Working memory training efficacy in COPD: the randomised, double-blind, placebo-controlled Cogtrain trial

Martijn van Beers; Sarah W. Mount; Katrijn Houben; Harry R. Gosker; Lisanne Schuurman; Frits M.E. Franssen; Daisy J.A. Janssen; Annemie M.W.J. Schols

doi:10.1183/23120541.00475-2021

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FIGURE 1
Study design.
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FIGURE 2
Study flowchart. WMT: working memory training.
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FIGURE 3
Working memory span over the course of the first (session 1–30) and second phase (session 31–42) of the working memory training.

TABLE 1

Outcome measures and time points at which they were taken

Instrument	T0	T1	T2	T3
Baseline demographic and clinical characteristics
Age, sex, educational level, smoking status	X
Spirometry	X
Manipulation check		X	X
Working memory span		X	X
Number of completed sessions		X	X
Primary outcome measures
Cambridge Neuropsychological Test Automated Battery^#	X	X	X	X
Addenbrooke's Cognitive Examination-Revised		X
Secondary outcome measures
Physical capacity and activity
6-min walk test		X	X	X
Short Physical Performance Battery		X	X	X
Accelerometry		X	X	X
Dietary intake
Alternative Healthy Eating Index-2010	X		X	X
Cognitive stress susceptibility and perception
Cortisol Awakening Response		X	X
Perceived Stress Scale		X	X	X
Socially Evaluated Cold Pressor Test		X	X	X
Healthy lifestyle goal recall^¶			X	X
Exploratory outcome measures
Healthy lifestyle motivation
Behavioural Regulation of Exercise Questionnaire-2	X			X
Regulation of Eating Behaviours Scale	X			X
Psychological wellbeing
Beck Depression Inventory-II		X	X	X
Generalised Anxiety Disorder-7		X	X	X

T0: baseline minus 1 week; T1: baseline; T2: after the first phase (baseline+12 weeks); T3: after the second phase (baseline+24 weeks). ^#: administration at T0 took place to compensate for learning effects. ^¶: healthy lifestyle goals were set at T1.

TABLE 2

Baseline demographic and clinical characteristics

	Intervention		Placebo
	n		n
Age (years)	33	66.0±6.8	31	66.4±7.8
Sex (male/female)	33	13/20	31	16/15
Educational level	33		31
Primary school		2 (6.1%)		0 (0.0%)
Initial vocational education		0 (0.0%)		3 (9.8%)
High school		10 (30.3%)		10 (32.3%)
Intermediate vocational education		6 (18.2%)		8 (25.8%)
Higher vocational education		12 (36.4%)		10 (32.3%)
Academic		3 (9.1%)		0 (0.0%)
Smoking status (never/current/former)	33	8/3/22	31	6/6/19
Lung function
GOLD stage (I/II/III/IV)	31	8/11/11/1	30	5/15/7/3
FEV₁ (L)	31	1.75±0.76	30	1.69±0.69
FEV₁ (% predicted)	31	58.5 (44.7–82.5)	30	60.6 (44.9–71.8)
FVC (L)	31	3.55±1.03	30	3.49±0.98
FEV₁/FVC (%)	31	49.0±14.7	30	48.4±14.7
ACE-R (0–100)	33	88 (82–93)	31	88 (83–94)

Data presented as mean±sd or median (interquartile range) depending on the normality of the distribution of the data, unless otherwise indicated. No parameters were significantly different between the groups. GOLD: Global Initiative for Obstructive Lung Disease; FEV₁: forced expiratory volume in 1 s; FVC: forced vital capacity; ACE-R: Addenbrooke's Cognitive Examination-Revised.

TABLE 3

Descriptive statistics of the primary (Cambridge Neuropsychological Test Automated Battery, CANTAB) outcome measures

