Fatigue during prolonged exercise is accompanied by temporary reductions in voluntary muscular force and poor physical performance. Although biochemical processes occurring within skeletal muscle are partly responsible for these impairments, a progressive reduction in the neural drive to the exercising muscle also contributes—a phenomenon termed central fatigue (45).
It has been proposed that central fatigue may be related to widespread alterations in the activity of neurotransmitters such as serotonin, dopamine, and norepinephrine (15,29). Although early exercise studies focused on serotonin as the key mediator of central fatigue, inconclusive findings in rodents and humans suggest that this neurotransmitter does not play a major role (44).
Comparatively, the role of the central catecholamines, dopamine and norepinephrine, has received less attention. Recent findings suggest that norepinephrine and dopamine availability may be differentially involved in the development of central fatigue. For example, acute dopamine reuptake inhibition (DRI) exerts a positive effect on exercise performance in warm environmental conditions (39). Conversely, acute norepinephrine reuptake inhibition (NRI) impairs exercise performance (38) and is accompanied by a measurable supraspinal component of fatigue (23,24).
Oculomotor tasks are well suited to assess the role of central catecholamines in exercise-induced fatigue as eye movements display sensitivity to changes in central dopaminergic and norepinephrinergic neurotransmission. For example, DRI has been associated with shortened saccade latencies, higher peak saccade velocity, and improvements in smooth pursuit gain (1). Saccades are rapid changes in fixation to align the foveae with salient targets, whereas smooth pursuit stabilizes visual images on the retina as objects of interest move through the visual field (26). Likewise, oculomotor control is sensitive to the pharmacological manipulation of norepinephrine with the administration of clonidine, an α2-agonist that inhibits norepinephrine release, causing substantial decrements in the peak velocity of saccades. Interestingly, when caffeine is coadministered with clonidine, decrements in saccadic control are prevented (43). Caffeine is associated with an upregulation of central dopamine and acceleration in the synthesis and turnover of norepinephrine because of its action as an adenosine antagonist within the central nervous system (20).
We have described similar fatigue-related disruptions to the oculomotor control of saccades after prolonged exercise. After 3 h of cycling, reductions in saccadic velocity were preventable with a moderate dose of caffeine (8). In a follow-up study, the fatigue-reversing influence of caffeine was also achieved by the administration of a dual dopamine–norepinephrine reuptake inhibitor (10). These findings highlight the potential role of central catecholaminergic activity in eye movement fatigue.
In this study, we examine the individual contribution of dopamine and norepinephrine to fatigue-related disturbances in oculomotor control by inducing DRI and NRI during an established endurance cycling protocol (8). Prolonged cycling has a lasting effect on the central nervous system, reducing voluntary activation of the knee extensors for up to 45 min after exercise cessation (42) and is capable of causing significant perturbations to cerebral energetics (33). The oculomotor system is functionally independent of the corticospinal motor system. Thus, assessment of oculomotor control allows for a measure of central fatigue from an unexercised motor system (the oculomotor system) driving unfatigued peripheral components (the extraocular muscles).
The present study assessed the oculomotor control of horizontal saccades, smooth pursuit, and optokinetic nystagmus (OKN) before and after exercise. OKN is an involuntary response elicited by large scale movement of the visual field, resulting in alternating tracking movements (slow phase) followed by rapid, resetting eye movements (quick phase), similar to smooth pursuit and saccades, respectively (4). In addition, a nonoculomotor task measuring covert spatial attention was incorporated to investigate the possible effects of our treatments on visuospatial attention. Covert shifts of attention recruit areas of the brain also involved in directing eye movements (32) and, thus, may also be susceptible to fatigue-related impairments. We hypothesized that decrements in oculomotor control after fatiguing exercise would respond to widespread changes in norepinephrine and/or dopamine activity. Given previous reports of an ergogenic effect of DRI during exercise and an exacerbation of fatigue with NRI, we expected to see an improvement of fatigue-induced impairments in oculomotor control with DRI, and no effect or a larger deterioration with NRI.
MATERIALS AND METHODS
Participants
Twelve healthy participants (seven females, maximal aerobic capacity = 57 ± 10 mL·kg−1·min−1) with a mean age of 25 (19–45) years and body mass of 70 ± 12 kg volunteered to participate. The cohort were categorized as trained cyclists according to a classification scheme for male (36) and female (11) research participants. Participants were recreational cyclists accustomed to cycling for 3 h. Participants gave written informed consent and visited the laboratory on four occasions to participate in a protocol conducted in accordance with the Declaration of Helsinki and approved by the University of Auckland Human Ethics Committee. A health-screening questionnaire confirmed that participants were free of contraindications to exercise, were not taking medications influencing central nervous system function, and had normal or corrected to normal vision.
Experimental Design
DRI, methylphenidate (Rubifen SR; AFT Pharmaceuticals, Barcelona, Spain), NRI, reboxetine (Edronax; Pfizer, Auckland, NZ), or placebo (maltodextrin) treatments were administered within a double-blind, placebo-controlled, repeated-measures, randomized crossover design. Participants completed three experimental trials involving 180 min of continuous cycling at a work rate equivalent to 60% of maximal aerobic capacity. A minimum of 5 d between crossover phases was enforced. Participants were provided a carbohydrate solution during exercise to maintain hydration and euglycemia (see Experimental Protocol section). In all experimental trials, participants completed a battery of visual tasks (see Visual Test Battery section) before exercise (preexercise), and immediately after the exercise protocol (postexercise).
