A Six-Month Cognitive-Motor and Aerobic Exercise Program Improves Executive Function in Persons with an Objective Cognitive Impairment: A Pilot Investigation Using the Antisaccade Task

Abstract

Persons with an objective cognitive impairment (OCI) are at increased risk for progression to Alzheimer’s disease and related dementias. The present pilot project sought to examine whether participation in a long-term exercise program involving cognitive-motor (CM) dual-task gait training and aerobic exercise training improves executive function in persons with an OCI. To accomplish our objective, individuals with an OCI (n = 12) as determined by a Montreal Cognitive Assessment (MoCA) score of less than 26 and older adults (n = 11) deemed to be cognitively healthy (i.e., control group: MoCA score ≥26) completed a six-month moderate-to-high intensity (65–85% maximum heart rate) treadmill-based CM and aerobic exercise training program wherein pre- and post-intervention executive control was examined via the antisaccade task. Notably, antisaccades require a goal-directed eye-movement mirror-symmetrical to a target and represent an ideal tool for the study of executive deficits because of its hands- and language-free nature. As well, the cortical networks mediating antisaccades represent regions associated with neuropathology in cognitive decline and dementia (e.g., dorsolateral prefrontal cortex). Results showed that antisaccade reaction times for the OCI group reliably decreased by 30 ms from pre- to post-intervention, whereas the control group did not produce a reliable pre- to post-intervention change in reaction time (i.e., 6 ms). Thus, we propose that in persons with OCI long-term CM and aerobic training improves the efficiency and effectiveness of the executive mechanisms mediating high-level oculomotor control.

Keywords

Aerobic exercise antisaccade cognitive decline cognitive-motor training executive control objective cognitive impairment

INTRODUCTION

The incidence of older adults with a cognitive impairment that does not meet the clinical diagnosis for dementia is twofold greater than Alzheimer’s disease (AD) and related dementias [1]. Cognitive impairment, not dementia (CIND) is a definition ascribed to individuals with a subjective cognitive complaint or an objective cognitive deficit [2], whereas mild cognitive impairment (MCI) is a term ascribed to individuals with subjective and objective cognitive deficits [3]. Regardless of which definition is used, persons with CIND and MCI have a greater risk of progression to dementia than their cognitively healthy counterparts [2]. Thus, identification of targeted intervention programs that ameliorate, CIND- and MCI-related cognitive decline represents an important area of inquiry.

Research has shown that aerobic exercise training improves cognition, and in non-demented older adults produces a marked benefit in executive-control [4]. Broadly speaking, executive-control relates to processing and attending single and multiple stimuli, updating and monitoring working memory functions, and asserting high-level inhibitory control [5]. In terms of individuals with dementia and those meeting the MCI and CIND definitions, the role of aerobic exercise and cognition is less clear. For example, Gates and colleagues’ [6] meta-analysis concluded: “There is very limited evidence that exercise improves cognitive function in individuals with MCI” (p. 1086), whereas Öhman et al.’s [7] systematic review concluded that aerobic exercise improves global cognition, executive function, and memory in persons with MCI but not individuals with AD. Of course, part of the discrepancy can be attributed to: (1) inadequate control of exercise intensity, (2) short-duration training protocols, and (3) imprecise operational definitions for the reported populations of interest. For those reasons, the authors of the aforementioned meta-analysis and systematic review concluded that there is need for further studies evaluating aerobic exercise effects in persons at risk, or experiencing, cognitive impairment and decline. Notably, two recent randomized control studies have shown that aerobic training benefits persons experiencing cognitive decline [8, 9]. Yang et al. showed that persons with mild AD who completed a three-month aerobic exercise training program (i.e., cycling at 70% maximum heart rate, 40 min/d) exhibited decreased disease-related deficits as assessed via standardized clinical scales (e.g., Mini-Mental Status Examination (MMSE), Quality of Life Alzheimer’s Disease Scale). As well, Sacco et al. showed that for persons meeting the MCI definition, a three-month aerobic training program (i.e., cycling at 60% maximum heart rate, 20 min/d) resulted in improved post-intervention performance on a go-no-go reaction time (RT) task. Because go-no-go task performance is thought related to high-level inhibitory control [10], it was proposed that aerobic training improved the efficiency and effectiveness of executive-related brain activity. Thus, convergent evidence suggests that participation in long-duration (i.e., >12-weeks) aerobic exercise training involving a moderate-to-high intensity protocol (i.e., 60–85% of maximum heart rate) may provide the requisite framework to elicit positive neurocognitive benefits in populations at risk for further cognitive decline [11].

