Effect of modafinil on impairments in neurobehavioral performance and learning associated with extended wakefulness and circadian misalignment

Abstract

Although worldwide millions of people work prolonged hours, at adverse circadian phases, evidence suggests that cognitive function is impaired under these conditions with important societal consequences. In a double-blind placebo-controlled laboratory-based study, we investigated the effect of the wakefulness-promoting drug modafinil as a countermeasure against such neurobehavioral impairments induced by both prolonged wakefulness and circadian misalignment. Neurobehavioral performance, alertness, and sleep were studied in young healthy participants (N=18) who underwent a 25-day forced desynchrony protocol in which the period of the sleep-wakefulness cycle was scheduled to be 42.85 h (duration of each wakefulness episode: 28.57 h; sleep/rest episode: 14.28 h). Each waking day, participants were treated with either 400 mg modafinil, divided into three doses, or placebo, according to a randomized, parallel-group design. Treatment with modafinil significantly attenuated the performance decrements seen for several parameters including cognitive-psychomotor speed, visual attention and reaction times both with progressive hours awake and when working at adverse circadian phases. Subjective alertness and sleep parameters were similar between treatment groups, but modafinil-treated participants had fewer bouts of inadvertent sleep during scheduled waking. Modafinil reduced the neurobehavioral impairment associated with work, both during prolonged wakefulness and at adverse circadian phases, without adversely affecting subjective alertness or subsequent sleep. These features suggest that modafinil might be a particularly relevant countermeasure against the deleterious effects of prolonged work hours, shift work, and transmeridian travel.

Figure 1

Double Raster Plot of the study protocol. Days 1–3 and 30–31 were 24-h days with 16-h episodes of scheduled wakefulness and 8-h episodes of scheduled rest/sleep. Participants were studied in forced desynchrony during calendar days 4–29 consisting of fourteen 42.85-h days with of 28.57 h of scheduled wakefulness and 14.28 h of scheduled rest/sleep.

Figure 2

Effect of modafinil on neurobehavioral function and core body temperature as derived from the forced desynchrony protocol (see Figure 1). Data are expressed as a function of both time since scheduled waking and circadian phase. Neurobehavioral parameters (a–d) and body temperature (e) were averaged across the fourteen 42.85-h forced desynchrony days and plotted in the left column as a function of time elapsed since scheduled wake-time and in the right column against circadian phase. (a) Addition task number of correct responses. (b) PVT-Slowest 10% of responses. (c) PVT-median reaction time. (d) PVT-lapses (trials with reaction times >500 ms). (e) Core body temperature (CBT). The placebo-treatment group is represented by open squares (□) and the modafinil-treatment group is represented by closed circles (•). The timing of modafinil or placebo administration is indicated in the lowest panel of the left column by a triangle (▴) with each triangle representing 100 mg of modafinil. The data represent mean values (±SEM). For the addition task, a value of 0 represents the mean value for each participant during the last baseline day before the forced desynchrony. PVT data are graphically represented without transformation; however, because the PVT data were not normally distributed, the statistical analyses on the PVT data were performed on transformed data, which are represented graphically in the Supplementary on-line materials. Baseline day 3 scores are provided in the results section of the text. Planned comparisons for individual circadian and hours awake bins were assessed using an f-test on the relevant data with significance levels indicated by an asterisk (^*) whenever the p-value was <0.0417 (modified Bonferroni correction). Note, scales are inverted for PVT measures.

Figure 3

Modulation of inadvertent sleep episodes (a) and slow eye movements (b) during scheduled wakefulness episodes, and of sleep efficiency during scheduled sleep (c). In the left column, data are plotted as a function of time since scheduled waking (a, b) or of time since scheduled sleep (c); in the right column data are plotted as a function of circadian phase. Inadvertent sleep and slow eye movements during scheduled wakefulness were each scored on a 30-s basis. Inadvertent sleep was expressed as a percentage of the total number of recorded epochs within each wakefulness bin or circadian phase bin, whereas slow eye movements were expressed as a percentage of all epochs scored as wake within a bin. 0 degrees corresponds to the nadir of core body temperature. Sleep efficiency was calculated as the percentage of the total recording within a bin scored as sleep. Planned comparisons for individual circadian and hours awake bins were assessed using an f-test with significance levels indicated by an asterisk (^*) whenever the p-value was <0.0417 (modified Bonferroni correction). The timing of modafinil or placebo administration is indicated in the lowest panel of the left column by a triangle (▴) with each triangle representing 100 mg of modafinil. The placebo-treatment group is represented by open squares (□) and the modafinil-treatment group is represented by closed circles (•). Data represent mean values (±SEM).

Figure 4

Modulation of subjective sleepiness as measured by the Karolinska Sleepiness Scale (KSS, a), alertness on the visual analog scale (VAS ‘Alert-Sleepy', b), and attentiveness on the visual analog scale (VAS ‘Attentive-Dreamy', c) plotted as a function of time since scheduled waking (left column) and circadian phase (right column). A value of zero represents the mean value for each participant during the last baseline day before the forced desynchrony. Baseline day 3 scores are provided in the results section of the text. Planned comparisons for individual circadian and hours awake bins were assessed using an f-test with significance levels indicated by an asterisk (^*) whenever the p-value was <0.0417 (modified Bonferroni correction). The timing of modafinil or placebo administration is indicated in the lowest panel of the left column by a triangle (▴) with each triangle representing 100 mg of modafinil. The placebo-treatment group is represented by open squares (□) and the modafinil-treatment group is represented by closed circles (•). Data represent mean values (±SEM).

Figure 5

Attentiveness on the visual analog scale (VAS ‘Attentive-Dreamy') plotted as a function of time since scheduled waking on the first and second active treatment days. A value of zero represents the mean value for each participant during the last baseline day before the forced desynchrony. The baseline day 3 scores are provided in the results section of the text. Higher scores represent higher alertness. The timing of modafinil or placebo administration is indicated by a triangle (▴) with each triangle representing 100 mg of modafinil. The placebo-treatment group is represented by open squares (□) and the modafinil-treatment group is represented by closed circles (•). Data represent mean values (±SEM).

Figure 6

Addition Task-number correct plotted as a function of the forced desynchrony wakefulness episodes. The data represent mean values (±SEM). A value of zero represents the mean value for each participant during the last baseline day before the forced desynchrony. The baseline day 3 scores are provided in the results section of the text. The placebo-treatment group is represented by open squares (□) and the modafinil-treatment group is represented by closed circles (•).