Drug Interventions
DRI (40 mg methylphenidate), NRI (8 mg reboxetine), or placebo treatments were ingested with breakfast, ~55 min before the exercise protocol. Methylphenidate and reboxetine doses were chosen with reference to dosages used in studies where exercise performance tests were administered in unchallenging environmental conditions (23,24,38). Methylphenidate and reboxetine are both rapidly absorbed, with maximum plasma concentration occurring between 1 and 3 h for methylphenidate (27), and within 2 h for reboxetine (22). In adults, the half-life of the slow release methylphenidate formulation (Rubifen SR) is 3.5 h, on average, whereas the half-life of reboxetine is 13 h (35). Two participants reported feelings of nausea with the NRI treatment.
Preliminary Tests
Participants were familiarized with study protocols at least 1 wk before the first experimental trial to ensure a baseline competency level on the visual test battery tasks (see Visual Test Battery section) and estimate maximal aerobic capacity (V˙O2max). Participants performed a maximal cardiopulmonary exercise test on an electromagnetically braked cycle ergometer to measure V˙O2peak (Velotron Dynafit Pro, Seattle, WA). Pulmonary ventilation was measured with a respiratory flow head (GAK-801; Hans Rudolph, Shawnee, KS). Gas composition was analyzed using an infrared carbon dioxide sensor and an optical oxygen detector (ML206 Gas Analyser; ADInstruments, Dunedin, NZ). Data were captured at 1 kHz by a Powerlab 16/35 and LabChart 7 acquisition system (ADInstruments) configured to provide breath-by-breath analysis of all physiological variables. From these data, V˙O2max was estimated and used to prescribe a power output requiring 60% V˙O2max for the experimental trials.
Experimental Protocol
On days of experimental trials, participants arrived at the laboratory between 0700 and 0800 h after a 12 h overnight fast. The start time for the first experimental trial was repeated for subsequent trials. Participants were asked to abstain from caffeine-containing items for 24 h before each experimental session. Body mass was measured after voiding of the bladder. After this, a breakfast cereal and the treatment drug were ingested. The quantity of breakfast cereal was self-selected on the first experimental trial and repeated for the following trials. Immediately after breakfast, a visual test battery was performed. Upon completion of the visual test battery (~40 min), participants began 180 min of continuous cycling performed in an exercise chamber maintained at a constant air temperature (18°C). A carbohydrate solution (0.7 g carbohydrate·kg−1·h−1) was ingested at 15-min intervals during the exercise protocol. Mean rates of fluid and carbohydrate ingestion were 613 ± 104 mL·h−1 and 49 ± 8 g·h−1, respectively. Heart rate was recorded at 15-min intervals during the exercise protocol using a chest strap heart rate monitor (FS1; Polar Electro, Kempele, Finland). Coincident with the recording of heart rate, participants' perceived exertion, mood, and felt arousal were self-rated on visual analog scales. After the exercise protocol, participants repeated the visual task battery. A postexercise measurement of body mass was obtained to assess fluid balance.
Visual Test Battery
The visual test battery consisted of five discrete tasks. Stimuli were presented on a cathode ray tube monitor (Philips 109S2; 1280 × 1024 pixel resolution; 85-Hz refresh rate) at a viewing distance of 66 cm. For the duration of the visual test battery, participants were comfortably seated in a quiet, darkened room. A chin and forehead reset minimized head movements during visual tasks. Eye movements were tracked with infrared cameras sampling at a rate of 400 Hz (ViewPoint Eye Tracker; Arrington Research Systems, Scottsdale, AZ). A 16-point calibration procedure was conducted before the beginning of each task.
Antisaccade task
The beginning of each trial was marked with presentation of a black, centrally located circular fixation point subtending a visual angle of 0.5°. A black, circular peripheral target stimulus (0.5° diameter) then appeared ±10° to the left or right of the central fixation point, where it remained visible for 1000 ms. The peripheral target was presented in gap or overlap conditions. In the gap condition, the central fixation point was presented for 800 ms and extinguished 200 ms before peripheral target presentation. In the overlap condition, the central fixation point remained visible throughout the trial. Participants were instructed to look away from the peripheral target stimulus to a mirror opposite position on the screen and to move their eyes to that position as quickly and accurately as possible. Each condition was presented 50 times, resulting in a total of 100 trials. The sequence of gap, overlap, right target location, and left target location was randomized.
Prosaccade task
The prosaccade task had identical stimulus characteristics to the antisaccade task, although participants received different instructions to those given in the antisaccade task. Participants were instructed to move their eyes to look at the target stimulus as quickly and accurately as possible.
Smooth pursuit task
A triangular target waveform was presented at three velocities (5°·s−1, 10°·s−1, and 30°·s−1). The target, consisting of a circular black dot with a diameter subtending 0.8° of visual angle, was presented in the center of the screen (0°) for a duration of 1000 ms at the beginning of each trial. After fixation, the target moved horizontally until it reached ±15°, where it reversed direction abruptly. A trial consisted of 5.5 passes of the target across the display screen. Each target velocity was presented seven times, resulting in 21 total trials. The sequence of target velocity and the initial ramp direction were randomized. Participants were instructed to follow the target with their eyes as accurately as possible.
OKN task
To evoke an OKN response, a stimulus screen consisting of a 100% contrast square wave grating with a fundamental spatial frequency of 0.833 cycles per degree was presented. The gratings were presented for 20 s per trial at two velocities (5°·s−1 and 10°·s−1) and two stimulus directions (right to left, or left to right) for two trials each, resulting in eight total trials. Participants were instructed to watch the screen, keeping the stimulus in focus. The objective of these instructions was to encourage a “stare” OKN.