The current investigation sought to provide a preliminary examination of whether a six-month exercise program involving combined cognitive-motor (CM) dual-task gait training and aerobic training improves executive control in older adults identified as having an objective cognitive impairment. Thus, we recruited individuals across the spectrum of cognitive impairment (i.e., MCI and CIND) to provide an encompassing framework for determining whether CM and aerobic exercise training improves cognitive performance across the putative precursors for dementia (henceforth referred to as objective cognitive impairment group: OCI). In addition, we employed a combined CM and aerobic training program based on evidence asserting that cognitively healthy older adults as well as those with a cognitive impairment elicit enhanced cognitive/executive benefits when training in a multiple-modality environment than aerobic training only [12]. To accomplish our objective, we contrasted the executive control of older adults deemed to be cognitively healthy (i.e., control group) to individuals identified as having an objective cognitive impairment (i.e., the OCI group). Notably, in each exercise session a 15-min treadmill-based CM dual-task was performed wherein participants monitored their ideal step length (i.e., via visual feedback) while concurrently performing semantic/phonemic and arithmetic tasks (i.e., naming out loud as many words from a particular category, or continuous addition or subtraction from a three digit number). As well, in each exercise session participants completed 15 min of treadmill based aerobic training at a moderate-to-high intensity (i.e., 65–85% of their maximum heart rate). At pre- and post-intervention time points, we assessed executive control via the antisaccade task wherein individuals completed goal-directed eye movements (i.e., saccade) mirror-symmetrical to a visual target [13]. Such a task is ‘challenging’ and represents an ideal tool for the assessment of individuals with a cognitive impairment because it is hands- and language free [14]. Moreover, extensive work has shown that correct antisaccade performance is contingent upon premovement activity within the dorsolateral prefrontal cortex (DLPFC) [15], a region supporting executive-control and an area known to be damaged in the later stages of AD [16, 17]. Thus, antisaccades provide a parsimonious task to determine whether an exercise intervention improves the efficiency and effectiveness of neural activity within executive-related brain regions and/or more generally improves the cortical networks supporting the top-down and cognitive control of antisaccades (e.g., frontal and supplemental eye fields, anterior cingulate cortex, lateral intraparietal area) (for review of cortical networks mediating antisaccades see [18]).

METHODS

2.1 Participants

Participants were recruited from communities surrounding London, ON. Older adults (60–90 years) without dementia (i.e., no previous dementia diagnosis and an MMSE score ≥24) [19] and preserved instrumental activities of daily living (i.e., Lawton-Brody Instrumental Activities of Daily Living (IADL) scale >6) [20] were invited to participate. Exclusion criterion included: (1) major depression based on a Centre for Epidemiological Studies-Depression Scale (CES-D) score >15 [21], or the clinical judgment of the study physician, (2) other neurological or psychiatric conditions, (3) recent history of severe cardiovascular disease, (4) orthopedic conditions limiting exercise, (5) blood pressure unsafe for exercise (i.e., >180/100 mmHg or <100/60 mmHg), and (6) the inability to comprehend study procedures. A total of 26 individuals were entered into the study and indicated that they would be available for the study duration (i.e., 24-week exercise intervention). Of the original sample, 23 completed the full protocol, whereas three did not due to family obligations/vacation plans (n = 2) and winter travel difficulties (n = 1). Data for the three participants that did not complete the protocol are not included in the following analyses.

