SLAAP- EN STEMMINGSSTOORNISSEN BIJ DE ZIEKTE VAN PARKINSON; EEN BEHANDELSTUDIE MET LICHTTHERAPIE. (Sleep and mood disorders in Parkinson’s disease: a treatment study using bright light therapy) Dr. Ysbrand D. van der Werf1,2,5, Dr. Odile A. van den Heuvel1,3,5, Dr. Henk W. Berendse4,5, Dr. Elisabeth M. Foncke4,5 Afdelingen 1Anatomie & Neurowetenschappen, 2Slaap en Cognitie, Nederlands Instituut voor Neurowetenschappen, 3Psychiatrie, 4Neurologie, VU University Medical Center (VUmc), 5Neuroscience Campus Amsterdam, Amsterdam, The Netherlands.

OVERZICHT Slaapstoornissen en depressie vormen een belangrijke bedreiging voor de kwaliteit van leven van mensen met de ziekte van Parkinson. Vaak treden deze stoornissen vroeg op in het beloop van de ziekte, nog voorafgaand aan de kenmerkende bewegingsstoornissen. Naast een directe invloed op het welzijn, verergeren deze symptomen de motorische verschijnselen. Helaas zijn er op dit moment beperkte, veelal medicamenteuze mogelijkheden om slaap en stemming bij Parkinson patiënten te verbeteren, waarbij regelmatig bijwerkingen optreden. Het verbeteren van slaap- en stemmingsstoornissen langs niet-farmacologische weg zou niet alleen direct bijdragen aan het verbeteren van de kwaliteit van leven, maar bovendien via een gunstig effect op de motorische verschijnselen een additioneel effect hebben op de kwaliteit van leven. Zeer recent hebben wij evidentie gekregen voor het gunstig effect van lichttherapie op stemming en slaap bij ouderen met en zonder dementie, vanuit onderzoek van onze afdelingen Psychiatrie (Vumc-GGZ inGeest) en Slaap en Cognitie (NIN). Licht is een goedkope en gemakkelijk te implementeren behandeling zonder bijwerkingen die potentieel een grote bijdrage kan leveren aan de kwaliteit van leven. De hier voorgestelde studie beoogt de effecten van lichttherapie bij Parkinson patiënten te onderzoeken in een gerandomiseerde placebo-gecontroleerde behandelstudie. Tachtig patiënten met de ziekte van Parkinson worden geïncludeerd en verdeeld over de placebo- en de echte behandeling. Na 3 maanden behandeling vindt een evaluatie plaats, waarna de placebo-groep alsnog de echte behandeling krijgt. Na nog eens drie maanden vindt dan een eindevaluatie plaats, waarmee de lange-termijn effecten van de behandeling worden gemeten. Als primaire uitkomstmaten worden stemmingsmaten genomen. Daarnaast willen wij slaap-parameters meten en (afhankelijk van additionele financiering) de motorische symptomen, een aantal fysiologische parameters (cortisol en melatonine uit speeksel) en biologische ritmes vaststellen (actigrafie). De behandeling en alle metingen zijn non-invasief.

DOEL Het directe doel van dit onderzoek is een therapie te ontwikkelen die ingezet kan worden in de klinische praktijk. Wij verwachten dat lichttherapie een gunstig effect zal hebben op stemming en de verstoorde slaap in de ziekte van Parkinson. Dit onderzoek past binnen de lijn van onderzoek van de afdelingen Neurologie, Anatomie en Neurowetenschappen en Psychiatrie van het VU Medisch Centrum, die een traditie hebben in onderzoek en behandeling van niet-motorische symptomen bij de ziekte van Parkinson. Het hier voorgestelde project is ingebed in een grotere lijn van onderzoek, waarvoor van verschillende bronnen financiering wordt gezocht. Het hier aangevraagde deel betreft de centrale financiering voor de behandeling en meting van slaap en stemming. De secundaire maten worden afhankelijk van additionele financiering meegenomen.