Test	Measure	T1		T2		T3
		Intervention	Placebo	Intervention	Placebo	Intervention	Placebo
MOT	Mean latency (ms)	896 (696–1031)	894 (761–1056)	903 (755–980)	865 (736–961)	860 (771–940)	827 (745–976)
PAL	Total errors (n)	13.0 (11.0–20.0)	13.0 (8.0–17.0)	13.0 (10.0–16.0)	13.0 (11.0–17.0)	13.0 (9.0–18.0)	13.0 (9.0–21.0)
	Adjusted total errors (n)	20.0 (12.0–39.0)	19.0 (10.0–41.0)	14.0 (10.0–42.0)	16.0 (11.0–24.0)	17.0 (9.0–36.0)	14.5 (9.0–21.0)
	First attempt memory score	9.76±3.83	10.55±4.56	10.89±4.34	10.56±3.53	10.88±3.17	12.27±3.06
SST	Stop-signal reaction time (ms)	244 (220–272)	240 (213–275)	258 (240–276)	236 (215–262)	249 (224–267)	223 (208–253)
RTI	Median simple reaction time (ms)	328 (308–349)	340 (316–366)	331 (311–350)	349 (325–365)	341 (320–361)	361 (338–386)
	Mean simple movement time (ms)	253 (216–286)	243 (207–302)	250 (225–288)	264 (229–313)	272 (214–303)	272 (223–326)
	Median five-choice reaction time (ms)	399 (366–429)	392 (370–412)	399 (366–426)	392 (358–425)	425 (382–441)	419 (379–450)
	Mean five-choice movement time (ms)	290 (240–313)	283 (245–331)	282 (271–339)	309 (258–331)	272 (239–312)	307 (250–336)
DMS	Correct responses (%)	85.0 (80.0–90.0)	85.0 (75.0–90.0)	90.0 (85.0–95.0)	85.0 (75.0–95.0)	85.0 (80.0–95.0)	85.0 (77.5–92.5)
	Median correct latency (ms)	3027 (2494–3370)	3294 (2593–3488)	3003 (2478–4305)	3255 (2475–4342)	3295 (2411–4243)	3159 (2534–4490)
	Probability of error given error (%)	0.0 (0.0–20.0)	0.0 (0.0–16.7)	0.0 (0.0–0.0)	0.0 (0.0–20.0)	0.0 (0.0–25.0)	0.0 (0.0–21.0)
SWM	Between-errors (n)	16.0 (6.0–21.0)	15.0 (6.0–23.0)	15.0 (7.0–20.0)	17.0 (10.0–20.0)	16.0 (9.0–21.0)	12.0 (4.0–19.0)
	Between-errors 4 boxes (n)	0.0 (0.0–1.0)	0.0 (0.0–2.0)	0.0 (0.0–0.0)	0.0 (0.0–1.0)	0.0 (0.0–2.0)	0.0 (0.0–0.0)
	Between-errors 6 boxes (n)	3.0 (0.0–6.0)	4.0 (0.0–7.0)	4.0 (1.0–7.0)	4.0 (1.0–7.0)	2.0 (0.0–7.0)	2.0 (0.0–6.0)
	Between-errors 8 boxes (n)	11.0 (4.0–15.0)	10.0 (5.0–14.0)	10.0 (5.0–14.0)	11.0 (6.0–14.0)	12.0 (8.0–14.0)	10.0 (3.0–14.0)
	Strategy	8.0 (7.0–10.0)	8.0 (6.0–10.0)	9.0 (7.0–10.0)	9.0 (6.0–10.0)	8.0 (6.0–9.0)	9.0 (7.0–9.0)

Data presented as mean±sd or median (inter-quartile range) depending on the normality of the distribution. MOT: motor orientation task; PAL: paired associates learning; SST: stop-signal task; RTI: reaction time task; DMS: delayed match-to-sample; SWM: spatial working memory.

TABLE 4

Effect sizes of the primary (Cambridge Neuropsychological Test Automated Battery, CANTAB) outcome measures

Test	Measure	Phase 1			Phase 2
		F time	F group	F int.	F time	F group	F int.
MOT	Mean latency (ms)	0.21	0.35	0.84	0.44	0.09	0.36
PAL	Total errors (n)	1.23	0.31	3.79	4.63*	0.35	0.88
	Adjusted total errors (n)	3.79	1.09	0.30	0.68	0.67	0.01
	First attempt memory score	0.58	0.45	1.16	1.82	0.67	2.32
SST	Stop-signal reaction time (ms)	0.04	4.76*	0.39	2.88	4.41*	0.78
RTI	Median simple reaction time (ms)	1.96	1.30	0.00	7.53**	2.47	0.26
	Mean simple movement time (ms)	2.61	0.42	3.73	2.96	1.20	0.02
	Median five-choice reaction time (ms)	0.88	0.00	2.47	9.13**	0.77	0.27
	Mean five-choice movement time (ms)	1.10	0.05	0.01	1.00	0.17	6.20*
DMS	Correct responses (%)	1.25	1.12	0.00	1.91	0.99	0.04
	Median correct latency (ms)	2.11	0.63	0.11	0.23	0.22	1.31
	Probability of error given error (%)	0.13	0.51	4.63*	0.00	1.15	1.06
SWM	Between-errors (n)	0.04	0.10	1.91	0.55	1.25	3.54
	Between-errors 4 boxes (n)	0.14	0.52	0.01	0.16	0.14	2.54
	Between-errors 6 boxes (n)	0.10	0.41	0.14	1.28	1.83	1.87
	Between-errors 8 boxes (n)	0.02	0.09	1.92	0.19	0.78	2.65
	Strategy	0.40	0.25	1.12	0.10	0.46	2.05

int.: interaction; MOT: motor orientation task; PAL: paired associates learning; SST: stop-signal task; RTI: reaction time task; DMS: delayed match-to-sample; SWM: spatial working memory. All data expressed as F-values. *p<0.05. **p<0.01.