Covert spatial attention
A cueing task with endogenous and exogenous cueing conditions assessed covert attentional orienting. At the beginning of each trial, a central fixation cross and two peripheral boxes located 10° laterally to the fixation cross were displayed for 1000 ms. A visual cue was then presented for 200 ms. After a time interval of 200 ms after the cue was extinguished, a peripheral target (black circle, radius of 0.5°) appeared in the right or left peripheral box for 150 ms. Participants were instructed to maintain fixation on the central cross and respond as quickly as possible with a key press (left arrow key or right arrow key) when they detected a peripheral target. Two types of cues were presented. Endogenous cues consisted of a centrally presented arrow pointing to the left or right peripheral box. Arrows were centered 0.2° above the visual fixation cross and subtended 0.5°. Exogenous cues consisted of an increase in the line width of the peripheral box from 0.15° to 0.20°. Cues were presented in valid, invalid, or neutral trials. In valid trials, the target appeared in the cued location, whereas in invalid trials, the peripheral target appeared opposite to the cued location. Neutral trials provided no information regarding the target location. Neutral cues consisted of a double-headed arrow or a change in line width of both peripheral boxes for endogenous and exogenous conditions, respectively. Ninety trials for each condition were presented. In the exogenous condition, valid, invalid, and neutral trials occurred with equal probability (30 trials per cue). For the endogenous condition, the valid cues correctly predicted target location 80% of the time; thus, neutral cues were presented in 30 trials, valid cues in 48 trials, and invalid cues in 12 trials. The cue-target contingency for exogenous and endogenous conditions was based on previous literature (37). In both conditions, targets appeared in the right or left peripheral box with equal probability. Cue type presented was randomized within endogenous and exogenous blocks.
In the preliminary testing session, participants completed abbreviated versions of all visual tasks to ensure they were familiar with stimulus presentation, experimental setup, and task requirements.
Data Treatment and Analysis
Stimulus presentation, data collection, and data analysis was performed using custom software written in Matlab (R2010b; MathWorks, Natick, MA). All eye movements were visually inspected by the experimenter. Final sample size satisfied a priori power analyses. This was estimated using an expected effect size of 0.4, derived from a previous study investigating eye movement kinematics within a similar experimental design (8). In addition, previous research suggests a high correlation (0.62–0.97) across repeated-measures for saccades and smooth pursuit (40). Thus, with power set to 0.95 and P < 0.05, a sample size of 12 participants was estimated to provide appropriate statistical power for eye movement kinematic measures.
Prosaccade and antisaccades
Initiation of a saccade was automatically identified using amplitude deviation (deviation of >1° from fixation) and a velocity criterion (≥30°·s−1). The end of the saccade was detected by a drop in the saccade velocity less than 30°·s−1 (13). Saccades with latencies less than 70 ms were excluded from analysis as these were considered anticipatory (1). Dependent variables derived from the saccade tasks were latency (ms), amplitude (°), peak velocity (°·s−1), and task performance (percentage of saccades in the correct direction). For kinematic measures, only saccades performed in the correct direction were included in statistical analysis.
Smooth pursuits
Pursuit gain (eye velocity/target velocity) was the dependent measure of the smooth pursuit task. Saccades and blinks during pursuit were identified by computing a velocity signal from the horizontal eye position during each trial and applying a velocity criterion (≥64°·s−1). Sections of pursuit containing saccades and blinks were removed before applying a linear interpolation to the remaining data to calculate eye velocity. Eye velocity was used to derive gain (eye velocity/target velocity). The initial ramp in which the target only completed a pass across half of the screen was not included in analysis.
OKN
Quick phases were identified using the same velocity criterion used for smooth pursuit analysis. Amplitude (°) and peak velocity (°·s−1) were derived from the quick phases. Quick phase identification served as a basis for slow phase determination, as slow phases were assumed to occur between quick phases. Eye velocity during slow phases was calculated by applying a linear interpolation to the slow phase, thus permitting the calculation of slow phase gain.
Covert spatial attention task
Keyboard responses (response time and left/right key) were collected using custom software written in Matlab (R2010b). A “validity effect” (6) in endogenous and exogenous task conditions for each participant was derived from response times to valid and invalid cues. This measure, which was calculated by subtracting valid response time from invalid response time, reflects the time required to disengage covert attention from an invalidly cued location and shift attention to the target location. Eye movements were monitored throughout the task. Trials in which the eyes deviated >1° from fixation, or if response time was >1000 ms were rejected from analysis.
Statistical Analyses
A one-way repeated-measures ANOVA with three levels of the factor treatment (DRI/NRI/placebo) was used to explore the effect of exercise on fluid loss. The validity effect in endogenous and exogenous conditions within the covert spatial attention task was explored using a two-way repeated-measures ANOVA with the factors treatment (DRI/NRI/placebo) and time point (preexercise/postexercise). A three-way repeated-measures ANOVA with the factors treatment (DRI/NRI/placebo), time point (preexercise/postexercise), and condition (gap/overlap) was performed on the dependent measures from the prosaccade and antisaccade tasks. Similarly, a three-way repeated-measures ANOVA with factors treatment (DRI/NRI/placebo), time point (preexercise/postexercise), and stimulus speed was performed on measures of smooth pursuit gain (5°·s−1, 10°·s−1, and 30°·s−1), OKN slow phase gain, and velocity and amplitude of OKN quick phases (5°·s−1 and 10°·s−1). There was no influence of stimulus direction in the dependent measures derived from the OKN task, so this was not included as a factor in statistical analysis. To explore the influence of intervention on subjective experiences and heart rate, a two-way repeated-measures ANOVA with the factors treatment (DRI/NRI/placebo) and time point (11 levels −15 min epochs) was performed.
