is a sort of mental juke-box. When you recall they use is movingly portrayed in the film The a song, it generates a specific brain signal. Diving Bell and the Butterfly. But Brain Computer Imagine your favourite Christmas carol and Interfacing (BCI) offers hope for a more efficient your computer directly links this to a specific communication. BCI is a general term for any device action. It’s relatively easy to recall songs and the

4 Donders Institute for Brain, Cognition and Behaviour Peter Desain

system can be tailored to your personal ‘There’s also a link to our neurocognition preferences. Though it is still quite hard research as ALS patients could benefit to detect these reliably by computer, the from RE-phrase as well. Instead of spelling New road example illustrate that the tasks inducing letter by letter, which is quite tiresome the BCI signal are vital for a quick and when using a BCI we store and recycle the Discriminating phonemes in an unfamiliar easy operating system. Improving BCI will phrases thus entered, and make a system language you’re studying, is one of the to a large extent depend on developing the based on entire sentences. Users just select hardest things to learn. When Japanese is task side, according to Desain. the phrase they need by looking at it. your mother tongue a /r/ and a /l/ simply sound the same. Intriguingly, long before Automated conversation Be generous we are consciously aware of the differ- ‘RE-phrase’ is the name of a Desain ‘It’s not rocket science, Desain admits, ence of these speech sounds, our brain discovery that’s closer to market. ‘Con- ‘but I’m sure that researchers can also reacts with a different signal to them. versations are often fairly standard. For benefit from these kinds of projects. New Together with Prof. McQueen from BSI, example, helpdesks often receive the same ideas, different views, unexpected research Desain’ team just started working on a questions and usually an answer elicits a questions.’ It’s one of his reasons for neuro-feedback method to speed up these follow-up question. So we thought: why stimulating business spin-offs from cogni- learning processes. ‘When you see what not automate this, representing ques- tive neuroscience. The Donders Institute the perceptual processes in your breain tions and answers in a huge conversation is currently starting up an Innovation Lab, already begin to pick up, you might be network? This works better than the usual a business incubator. Desain is person- able to enhance that further.’ FAQs. It’s more structured and presents ally inspired by the attitude of Stanford only relevant responses at any point in University, where he enjoyed a sabbatical the dialogue. The method is also more leave several years ago. ‘The motto of their interactive and learns from new input Office of Technology Transfer is: Be gener- by users. As the sentences can be stored ous. And that’s how it should be. Dare in many languages, the system can help to invest. Be generous to many ideas for with communication while travelling. An start ups. Most won’t survive. Some will application called RE-phrase Trip is now make a living. And once in a decade or so available for iPhones and iPods and the you’ll have helped start a Google. I really same technology is being tested for use hope we can change the mind set of our Van Gerven, M., Farquhar, J., Schaefer, R., Vlek, R., as an electronic coach for children with researchers. Society and research can both Geuze, J., Nijholt, A., Ramsey, N., Haselager, P., Vuur- autism, together with the Dr Leo Kanner- benefit from a more entrepreneurial at- pijl, L., Gielen, S. & Desain, P. (2009). The brain-com- huis. This device helps to structure tasks titude. I’m happy to see that these changes puter interface cycle. Journal of Neural Engineering, 6 and gives advice when flexible behaviour are now happening at our University too.’ 041001 (10pp) doi: 10.1088/1741-2560/6/4/041001 is needed. For a panic-stricken person − Iris Roggema with autism who, for example, has just Desain, P, & C. Jansen (2000). Method and System missed a train, it can be a real benefit to for Providing Communication via a Network. Patent have such a digital assistant. PCT/NL00/00425

Newsletter 15 October 2009 5 Sigrid, Nens and their two month-old daughter Tess live in a modest upstairs apartment in East Nijmegen. At least for now; because soon they will be moving to a house with a garden just 200 metres away. Tess is very well behaved during the inter- view, lying content on Nens’ lap, beside the laptop she already seems quite familiar with.

