A 24-Week Multi-Modality Exercise Program Improves Executive Control in Older Adults with a Self-Reported Cognitive Complaint: Evidence from the Antisaccade Task

Abstract

Exercise programs involving aerobic and resistance training (i.e., multiple-modality) have shown promise in improving cognition and executive control in older adults at risk, or experiencing, cognitive decline. It is, however, unclear whether cognitive training within a multiple-modality program elicits an additive benefit to executive/cognitive processes. This is an important question to resolve in order to identify optimal training programs that delay, or ameliorate, executive deficits in persons at risk for further cognitive decline. In the present study, individuals with a self-reported cognitive complaint (_SCC) participated in a 24-week multiple-modality (i.e., the M2 group) exercise intervention program. In addition, a separate group of individuals with a _SCC completed the same aerobic and resistance training as the M2 group but also completed a cognitive-based stepping task (i.e., multiple-modality, mind-motor intervention: M4 group). Notably, pre- and post-intervention executive control was examined via the antisaccade task (i.e., eye movement mirror-symmetrical to a target). Antisaccades are an ideal tool for the study of individuals with subtle executive deficits because of its hands- and language-free nature and because the task’s neural mechanisms are linked to neuropathology in cognitive decline (i.e., prefrontal cortex). Results showed that M2 and M4 group antisaccade reaction times reliably decreased from pre- to post-intervention and the magnitude of the decrease was consistent across groups. Thus, multi-modality exercise training improved executive performance in persons with a _SCC independent of mind-motor training. Accordingly, we propose that multiple-modality training provides a sufficient intervention to improve executive control in persons with a _SCC.

Keywords

Executive-control exercise mind-motor training multiple-modality training subjective cognitive complaint

INtroduction

Older adults (i.e., ≥55 years of age) with self-reported cognitive complaints or mild cognitive impairment (MCI) exhibit specific, yet subtle, cognitive deficits linked to the prodromal stages of Alzheimer’s disease (AD) [1 –4]. In particular, these individuals display executive deficits of perceptual speed [1], response inhibition [5, 6], strategic planning [7], and explicit memory [8]. These observations indicate that older adults reporting a subjective cognitive complaint or individuals meeting the MCI definition exhibit salient— and early— milestones for an increased risk of continuing cognitive decline and draws attention to the need to develop intervention strategies that ameliorate, or preclude, further decline in these groups.

One intervention shown to produce neurocognitive benefits and improve general physical and psychological well-being in non-demented older adults is the participation in long-term aerobic fitness training programs. For example, Colcombe et al.’s [9] seminal functional MRI study found that non-demented, but sedentary, older adults who participated in a 24-week walking program showed improved supervisory attentional control and task-appropriate modulation of executive-related cortical structures compared to a non-aerobic control group (i.e., 24-week “stretching and toning” group). Such findings indicate that aerobic training is causally linked to improved task-appropriate cortical activation (i.e., cortical efficiency) and enhanced transfer and quality of communication between and within cortical structures (i.e., cortical effectiveness). Moreover, exercise programs combining aerobic and resistance training (i.e., multiple-modality training) lead to greater cognitive benefits than single-modality training (i.e., aerobic or resistance), and multiple-modality programs engender the largest training-related benefit to high-level executive functioning [10, 11; cf. 12]. Indeed, because executive control reflects the ability to attend to task-relevant stimuli, the updating and monitoring of working memory, and the evocation of high-level inhibitory control [13], its improved function imparts an important benefit to activities of daily living [14].

Work involving persons with MCI and AD have reported conflicting findings related to the role of aerobic/resistance training programs and cognition. Gates and colleagues [15] meta-analysis concluded, “There is very limited evidence that exercise improves cognitive function in individuals with MCI” (p. 1086). In contrast, Öhman et al.’s [16] systematic review concluded that aerobic exercise improves global cognition, executive function, and memory in persons with MCI but not individuals with AD [see also 17,18]. Of course, the discrepancy most likely relates to the fact that many of the reviewed studies did not: (1) provide operational definitions for AD or MCI, (2) provide adequate samples sizes, (3) provide measures of participant compliance or adherence, or (4) provide objective measures of cognitive impairment with sufficient resolution to detect subtle executive deficits. Thus, the authors of the aforementioned meta-analysis and systematic reviews proposed that there is need for high-quality studies evaluating exercise effects in persons at risk, or experiencing, cognitive decline. Moreover, the majority of the studies examining the link between exercise and cognitive decline have relied on single-modality (i.e., aerobic) training programs— a training program type that may not maximize neurocognitive benefits. To highlight this point, recent randomized controlled trials involving persons experiencing cognitive decline (i.e., self-reported cognitive complaint or objective cognitive impairment) [19] and those recovering from stroke [20] have shown that multiple-modality training programs (>9 weeks of duration) elicit reliable post-intervention benefits to neurocognitive function. Accordingly, it has been proposed that the contextual variety and/or the biochemical consequences (i.e., neuroprotective factors responsible for neuronal growth and differentiation) associated with multiple-modality training provide an ideal environment for attaining exercise-related benefits in persons experiencing cognitive decline [21].