There was a possibility of task learning influencing our dependent variables because of the repeated-measures design of the experiment. This was explored using the same repeated-measures ANOVA described earlier, with the factor trial used in place of treatment. The presence of a task learning effect is highlighted where relevant.
Interaction effects were explored using within-subject paired t-tests where necessary. A false discovery rate criterion procedure was followed to control the multiple comparison type I error rate (3). Violations of sphericity were addressed with the Greenhouse–Geisser correction. Statistical significance was set at α = 0.05. Results are reported as mean ± SD unless otherwise stated. Effect sizes are reported where the magnitude of a change in a measure across time was of interest. Effect size was calculated as the difference between postexercise and preexercise outcomes divided by the preexercise SD as follows (34):
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RESULTS
Prosaccades
Changes in peak prosaccade velocity after exercise were modulated depending on the experimental treatment received (three-way ANOVA: treatment–time point interaction, F2,22 = 8.35, P = 0.002). These changes in velocity after exercise were similar in magnitude for gap and overlap conditions (Fig. 1A). Post hoc analysis revealed that exercise-induced fatigue (placebo treatment) significantly reduced the peak velocity of prosaccades after exercise by 6% ± 8% compared with preexercise (paired samples t-test; t23 = 3.160, P = 0.00). Figure 1B depicts average peak velocity (collapsed across gap and overlap conditions) pre- and postexercise with placebo, NRI, and DRI treatments for each individual. In the majority of participants, peak velocity was influenced by exercise-induced fatigue, with 9 of 12 participants exhibiting a lower peak velocity postexercise compared with preexercise in the placebo trial (Fig. 1B). To explore the magnitude of this change while accounting for within-subject variability, an effect size comparing preexercise prosaccade velocity to postexercise was calculated for each participant. The average effect size of the nine participants that exhibited slower peak velocities with placebo was 0.39 ± 0.22. The remaining participants displayed no change or an increase in peak velocity postexercise with an average effect size of 0.17 ± 0.17. Conversely, NRI and DRI treatments prevented exercise-induced decrements in prosaccade velocity. With NRI, peak velocity was slightly lower after exercise (−3% ± 11%), although post hoc comparisons revealed that this drop was not significantly different from preexercise values (paired samples t-test; t23 = 1.24, P = 0.23). Three participants displayed small decrements in peak velocity (effect size ≤ 0.3), and two participants experienced very large magnitude decrements in peak velocity after exercise (effect size ≥ 1) (see Fig. 1B, middle panel). Four remaining participants showed slight increases in peak velocity (average effect size, 0.48 ± 0.41). The DRI treatment also prevented fatigue-related drops in peak velocity and promoted significantly faster prosaccades after exercise (9% ± 11%, paired samples t-test; t23 = −3.95, P = 0.00) (Fig. 1B, right panel). With DRI, 10 of 12 participants exhibited an increase in peak velocity above preexercise levels (average effect size, 0.50 ± 0.36). Two participants exhibited decreased peak velocity after exercise however this was only of a small magnitude (average effect size, 0.25 ± 0.08).
FIGURE 1: Prosaccade peak velocity and latency for placebo (PLA), reboxetine (NRI), and methylphenidate (DRI) treatments. A, Percentage change of postexercise peak prosaccade velocity in gap and overlap task conditions compared with preexercise (baseline); B. Peak prosaccade velocity collapsed across task condition pre- and postexercise PLA, NRI, and DRI. Each point represents mean peak prosaccade velocity ±95% confidence interval for each participant; C. Prosaccade latency for gap (dashed line) and overlap (solid line) conditions before and after rest in PLA, NRI, and DRI. Significance labeling between gap and overlap conditions indicates a main effect of condition. Data represent mean ± SE. *P < 0.05.
A robust main effect of condition was observed for prosaccade latency (three-way ANOVA: F1,11 = 36.02, P < 0.00), whereby prosaccades in the overlap condition were performed with slower latencies compared with the gap condition. The influence of condition on latency pre- and postexercise for each treatment is illustrated in Figure 1C. No significant changes were observed across time point or between experimental treatments for latency. Similarly, condition also influenced task performance, with higher performance in the overlap condition (three-way ANOVA: main effect of condition, F1,11 = 25.70, P = 0.00). There were no alterations in prosaccade amplitude as a result of condition, time point, or experimental treatment.
Antisaccades
No alterations to the peak velocity of antisaccades were observed after prolonged exercise with placebo, NRI, or DRI. Antisaccade latencies were modulated by an interaction between treatment and time point (three-way ANOVA: F2,22 = 6.73, P = 0.00). Post hoc comparisons confirmed that this effect resulted from shorter antisaccade latencies in the DRI treatment postexercise (218 ± 26 ms) compared with preexercise (238 ± 24 ms) (paired samples t-test; t23 = 7.35, P = 0.00), in both gap and overlap stimulus conditions. In addition, an interaction between condition and time point was observed for latency (three-way ANOVA: F1,11 = 7.74, P = 0.02). This effect stems from slightly faster latencies in the gap condition after exercise, although this difference was not statistically significant after correcting for multiple comparisons. Antisaccade latency was subject to between-trial task learning effects (three-way ANOVA: main effect of trial, F2,22 = 3.96, P = 0.02; trial–condition interaction, F2,22 = 5.85, P = 0.01), whereby the latency of antisaccades in the gap condition was significantly faster in the second and third trials compared with the first. Antisaccade amplitudes were slightly shorter in the gap compared with the overlap condition (three-way ANOVA: main effect of condition; F1,11 = 9.48, P = 0.01). Task performance was modulated by a main effect of condition (three-way ANOVA: F1,11 = 34.47, P = 0.00) due to participants performing more saccades in the correct direction in the overlap condition compared with the gap task condition.