Cognitive impairment was defined using a combination of two valid and reliable cognitive screening tools, the MMSE and the Montreal Cognitive Assessment (MoCA) [22]. The MMSE has been traditionally used to identify older adults with significantly progressed cognitive impairment and dementias [19], whereas the MoCA contains higher complexity tasks that are able to identify individuals who may be exhibiting the initial stages of cognitive impairment [23]. By using the MMSE scores to exclude dementia and the MoCA to identify evidence of an objective cognitive impairment, we were able to identify a heterogeneous population of older adults at increased risk for future cognitive decline [22]. Specifically, of the 23 participants who completed the full protocol those with a MoCA scores <26 were selected into the OCI group (n = 12) and those with MoCA scores ≥26 were selected into a control group (i.e., cognitively healthy) (n = 11) (see Table 1 for participant demographics). Moreover, we emphasize that identification of the OCI group was based on the Vascular Cognitive Disorders Harmonization Standards paper’s assertion that a screening package including the MMSE, MoCA, CES-D, and IADL provide a valid and reliable means to identify individuals with an OCI [24]. In addition, we recognize that we did not record whether participants in the OCI group self-reported a subjective cognitive complaint. Indeed, had we documented a subjective cognitive complaint then we would have been able to ascribe individual participants within the CIND and MCI definitions. Notably, however, that was not the specific goal of the present study; rather, we sought to provide a directed examination of whether any individual with an objective cognitive impairment (MoCA scores <26) demonstrates an executive-related benefit following participation in long-term exercise training program. The Health Sciences Research Ethic Board, University of Western Ontario, approved this study, and all participants provided written informed consent.

Exercise intervention

Participants performed a treadmill-based (Biodex GaitTrainer2, Biodex Medical Systems, Inc., Shirley, NY, USA) cognitive-motor (CM; i.e., dual-task gait training) and aerobic exercise-training program. Each exercise session involved a 5-min warm up, 15 min of CM exercise, 15 min of moderate-to-high intensity aerobic exercise, and a 5-min cool-down (i.e., 40 min/session). Sessions were performed three times a week for 24 weeks.

Upon entry to the study, an ‘ideal’ step length estimate was calculated for each participant to provide an individualized step length reference point for the CM portion of the exercise sessions [25]. During CM training, participants walked at a comfortable, self-selected pace while receiving online visuospatial feedback related to their gait (i.e., step length) from a LCD display mounted atop the treadmill. In particular, the LCD provided heart rate feedback and presented a stride-by-stride graphic of whether a participant’s previous footfall was within the target boundary of their ideal step length (i.e., the display showed a schematic ‘foot’ and whether the foot was within the boundary associated with their ideal step length) (Fig. 1). Participants were required to modify their stride to achieve or surpass their individualized step length goal while responding to cognitively challenging questions. Half of the CM gait-training required responses to semantic and phonemic verbal fluency categories (i.e., naming out loud as many words that start with a particular letter or naming as many objects from a certain category), whereas the other half entailed simple arithmetic tasks (i.e., adding or subtracting a 2-digit number from a 3-digit number). The presentation of the verbal fluency and arithmetic tasks was counterbalanced across sessions with each performed for 7 min, with 1-min of dual-task rest in between. The variable priority method of CM training was followed and participants were instructed to focus more so on: (1) answering the cognitively challenging questions correctly during the first 7 min of CM training and, (2) their gait, and modifying their step length as required during the final 7 min of training [26]. The CM training component was used here because previous work has suggested that aerobic exercise performed in a cognitively challenging environment may lead to a more robust cognitive benefit than aerobic exercise alone [27].

Following the CM training, participants performed 15 min of moderate-to-high intensity aerobic exercise. Specifically, participants were coached to increase the speed and slope of the treadmill to reach their individualized training heart rate (65–85% of their maximum heart rate) determined via the Step Test and Exercise Prescription (STEP^TM) tool [28]. After the 15-min aerobic exercise component, the treadmill was returned to a 0% grade and the speed of the belt was reduced to a slow walking pace to allow participants to complete a 5-min cool down.