In addition to work reporting that multi-modality training enhances executive-related processes, some evidence from animal and human studies suggests that physical activity performed in a cognitively challenging environment elicits an additive benefit to executive/cognitive function. For example, Fabel and colleagues [22] reported that female mice that completed a wheel running task in an enriched environment showed greater neuronal proliferation than animals that performed in a standard wheel running task (i.e., no environmental enrichment). Moreover, the authors reported that their conjoint morphological, molecular, and behavioral data demonstrate that physical activity and cognitive training “ ... can be combined to obtain specific additive (italics added) regulatory effects” (p. 5). In addition, Oswald et al. [23] reported that cognitively healthy older adults who participants in a combined multi-modality physical activity and cognitive training program showed larger, and long-lasting, benefits to cognition (as assessed via memory and perceptual speed) than those who participated in multi-modality training alone. Notably, however, the salience of combined physical activity and cognitive training is tempered by evidence reporting that such an affect may not extend to populations with cognitive impairment. In particular, Law et al.’s [24] systematic review concluded that in populations with cognitive impairment “ ... well-designed studies are still needed to explore the potential benefits of this new intervention paradigm” (p. 61). As such, the primary objective of this study was to determine whether a cognitive-based visuo-spatial stepping task included in a multiple-modality exercise training program (i.e., multiple-modality, mind-motor intervention) renders an additive post-intervention benefit in executive control for persons self-reporting a cognitive complaint (_SCC). To that end, older adults with a _SCC were randomly assigned to one of two groups that completed a 24-week exercise training program. The first group completed a multiple-modality exercise program that involved resistance (as well as balance, range-of-motion, and breathing exercises) and moderate-to-vigorous intensity aerobic training [25] (65–85% maximum heart rate, for 20 min/d, 3x/wk) (i.e., the multiple-modality intervention group: M2). The second group completed the same aerobic and resistance training as the M2 group; however, in the place of balance, range of motion and breathing exercises a cognitively demanding task was performed (i.e., multiple-modality, mind-motor intervention group: M4). In particular, in each exercise session the M4 group performed 15 min of square-stepping exercises (SSE), a contextually varied visuo-spatial working memory task requiring that participants memorize and execute progressively more complex foot placement patterns that involve forward, backwards, lateral, and diagonal steps. The SSE was originally designed to improve balance for individuals at risk for falling [26]; however, it has also shown promise for improving cognition in non-demented older adults [27, 28]. As such, the M4 group provided a framework to determine whether multiple-modality, mind-motor training enhances executive control more than multiple-modality training alone. Moreover, we purpose-designed the M4 group based on Law and colleagues’ [24] assertion that the empirical evaluation of an additive benefit of a cognitive-motor task in persons at risk for cognitive decline requires the direct comparison to an ‘active’ control group (i.e., the M2 group).

To address our primary objective, M2 and M4 group pre- and post-intervention executive control was examined via the antisaccade task. The antisaccade task requires a goal-directed eye movement (i.e., saccade) mirror-symmetrical to the location of a visual target. Notably, the task is cognitively ‘challenging’ and extensive behavioral and neuroimaging work in humans as well as single-cell recording work in non-human primates has shown that correct antisaccade performance is contingent upon premovement activity within the prefrontal cortex [29 –33], a region supporting executive control [34] and known to be compromised in AD [35]. In particular, Munoz and Everling [33] proposed that the wealth of behavioral and neurophysiological evidence accumulated from the antisaccade task provides for specific predictions regarding the neural mechanisms impaired in clinical populations. Moreover, Peltsch et al. [36] demonstrated that persons meeting Petersen’s et al.’s [37] definition for amnestic MCI (i.e., aMCI: cognitive complaint not normal for age, not demented, memory decline, essentially normal functional activities) exhibited antisaccade reaction time (RT) costs that were larger than cognitively healthy older adults. As well, Peltsch et al. reported that antisaccade metrics were more effective at differentiating executive function between controls and individuals with aMCI than standardized neuropsychological tests (i.e., California Verbal Learning Test, Wisconsin Card Sorting Task). Thus, the hands- and language-free nature of the antisaccade task coupled with the temporal and spatial resolution of eye-tracking provides an ideal tool for the assessment of subtle executive deficits/improvements in persons with a cognitive complaint/impairment [36, 38].

As a secondary research goal, we examined whether our exercise interventions differentially influenced executive control in persons with a selective _SCC and those meeting the definition for MCI. The basis for this question was motivated by evidence that persons meeting the MCI definition are progressed further along the continuum of cognitive decline than individuals with a selective _SCC [39]. As such, it is possible that persons with MCI may show an increased (or decreased) benefit to executive control following a 24-week multi-modality exercise training program than those with a selective _SCC. To accomplish our secondary goal, we dichotomized all the M2 and M4 _SCC participants included in our primary research goal into those: (1) having a selective _SCC, and (2) meeting the definition for MCI (i.e., an individual with a _SCC and an associated objective cognitive impairment as determined by a Montreal Cognitive Assessment (MoCA) score of less than 26) [40]. Subsequently, we evaluated whether persons with _SCC and MCI elicited differential executive-related oculomotor benefits following M2 and M4 interventions.