KOSTEN EN AANGEVRAAGD BEDRAG 2011 2012 2013 2014 Aanvraag: Onderzoeks-assistent 0.5 fte, 3 jaar

€ 10.000 € 20.000 € 20.000 € 10.000 € 60.000

Materiaal: testen, vervoerskosten, hardware voor lamp plaatsen, vragenlijsten, etc.

€ 20.000 € 20.000

Extra financiering aangevraagd bij ZonMW clinical fellow/Hersenstichting (dr O.A. van den Heuvel): Assistent in opleiding, 1.0 fte, 4 jaar

€ 37.000 € 38.000 € 39.000 € 40.000 € 164.000

Totaal € 244.400 Totaal elders € 164.400 Aanvraag € 80.000 Deze aanvraag zal ons, bij toekenning, in staat stellen om de 1) lichttherapie uit te voeren, 2) de slaapscores en stemmingsmetingen te doen en 3) de gedragsmatige ritmes te meten, met de hulp van een onderzoeksassistent. Mochten wij extra financiering verkrijgen bij de ‘Hersenstichting’ of NWO ZonMW, breiden wij het personeel uit met een promovendus, bepalingen van cortisol en melatonine in het speeksel. Dit levert, naast een promotie en kennis over de fysiologische ritmes, meer armslag op om de gegevens vlot uit te werken en te publiceren.

APPENDIX: ACHTERGROND EN UITGEWERKT PROTOCOL

BACKGROUND Disturbances of mood and sleep in Parkinson’s disease Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder. PD has long been considered as a pure motor disorder secondary to basal ganglia degeneration with typical motor symptoms, such as bradykinesia, rigidity, tremor, and postural imbalance. However, it has become well established that Parkinson’s disease affects patients’ lives in a much broader sense than merely the motor impairment (Rodriquez-Oroz et al. 2009; Park & Stacy 2009). The quality of life of PD patients as well as their caregivers largely depends on the presence of so-called non-motor features, which are highly prevalent in PD. Frequent non-motor disorders in PD are autonomic dysfunctions, olfactory impairments, sleep disorders, depression, anxiety, psychosis, cognitive dysfunctions/dementia, and impulse-control disorders. Some non-motor features appear in the course of the disease or in response to dopaminergic treatment, but other symptoms (including depression and sleep disturbances) appear before motor symptoms are even recognized. Depression occurs in about 40-50% of patients throughout the course of the disease (Cummings, 1992). Sleep dysfunction is even more common, occuring in about 60-95% of all PD patients (Stacy 2002; Menza et al. 2010). Sleep disorders in PD include a reduced total sleep time, reduced sleep efficiency, increased sleep fragmentation and excessive daytime sleepiness. The relationship between depression and sleep is complex and not well understood. Depressed mood is one of the major risk factors for sleep disorders in PD (Larsen and Tandberg, 2001). Conversely, a major concern of chronic poor sleep is its propensity to facilitate the development of depression (Pigeon et al, 2008; Roane and Taylor, 2008; Thase et al, 1997), for which Parkinson patients are already at high risk. Despite the high prevalence of mood and sleep disorders in PD and despite the fact that the primary determinants of poor quality of life in patients with PD are sleep disturbances, depression and lack of independence, these symptoms are commonly underdiagnosed and undertreated. Chronic sleep disorders compromise mental and physical health, autonomy and well-being of elderly subjects (Van Someren, 2000). Controlled studies in healthy elderly people, moreover, show that even a mild sleep disturbance is detrimental to cognitive performance and brain function (Van der Werf et al, 2009). Finally, the benefit derived from a good night’s sleep on motor function is well-known among PD patients (Tandberg et al, 1999). Therefore, it is important to recognize disturbances of mood and sleep in patients with PD and to start adequate treatment as soon as such disorders have been diagnosed. ‘Unmet needs’ for treatment of depression and sleep disorders in PD Adequate treatment of these chronic sleep and mood disorders in PD constitutes one of the greatest ‘unmet needs’ in the care of PD patients. The treatment alternatives for depression in PD patients have been poorly studied and no evidence-based parkinson-specific depression treatment guideline exists. The general guideline for the treatment of depression consists of the following 6 steps: 1) selective serotonergic re-uptake inhibitor (SSRI)/serotonergic-noradrenergic re-uptake inhibitor (SNRI), 2) SSRI/SNRI 3) tricyclic antidepressant (TCA), 4) lithium addition to TCA, 5) MAO-inhibitor, 6) electro-convulsive treatment (ECT). Due to both the side-effects and non-response or incomplete response to SSRI/SNRI/TCAs, the treatment of depressive PD patients is often difficult. Lithium addition and, to a lesser degree, MAO-inhbitors are not optimal due to the unfavourable influence on the motor symptoms (mainly tremor) and the autonomic functions. Moreover, PD patients, who already use multiple types of dopaminergic medication, often hesitate or refuse to