Oculomotor assessment

Antisaccades entail a saccade mirror-symmetrical to a visual target and require executive inhibition of a pre-potent response (i.e., suppression of a stimulus-driven prosaccade) [18]. In contrast, prosaccades require a response to the veridical target location and are implemented largely independent of executive control processes. Thus, the present study examined pro- and antisaccades to determine whether a combined CM and aerobic exercise intervention selectively benefits an executive-mediated oculomotor response. Pro- and antisaccades were completed in separate blocks pre- and post-exercise intervention. The pre-intervention assessment was completed 11±17 days prior to the beginning of aerobic and CM training, and the post-intervention assessment was completed 6±9 days after finishing the training program. For each session participants sat in front of a tabletop (height 775 mm) with their head placed in a head/chin rest. A 30-inch LCD monitor (60 Hz, 8 ms response rate, 1,280×960 pixels; Dell 3007WFP, Round Rock, TX, USA) located at participants’ midline and 550 mm from the front edge of the tabletop was used to present visual stimuli. Visual stimuli were presented against a high-contrast black background and included a white fixation cross (1°: 135 cd/cm²) placed at the center of the monitor and yellow target crosses (1°: 127 cd/cm²) 12° and 14° left and right of the fixation and in the same horizontal axis. The gaze location of participants’ left eye was measured via a video-based eye-tracking system (Eye-Trac6: Applied Sciences Laboratories, Bedford, MA, USA) sampling at 360 Hz. Oral and written instructions at the start of a trial block indicated whether the upcoming series of trials would entail pro- or antisaccades. All trials started with the appearance of the fixation cross which instructed participants to direct their gaze to its location. Once a stable gaze was attained (±1.5° for 450 ms) a randomized foreperiod was initiated (i.e., 1,000 to 2,000 ms) after which a target was presented for 50 ms. Target onset served as the imperative to pro- or antisaccade and the fixation cross was extinguished following target presentation. The ordering of target eccentricity and the visual field a target was presented was randomized and presented ten times within a block (i.e., 80 pro- and antisaccade trials in each pre- and post-exercise intervention session). Computer and visual events were controlled via MATLAB (7.8.0: The MathWorks, Natick, MA) and the Psychophysics Toolbox extensions (ver. 3.0) [29].

Dependent variables and statistical analysis

Pre-intervention body mass index (BMI) and maximal aerobic capacity (i.e., VO₂ max determined via the STEP^TM tool) [28] were computed and control and OCI group data were contrasted via independent samples t-tests. For the oculomotor assessment, gaze position data and saccade onset were analyzed identical to previous work [30]. Reaction time (RT: time between target onset and movement onset) and the percentage of directional errors (i.e., a prosaccade instead of an instructed antisaccade or vice versa) were examined via 2 (group: control, OCI) by 2 (exercise intervention: pre-, post-intervention) by 2 (task: pro-, antisaccade) mixed-designANOVAs.

RESULTS

Pre-intervention BMI and VO₂ max for OCI and control groups

Neither BMI (control = 28.2 kg/m², SD = 3.2; OCI = 29.3 kg/m², SD = 4.3) nor VO₂ max (control = 29.6 mL/kg/min, SD = 5.3; OCI = 26.1 mL/kg/min, SD = 6.1) measures reliably differed between groups, ts(21) <1. These findings indicate comparable pre-intervention fitness levels for control and OCI groups.

Pre- and post-intervention oculomotor assessment for OCI and control groups

Prosaccades produced shorter RTs (296 ms, SD = 48) and fewer directional errors (3%, SD = 4) than antisaccades (RT = 411 ms, SD = 52; directional errors = 22%, SD = 19), Fs(1,21) = 136.23 and 44.21, all p < 0.001, η_p² = 0.87 and 0.68. In addition, Fig. 2 shows that RT produced a group by exercise intervention by task interaction, F(1,21) = 12.50, p < 0.01, η_p² = 0.37. The interaction was decomposed in two-steps. First, between-groups contrasts indicated that RTs for control and OCI groups did not reliably differ across any of the pre- and post-intervention pro- and antisaccade conditions (ts(21) <1). Second, within-groups contrasts indicated that the OCI group showed reduced antisaccade— but not prosaccade— RTs from pre- to post- intervention (ts(11) = 3.16 and –0.49, ps = 0.009 and 0.68), whereas control group pro- and antisaccade RTs did not reliably vary across pre- and post-intervention (ts(10) = 1.44 and 0.97, ps = 0.18 and 0.35). Further, and given the nature of the current research question, we note that directional errors did not elicit reliable main effects for group or exercise intervention or any higher-order interactions within the ANOVA model (Fs < 1). In other words, directional errors did not differ between groups and did not vary as a function of the exerciseintervention.

