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SLAAP- EN STEMMINGSSTOORNISSEN BIJ DE ZIEKTE VAN PARKINSON; EENBEHANDELSTUDIE MET LICHTTHERAPIE.(Sleep and mood disorders in Parkinson’s disease: a treatment study using brightlight 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. Foncke4,5Afdelingen 1Anatomie & Neurowetenschappen, 2Slaap en Cognitie, NederlandsInstituut voor Neurowetenschappen, 3Psychiatrie, 4Neurologie, VU University MedicalCenter (VUmc), 5Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. OVERZICHTSlaapstoornissen en depressie vormen een belangrijke bedreiging voor de kwaliteitvan leven van mensen met de ziekte van Parkinson. Vaak treden deze stoornissenvroeg op in het beloop van de ziekte, nog voorafgaand aan de kenmerkendebewegingsstoornissen. Naast een directe invloed op het welzijn, verergeren dezesymptomen de motorische verschijnselen. Helaas zijn er op dit moment beperkte,veelal medicamenteuze mogelijkheden om slaap en stemming bij Parkinsonpatiënten te verbeteren, waarbij regelmatig bijwerkingen optreden. Het verbeterenvan slaap- en stemmingsstoornissen langs niet-farmacologische weg zou niet alleendirect bijdragen aan het verbeteren van de kwaliteit van leven, maar bovendien viaeen gunstig effect op de motorische verschijnselen een additioneel effect hebben opde kwaliteit van leven.Zeer recent hebben wij evidentie gekregen voor het gunstig effect van lichttherapieop stemming en slaap bij ouderen met en zonder dementie, vanuit onderzoek vanonze afdelingen Psychiatrie (Vumc-GGZ inGeest) en Slaap en Cognitie (NIN). Lichtis een goedkope en gemakkelijk te implementeren behandeling zonder bijwerkingendie potentieel een grote bijdrage kan leveren aan de kwaliteit van leven.De hier voorgestelde studie beoogt de effecten van lichttherapie bij Parkinsonpatiënten te onderzoeken in een gerandomiseerde placebo-gecontroleerdebehandelstudie. Tachtig patiënten met de ziekte van Parkinson worden geïncludeerden verdeeld over de placebo- en de echte behandeling. Na 3 maanden behandelingvindt een evaluatie plaats, waarna de placebo-groep alsnog de echte behandelingkrijgt. Na nog eens drie maanden vindt dan een eindevaluatie plaats, waarmee delange-termijn effecten van de behandeling worden gemeten. Als primaireuitkomstmaten worden stemmingsmaten genomen. Daarnaast willen wij slaap-parameters meten en (afhankelijk van additionele financiering) de motorischesymptomen, een aantal fysiologische parameters (cortisol en melatonine uitspeeksel) en biologische ritmes vaststellen (actigrafie). De behandeling en allemetingen zijn non-invasief. DOELHet directe doel van dit onderzoek is een therapie te ontwikkelen die ingezet kanworden in de klinische praktijk. Wij verwachten dat lichttherapie een gunstig effect zalhebben op stemming en de verstoorde slaap in de ziekte van Parkinson. Ditonderzoek past binnen de lijn van onderzoek van de afdelingen Neurologie,Anatomie en Neurowetenschappen en Psychiatrie van het VU Medisch Centrum, dieeen traditie hebben in onderzoek en behandeling van niet-motorische symptomen bijde ziekte van Parkinson. Het hier voorgestelde project is ingebed in een grotere lijnvan onderzoek, waarvoor van verschillende bronnen financiering wordt gezocht. Hethier aangevraagde deel betreft de centrale financiering voor de behandeling enmeting van slaap en stemming. De secundaire maten worden afhankelijk vanadditionele financiering meegenomen.