take antidepressant medication. Hypnotic drugs indicated for sleep disturbances are not suitable for chronic use due to the development of tolerance and the risk of decreased daytime functioning (e.g. excessive daytime sleepiness) and falling, where PD patients already have daytime sleepiness and postural imbalance. Based on these limitations in available treatment strategies, there is a high need for an ‘easily available’, ‘patient-friendly’ and effective therapy for mood and sleep disorders in PD. There are indications that improved sleep, for instance after bright light therapy, contributes to both motor and cognitive functioning in PD, to the extent that even dopaminergic medication may be lowered (Willis and Turner, 2007). PD patients often report being less disabled for 40 to 60 minutes after waking as compared to later in the day, a phenomenon called 'sleep benefit' (Parkes, 1983). Also, PD patients report better motor function after a night of good sleep (Tandberg et al, 1999). Such findings indicate that improving sleep of PD patients optimizes the compensatory potential of PD patients, within the limits of their disease. An obvious immediate benefit of improved sleep and mood would be the reduction in dopaminergic, antidepressant and sleep medication. Circadian rhythms and PD PD is characterized by extensive sleep problems, affecting both night and daytime functioning: night-time sleep is less efficient and more fragmented, whereas daytime sleepiness is markedly enhanced. Such a pattern of too much wake during the night and too much sleep during the day is indicative of impaired circadian rhythmicity. Indeed, several reports show that PD patients are phase-advanced (Bordet et al., 2003; Fertl et al., 1991, 1993): the peak plasma concentrations of melatonin secretion occur earlier in PD patients compared to age-matched controls. This, in combination with the insecurity patients feel about their postural balance or the need for help to move, leads to a downward spiral where patients expose themselves less frequently to bright environmental light, further aggravating the circadian problems. In addition, photoreception declines with aging, which may result in partial light deprivation of the photo-sensitive regions of the brain regulating rhythmicity, i.e. the suprachiasmatic nucleus (SCN) and pineal gland. Together, these factors contribute to the attenuated circadian rhythm in older age and specifically in PD (Willis, 2008). Circadian rhythmicity can be assessed using actigraphy, i.e. a wrist-worn measurement device providing information about movement density and duration. When the actigraphic recording is coupled to bedtimes, obtained from the patient either in the form of a diary or by measurements using a pressure-pad and ambient light recordings, sleep parameters such as fragmentation and efficiency can be measured as well (van Someren, 2006). Actigraphy has proven to be a valid method for measuring sleep and rhythm disturbances in PD (Stravitsky et al, 2010) and it has been shown by our group to be a sensitive marker for sleep improvement in PD patients (van Dijk et al, 2009). Stimulation of the light-sensitive regions of the brain, by means of bright environmental light (bright light therapy, BLT) may thus help to normalize mood, sleep, circadian rhythms and hypothalamic-pituitary axis (HPA) activity. Phase-advanced rhythms warrant the use of relatively late bright light administration, to interfere with the early onset of melatonin secretion. BLT could be hypothesized to be particularly suitable in the management of depression in PD, especially since antidepressants tend to have substantial side effects in PD patients. The combined use of bright light therapy with actigraphy will help to judge the effects of the treatment on circadian rhythms. Bright light and disturbance of mood and sleep The beneficial effect of BLT in seasonal affective disorder (SAD) is well accepted, with an early onset of action, and a mild side effect profile. Results of BLT in non- seasonal depression were inconclusive until recently. In Amsterdam a large RCT was performed in elderly residents of group care facilities, with a variety of

