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A.E.Q. van Delden MSc (Lex)

  • Kamernr:b-662
  • E-mail:l.van.delden@vu.nl
  • Onderdeel:faculteit der bewegingswetensc (afdeling bewegingsgedrag)

Research

Het ULTRA-stroke onderzoek (English below)

Introductie
In Nederland zijn er jaarlijks meer dan 32.000 patiënten die een CVA hebben doorgemaakt (Loor et al., 1999) en de incidentie zal de komende jaren toenemen (Ruwaard & Kramers, 1997). 80% van deze patiënten heeft een parese van de bovenste extremiteit (Nakayama et al,. 1994). Hoewel veel patiënten blijvende problemen ondervinden met arm- en handfunctie, zijn er recentelijk goede resultaten geboekt met specifieke interventies. Een van deze interventies is bilaterale arm training met ritmisch auditieve cues (BATRAC; Whitalll et al., 2000). Cross-talk tussen beide hersenhemisferen zou de voornaamste reden kunnen zijn van het succes van deze therapie (Cauraugh & Summers, 2005; Luft et al., 2004). Een andere therapievorm is constrained-induced movement therapy (CIMT), waarbij de alleen de aangedane arm wordt geoefend, terwijl de niet-aangedane arm geïmmobiliseerd wordt (Wolf et al., 2006). Uitgangspunt bij deze therapie is een functionele aanpassing in de aangedane hersenhemisfeer. Dit onderzoek, in de vorm van een randomized clinical trial (RCT), is gericht op de verschillen in klinische effecten en onderliggende mechanismen tussen BATRAC en CIMT.

Doel van het onderzoek
Het onderzoeken van 1) de relatieve effectiviteit van drie interventies gericht op de bovenste extremiteit na CVA: BATRAC, CIMT en standaardtherapie, en 2) de functionele en neurofysiologische veranderingen die gepaard gaan met de klinische interventie effecten.

Onderzoeksopzet
Patiënten worden gerekruteerd bij het Revalidatiecentrum Amsterdam (RCA). De patiënten worden gestratificeerd op basis van handfunctie en gerandomiseerd over drie groepen. De patiënten krijgen drie maal per week therapie voor zes weken. Voorafgaand aan de interventie vindt een voormeting plaats, na de interventie vindt de nameting plaats en weer 4 weken later vindt de retentiemeting plaats.

Onderzoekspopulatie
Patiënten aangemeld bij het RCA met een eerste ischemische of hemorrhagische subacuut CVA in een van beide hemisferen (verificatie via CT en/of MRI); parese van bovenste extremiteit, maar enige functie aanwezig: 1) >10 graden duimextensie/abductie, 2) >10 graden extensie in twee andere vingers, 3) >10 graden polsextensie; minder dan 53 punten op de Action Research Arm Test; 18-80 jaar; gemotiveerd deel te nemen; schriftelijke of mondelingen toestemming.

Interventies
CIMT:
Gedurende 6 weken, 3 maal per week 1 uur therapie. Tijdens deze therapie oefent de patiënt alleen met de aangedane arm. De andere arm mag dan niet gebruikt worden. De oefeningen zijn dagelijkse handelingen die herhaaldelijk uitgevoerd worden of die in kleine stappen zijn opgedeeld. De therapeut geeft daarbij aanwijzingen en aanmoedigingen. Naarmate de handelingen beter uitgevoerd worden, worden de oefeningen moeilijker gemaakt of is er bijvoorbeeld minder tijd voor de oefening. Daarnaast krijgt de goede, niet verlamde arm, voor minimaal 6 uur per dag een soort mitella om, zodat de goede arm de taken van de verlamde arm niet kan overnemen.
BATRAC:
Gedurende 6 weken, 3 maal per week 1 uur therapie. De oefeningen in deze therapie worden zittend uitgevoerd. Tijdens de therapie krijgt de patiënt een koptelefoon op, rusten de onderarmen op armleuningen en worden de handen verticaal geplaatst op twee beweegbare handsteunen. Zodoende kan alleen rond de pols worden bewogen. Tijdens de therapie dienen de handen van links naar rechts ritmisch heen en weer bewogen te worden op het ritme van de tonen, die via een koptelefoon te horen zijn. Soms bewegen beide handen tegelijk naar links of rechts (d.w.z. in tegenfase) en soms bewegen beide handen naar elkaar toe en van elkaar af (d.w.z. in fase). Telkens worden 3 minuten oefenen afgewisseld met 5 minuten rust. De therapie wordt groepsgewijs gegeven in groepen van maximaal 3 personen, onder leiding van een getrainde therapeut.

Standaard oefentherapie:
Gedurende 6 weken, 3 maal per week 1 uur gebruikelijke fysio-/ ergotherapie zonder elementen van bovenstaande therapieën.