On 26 May 2009, a few days before begin- ning her maternity leave, Sigrid was awarded her doctorate, cum laude, for her thesis on ‘Quantitative muscle ultrasound in child- hood neuromuscular disorders.’ “It turned into a sort of handbook for people starting to use this diagnostic technique,” says Pillen, leafing through the 254 page-thick thesis. She did her PhD research at the Department of Clinical Neurophysiology of RUNMC Sigrid Pillen makes muscle ultrasonography her life’s work within the programme of the Donders Centre for Neuroscience, with Prof. Machiel ‘Exploring new territory’ Zwarts as her promoter. Identifying muscular diseases Muscle ultrasonography is a technique that’s easy to use for making a picture of muscle thickness and structure, explains Pillen. ‘In the early 1980s it was known that you could use this technique to identify neuromuscular disorders, but it was not widely applied. There were only two centres where muscle ultrasonography was used as a standard diagnostic tool, in London and in Philadelphia, but nowhere else until we started in Nijmegen. Muscle ultrasound scans are made in the same way as a preg- nancy ultrasound, but seeing a muscular disorder in such a scan with the naked eye is often difficult. Qualitative, visual analysis requires a lot of experience, which is often lacking. That’s why we decided to try com- puter-aided quantitative analysis.”

Pillens’ interest in neuromuscular disorders arose while she was studying medicine at Radboud University Nijmegen. ‘In my third year another student, Ralph Scholten, and I contacted the paediatric neurology depart- ment, where they were eager to try this new and non-invasive technique of muscle ultrasonography. We set it up, often working Sigrid Pillen (29) is a paediatrician-in-training at the Radboud University more than forty hours a week, and were Nijmegen Medical Centre (RUNMC), where scientifi c work is affi liated given a lot of freedom. I love research: work- to the Donders Centre for Neuroscience. She already has numerous sci- ing to the limits of your intellectual capacity. entifi c publications to her name, and has received various prizes for her Fundamental research is wonderful, but I research. At the end of May she was awarded her doctorate, cum laude, want to discover something you can actually for a bulky thesis on muscle ultrasound. She has also recently given apply to a real-life problem. I like to take birth to a daughter, Tess. A portrait of a promising neuroscientist. research in that direction.

6 Donders Institute for Brain, Cognition and Behaviour Wriggling babies medical centre. This training will take Until recently muscular disorders were about two and a half years. At the same diagnosed by taking biopsies, generally time, she is continuing her research on from the thigh muscle, with a thick needle using muscle ultrasonography for better or an operation. As a screening tool you detection of neuromuscular disorders. could apply electromyography (EMG, a “Many muscular disorders are incurable, technique used to measure the electrical but you can do so much for patients! activity of muscles). “For EMG you also People stretch their limits and achieve need to insert needles into the muscles, something despite their condition. That’s and then move the needle within the wonderful. Many of these patients are muscle. This causes discomfort, which is now adults, which brings new challenges. hard to explain to children. We know that A future goal for example is to ensure that in over 50% of these children no muscular these people have a place in Dutch society disorder will be found. Which is wonder- despite their limitations, and early detec- ful for the child, but why should they go tion can help.” through a painful examination to find that out? This is why we wanted to develop In the past two years there has been more a screening technique that’s non-intru- interest in using muscle ultrasonography sive, particularly for children.” as a basic diagnostic tool. “Now we’re trying to distinguish between the different Muscular disorders can also be imaged us- muscular disorders, and we want to devel- ing Magnetic Resonance Imaging (MRI), op the diagnostic technique further with Sigrid Pillen but then the subject has to lie still for 45 adults. Muscle ultrasonography should minutes. That’s difficult, again especially be a standard test for every neurologist Muscular disorders: relatively rare and for children. “For a muscle ultrasound or paediatrician dealing with muscular often hereditary you only need to lie still for a few seconds. disorders. We are organising a course to That can be done even with a wriggling promote it in November.” There are more than six hundred mus- baby,” laughs Pillen. Nowadays the pic- cular or neuromuscular disorders, from tures are analysed using simple software As a paediatrician you have to be fairly those affecting the motor neuron in the on a PC. “In the past the images were resilient, says Pillen. “Children can be spinal cord, the nerve and neuromuscular analyzed using the naked eye, which could little darlings, but mainly when they are junction to the muscle itself. Most are only detect 70% of the muscular disorders. not ill. You have to be able to cope with hereditary. The best known of these is The missing 30% represented a big grey that. As a young mother? Yes, I’m curious Duchenne’s disease (muscular dystrophy), area. With the computer we can detect to see if that will make a difference when in which an important protein is lacking in about 90% of neuromuscular diseases. I return to work. But I’m not the type to the muscle, which therefore steadily dete- Ultrasound equipment is also much more stay at home. Changing nappies and doing riorates. Muscular disorders are almost all sophisticated now.” housework is fun for a while, but when progressive and incurable, with the excep- that’s done I want to use my brain again.” tion of inflammatory muscle diseases that Why not 100%? − Myrna Tinbergen are often treatable, albeit with significant “Some muscular disorders do not show side effects. up as whiter muscles on the scan. These are the ones that result mainly in defects Sixty in every 100,000 children are born in energy production (rather than tissue with a muscular disorder, so they are destruction), which cannot be seen in relatively rare. The Radboud University an image of the muscle structure. White Nijmegen Medical centre sees thirty to spots indicate connective tissue and fat forty new children each year. Curative that don’t belong in healthy muscles. treatments for many muscular disorders And in very small children it’s difficult are still in their infancy. to detect muscular disorders at all. Their muscles are not yet damaged to the point that we can spot a possible disorder with Muscles alive: ultrasound detects fibrillations. an ultrasound scan.” Pillen S, Nienhuis M, van Dijk JP, Arts IM, van Alfen N, Zwarts MJ. Clin Neurophysiol. 2009 Stretching the limits May;120(5):932-6. Epub 2009 Apr 7. After her training as a paediatrician, which she will complete next year, Pillen Muscle ultrasound in neuromuscular disorders. will begin training as a paediatric neurolo- Pillen S, Arts IM, Zwarts MJ. Muscle Nerve. 2008 gist, possibly through a fellowship at the Jun;37(6):679-93. Review.