Methods

Participants

Community-dwelling older adults (≥55 years of age) from the communities in and around Woodstock, ON, Canada, were recruited for this study. Study recruitment involved: (1) advertisement in local newspapers and partnership publications, (2) posters at local businesses, (3) health fairs, and (4) word of mouth. Individuals within the aforementioned age range were eligible for participation based on a self-reported cognitive complaint (i.e., answering yes to the question: “Do you feel that your memory or thinking skills have gotten worse recently?”), and preserved instrumental activities of daily living (i.e., Lawton-Brody Instrumental Activities of Daily Living, IADL scale > 6) [41]. Participants were excluded from participation based on: (1) probable dementia (i.e., self-reported diagnosis or Mini Mental State Exam (MMSE) score < 24) [42], (2) major depression (i.e., score≥16 on the Center for Epidemiological Studies Depression scale) or the clinical judgment of the study physician (RJP), (3) diagnosis of other neurological or psychiatric disorders, (4) recent history of severe cardiovascular conditions, (5) significant orthopedic conditions (i.e., limiting the ability to exercise), (6) blood-pressure considered unsafe for exercise (i.e., >180/100 and/or <100/60 mm/Hg) [43], (7) severe sensory impairment, (8) unable to comprehend the study letter of information, (9) unable to commit to 80% of exercise sessions over the 24-week intervention period, and (10) any other factors that could limit the ability to fully participate in the intervention. In addition, we computed MoCA scores for all participants to address our secondary research goal (i.e., to contrast persons with a selective _SCC from those meeting the definition for MCI). Further, by including MoCA, MMSE, CES-D, and IADL scales we used a screening package identified by the Vascular Cognitive Disorders Harmonization Standards paper as providing a valid means for identifying individuals with a possible cognitive deficit but not meeting the definition for AD or other dementias [44].

A total of 179 individuals showed initial interest and 127 met the inclusion criteria and were enrolled in the full study. The study was conducted in four waves, with participants beginning the 24-week intervention in groups. The first 41 participants were excluded from the oculomotor analyses presented below due to technical difficulties with our eye-tracker. Of the remaining 86 participants, nine were excluded because the eye-tracker could not be calibrated to their eye movements, two did not have usable pre-intervention baseline data, eight dropped out of the study prior to their post-intervention assessment, and four produced an extensive number of saccade anticipation errors (see details below). Thus, 63 participants were used in our final analyses (see Table 1 for participant demographics). The Health Sciences Research Ethics Board, University of Western Ontario, approved this study and this work was conducted according to the ethical standards laid down in the Declaration of Helsinki. All participants provided written informed consent prior to taking part in any study procedures.

Exercise intervention

Participants were randomly allocated (1:1) to a: (1) multiple-modality exercise intervention group (i.e., M2 group) or (2) multiple-modality, mind-motor exercise intervention group (i.e., M4 group). As will be detailed below, the M2 group (n = 32) completed a 24-week multiple-modality training program, whereas over the same time range the M4 group (n = 31) completed a multiple-modality, mind-motor training program. Both M2 and M4 interventions involved group-based exercise classes in which individual participants completed three sessions per week over the course of the intervention period.

The multiple-modality exercise intervention: the M2 group

The M2 group participated in a 60-min group-based multiple-modality (i.e., M2) exercise classes, 3 days per week over 24 weeks. As shown in Table 2, each exercise session involved: (1) a 5-min warm up, (2) 20 min of moderate-to-vigorous intensity aerobic training (i.e., 65–85% maximum heart rate), (3) 5-min aerobic cool-down, (4) 10 min of resistance training, (5) 15 min of balance training, range of motion, and breathing exercises, and (6) 5 min of stretching. The balance, range of motion, and breathing exercises did not include the use of additional loading (i.e., hand weights or resistance bands) and were selected as suitable control exercises within the M2 group because they do not impart cognitive benefits [9]. Table 2 provides a complete description (and sequence) of the exercises performed during the 10-min resistance and 20-min aerobic components of each exercise session. As well, the design of our exercise program was based on: (1) extensive pilot work involving group-based exercise classes and feedback from participants indicating that they wished for exercise sessions to be completed within a 60-min timeframe, (2) physical activity guidelines published by the Public Health Agency of Canada and endorsed by the Canadian Society for Exercise Physiology stating that 150–180 min of moderate-to-vigorous intensity activity completed across three days per week promotes healthy aging [45].

The multiple-modality and mind-motor exercise intervention: the M4 group

The M4 group completed the same multiple-modality exercise training as the M2 group with one exception. In particular, the M4 group completed 15 min of mind-motor exercise (i.e., progressive square-stepping exercise: SSE) in place of the 15 min balance, range of motion, and breathing exercises. As such, the M2 and M4 groups completed the same duration of activity (60-min classes, 3 times per week) and were afforded the same amount of social interaction and attention from study personnel (see Table 2 for details).

As mentioned above, the SSE was used as the mind-motor training component of this study. The SSE is a simple, low-cost, indoor, and group-based exercise program for older adults [27]. The task required that participants memorize and execute progressively more complex foot placement patterns that involved forward, backwards, lateral, and diagonal steps using a gridded floor mat (250 cm by 100 cm, portioned into 10 rows of 4 equal-sized squares; for schematic see Fig. 1). The SSE involves over 200 stepping patterns (i.e., ranging from simple to complex) and the M4 group progressed across patterns over the duration of the training intervention with each exercise session beginning with the SSE pattern attained during the previous session. The goal for the M4 group was to progress as far as possible over the 24-week intervention period. At the beginning of each SSE session, the participants watched an instructor demonstrate a pattern and then attempted to repeat the pattern (i.e., via memory) on the SSE mat. Participants worked in small groups (N≤6) on an individual SSE mat. To promote a positive social environment, participants were encouraged to assist each other during the SSE component of the group exercise class. To progress to the next SSE pattern, at least 80% of the group (i.e., class) was required to have successfully completed the pattern at least four times in a row in a reasonable period of time (i.e., 2-3 sessions). If the group did not successfully complete a specific pattern after three classes then the group would progress to the next pattern within the same difficulty level.

