Exercise Plus Cognitive Performance Over and Above Exercise Alone in Subjects with Mild Cognitive Impairment

Abstract

Background:

Epidemiological studies highlight the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments.

Objectives:

The aim of this study was to ascertain the effect of aerobic exercise associated with cognitive enrichment on cognitive performance in subjects with mild cognitive impairment (MCI).

Method:

Eight participants with MCI (72 ± 2 years) were enrolled in a 9-month study that consisted of two 3-months experimental interventions separated by a training cessation period of 3 months. The interventions included either aerobic exercise alone or aerobic exercise combined with cognitive enrichment. The exercise program involved two 20-min cycling exercise bouts per week at an intensity corresponding to 60% of the heart rate reserve. Cognitive performance was assessed using a task of single reaction time (SRT) and an inhibition task (Go-no-Go) before, immediately after, and 1 month after each intervention.

Results:

The exercise intervention improved the speed of responses during the Go-no-Go task without any increase in errors. This improvement was enhanced by cognitive enrichment (6 ± 1% ; p > 0.05), when compared with exercise alone (4 ± 0.5% ,). Following exercise cessation, this positive effect disappeared. No effect was observed on SRT performance.

Conclusion:

Regular aerobic exercise improved cognitive performance in MCI subjects and the addition of cognitive tasks during exercise potentiated this effect. However, the influence of aerobic exercise on cognitive performance did not persist after cessation of training. Studies involving a larger number of subjects are necessary to confirm these results.

Keywords

Alzheimer’s disease cognition interaction between physiological and cognitive process

Introduction

Mild cognitive impairment (MCI) is considered to be the prodromal stage of various cognitive pathologies, especially Alzheimer’s disease. In the literature, the prevalence reported for MCI ranges between 3 and 42% [1]. Several epidemiological studies highlighted the relationship between the level of physical activity throughout life and cognitive functioning [2] with physically active individuals exhibiting better neurocognitive function relative to inactive individuals. The question arising from these studies is the relevance of regular exercise interventions to enhance or maintain neurocognitive function in subjects with cognitive impairments [3 –8].

Several hypotheses have been proposed to explain the positive effect of exercise on cognition in elderly people [9 –13]. It has been suggested that exercise could improve cognitive function through increased brain perfusion and reduced risk of stroke, which is a risk factor in the development of dementia [14, 15]. More recently it has been suggested that improvement in the cognitive performance observed with exercise can be explained by exercise-induced increase in arousal in the central nervous system, particularly in the dorso-lateral prefrontal cortex which is involved in executive functions [16]. Furthermore, animal research has shown that enriched environments, through either exercise or cognitive tasks, have a positive effect on neuroplasticity [17 –19]. Neurotrophic factors, such as the brain-derived neurotrophic factor (BDNF), seem to be involved in this effect. Both acute and chronic aerobic exercise increased the release of BDNF while training cessation abolished this exercise-induced response [18, 20]. Among strategies having the potential to improve or maintain cognition with aging, recent studies have highlighted the role of mental stimulation or cognitive training [21 –23]. Such strategies have been shown to improve a number of cognitive processes and functions, such as attention and memory, or visuo-spatial abilities and to also positively impact on mood and sociability (e.g., [22, 24]). Within this framework, cognitive training seems to have task-specific benefits with larger effect sizes for executive measures of reasoning and processing speed compared to measures of memory [22].

The primary aim of our current study was to investigate the efficacy of an aerobic exercise program to improve cognitive performance in older adults with MCI. The second aim of our study was to determine whether adding cognitive tasks during exercise could potentiate the positive effect of aerobic exercise on cognition. Finally, a third aim of the study was to observe the effect of training cessation.