neuropsychiatric disorders (Riemersma-van der Lek et al, 2008). The study showed that BLT strongly attenuated depressive symptoms in these patients. Another double blind placebo controlled RCT in Amsterdam focused on the effect of BLT on mood, sleep and circadean rhythm in non-seasonal depression in elderly (Lieverse et al. 2010). The results showed that BLT improves mood, sleep and circadian activity and hormonal rhythms (melatonin and cortisol) in these depressed elderly. The effects of bright light therapy on sleep disturbances has been well-documented, both in primary and secondary sleep disorders: in primary insomnia, bright light treatment ameliorates sleep quality, cognitive functioning and brain activation indices (Altena et al, 2008a/2008b), and in elderly with dementia BLT for 2 years improved sleep characteristics and slowed mental deterioration (Riemersma-van der Lek et al, 2008). Effects of bright light on motor, mood and sleep in PD: earlier studies In PD, very few investigations have addressed the use of BLT for sleep and mood disturbances, and the effects have been inconclusive (Willis and Turner, 2007; Paus et al, 2007). One pilot study used 15 days of BLT in a placebo controlled design; the authors investigated sleep and depression and found an improvement of depression scores in the treated group but not the placebo group; as sleep measures the only parameter investigated was a one-item daytime sleepiness scale, which did not show a differential effect between groups. An effect on other sleep parameters may thus have gone unnoticed and the authors themselves agree that their study is exploratory and that the data need to be followed up with studies using longer treatments (Paus et al, 2007). Another study was an open-label non-placebo-controlled case series study in 12 patients with PD, who received between 2 and 5 weeks of BLT. The results show improvements in psychiatric wellbeing, motor function and sleep. Interestingly, the improvement in motor functions even allowed to reduce the daily dose of dopaminergic medication (Willis and Turner, 2007). A Russian study (english abstract available only) reports improvements in 40 PD patients receiving 10 exposures of BLT, both in motor and in mood scores (Artemenko and Levin, 1996) These first preliminary reports of BLT in PD provide positive findings that warrant further study. In addition, the studies indicate that the treatment was well tolerated by the patients.

PROPOSAL A randomized, double-blind, placebo-controlled clinical trial design in combination with naturalistic follow-up will be used to compare the effects of BLT versus placebo light on mood and sleep; upon obtaining additional funding, we will also measure circadian rhythms, and quality of life. We hypothesize that BLT will improve mood and sleep, in accord with earlier findings. We expect that actigraphic measures of circadian rhythmicity will show a normalized, greater amplitude; and that salivary cortisol and melatonin rhythms will show a return of initially phase-advanced rhythms to normal circadian variation. Participants We will include 80 patients with Parkinson’s disease who fullfill the DSM-IV criteria of a major depressive disorder (MDD), possibly in combination with a sleep disorder (insomnia). Exclusion criteria will be: psychosis, mania, suicidality, use of lithium, carbamazepine or valproate, retinopathy, and severe side effects in response to light therapy in the past. Based on a previous study of our institute using BLT in elderly with non-seasonal depression (Lieverse et al, 2010), the required sample size to detect a difference in HDRS scores between two groups, given the reported effect size of 0.93 (Cohen’s d), is 32 patients per group for two sided-testing and 26 per