Uitkomstmaten
Klinimetrie:
Action Research Arm Test
Motricity Index
Fugl-Meyer arm/hand test
Nine Hole Peg Test
Erasmus Modification of the (revised) Nottingham Sensory Assessment
Motor Activity Log
Stroke Impact Scale

Perifere stijfheid van het polsgewricht:
Gebruik van haptische robot ter verificatie van intrinsieke en reflexmatige eigenschappen van gewrichtsstijfheid

Tussenledemaatinteracties:
Methodologie Ridderikhoff (Ridderikhoff et al. 2005); relatieve fase en correlaties

Hersendynamica:

MEG; power in frequentiebanden en oscillatie-coherentiematen

2. Patiënteninformatiebrief

“Geachte mevrouw/mijnheer,
In deze brief vindt u informatie over een wetenschappelijk onderzoek met bovenstaande titel. U bent enige tijd geleden getroffen door een beroerte die onder andere heeft geleid tot een gedeeltelijke verlamming van uw arm. De Vrije Universiteit en het Revalidatiecentrum Amsterdam doen onderzoek naar de effectiviteit van verschillende vormen van therapie bij mensen die een beroerte hebben doorgemaakt. De verschillende therapieën zijn gericht op het verbeteren van uw arm/handvaardigheid die als gevolg van het doormaken van een beroerte minder functioneert. In deze brief willen we uitleggen wat dit onderzoek inhoudt en waarom het wordt uitgevoerd.

Achtergrond en doel van het onderzoek
Met dit onderzoek willen wij het effect van twee nieuwe behandelvormen ten behoeve van het herstel van de functie van uw arm vergelijken. De eerste therapie betreft het ritmisch oefenen met beide armen tegelijk met behulp van een geluidsritme. Deze therapie wordt (afgekort) BATRAC genoemd. De tweede therapie betreft het oefenen van alleen de aangedane arm en wordt (afgekort) CIMT genoemd. Voor beide therapieën zijn er aanwijzingen dat ze een gunstig effect hebben op het herstel van arm- en handvaardigheid, maar onduidelijk is welke therapie beter is. Bovendien is onduidelijk of één van beide of beide therapieën ook beter werken dan de gebruikelijke oefentherapie die op dit moment gegeven wordt. Om het effect van deze twee therapieën te kunnen vaststellen is het noodzakelijk dat één groep patiënten, de zogenoemde controlegroep, op een gebruikelijke manier oefent. De andere twee groepen oefenen met de eerder genoemde therapieën. Zo kunnen we achteraf de groepen met elkaar vergelijken. Om de samenstelling van de groepen zo evenwichtig mogelijk te maken, zal de indeling op basis van loting plaatsvinden. Wanneer u de reguliere behandeling loot, krijgt u dus de therapie die u zou krijgen wanneer u niet aan het onderzoek meedoet. Het effect van de behandelingen wordt bij elke deelnemer vastgelegd in een aantal metingen, die in de komende 3 maanden zullen gaan plaatsvinden.

Wat houdt de BATRAC therapie in?
Gedurende 6 weken krijgt u 3 maal per week 1 uur therapie. De oefeningen in deze therapie voert u zittend uit. Tijdens de therapie krijgt u een koptelefoon op, rusten uw onderarmen op armleuningen en worden uw handen verticaal geplaatst op twee beweegbare handsteunen. Zodoende kunt u alleen rond uw pols bewegen. Tijdens de therapie zult u uw handen van links naar rechts ritmisch heen en weer bewegen op het ritme van de tonen, die u via de koptelefoon te horen krijgt. Soms beweegt u beide handen tegelijk naar links of rechts (d.w.z. in tegenfase) en soms beweegt u uw handen naar elkaar toe en van elkaar af (d.w.z. in fase). Telkens worden 3 minuten oefenen afgewisseld met 5 minuten rust. De therapie doet u tegelijk met twee andere deelnemers onder leiding van een therapeut.

Wat houdt de CIMT therapie in?
Gedurende 6 weken krijgt u 3 maal per week 1 uur therapie. Tijdens deze therapie oefent u alleen met uw aangedane arm. Uw andere arm mag dan niet gebruikt worden. De oefeningen die u gaat doen zijn dagelijkse handelingen die u herhaaldelijk uitvoert of die in kleine stappen zijn opgedeeld. De therapeut geeft u daarbij aanwijzingen en aanmoedigingen. Naarmate u de handelingen beter kunt uitvoeren worden de oefeningen moeilijker gemaakt of krijgt u bijvoorbeeld minder tijd voor de oefening. Daarnaast krijgt uw goede, niet verlamde arm, voor minimaal 6 uur per dag een soort mitella om, zodat uw goede arm de taken van de verlamde arm niet kan overnemen.

