1. INTRODUCTION:

Stroke patients with cognitive impairment experience considerable difficulty in exercise learning during rehabilitation training¹, with limited active participation in physical training, and may temporarily or permanently lose normal posture control mechanisms that were automatically processed². Therefore, cognitive impairment is an essential management item for stroke rehabilitation³.

Dual-task training, one of the methods for improving cognitive function, involves performing multiple tasks simultaneously⁴, and requires individuals to perform a cognitive task while performing a motor function, thereby inducing a mutual conflict situation between the efforts to perform the 2 tasks⁵. Compared with performing a single task, a dual task reportedly provides more stimulation to the prefrontal lobe of the brain that is responsible for cognitive function, and induces extended brain activation⁶.

Neurotrophic factors are neurophysiological substances that affect cognitive function^7,8. These have been shown to have positive effects on cognitive function, including neuronal production⁹, regrowth of damaged neurons¹⁰, capillary creation, and growth promotion¹¹. One method used to stimulate the production of neurotrophic factors is exercise¹².

Dual-task training has been investigated in studies that performed 2 kinds of exercise tasks at the same time and other studies that performed an exercise task and a cognitive task at the same time^13,14. In the present study, different intensity of treadmill training was used as an exercise task and a cognitive task was applied at the same time. Treadmill aerobic exercise was performed at low intensity, moderate intensity and high intensity, based on the estimation of exercise amount, time, and speed. The present study aimed to investigate the effects of dual-task training with different intensity of aerobic exercise on cognitive function and neurotrophic factors in chronic stroke patients.

2. MATERIALS AND METHODS:

2.1. Study participants:

A total of 27 patients with chronic stroke in this study provided signed informed consent after receiving an explanation of the purpose and methods of the study. Resting heart rates were measured. The study was conducted in compliance with the Declaration of Helsinki. Inclusion criteria were as follows: duration of stroke between 6 months and 2 years, mild cognitive decline with an MMSE-K score of 18 to 23, ability to communicate, no contraindication to exercise testing using American College of Sports Medicine (ACSM) guidelines, ability to independently perform the 10-m walk within 12 s, and taking no medication that could affect the experiment (Table 1). The subjects were randomly assigned to group I (low-intensity aerobic exercise plus dual-task training, n=9), group II (moderate-intensity aerobic exercise plus dual-task training, n=9), and group III (high-intensity aerobic exercise plus dual-task training, n=9) based in the results of screening tests (MMSE-K, VO_2max). Cognitive function (MMSE-K, Stroop test, Trail making test) was assessed and blood analysis (BDNF, IGF-1) was performed to evaluate the results of training.

Table 1. Characteristics of study participants

Characteristics	Group I	Group II	Group III
Age (years)	59.77±4.40	58.22±4.46	5755±5.52
Sex (male/female)	4/5	5/4	5/4
Duration (month)	14.66±3.39	15.11±2.14	14.88±2.20
Causes (Infar/Hemorr)	6/3	5/4	5/4
Affected side (Lt/Rt)	5/4	5/4	4/5

All data are expressed as means with standard deviation (M±SD)

Group I: Low intensity aerobic exercise group by dual task training (40% VO₂max)

Group II: Moderate intensity aerobic exercise group by dual task training (55% VO₂max)

Group III: High intensity aerobic exercise group by dual task training (70% VO₂max)

2.2. Procedures:

2.2.1. Measurement of maximum oxygen uptake:

Maximum oxygen uptake was measured using a modified Bruce protocol¹⁵with a treadmill (WNT-2000i, GE Medical System Co., Korea) exercise test and a portable wireless respiratory gas analyzer (K4b2; COSMED Srl, Rome, Italy). Heart rate, Borg Rating of Perceived Exertion Scale (Borg RPE), oxygen uptake (VO₂), and respiratory exchange ratio (RER) were recorded every minute¹⁶. VO_2max was determined when 2 or more of the following 4 criteria were present: 1) when there was no further increase in heart rate and oxygen uptake (VO₂) despite increased exercise intensity and exercise load, 2) when the RER was greater than 1.15, (3) when the perceived exercise intensity was greater than 17 (very difficult), and (4) the heart rate was greater than 90% of maximum¹⁵.

2.2.2. Calculation of exercise amount, intensity, time and speed:

Based on exercise intensity as described by the ACSM (2006)¹⁵, 40% VO_2max was set for group I, with 55% for group II and 70% for group III. In order to equalize exercise amount, an exercise time equivalent to 200 kcal consumption per session was calculated and applied for each subject. The exercise time and speed were calculated using formulas published by the ACSM (2006)¹⁵. The exercise time calculation formula is shown in Table 2.

