Daily circadian misalignment impairs human cognitive performance task-dependently

We live in an “around-the-clock” 24/7 society, to the extent that ~10% of Americans work at night, on fixed, rotating, or irregular schedules^1,2, and these numbers are only likely to increase. Epidemiological data suggest that up to a third of night shift workers meet the minimal diagnostic criteria for shift work disorder (SWD)³, defined by the International Classification of Sleep Disorders (ICSD-2) as a major circadian rhythm sleep disorder (CRSD)⁴. The consequences of working beyond our biological capabilities include symptoms ranging from wake-time sleepiness to disorders of sleep and cardiometabolic function^5–8. Shift work increases the risk for human operational errors, such that drowsiness due to shift work has contributed to key industrial disasters, including Space Shuttle Challenger, Chernobyl and Alaska Oil Spill disasters⁹. Overnight operations challenge our circadian biology, which promotes daytime vigilance and nocturnal sleep¹⁰, thus resulting in a misalignment between the internal circadian (biological) rhythms and the required society demands for sleep/wake times¹¹. Importantly, our endogenous circadian system inhibits cognitive performance in the biological nighttime hours⁷, although it remains to be fully established whether this increased cognitive vulnerability extends in a similar way across multiple cognitive domains or it is cognitive-domain specific¹². Indeed, recent evidence suggests that fMRI-BOLD cognitive brain responses exhibit different 24-h circadian dynamics specific to a given task¹³, which highlights the task-dependent nature of the circadian deterioration in nighttime performance.

Cognitive throughput, indexed by the participant’s ability to accurately sum as many pairs of two-digit number as fast as possible²⁴ [Addition Task (ADD) number of correct responses/min], significantly varied by the interaction of “circadian alignment/misalignment condition” and “test day” (F_5,276 = 7.1, p < 0.001) (Fig. 2B). Accordingly, cognitive throughput performance improved by ~12% over multiple days of circadian alignment (test days 2–4, as compared to baseline; Bonferroni correction, p < 0.05), while no daily improvement occurred when the same individuals were misaligned (p > 0.05). In a similar vein, information processing that requires matching symbols and numbers²⁵ [number of correct Digit Symbol Substitution Task (DSST) responses/min] significantly varied by the interaction of “circadian alignment/misalignment condition” and “test day” (F_5,558 = 3.1, p = 0.01). We observed a performance improvement of ~12% only under circadian alignment during test days 3–4 (T3-T4) (Bonferroni correction, p < 0.05) (Fig. 2C). Normalizing to individual baseline performance further confirmed the daily improvement in cognitive throughput and information processing performance only during circadian alignment (day shifts) (Fig. 3B,C). Accordingly, baseline-adjusted cognitive throughput [Addition Task (ADD) performance] significantly improved throughout days under circadian alignment (r² = 0.61; p = 0.02), while no daily improvement was observed under circadian misalignment (r² = 0.14; p = 0.34). Similarly, baseline-adjusted information processing [Digit Symbol Substitution Task (DSST) performance] significantly improved across days under circadian alignment (r² = 0.47; p = 0.003), but not under circadian misalignment (r² = 0.16; p = 0.13).

We subsequently investigated visual-motor performance, indexed by the number of losses participants have during a dynamic-load tracking task, which represents a model of human operational performance, such as in space transportation, whereby complex displays and activities are required²⁶. Daily dynamics of visual-motor performance [number of Unstable Tracking Task (TKT) losses] yielded significant differences by the interaction of “circadian alignment/misalignment condition” and “test day” (F_5,560 = 3.7, p = 0.02), although multiple time-series correction indicated no post-hoc significances (p > 0.1) (Fig. 2D). However, normalizing to baseline performance indicated significant improvement by ~15% over days under circadian alignment (r² = 0.28; p = 0.04), which was absent when the same individuals were misaligned (r² = 0.04; p = 0.43) (Fig. 3D). Lastly, declarative memory, indexed by the capacity to recall six word pairs 10-min after learning²⁴ [Probed recall memory Task (PRM) percentage of correct responses], did not significantly vary by the interaction of “circadian alignment/misalignment condition” and “test day” (p > 0.1), with similar performance levels over successive days of either circadian alignment or misalignment (Supplementary Figure 2A). Normalizing to individual baseline performance further confirmed that declarative memory performance remained stable over days of circadian alignment and misalignment (respectively, r² = 0.03; p = 0.69 and r² = 0.13; p = 0.32) (Supplementary Figure 2B).