group for one-sided testing (if we hypothesize that BLT will prove effective in treating depression). Our proposed sample size of 40 per group is thus amply powered to detect a difference and allows to add covariates controlling for possibly confounding factors such as apathy and cognitive dysfunction. Intervention Patients will be randomly assigned to one of the two treatment conditions (Bright Light Therapy and Placebo Light). Both study investigators and patients are blind with respect to treatment conditions. Both treatment conditions consist of twice-daily exposure to light for 30 minutes in the morning and 30 minutes in the evening, during a period of 3 months. The study design consists of 2 phases: a randomized controlled trial (RCT) phase and a open-label naturalistic follow-up phase. This enables the study of long-term effects of BLT until 3 months after completion of light exposure with parallel treatment of the initially non-treated patients from the placebo group. All participants will receive a fixed light box (Philips Lighting, Eindhoven, the Netherlands) at home, suspended from the ceiling. The active light boxes contain 4 TL-5 24Watt tubes covered by a Plexiglas diffuser, having a light intensity of ~10,000 lux measured at the eye level in the gaze direction. Identically shaped light boxes in the placebo condition accommodate concealed band-stop filters (type 209 0.3ND, Lee Filters, Hampshire, UK) and dimmed, less powerful tubes (4 TL-5 14Watt), installed in such a way that light intensity does not exceed ~300 lux at eye level. Intensities will be quantified using a lux meter (Mavolux Digital, Gossen, Nürnberg, Germany). Participants will expose themselves twice-daily to light in sessions lasting 30 minutes every morning and evening. They are free to choose their exposure sessions during a 90 minute time-window, when light is automatically switched on and could not be switched off. Lights can be switched on and off or dimmed manually at all other times to use as normal lighting. The timer adjusts automatically to daylight-saving time. All participants will be asked afterwards as to which condition they think they were assigned to, in order to control for blinding success. A previous study using the same intervention conditions showed that participants in the active condition did not experience the atmosphere of the light to be different (Most et al, in preparation). After disclosure of the randomization key, patients from the placebo group will receive active BLT for 3 months as well and will be followed-up for 3 months after completion of the therapy. Outcome measures All measures of mood, sleep, circadian rhythm (actigraphy, salivary melatonin and cortisol day curves) and quality of life will be taken pretreatment, half-way therapy, at completion of therapy and 3 months after completion of therapy. > Primary outcome measures: 1. Mood: 17-item Hamilton Depression Rating Scale (HDRS): * immediate improvement: change HDRS between baseline (T0) and end of treatment (T2) * lasting effect: change HDRS between baseline (T0) and at follow-up 3 months after treatment discontinuation (T4) * dichotomized treatment response (i.e., ≥50% reduction on the HDRS-17) at T2 (end of treatment), allowing for absolute risk reductions and calculation of Numbers Needed To Treat (NNT). > Secondary outcome measures: 1. Sleep: Scales for Outcomes in Parkinson’s disease – Sleep (SCOPA-sleep) 2. Motor: Unified Parkinson’s Disease Rating Scale (UPDRS)

3. Circadian rhythm: - Salivary cortisol curves - Salivary melatonin curves - Actigraphy Cortisol and melatonin day curves will be measured using saliva samples (Salivette, Sartstedt, Germany) at four time points in the morning (30 minute intervals starting 30 minutes after getting up) and four time points in the evening (samples at hourly intervals starting) four hours before bedtime. Actigraphy will be done during a period of 1 week using a watch-sized wrist-worn recorder (Actiwatch-L; Cambridge Neurotechnology, Cambridge, U.K.).

4. Quality of Life: 37-item Parkinson’s Disease Quality of Life questionnaire (PDQL) > confounding factors Primary and secondary outcome measures will be controlled for confounding factors such as the presence of apathy and cognitive dysfunction.