KOSTEN EN AANGEVRAAGD BEDRAG 2011 2012 2013 2014Aanvraag:Onderzoeks- € 10.000 € 20.000 € 20.000 € 10.000 € 60.000assistent 0.5 fte, 3jaarMateriaal: testen, € 20.000 € 20.000vervoerskosten,hardware voor lampplaatsen,vragenlijsten, etc.Extra financiering aangevraagd bij ZonMW clinical fellow/Hersenstichting (dr O.A. vanden Heuvel):Assistent in € 37.000 € 38.000 € 39.000 € 40.000 € 164.000opleiding,1.0 fte, 4 jaar Totaal € 244.400 Totaal elders € 164.400 Aanvraag € 80.000Deze aanvraag zal ons, bij toekenning, in staat stellen om de 1) lichttherapie uit tevoeren, 2) de slaapscores en stemmingsmetingen te doen en 3) de gedragsmatigeritmes te meten, met de hulp van een onderzoeksassistent. Mochten wij extrafinanciering verkrijgen bij de ‘Hersenstichting’ of NWO ZonMW, breiden wij hetpersoneel uit met een promovendus, bepalingen van cortisol en melatonine in hetspeeksel. Dit levert, naast een promotie en kennis over de fysiologische ritmes, meerarmslag op om de gegevens vlot uit te werken en te publiceren.
APPENDIX: ACHTERGROND EN UITGEWERKT PROTOCOL BACKGROUNDDisturbances of mood and sleep in Parkinson’s diseaseParkinson’s disease (PD) is the second most frequent neurodegenerative disorder.PD has long been considered as a pure motor disorder secondary to basal gangliadegeneration with typical motor symptoms, such as bradykinesia, rigidity, tremor, andpostural imbalance. However, it has become well established that Parkinson’sdisease affects patients’ lives in a much broader sense than merely the motorimpairment (Rodriquez-Oroz et al. 2009; Park & Stacy 2009). The quality of life of PDpatients as well as their caregivers largely depends on the presence of so-callednon-motor features, which are highly prevalent in PD. Frequent non-motor disordersin PD are autonomic dysfunctions, olfactory impairments, sleep disorders,depression, anxiety, psychosis, cognitive dysfunctions/dementia, and impulse-controldisorders. Some non-motor features appear in the course of the disease or inresponse to dopaminergic treatment, but other symptoms (including depression andsleep 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 PDinclude a reduced total sleep time, reduced sleep efficiency, increased sleepfragmentation and excessive daytime sleepiness. The relationship betweendepression and sleep is complex and not well understood. Depressed mood is one ofthe 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 thedevelopment of depression (Pigeon et al, 2008; Roane and Taylor, 2008; Thase etal, 1997), for which Parkinson patients are already at high risk. Despite the highprevalence of mood and sleep disorders in PD and despite the fact that the primarydeterminants of poor quality of life in patients with PD are sleep disturbances,depression and lack of independence, these symptoms are commonlyunderdiagnosed and undertreated. Chronic sleep disorders compromise mental andphysical health, autonomy and well-being of elderly subjects (Van Someren, 2000).Controlled studies in healthy elderly people, moreover, show that even a mild sleepdisturbance is detrimental to cognitive performance and brain function (Van der Werfet al, 2009). Finally, the benefit derived from a good night’s sleep on motor function iswell-known among PD patients (Tandberg et al, 1999). Therefore, it is important torecognize disturbances of mood and sleep in patients with PD and to start adequatetreatment as soon as such disorders have been diagnosed.‘Unmet needs’ for treatment of depression and sleep disorders in PDAdequate treatment of these chronic sleep and mood disorders in PD constitutes oneof the greatest ‘unmet needs’ in the care of PD patients. The treatment alternativesfor depression in PD patients have been poorly studied and no evidence-basedparkinson-specific depression treatment guideline exists. The general guideline forthe treatment of depression consists of the following 6 steps: 1) selectiveserotonergic 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-effectsand non-response or incomplete response to SSRI/SNRI/TCAs, the treatment ofdepressive PD patients is often difficult. Lithium addition and, to a lesser degree,MAO-inhbitors are not optimal due to the unfavourable influence on the motorsymptoms (mainly tremor) and the autonomic functions. Moreover, PD patients, whoalready use multiple types of dopaminergic medication, often hesitate or refuse to
