Randomized Controlled Trial of Combined Optokinetic Stimulation and Cueing-based Reading Therapy to Treat Hemispatial Neglect Following Stroke (OKS-READ Study)
Phase: NA
Conditions: Spatial Neglect
Sponsor: University of Luebeck

 
 
Study protocol 
 
 
 
 
Randomized controlled trial of combined  
optokinetic stimulation and cueing-based reading therapy 
to treat hemispatial neglect following stroke  
(OKS-READ study) 
 
 
 
 
 
 
 
PD Dr. med. Björn Machner 
 
Department of Neurology - University of Lübeck 
 
2019 
 
 
 
 

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1.1 
Principle Investigator – Contact details 
 
Name, Academic Degree: 
Björn Machner, PD Dr. med.  
Position: 
Consultant Neurologist  
Date of Birth, Nationality: 
20.03.1980, German 
Institution and Department: 
University of Lübeck  
Department of Neurology 
Address: 
Ratzeburger Allee 160  
23538 Lübeck 
Germany 
Phone: 
+49-451-50075827 
Fax: 
+49-451-50043404 
E-mail: 
Bjoern.Machner@neuro.uni-luebeck.de 

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1.2 
Study summary 
Title: 
 
A randomized, controlled trial of combined optokinetic stimulation and 
cueing-based reading therapy in hemispatial neglect following stroke  
Objectives: 
 
To assess the effect of a combined treatment with optokinetic 
stimulation (OKS) and cueing-based reading therapy (READ) on 
hemispatial neglect and neglect-related functional disability in right-
hemisphere stroke patients. 
Study design: 
This study will be a mono-centric, randomized, controlled, clinical trial. 
Using a crossover design with two arms, patients will either receive the 
intervention therapy first and then the control treatment or they will start 
in the control arm and then switch to the intervention. Each treatment 
phase consists of 15 therapy sessions lasting 30 to 45 minutes.  
 
Each patient will be assessed at 6 test sessions: 
 
T1 and T2 as baseline measurement (min. 24 hours between 
the two sessions)  
 
T3 after the first treatment phase 
 
T4 before the second treatment phase 
 
T5 after the second treatment phase 
 
T6 as follow-up two weeks after T5. 
Planned Sample Size: 
30 recruited subjects who completed all test sessions (plus an expected 
drop-out of n=6). An interim analysis is planned after successful 
inclusion of 22 subjects.  
Setting: 
Neurological Rehabilitation Center (Bad Segeberg, Germany) 
Participants: 
 
Eligible participants are in-patients with a right hemisphere stroke, 
signs of hemispatial neglect in at least one screening test and the ability 
to read and understand German language. Exclusion criteria are a pre-
existing dementia, other structural lesions of the brain besides the 
unilateral stroke, low vision (corrected <0.7) and the inability to give 
informed consent.    
Intervention: 
The intervention consists of a combination of optokinetic stimulation 
(OKS) and an adaptive, cueing-based reading (READ) therapy. Within 
the intervention session, the OKS will always be performed first (at least 
15 minutes) followed by the reading therapy (at least 15 minutes). 
During 
the 
control 
phase, 
patients 
will 
receive 
a 
general 
neuropsychological treatment without specifically targeting spatial 
attention. Each phase will contain 15 individual therapy sessions 
applied within a period of max. 28 days.  
Primary outcome: 
 
Composite score of different established neuropsychological tests 
assessing spatial neglect and a clinical score of neglect-related 
functional disability (Catherine Bergego scale)  
Data Analysis Plan: 
 
The difference in the primary outcome parameters between the 
intervention and control phase will be analyzed using adequate 
statistical tests for this within-subject crossover design (independent t-
test of the intra-individual differences between intervention and control).  
 
 
 
 