Instructor training, class size, and intensity

Two Seniors Fitness Instructors certified through the Canadian Centre for Activity and Aging led the exercise classes. The M2 and M4 exercise classes were held during morning time slots, with class sizes varying from eight to 23. At the start of the study, participants were provided an individualized target heart rate (65–85% of estimated maximum heart rate) determined via the Step Test and Exercise Prescription (STEP™) tool [46]. During the aerobic exercise component of each training session, participants were encourage to exercise at their prescribed training heart rate and/or at a rating of 5–8 on the 10-point modified Borg Rating of Perceived Exertion (RPE). During the balance/range-of-motion/breathing (i.e., M2 group) or the SSE (i.e., M4 group) components, participants were encouraged to keep their heart rates below their training heart rate to ensure that the aerobic exercise component was comparable between groups. At the end of each aerobic and each balance/range-of-motion or SSE component participants were instructed to record their heart rate and RPE. To ensure progression in aerobic training, individualized training heart rates were recalculated at the midpoint of the intervention (i.e., 12 weeks) via the STEP™ tool.

Oculomotor assessment

Antisaccades require a saccade mirror-symmetrical to a target stimulus. The task therefore requires the top-down (i.e., executive) and two-component processes of suppressing of a pre-potent response (i.e., suppression of a prosaccade) and inverting a target’s spatial coordinates (180° spatial transformation: i.e., visual vector inversion) [33]. In contrast, a prosaccade requires a saccade to a target’s veridical location, and the direct stimulus-response mapping associated with this task allows for motor output via direct retinotopic maps in the superior colliculus that operate largely independent of cortical mechanisms (i.e., the visual ‘grasp’ reflex) [47]. Indeed, by contrasting pro- and antisaccades our investigation provided a framework to determine whether our exercise interventions rendered a general improvement in oculomotor control per se, or imparted a selective benefit to an oculomotor response requiring high-level executive control (i.e., antisaccades only).

Pro- and antisaccades were completed pre- and post-intervention. The pre-intervention was completed on average 19.8±13.0 days prior to the beginning of the exercise program and the post-intervention was completed on average 10.0±5.5 days following the end of the exercise program. For each session, participants sat in a height-adjustable chair located 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 by 960 pixels; Dell 2007WFP, Round Rock, TX, USA) located at participants’ midline and 600 mm from the front edge of the table-top 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°: 135 cd/cm²) located 11° 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 (EyeLink 1000: SR Research, Mississauga, ON, Canada) sampling at 500 Hz. In addition, two monitors visible only to the experimenter provided: (1) real-time point of gaze information, (2) trial-to-trial information on saccade kinematics (i.e., displacement and velocity), and (3) information about the accuracy of the eye-tracking system (i.e., to permit a recalibration when necessary). All visual and computer events were controlled via MATLAB (ver 7.6: The MathWorks, Natick, MA, USA) and the Psychophysics Toolbox extensions (ver 3.0) [48]. The lights in the experimental suite were extinguished during datacollection.

At pre- and post-intervention oculomotor assessments pro- and antisaccades were completed in separate and randomly ordered blocks. The beginning of each block provided a written instruction screen indicating the nature (i.e., pro- or antisaccade) of the upcoming series of trials. Participants were also provided five practice trials at the beginning of each block. All trials started with the appearance of the fixation cross which instructed the participant to direct their gaze to its location. Once a stable fixation was achieved (i.e.,±1.5° for 450 ms) a randomized foreperiod was introduced (i.e., 1,000–2,000 ms) after which time the fixation was extinguished (i.e., gap paradigm). After a 200 ms interval one of the target stimuli was briefly (i.e., 50 ms) presented and its onset served as the imperative to pro- (i.e., look to veridical target location) or antisaccade (i.e., look mirror-symmetrical to the target) as “quickly and accurately” as possible. The ordering of target eccentricity (i.e., 11° and 14°) and the visual field the target appeared (i.e., left or right of fixation) was randomized and presented 20 times within a block of trials (i.e., 80 pro- and 80 antisaccades within each pre- and post-intervention session). Last, and as noted above, we employed a gap paradigm because it is cognitively more challenging then its overlap counterpart (i.e., when fixation and target are visible at response onset), and as such served as a viable framework to examine exercised-induced changes in executive oculomotor control [33].