Schematic figure of study design:

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EMBEDDING The departments of Neurology and Anatomy & Neurosciences (VUmc) have a strong tradition in fundamental research in non-motor symptoms and neural correlates of neurodegeneration, using a variety of neuroimaging techniques. Dr. van der Werf (Dept of Anatomy & Neurosciences) has over the last few years succesfully treated sleep disorders using cognitive behavioural therapy, bright light treatment and repetitive transcranial magnetic stimulation, in both Parkinson’s disease and sleep disorders, through his co-appointment at the Netherlands Institute for Neuroscience. Since two years, the outpatient department for Neuropsychiatry in Parkinson’s disease has been developed as an integral part of the outpatient department for Movement Disorders of the Department of Neurology (head: dr. H.W. Berendse) at the VU University Medical Center (VUmc). Dr. van den Heuvel has initiated this outpatient clinic in response to the increasing need to diagnose and treat neuropsychiatric disorders in Parkinson’s disease, such as depression, anxiety disorders, sleep disorders, psychosis and impulse-control disorders. We are actively pursuing alternative treatment strategies as part of the research into movement disorders. Recently our department of Psychiatry finished a high impact study on BLT in elderly with non-seasonal depression, showing a positive effect on mood, sleep and circadian rhythm. The proposed RCT in Parkinson’s disease will be an important extension to this work. The aim of this project is an immediately available novel therapy, widening our range of treatment options for non-motor symptoms in PD. Potential support from other sources We will seek to obtain further funding to extend the project proposed here into a fullblown line of research and to attract further scientific personnel to be able to extend the number of participants and perform additional measurements. It should be stressed that the current application is the first of these and is instrumental in setting up the study and establishing this line of research in the Movement Disorders group of the VUmc. The current grant will allow to perform the BLT intervention, actigraphy, sleep measurements, psychiatric assessments and questionnaires with the help of a research assistant. Should we be able to obtain the clinical fellowship from the ‘Hersenstichting’ or the Dutch Organization for Scientific Research (NWO), we will extend the personnel with a PhD student for the cortisol and melatonin measurements, and allowing to speed up data analysis and publishing in international peer-reviewed journals. We also applied for additional funding with the Philips Research Grant. Applicants: Ysbrand D. van der Werf Dr. van der Werf is a biologist and neuropsychologist at the department of Anatomy & Neurosciences of the VU University Medical Center (VUmc) and Dept Sleep&Cognition at the Netherlands Institute for Neuroscience. He finished his PhD (‘The Thalamus and Memory. Contributions to prefrontal and medial temporal memory processes’) in 2000 and then did a postdoc in Montreal, Canada, at the renowned Montreal Neurological Institute/Hospital to learn brain stimulation (TMS) and imaging techniques (PET, EEG, fMRI). He returned in 2003 and set up two fruitful lines of preclinical research, one into sleep disturbances and memory complaints and one into cognitive disturbances of patients with Parkinson’s Disease. He received numerous important grants (VIDI 2008, STW 2009, Brain & Cognition 2010) and is a member of ‘De Jonge Akademie’, part of the Royal Netherlands Society of Arts and Sciences. His national and international collaborations include Prof. C.I. de Zeeuw (NIN/EUR), Dr. J.J.G. Geurts (VUmc), Prof. T. Paus (Notthingham), Dr. A. Strafella and Dr. M.P. McAndrews (Univ Toronto) and Dr. L.

Miller (Univ Sydney). Selected recent key publications: • Van Der Werf YD, Altena E, Van Dijk KD, Strijers RLM, De Rijke W, Stam CJ, Van Someren

EJW. Is disturbed intracortical excitability a stable trait of chronic insomnia? A study using transcranial magnetic stimulation before and after multimodal sleep therapy. In press Biological Psychiatry 2010

• van Dijk KD, Most EI, Van Someren EJ, Berendse HW, van der Werf YD (2009) Beneficial effect of transcranial magnetic stimulation on sleep in Parkinson's disease. Movement Disorders 24:878-884.

• Van Der Werf YD, Altena E, Schoonheim MM, Sanz-Arigita EJ, Vis JC, De Rijke W, Van Someren EJ (2009) Sleep benefits subsequent hippocampal functioning. Nature neuroscience 12:122-123.