Smooth pursuit
Smooth pursuit gain was modulated by an interaction between stimulus speed and treatment (three-way ANOVA: F4,44 = 3.80, P = 0.01). Post hoc tests revealed that this effect originated from slightly lower smooth pursuit gain in response to the 5°·s−1 stimulus speed with the DRI (0.93 ± 0.09) compared with the NRI treatment (0.97 ± 0.10). However, this difference was not statistically significant after correcting for multiple comparisons. No other alterations to smooth pursuit gain were observed because of time point or treatment.
OKN
Slow phase gain of OKN was unaffected by stimulus speed, exercise, or treatments. The peak velocity of OKN quick phases was faster in response to the 10°·s−1 stimulus speed (three-way ANOVA: main effect of stimulus speed; F1,11 = 8.92, P = 0.01) and after exercise, irrespective of experimental treatment (three-way ANOVA: main effect of time point; F1,11 = 8.54, P = 0.01). Quick phase amplitude was modulated by a main effect of stimulus speed also (three-way ANOVA: F1,11 = 6.18, P = 0.03), where larger amplitude quick phases were performed in response to the 10°·s−1 stimulus speed compared with the 5°·s−1 stimulus speed. A summary of the kinematic data from all visual performance tasks can be found in Table 1.
TABLE 1: Measures of oculomotor control.
Covert spatial attention
The validity effect in endogenous and exogenous cueing conditions was equivalent between treatments and across time points. Table 2 reports the validity effect for both task conditions across time for each treatment.
TABLE 2: Measures of covert spatial attention.
Physiological and subjective measures
Fluid loss associated with exercise did not differ between treatments (one-way ANOVA: F2,22 = 2.02, P = 0.16). Placebo, NRI, and DRI were accompanied with postexercise body mass changes of 0.0% ± 0.7%, 0.2% ± 1.1%, and −0.2% ± 1.2%, respectively. Average heart rate (bpm) was modulated across exercise depending on the treatment received (two-way ANOVA: treatment–time point interaction; F20,220 = 3.53, P = 0.00). Heart rate increased gradually during exercise with DRI but remained stable with NRI and placebo. A priori post hoc comparisons performed on heart rates occurring at the 165-min time point revealed significantly higher heart rates with DRI (168 ± 10 bpm) compared with NRI (158 ± 10 bpm) (paired samples t-test; t11 = 2.93, P = 0.01) and placebo (152 ± 10 bpm) (paired samples t-test; t11 = 6.95, P = 0.00), and NRI compared with placebo (paired samples t-test; t11 = 2.66, P = 0.02). Figure 2A illustrates heart rate over the exercise protocol for each treatment.
FIGURE 2: Heart rate, felt arousal, and perceived exertion during exercise for placebo (PLA), reboxetine (NRI), and methylphenidate (DRI). A. Heart rate over the duration of the 180 min exercise protocol in experimental treatments. Significance labeling represents a statistically significant post hoc comparison between heart rate in at the 165-min time point through exercise for PLA versus DRI, PLA versus NRI, and DRI versus NRI; B. Felt arousal across the 180-min exercise protocol; C, Mood across the 180-min exercise protocol; D. Ratings of perceived exertion during the exercise protocol. Error bars represent standard error. *P < 0.05.
Figures 2B–2D show average ratings of felt arousal, mood, and perceived exertion over the duration of the exercise protocol for each treatment. Subjective ratings of mood were modulated by a treatment–time point interaction (two-way ANOVA: F20,220 = 1.83, P = 0.02). Higher mood ratings occurred with the DRI treatment between 60 and 120 min compared with NRI and placebo treatments (Fig. 2C). However, at 165 min, ratings of mood were similar between treatments, as revealed by a priori post hoc comparisons. Similarly, an interaction between treatment and time point (two-way ANOVA: F20,220 = 2.01, P = 0.01) was detected for ratings of perceived exertion. Perceived exertion increased steadily during exercise for placebo and NRI, whereas DRI ratings were low until 120 min, at which point perceived exertion rose to similar levels as placebo and NRI treatments (165 min) (Fig. 2D). An a priori post hoc comparisons detected no difference in perceived exertion between treatments at 165 min. Felt arousal (Fig. 2B) appears to be maintained at a higher average level throughout exercise with DRI and NRI compared with placebo; however, this difference was not statistically significant (two-way ANOVA: treatment, F2,22 = 2.36, P = 0.12).
DISCUSSION
This study demonstrates that acute DRI and NRI prevent fatigue-related impairments in oculomotor control. Contrary to findings examining the corticospinal system (23,24), NRI did not exacerbate the effects of oculomotor fatigue. The detrimental effect of exercise fatigue was restricted to prosaccade velocity. Smooth pursuit, OKN, antisaccades, and visual attention were robust to fatigue and manipulations of central catecholamines.
Previously, we proposed that reductions in saccade velocity after prolonged exercise reflected the presence of central fatigue within the oculomotor system (8). Here we extend these findings, observing that prolonged exercise also causes decrements in the peak velocity of prosaccades. A 6% reduction in velocity was observed postexercise in placebo, with no concurrent changes to saccade amplitude. The effect size associated with this velocity reduction (0.39) is similar to our previous work (effect size of 0.40) (8). Slower saccades may lengthen the time required to gather visual information. Future studies are required to determine whether a velocity reduction of this magnitude has a discernible influence on overall visual function. A reduction in saccadic velocity of this magnitude could feasibly affect performance in sports and occupations that demand high-speed acquisition of information within the visual field. Optimal saccades are required for many competitive sports, particularly those involving high-speed projectiles.