Data reduction and dependent variables

Pre- and post-intervention body mass index (BMI) and predicted maximal aerobic capacity (i.e., _PVO₂ max determined via the STEP^TM tool) [46] were computed. Gaze position data were filtered offline using a dual-pass Butterworth filter employing a low-pass cut-off frequency of 15 Hz. Filtered displacement data were used to compute instantaneous velocities via a five-point central finite difference algorithm. Acceleration data were similarly obtained from the velocity data. Saccade onset was defined as the first frame wherein velocity and acceleration values respectively exceeded 30°/s and 8,000°/s². In turn, saccade offset was defined as the first frame wherein velocity fell below a criterion of 30°/s for 20 frames (i.e., 40 ms). Dependent variables for the oculomotor assessment included RT (time from target onset to saccade onset), the coefficient of variation (CV) of RT (standard deviation/mean×100%), the percentage of directional errors (i.e., the completion of a prosaccade instead of an instructed antisaccade and vice versa) and saccade amplitude in the primary (i.e., horizontal) movement direction. Individual trial data were excluded from further analyses if RTs were less than 100 ms (i.e., an anticipatory or express saccade) [49] or were greater than two standard deviations above a participant-specific mean. In addition, data were excluded if saccade amplitude was less than 2.5° or greater than 24° [50]. Less than 8% of all experimental trials were removed due to the exclusion criteria and less than 4% of trials were removed due to signal loss (i.e., blinking). Further, and in line previous work, the RT and amplitude data used here involved only directionally correct trials because trials involving an antisaccade directional error are supported via planning and control mechanisms that are distinct from their directionally correct counterparts [31 , 50–52].

Results

Pre-intervention MMSE and MoCA scores

At baseline participants were an average age of 67.0±1.5 years of age, 74% female, 98% white race, 14.2±2.8 years of education, and had a blood pressure of 134.7±19.4 / 78.9±11.8 mmHg. The MMSE has been traditionally used to identify older adults with significantly progressed cognitive impairment and dementias [42], whereas the MoCA, which contains more complex tasks than the MMSE, has been used to identify individuals exhibiting the early stages of cognitive decline [40, 53]. We used the MMSE and MoCA to provide a general pre-intervention evaluation of the cognitive status of M2 and M4 groups. Results indicated that MMSE (M2:29.0, SD = 1.1; M4:29.3, SD = 0.9) and MoCA (M2:25.1, SD = 2.2; M4:26.3, SD = 2.6) values did not reliably differ between groups (all t(61) = 1.08 and 1.91 for MMSE and MoCA, respectively, ps = 0.28 and 0.07, d_z = 0.28 and 0.49).

Pre- and post-intervention BMI and _PVO₂ max

BMI and _PVO₂ max measures were examined via 2 (group: M2, M4) by 2 (time: pre-, post-intervention) mixed-groups ANOVA. Results for BMI showed that values for M2 (27.5 kg/m², SD = 4.7) and M4 (28.0 kg/m², SD = 3.8) groups did not reliably vary and that values did not reliably vary with time or elicit a group by time interaction, all F(1,61)<1. For _PVO₂, M2 (28.5 O₂/kg/min, SD = 7.6) and M4 (30.7 mL O₂/kg/min, SD = 3.8) groups did not reliably differ, F(1,61)<1; however, a main effect for time indicated that values for both groups increased from pre- to post-intervention, F(1,61) = 36.90, p < 0.001, η_p² = 0.38 (Table 1). Thus, pre-intervention fitness scores were comparable for M2 and M4 groups and both groups showed a post-intervention improvement in _PVO₂ max.

Square-stepping exercise (SSE) progression (M4 group only)

The SSE program is separated by difficulty: Beginner 1, Beginner 2, Intermediate 1, Intermediate 2, Intermediate 3, Advanced 1, Advanced 2, Advanced 3; with a range of 8–36 patterns in each difficulty level. All waves of M4 groups progressed to the Advanced 1 patterns, with one group progressing to the Advanced 2 patterns by the end of the 72 sessions. The level of progression varied between groups because of: (1) the waves progressing as a group rather then individually, (2) class size (i.e., smaller class sizes progressed faster), and 3) the cognitive level of some participants varied in the waves (e.g., a participant with a more advanced cognitive decline may have decreased a group’s progression rate). Since all of the waves reached the Advanced 1 pattern, we are confident that each progressed at a similar rate and attained a comparable level of cognitive-motor training.

Attendance and exercise intensity compliance following aerobic and balance/range of motion/breathing (i.e., M2 group) and SSE (i.e., M4 group) training

All participants were requested to attend 72 exercise sessions across the 24-week intervention period. Table 3 shows the average number of classes attended by M2 (56/72 or 77%) and M4 (53/72 or 73%) participants. In addition, Table 3 presents the percentage of M2 and M4 participants that achieved their prescribed heart rate as assessed immediately following aerobic training. Table 3 shows the percentage of participants for which we did not obtain heart rate values (i.e., Absent) and participants’ whose post-aerobic performance was below, at, or above, their prescribed heart rate. For M2 and M4 groups, the percentage of participants achieving their prescribed heart rate (M2 = 53%; M4 = 51%) was greater than any of the other categories and this compliance did not differ between groups (χ² = 1.69, p = 0.64). In addition, we assessed heart rate immediately following the balance/range of motion/breathing (i.e., the M2 group) and SSE (i.e., the M4 group) components of each exercise session and found that 81% of M2 and 90% of M4 participants were below their prescribed heart rate during this time. Further, the frequency of participants who were below their prescribed heart rate did not vary between M2 and M4 groups (χ² = 1.98, p = 0.37) (Note: no participant from M2 or M4 groups attained a heart rate above their prescribed level during balance/range of motion/breathing (i.e., M2 group) and SSE (i.e., M4 group) exercise components, thus our chi-squared test did not include the category “Above target heart rate”). As such, the SSE component did not result in M4 participants having a longer within-session prescribed aerobic heart rate than the M2 group.