• Van Der Werf YD, Van Der Helm E, Schoonheim MM, Ridderikhoff A, Van Someren EJW. Learning by observation requires an early sleep window. Proc Natl Acad Sci U S A 106:18926-18930, 2009

• Van Der Werf YD, Sadikot AF, Strafella AP, Paus T (2006) The neural response to transcranial magnetic stimulation of the human motor cortex. II. Thalamocortical contributions. Experimental brain research 175:246-255.

Odile A. van den Heuvel Dr. O.A. van den Heuvel, is neuropsychiatrist and senior researcher at the department of Psychiatry and the department of Anatomy & Neurosciences of the VU University Medical Center (VUmc). She finished her PhD (topic: ‘Neuroimaging in OCD, investigation of the frontal-striatal and limbic circuits’) with honor. After her PhD (2005) and medical specialization in Psychiatry (2007) she received the prestigious VENI grant from the Dutch Organization for Scientific Research (NWO) and the NARSAD Young Investigator Award 2009. Her studies on OCD have been extended to Parkinson’s disease (co-PI: dr. van der Werf, neuroscientist, and in collaboration with dr. H.W. Berendse, neurologist, and prof. dr. D.J. Veltman, psychiatrist) to enable the study of frontal-striatal dysfunctions, cognitive flexibility and brain connectivity in a broader spectrum of disorders. Dr. van den Heuvel closely collaborates with dr. David Mataix-Cols, senior lecturer at the Institute of Psychiatry, King’s College London (London, UK). In 2008, dr. van den Heuvel initiated a specialized outpatient department for neuropsychiatric disorders in Parkinson’s disease, in close collaboration with the head of the outpatient department for movement disorders (VUmc), dr. H.W. Berendse, neurologist.

Selected recent key publications: • van den Heuvel OA, van der Werf YD, Verhoef KMW, de Wit S, Berendse HW, Wolters

ECh, Veltman DJ, Groenewegen HJ. Frontal-striatal abnormalities underlying behaviours in the compulsive-impulsive spectrum. Journal of Neurological Sciences, 2010; 289: 55-59.

• Radua J, van den Heuvel OA, Surguladze S, Mataix-Cols D. Is OCD an anxiety disorder? A meta-analytical comparison of voxel-based morphometry studies in OCD vs. other anxiety disorders. Archives of General Psychiatry, 2010; 67: 701-711

• van den Heuvel OA, Remijnse PL, Mataix-Cols D, Vrenken H, Groenewegen HJ, Uylings HBM, van Balkom AJLM, Veltman DJ. The major symptom dimensions of OCD are mediated by partially distinct neural systems: voxel-based morphometry of 55 unmedicated patients. Brain, 2009; 132: 853-68

• Wolters Ech, van der Werf YD, van den Heuvel OA. Parkinson’s disease-related disorders in the impulsive-compulsive spectrum. Journal of Neurology, 2008; 255 Suppl 5: 48-56

Henk W. Berendse Dr. Henk W. Berendse is a consultant neurologist at the department of Neurology of the VU University Medical Center (VUmc) in Amsterdam, the Netherlands. He received his MD in 1988 and his PhD in basal ganglia neuroanatomy in 1991 (both with honours). From 1991 to 1992 he worked as a Visiting Scientist at the department of Neurology of the University of Rochester, Rochester NY, USA. Subsequently, from 1992 until 1998 he was trained in Neurology at the VU University Medical Center in Amsterdam, the Netherlands. Since 2008 he runs the Movement Disorders service at the VUmc. His research activities are conducted through

Neuroscience Campus Amsterdam. His current research interests include non-motor disturbances in Parkinson’s disease and the development of early diagnostic procedures and biomarkers of the disease process. He was Secretary of the Dutch Federation of Neuroscience Organizations (2004-2006) and Secretary of the International Basal Ganglia Society (2004-2007). Presently, he serves as board member of the International Basal Ganglia Society, board member of the Nederlandse Werkgroep Bewegingsstoornissen (Dutch Working Group on Movement Disorders) and as a member of the Research Advisory Panel of the Dutch Parkinson’s Disease Society.