take antidepressant medication. Hypnotic drugs indicated for sleep disturbances arenot suitable for chronic use due to the development of tolerance and the risk ofdecreased daytime functioning (e.g. excessive daytime sleepiness) and falling,where PD patients already have daytime sleepiness and postural imbalance. Basedon these limitations in available treatment strategies, there is a high need for an‘easily available’, ‘patient-friendly’ and effective therapy for mood and sleep disordersin PD. There are indications that improved sleep, for instance after bright lighttherapy, contributes to both motor and cognitive functioning in PD, to the extent thateven dopaminergic medication may be lowered (Willis and Turner, 2007). PDpatients often report being less disabled for 40 to 60 minutes after waking ascompared 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 (Tandberget al, 1999). Such findings indicate that improving sleep of PD patients optimizes thecompensatory potential of PD patients, within the limits of their disease. An obviousimmediate benefit of improved sleep and mood would be the reduction indopaminergic, antidepressant and sleep medication.Circadian rhythms and PDPD is characterized by extensive sleep problems, affecting both night and daytimefunctioning: night-time sleep is less efficient and more fragmented, whereas daytimesleepiness is markedly enhanced. Such a pattern of too much wake during the nightand 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 occurearlier in PD patients compared to age-matched controls. This, in combination with theinsecurity patients feel about their postural balance or the need for help to move,leads to a downward spiral where patients expose themselves less frequently tobright environmental light, further aggravating the circadian problems. In addition,photoreception declines with aging, which may result in partial light deprivation of thephoto-sensitive regions of the brain regulating rhythmicity, i.e. the suprachiasmaticnucleus (SCN) and pineal gland. Together, these factors contribute to the attenuatedcircadian rhythm in older age and specifically in PD (Willis, 2008).Circadian rhythmicity can be assessed using actigraphy, i.e. a wrist-worn measurementdevice providing information about movement density and duration. When the actigraphicrecording is coupled to bedtimes, obtained from the patient either in the form of a diary orby measurements using a pressure-pad and ambient light recordings, sleep parameterssuch 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 disturbancesin PD (Stravitsky et al, 2010) and it has been shown by our group to be a sensitivemarker for sleep improvement in PD patients (van Dijk et al, 2009).Stimulation of the light-sensitive regions of the brain, by means of brightenvironmental 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 interferewith the early onset of melatonin secretion.BLT could be hypothesized to be particularly suitable in the management ofdepression in PD, especially since antidepressants tend to have substantial sideeffects in PD patients. The combined use of bright light therapy with actigraphy willhelp to judge the effects of the treatment on circadian rhythms.Bright light and disturbance of mood and sleepThe 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 RCTwas performed in elderly residents of group care facilities, with a variety of
neuropsychiatric disorders (Riemersma-van der Lek et al, 2008). The study showedthat BLT strongly attenuated depressive symptoms in these patients. Another doubleblind 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 andhormonal rhythms (melatonin and cortisol) in these depressed elderly. The effects ofbright light therapy on sleep disturbances has been well-documented, both in primaryand secondary sleep disorders: in primary insomnia, bright light treatmentameliorates sleep quality, cognitive functioning and brain activation indices (Altena etal, 2008a/2008b), and in elderly with dementia BLT for 2 years improved sleepcharacteristics and slowed mental deterioration (Riemersma-van der Lek et al, 2008).Effects of bright light on motor, mood and sleep in PD: earlier studiesIn PD, very few investigations have addressed the use of BLT for sleep and mooddisturbances, and the effects have been inconclusive (Willis and Turner, 2007; Pauset al, 2007). One pilot study used 15 days of BLT in a placebo controlled design; theauthors investigated sleep and depression and found an improvement of depressionscores in the treated group but not the placebo group; as sleep measures the onlyparameter investigated was a one-item daytime sleepiness scale, which did not showa differential effect between groups. An effect on other sleep parameters may thushave gone unnoticed and the authors themselves agree that their study isexploratory and that the data need to be followed up with studies using longertreatments (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 5weeks of BLT. The results show improvements in psychiatric wellbeing, motorfunction and sleep. Interestingly, the improvement in motor functions even allowed toreduce the daily dose of dopaminergic medication (Willis and Turner, 2007). ARussian study (english abstract available only) reports improvements in 40 PDpatients 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 warrantfurther study. In addition, the studies indicate that