Oculomotor planning and control pre- and post-intervention: reaction time, directional errors, and saccade amplitude

Figure 2 provides pro- and antisaccade RT percent frequency histograms for M2 and M4 groups separately for pre- and post-intervention assessments. We present the histograms to document the number of trials associated with our experimental conditions and to demonstrate the basic finding that antisaccade RTs were longer than prosaccades regardless of group and intervention time point. In terms of quantitative analyses, mean RT were examined via 2 (group: M2, M4) by 2 (time: pre-, post-intervention) by 2 (task: pro-, antisaccade) mixed-groups ANOVA. Results produced main effects for time, F(1,61) = 6.85, p < 0.02, η_p² = 0.10, task, F(1,61) = 534.47, p < 0.001, η_p² = .90, and their interaction, F(1,61) = 24.52, p < 0.001, η_p² = 0.29. Figure 3 shows that prosaccade RTs did not vary from pre- to post-intervention (t(62) <1), whereas antisaccade RTs decreased from pre- to post-intervention (t(62) = 3.90, p < 0.001). As well, and in light of our primary research objective, we note that neither group nor any higher-order interactions involving group elicited a significant effect/interaction (all F < 1).

Results for the CV of RT produced an effect for task, F(1,61) = 63.45, p < 0.001, η_p² = 0.51: the CV for prosaccades (21, SD = 8) was greater than antisaccades (15, SD = 6); however, neither group nor any higher-order interaction involving group elicited a significant effect (all F < 1). We believe it important to highlight these null effects because they demonstrate that the post-intervention decrease in antisaccade RTs was not associated with a reliable change in its CV.

Figure 4 presents participant-specific pre- and post-intervention directional errors for M2 and M4 groups. The figure shows that for prosaccades a number of M2 (n = 17) and M4 (n = 24) participants produced error-free performance. The floor-level performance precluded examination via ANOVA model. As such, pro- and antisaccades were contrasted qualitatively and Fig. 4 shows that the former were associated with fewer directional errors across pre- and post-intervention sessions. In terms of antisaccades, directional errors were examined quantitatively via 2 (group: M2, M4) by 2 (time: pre-, post-intervention) mixed-groups ANOVA and results did not indicate reliable main effects or an interaction (all F(1,61)<1.13, ps > 0.29, all η_p² < 0.03).

Saccade amplitude was examined via 2 (group: M2, M4) by 2 (time: pre-, post-intervention) by 2 (task: pro-, antisaccade) by 2 (target eccentricity: 11° [i.e., proximal] and 14° [i.e., distal] mixed-groups ANOVA. Results revealed a main effect for target eccentricity, F(1,61) = 308.99, p < 0.001, η_p² = 0.83, and a task by target eccentricity interaction, F(1,61) = 160.73, p < 0.001, η_p² = 0.72. Pro- (9.8°, SD = 0.8) and antisaccade (10.4°, SD = 2.0) amplitudes to the proximal target were shorter than their distal target counterparts (prosaccade: 12.0°, SD = 0.9; antisaccade: 10.8°, SD = 1.7) (all t(62) = 34.22 and 3.03, for pro- and antisaccades, respectively, ps < 0.01). In other words, amplitude increased with increasing target eccentricity. To further decompose the interaction, we computed participant-specific target eccentricity difference scores (i.e., distal target minus proximal target) separately for pro- and antisaccades. Results showed that the difference score was larger for pro- (2.1°, SD = 0.4) than antisaccades (0.3°, SD = 1.0), t(62) = 12.58, p < 0.001 –a result evincing that prosaccade amplitudes scaled to veridical target eccentricity more than antisaccades. Notably, however, no further effects/interactions were reliable (all Fs < 1). Thus, the accuracy of saccades was consistent across M2 and M4 groups and did not vary pre- to post-intervention.

Oculomotor control in persons with a selective _SCC and those meeting the definition for MCI

Recall that the secondary goal of this investigation was to determine whether our exercise interventions differentially influenced executive control in persons with a selective _SCC and those meeting the definition for MCI. To address that goal, we identified individual M2 and M4 participants with an objective cognitive impairment; in other words, we classified individuals as meeting the definition for MCI from those with a selective _SCC. The identification of an objective cognitive impairment was based on a MoCA score of less than 26. For the M2 and M4 groups, 17 (53%) and 20 (65%) participants were classified as meeting the MCI definition, respectively. Notably, the frequency of individuals identified with a MCI or _SCC did not vary between M2 and M4 groups (χ² = 1.98, p = 0.16). Further, we employed 2 (group: M2, M4) by 2 (MoCA classification: _SCC, MCI) mixed-groups ANOVA to contrast antisaccade RT difference scores (i.e., pre-intervention minus post-intervention). The basis for this analysis was to determine whether the magnitude of the post-intervention antisaccade benefit differed as a function of M2 and M4 participants classified as meeting the _SCC and MCI definitions. Figure 5 presents the difference scores and results did not yield any reliable effects or interactions (all F < 1). Thus, the magnitude of the post-intervention antisaccade benefit reported in our general analysis (see Oculomotor planning and control pre- and post-intervention: Reaction time, directional errors, and saccade amplitude) did not vary across M2 and M4 participants with MCI or _SCC. Moreover, the above analyses demonstrate that the absence of an additive post-intervention antisaccade benefit for the M4 group reported in our general analysis cannot be attributed to group-based differences in the frequency of MCI.