Wat houden de metingen in?
Voor het meten van de effecten van de therapieën op het functioneren van uw arm, willen wij 3 maal testmetingen bij u afnemen. Eenmaal voorafgaand aan de 6 weken durende therapie, eenmaal in de week na afsluiting van de therapie en eenmaal 6 weken na afsluiting van de therapie. De metingen worden verricht op twee dagen. De ene dag gebeurt dat bij het Revalidatiecentrum Amsterdam (RCA) en de andere dag in het VU medisch centrum (VUmc). In het RCA testen we uw armfunctie aan de hand van enkele klinische tests. Dat wil zeggen dat u met uw aangedane arm diverse taken uitvoert die door de onderzoeker gescoord worden. Daarnaast test de onderzoeker, met een speciaal hiervoor ontwikkeld apparaat, de bewegingscoördinatie van uw armen. Op deze dag zullen ook enkele vragenlijsten bij u worden afgenomen. De klinische tests en coördinatietests zijn verdeeld over ochtend en middag. In het VUmc gebruiken we twee andere testapparaten. Het eerste is een robot waarmee de stijfheid van uw polsgewricht wordt gemeten. De robot beweegt uw hand heen en weer, terwijl u wordt gevraagd de beweging tegen te houden of mee te bewegen. Met het andere apparaat, dat MEG wordt genoemd, meten we de activiteit van uw hersenen tijdens het bewegen van uw handen. Bij dit onderzoek meet het apparaat de magnetische velden rond uw hoofd. Deze velden ontstaan door zwakke elektrische stroompjes die de hersenen afgeven als ze actief zijn. Alle apparaten die gebruikt worden tijdens de tests zijn veilig, niet invasief en worden bediend door ervaren onderzoekers. Het spreekt voor zich dat het vervoer naar het VU Medisch Centrum door ons zal worden vergoed. De metingen zijn verdeeld over ochtend en middag.

Voor- en nadelen van het onderzoek
Het onderzoek waaraan wij u vragen deel te nemen, heeft een wetenschappelijk karakter. Het is daarom bij deelname aan het onderzoek voor uzelf niet zeker of een direct gezondheidsvoordeel is te verwachten. Voor alle therapieën, tests en metingen die gebruikt worden geldt dat geen ingreep wordt gedaan in het lichaam, noch dat medicijnen worden toegediend. Belangrijk is te realiseren dat alle behandelingen tijdens uw opname in het RCA over de komende 6 weken worden gegeven door getrainde fysio- of ergotherapeuten. Mocht u binnen de komende 6 weken met ontslag gaan, dan willen wij de behandeling graag poliklinisch in het RCA voorzetten, zodat wij zeker zijn dat u ondanks uw ontslag toch alle 18 behandelingen heeft gekregen. Praktisch komt het er op neer dat u bij eerder ontslag 3 keer per week poliklinisch zal worden behandeld.

Bedenktijd
Wij adviseren u voldoende tijd te nemen om na te denken of u aan dit onderzoek wilt meewerken. Ook zult u er wellicht met anderen over willen praten. Hiervoor krijgt u uiteraard de gelegenheid.

Verzekering
Voor eventuele schade die het gevolg is van het onderzoek, is in overeenstemming met de wettelijke vereisten door het VUmc een verzekering afgesloten. Wij zijn verplicht u deze informatie te verstrekken, maar gezien de uiterst geringe risico’s van dit onderzoek verwachten wij geen problemen. Het contactadres van de verzekeringsmaatschappij is:
Onderlinge Waarborgmaatschappij Centramed B.A.
Postbus 191
2270 AD Voorburg

Indien u meent schade te hebben opgelopen, dan kunt u hierover contact opnemen met uw arts of met het bureau medische zaken van het VUmc.

Vrijwilligheid van deelname
Deelname aan het onderzoek is geheel vrijwillig en zonder verplichting. Dit betekent, dat als u niet wilt meedoen, dit geen invloed heeft op de zorg of aandacht die u (en mogelijk uw partner) in het RCA zullen krijgen. Als u wel meedoet aan het onderzoek, dan heeft u het recht om op elk gewenst moment, zonder opgave van redenen, van verdere deelname af te zien. Ook dit zal geen gevolgen hebben voor uw verdere behandeling.

Vertrouwelijkheid van uw gegevens
De gegevens die in het kader van dit onderzoek verzameld zullen worden, zullen vertrouwelijk en geanonimiseerd worden behandeld. De gegevens worden op aparte formulieren ingevuld waarop alleen een nummer voorkomt, niet uw naam en persoonlijke gegevens. De gegevens worden dus onder code verwerkt. Bij publicatie van de resultaten in wetenschappelijke tijdschriften zullen uw gegevens niet herleidbaar zijn. Alle gebruikelijke waarborgen ter bescherming van uw privacy in het RCA en het VUmc zullen ook tijdens dit onderzoek gelden.

Toestemmingsverklaring
Als u besluit deel te nemen aan het onderzoek, zullen wij u vragen een toestemmingsverklaring te ondertekenen. Hiermee bevestigt u uw voornemen om aan het onderzoek mee te werken. U blijft de vrijheid houden om, zonder opgave van redenen, uw deelname te beëindigen. De onderzoeker zal het formulier eveneens ondertekenen en bevestigt zo dat hij u voldoende heeft geïnformeerd over het onderzoek, deze informatiebrief heeft overhandigd en bereid is om waar mogelijk in te gaan op nog opkomende vragen.

Vergoeding
De reiskosten, verband houdend met de tests en metingen in het VUmc, zullen worden vergoed.