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2 Introduction 
 
 
2.1 
 Background and objectives  
Every two seconds, someone in the world is having a stroke (Stroke association 2018). In Germany the 
lifetime 
prevalence 
of 
having 
a 
stroke 
in 
adults 
between 
40 
and 
79 
years 
is  
2.9 %. With growing age, the prevalence increases up to 7.2% at the age of 70 to 79 (Busch et al. 2013).  
Hemispatial neglect represents one of the major cognitive disorders following a stroke (Parton et al. 
2004). Neglect is typically defined as the impaired or lost ability to respond to sensory stimuli presented 
in the contralesional hemispace. It can appear in all modalities, impairing seeing, hearing, feeling and 
smelling (Kerkhoff 2004). Neglect patients predominantly explore the ipsilesional space in the room, 
miss or react less to objects, people or obstacles in the contralesional hemispace and search repeatedly 
in the same areas in the room (perseveration). Neglect represents a supramodal “secondary” disorder 
with symptoms that are not explained by a primary sensory or motor impairment (Kerkhoff 2004).  
Neglect is thought to be a multicomponent deficit (Milner und McIntosh 2005; Parton et al. 2004) and 
the combination and severity of each of the deficits varies strongly between patients (Parton et al. 2004). 
Neglect patients frequently deny that there is anything wrong with their perception, which itself is a core 
symptom of the syndrome called anosognosia (Parton et al. 2004; Kerkhoff 2004). Due to this 
heterogeneity, the anosognosia and the numerous phenomena occurring with the syndrome, neglect is 
difficult to treat.  
While both left-sided and right-sided neglect can occur, the former is much more frequent and severe 
and persists more often up to the chronic stage (Bowen et al. 1999; Parton et al. 2004). A left-sided 
neglect is caused by a lesion in the right hemisphere, commonly cerebral infarction or hemorrhages. 
The brain areas predominantly injured in neglect patients are the right temporo-parietal junction and 
ventral frontal cortex, but neglect also occurs after damage to subcortical regions (thalamus, basal 
ganglia) and fronto-parietal white matter tracts (Parton et al. 2004; Bartolomeo und Chokron 2002; 
Milner und McIntosh 2005; Verdon et al. 2010; Doricchi und Tomaiuolo 2003). The prevalence of a left-
sided neglect after a right-hemispheric brain lesion is hard to determine and depends on the criteria to 
diagnose neglect and on the phase of stroke patients are assessed in (Bowen et al. 1999). In the acute 
phase 28 to 53% of all right hemispheric patients suffer from neglect (Kerkhoff 2004). While some 
patients recover spontaneously, one third of the right hemispheric patients still suffer from neglect three 
months after the lesion. 
Since neglect patients have a worse rehabilitation outcome than other stroke patients without neglect 
(even worse than patients with aphasia and hemiparesis), they require especially intense rehabilitation 
therapy (Kerkhoff 2004; Mainetti et al. 2013). Neglect not only impairs cognitive functions but affects 
motor recovery and the social rehabilitation of the patient (Bartolomeo und Chokron 2002; Denes et al. 
1982). It is a major independent predictor for poor functional outcome (loss of independence) after a 
stroke (Parton et al. 2004). If neglect remains untreated, it leads to a worse general rehabilitation 
outcome (Kerkhoff et al. 2012) and massive impairments in everyday life (Katz et al. 1999). Hence, the 
burden of the disease and the demand for a successful treatment of neglect is high. 

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2.2 
Scientific background and explanation of rationale  
Over the last years, different interventional approaches were investigated to treat spatial neglect but 
there is no single therapy that reached wide acceptance or an establishment in clinical practice. This is 
due to different reasons:  There is certainly a lack of high-quality studies. Common problems are a small 
sample size, lack of adequate blinding, lack of transfer of effects to the everyday life of patients or 
missing evidence for a persistence of effects at follow up (Azouvi et al. 2017). Thus, Kerkhoff and Schenk 
(Kerkhoff und Schenk 2012) claimed that the aim of future neglect therapy research should be to identify 
the best treatment, the best treatment combination, the best therapy frequency and patient specific 
predictors for therapy success. 
Beside medication and non-invasive brain stimulation treatments, most interventions are so-called 
“cognitive” rehabilitation interventions. These can be further differentiated into top-down and bottom-up 
interventions. Top-down interventions encourage awareness of the disability and potential 
compensatory strategies and include visual scanning therapy, any form of feedback of cueing or mental 
practice or imagery. Bottom-up interventions address the impairment directly and do not require 
awareness or behavioral change. They include for example prisma adaptation or hemifield eye patching 
(Bowen et al. 2002).  
 
There is evidence that combined therapy approaches may be more effective in treating the 
multicomponent neglect syndrome than monotherapies (Saevarsson et al. 2011). Due to the variety of 
neglect symptoms even within a single patient a monotherapy approach is probably not able to improve 
all the symptoms. Currently there is too little knowledge about which therapy is the best for which 
symptom, so that a general combined therapy covering a broad spectrum of symptoms is preferable 
(Saevarsson et al. 2011). Combining therapies with different underlying mechanism of action could be 
a powerful approach to address the variety of symptoms. Following this reasoning, Kortte and Hillis 
(Kortte und Hillis 2011) argue that a combination of a bottom-up and a top-down approach could be the 
most effective combined therapy for neglect patients.  
 