Discussion

The primary objective of this study was to determine whether persons with a self-reported cognitive complaint (_SCC) who completed a 24-week multiple-modality, mind-motor exercise training program (M4 group: i.e., aerobic and resistance training with a cognitive-motor component) show an additive post-intervention benefit to executive-related oculomotor control than counterparts involved in multiple-modality training only (M2 group: i.e., aerobic and resistance training). Before discussing our primary objective, we first provide a general description of the difference between pro- and antisaccades. In particular, prosaccades had shorter RTs, produced fewer directional errors, and were more accurate than antisaccades. Results for prosaccades evince that saccades with spatial overlap between stimulus and response are mediated via direct retinotopic projections within the superior colliculus [54], and operate with minimal top-down cortical control [47]. In turn, the longer RTs, more errorful and less accurate performance of antisaccades has been tied to the time-consuming demands of suppressing a prepotent response and evoking a saccade to a mirror-symmetrical location [33 , 56]. Further, ample evidence has attributed the longer RTs of directionally correct antisaccades to the activation of executive networks within the prefrontal cortex [32]. Thus, the behavioral properties associated with the antisaccades studied here demonstrate a cognitively challenging task providing a framework to evaluate whether multiple-modality or multiple-modality, mind-motor exercise training programs differentially influences executive-related training benefits in persons with a _SCC.

Pre- and post-intervention pro- and antisaccade performance

At the pre-intervention oculomotor assessment, M2 and M4 groups exhibited comparable pro- and antisaccade performance. The comparable antisaccade performance in combination with null group differences in general clinical assessment measures (i.e., MMSE and MoCA) demonstrate similar pre-intervention executive and cognitive status for M2 and M4 groups. As well, our pre-intervention assessment of body mass index and predicted VO₂ max indicated comparable values for M2 and M4 groups— a result indicating similar group fitness levels.

In terms of pre- and post-intervention differences, prosaccade planning (i.e., RT and directional errors) and control (i.e., amplitude) did not reliably vary for M2 or M4 groups. This is an expected finding and as indicated above is attributed to prosaccade evocation via retinotopic projections within the superior colliculus [54]. In other words, the subcortical mediation of prosaccade renders their control independent of cortically based modifications associated with an exercise intervention [10]. More notably, results for antisaccades showed that post-intervention RTs were shorter than their pre-intervention counterparts and the magnitude of this reduction did not reliably differ between M2 and M4 groups. M2 and M4 groups showed a 20 ms and 26 ms post-intervention RT reduction, respectively. Moreover, when we decomposed our M2 and M4 participants based on those with a selective _SCC and those meeting the definition for MCI (see secondary research objective) we found that the post-intervention antisaccade benefit did not vary across M2 and M4 sub-groups. In other words, exercise training elicited a global benefit to persons reporting a _SCC regardless of an accompanying objective cognitive impairment.

In outlining the salience of our antisaccade RT findings we highlight four points. First, antisaccade directional errors and endpoint accuracy did not differ from pre- to post-exercise intervention. These findings demonstrate that participants did not ‘improve’ their antisaccade planning times at the cost of increased directional errors and endpoint accuracy (i.e., speed-accuracy trade-off). Second, it is unlikely the improved post-intervention RTs are tied to a ‘learning event’ as work involving healthy young and older adults has reported that antisaccade RTs are stable when tested in deliberate practice sessions completed over a 4-week period [57 –59]. Third, the magnitude of the post-intervention antisaccade RT reduction is in line with a previous study by our group showing a similar magnitude training effect (i.e., 30 ms) for individuals with objective cognitive impairments who completed a 24-week aerobically based gait training program [60]. Moreover, in the extant antisaccade literature, the RT reduction observed here can only be described as ‘large’ in magnitude [33] and is a finding that has been directly tied to the improved efficiency and effectiveness of executive-related oculomotor mechanisms. Fourth, Peltsch et al. [36] proposed that antisaccade metrics are more effective at differentiating executive function between controls and individuals with aMCI than standardized neuropsychological tests (i.e., California Verbal Learning Test, Wisconsin Card Sorting Task). Thus, accumulating evidence indicates that the antisaccade task, and associated temporal resolution (i.e., 500 Hz) of eye-tracking technology, provides a viable tool for identifying executive deficits/improvements in persons experiencing cognitive decline [38]. Accordingly, we believe that a parsimonious interpretation for the post-intervention RT reduction is that exercise training improves executive-related oculomotor control in persons with a _SCC. Although we do not have a direct mechanism to account for our finding, it may be that exercise benefits functional connectivity of fronto-parietal structures associated with high-level executivecontrol [61].