Prosaccade velocity was preserved in DRI and NRI treatments. DRI was capable of increasing velocity postexercise, whereas no decrements were observed with NRI. These findings imply that increased dopaminergic and norepinephrinergic activity exerts a protective effect on oculomotor control in the context of exercise-induced fatigue. However, responses to NRI across exercise were more variable than DRI (Fig. 1).
Research involving rodents has demonstrated a link between exercise-induced changes to central catecholamines and fatigue (18). We suggest that prolonged exercise perturbs the synthesis and metabolism of dopamine and norepinephrine, resulting in an inhibitory tone that disrupts the oculomotor regions controlling saccades. Reflexive prosaccades rely on subcortical oculomotor areas such as the paramedian pontine formation (PPRF), superior colliculus, and basal ganglia for their execution (21,28). Thus, the effects of exercise fatigue on saccades could be mediated at the level of these oculomotor areas, possibly by affecting the behavior of excitatory burst neurons in the PPRF, which are responsible for encoding eye movement velocity.
Dopamine and norepinephrine are synthesized by concentrated regions of cells in the brainstem, thalamus, and basal forebrain before they project widely throughout the brain (25). Oculomotor areas such as the superior colliculus receive catecholaminergic input (5,30). The superior colliculus drives neurons within the PPRF that comprise the “saccadic burst generator” (17). Thus, it is conceivable that alterations to dopamine or norepinephrine abundance could directly influence the activity within these oculomotor circuits, resulting in detectable alterations in prosaccade kinematics.
It is interesting that OKN quick phases were not influenced by fatigue, as these eye movements share similar neural circuitry to prosaccades (7). However, OKN quick phases were small and variable in amplitude, whereas prosaccades were guided to a fixed target amplitude. It is possible that changes in quick phase velocity are more difficult to detect due to their smaller amplitude and higher variability.
In addition, no fatigue-related impairments in antisaccade velocity were observed. This may be a consequence of differences in saccade dynamics between antisaccades and prosaccades. Antisaccades were generally slower compared with prosaccades, with variable amplitudes, which may have compromised the sensitivity of this measure. This disparity has been attributed to action of distinct neuronal subsystems responsible for the generation of antisaccades and prosaccades (2).
Exercise fatigue did not affect the oculomotor control of smooth pursuit or OKN slow phases. Similarly, visual attention was unaffected, as indicated by a clear gap-overlap effect on latency and task performance, similar across treatments in both saccade tasks. Latencies in the gap condition were shorter than those in the overlap condition. Gap trials are associated with higher preparatory neural activity in the frontal eye fields, the superior colliculus, and the PPRF (12,14). This pattern of neural activity promotes a reduction in saccade latency and lower task performance in the gap condition. Conversely, in overlap trials, fixation-related neural activity persists after target appearance, causing slower saccade latencies (2). On the basis of our findings, it appears that exercise-induced fatigue in combination with DRI and NRI does not selectively influence the release or maintenance of visual fixation. In addition, the orienting of covert spatial attention was robust to exercise fatigue and the drug treatments. This is consistent with previous findings suggesting that spatial orienting is unaffected by prolonged exercise or caffeine (9). Thus, alterations in the disengagement, orienting, and reengagement of visual attention are unlikely to have contributed to the observed alterations in prosaccade kinematics.
Antisaccade latencies were faster with DRI postexercise, across gap and overlap conditions. A similar effect on the latency of visually guided saccades has been reported with DRI in alert participants (1). This effect may be due to the influence of DRI on the caudate nucleus. The dopamine-reuptake inhibitor administered in this study, methylphenidate, primarily acts in the striatum, where it binds to dopamine transporters and inhibits reuptake, resulting in an increase in dopamine concentration (47). The caudate nucleus encodes saccade latency by a series of connections extending via the basal ganglia direct pathway that gates the firing of the motor output layers of the superior colliculus (19). Increased activity in the caudate nucleus due to greater dopamine availability may have shortened antisaccade latencies by disinhibiting the basal ganglia direct pathway. This would explain the decrease in latency across both gap and overlap conditions. However, a between-trial learning effect was found in these data, with shorter antisaccade latencies observed after participants completed experimental trial two. Thus, the influence of DRI on antisaccade latency should be interpreted with caution.
Because we imposed an equivalent exercise workload between treatments, we were able to contrast the influence of DRI and NRI on arousal, mood, perceived exertion, and heart rate during exercise. Both drug treatments promoted higher levels of arousal compared with placebo during the latter half of exercise, with no significant differences detectable between drug treatments at 165 min. DRI also improved mood and lowered perceived exertion in the second hour of exercise compared with NRI and placebo. These findings suggest that DRI improves mood and promotes a positive perception of effort during exercise, whereas NRI contributes to only changes in arousal. This supports the notion presented in the wider literature that caffeine's action on dopamine mediates its positive effects on motor activity and mood, whereas its ability to increase in norepinephrinergic activity may contribute to improvements in arousal (31). Lastly, DRI and NRI were associated with higher heart rate after 165 min of exercise compared with placebo. The presence of this tachycardic effect confirms adequate therapeutic dosing of the drug treatments administered, as higher heart rates are commonly reported alongside central actions (41,46). Interestingly, heart rate was significantly lower in NRI compared with the DRI. Heart rate with NRI appears to diverge from DRI after approximately 60 min. A comparative decrease in heart rate was not reported in previous research that administered NRI to participants during prolonged exercise (38).