Newsletter 15 October 2009 7 Donders Backbone lab assistant. Standards being much higher Due to its academic nature and high than they used to be, an average PhD thesis ambitions, staffing at the Nijmegen-based on cognitive neuroscience consists of MRI Donders Institute is extremely dynamic. studies, behavioural and genetic studies plus Postdoctoral researchers and PhD students the histological identification of protein or fly in from around the globe. Technicians, neurotransmitter changes in response to lab workers and research assistants form the illness, feeding or a particular (pathological) backbone of the institute. Jos Dederen is one of its vertebrae, ever since he came behaviour. This need for multidisciplinarity to work at the Department of Anatomy more than thirty years ago. For anything explains why most PhD students are sup- to do with histology, just ask Jos. ported by expert technical assistants.

‘In the old days, we built Styrofoam jigsaw models based on sections of brains Dederen, who works together with research- in three dimensions. Nowadays computer modelling creates these in a matter ers in and outside the Donders Institute, of seconds.’ It’s not the only method Jos has seen become outdated. ‘We used to likes to have open scientific discussions with study neuronal connections in living animals using tracers in the brain,’ he says. researchers about what’s technically possible ‘This is not appreciated anymore, so we’re currently working on post-mortem to meet their demands, especially because, techniques. For this, you need extremely fresh brain tissue, collected as soon as when you’re engaged in multidisciplinary possible after death. After chemically stabilizing the tissue, we show that some research, a compromise in handling the tis- tracer molecules can penetrate and spread through the tissue, making it possible Jos Dederen sue often has to be found. to visualize neuronal connections. We’ve done this in animal studies and we’re about to make the step to human tissue.’ He hopes the vacant chair in Anatomy will be granted to a real neuro-anatomist and that the research potential of the group will be restored to its former level. As one of the first qualified histological technicians, it was easy for Dederen With his work at the Donders Institute he feels he’s made a good start towards to get an academic job back in 1975. He started working for Dr Jessie Gribnau, achieving this goal. an embryologist in the Anatomy Department. She encouraged him to keep on developing, so he specialized in neurohistology. These days he mainly performs Anything more the dedicated analyst wants to add? Sure. ‘I’d really like to immunological work in which antibodies are used to detect, locate and quantify advertise a slide series on the development of the brain from embryonic to foetal specific molecules in the brain. stage in Chinese hamsters, rats and rhesus monkeys. These were made in our department a long time ago. It’s excellent reference material; if only people knew Dederen demonstrates his advanced lab equipment and pulls samples out of the it was here!’ fridge, while muttering comments on the quality of the work done by a student − Iris Roggema