Vragen
Wanneer u na het lezen van deze brief (en bijlagen) aanvullende informatie wilt ontvangen, dan kunt u op werkdagen bellen met de coördinator van het onderzoek, L. van Delden, telefonisch bereikbaar onder nummer 020 – 5988495. Dit geldt ook wanneer tijdens of na het onderzoek nog vragen bij u opkomen. Indien u er prijs op stelt informatie over dit onderzoek in te winnen bij een arts die niet bij de uitvoering van het onderzoek is betrokken, maar wel over de gegevens ervan beschikt, dan is dokter V. de Groot, van de afdeling revalidatiegeneeskunde, bereid uw vragen te beantwoorden. Hij is telefonisch bereikbaar via 020 – 4440763.”

 

The ULTRA-stroke project

Summary
Prospective cohort studies show that about 80% of all stroke survivors have an upper limb paresis immediately after stroke. Unfortunately, 60 to 70% of stroke survivors will continue to experience upper extremity functional limitations, which is associated with diminished health related quality of life after stroke. Recent studies have indicated that stroke patients’ upper limb function may be improved using specific therapeutic protocols with a strong conceptual motivation. Therefore, powerful randomised clinical trials (RCTs) investigating the effectiveness and testing the conceptual motivation of innovative therapies are urgently needed in stroke rehabilitation. In addition, a better understanding is needed of mechanisms associated with treatment-induced effects in order to improve future treatment strategies.
Here, we propose such an RCT that is both clinically and theoretically relevant. The RCT is aimed at investigating the effects of Bilateral Arm Training with Rhythmic Auditory Cueing (BATRAC) and Constrained Induced Movement Therapy (CIMT) in subacute stroke patients with an upper limb deficit. Both interventions will be compared to a Dose-Matched Control Treatment (DMCT) based on usual practice. Apart from an assessment of the intervention-induced changes in upper limb functionality (i.e., primary outcome measure Action Research Arm Test (ARAT)), this ATRACCIMT study explicitly aims at uncovering the mechanisms that are associated with regaining dexterity. For this latter purpose, included patients will be stratified with respect to the severity of upper limb paresis (reflecting the intactness of the primary motor system). Moreover, specific predictions regarding intervention-induced changes will be examined with respect to 1) peripheral stiffness of the upper paretic limb (using a haptic robotic), 2) interlimb interactions governing bimanual coordination (based on kinematics), and 3) cortical activation patterns of ipsi- and contralateral hemisphere as well as cerebellum (using MEG). Thus, besides an evaluation of the relative effectiveness of the treatments of interest, this RCT will shed light on whether exerciseinduced improvements in upper limb coordination and dexterity are associated with either ipsi- or contralesional adaptations in the affected and non-affected hemisphere or contralesional cerebellum.

INTRODUCTION AND RATIONALE
In the Netherlands, each year more than 32,000 patients sustain a stroke (Loor et al., 1999) and the incidence is expected to have increased by 30–45% in 2015 (Ruwaard & Kramers, 1997). About 80% of the survivors have an upper limb paresis immediately after stroke (Nakayama et al, 1994), hampering movement of the paretic arm and bimanual coordination (Ustinova et al., 2006). Unfortunately, with conventional treatment programs only one third of all stroke patients regain some dexterity within 6 months post-stroke (Dobkin et al., 2005). However, recent studies have revealed promising results with specific interventions aimed at arm-function improvement. One such intervention is bilateral arm training with rhythmic auditory cues (BATRAC), which has been shown to have beneficial effects on the paretic arm (Whitall et al., 2000), possibly as a result of changes in contralesional cortical networks (Luft et al., 2004). This suggests that motor function in the impaired paretic arm may be regained by exploiting interhemispheric interactions (Cauraugh & Summers, 2005). In particular, based on the principle of interhemispheric recruitment from the nonaffected hemisphere (i.e., exercise-induced neuroplasticity by means of “neural cross-talk”), BATRAC may serve as an effective therapy for patients in whom the corticospinal tract (CST) system is seriously affected (Stinear et al., 2007) ? a group of patients for whom effective therapies are lacking (Kwakkel et al., 2003, 2004). Furthermore, a recent meta-analysis indicated that distally oriented repetitive bilateral arm training is more effective than a more proximally oriented approach (Kwakkel et al., 2008), suggesting that the effectiveness of BATRAC may be enhanced by performing repetitive extension and flexion movements of wrist and fingers, rather than training more proximal parts of the arm.
In contrast, various controlled trials have suggested that intensive unilateral training by constraining movements of the nonparetic arm (constrained-induced movement therapy; CIMT) is an effective method for improving upper limb function (Hakkenness & Keating 2005; Wolf et al., 2006). This suggests that training may also induce beneficial changes in the affected rather than nonaffected hemisphere and raises the question whether in BATRAC the improved functionality of the paretic arm indeed results from exploiting interhemispheric interactions, or merely from training with the affected arm (cf. Luft et al., 2004). To address this question (cf. Rose & Winstein, 2005) the proposed project entails a randomized control trial (RCT) in which the expected merits of both BATRAC and CIMT are compared with those of an equally intensive (i.e., dose-matched) conventional treatment program (DMCT), while also the effects of BATRAC and CIMT are compared on several outcome measures. To this end, participants are divided over three intervention groups and the effects of the interventions are assessed (1) prior to training, (2) after 6 weeks of training, and (3) 6 weeks after training.