For this study we chose a combined therapy consisting of smooth pursuit eye movements elicited by 
optokinetic stimulation (OKS) and an adaptive reading therapy (READ). Each of these therapies, when 
applied as a monotherapy, has previously shown promising results in improving the neglect syndrome 
and functional disability (Kerkhoff et al. 2014; Turgut et al. 2018). There are several reasons why we are 
confident that a combination of OKS and READ could be highly effective: Firstly, OKS is commonly 
classified as a bottom-up approach while the reading therapy can be considered as predominantly top-
down approach. Therefore, although both therapies include components of the other approach, we 
follow the argument outlined above of combining bottom-up and top-down approaches. Secondly, there 
are concrete synergies between the two therapies. OKS facilitates the reading capacity of the neglect 
patients at least for a short time (Kerkhoff 2004), so that the reading won’t be that exhausting and 
frustrating for the patients. At the same time, many patients are eager to regain their reading ability, so 

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the reading therapy with individualized texts will improve the patients’ motivation. This in turn could result 
in increased engagement during the rather monotonous OKS task. Finally, both therapies are feasible 
and practicable, so - if the combined approach proves effective - therapists could easily apply them in 
their patients. 
 
In the following, detailed information on each of the two therapeutic approaches are provided. 
 
OKS 
During OKS-therapy the patients watch a display with stimuli moving coherently towards the neglected 
hemispace. The patients should follow the stimuli with their eyes. Many studies demonstrated that OKS 
can reduce the neglect symptoms. One session of OKS can reduce the neglect directly afterwards 
(Keller et al. 2009) and a repetitive stimulation over several days can have long-term benefits for the 
neglect patients (Hill et al. 2015). Kerkhoff and colleagues (Kerkhoff et al. 2014) showed that the 
stimulation reduced not only the visual, but also the auditory neglect symptoms. In the same paper, they 
also demonstrated that the neglect was not only reduced in standard neglect tests but also in activities 
of daily life (ADLs).  
According to Kerkhoff, smooth pursuit training modulates and reduces neglect in at least three ways: 
Firstly, it activates a cortico-subcortical network, including many brain regions which are involved in gaze 
and attention shift (occipitotemporal, parietal, insular, occipital cortex, basal ganglia, cerebellum, and 
brain stem). Thus, activating these brain regions can lead to more accurate behavior in space. Secondly, 
SPT may activate the vestibulo-ocular system via optokinetic nystagmus. Through this mechanism, SPT 
may recalibrate the egocentric spatial orientation and correct the ipsilesional neglect bias into a more 
symmetrical midline position. Third, the dynamic features inherent in moving displays that elicit smooth 
pursuit eye movement may increase perceptual saliency of contralesional targets. 
One OKS study that instructed patients to refrain from pursuit eye movements yielded a negative result 
(Pizzamiglio et al. 2004) which highlights the importance of smooth pursuit eye movements as a 
therapeutic ingredient of the OKS training. 
To perform smooth pursuit eye movements during OKS and follow the stimuli accurately it is important 
to be able to predict where and with which velocity the stimuli is moving. Therefore, smooth pursuit eye 
movements also have an active component, which is why it is thought to use top-down processes as 
well. Heide and colleagues (Heide et al. 1996) showed that in stroke patients damage to the parietal or 
frontal lobes can lead to deficits in performing smooth pursuit eye movements. In combination with areas 
such as the cerebellum, the medial superior temporal and middle temporal areas are most involved in 
processing, predicting and relaying visual information (Krauzlis 2004). Thimm and colleagues (Thimm 
et al. 2009) could show that after three weeks of OKS training the neglect patients showed increased 
activation of bilateral parietooccipital regions when performing a spatial attention task. Moreover, this 
increase, e.g. in the bilateral precuneus which is known to be involved in performing smooth pursuit eye 
movements (Petit und Haxby 1999), was related to the amelioration of neglect symptoms.  

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In our study we record the eye movements of the patients during the OKS. This will not only allow us to 
control patients’ adherence to the OKS task. It will also allow us to answer the following questions: Is 
OKS able to reduce neglect symptoms even if the patients are impaired in following the OKS with their 
eyes? Do the patients improve in executing smooth pursuit eye movements during the OKS therapy? Is 
the accuracy in performing smooth pursuit eye movements during the OKS a predictor for its success 
in ameliorating neglect symptoms and functional disability?  
 
Cueing-based reading therapy 
The second part of the intervention in our study will be an adaptive, cueing-based reading therapy.  
Cueing as a therapy approach for neglect patients attempts to use cues to shift the patient’s attention 
to the neglected side (Posner 1980; Pizzamiglio et al. 1992). The cues used can differ in modality (visual, 
auditory, etc.) as well as in how the shift of attention is provoked. If the cue elicits an automatic shift of 
attention like a moving bright light, then the cue and the shift of attention would be classified as 
exogenous. But there are also endogenous cues, which require effort on the side of the patient, for 
example when he or she is asked to search for a special object on the left. 
 