the treatment was well tolerated bythe patients. PROPOSALA randomized, double-blind, placebo-controlled clinical trial design in combinationwith naturalistic follow-up will be used to compare the effects of BLT versus placebolight on mood and sleep; upon obtaining additional funding, we will also measurecircadian rhythms, and quality of life. We hypothesize that BLT will improve moodand sleep, in accord with earlier findings. We expect that actigraphic measures ofcircadian rhythmicity will show a normalized, greater amplitude; and that salivarycortisol and melatonin rhythms will show a return of initially phase-advanced rhythmsto normal circadian variation.ParticipantsWe will include 80 patients with Parkinson’s disease who fullfill the DSM-IV criteria ofa 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 lighttherapy in the past. Based on a previous study of our institute using BLT in elderlywith non-seasonal depression (Lieverse et al, 2010), the required sample size todetect a difference in HDRS scores between two groups, given the reported effectsize 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 treatingdepression). Our proposed sample size of 40 per group is thus amply powered todetect a difference and allows to add covariates controlling for possibly confoundingfactors such as apathy and cognitive dysfunction.InterventionPatients will be randomly assigned to one of the two treatment conditions (BrightLight Therapy and Placebo Light). Both study investigators and patients are blindwith respect to treatment conditions. Both treatment conditions consist of twice-dailyexposure to light for 30 minutes in the morning and 30 minutes in the evening, duringa period of 3 months. The study design consists of 2 phases: a randomizedcontrolled trial (RCT) phase and a open-label naturalistic follow-up phase. Thisenables the study of long-term effects of BLT until 3 months after completion of lightexposure with parallel treatment of the initially non-treated patients from the placebogroup.All participants will receive a fixed light box (Philips Lighting, Eindhoven, theNetherlands) at home, suspended from the ceiling. The active light boxes contain 4TL-5 24Watt tubes covered by a Plexiglas diffuser, having a light intensity of ~10,000lux measured at the eye level in the gaze direction. Identically shaped light boxes inthe 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 lasting30 minutes every morning and evening. They are free to choose their exposuresessions during a 90 minute time-window, when light is automatically switched onand could not be switched off. Lights can be switched on and off or dimmed manuallyat all other times to use as normal lighting. The timer adjusts automatically todaylight-saving time. All participants will be asked afterwards as to which conditionthey think they were assigned to, in order to control for blinding success. A previousstudy using the same intervention conditions showed that participants in the activecondition did not experience the atmosphere of the light to be different (Most et al, inpreparation).After disclosure of the randomization key, patients from the placebo group willreceive active BLT for 3 months as well and will be followed-up for 3 months aftercompletion of the therapy.Outcome measuresAll measures of mood, sleep, circadian rhythm (actigraphy, salivary melatonin andcortisol day curves) and quality of life will be taken pretreatment, half-way therapy, atcompletion 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 oftreatment (T2)* lasting effect: change HDRS between baseline (T0) and at follow-up 3 months aftertreatment discontinuation (T4)* dichotomized treatment response (i.e., ≥50% reduction on the HDRS-17) at T2 (endof treatment), allowing for absolute risk reductions and calculation of NumbersNeeded 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 factorsPrimary and secondary outcome measures will be controlled for confounding factorssuch as the presence of apathy and cognitive dysfunction.
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 Parkinsons disease. Clinical Neuropharmacology 26:65-72.Cummings JL (1992) Depression and Parkinsons 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 Parkinsons disease. Journal of Neural Transmission - Parkinsons Disease & Dementia Section 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 Parkinsons 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 Parkinsons disease. Mov Disord 25 Suppl 1:S117-122.Park A, Stacy M (2009) Non-motor symptoms in Parkinsons disease. Journal of neurology 256 Suppl 3:293-298.Parkes JD (1983) Variability in Parkinsons disease; clinical aspects, causes and treatment. Acta Neurol Scand Suppl Supplementum. 95:27-35.Paus S, Schmitz-Hubsch T, Wullner U, Vogel A, Klockgether T, Abele M (2007) Bright light therapy in Parkinsons disease: a pilot study. Mov Disord 22:1495-1498.