OBJECTIVES
The project has two principal aims: (1) to assess the relative effectiveness of the three interventions, also as a function of patient characteristics, and (2) to delineate the functional and neurophysiological changes that are associated with those intervention effects. To assess the effectiveness, a range of functional outcome measures will be determined pertaining to ADL functioning, motor ability of the paretic arm, bimanual coordination, and peripheral motor functioning. Besides shedding further light on the merits of bilateral versus unilateral upper limb training in general (Stewart et al., 2006), the study will generate specific insights into the effectiveness of distally oriented BATRAC, aimed at improving wrist and finger extension (Kwakkel & Kollen., 2007). In light of contrasting results and divergent perspectives on associated mechanisms (Richards et al., 2008), the potential dependence of the effectiveness of the interventions on neurological characteristics of stroke survivors will also be examined. It has been proposed that the effectiveness of CIMT is dependent on CST integrity (Ward et al., 2003; Newton et al., 2006), which is essential for motor control of the distal part of the upper limb. BATRAC may be expected to be less dependent on the integrity of the CST, as it appears to induce reorganizations in cortical inter- and intrahemispheric neural networks (Cauraugh & Summers, 2005; Stinear et al., 2007).To address this issue, participants will be stratified in terms of the motor ability of the distal part of the arm (Kwakkel et al., 2004). To uncover the mechanisms associated with therapy-induced functional improvement, two kinds of analysis are included. First, changes in three empirically identified (and functionally defined) sources of interlimb interaction will be examined. Specifically, BATRAC is expected to induce more improvement in these interactions than both CIMT and DMCT. Second, MEG recordings will be analysed to identify treatment-induced neuronal reorganizations. CIMT is expected to result primarily in changes in ipsilesional hemisphere functioning, which may be related to restitution of its former functionality.  ATRAC, on the other hand, is expected to induce primarily adaptations in the contralesional hemisphere (Luft et al., 2004), which would indicate compensatory cortical reorganization in which the coupling to the nonaffected hemisphere gains a special role in the motor control of the paretic arm. In short, the primary research questions are: 1) Is BATRAC or CIMT, when compared to DMCT, more effective in terms of recovery of (unimanual and bimanual) hand and arm function in subacute stroke patients? 2) How are the observed changes in functionality related to changes in peripheral stiffness, interlimb interactions and cortical inter- and intrahemispheric neural networks?

STUDY DESIGN
Subjects will be recruited from the Rehabilitation Centre Amsterdam (RCA). After registration at the RCA (thus with a variable time after stroke onset, dependent on the hospitalisation time), the subjects that meet the criteria (see paragraph 6.3 and 6.4) will be asked to participate in the RCT. Potential subjects are given two weeks respite. The first assessment will take place in the week that subjects give informed consent (Appendix B). That means the time after stroke onset varies between patients, yet the start of the project for each patient is considered to take place in the subacute phase after stroke, 1, 2 or 3 weeks after registration at the RCA. First, subjects are stratified in those with some dexterity (i.e., able to execute > 10º finger extension of each metacarpophalangeal and interphalangeal joint of all digits and > 20º wrist extension) and those with minimal control of the paretic wrist and finger extension (at least 10° of active wrist extension, at least 10° of thumb abduction/extension, and at least 10° of extension in at least 2 additional digits). After stratification, subjects are randomised in permuted blocks and allocated to one of the three treatment arms. (i.e., CIMT, DMCT or BATRAC). Concealed allocation is effectuated with sealed opaque envelopes. Other therapists and social workers will provide regular care depending on patient needs. After the first assessment an intervention period will take place for 6 consecutive weeks, 3 times a week for 1 hour. The effects of the interventions are examined using a pretest-posttest design. Whereas the pretests (t0) are performed in the week prior to the intervention, posttests (t1) are performed in the week after the intervention. The degrees to which changes are sustained are examined using retention tests (t2), 6 weeks after completion of the intervention.