In our study, we will apply cues while the patient is reading words or a whole text out loud. The basic 
approach is derived from the reading therapy used by Turgut and colleagues (Turgut et al. 2018). This 
study showed that the neglect in stroke patients was reduced after an intense three-week therapy. 
Compared to a neuropsychological treatment that was not neglect-specific, the patients’ performance 
improved in standard neuropsychological bedside tests for spatial neglect but also in activities of daily 
living. Both, exogenous and endogenous cues were implemented.  
Usually, a reading therapy would be classified as a top-down approach. However, by additionally using 
exogenous cues to direct the patient’s attention to the left, bottom-up processes are utilized as well. The 
patients’ anosognosia often goes along with reduced compliance to rehabilitation. We are convinced 
that our reading therapy, which uses both bottom-up and top-down influences, has a good chance of 
overcoming this problem by keeping the patient motivated. Patients are generally aware that their 
reading ability suffered from the stroke and are eager to regain this skill. Furthermore, we will construct 
the therapy in an adaptive manner to keep the difficulty at an appropriate level for the individual patient. 
 
 
2.3 
Specific objectives and hypotheses 
We hypothesize that a combined therapeutic intervention consisting of OKS and READ applied in 15 
sessions within 21 days, will significantly reduce neglect symptoms of right-hemispheric stroke patients 
and their neglect-related functional disability. The reduction will be greater than the improvement of 
symptoms during a control treatment of the same duration and frequency, a general neuropsychological 
rehabilitation without specifically targeting the neglect and spatial attention. The outcome will be 
measured by use of a computerized neuropsychological test battery and a clinical scale of neglect-
related functional impairment in the activities of daily living, both directly after the intervention/control 
phase (immediate effects) and at a follow-up 8 weeks after study inclusion (long-term effects). We 

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expect the positive effects to emerge directly after the two-week intervention and to persist up to the 
follow-up measurement. We further speculate that those patients that receive the OKS-READ 
intervention first (and the control therapy second) will show greater improvement at follow-up than those 
patients that started with the control therapy (advantage of an early versus delayed treatment).  
 
 
 
3 
Methods 
 
3.1 
Trial design 
The study will be a randomized controlled trial. We implement a crossover design with two treatment 
phases (Figure 1). After a screening (T0) and the fulfilment of the inclusion criteria for the study, the 
baseline measurement is conducted at two different time points (T1, T2) separated by at least 24 hours. 
One group of patients (IC) receives the intervention first and then the control therapy. The other patients 
receive the control treatment first and then the intervention (group CI). During the intervention and the 
control phase the patients receive 15 therapy sessions within a 28-day period, each session lasting 
between 30 and 45 minutes. We will assess neglect severity directly after the first phase (T3) and again 
right before the beginning of the second phase (T4). After finishing the second therapy phase there will 
be another neglect assessment (T5). Two weeks later, we will measure the long-term effects of the 
therapy at the follow-up assessment (T6). 
 
 
 
Figure 1. Study design: randomized controlled trial with crossover. There are two randomized groups 
of patients. One receives the intervention first, and then the control therapy (IC, bold). The other receives 
the control therapy first and then the intervention (CI). Assessments (T 1-6) will be performed directly 
before and after each therapy phase and at a 2-week follow up.   
 
 
 
 

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4 
Participants 
 
4.1 
Eligibility criteria for participants  
Inclusion criteria are  
 
a first-time stroke in the right hemisphere (confirmed by cranial CT or MRI) within the last six 
months, 
 
a left-sided hemispatial neglect (as detected in at least one subtest of the screening test battery, 
see also “Outcome” section),  
 
the ability to read and understand German language and   
 
the ability to give informed consent. 
 
Patients are excluded from the study if they have any of the following: 
 
dementia 
 
structural lesions of the brain besides the unilateral stroke (e.g. multiple or bilateral stroke 
lesions, hydrocephalus, inflammatory lesions, etc.) 
 
low vision (corrected <0.7) due to ophthalmological diseases. 
 
 
4.2 
Settings and locations where the data are collected 
The data will be collected at the neurological rehabilitation center (NRC) in Bad Segeberg, Germany. 
The patients will be recruited from three different wards.  
The diagnostic and therapy sessions will always take place in the same room in the NRC, where the 
computer, screens, eye tracker, etc. will be permanently installed.  
 