Pigeon WR, Hegel M, Unutzer J, Fan MY, Sateia MJ, Lyness JM, Phillips C, Perlis ML (2008) Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep 31:481- 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.Roane BM, Taylor DJ (2008) Adolescent insomnia as a risk factor for early adult depression and substance abuse. Sleep 31:1351-1356.Rodriguez-Oroz MC, Jahanshahi M, Krack P, Litvan I, Macias R, Bezard E, Obeso JA (2009) Initial clinical manifestations of Parkinsons disease: features and pathophysiological mechanisms. Lancet neurology 8:1128-1139.Stacy M (2002) Sleep disorders in Parkinsons disease: epidemiology and management. Drugs & aging 19:733-739.Tandberg E, Larsen JP, Karlsen K (1999) Excessive daytime sleepiness and sleep benefit in Parkinsons disease: a community-based study. Mov Disord 14:922-927.Thase ME, Buysse DJ, Frank E, Cherry CR, Cornes CL, Mallinger AG, Kupfer DJ (1997) Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles. The American journal of psychiatry 154:502-509.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 Dijk KD, Most EI, Van Someren EJ, Berendse HW, van der Werf YD (2009) Beneficial effect of transcranial magnetic stimulation on sleep in Parkinsons disease. Mov Disord 24:878-884.Van Someren EJW (2000) Circadian and sleep disturbances in the elderly. Experimental Gerontology 35:1229-1237.Van Someren EJW (2006) Actigraphic monitoring of sleep and circadian rhythms. In: Handbook of Clinical Neurology: Sleep Disorders (Aminoff M, Boller F, Swaab D, eds), p in press. Amsterdam: Elsevier.Willis GL (2008) Parkinsons disease as a neuroendocrine disorder of circadian function: dopamine- melatonin imbalance and the visual system in the genesis and progression of the degenerative process. Reviews in the neurosciences 19:245-316.Willis GL, Turner EJ (2007) Primary and secondary features of Parkinsons disease improve with strategic exposure to bright light: a case series study. Chronobiol Int 24:521-537.
EMBEDDINGThe departments of Neurology and Anatomy & Neurosciences (VUmc) have a strongtradition in fundamental research in non-motor symptoms and neural correlates ofneurodegeneration, using a variety of neuroimaging techniques. Dr. van der Werf(Dept of Anatomy & Neurosciences) has over the last few years succesfully treatedsleep disorders using cognitive behavioural therapy, bright light treatment andrepetitive transcranial magnetic stimulation, in both Parkinson’s disease and sleepdisorders, through his co-appointment at the Netherlands Institute for Neuroscience.Since two years, the outpatient department for Neuropsychiatry in Parkinson’sdisease has been developed as an integral part of the outpatient department forMovement Disorders of the Department of Neurology (head: dr. H.W. Berendse) atthe VU University Medical Center (VUmc). Dr. van den Heuvel has initiated thisoutpatient clinic in response to the increasing need to diagnose and treatneuropsychiatric disorders in Parkinson’s disease, such as depression, anxietydisorders, sleep disorders, psychosis and impulse-control disorders.We are actively pursuing alternative treatment strategies as part of the research intomovement disorders. Recently our department of Psychiatry finished a high impactstudy on BLT in elderly with non-seasonal depression, showing a positive effect onmood, sleep and circadian rhythm. The proposed RCT in Parkinson’s disease will bean important extension to this work.The aim of this project is an immediately available novel therapy, widening our rangeof treatment options for non-motor symptoms in PD.Potential support from other sourcesWe will seek to obtain further funding to extend the project proposed here into afullblown line of research and to attract further scientific personnel to be able toextend the number of participants and perform additional measurements. It should bestressed that the current application is the first of these and is instrumental in settingup the study and establishing this line of research in the Movement Disorders groupof the VUmc. The current grant will allow to perform the BLT intervention, actigraphy,sleep measurements, psychiatric assessments and questionnaires with the help of aresearch assistant. Should we be able to obtain the clinical fellowship from the‘Hersenstichting’ or the Dutch Organization for Scientific Research (NWO), we willextend the personnel with a PhD student for the cortisol and melatoninmeasurements, and allowing to speed up data analysis and publishing ininternational peer-reviewed journals. We also applied for additional funding with thePhilips Research Grant.Applicants:Ysbrand D. van der WerfDr. van der Werf is a biologist and neuropsychologist at the department of Anatomy& Neurosciences of the VU University Medical Center (VUmc) and