Existing research that compared DRI and NRI during exercise reported that NRI may exacerbate central fatigue. This was evidenced by impairments in exercise performance and reductions in the voluntary activation of knee extensor muscles with NRI. These effects were not seen with placebo and DRI treatments (24). A follow-up study investigating the impact of NRI on cortical output and endurance time suggested that NRI leads to a faster degradation in motor cortical output during isometric contraction of the knee extensors (23). Our findings contrast with these theories as NRI was not associated with decreased eye movement velocity. Instead, the present findings suggest that NRI prevents fatigue-induced disruptions in oculomotor control.
The dosing regimen and differing pharmacokinetic profile of the DRI and NRI used in this study restricts us to a directional comparison between the treatments and their effects on oculomotor control. However, the differential effect of DRI on antisaccade latency and increases in postexercise prosaccade velocity suggests that DRI may play a more potent role in mediating a fatigue-reversing effect than norepinephrine. It is also likely that synergies occur, given the functional interactions between the monoaminergic neurotransmitter systems (16).
Overall, our findings suggest that alterations in norepinephrinergic and dopaminergic neurotransmission are linked with the development of fatigue within circuits that control eye movements. DRI prevented fatigue-related impairments to the peak velocity of saccades. In contrast to previous observations in the locomotor system, NRI did not exacerbate the effects of fatigue in the oculomotor system. These observations cannot be explained by direct stress to the brain circuitry controlling the extraocular muscles, as the oculomotor system is functionally independent of locomotion and was not challenged during cycling exercise. The results also demonstrate that acute doses of psychiatric medications that target central catecholamines are capable of improving brain function after prolonged exercise.
The authors thank all the participants who volunteered their time to take part in the study. The results of this study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results presented here do not constitute endorsement by the American College of Sports Medicine.
The authors have no competing financial interests to declare. This study is unfunded.
REFERENCES
1. Allman AA, Ettinger U, Joober R, O'Driscoll GA. Effects of methylphenidate on basic and higher-order oculomotor functions.
J Psychopharmacol. 2012;26(11):1471–9.
2. Bell AH, Everling S, Munoz DP. Influence of stimulus eccentricity and direction on characteristics of pro- and antisaccades in non-human primates.
J Neurophysiol. 2000;84(5):2595–604.
3. Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I. Controlling the false discovery rate in behavior genetics research.
Behav Brain Res. 2001;125(1–2):279–84.
4. Bense S, Janusch B, Vucurevic G, et al. Brainstem and cerebellar fMRI-activation during horizontal and vertical optokinetic stimulation.
Exp Brain Res. 2006;174(2):312–23.
5. Camps M, Kelly PH, Palacios JM. Autoradiographic localization of dopamine D1 and D2 receptors in the brain of several mammalian species.
J Neural Transm Gen Sect. 1990;80(2):105–27.
6. Chica AB, Martín-Arévalo E, Botta F, Lupiáñez J. The spatial orienting paradigm: how to design and interpret spatial attention experiments.
Neurosci Biobehav Rev. 2014;40:35–51.
7. Cohen B. Origin of quick phases of nystagmus.
Prog Brain Res. 1972;37:544–5.
8. Connell CJ, Thompson B, Kuhn G, Claffey MP, Duncan S, Gant N. Fatigue related impairments in oculomotor control are prevented by caffeine.
Sci Rep. 2016;6:26614.
9. Connell CJ, Thompson B, Kuhn G, Gant N. Exercise-induced fatigue and caffeine supplementation affect psychomotor performance but not covert visuo-spatial attention.
PLoS One. 2016;11(10):e0165318.
10. Connell CJ, Thompson B, Turuwhenua J, Srzich A, Gant N. Fatigue-related impairments in oculomotor control are prevented by norepinephrine-dopamine reuptake inhibition.
Sci Rep. 2017;7:42726.
11. Decroix L, De Pauw K, Foster C, Meeusen R. Guidelines to classify female subject groups in sport-science research.
Int J Sports Physiol Perform. 2016;11(2):204–13.
12. Dorris MC, Pare M, Munoz DP. Neuronal activity in monkey superior colliculus related to the initiation of saccadic eye movements.
J Neurosci. 1997;17(21):8566–79.
13. Ettinger U, Kumari V, Crawford TJ, Davis RE, Sharma T, Corr PJ. Reliability of smooth pursuit, fixation, and saccadic eye movements.
Psychophysiology. 2003;40(4):620–8.
14. Everling S, Munoz DP. Neuronal correlates for preparatory set associated with pro-saccades and anti-saccades in the primate frontal eye field.
J Neurosci. 2000;20(1):387–400.
15. Foley TE, Fleshner M. Neuroplasticity of dopamine circuits after exercise: implications for central fatigue.
Neuromolecular Med. 2008;10(2):67–80.
16. Guiard BP, El Mansari M, Merali Z, Blier P. Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions.
Int J Neuropsychopharmacol. 2008;11(5):625–39.
17. Hanes DP, Wurtz RH. Interaction of the frontal eye field and superior colliculus for saccade generation.
J Neurophysiol. 2001;85(2):804–15.
18. Hasegawa H, Piacentini MF, Sarre S, Michotte Y, Ishiwata T, Meeusen R. Influence of brain catecholamines on the development of fatigue in exercising rats in the heat.
J Physiol. 2008;586(1):141–9.
19. Hikosaka O, Takikawa Y, Kawagoe R. Role of the basal ganglia in the control of purposive saccadic eye movements.
Physiol Rev. 2000;80(3):953–78.
20. Kalmar JM, Cafarelli E. Caffeine: a valuable tool to study central fatigue in humans?
Exerc Sport Sci Rev. 2004;32(4):143–7.