INTERVENTIONS
The interventions are applied by physiotherapists and/or occupational therapists working at the RCA. Where possible, interventions in groups is preferred (no more than 3 patients per group). The BATRAC group receives 60-minute sessions, 3 days a week for 6 consecutive weeks. Treatment will be applied in 5-minute movement periods interspersed with 5-minute rest periods. The lower arms are fixated and the subject performs flexion and extension movements about the wrist in the horizontal plane, paced by an auditory metronome. The tempo of the auditory cues depends on the severity of upper limb deficit and is selected individually. Over the course of training the tempo is adjusted in response to improvement in task performance. The movements are performed in phase (simultaneous flexion or extension) and antiphase (flexion of one wrist coincides with extension of the other), where maximal flexion/extension should coincide with the auditory cue. Changes between the two modes are included to avoid loss of motivation. The CIMT group receives 60 minutes of task-oriented training of the upper extremity, aimed at improving dexterity of the paretic arm (i.e., shaping), 3 days a week for 6 consecutive weeks. Task difficulty is increased progressively using behavioural techniques of shaping and successive approximation (Taub et al., 1999). In addition, the Padded Safety Mitt (Samson Preston # 6727; Sammons Preston, Inc, Bolingbrook, IL, USA) is applied to immobilize the non-paretic arm for at least six waking hours each working day to prevent from the non-paretic arm taking over tasks of the paretic arm. A therapist, nurse or family member should help putting on and taking of the mitt. The mitt should be taken off during bathroom activities. Patients that go walking by themselves are only allowed to wear the mitt if they score more than 3 points on the Functional Ambulation Categories (FAC). Patients are not allowed to wear the mitt near fire. The 100% cotton mesh-covered safety mitt prevents contracture with firm polyester filling. The mitt also allows (preventive) elbow extension, leaving sufficient movement when needed, for example in case the patient threatens to fall. The content and duration of the CIMT therapy as well as the shaping exercises are recorded in a patients’ log reflecting the progress in reaching treatment goals.
Dose-matched control treatment (DMCT) consists of exercise therapy based on existing guidelines for exercise therapy as shown by Dutch Society of Occupational Therapy (NVE) and Royal Dutch Society of Physical Therapy (KNGF) (van Peppen et al, 2004). Therapy will be applied 60 minutes per treatment session, 3 days a week for 6 consecutive weeks and will not contain elements of the other two therapies. The content and duration of the sessions is recorded in patient logs.

METHODS
Study parameters/endpoints
As stated above, the effects of the interventions are examined using a pretest-posttest design. The pretests are performed in the week prior to the intervention, whereas posttests are performed in the week after the intervention. The degrees to which changes are sustained are examined using retention tests, 6 weeks after completion of the intervention. The three test moments all involve the assessments described in the next section. The tests are conducted without knowledge of which intervention group the subject is assigned to.

Clinimetrics
Motivation and methods: Using a series of clinimetric tests the effectiveness of the interventions is examined regarding ADL and functionality of the paretic arm/hand. The clinical test battery includes the following validated assessment instruments to determine muscle strength (Motricity Index for the arm), motor performance and dexterity (ARAT; Fugl-Meyer for the arm; Nine Hole Peg test), sensory discrimination and propriocepsis (Erasmus modification of the Nottingham Sensory Assessment); self-perceived ADL functioning (structured participant interview of real arm use using the Motor Activity Log; Stroke Impact Scale, version 3.0). The battery will take about 1 hour.

Primary outcome measure; effect of the intervention:
ARAT:
The Action Research Arm Test (ARAT) serves as primary outcome measure. This is a valid, reliable, and responsive performance test (van der Lee et al., 2001) of the ability to perform gross movements and to grasp, move and release objects differing in size, weight and shape (Lyle, 1981). The minimal clinically important difference is set at about 10% of the scale’s range, i.e. 6 points (Van der Lee et al., 1999); improvement by > 10 points is defined as return of dexterity (Kwakkel et al., 2003).

Secondary outcome measures; detecting confounders, comparing groups, and tracing changes per patient in time:
Motricity Index (MI):
This test will be used to measure strength in upper extremities (Collin et al, 1990). Higher scores represent greater strength in the upper limb. This instrument reliably and validly assesses the presence of paresis in stroke patients by testing 6 functions rated for each limb (Collin et al, 1990; Kwakkel et al, 1999).
Fugl-Meyer arm/hand test (FM)-arm:
The Fugl-Meyer arm score is a reliable and valid motor performance test consisting of 33 tasks performed by the affected upper limb (Badke et al, 1983; Duncan et al, 1983). The FM-arm test evaluates the ability to make movements outside the synergistic pattern. Performance on each task is rated as 0, 1, or 2, with higher rates representing better performance. The FM-arm measure will be used as the sum of 33 ratings (possible range 0 to 66 points).
Nine Hole Peg Test (NHPT):
The Nine Hole Peg Test (NHPT) is a reliable and valid test that measures manual dexterity (Mathiowetz et al, 1985; Heller et al, 1987). It measures the speed with which a patient grasps and inserts (and removes) 9 pegs into a grip of vertical holes. The test will be discontinued after 150 seconds if the patient is still unable to insert any pegs. The NHPT measure for each hand is calculated by the number of pegs placed per second. The affected as well as the unaffected hand will be measured. Reliability and validity have been assessed and norms are available (Mathiowetz et al, 1985; Heller et al, 1987).
Erasmus MC modification of the (revised) Nottingham Sensory Assessment (EmNSA):
The EmNSA is a 3 point ordinal scale that measures:
1. sharp-blunt discrimination;
2. 2 point discrimination;
3. Proprioception of upper and limb.
The EmNSA will be restricted to the paretic upper limb (i.e., fingers, hand, and forearm). With exception of the two-point discrimination, intra- and interrater reliability of tactile sensations, sharp-blunt discrimination and proprioception items are good to excellent (Kappa: 0.58 to 1.00; Stolk-Hornsveld et al, 2006).
Motor Activity Log (MAL):
A translated and adapted version of the Motor Activity Log will be used (Van der Lee et al, 2004), which contains the 14 original activities, 11 additional activities, and 1 optional activity chosen by the patient. Reliability and validity of the MAL has been proved in a number of studies (Van der Lee et al, 2004). The MAL will be administered to each applicant and, if available, their caregivers. It will be used to independently rate how well (11-point Quality of Movement [QOM] scale) and how much (11-point Amount of Use [AOU] scale) the paretic arm was used spontaneously to accomplish 30 activities of daily living outside the laboratory (Van der Lee et al, 1999; Uswatte et al, 2005).
Stroke Impact Scale (SIS):
The arm-hand domain of the Stroke Impact Scale (SIS, version 3.0) will be used to evaluate patients’ perceived outcome for the paretic upper limb. Version 3.0 of the SIS is a full-spectrum health status interview that measures changes in 8 impairments, function and quality of life subdomains following stroke and will be used as a secondary outcome measure (Duncan et al., 2003). Each domain will be analyzed separately. The upper limb part of the SIS includes 5 questions about patients’ perceived competency to keep their balance, to transfer, to walk in the house and negotiate stairs, to get in and out of a car and to move about in their own community. Each item is scored from ‘not difficult at all’ to ‘cannot do at all’ on a 5 point rating scale. A difference of 5 points (10%) on the ‘hand function’ domain of the SIS is perceived as clinically relevant (Wolf et al, 2006). The SIS has shown excellent clinimetric properties in terms of concurrent and construct validity, test-retest reliability and responsiveness (Duncan et al., 1999).