Here we show, with a biological paradigm mimicking what night shift workers typically experience, that daily circadian misalignment – which was confirmed by each individual’s endogenous melatonin phase assessment²³ - adversely impacts on cognition, as compared to when the same individuals perform during the day. Importantly, circadian misalignment differentially affected cognitive performance, such that basic sustained attention was acutely impaired and gradually recovered upon repeated exposure to circadian misalignment. Conversely, cognitive throughput, information processing and visual-motor performance during misalignment lost the daily improvements during circadian misalignment that were observed when the same individuals were under circadian alignment. Lastly, declarative memory performance was not substantially affected.

Previous forced desynchrony data indicate an increased rate of deterioration in sustained attention (PVT performance) across wakefulness, particularly during the circadian “night”^24,28. Similar to those circadian paradigms, our simulated shift work design points to a larger misalignment-induced decline in sustained attention 11 h after scheduled awakening (6AM), as compared to 7 h (2AM). Putative mechanisms include the stronger circadian sleep-promoting signal (6AM vs. 2AM) and homeostatic sleep pressure load (11 h vs. 7 h after scheduled awakening)¹⁶. Cognitive vulnerability is known to be maximum during the early morning hours^13,29, and in real-life settings, these sensitive hours correspond to when most operational failures and motor vehicle crashes seem to happen²⁹. Neurobiological mechanisms for higher cognitive vulnerability during overnight wakefulness may include increased nocturnal cortical excitability³⁰ and a relative increase of GABA_A receptor function³¹. Thus, the neuronal milieu during the night may favor sleep by increasing a “GABAergic tone”, potentially leading to cognitive decline. Furthermore, repeated exposure to circadian misalignment was associated with daily dynamic changes in the deployment of basic attention resources, with acute cognitive deterioration and subsequent amelioration over days of misalignment. The dual effects of circadian misalignment and acute sleep loss have been shown to impair sustained and selective attention on the first night of simulated shift work (subsequent to an extended wake period of more than 24 h)¹⁹. In a similar vein, our data indicate that sleep efficiency significantly predicts sustained attention, such that following the first day of misalignment, lower sleep efficiency predicted slower reaction times in PVT performance. Subsequent recovery in vigilant attention across days of misalignment (see Figs 2A and 3A) may be due to lower homeostatic sleep pressure during the scheduled nocturnal wake period due to improved daytime sleep (see Fig. 5) and/or the circadian system becoming slightly more appropriately aligned with the daytime sleep opportunity²³. Brain mechanisms accounting for the effects of acute sleep loss (e.g., sleep before test day 2) on sustained attention include adenosine and functional A₁ adenosine receptor (A₁AR) availability, which are posited to mediate sleep–wake regulation and cognitive performance³². Indeed, recent Positron Emission Tomography (PET) data in humans indicate that extending wakefulness into the circadian night may result in a higher A₁AR availability in the human brain with concomitant detrimental effects on sustained attention performance³².

Our current understanding of cognitive vulnerabilities in shift work paradigms comes from data on vigilant attention^16,18,19,33. Subjective alertness and objective attention are negatively affected by staying awake at night, as compared to a normal waking day^19,34. To our knowledge, it is unknown if cognitive abilities including cognitive throughput, information processing, visual-motor performance and declarative memory are hindered by multiple days of simulated shift work. As these cognitive domains heavily depend on the effects of sleep pressure and circadian phase^12,17, we investigated the impact of circadian misalignment to tasks associated with these cognitive processes. Here we show that, within a single 24-h period, performance on these tasks [including visual-motor task (TKT)] is fairly stable between both circadian conditions, but that across multiple days of circadian misalignment, performance does not progressively improve as observed during circadian alignment. Previous forced desynchrony data indicated increased vulnerability of cognitive throughput (ADD) and information processing (DSST) when individuals perform during the circadian night²⁴, and that, across multiple days of circadian misalignment, performance does not improve as compared to when individuals are under circadian alignment¹⁴. Inherent to the study design of these previous studies and the current study, it is not possible to distinguish whether the impaired improvement across multiple days of misalignment is due to a lack of learning, or that they were unable to express benefits gained from learning. This distinction only becomes visible during recovery. In sleep restriction studies, neurobehavioral deficits (e.g., DSST) induced by consecutive nights of sleep restriction improved with acute recovery sleep, reaching baseline performance levels³⁵. Although it may be difficult to rapidly both sleep debt and realign the multi-oscillator circadian system following circadian misalignment, as compared to after ‘simple’ sleep restriction, future studies are needed to test whether the inability to improve cognitive throughput and information processing performance during days of circadian misalignment is restored to baseline levels following sleep recovery and circadian realignment.