DeptSleep&Cognition at the Netherlands Institute for Neuroscience. He finished his PhD(‘The Thalamus and Memory. Contributions to prefrontal and medial temporalmemory processes’) in 2000 and then did a postdoc in Montreal, Canada, at therenowned Montreal Neurological Institute/Hospital to learn brain stimulation (TMS)and imaging techniques (PET, EEG, fMRI). He returned in 2003 and set up twofruitful lines of preclinical research, one into sleep disturbances and memorycomplaints and one into cognitive disturbances of patients with Parkinson’s Disease.He received numerous important grants (VIDI 2008, STW 2009, Brain & Cognition2010) and is a member of ‘De Jonge Akademie’, part of the Royal NetherlandsSociety of Arts and Sciences. His national and international collaborations includeProf. 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 Parkinsons 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 HeuvelDr. O.A. van den Heuvel, is neuropsychiatrist and senior researcher at thedepartment of Psychiatry and the department of Anatomy & Neurosciences of the VUUniversity Medical Center (VUmc). She finished her PhD (topic: ‘Neuroimaging inOCD, investigation of the frontal-striatal and limbic circuits’) with honor. After her PhD(2005) and medical specialization in Psychiatry (2007) she received the prestigiousVENI grant from the Dutch Organization for Scientific Research (NWO) and theNARSAD Young Investigator Award 2009. Her studies on OCD have been extendedto Parkinson’s disease (co-PI: dr. van der Werf, neuroscientist, and in collaborationwith dr. H.W. Berendse, neurologist, and prof. dr. D.J. Veltman, psychiatrist) toenable the study of frontal-striatal dysfunctions, cognitive flexibility and brainconnectivity in a broader spectrum of disorders. Dr. van den Heuvel closelycollaborates 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 aspecialized outpatient department for neuropsychiatric disorders in Parkinson’sdisease, in close collaboration with the head of the outpatient department formovement 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: 48-56Henk W. BerendseDr. Henk W. Berendse is a consultant neurologist at the department of Neurology ofthe VU University Medical Center (VUmc) in Amsterdam, the Netherlands. Hereceived his MD in 1988 and his PhD in basal ganglia neuroanatomy in 1991 (bothwith honours). From 1991 to 1992 he worked as a Visiting Scientist at thedepartment of Neurology of the University of Rochester, Rochester NY, USA.Subsequently, from 1992 until 1998 he was trained in Neurology at the VU UniversityMedical Center in Amsterdam, the Netherlands. Since 2008 he runs the MovementDisorders service at the VUmc. His research activities are conducted through
Neuroscience Campus Amsterdam. His current research interests include non-motordisturbances in Parkinson’s disease and the development of early diagnosticprocedures and biomarkers of the disease process. He was Secretary of the DutchFederation of Neuroscience Organizations (2004-2006) and Secretary of theInternational Basal Ganglia Society (2004-2007). Presently, he serves as boardmember of the International Basal Ganglia Society, board member of theNederlandse Werkgroep Bewegingsstoornissen (Dutch Working Group on MovementDisorders) and as a member of the Research Advisory Panel of the DutchParkinson’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 Parkinsons 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 Parkinsons 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 Parkinsons 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. FonckeDr. E.M.J. Foncke is a clinical neurologist with special expertise in the diagnosis andtreatment of hypo- and hyperkinetic movement disorders. She worked as researchneurologist at the movement disorder department of the Academic Medical CenterAmsterdam under the stimulating guidance of dr. J.D. Speelman. She defended herdissertation “Clinical and functional studies in Myoclonus-Dystonia” in September2008. She is currently working at the dept. of Neurology of the VU University MedicalCenter as a specialist in movement disorders with a particular focus on Parkinson’sDisease. She initiated a Voxel-Based-Morphometry MRI study in hallucinating PDpatients. In this study, cholinergic brain structures including the pedunculopontinenucleus and the nucleus basalis of Meynert and their projection areas including thereticular thalamus and different neocortical areas are studied in demented and non-demented PD patients and Dementia with Lewy Bodies (DLB) patients with andwithout VH. In addition, these brain regions are studied in postmortem brain tissueby means of alpha-synuclein immunostaining and measuring cholineacetyltransferase (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.