Patient population
This study will include a population of patients with COPD from the region of South Limburg, the Netherlands. Patients are eligible if they have a diagnosis of COPD based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (3) and if they are not affected by any of the exclusion criteria (Table 1). Once participants have agreed to participate in the study they will be randomly allocated into the treatment or control arm. All measurements will be performed at Maastricht University Medical Center.
Table 1: Exclusion Criteria
Exclusion criteria
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Disease and/or disability limiting ability to undergo neuropsychological testing and/or WMT (e.g. blindness, stroke, or lack of hand control)
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Neurological disorders (e.g. Alzheimer’s Disease, Parkinson’s, Huntington’s disease)
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Insufficient mastery of the Dutch language
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Participation in an inpatient PR programme during study period
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Participation in another intervention study during study period
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Patients will be recruited using local advertising in newspapers, magazines, and local physiotherapy practices. In addition, patients who have participated in previous studies and have indicated that they may be contacted for future studies, as well as COPD patients visiting the outpatient clinics will be approached.
Intervention
A double blind, placebo-controlled randomised trial will be conducted on 60 patients with COPD. The trial consists of two phases; 12 weeks of intensive training (n=30) or sham training (n=30) (T0-T12) followed by 12 weeks of active follow-up (T12-T24) (figure 1). Of the 30 sessions, patients may miss five sessions. After they have missed three sessions the investigators will be notified and contact the participants. If patients miss more than five training sessions they will be withdrawn from the study. Patients will be evaluated at a screening appointment, baseline, T12 and T24.
This study followed the Spirit Guidelines (54), refer to supplementary materials and Supplementary table 1. All assessments will be performed by MvB, LS and SM.
Working memory training
The WMT consists of three different tasks: a visuospatial task, a backward digit span task, and a letter span task. In the visuospatial task, participants will be shown a four-by-four grid of squares, some of which flash in blue one after the other. Participants will be required to recall which squares flashed in blue and in which order, by clicking the squares. In the backward digit span task, numbers will be presented on a computer screen, and the participants will be required to reproduce the sequence in the reverse order. Lastly, in the letter span task, letters will be presented one by one in the centre of the screen, and simultaneously with every letter, an accompanying arm will light up (see Figure 2). After all letters have been presented along with their corresponding arms, one arm will light up in red, and participants are required to indicate the letter belonging to that arm on the keyboard of the computer. Participants in the control (sham) group will receive the same tasks as those in the training group but in contrast to the intervention group the tasks will not increase in difficulty by increasing the number of digits, or complexity of the pattern to be recalled (45).
In the first phase of the study, participants will receive 30 training sessions over a 12-week period, and have to complete at least 25 sessions. Participants will receive a link to every session through e-mail, and have 48 hours to complete a session after receiving the e-mail. In phase two (T12-T24) we will investigate the longer-term effects of the intervention. There is evidence to support the maintenance of the training effect after the cessation of the intervention (55-58). However, providing booster sessions could greatly enhance the long-term effects of the training. Ball et al. (59) demonstrated that one booster session compensated for nearly five months of cognitive decline, and the positive results of the training intervention were apparent for years after it ended. Given the potential benefits of booster sessions we will therefore offer the participants one booster session per week for three months in the maintenance phase (phase two) after completion of the training.
Goal setting
Behaviour with respect to physical activity and dietary intake will be measured at T0 and at the end of phase 1 (T12) and 2 (T24) in both the intervention and the control group. Physical activity data will be collected by an ActivPALTM accelerometer. This device provides a well-established measurement of both physical activity and sedentary time. Subjects wear the accelerometer fastened to their leg with TegadermTM adhesive tape for 7 consecutive days. The ActivPALTM calculates body posture as sitting/lying, standing, and stepping and energy expenditure (METs) using static and dynamic acceleration information (60). Energy expenditure can then be classified from the ActivPALTM into sedentary (G1.5 METs), light (1.5–2.99 METs), and MVPA (>3 METs) intensity (60).
Dietary intake will be monitored using a 24-hour recall questionnaire in the form of an interview. Participants will be asked if the past 24 hours were reflective of typical dietary intake. If dietary intake varied significantly from normal, participants will be asked to recall their intake on the previous day.
After having analysed the accelerometry data and the dietary questionnaire, participants will be informed about the results by a trained research assistant. Dietary and/or physical activity goals will then be set by the patients together with the research assistant. Representative scores will be calculated based on the Alternative Healthy Eating Index (AHEI) (61) to aid participants in understanding how they can improve their diets. Information will be presented as a score and in graphical form for individual categories such as fruit, vegetable, red meat, excessive alcohol consumption, among others, for easy interpretation and guided goal setting discussions. Physical activity will be presented as daily step counts, and percent time spent in sitting, standing and moving activities in the form of graphs. The graphs will also clearly show the time of day which type of activity was performed. Goals can include dietary changes such as reducing alcohol, red meat, increasing whole grains, fruit and or vegetable consumption; physical activity will be in the form of steps per day.
