Behavioral task

The monkeys were instructed to covertly sustain attention to one of four Gabor stimuli presented on a screen while ignoring the other three Gabor stimuli (distractors; Fig. 1A). A trial would begin with one Gabor stimulus appearing at one out of four locations on the screen for a brief period while the monkey keeps its gaze on a central fixation point (363 ms). This early Gabor stimulus was defined as the “cue,” indicating that this target had to be covertly attended to during the entire trial (while keeping gaze on the central fixation point). After the cue presentation, three other Gabor stimuli would appear on the screen at the three remaining locations. A variable delay period would follow (585–1755 ms). Three different trial types were randomly interleaved within a session. In “target” trials, after a variable delay interval, the target Gabor quickly changed orientation (90° clockwise rotation) indicating the monkey to saccade toward the target location to earn a juice reward (250-ms response time window). In “distractor” trials, the orientation change occurred in the distractor Gabor opposite to the target location. To earn a reward on those trials, the monkey had to inhibit saccading to the distracting Gabor and maintain fixation on the central dot. In “target + distractor” trials, two simultaneous orientation changes co-occurred in the target Gabor and in the distractor opposite to the target. The monkeys had to make a saccade toward the target and not toward the distractor to earn the reward. Every trial was divided into three time epochs: (1) the cue epoch (cue onset to 200-ms postcue onset); (2) the attention epoch (600-ms postcue onset to 1000-ms postcue onset); (3) the saccade epoch (50 ms before to 50 ms after saccade onset). The monkeys’ gaze position was monitored at a rate of 500 Hz using an infrared video-based eye-tracking system (Eyelink 1000, SR Research). Monkey “F” completed a mean (STD) of 817.22 (93.43) trials per session. Monkey “JL” completed an average of 715.00 (100.44) trials per session. The average length of a session for monkey “F” was 2.26 (0.28) h, and 1.44 (0.19) h for monkey “JL.”

Behavioral task and performance. A, Behavioral task with the three randomly interleaved trial types. Blue dashed circles represent the focus of covert attention. Pink dashed circles indicate orientation change(s). Pink arrows indicate saccadic eye movements. Blue dot represents gaze position. B, Average behavioral performance of each subject under placebo sessions only. The colors indicate the proportion of each trial outcome in a behavioral session. Fixation break represents errors where the subject would respond before a Go signal was given. Sac. to distractor represents errors where the subject would respond to a distracting stimulus. No response represents trials where the subject would not provide a response. C, D, Line plots representing the change in overall hit rate relative to matched placebo sessions in the attention task following various doses of MPH. Hit rate is considered a proportion (Hit/Hit+Errors). Differences in proportion (hit rate) across treatment conditions are computed with χ² tests. Asterisks represent statistically significant changes in hit rate relative to placebo sessions (χ² test, p < 0.05). E, F, Same format as C, D but representing the proportion of specific error types across treatment conditions. Up means more errors. Refer to Materials and Methods for definitions. Error bars represent the SE of the sample proportion estimate.

Our subjects could make several different types of errors while performing this attention task, which can be broadly related to different types of maladapted behaviors in humans. For one, monkeys could erroneously break fixation during the cue or the delay epoch, that is, before a Go signal (the change in orientation) is presented. This error type could loosely be related to impulsivity, that is, the propensity to respond prematurely without foresight (Winstanley et al., 2006). A second error type noticeable in our behavioral task is the propensity to respond to a distractor Go signal. For example, monkeys would sometime saccade to the distractor location on a change in the distractor stimulus orientation that ought to be ignored to successfully complete the trial. We can loosely relate this error type to the concept of distractibility in humans, which is the propensity to pay attention to stimuli irrelevant for the task at hand. These two error types, impulsivity and distractibility, will be analyzed for each drug dose in addition to overall task performance. Finally, a general indicator of motivation while be inferred from the total number of trials completed by the animals in a given session. Motivation has also been shown to be influenced by MPH in some studies with nonhuman primates (Rajala et al., 2012). Nowhere in this study will we pretend that our experiment offers an “animal model” of ADHD, impulsivity, or distractibility. The terms “impulsivity” and “distractibility” are used without direct connection to the symptomatology of ADHD in humans.