5 
Interventions 
 
5.1 
Intervention therapy 
OKS 
At the beginning of each session the patients will receive OKS for at least 15 minutes. The stimuli are 
presented on a computer screen in front of the patients. There will be a black background with a pattern 
of 70 stimuli (size 0.5°/ 0.75°/ 1°), which coherently and continuously move to the left (Figure 2). Both, 
the stimuli (squares, dots, triangles and stars) and the velocity (7 – 13 ° per sec.) change every 45 
seconds (see figure 2 for an example). The patients will be instructed to continuously choose one 
stimulus dot and follow it with their eyes until it has reached the left side of the screen and then to jump 
to the right edge of the screen and start again. This instruction and the rather slow stimulus speeds have 
been shown to successfully elicit smooth pursuit eye movements (look-nystagmus) which appears 
crucial for the therapeutic effect of OKS (Kerkhoff & Schenk, 2012).  

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Figure 2. Optokinetic Stimulation (OKS).  
 
Adaptive, cueing-based reading therapy 
The second part of each therapy session in the intervention condition is the cueing-based reading 
therapy, which will last at least 15 minutes. The task of the patient is to read out loud words or a text 
presented on a paper in front of them. Like Turgut and colleagues (Turgut et al. 2018), we will use 
exogenous and endogenous cues to facilitate an attentional shift to the left while the patients are 
reading. To give exogenous cues, the therapist will highlight words at the beginning of the line or when 
they were omitted. Endogenous cues are verbal instructions which require intrinsic actions by the 
patient. For example, the therapist will name the first letter of the omitted word and ask the patient to 
search for it or to establish eye contact with the therapist. The therapist will always sit on the left side of 
the patient because he or she also functions as a cue. The cues will be inserted depending on the 
severity of neglect (Table 1) estimated by the therapist (adaptive therapy). If the reading ability increases 
and neglect dyslexia symptoms decrease, the cueing will be reduced, and the task difficulty will be 
increased by adapting font size and line spacing. Following the protocol established by Turgut et al., the 
reading material will be chosen depending on the patient’s preference to increase the patient’s 
motivation and adherence to the therapy.  
 
 
Exogenous Cues 
Endogenous Cues 
Severe – 
Moderate 
● 
Colored highlight of most of the 
first letters in a word/first word in 
a line  
● 
Colored highlight of the first letter 
of omitted words 
● 
Therapist asks to search for marked 
letter/ word  
● 
Therapist asks to search for her index 
finger, which is positioned at the 
beginning of the line 
● 
Therapist asks for eye contact 
Moderate 
● 
Colored highlight of the first letter 
of omitted words if necessary 
● 
Therapist names first letter of omitted 
word and asks to search for it (if 
necessary, add colored marking) 
● 
Indirect request for eye contact 
Moderate – 
Mild 
● 
Colored highlight of the first letter 
of omitted words if necessary 
● 
Therapist names first letter of omitted 
word and asks to search for it (less 
need for colored marking) 
Mild 
 
● 
Therapist asks to search further to the 
left 
● 
If a word is omitted, therapist asks to 
read the sentence again 
 
Table 1. READ Cueing Protocol. Adapted from Turgut et al. (2018), modified for the present study.  
 
 Flow direction 

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5.2 
Control therapy 
During the control therapy the patients will also receive neuropsychological treatment, but without 
targeting visuospatial attention. Examples for components implemented are supporting conversations, 
diagnostic assessments (e.g. memory diagnostics) and training of memory and executive functions. 
 
 
6 
Outcomes  
 
6.1 
Performance in a computerized neuropsychological test battery  
The neuropsychological assessment of neglect severity will happen by use of a largely investigator-
independent computerized test battery presented on a computer tablet with 17 inches touch screen.  
 
In the screening phase, patients will be confronted with a brief version of the neuropsychological test 
battery to detect signs of hemispatial neglect. This version will include the following subtests: Bells 
cancellation (Gauthier et al. 1989), line bisection, and figure copying (Ogden 1985).  Additionally, 
patients will perform a reading task taken from the German version of the Behavioral Inattention Test 
(BIT). 
 
After the enrolment, during the further course of the study the patients will repeatedly perform a more 
extensive version of the computerized test battery that includes 11 subtests. The tests are executed at 
a tablet screen with touch screen. During the performance of some of these tests (Table 2) eye 
movements will be recorded by use of a non-invasive, video-based remote eye tracking device (EyeLink 
Portable Duo). 
  
The subtests (and parameters that will be analyzed) are the following: 
 
I. 
Word reading: 40 words are successively presented in the center of the screen. We will use two 
different sets of words composed by Reinhart and Kerkhoff (Reinhart und Kerkhoff 2016). The sets 
will be presented alternately (Set 1: T1, T3, T5; Set 2: T2, T4; T6). The patient is asked to read the 
words out loud. The number of correct words is counted. An audio file of the patient’s performance 
will be recorded. 
 