DISCUSSION

The present study provides preliminary evidence that a six-month combined CM and aerobic training program improves executive-related oculomotor control in persons with an objective cognitive impairment. Moreover, our findings indicate that the antisaccade task provides a useful tool for evaluating training-related executive improvements for individuals with a cognitive impairment. In the following paragraphs, we first outline the general results associated with our oculomotor assessment and subsequently discuss the similarity/difference in antisaccade performance between control and OCI groups at pre- and post-intervention sessions.

Antisaccades produced longer RTs and more directional errors than prosaccades. This finding supports well-documented evidence that antisaccades require the time-consuming demands of inhibiting of a pre-potent response (i.e., a prosaccade) and implementing a saccade mirror-symmetrical to a target [30]. Moreover, convergent clinical, neuroimaging, and electrophysiological evidence indicates that correct antisaccade performance requires activation of high-level executive networks within the dorsolateral prefrontal cortex [15] and an extensive fronto-parietal network [18]. Thus, the behavioral properties of the antisaccades studied here documents that the task provided a cognitively challenging task to examine executive control.

Control and OCI groups exhibited comparable pro- and antisaccade RTs and directional errors at pre- and post-intervention sessions. For prosaccades (pre- and post-intervention), the comparable between-groups performance is expected and is taken to evince that spatial overlap between stimulus and response permits motor output via direct retinotopic maps within the superior colliculus [31]. As such, the stimulus-driven nature of prosaccades does not provide a basis to differentiate between individuals with and without an executive-related cognitive impairment. More notably, however, the null between-groups difference in pre-intervention antisaccade performance counters an earlier study (and one not involving an exercise intervention) showing that individuals meeting the MCI definition exhibit longer antisaccade RTs and more directional errors than healthy controls [32]. Accordingly, the authors proposed that antisaccades provide a valid tool for identifying executive deficits. One possible explanation for the between-experiment different is that Peltschet al. examined individuals with MCI (i.e., objective impairment and subjective cognitive complaint) and that group may have therefore been further along the cognitive decline continuum than the OCI individuals recruited here. A second explanation is that Peltsch et al. employed a larger sample size (i.e., 24 individuals with MCI; 74 healthy controls) than used here. Indeed, the larger sample size likely reflects that recruitment in Peltsch et al.’s study required commitment to a single, and brief duration, oculomotor assessment, whereas our study involved commitment to a six-month CM and aerobic exercise training program. Furthermore, it is possible that personality traits associated with willingness to participate in a long-term training program coupled with evidence that such individuals exhibit an expanse in ‘cognitive reserve’ and ‘fluid’ executive processes may account for the null difference in our study [33]. In particular, our OCI group may have called upon their ‘cognitive reserve’ during the pre-intervention assessment to produce antisaccade performance on par to healthy controls. In support of this view, persons with mild to moderate cognitive deficits (i.e., MCI, CIND, early-AD) have been show to deploy compensatory and sub-optimal coping mechanisms (i.e., increased attentional resources directed to task-based executive demands) to accommodate for their cognitive deficit [34]. As will be discussed in the following paragraph, we believe that the cognitive reserve strategy is supported via the conjoint examination of the OCI group’s post-intervention antisaccade RT and directional error data.

