A time to think: Circadian rhythms in human cognition

Although peaks and troughs in cognitive performance characterize our daily functioning, time-of-day fluctuations remain marginally considered in the domain of cognitive psychology and neuropsychology. Here, we attempt to summarize studies looking at the effects of sleep pressure, circadian variations, and chronotype on cognitive functioning in healthy subjects. The picture that emerges from this assessment is that beyond physiological variables, time-of-day modulations affect performance on a wide range of cognitive tasks measuring attentional capacities, executive functioning, and memory. These performance fluctuations are also contingent upon the chronotype, which reflects interindividual differences in circadian preference, and particularly upon the synchronicity between the individuals' peak periods of circadian arousal and the time of the day at which testing occurs. In themselves, these conclusions should direct both the clinician's and the researcher's attention towards the utmost importance to account for time-of-day parameters when assessing cognitive performance in patients and healthy volunteers.     

Chronotype and time-of-day influences on the alerting,orienting, and executive components of attention

Recent research on attention has identified three separable components, known as alerting, orienting, and executive functioning, which are thought to be subserved by distinct neural networks. Despite systematic investigation into their relatedness to each other and to psychopathology, little is known about how these three networks might be modulated by such factors as time-of-day and chronotype. The present study administered the Attentional Network Test (ANT) and a self-report measure of alertness to 80 participants at 0800, 1200, 1600, and 2000 hours on the same day. Participants were also chronotyped with a morningness/eveningness questionnaire and divided into evening versus morning/neither-type groups; morning chronotypes tend to perform better early in the day, while evening chronotypes show enhanced performance later in the day. The results replicated the lack of any correlations between alerting, orienting, and executive functioning, supporting the independence of these three networks. There was an effect of time-of-day on executive functioning with higher conflict scores at 1200 and 1600 hours for both chronotypes. The efficiency of the orienting system did not change as a function of time-of-day or chronotype. The alerting measure, however, showed an interaction between time-of-day and chronotype such that alerting scores increased only for the morning/neither-type participants in the latter half of the day. There was also an interaction between time-of-day and chronotype for self-reported alertness, such that it increased during the first half of the day for all participants, but then decreased for morning/neither types (only) toward evening. This is the first report to examine changes in the trinity of attentional networks measured by the ANT throughout a normal day in a large group of normal participants, and it encourages more integration between chronobiology and cognitive neuroscience for both theoretical and practical reasons. An erratum to this article can be found at     

Impact of sleep inertia on visual selective attention for rare targets and the influence of chronotype

Sleep inertia is affected by circadian phase, with worse performance upon awakening from sleep during the biological night than biological day. Visual search/selective visual attention performance is known to be sensitive to sleep inertia and circadian phase. Individual differences exist in the circadian timing of habitual wake time, which may contribute to individual differences in sleep inertia. Because later chronotypes awaken at an earlier circadian phase, we hypothesized that later chronotypes would have worse visual search performance during sleep inertia than earlier chronotypes if awakened at habitual wake time. We analysed performance from 18 healthy participants [five females (22.1 ± 3.7 years; mean ± SD)] at ~1, 10, 20, 30, 40 and 60 min following electroencephalogram‐verified awakening from an 8 h in‐laboratory sleep opportunity. Cognitive throughput and reaction times of correct responses were impaired by sleep inertia and took ~10–30 min to improve after awakening. Regardless whether chronotype was defined by dim light melatonin onset or mid‐sleep clock hour on free days, derived from the Munich ChronoType Questionnaire, the duration of sleep inertia for cognitive throughput and reaction times was longer for later chronotypes (n = 7) compared with earlier chronotypes (n = 7). Specifically, performance for earlier chronotypes showed significant improvement within ~10–20 min after awakening, whereas performance for later chronotypes took ~30 min or longer to show significant improvement (P < 0.05). Findings have implications for decision making immediately upon awakening from sleep, and are consistent with circadian theory suggesting that sleep inertia contributes to longer‐lasting impairments in morning performance in later chronotypes.     