II. 
The Menu reading task is a subtest of the BIT for assessing functional reading. 24 words are 
presented in 4 columns simultaneously. The words are predominantly compound words (e.g. 
“Erbsensuppe”, engl.: “pea soup”). The patient is asked to read the words out loud. The number of 
correct words is counted. An audio file of the patient’s performance will be recorded. 
 
III. 
Text reading: We will use one out of six texts (Kerkhoff et al. 2012) for each test session. Each text 
consists of 180 words and is presented on the tablet screen. The order of the texts will be always 

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the same (T1: Text A; T2: Text B; T3: Text C; …). The patient is asked to read the text out loud. The 
number of correct words is counted. An audio file of the patient’s performance will be recorded. 
 
IV. 
Free viewing: We will use 60 different pictures, downloaded from the free-to-use web-based photo 
stock Pixabay (Figure 3, Appendix A1). They contain for example landscapes, shelfs with books, 
food, etc.. We will split them up randomly into 6 sets à 10 pictures. At each test session the patients 
will be confronted with one of the sets, including the 10 pictures in a random order, each being 
presented for 10 seconds. The patients will be instructed to just look at the pictures and we will 
record the eye movements. The median of all gaze points (fixations) will be analysed with a special 
regard to the neglect-typical rightward bias.  
 
 
  
Figure 3. Examples for pictures of the Free viewing task.  
 
V. 
Posner paradigm: We will implement a version of the classical Posner task (Posner 1980). During 
the task, the display shows a dark-gray background with a light-gray fixation cross at the center and 
two light-gray square frames, positioned on the horizontal meridian at either side with. The cue 
consists of one of the rectangle frames turning yellow for 300ms. After a delay of 150 or 400 ms, 
the target (a light gray asterisk) appears within one of the two frames and remains present until a 
response (press the space-bar) is made, or 2 s have elapsed. In 75 % of the cases the target 
appears in that frame, which before had turned yellow (valid trial). Each block consists of 40 trials, 
and there will be a maximum of 3 blocks. Reaction times and eye movements will be recorded in 
order to calculate an index of lateralized spatial attention (bias). 
Figure 4. Example of a valid trial (cue and target at the same side, here: left) of the Posner task. 
The patient is asked to press the space-bar   when the target (asterisk) appears.   
 
VI. 
Visual search: The patients will perform a visual search task while eye movements are recorded 
(Machner et al. 2018). Each trial will start with a central fixation cross, followed by the presentation 
of a naturalistic image of a desk scene (Figure 5). On the desk, there are 30 different every-day 

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objects (pen, coin, key, etc.). The patients will be instructed to search for a paperclip that could be 
either red or blue. As soon as they find the target, they should press a response button. Each trial 
will be finished after a maximum of 12 s or earlier by a button press upon target detection. In 80% 
of the images there will be a target present, 20 % are no-target trials. At each test session there will 
be 15 trials. The median of gaze points, reaction times and the number of detected targets will be 
recorded in order to analyze the extent of the rightward spatial attention bias. 
 
Figure 5. Desk task stimulus.   
 
VII. 
The Bells test is a cancellation test, which consists of 35 targets (bells) and 280 distractors. The 
stimuli are presented on a tablet screen in the same size as in the paper-and-pencil (PnP)-version. 
The patient will be asked to tick the bells with a stylus/ pen. Ticked stimuli will be marked with a red 
circle (figure 6). Maximum time for processing will be 7 minutes. Dependent variables will be the 
point of beginning (pob, distance of the left border of the screen), the Center of Cancellation (CoC, 
calculated as in (Rorden und Karnath 2010), the relative test performance (100 * (bells circled / 35)) 
and the oculomotor median.  
 
Figure 6. The bells test. Stimuli ticked by the patients will be marked with a green line irrespective 
of whether they are targets (bells) or distractors.  
 

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VIII. 
In the line bisection task 3 lines, each 20 cm long, are successively presented on the tablet. The 
patient is instructed to mark the middle of each line. Mean deviation from the center will be assessed.  
 
IX. 
The Hearts Cancellation task (figure 7) is part of the Oxford Cognitive Screen (Demeyere et al. 
2015). It’s a cancellation task consisting of 50 targets (hearts without a gap), and 100 distractors 
(50 hearts with a gap on the left, 50 hearts with a gap on the right). The patient’s task is to tick all 
the hearts without a gap. Maximum time for processing will be 5 minutes. The number of ticked 
targets and distractors is counted and will be used to calculate the spatial bias with regards to the 
whole test sheet (egocentric) and with regards to the individual objects (allocentric).  
 
Figure 7. Hearts Cancellation Task. The targets are the ones without a gap, the others are 
distractors with a gap on the left or on the right side.  
 