Expectations: Both CIMT and BATRAC are expected to significantly improve upper limb function when compared to the DMCT group. CIMT is expected to have a larger impact on those subjects who already showed some dexterity at recruitment, given the importance of CST integrity for motor control of the distal part of the upper limb (Kwakkel et al., 2007). BATRAC, on the other hand, is expected to be also effective for subjects that were more restricted in this regard, thanks to influences stemming from and reorganizations in the contralesional hemisphere. The effects of BATRAC and CIMT are both expected to sustain over the retention period.

Peripheral stiffness
Motivation: In active posture tasks the negative signs of post-stroke limb dysfunction prevail, (viz., paresis and poor adaptation of reflexes; Schouten et al., 2008). Under passive conditions, however, enhanced joint stiffness and hyper-excitability of the reflex loop (viz. enhanced tendency for synchronous and self-sustained firing of the motor neuron pool) are evident (Gracies, 2005a&b). Because the spinal reflex loop is under control of higher brain areas, loss of CST integrity and persistent CNS reorganization is anticipated to be related to high joint stiffness, absence of reflex modulation, and signs of hyper-excitability of the reflex loop.

Methods: Endpoint mechanical behavior, resulting from a mix of visco-elastic (intrinsic) and proprioceptive reflex (reflexive) properties, will be assessed under both passive and active conditions using a haptic robot for the wrist (‘Wrist-analyzer’, Moog FCS Inc). This powerful, force-controlled manipulator applies quasi-random variations of the net moment of force over a wide range of frequencies, as well as controlled force perturbations. Surface EMG is measured for additional validation.

Expectations: In particular BATRAC is expected to reduce peripheral stiffness, not only because wrist extension is practised repeatedly, but also given the assumption that increased joint stiffness is specifically associated with loss of CST integrity in combination with the expectation that BATRAC is more proficient in this situation than CIMT. On the same note, the beneficial effects of BATRAC are predicted to be most pronounced in participants with minimal hand/finger control.

Interlimb interactions
Motivation: Bimanual coordination is characterized by interlimb interactions that result in stabilization of specific bimanual coordination patterns. The success of bilateral training protocols (such as BATRAC) has been ascribed to such interlimb interactions (Cauraugh & Summers, 2005), suggesting that influences stemming from the contralesional hemisphere are beneficial for performance of the paretic limb. Bilateral training may also induce adaptations in these interactions, potentially strengthening its advantageous influence on paretic arm performance as well as improving bimanual performance. For this reason the effects of the interventions on the interactions between the paretic and nonparetic hand are examined.