Table 2. Method for calculating exercise time and exercise speed

[(VO₂max – VO₂rest) x (exercise intensity)] + VO₂rest = Target VO₂max

(Target VO₂ x Body weight in kg) / 200 kcal = ( ) kcal/min

200 kcal / ( ) kcal/min = Exercise time

Walking: VO₂max = (speed x 0.1) + (1.8 x speed x grade) + VO₂rest

Exercise intensity in HR: Karvone¹⁷ formula

[(HRmax – Hrrest) x %HRR] + HRrest = Target HR

The subjects performed walking on a treadmill. The treadmill inclination for each group was equally applied at 0°, and treadmill walking was performed according to the exercise intensity group. The target oxygen uptake, target heart rate, exercise time, and exercise speed for each group are shown in Table 3. In order to reduce errors in exercise speed, the subjects were instructed to wear a heart rate monitor (Polar RS-400, POLAR, Finland) to adjust time and speed, so that each group could maintain the target heart rate shown in Table 3 during tread mill exercise.

2.2.3. Dual task training:

Dual-task training was performed on a treadmill 5 times a week, a total of 30 times in 6 weeks. A subject was allowed to rest if he or she complained of pain or discomfort. In order to prevent falls, the subjects were allowed to maintain walking at their maximum walking speed using a weight suspension device (MTS-720, GE Medical System Co., Denmark). The task difficulty was gradually increased according to the measured cognitive level (Table 4).

Table 3. Exercise protocol

Parameter	Group I	Group II	Group III
Target VO₂ (ml/kg/min)	19.78±1.09	24.95±1.73	31.68±1.48
Target HR (bpm)	126.25±2.77	145.38±2.41	161.14±1.58
Exercise (min)	46.36±3.24	35.19±2.83	26.24±3.13
Exercise speed (km/h)	3.85±0.36	5.22±0.88	7.54±1.17

All data are expressed as means with standard deviation (M±SD)

Group I: Low intensity aerobic exercise group by dual task training (40% VO₂max)

Group II: Moderate intensity aerobic exercise group by dual task training (55% VO₂max)

Group III: High intensity aerobic exercise group by dual task training (70% VO₂max)

Table 4. Dual task training program

Time	Program
1~2 week	1. Speaking random numbers : ex) 3, 6, 20, 98, 150, …. 2. Counting backward numbers : ex) 3-2-41, 5-4-3-2-1, …. 3. Memorizing backward : ex) 12, 11, 10 month …
3~4 week	4. Remembering objects : ex) 010-1234-5678, desk, chair, … 5. Speaking objects or words : ex) flower-rose, lily, tulip, … 6. Completing sentences : ex) create a sentence using the apple – princess
5~6 week	7. Speaking backward letters : ex) apple → elppa, banana → ananab, … 8. Storying : ex) who do you have to speak in the morning 9. Imitating sentences : ex) speaking fluently difficult sentences …

2.3. Cognitive function measurement:

2.3.1. MMSE-K:

Cognitive function was measured using the MMSE-K which was standardized for Korea by Kwon and Park (1989)¹⁸, based on the MMSE developed by Folstein et al. (1975)¹⁶. This tool has high reliability and is used to screen for dementia and cognitive impairment. The maximum score is 30, and those with a score of 24 or higher are classified as normal, those with a score of 18-23 as mild cognitive decline, and those with a score of 17 or lower as high cognitive decline¹⁸.

2.3.2. Tail making test:

The trail making test was used to examine and evaluate the tracking of complex concepts of binary (simultaneous) concentration, various stimuli, and consciousness levels. The subjects were instructed to connect the circles with lines in ascending order of the numbers in the circles as quickly as possible, without lifting the pencil from the paper, and the time required to complete the task was measured¹⁹.

2.3.3. Stroop test:

The Stroop test was used to evaluate selective concentration. The standard Stroop test asks the participants to say the name of a printed ink color, ignoring the word written on the paper. The total time spent and the number of incorrect answers were evaluated²⁰.

2.4. Blood analysis:

Blood was collected 7 days before training and 1 day after training. Patients were asked to fast from 9:00 pm on the day before blood collection. On the day of collection, 10 ml of blood was withdrawn from an antecubital vein using a disposable syringe after allowing each subject to rest for 30 min. The collected blood was placed in an anticoagulated tube, and was centrifuged at 3,000 rpm for 15 min. Plasma and serum were separated and placed in storage tubes. After storage at -80°C, they were sent to S Clinical Pathology Center for analysis of BDNF and IGF-1.