M2 and M4 group post-intervention RT performance

Recall that the M4 group performed that same aerobic and resistance exercise-intervention as the M2 group, but also completed a SSE task to provide a cognitively challenging training environment. The motivation for including the M4 group was based on animal and human work (cognitively healthy participants) reporting that aerobic/resistance training programs including a cognitive training component enhance cerebral blood flow and render additive neurocognitive benefits than aerobic/resistance training alone [22 , 63]. Notably, however, the present results provide no evidence that the M4 group elicited enhanced executive-related oculomotor benefits. Of course, we recognize that the M4 group’s cognitive-training was limited to 15 minutes per exercise session, and as such it could be argued that the duration was not sufficient to elicit a reliable effect. As well, our conclusion is restricted to executive-related cognitive processes; that is, from our results it is unclear whether the M4 group would produce additive benefits to visuo-spatial skills, memory, and general cognition. That being said, Law et al.’s [24] systematic review has argued that the conclusions drawn from the four previous studies reporting a beneficial effect of a multiple-modality, mind-motor training in persons experiencing cognitive decline may not relate to a cognitive training component per se. For example, Coehlo et al. [64] reported that persons with AD demonstrated improved cognitive performance following 16 weeks of multi-modality, mind-motor training (i.e., the active group) compared to an inactive control group. Kounti et al. [65] and Suzuki et al. [66] employed a similar inactive control group when examining multi-modality, mind-motor training benefits in persons with MCI. The use of inactive control groups in all three cases raises concern as to whether improved cognition is related to the inclusion of cognitive training or reflects the general (and documented) benefit of aerobic/resistance training. Moreover, Schwenk et al. [67] examined the effect of multiple-modality, mind-motor training in persons with confirmed AD relative to a control group that performed “unspecific low-intensity exercise”. Because moderate-to-vigorous intensity exercise is more beneficial to executive/cognitive processes [10], it is possible that the between-group differences reported by Schwenk et al. reflect an effect of exercise intensity. It is also worthy to note that cognitive training in each of the aforementioned studies (as well as the current study) was distinct from the clinical scales and/or experimental tools used to assess cognitive/executive functioning. For example, we used the SSE as the cognitive training program and employed the antisaccade task to determine exercise-related changes in executive control. Thus, the absence of a transfer from the SSE to the antisaccade task may speak to the fact that cognitive training is task-specific and does not generalize across global cognitive/executive processes (i.e., specificity of practice hypothesis) [68]. That said, and regardless of the specificity of cognitive training, we believe that our work adds importantly to the literature insomuch as it provides the first demonstration that when equated for exercise-intensity a multiple-modality, mind-motor training program does not engender an additive executive-related cognitive benefit than multiple-modality trainingalone.

Study limitations

The pre-intervention oculomotor assessment was completed from 19.8±13.0 days prior to onset of the exercise intervention. The basis for the extended timeframe was scheduling conflict for the individual participants prior to their beginning in one of the four intervention waves used here. It is therefore possible that the extended timeframe of the pre-intervention assessment may have introduced within-groups variability in antisaccade performance. A second limitation to our conclusions is that the group-based training for M2 and M4 groups afforded an interactive social environment, and as a result we cannot directly disentangle the beneficial neurocognitive effects of social engagement and physical activity [69]. That being said, we structured the present investigation on the basis of overwhelming evidence that group-based exercise programs elicit global benefits to physical and mental health. Further, and although pre- and post-exercise intervention antisaccade RT difference scores did not produce reliable correlations with pre- and post-intervention BMI and _PVO₂ max difference scores (all r < 0. 02), _PVO₂ max values for M2 and M4 groups increased from pre- to post-intervention assessments. Thus, our results provide evidence that our exercise interventions improved aerobic physical fitness. A third limitation identified in the review process was whether we captured data regarding the frequency of a self-reported cognitive complaint at the end of our exercise intervention. This is an interesting issue and unfortunately we treated self-reported cognitive complaints as an inclusion criterion and not as an outcome measure. Future work should consider this issue and evaluate whether an individual participant’s post-exercise intervention improvement in executive control (e.g., the antisaccade task) is linked to a perceived improvement in their subjective cognitive abilities. Indeed, if a participant exhibits a conjoint objective and subjective improvement to executive/cognitive processes then it may impart increased confidence and efficiency in their ability to carryout activities of daily living.

CONCLUSIONS

The present findings demonstrate that executive-related oculomotor processing in persons with a _SCC is improved following a 24-week multiple-modality training program. Moreover, we show that improved executive control is unrelated to whether multiple-modality training involves a concurrent cognitive training component.

Acknowledgments

This work was supported by the Canadian Institutes of 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. In addition, we wish to thank Douglas P. Munoz (Queen’s University) and the Parkwood Institute (London, Ontario) for access to the eye-tracking equipment used in this investigation.

Authors’ disclosures available online (http://j-alz.com/manuscript-disclosures/16-0627r2).

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A 24-Week Multi-Modality Exercise Program Improves Executive Control in Older Adults with a Self-Reported Cognitive Complaint: Evidence from the Antisaccade Task

Abstract

Keywords

INtroduction

Methods

Participants

Exercise intervention

The multiple-modality exercise intervention: the M2 group

The multiple-modality and mind-motor exercise intervention: the M4 group

Instructor training, class size, and intensity

Oculomotor assessment

Data reduction and dependent variables

Results

Pre-intervention MMSE and MoCA scores

Pre- and post-intervention BMI and PVO2 max

Square-stepping exercise (SSE) progression (M4 group only)

Attendance and exercise intensity compliance following aerobic and balance/range of motion/breathing (i.e., M2 group) and SSE (i.e., M4 group) training

Oculomotor planning and control pre- and post-intervention: reaction time, directional errors, and saccade amplitude

Oculomotor control in persons with a selective SCC and those meeting the definition for MCI

Discussion

Pre- and post-intervention pro- and antisaccade performance

M2 and M4 group post-intervention RT performance

Study limitations

CONCLUSIONS

Acknowledgments

References

Pre- and post-intervention BMI and _PVO₂ max

Oculomotor control in persons with a selective _SCC and those meeting the definition for MCI