For the control group, pro- and antisaccade RTs and directional errors did not vary from pre- to post- intervention. These findings counter work reporting that aerobic training in healthy older adults yields a selective benefit in executive control [4]. That said, it is important to recognize that no previous work (i.e., young or older participants) has evaluated differences in pro- or antisaccade performance following a long-term combined CM and aerobic exercise intervention. Moreover, work involving healthy young adults [35, 36] and older adults with cardiovascular disease [37] has shown that neither pro- nor antisaccade RTs are reliably modulated following deliberate practice sessions. Thus, a parsimonious interpretation for the present findings is that the executive control of an oculomotor task does not provide the requisite sensitivity to detect long-term exercise-related benefits in cognitively healthy older adults. In terms of the OCI group, results showed a 30 ms reduction in antisaccade RT from pre- to post-intervention without a concomitant change in the percentage of directional errors. Further, we wish to emphasize that in the oculomotor literature the RT reduction observed here represents a large magnitude effect and is one that represents a reliable modulation of executive-related oculomotor control mechanisms [18]. In addition, the measurement system associated with our investigation provides a temporal resolution (i.e., 360 Hz) that can identify executive deficits (or improvements) that is not available in most neuropsychological tests. Moreover, the conjoint RT and directional error data demonstrate that the shorter post-intervention RTs do not reflect a speed-accuracy trade-off; that is, participants did not simply ‘improve’ their planning times at the cost of increased directional errors. Instead, we propose that results for the OCI group indicate that our long-term CM and aerobic training program improved the efficiency and effectiveness of executive-related oculomotor mechanisms. Indeed, it may be that the CM and aerobic training for the OCI group resulted in diminished reliance on a sub-optimal executive strategy (i.e., ‘cognitive reserve’) and provided improved antisaccade performance via the evocation of a standard network of oculomotor executive mechanisms. In other words, training programs that combine cognitive, motor and aerobic components may provide a ‘cognitive boost’ for individuals with an objective cognitive impairment [38]. As mentioned in the Introduction, the DLPFC plays a pivotal role in setting the high-level task-rules necessary for implementing directionally correct antisaccades [15]. It is therefore possible that improved post-intervention antisaccade performance for the OCI group may selectively reflect improved efficiency and effectiveness of executive-related processing within the DLPFC. That said, antisaccades are additionally associated with the activation of an extensive fronto-parietal network (e.g., frontal and supplemental eye fields, anterior cingulate cortex, lateral intraparietal area) [18]. As such, it may be that the exercise training program used here improved the functional connectivity of fronto-parietal structures [39] and rendered a more global benefit to cognitive and executive processes. Our current work is directly addressing this issue via examination of the event-related brain potentials associated with pre- and post-intervention antisaccade performance.

Of course, in outlining our findings we recognize that our study is associated with certain limitations. First, the pre-intervention oculomotor assessment ranged from 11±17 days prior to onset of the combined CM and aerobic training program. As such, the timeframe may have introduced within-groups variability in antisaccade performance. To address this issue, we performed a median-split of pre-intervention pro- and antisaccade RTs for control and OCI groups and observed no reliable between-groups difference in any of the reported oculomotor measures (ts <1). Second, the present study employed a small corpus of individuals, and as such future work by our group is aimed at extending our findings via a more robust sample. Third, and a recognized limitation of most studies in the extant literature, an increased understanding of the role of aerobic exercise (and cognitive training) in persons with a cognitive impairment or experiencing a cognitive decline would benefit from comparison not only to a group of cognitively healthy older adults (as was done here) but also to a group with a similar cognitive impairment not exposed to any aerobic and/or cognitive training. Indeed, by including a non-aerobic group future work might better evaluate whether social engagement via an exercise intervention program or the intervention program itself supports improved cognitive function. In spite of the above limitations, we believe that the present results add importantly to the literature insomuch as they provide first evidence that executive-related oculomotor processing in persons with OCI is improved following a six-month combined CM and aerobic exercise training program.

Footnotes

ACKNOWLEDGMENTS

Supported by the Canadian Institutes for Health Research, the Natural Sciences and Engineering Research Council of Canada, and Academic Development Fund and Faculty Scholar Awards from the University of Western Ontario.

Authors’ disclosures available online ().

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A Six-Month Cognitive-Motor and Aerobic Exercise Program Improves Executive Function in Persons with an Objective Cognitive Impairment: A Pilot Investigation Using the Antisaccade Task

Abstract

Keywords

INTRODUCTION

METHODS

2.1 Participants

Exercise intervention

Oculomotor assessment

Dependent variables and statistical analysis

RESULTS

Pre-intervention BMI and VO2 max for OCI and control groups

Pre- and post-intervention oculomotor assessment for OCI and control groups

DISCUSSION

Footnotes

ACKNOWLEDGMENTS

References

Pre-intervention BMI and VO₂ max for OCI and control groups