X. 
Figure copying: Patients are asked to copy the Ogden scene (Ogden 1985), i.e. drawing a tree, a 
fence, a house and a second tree. Performance is evaluated on a five-level scale ranging from 0 
(no omissions) to 4 (omission of at least one left sided object and a left part of another object). 
 
XI. 
Clock drawing: The task is part of the BIT, in which the patient has to write the numbers of a clock 
(from 1 to 12) clockwise in an empty circle (xx cm in diameter). Then we ask the patient to add two 
pointers at the right place so that the clock shows “10 past 11”. The scoring will be a value between 
1 (perfect performance) and 6 (no representation of a clock). 
 
There are several benefits of executing the neglect assessment digitally. On the one hand test execution 
is more standardized and the evaluation of the data is less time-consuming for the therapist. On the 
other hand, which is even more important, more parameter can be recorded, like reaction times, order 
of processing or eye movements. Several studies have shown, that computerized tasks measuring 
reaction times are more sensitive than standard paper-and-pencil tasks. Those digital performed 
reaction time tasks can reveal an ipsilesional spatial attention bias in patients without clinical signs of 
neglect. To uncover this “hidden” neglect is essential, because it can have an impact on everyday life 
situation, for example during orientation in traffic (Machner et al. 2018).    
 
 

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Eye movement 
recordings 
Audio file 
recording 
Evaluation/ 
Scoring 
 
Subtests 
 
 
 
I 
Reading: word 
x 
x 
manually 
II 
Reading: menu 
x 
x 
manually 
III 
Reading: text 
x 
x 
manually 
IV 
Free viewing 
x 
 
digital 
V 
Posner-Task 
x 
 
digital 
VI 
Visual search 
x 
 
digital 
VII 
Bells-Test 
 
 
digital 
VIII 
Line bisection 
 
 
digital 
IX 
Heart Cancellation task 
 
 
digital 
X 
Clock test 
 
 
manually 
XI 
Figure copying 
 
 
manually 
 
Table 2. Overview of the subtests included in the neuropsychological test battery  
(including information on eye movement and audio file recordings) 
 
 
6.2 
Functional impairment as assessed by a clinical scale for neglect-related disability 
We will assess the neglect-related impairments in activities of daily living (ADL) using the German 
version of the Catherine Bergego Scale (CBS) (Bergego et al. 1995). To obtain information about the 
degree of anosognosia the patient her-/himself will fill out the CBS, so that we can compare the patient’s 
score and the value scored by the investigator (care-providers on the ward). Notably, the investigator 
version of the CBS will be evaluated by therapeutic staff not involved in the study to ensure a maximum 
of objectivity.  
In addition, we will score the Barthel Index (BI) and the Functional Independence Measurement (FIM) 
as an assessment of the patients’ overall ability in ADLs.  
 
 
6.3 
Definition of primary and secondary outcome measures 
As relevant outcome measures we will calculate the within-subject difference between the test sessions 
T3 and T5 for the following parameters: 
 
Primary outcome: 
I. 
Composite score of the performance in the neuropsychological test battery (mean of the 
normalized values of the different subtests, range: 0 - 100%) as a measure of neglect severity 
and the ipsilesional spatial attention bias 
 
II. 
Score of the Catherine Bergego Scale (investigator version, range: 0-30 points) as a measure 
of neglect-related functional disability 
 
 

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Secondary outcome:  
I. 
Performance in the individual subtests of the computerized test battery  
II. 
Anosognosia (difference between CBS_other and CBS_self) 
III. 
Non-neglect specific functional outcome scores (BI, FIM) 
 
 
 
7 
Sample size  
Based on the successful inclusion of 30 patients in this two-arms crossover study, the probability is 80 
percent (power) that the study will detect a treatment difference at a two-sided 0.05 significance level, if 
the true difference between treatments is 0.25 units (25% effect size). This is based on the assumption 
that the within-patient standard deviation of the response variable is 0.33 (33% standard deviation). With 
respect to an estimated drop-out rate of 20%, we are going to enroll 36 patients in total. 
 
 
8 
Randomisation 
 
8.1 
Method used to generate the random allocation sequence 
The random allocation sequence will be generated using a web-based randomization tool 
(https://www.sealedenvelope.com/simple-randomiser/v1/lists).  
 
8.2 
Type of randomization 
A permuted block technique with randomly varying block lengths will be used to randomize patients into 
either the IC (Intervention first) or the CI (Control treatment first) group. The ratio will be 1:1 (balanced 
randomization). 
 