2.5. Data analysis:

The data obtained from the experiment were calculated as the mean and standard deviation using SPSS 18.0 version for windows^®. The Kolmogorov-Smirnov test was used to test for normal data distribution, and a parametric statistical method was used. The paired t-test was performed to compare changes in cognitive function and neurotrophic factors before and after training in each group. One-way analysis of variance was performed to compare changes in cognitive function and neurotrophic factors between the groups, and the least significant difference (LSD) was determined in a post-hoc test. All statistical significance levels were set at α = .05.

3. RESULTS:

3.1. Comparison of changes in cognitive function and neurotrophic factors according to different intensity aerobic exercise dual task training:

There was no significant difference in all measured items of cognitive function and neurotrophic factors after low-intensity aerobic exercise plus dual-task training. There were significant differences in all measured items of cognitive function and neurotrophic factors after moderate-intensity aerobic exercise plus dual-task training (p<.01). There were significant differences in all measured items of cognitive function and neurotrophic factors after high-intensity aerobic exercise and dual-task training (p<.01) (Table 5).

Table 5. Change of cognitive function and neurotrophic factors according to different intensity aerobic exercise with dual task training

		Parameters	Pre	Post	t	p
Low-intensity (40%VO₂max)	Cognitive function	MMSE-K (score)	19.88±1.45	20.44±1.42	-1.890	.095
		Trail making test (sec)	37.35±5.01	35.43±6.26	1.609	.146
		Stroop test (sec)	55.30±9.33	53.52±5.10	.982	.355
		Stroop test (ea)	4.33±0.50	3.88±0.60	1.512	.169
	Neurotrophic factor	BDNF (pg/ml)	18894.98±1983.24	19667.54±1456.09	-1.681	.131
	Neurotrophic factor	IGF-1 (ng/ml)	117.62±16.48	120.48±15.69	-1.351	.214
Moderate-intensity (55%VO₂max)	Cognitive function	MMSE-K (score)	19.44±1.33	21.11±1.90	-3.780	.005^**
		Trail making test (sec)	34.98±4.79	31.57±4.75	4.302	.003^**
		Stroop test (sec)	57.44±8.14	51.24±4.98	3.489	.008^**
		Stroop test (ea)	4.55±0.72	3.55±0.88	3.464	.009^**
	Neurotrophic factor	BDNF (pg/ml)	19528.40±2021.14	21455.21±2196.42	-3.801	.005^**
	Neurotrophic factor	IGF-1 (ng/ml)	121.87±15.55	130.54±13.92	-4.044	.004^**
High-intensity (70%VO₂max)	Cognitive function	MMSE-K (score)	20.88±1.76	23.55±1.13	-9.141	.000^***
		Trail making test (sec)	34.85±6.20	24.22±5.01	6.800	.000^***
		Stroop test (sec)	56.34±7.16	43.18±4.92	10.549	.000^***
		Stroop test (ea)	4.11±0.60	2.55±0.52	8.854	.000^***
	Neurotrophic factor	BDNF (pg/ml)	18992.28±2088.42	23596.78±2067.04	-5.629	.000^***
	Neurotrophic factor	IGF-1 (ng/ml)	118.93±14.60	147.01±10.58	-5.767	.000^***

All data are expressed as means with standard deviation (M±SD)

MMSE-K: Mini-Mental State Examination – Korea, BDNF: Brain-Derived Neurotrophic Factor, IGF-1: Insulin-like Growth Factor – 1

Tested by paired t-test (^**; p<.01, ^***; p<.001)

Table 6. Comparison of change between each groups on cognitive function and neurotrophic factors after different intensity of aerobic exercise and dual task training

	Parameters	Group I	Group II	Group III	t	p
Cognitive function	MMSE-K (score)	20.44±1.42	21.11±1.90	23.55±1.13^1)*2)	10.474	.001^###
	Trail making test (sec)	35.43±6.26	31.57±4.75	24.22±5.01^3)*4)	10.058	.001^###
	Stroop test (sec)	53.52±5.10	51.24±4.98	43.18±4.92^5)*6)	10.596	.001^###
	Stroop test (ea)	3.88±0.60	3.55±0.88	2.55±0.52^7)*8)	9.176	.001^###
Neurotrophic factor	BDNF (pg/ml)	19667.54±1456.09	21455.21±2196.42	23596.78±2067.04^9)**10)	9.316	.001^###
Neurotrophic factor	IGF-1 (ng/ml)	120.48±15.69	130.54±13.92	147.01±0.58^11)**12)	8.766	.001^###