Materials and Methods

Subjects

Volunteers aged 50 years or older were screened for MCI between 2012 and 2014 at the university hospital of Nice, France [25]. MCI was assessed using the Mini Mental State Examination (MMSE) [26]. MMSE scores range from 30 (normal) to 0 (very severe impairment) and scores over 26 are classically considered as normal. This test was chosen because of its good inter tester reliability (Pearson R = 0.83) and low variability in stable clinical condition between 24 h (Pearson R = 0.89) and 28 days (Pearson R = 0.99). Participants were included if they were diagnosed with MCI according to Petersen criteria [27], however, with a MMSE higher than 22 since they had to be able to exercise. Participants also needed to present no other contraindication to exercise. Exclusion criteria included psychiatric or cardiovascular disorders, history of alcoholism, cerebral trauma, disturbances of consciousness, and participation in other research projects. Twenty-four volunteers with MCI were screened and only eight participants (72 ± 2 years) were included in this study after a medical evaluation indicating no physical risks to perform regular moderate exercise. The procedures followed were in accordance with the Declaration of Helsinki 1975, revised Hong Kong 1989. The study was promoted by the University Hospital of Nice (ref 11-AOI-03; VAT number FR 72 260 600 705) and approved by South Mediterranean V Ethical Review Board (Comité de Protection des Personnes Sud Méditérrannée V, ref CPP 11.089), as well as by the French Agency for the Safety of Health Products (ANSM, n°ID-RCB 2011-A01398-33, ref AFSSAPS B111501-40). The study protocol was explained in details to participants who all gave their informed written consent before participation.

Interventions

Each subject was his own control and participated in two experimental treatments presented in a random order during a 9-month period. There was a 3-month period without any physical or cognitive training between each treatment (Fig. 1). The first visit served to familiarize the participants with the cognitive tasks and to collect their physiological characteristics. During the familiarization, subjects performed five blocks of 64 trials for each cognitive task in order to prevent a potential learning effect. Additional blocks were done if necessary until reaching learning criteria as previously described for a Simon task in elderly subjects [28].

Each intervention period consisted in a 3-month aerobic exercise. Each week, the participants performed two 20-min cycling bouts in a sitting position on an electro magnetic brake ergometer (NeuroActive’s^® brainbike, Rolling Meadows, IL, USA) at an intensity corresponding to 60% of the heart rate reserve (difference between resting heart rate and estimated maximum heart rate). Maximal heart rate was estimated from Tanaka et al. regression equation [29]. One intervention was only aerobic exercise (E) whereas the other one was aerobic exercise associated with cognitive enrichment during exercise (E + C). The cognitive enrichment proposed during pedaling was presented with a computer screen in front of the subjects and were composed by funny and easy cognitive exercises involving in a same session different cognitive processes such as processing speed, selective attention, working memory, arithmetic, visual scanning, or temporal perception. These games have been developed by a team of neuropsychologists and medical specialists to stimulate the brain’s cognitive activity, especially in older adults [30].

For example, a typical training session could include cognitive activities in which subjects had to pick out rightly priced items adding up to the bill total, appropriately group diagrams which evoked a similar theme, or select the shorter time between two musical notes played.

Borg’s category-ratio scale (CR-10) was used to assess the rate of perceived exertion (RPE) [31]. Subjects were instructed to give CR-10 values immediately at the end of each exercise session.

After each training period, a one-month period without training was applied to observe a possible training cessation effect.

Assessment of cognitive function

Cognitive function was assessed with two different tests: a response inhibition test (Go-no-Go) and a simple reaction time (SRT) test. Cognitive testing was performed at different times during the study: before training (P1), immediately after training (P2), and 1 month after training cessation (P3).

Go-no-Go test

This test assessed response inhibition and was designed as follows in our study: the stimuli, which consisted of the letters H or an S, were presented in white character on a black background. Participants were instructed to respond by pressing a button if the stimulus was an H, and not to respond if the stimulus was an S, both stimuli being equiprobable. Stimuli remained on the screen until a response was made or until 1200 ms had elapsed. The cognitive task consisted in 64 trials separated by an interval of 400–600 ms. Participants were asked to make a choice, as quickly and accurately as possible. The performance was assessed by measuring the promptness of response by averaging the reaction time (RT) for “Go” responses or by recording the number of errors for all responses.