Agenda PhD defences

20 October 2009, 15:45 − MPI Colloquium Riitta Salmelin. Max Planck Insti- 2-11-2009 − Drs. M.A.H. Steegers, Nerve injury and chronic pain after surgery: tute (Room 1.63), Wundtlaan 1, Nijmegen perspectives on epidemiology and mechanisms. Promoters: Prof. G.J. Scheffer, Prof. K.C.F. Vissers. Co-promoter: Dr. O. Wilder-Smith 20 November 2009, 15:00 to 16:00 − Formal Donders Colloquium Marty Sereno. Centre for Cognitive Neuroimaging, Kapittelweg 29, Nijmegen 4-11-2009 − Drs. M. Stulemeijer, Recovery after mild traumatic brain injury. Promoters: Prof. F.W. Kraaimaat, Prof. G.W.A.M. Padberg. Co-promoters: Dr. P.E. 27 November 2009, from 15:00 to 17:00 − Donders Lecture by Wolfgang Vos, Dr. S.P. van der Werf Maass. Linnaeusgebouw (LIN6), Heydendaalseweg 137, Nijmegen 06-11-2009 − Drs. W.B. Groen, Language, perception and the brain in autism. Promoters: Prof. J.K. Buitelaar, Prof. P. Hagoort, Prof. R.J. van der Gaag. Copromoter: Dr. M.P. Zwiers Latest additions to the Donders Series 9-11-2009 − Drs. R. Kerkhofs, Discourse and prosody in sentence processing: An 18. Prinz, S. (2009). Waterbath stunning of chickens – Effects of electrical parameters electrophysiological investigation. Promoters: Prof. H.J. Schriefers, Prof. W. Vonk. on the electroencephalogram and physical reflexes of broilers. Radboud University Copromoter: Dr. D.J. Chwilla Nijmegen, Nijmegen, The Netherlands. 30-11-2009 − Drs. M.S. Kouzakova, Subtle Signs of Exclusion: How lack of mim- 19. Knippenberg, J.M.J. (2009). The N150 of the Auditory Evoked Potential from the icry affects the perception of self and others. Promoter: Prof. A. van Knippenberg, rat amygdala: In search for its functional significance. Radboud University Nijmegen, Copromoter: Dr. R. van Baaren Nijmegen, The Netherlands. 21-12-2009 − Drs. L. Hogeweg, Word in process: On the interpretation, acquisi- 20. Dumont, G.J.H. (2009). Cognitive and physiological effects of 3,4-methylenedi- tion, and production of words. Promoter: Prof. H. de Hoop oxymethamphetamine (MDMA or ’ecstasy’) in combination with alcohol or cannabis in humans. Radboud University Nijmegen, Nijmegen, The Netherlands. 5-2-2010 − Drs. P.M. van Dam, The shortest path to cardiac activation. Promoter: Prof. A. van Oosterom, Copromoter: Dr. T.F. Oostendorp 21. Pijnacker, J. (2010). Defeasible inference in autism: a behavioral and electrophysi- ogical approach. Radboud Universiteit Nijmegen, The Netherlands. 25-2-2010 − M.L.T. Vergeer, Perceptual visibility and appearance effects of color and form. Promoter: Prof. Ch.M.M. de Weert, Copromoter: Dr. J. van Lier

Donders Institute Newsletter

Editors: Arjan Vink ([email protected]) and Iris Roggema Translation/language editing: Michael Gould Associates ([email protected]) Photography: Dick van Aalst, photo archives Radboud University Editorial Board: Ellen de Bruijn (DCC), Robert Oostenveld (DCCN), Eric Roubos Graphic design and layout: Sander Hermsen (www.sander-hermsen.nl) (DCN), Machiel Zwarts (DCN), Arjan Vink and Iris Roggema Printing: Thieme Deventer

Journalism: Iris Roggema and Myrna Tinbergen Archives: www.ru.nl/donders www.ru.nl/donders