All data are expressed as means with standard deviation (M±SD)

Tested by one-way ANOVA (^###; p<.001) and post-hoc was LSD

^{1),3),5),7),9),11)}; Group I – III (^***; p<.001), ^{2),4),6),8),10),12)}; Group II – III (^*; p<.05, ^**; p<.01)

MMSE-K: Mini-Mental State Examination – Korea, BDNF: Brain-Derived Neurotrophic Factor, IGF-1: Insulin-like Growth Factor – 1

Group I: Low intensity aerobic exercise group by dual task training (40% VO₂max)

Group II: Moderate intensity aerobic exercise group by dual task training (55% VO₂max)

Group III: High intensity aerobic exercise group by dual task training (70% VO₂max)

4. DISCUSSION:

In the present study, a treadmill was used in dual-task training. This aerobic exercise enhances cardiovascular function, thereby increasing cerebral blood flow to prevent cognitive decline²¹ by increasing gray and white matter volume to improve central nervous system health and cognitive function²². In this regard, there is growing interest in training in the field of cognitive therapy for stroke patients.

Previous studies have been limited to simple exercise and cognitive tasks performed at the same time, using a simple evaluation method. The present study aimed to investigate the effects of different intensities of aerobic exercise on cognitive function and neurotrophic factors.

In the present study, no significant differences were found in cognitive function and neurotrophic factors after low-intensity aerobic exercise plus dual-task training. However, a significant difference was found after moderate-intensity aerobic exercise plus dual-task training (p<.01), and after high-intensity aerobic exercise plus dual-task training (p<.001). In addition, there were significant differences in all cognitive measurement items (MMSE-K, Trail making test, Stroop test) after different intensities of aerobic exercise plus dual-task training (p<.001); there was a significant difference when using dual-task training plus high-intensity aerobic exercise (group III), compared to that using low-intensity aerobic exercise (group I) or moderate-intensity aerobic exercise (group II). It is thought that high-intensity aerobic exercise, which requires more physical activity, may enhance vascular function and oxygen delivery, increase circulation and neurotransmitter synthesis²³, and increase cerebral blood flow²⁴, thereby enhancing cognitive processes.

Meanwhile, aerobic exercise is known to enhance brain and cognitive function by increasing core proteins (BDNF, IGF-1, vascular endothelial growth factor, etc.) that induce neuroplasticity in the hippocampal region^25,26. BDNF is a biomarker of cognitive functions^27,28, and IGF-1 plays a pivotal role in enhancing cognitive function^25,29. In the present study, there were significant differences in all neurotrophic factors after different intensities of aerobic exercise plus dual-task training (p<.001), and a significant difference was found when using dual-task training plus high-intensity aerobic exercise (group III) compared to that using dual-task training plus low-intensity (group I) or moderate-intensity aerobic exercise (group II). The levels of BDNF and IGF-1 in the brain vary depending on exercise amount^25,30,31. As previously reported by Ferris et al.²⁷, Tsai et al.³¹, and Schmidt et al.³², the present study found that as exercise intensity increased, BDNF and IGF-1 expression levels increased.

It is thought that performing dual-task training plus high-intensity aerobic exercise improves cognitive function through a complex process³³, such as increasing synaptic plasticity due to physiological changes in the brain, increasing arousal level, and increasing neurotrophic factors involved in learning and memory. Because most clinical settings for cognitive training in stroke patients are limited to tabletop activity, the preventive and therapeutic effects of physical activity are overlooked³⁴. Therefore, the present study findings suggest that applying differentiated aerobic exercise to various cognitive training processes can enhance the effectiveness of cognitive rehabilitation in stroke patients.

5. CONCLUSION:

The present study aimed to investigate the effects of dual-task training using different intensities of aerobic exercise on cognitive function and neurotrophic factors in chronic stroke patients. The study found that the use of high-intensity aerobic exercise plus dual-task training more effectively stimulated the prefrontal region, which is responsible for cognitive function, and led to positive physiological changes in the brain, thus enhancing cognitive function. The results of the present study suggest that the effectiveness of cognitive rehabilitation training for stroke patients in clinical practice can be enhanced when using differentiated aerobic exercise rather than limited desktop activity.

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Received on 17.09.2018 Modified on 10.10.2018

Research J. Pharm. and Tech 2019; 12(2):693-698.

DOI: 10.5958/0974-360X.2019.00123.9