Study parameters and endpoints
The study parameters are listed in Table 2. Study participants will visit twice, separated by a week, before the study (T0) to determine baseline performance. Additionally, they will be tested at the end of phase one after 12 weeks (T12) and at the end of phase two after 24 weeks (T24). All measurements will be taken by the trained investigators.
Primary outcome: measures of cognitive function
The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a widely used cognitive function assessment tool which has been used in a large range of clinical and non-clinical studies. Using the CANTAB system, we will test WM, cognitive flexibility, and planning with the motor screening task, paired associated learning task, reaction time task, delated matching to sample task and a spatial WM task. Furthermore, we will administer the Stop-Signal Task (SST) as a measure of impulsivity.
As an additional measure of cognitive function, we administer the Addenbrooke’s Cognition Examination Revised (ACE-R); a brief test battery which assesses five domains, namely: orientation and attention, memory, verbal fluency, language and visuospatial ability. The ACE-R is a comprehensive screening tool, and has good psychometric properties: both sensitivity and specificity are around 0.9 (62-64).
Secondary measurement outcomes
Additional outcome measures will include a measure of perceived stress (Cohen’s Perceived Stress Scale (PSS)) (65), chronic stress (hair cortisol) (66), acute stress (salivary cortisol awakening response (CAR)) (67), stress response (socially evaluated cold pressor test (SECPT)) (68), functional exercise capacity (6 minute walk test) (69), physical performance (short performance test battery (SPBB)) (70), disease-specific health status (COPD assessment test, (CAT)) (71), motivation for exercise and dietary intake (Behavioral Regulation in Exercise Questionnaire-2 (BREQ-2)) (72), the Regulation of Eating Behavior Scale REBS (73), depression (Beck depression inventory (BDI-II)) (74), anxiety (generalised anxiety disorder-7 (GAD-7)) (75) and dietary intake (Food frequency questionnaire (FFQ)).
Table 2 – Measurement timing of study parameters
Primary outcomes
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Instrument
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T0
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T1
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T12
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T24
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Cognitive performance
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|
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Cambridge Neuropsychological Test Automated Battery
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X*
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X
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X
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X
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The Addenbrooke's Cognitive Examination Revised
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X
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|
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Secondary outcomes
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Cognitive stress susceptibility and perception
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Chronic stress
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The Perceived Stress Scale
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X
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X
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X
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Hair cortisol
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X
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X
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Salivary cortisol awakening response
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X
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X
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Acute stress
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Socially Evaluated Cold pressor test
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X
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X
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X
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Physical activity
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|
|
|
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Accelerometer: step count, gait variability
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X
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X
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X
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6-minute walking test
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X
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X
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X
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X
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Balance
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|
Short Performance Battery
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X
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X
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X
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Quality of life
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|
|
|
|
|
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COPD assessment test
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X
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X
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X
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Motivational questionnaires
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Behavioural Regulation in Exercise Questionnaire-2
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X
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|
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X
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Regulation of Eating Behaviour Scale
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X
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|
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X
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Psychological wellbeing
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Beck Depression Inventory- second edition
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X
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X
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X
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Generalised Anxiety Disorder-7
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X
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X
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X
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Dietary intake
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|
|
|
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Food Frequency Questionnaire
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X
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X
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X
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|
|
|
|
|
|
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Other characteristics
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Socioeconomic variables
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|
|
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Age, gender, education level
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X$
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X$
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|
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Anthropometry
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|
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Height
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X$
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X$
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|
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Bioelectrical impedance
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X$
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X$
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X
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X
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Waist circumference
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X$
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X$
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|
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Weight
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X$
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X$
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X
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X
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Other clinical characteristics
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|
|
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Smoking status, , exacerbations, COPD Gold classification, spirometry
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X
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|
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Medication
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|
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|
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Questionnaire
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|
X
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X
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X
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Manipulation Check
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|
|
|
|
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Manipulation check
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|
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X
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X
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Compliance and accessibility
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Training compliance
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X
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X
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* Required to compensate for any possible learning effects.
$ Measurements may be taken at screening or T1.
Manipulation check
This will be done in the form of a very short structured interview in which the participant will be asked to recall and name the specific dietary and physical activity goals they made at the beginning of the intervention. This test will be administered in a way similar to that of Hatchell and colleagues (76), where participants are asked to recall key health messages from their personalised healthy lifestyle advice sessions. Patient responses will be recorded in writing. The recalled points will be compared to the personalised advice given to the participant. Responses will then be scored as follows: 0 points – field blank or no recall of the message content; 1 point – key points not directly related to the message themes; 2 points – key points directly related to the message themes (76). Patients who recall more information will be given higher scores.
Compliance and accessibility
Training compliance will serve as a measure of compliance and accessibility of the WMT. During the trial, patient participation in the online sessions will be recorded. Here we can examine participant engagement to the training (total time spent), number of completed sessions, answer patterns as well as monitor attrition rate.