TABLE 5

Descriptive statistics of the secondary outcomes of the intervention

	T1		T2		T3
	Intervention	Placebo	Intervention	Placebo	Intervention	Placebo
Physical capacity and activity
6MWD (m)	456.5±94.1	459.0±74.7	463.9±88.0	452.9±76.3	454.4±108.0	448.2±86.8
6MWD (% predicted)	73.6±13.9	72.5±10.9	74.9±13.8	71.9±12.5	73.2±16.7	71.3±15.2
SPPB total score (0–12)	10.0 (9.0–11.0)	11.0 (9.0–12.0)	10.0 (9.0–11.0)	10.0 (9.0–11.0)	11.0 (10.0–12.0)	10.0 (9.0–11.0)
Sedentary time (h·day⁻¹)	18.1±1.9	18.4±1.7	18.3±1.8	18.5±1.8	18.3±1.6	18.2±1.7
Standing time (h·day⁻¹)	4.2 (2.8–5.3)	3.8 (3.0–5.1)	4.0 (3.0–5.2)	3.7 (3.4–4.6)	3.7 (3.2–5.2)	4.0 (3.4–5.2)
Stepping time (h·day⁻¹)	1.8 (1.1–2.2)	1.6 (1.0–1.8)	1.7 (1.1–2.1)	1.3 (0.9–1.9)	1.5 (1.2–2.2)	1.5 (1.1–1.9)
Sedentary breaks (number·day⁻¹)	31.7 (26.1–40.9)	31.5 (25.4–39.6)	36.4 (27.6–40.1)	34.7 (30.1–38.3)	37.1 (29.0–39.7)	35.1 (27.9–38.6)
Sedentary bouts (>30 min) (number·day⁻¹)	35±12	31±13	38±12	32±15	34±14	33±11
High-intensity PA	8.73 (4.09–20.21)	7.74 (4.08–17.86)	8.68 (2.29–26.58)	9.36 (4.29–16.07)	9.13 (3.42–15.64)	8.62 (2.75–15.31)
Dietary quality
AHEI-2010	50.0±12.8	50.0±9.6	53.7±13.3	55.9±8.7	51.0±13.5	52.1±12.4
Cognitive stress susceptibility and perception
AUC (CAR) (arbitrary units)	534 (270–609)	512 (341–690)	459 (264–759)	424 (342–630)	—	—
Delta (SECPT) (μmol·L⁻¹)	0.00 (0.00–1.66)	0.00 (0.00–2.68)	0.00 (0.00–0.06)	0.00 (0.00–0.58)	0.00 (0.00–2.04)	0.00 (0.00–0.72)
Perceived Stress Scale	10.9±5.3	13.3±6.9	11.7±4.8	13.4±5.8	10.3±5.5	13.3±6.7
Healthy lifestyle goal recall
Content recall (0–4)	—	—	0.3 (0.0–1.0)	0.3 (0.0–0.5)	0.0 (0.0–0.6)	0.0 (0.0–0.4)
Procedure recall (0–2)	—	—	1.0 (0.0–2.0)	0.0 (0.0–1.3)	0.0 (0.0–2.0)	0.0 (0.0–2.0)

All data expressed as mean±SD or median (inter-quartile range) depending on the normality of the distribution of the data. 6MWD: 6-min walk distance; SPPB: Short Physical Performance Battery; PA: physical activity; AHEI: Alternative Healthy Eating Index; AUC: area under the curve; CAR: cortisol awakening response; SECPT: socially evaluated cold pressor test; —: not taken at this time point.

TABLE 6

Effect sizes of the secondary outcomes of the intervention

Measure	Phase 1			Phase 2
	F time	F group	F int.	F time	F group	F int.
Physical capacity and activity
6MWD (m)	0.10	0.05	0.61	1.00	0.11	0.20
6MWD (% predicted)	0.25	0.46	0.70	1.23	0.39	0.29
SPPB total score (0–12)	0.05	0.03	0.00	0.30	0.96	1.48
Sedentary time (h·day⁻¹)	0.00	1.16	1.17	1.24	2.74	0.80
Standing time (h·day⁻¹)	0.60	0.10	0.07	0.07	0.07	0.10
Stepping time (h·day⁻¹)	0.35	1.04	0.03	0.19	1.14	2.01
Sedentary breaks (number·day⁻¹)	9.14**	0.43	0.50	0.05	2.17	0.18
Sedentary bouts (>30 min) (number·day⁻¹)	0.42	1.29	0.03	0.99	2.21	0.99
High-intensity PA	2.45	0.20	0.12	0.26	0.64	0.11
Dietary quality
AHEI-2010	5.04*	0.11	0.26	1.87	0.31	0.00
Cognitive stress susceptibility and perception
AUC (CAR) (arbitrary units)	0.02	0.14	0.74	—	—	—
Delta (SECPT) (μmol·L⁻¹)	6.05*	0.08	0.14	0.93	1.46	4.19*
Perceived Stress Scale	0.52	2.41	0.10	2.55	2.27	1.05
Healthy lifestyle goal recall
Procedure recall (0–4)	—	—	—	0.00	1.63	1.02
Content recall (0–2)	—	—	—	3.16	2.14	0.15

All data expressed as F-values. 6MWD: 6-min walk distance; SPPB: Short Physical Performance Battery; PA: physical activity; AHEI: Alternative Healthy Eating Index; AUC: area under the curve; CAR: cortisol awakening response; SECPT: socially evaluated cold pressor test; —: not taken. *p<0.05. **p<0.01.

Supplementary Materials

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Supplementary Material
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