Declarative memory performance remained relatively stable across days for both circadian alignment and circadian misalignment, which could be due to a myriad of factors. Any circadian/sleep homeostatic effects on cognitive performance heavily rely on the intrinsic properties/parameters of a given task [e.g., duration of task, speed, timing of when task is administered, “difficulty” (e.g., speed response vs. recall of learned content), and so forth¹². Furthermore, the impact of circadian/sleep homeostatic effects seems to differ across cognitive domains, with more prominent effects of extended wakefulness into the circadian night on basic sustained attention as compared to working memory performance¹⁴. These cognitive domain-specific effects may be due to the tasks tapping onto different underlying brain regions, which are themselves differentially affected by circadian misalignment/sleep loss¹³. Indeed, functional magnetic resonance imaging (fMRI-BOLD) cognitive brain function seems to be under local modulation of cerebral circadian phase¹³. These data suggest that the circadian rhythmicity imposed by the master clock, located in the suprachiasmatic nucleus, can be locally altered in cortical and subcortical regions partially due to task-specific requirements, such as task complexity. In other words, not all cognitive brain regions associated to a given task show similar 24-h dynamics. Therefore, one may hypothesize that circadian misalignment impacts cognition task-dependently, as suggested by our differential circadian misalignment effects on basic sustained attention and daily improvement for cognitive throughput, information processing and visual-motor performance.

Potential limitations of our study include the limited number of cognitive tests during each individual’s scheduled wakefulness, as metabolic and cardiovascular measurements were also conducted throughout the study in order to test separate hypotheses^23,36–38. Given that we only had a limited number of circadian phases and times awake, we may not have captured the combination of highest homeostatic sleep pressure and worst circadian phase. Thus, the circadian misalignment-induced cognitive vulnerability may be even larger than observed. Despite our robust cross-over study design, the relatively low study sample may limit generalizations to a broader population. Lastly, while our study mimicked what shift workers may typically experience daily, it included only 4 days of circadian alignment/misalignment. Thus, the long-term effects of repeated exposure to circadian misalignment on cognitive function remain to be fully established.

Misalignment between behavioral cycles and the internal circadian timing system occurs in many occupational groups in our 24-hr society, including – but not limited to - emergency medical and safety personnel, transportation, and industrial power plants. This misalignment occurs mostly because the internal biological timekeeping system of humans is evolutionary conserved to optimally perform during the day and to support sleep at night. This scenario is at odds with nighttime work³⁹, and poses a risk for reduction in productivity and an increased likelihood for accidents⁴⁰. This risk could also be further worsened by a discrepancy between an individuals’ objective performance on tasks versus how they subjectively rate their performance and sleepiness. Attention processes are discussed in light of the interrelationship of subjective perception of alertness and objective attention, such that if an individual experiences impaired objective attention, subjective alertness may or may not also be impaired¹⁸. For instance, under chronic sleep restriction, individuals who rate themselves as alert and competent can exhibit clear attention deficits³⁵. Conversely, observational data using subjective sleepiness scales and measures of vigilant attention indicate that shift workers display substantial sleepiness levels and decrements in vigilant attention while working consecutive 12-h shifts⁴¹. Here we observed that, while individuals felt progressively sleepier under circadian misalignment albeit rating their performance as unchanged, it did not predict performance impairments across diverse cognitive tasks, similar to that shown during repeated partial sleep restriction⁴². This discrepancy between deterioration of objective performance and a lack of self-awareness in operational settings may pose additional risk for human operational errors. A single exception in our data was that subjective ratings of sleepiness significantly predicted decrements in sustained attention (but no other cognitive function measure), suggesting that participants at least seemed to be aware that they were sleepier when misaligned. Interventions could perhaps target this self-awareness to help workers become attentive to potential impairments.

As nontraditional work schedules beyond the 9AM-5PM timeframe are becoming ever more common, it becomes increasingly important to understand who may be at risk of unintended work-related cognitive impairment, and why. From that knowledge, employers, workers, and practitioners can better craft practical, effective interventions. In this context, our current findings indicate that daily circadian misalignment may help to explain cognitive vulnerabilities experienced by night workers beyond differences in work conditions, and provide a biological framework for the development of countermeasures against adverse cognitive effects in vulnerable shift work populations.

Different aspects of this study, which was designed to test separate hypotheses, have been published previously^23,36–38.