1. 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.

2. KOSTEN EN AANGEVRAAGD BEDRAG
2011 2012 2013 2014
Aanvraag:
Onderzoeks- € 10.000 € 20.000 € 20.000 € 10.000 € 60.000
assistent 0.5 fte, 3
jaar
Materiaal: testen, € 20.000 € 20.000
vervoerskosten,
hardware voor lamp
plaatsen,
vragenlijsten, etc.
Extra financiering aangevraagd bij ZonMW clinical fellow/Hersenstichting (dr O.A. van
den Heuvel):
Assistent in € 37.000 € 38.000 € 39.000 € 40.000 € 164.000
opleiding,
1.0 fte, 4 jaar
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.

3. 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

4. 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

5. 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

6. 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)

7. 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.

8. Schematic figure of study design:
References:
Altena E, Van Der Werf YD, Strijers RL, Van Someren EJ (2008a) Sleep loss affects vigilance: effects of
chronic insomnia and sleep therapy. Journal of sleep research 17:335-343.
Altena E, Van Der Werf YD, Sanz-Arigita EJ, Voorn TA, Rombouts SA, Kuijer JP, Van Someren EJ
(2008b) Prefrontal hypoactivation and recovery in insomnia. Sleep 31:1271-1276.
Artemenko AR, Levin Ia I (1996) [The phototherapy of parkinsonism patients]. Zhurnal nevrologii i
psikhiatrii imeni SS 96:63-66.
Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa C, Destee A (2003) Study of circadian
melatonin secretion pattern at different stages of Parkinson's disease. Clinical
Neuropharmacology 26:65-72.
Cummings JL (1992) Depression and Parkinson's disease: a review. The American journal of psychiatry
149:443-454.
Fertl E, Auff E, Doppelbauer A, Waldhauser F (1991) Circadian secretion pattern of melatonin in
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3:41-47.
Fertl E, Auff E, Doppelbauer A, Waldhauser F (1993) Circadian secretion pattern of melatonin in de
novo parkinsonian patients: evidence for phase-shifting properties of l-dopa. J Neural Transm
Park Dis Dement Sect 5:227-234.
Larsen JP, Tandberg E (2001) Sleep disorders in patients with Parkinson's disease: epidemiology and
management. CNS drugs 15:267-275.
Lieverse R, Van Someren EJW, Nielen MMA, Uitdehaag BMJ, Smit JH, Hoogendijk WJG (2010). Bright
light treatment in elderly patients with non-seasonal major depressive disorder: A Randomized
Placebo Controlled Trial. Archives of General Psychiatry, in press.
Menza M, Dobkin RD, Marin H, Bienfait K (2010) Sleep disturbances in Parkinson's disease. Mov
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Park A, Stacy M (2009) Non-motor symptoms in Parkinson's disease. Journal of neurology 256 Suppl
3:293-298.
Parkes JD (1983) Variability in Parkinson's disease; clinical aspects, causes and treatment. Acta Neurol
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Paus S, Schmitz-Hubsch T, Wullner U, Vogel A, Klockgether T, Abele M (2007) Bright light therapy in
Parkinson's disease: a pilot study. Mov Disord 22:1495-1498.

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488.
Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, Van Someren EJ (2008)
Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of
group care facilities: a randomized controlled trial. Jama 299:2642-2655.
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substance abuse. Sleep 31:1351-1356.
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(2009) Sleep benefits subsequent hippocampal functioning. Nature neuroscience 12:122-123.
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10. 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.

11. 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

12. 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.