Circadian rhythms in cognitive performance: methodological constraints, protocols, theoretical underpinnings

The investigation of time-of-day effects on cognitive performance began in the early days of psychophysiological performance assessments. Since then, standardised, highly controlled protocols (constant routine and forced desynchrony) and a standard performance task (psychomotor vigilance task) have been developed to quantify sleep-wake homeostatic and internal circadian time-dependent effects on human cognitive performance. However, performance assessment in this field depends on a plethora of factors. The roles of task difficulty, task duration and complexity, the performance measure per se, practice effects, inter-individual differences, and ageing are all relevant aspects. Therefore, well-defined theoretical approaches and standard procedures are needed for tasks pinpointing higher cortical functions along with more information about time-dependent changes in the neural basis of task performance. This promises a fascinating challenge for future research on sleep-wake related and circadian aspects of different cognitive domains.     

Chronic insomnia and performance in a 24-h constant routine study

Insomniacs report daytime functioning problems, but studies of neurobehavioral functioning in insomniacs have shown little objective evidence of impairment. In addition, very little is known about the influence of the circadian clock on performance in chronic insomniacs. In the present study, we investigated whether chronic insomnia is associated with an overall performance deficit, and what the effect is of circadian rhythmicity, under strictly controlled laboratory conditions. A 24-h experiment was carried out under constant routine conditions. Psychomotor performance, body temperature, and subjective functioning of 11 insomniacs and 13 healthy subjects were assessed. The insomniacs showed significant overall performance impairments in vigilance, working memory, and motor control. In addition, body temperature, performance and subjective functioning showed a circadian pattern similar to healthy subjects, with trough values in the late night/early morning and peak values in the early evening. Self-reported functioning among the insomniacs indicated mood disturbances, concentration problems, elevated fatigue and elevated sleepiness. The results indicated that chronic insomnia is associated with a substantial lowering of the 24-h level of performance and subjective functioning, irrespective of the type of task and/or the particular parameter, and without differential effects of circadian rhythmicity. Apparently, chronic insomnia has a negative impact upon performance as measured under strictly controlled, unmasked conditions.     

Overlapping prefrontal systems involved in cognitive and emotional processing in euthymic bipolar disorder and following sleep deprivation: A review of functional neuroimaging studies

Prefrontal cortex (PFC) mediated cognitive and emotional processing deficits in bipolar disorder lead to functional limitations even during periods of mood stability. Alterations of sleep and circadian functioning are well-documented in bipolar disorder, but there is little research directly examining the mechanistic role of sleep and/or circadian rhythms in the observed cognitive and emotional processing deficits. We systematically review the cognitive and emotional processing deficits reliant upon PFC functioning of euthymic patients with bipolar disorder and in healthy individuals deprived of sleep. The evidence from two parallel lines of investigation suggests that sleep and circadian rhythms may be involved in the cognitive and emotional processing deficits seen in bipolar disorder through overlapping neurobiological systems. We discuss current models of bipolar highlighting the PFC-limbic connections and discuss inclusion of sleep-related mechanisms. Sleep and circadian dysfunction is a core feature of bipolar disorder and models of neurobiological abnormalities should incorporate chronobiological measures. Further research into the role of sleep and circadian rhythms in cognition and emotional processing in bipolar disorder is warranted.     

Age and time-of-day effects on learning and memory in a non-matching-to-sample test

This study provides further evidence that the time-of-day (TOD) when testing is conducted affects cognitive performance in old rats and, for the first time in an animal model, in young adult rats as well. Groups of young and old rats were entrained to a 12-h light-dark schedule and administered tests of learning and memory in a non-matching-to-sample (NMTS) task in a water maze. Testing was conducted at the beginning of the rats' activity cycle (AM) or at the end of the cycle (PM). In addition to age differences in performing the task, there were major findings with respect to time of testing: (1) young rats tested in the PM were better than young rats tested in the AM at learning the NMTS rule and in the delayed-NMTS (DNMTS) task; (2) old rats tested in the AM were better than PM-tested old rats on the DNMTS task, with the former attaining performance levels that approximated those of young rats; (3) the TOD effect in old rats extended to a DNMTS reversal (DNMTS-R) condition in which rats, originally tested in the AM, subsequently were administered the test in the PM, and vice versa; (4) the TOD effects in young and old rats in the DNMTS and DNMTS-R tests were strongest at relatively long delays, suggesting that hippocampal function may be particularly vulnerable to such effects; (5) there was evidence in the old rats of a relationship between diurnal drinking patterns and performance at the longest delay in the DNMTS test. These results, which parallel similar findings with human subjects, emphasize a linkage between circadian rhythmicity and cognitive performance throughout adulthood, and indicate the importance of circadian disruption in old age as a contributing factor to age differences in learning and memory performance.     