Simple reaction time (SRT) test

SRT was measured from impulses recorded on a handgrip while the subject was seated. The subject was instructed to hold the handgrip in his preferred hand and to place his thumb on a button. SRT was calculated as the time required by the subject to remove his thumb from the button when the stimuli were displayed. This device was connected the microcomputer with a sampling frequency of 120 Hz. The luminous stimuli appeared at the center of a screen and were separated by an irregular foreperiod varying from 3–5 s. Participants were asked to respond, i.e., to release the button, as quickly as possible. The cognitive task consisted in 64 trials and mean SRT were calculated with any SRT under 160 ms were considered as an error and reported as an anticipated responses [32].

Statistical analysis

All statistical analyses were conducted using Statistica 7.1 software (StatSoft). The arcsine transformations of the error rate, the mean RT were submitted to repeated measures analyses of variance (ANOVA) with time (P1, P2, P3) and condition (E versus E + C) as within-subject factors. Post-hoc Newman-Keuls analyses were conducted on all significant interactions. Effect sizes for group differences were calculated using cohen’s d. Values of 0.2, 0.5, and over 0.8 were considered small, medium and large, respectively (Cohen 1988). Significance was set at p < 0.05 for all analyses.

Results

Participant’s anthropometry and physiological characteristics are presented in Table 1.

Perceived exertion during training

For a same absolute intensity, RPE values were significantly lower after the intervention (difference between pre and post training: delta RPE = –1.6 ± 0.2 and –1.7 ± 0.4, p < 0.05, for E and E + C respectively) with no difference between interventions.

Go-no-Go performance

Accuracy was determined as the percentage of decisions errors, i.e., error rate. The analysis showed that there was no time effect (F (2.28) = 0.90, p = 0.41), and no interaction effect between time and condition on error rate (F (2.28) = 0.30, p = 0.74).

The ANOVA analysis performed on RT highlighted a main effect for time (F (2.28) = 5.6, p < 0.05) and an interaction effect between time and condition on RT (F (2.28) = 4.20, p < 0.05, Fig. 2). A significant improvement in RT during the Go-no-Go task was observed independent of the type of intervention with a large effect for the E + C intervention (6 ± 2.4% , 95% CI: –8.2 and –4% ; Cohen’s d = 0.99), and a medium effect for E (4 ± 2.7% , 95% CI: –6.3 and –1.7% ; Cohen’s d = 0.69). This improvement represents 31 ± 11 ms (95% CI: 40.7 and 21.3) for E + C and 20.7 ± 13 ms (95% CI: 31.8 and 9.6) for E, and was more important for E + C than for E (p < 0.05; Cohen’s d = 0.85) One month after the end of the intervention, the performance on the cognitive task was similar to pre-intervention, indicating a loss of intervention-induced benefit.

Simple reaction time performance

The analysis showed that the interventions had no effect on SRT (F (2.28) = 0.60, p = 0.55, Fig. 3) or anticipated responses (F (2.28) = 1.68, p = 0.20), and no interaction effect between period and condition on SRT performance (F (2.28) = 1.90, p = 0.16).

Discussion

The aim of this study was to investigate the effect of regular aerobic exercise and cognitive enrichment on cognitive performance in subjects with impaired cognition. We confirm that regular aerobic exercise improves cognitive performance in MCI subjects. A novel finding of this study is that the addition of cognitive tasks during exercise could potentiate this positive effect. Importantly, this effect does not last after cessation of the intervention, pointing to the importance of continuous adherence to regular exercise for cognitive benefits. Within this framework, dose-response relationships of training benefits need to be considered in future research. Recently, in 55 older adults with multiple dementia risk factors, Lampit et al. [33, 34], investigated the time course of cognitive gains from cognitive training during and after training cessation. They have reported distinct time courses by cognitive domain: processing speed and executive function displayed benefits after only 3 weeks of training, whereas memory required 12 weeks. By contrast, following the offset of training, therapeutic gains decayed quickly for memory benefits while speed effects were durable for at least 3 months after stopping the training.