9 
Implementation of the allocation process  
The random allocation sequence list will be stored at the office of an employee of the University of 
Lübeck, Dept. of Neurology, who has no direct clinical involvement in the trial. After successful 
screening, check of the inclusion and exclusion criteria and reception of the patient’s informed consent, 
the investigator at the Rehabilitation Centre will contact the keeper of the generated randomization list 
at the University of Lübeck via email, he will provide the patient’s study ID and whether the necessary 
preconditions for the allocation are fulfilled (inclusion/exclusion criteria checked, informed consent 
obtained) and finally ask for the randomized allocation. The keeper of the list will then tell the 
randomization result, i.e. whether the patient is allocated to the IC or the CI group.  
Notably, the therapist at the Rehabilitation Center is never aware of the order of the sequence nor the 
block lengths, hence he is not able to predict the randomization result (no selection bias).  
 

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10 Blinding 
Due to the implicit constraints of cognitive interventions (no placebo possible as opposed to drug 
studies), neither the patient himself nor the therapist of the study can be blinded to the patient’s allocation 
arm. However, the assessment of the functional impairment (CBS score as a primary outcome) will be 
performed by rehabilitation staff who are blind to the patient’s allocation. Furthermore, the assessment 
of the neglect severity by use of a computerized neuropsychological test battery is robust and objective 
and largely independent of the investigator who is administering the test.  
 
11 Statistical methods 
 
11.1 
Statistical methods used to compare groups for primary and secondary outcomes 
Statistical analyses will follow the rules of proper use of the crossover design in clinical studies (Wellek 
and Blettner 2012). First, the intra-individual difference (Delta) between the outcome results of the two 
treatment phases (I and C) will be calculated for each patient in the two study groups (IC and CI). Next, 
an independent t-test will be applied to assess a significant difference between the intra-individual Delta 
of study group IC and the ones of study group CI.  
This way of statistically analyzing the efficacy of an intervention investigated by a crossover design 
applies to all the primary and secondary outcome measures in our study.  
 
11.2 
Methods for additional analyses, such as subgroup analyses and adjusted analyses 
There are no pre-specified subgroups.  
 
12 Data monitoring (Interim Analysis) 
An interim analysis will be performed on the primary endpoints when n=22 patients have been 
randomized and have successfully completed the trial. This number is derived from an adjusted sample 
size calculation with an assumed higher effect size of 30% (see also section 7 Sample size; current 
assumption 25% effect size). The statistical method used for the interim analysis is the same approach 
as stated above (section 11.1 Statistical methods). In case of superiority or inferiority of the intervention 
(vs. control treatment) at this stage, the study will be prematurely terminated. We do not plan to stop the 
trial at this stage for other reasons (e.g. futility).  
 
 

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Appendix 
 
A1 Stimuli for the free viewing task 
List of pictures downloaded at https://pixabay.com/ (title and number).  
 
1 
Animal 
3437467 
 
31 Flea_market 
1681489 
2 
Auto 
3091234 
 
32 Food 
1679815 
3 
Avenue 
2215317 
 
33 Fruit_basket 
1114060 
4 
Away 
3024773 
 
34 Home 
1438326 
5 
Bathroom 
3563272 
 
35 Houses 
1622066 
6 
Berries 
1546125 
 
36 Kitchen 
1566964 
7 
Bookcase 
3532950 
 
37 Kitchen 
2565105 
8 
Bookcase 
3532957 
 
38 Landscape 
3714664 
9 
Books 
2463779 
 
39 Living_room 
670237 
10 
Bowling 
596766 
 
40 Marbles 
1659398 
11 
Bowling_shoes 
2779989 
 
41 Music 
2060616 
12 
Breads 
387544 
 
42 Nuclear_waste 
1471361 
13 
Bridge 
192982 
 
43 Parking 
825371 
14 
Cafe 
3537801 
 
44 Pier 
349672 
15 
California 
106943 
 
45 Potatoes 
411975 
16 
Christmas 
1075121 
 
46 Raspberry 
2023404 
17 
Church 
3481187 
 
47 Road 
220058 
18 
Closet 
3725417 
 
48 Salt_harvesting 
3060093 
19 
Clubs 
518192 
 
49 Sand 
1573326 
20 
Cock 
2522623 
 
50 Shelf 
1853439 
21 
Coffee 
751619 
 
51 Still_life 
562357 
22 
Coffee 
2390136 
 
52 Still_life 
851328 
23 
Colorful 
2653188 
 
53 Store 
984393 
24 
Computer 
627220 
 
54 Summer 
814679 
25 
Countryside 
2326787 
 
55 Summer 
2391348 
26 
Daisy 
324403 
 
56 Tray 
2546077 
27 
Dolls_kitchen 
546966 
 
57 Wash 
1141774 
28 
Fashion 
1031469 
 
58 Wheelie_bin 
2270582 
29 
Flea_market 
851970 
 
59 Woodland 
656969 
30 
Flea_market 
851978 
 
60 Workshop 
984022