Methods: Ridderikhoff et al. (2005) developed a methodology that dissociates between the contributions of three sources of interlimb interaction: 1) integration of feedforward control signals to both hands; 2) error correction of the phasing between the hands, based on afferent signals; 3) (unintended) phase entrainment by contralateral afferent signals, probably resulting from spinal reflexes. It is based on systematic comparisons between four coordination tasks involving bimanual performance (in- and antiphase coordination) or unimanual performance with or without comparable motor-driven movements of the contralateral hand: (a) unimanual rhythmic coordination with an auditory pacing signal (UN); (b) idem, while the contralateral hand is moved passively with a phase shift of 30º with respect to the required movements of the active hand (UNm); (c) kinesthetic tracking (KT): unimanual active movements are to be coordinated (in- or antiphase) with the passive rhythmic movements of the contralateral hand (identical to those used in [b]); (d) active auditorily-paced bimanual coordination (in- or antiphase; AB). This method, with minor modifications, is applied in the proposed study. The tasks are performed in an experimental set-up in which passive movements can be imposed using a servo-motor and the active movements are measured using potentiometers. All tasks are performed at the movement frequency at which the subject can comfortably perform the antiphase pattern in the first test session (pretest). Depending on the task conditions, the motor-driven, passive movements are based on either the movements of the to-be-moved hand as recorded during condition (d), which is therefore the first task to be performed, or a predefined sinusoidal pattern (with added random noise). Given the inherent functional asymmetry in the subjects, tasks (a)-(c) are performed with both the paretic and the non-paretic hand as active hand (order counterbalanced over subjects; yielding 2 sessions of 1 hour each). For the associated analyses, see Ridderikhoff et al. (2005). Surface EMG is measured for additional validation.

Expectations: Both CIMT and BATRAC are expected to yield improvements for all three sources of interlimb interaction, due to improved control over the paretic hand, enhanced processing of sensory feedback stemming from this hand, and increased inhibition of spinal reflexes. For both interventions stronger supraspinal inhibition of entrainment effects on the paretic side (inhibiting hyperactive reflexes) is expected, whereas for the nonparetic side such changes in the strength of phase entrainment are not expected (given the absence of hyperactive reflexes). Hence, a stronger asymmetry in phase entrainment is expected before the intervention than after. A larger improvement in error correction is predicted for BATRAC, since in that protocol such corrections of the phasing between both hands are trained as well. Thus, kinesthetic tracking performance of both hands will benefit from this training, but tracking with the nonparetic hand is expected to show larger improvement due to enhanced processing of sensory signals from the (passively moved) paretic hand. Also regarding the integration of the feedforward signals (and, thus, active bimanual coordination), BATRAC is predicted to yield larger improvements than CIMT, since integration of the commands for both limbs is an integral part of the training.

Brain dynamics
Motivation: So far, studies of the neural effects of CIMT and BATRAC have been limited to fMRI (e.g., Juenger et al., 2007; Luft et al. 2004) and TMS (e.g., Ro et al., 2006; Summers et al., 2007). The fMRI studies indicated that, during paretic arm movement, CIMT results in increased activation in the primary sensorimotor cortex of the affected hemisphere, whereas BATRAC results in increased activation in the contralesional cerebrum and ipsilesional cerebellum. However, the way in which the activity in these areas changes during both unimanual (paretic arm) and bimanual performance is unknown, and pertinent hypotheses in this regard have yet to be tested. To this end, brain activitiy during unimanual and bimanual rhythmic tasks will be recorded before and after interventions, using a measurement device with high temporal resolution (MEG), to determine patterns of correlated brain activity within and across hemispheres, using state-of-the-art analyses. MEG is one of the available imaging techniques to allow studies of the human brain in a totally non-invasive way.

Methods: All subjects perform simple unimanual and bimanual isometric force production tasks with their fingers, while whole-head magneto-encephalographic (MEG) recordings are made. Task performance (onset and displacement) is monitored by a self-produced device measuring the Cauchy strain.

Expectations: Based on previous findings as well as theoretical considerations, CIMT is expected to result in greater activity in the primary sensorimotor cortex of the affected hemisphere and in increased phase synchronization between the lesioned hemisphere and the contralesional hemisphere. BATRAC is expected to yield an additional increase in activity in the (ipsilesional) cerebellum (possibly reflecting enhanced timing abilities) as well as a markedly greater increase in the degree of phase synchronization between the lesioned hemisphere and the contralesional hemisphere than will occur as a result of CIMT. Although also DMCT may induce some of the aforementioned effects, it is expected to do so in a more diffuse and less pronounced manner.

STUDY POPULATION
Recruitment
Subjects will be recruited from the RCA. Subacute stroke patients with a first-ever ischemic or hemorrhagic lesion in one of the hemispheres, verified by CT and/or MRI scan, and an upper limb deficit will be asked to participate. Patients will receive a Patient Information Letter (Appendix C), that explains the background and methods of the study. The number of subjects is based on power analysis of primary outcome measurements on the ARAT (statistical power ? 80%; ? ? 5%; including 10-20% drop-out). Patients are stratified in those with some dexterity (i.e., able to execute > 10º finger extension of each metacarpophalangeal and interphalangeal joint of all digits and > 20º wrist extension) and those with minimal control of the paretic wrist and finger extension (i.e., able to execute > 10° of active wrist extension, and > 10° of thumb abduction/extension, and > 10° of extension in at least 2 additional digits). After given consent and assessment for criteria, patients will be randomly distributed over the three intervention groups (BATRAC, CIMT, DMCT; 20 subjects each). After distribution an appointment will be made for an intake procedure, comprising the pretest. Concealed allocation will be effectuated with sealed opaque envelopes. The intensity and content of all therapies applied will be recorded in a patient log-book.

 

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