Selected key publications: • Berendse HW, Booij J, Francot CM, Bergmans PL, Hijman R, Stoof JC, Wolters EC (2001)

Subclinical dopaminergic dysfunction in asymptomatic Parkinson's disease patients' relatives with a decreased sense of smell. Annals of neurology 50:34-41.

• Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters E, Berendse HW (2004) Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Annals of neurology 56:173-181.

• Stoffers D, Bosboom JLW, Deijen JB, Wolters EC, Berendse HW, Stam CJ. (2007) Slowing of oscillatory brain activity is a stable characteristic of Parkinson’s disease without dementia. Brain 130:1847-1860.

• Boesveldt S, Stam CJ, Knol DL, Verbunt JP, Berendse HW (2009) Advanced time-series analysis of MEG data as a method to explore olfactory function in healthy controls and Parkinson's disease patients. Human Brain Mapping 30:3020-3030.

• Munneke M, Nijkrake MJ, Keus SHJ, Kwakkel G, Berendse HW, Roos RAC, Borm GF, Adang EM, Overeem S, Bloem BR (2010) Efficacy of community-based physiotherapy networks for patients with Parkinson’s disease: a cluster-randomised trial. Lancet Neurol 9:46-54.

• Ponsen MM, Stoffers D, Wolters ECh, Booij J, Berendse HW (2010) Olfactory testing combined with dopamine transporter imaging as a method to detect prodromal Parkinson’s disease. J Neurol Neurosurg Psychiatry 81:396-399.

Elisabeth M.J. Foncke Dr. E.M.J. Foncke is a clinical neurologist with special expertise in the diagnosis and treatment of hypo- and hyperkinetic movement disorders. She worked as research neurologist at the movement disorder department of the Academic Medical Center Amsterdam under the stimulating guidance of dr. J.D. Speelman. She defended her dissertation “Clinical and functional studies in Myoclonus-Dystonia” in September 2008. She is currently working at the dept. of Neurology of the VU University Medical Center as a specialist in movement disorders with a particular focus on Parkinson’s Disease. She initiated a Voxel-Based-Morphometry MRI study in hallucinating PD patients. In this study, cholinergic brain structures including the pedunculopontine nucleus and the nucleus basalis of Meynert and their projection areas including the reticular thalamus and different neocortical areas are studied in demented and non-demented PD patients and Dementia with Lewy Bodies (DLB) patients with and without VH. In addition, these brain regions are studied in postmortem brain tissue by means of alpha-synuclein immunostaining and measuring choline acetyltransferase (ChAT)-activity.

Selected key publications: • Beukers RJ, Foncke EM, van der Meer JN, Nederveen AJ, de Ruiter MB, Bour LJ, Veltman

DJ, Tijssen MA. Disorganized sensorimotor integration in mutation-positive myoclonus-dystonia: a functional magnetic resonance imaging study. Arch Neurol. 2010 Apr;67(4):469-74.

• Foncke EM, Beukers RJ, Tijssen CC, Koelman JH, Tijssen MA. Myoclonus-dystonia and spinocerebellar ataxia type 14 presenting with similar phenotypes: trunk tremor, myoclonus, and dystonia. Parkinsonism Relat Disord. 2010 May;16(4):288-9

• Foncke EM, Cath D, Zwinderman K, Smit J, Schmand B, Tijssen M. Is psychopathology part of the phenotypic spectrum of myoclonus-dystonia?: a study of a large Dutch M-D family. Cogn Behav Neurol. 2009 Jun;22(2):127-33.

• Foncke EM, Bour LJ, van der Meer JN, Koelman JH, Tijssen MA. Abnormal low frequency drive in myoclonus-dystonia patients correlates with presence of dystonia..Mov Disord. 2007 Jul 15;22(9):1299-307.

• Foncke EM, Gerrits MC, van Ruissen F, Baas F, Hedrich K, Tijssen CC, Klein C, Tijssen MA. Distal myoclonus and late onset in a large Dutch family with myoclonus-dystonia. Neurology. 2006 Nov 14;67(9):1677-80.