The positive impact of an aerobic exercise intervention on cognitive performance could be related to structural changes in brain regions, particularly the hippocampus. A 4% increase in the total volume of hippocampus was recently been reported after 6 month of aerobic training in healthy older adults with possible MCI [8]. Among the mechanisms underlying brain plasticity, the synthesis and release of BDNF, which is known to stimulate neurogenesis, could play a crucial role [18]. Studies investigating the effects of acute or chronic exercise on the circulating levels of BDNF in animal models [35] or humans [17] have shown that exercise increased BDNF release into the circulation. Interestingly, training cessation led to decreased BDNF levels [36], suggesting that exercise intervention should be sustained for long-term effect. This may explain our results indicating a significant improvement in Go-no-Go performance after a 3-month aerobic exercise intervention but the disappearance of this effect after training cessation.

Recent studies researching the effect of exercise on cognition have focused on specific population and explored whether the observed effects were task specific from basic information to executive function [37]. Sanders model [38] provides a coherent framework to identify which processes are or are not facilitated by exercise. In our study the positive effect was only observed on decisional performance (i.e., Go-no-Go) but not on simple reaction time. It has been reported that exercise leads to an activation of the reticular-activating system, regulating ascending projections to the prefrontal cortex, mainly involved in high cognitive functions such as decision-making [39]. Therefore, the positive effect of aerobic exercise intervention seems to affect executive rather than simple cognitive functions. The Go/no-go paradigm is supposed to ensure a reliable probing of response inhibition mechanisms. Go/no-go tasks activate many areas of the lateral frontal cortex (including superior, middle, and inferior frontal gyri), the insula, the dorsal medial frontal cortex, the anterior cingulate cortex, the inferior parietal cortex, and the precuneus, as well as the striatum [40]. Gyri in particular are involved in apathy. which is one of the most common behavioral symptoms associated with MCI. This is also a risk factor for more severe cognitive impairment since conversion into Alzheimer’s disease is significantly higher in patients with lack of interest [41]. Therefore, from a clinical point of view, a 4 to 6% improvement in Go-no-Go performance could be in particular associated with a stronger commitment to the task and could be beneficial to prevent Alzheimer’s disease [42].

Our study also provides a unique insight into the beneficial effects of combining physical exercise and cognitive activity. Indeed we showed that adding a cognitive task during exercise could potentiate the positive effect of exercise on cognitive performance in individuals with MCI. This result is in line with the idea that an enriched environment may lead to preservation of cognitive function in people with MCI or Alzheimer’s disease. Although our study does allow us to investigate the underlying mechanisms, we can refer to recent studies showing that intervention such as cognitive environmental enrichment, regular physical exercise, and adequate diet have the potential to enhance cognition in animal models [43] and to induce significant changes in the brain [44]. Exposure to an enriched environment can increase synaptic plasticity, neuronal signaling, learning, and memory [45] and induce beneficial effects in a range of different animal models of brain disorders [46]. Similarly to these studies using animal models, our results support the case for the benefits of cognitive stimulation to correct cognitive deficits.

Our results also showed a significant decrease in RPE during exercise with aerobic training. The effects of aging on perceived exertion are not well documented; however, some authors indicated that RPE could be a valid tool to monitor training even in the eldest [47, 48]. Therefore, the decrease in RPE during training with time suggests a decrease in perceived metabolic load for a same absolute load and thus a decrease in hardness. However, we cannot completely exclude that participants’ evaluation of RPE was affected by MCI.

Several limitations of this study need to be considered: (1) due to ethical constraints aerobic fitness was not directly measured; (2) due to a small sample size, the generalization of such intervention on a larger scale still needs to be addressed in further studies; (3) a measure of the size of hippocampus or systemic BDNF would have supported the discussion on potential mechanisms for improvement of reaction time with the interventions; and (4) addition of a control group and a sham group would strengthen the design of the study.

In conclusion, our study shows that a 3-month aerobic exercise intervention is effective in maintaining cognitive performance in elderly with MCI and that adding a cognitive task during exercise enhances this positive effect. Given the growing evidence that regular exercise is beneficial for brain health, physical activity should be a standard recommendation for all older adults with MCI. This pilot study was conducted with a small sample size and its results need to be validated with a larger sample size in future research studies.

DISCLOSURE STATEMENT

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/15-0194r2).

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