21. Kashou NH, Leguire LE, Roberts CJ, Fogt N, Smith MA, Rogers GL. Instruction dependent activation during optokinetic nystagmus (OKN) stimulation: an fMRI study at 3T.
Brain Res. 2010;1336:10–21.
22. Kasper S, Giamal NE, Hilger E. Reboxetine: the first selective noradrenaline re-uptake inhibitor.
Expert Opin Pharmacother. 2000;1(4):771–82.
23. Klass M, Duchateau J, Rabec S, Meeusen R, Roelands B. Noradrenaline reuptake inhibition impairs cortical output and limits endurance time.
Med Sci Sports Exerc. 2016;48(6):1014–23.
24. Klass M, Roelands B, Levenez M, et al. Effects of noradrenaline and dopamine on supraspinal fatigue in well-trained men.
Med Sci Sports Exerc. 2012;44(12):2299–308.
25. Kori A, Miyashita N, Kato M, Hikosaka O, Usui S, Matsumura M. Eye movements in monkeys with local dopamine depletion in the caudate nucleus. II. Deficits in voluntary saccades.
J Neurosci. 1995;15(1):928–41.
26. Lencer R, Trillenberg P. Neurophysiology and neuroanatomy of smooth pursuit in humans.
Brain Cogn. 2008;68(3):219–28.
27. Leonard BE, McCartan D, White J, King DJ. Methylphenidate: a review of its neuropharmacological, neuropsychological and adverse clinical effects.
Hum Psychopharmacol. 2004;19(3):151–80.
28. McDowell JE, Dyckman KA, Austin BP, Clementz BA. Neurophysiology and neuroanatomy of reflexive and volitional saccades: evidence from studies of humans.
Brain Cogn. 2008;68(3):255–70.
29. Meeusen R, Sarre S, De Meirleir K, Ebinger G, Michotte Y. The effects of running speed and running duration on extracellular dopamine levels in rat striatum, measured with microdialysis.
Medicina Sportiva. 2003;7(1):E29–36.
30. Morrison JH, Foote SL. Noradrenergic and serotoninergic innervation of cortical, thalamic, and tectal visual structures in old and new world monkeys.
J Comp Neurol. 1986;243(1):117–38.
31. Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects.
Brain Res Brain Res Rev. 1992;17(2):139–70.
32. Nobre AC, Gitelman DR, Dias EC, Mesulam MM. Covert visual spatial orienting and saccades: overlapping neural systems.
Neuroimage. 2000;11(3):210–6.
33. Nybo L, Dalsgaard MK, Steensberg A, Møller K, Secher NH. Cerebral ammonia uptake and accumulation during prolonged exercise in humans.
J Physiol. 2005;563(1):285–90.
34. Olejnik S, Algina J. Measures of effect size for comparative studies: applications, interpretations, and limitations.
Contemp Educ Psychol. 2000;25(3):241–86.
35. Page ME. The promises and pitfalls of reboxetine.
CNS Drug Rev. 2003;9(4):327–42.
36. De Pauw K, Roelands B, Cheung SS, De Geus B, Rietjens G, Meeusen R. Guidelines to classify subject groups in sport-science research.
Int J Sports Physiol Perform. 2013;8(2):111–22.
37. Peelen MV, Heslenfeld DJ, Theeuwes J. Endogenous and exogenous attention shifts are mediated by the same large-scale neural network.
Neuroimage. 2004;22(2):822–30.
38. Roelands B, Goekint M, Heyman E, et al. Acute norepinephrine reuptake inhibition decreases performance in normal and high ambient temperature.
J Appl Physiol (1985). 2008;105(1):206–12.
39. Roelands B, Hasegawa H, Watson P, et al. The effects of acute dopamine reuptake inhibition on performance.
Med Sci Sports Exerc. 2008;40(5):879–85.
40. Roy-Byrne P, Radant A, Wingerson D, Cowley DS. Human oculomotor function: reliability and diurnal variation.
Biol Psychiatry. 1995;38(2):92–7.
41. Schüle C, Baghai T, Schmidbauer S, Bidlingmaier M, Strasburger CJ, Laakmann G. Reboxetine acutely stimulates cortisol, ACTH, growth hormone and prolactin secretion in healthy male subjects.
Psychoneuroendocrinology. 2004;29(2):185–200.
42. Sidhu SK, Bentley DJ, Carroll TJ. Locomotor exercise induces long-lasting impairments in the capacity of the human motor cortex to voluntarily activate knee extensor muscles.
J Appl Physiol. 2009;106(2):556–65.
43. Smith A, Brice C, Nash J, Rich N, Nutt DJ. Caffeine and central noradrenaline: effects on mood, cognitive performance, eye movements and cardiovascular function.
J Psychopharmacol. 2003;17(3):283–92.
44. Taylor JL, Amann M, Duchateau J, Meeusen R, Rice CL. Neural contributions to muscle fatigue: from the brain to the muscle and back again.
Med Sci Sports Exerc. 2016;48(11):2294–306.
45. Taylor JL, Todd G, Gandevia SC. Evidence for a supraspinal contribution to human muscle fatigue.
Clin Exp Pharmacol Physiol. 2006;33(4):400–5.
46. Volkow ND, Wang G-J, Fowler JS, et al. Cardiovascular effects of methylphenidate in humans are associated with increases of dopamine in brain and of epinephrine in plasma.
Psychopharmacology (Berl). 2003;166(3):264–70.
47. Volkow ND, Wang G, Fowler JS, et al. Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain.
J Neurosci. 2001;21(2):RC121.