Regularity of daily life in relation to personality, age, gender, sleep quality and circadian rhythms

A diary-like instrument to measure lifestyle regularity (the 'Social Rhythm Metric'-SRM) was given to 96 subjects (48 women, 48 men), 39 of whom repeated the study after at least one year, with additional objective measures of rest/activity. Lifestyle regularity as measured by the SRM related to age, morningness, subjective sleep quality and time-of-day variations in alertness, but not to gender, extroversion or neuroticism. Statistically significant test-retest correlations of about 0.4 emerged for SRM scores over the 12-30 month delay. Diary-based estimates of bedtime and waketime appeared fairly reliable. In a further study of healthy young men, 4 high SRM scorers ('regular') had a deeper nocturnal body temperature trough than 5 low SRM scorers ('irregular'), suggesting a better functioning circadian system in the 'regular' group.     

Low-dose repeated caffeine administration for circadian-phase-dependent performance degradation during extended wakefulness

OBJECTIVE: To investigate whether the effectiveness of a novel high-frequency low-dose caffeine regimen in counteracting the deterioration of performance during extended wakefulness is related to its interaction with homeostatic or circadian signals modulating performance and sleep propensity. DESIGN: Double-blind, placebo-controlled, parallel-group design in a 29-day forced desynchrony paradigm in which the period of the sleep-wake cycle was scheduled to be 42.85 hours, i.e., far removed from the circadian range. This design allowed for separate estimation of the sleep homeostatic, circadian, and caffeine contributions to performance deficits or improvements. SETTING: Private suite of a general clinical research center, in the absence of time of day information. PARTICIPANTS: Sixteen healthy normal-sleeping men (aged 18-30 years) INTERVENTIONS: Caffeine (0.3 mg per kg per hour) or placebo was administered hourly during the 28.57-hour wake episodes. RESULTS: Plasma caffeine concentrations rose in an exponential saturating manner during wakefulness. Rising caffeine levels markedly attenuated wake-dependent deterioration of a number of measures of cognitive performance, particularly at the circadian performance nadir. Moreover, caffeine enhanced the ability of subjects to remain consistently awake for extended periods, holding subjects back from completing the full transition to sleep, but at the expense of increasing subjective sleepiness. CONCLUSIONS: High-frequency low-dose caffeine administration is effective in countering the detrimental performance effects of extended wakefulness. These data are in accordance with the hypothesis that adenosine is a mediator of performance decrements associated with extended wakefulness and may lead to new strategies to use caffeine in situations in which neurobehavioral functioning is affected by sleep loss.     

Visual search performance across 40 h of continuous wakefulness: Measures of speed and accuracy and relation with oculomotor performance

The aim of the study was to estimate the sensitivity of a brief self-paced visual search task to increased levels of sleepiness as a consequence of 40 h of sleep deprivation. Time-of-day effects on this task, on subjective sleepiness and on oculomotor performance changes, were also assessed. Eight normal subjects slept for three nights in the laboratory (adaptation, baseline, recovery). Baseline and recovery nights were separated by a period of 40 h of continuous wakefulness, during which subjects were tested every 2 h from 10:00 to 22:00 h on both days preceding and following the sleep deprivation night, as well as from 24:00 to 08:00 h during the deprivation period. At the same time, subjects filled in a visual analogue sleepiness scale and the Stanford Sleepiness Scale (SSS). As regards cognitive performance, significant effects were found on speed measures, while accuracy was not affected. The number of explored rows was higher after the baseline night than after the sleepless night, and showed a consistent time-of-day trend. Omissions ratio (OR), false positives ratio (FPR) and hits ratio (HR) did not show any significant effect. Subjective ratings of sleepiness varied according to speed measures, being affected by sleep deprivation and time of day. Since similar effects were found with an oculomotor task, detrended functions for all variables across the 40 h of continuous wakefulness were calculated. A circadian effect was found, in which speed measures seem to be more affected than accuracy ones in both visual search and oculomotor tasks. It is concluded that 40 h of prolonged wakefulness significantly impairs performance in a brief cognitive visual search task. Such a performance worsening is evident on speed, but not on accuracy indices, and is strictly related to the deterioration of oculomotor performance, indicating a clear circadian effect.     

Sleep inertia,sleep homeostatic and circadian influences on higher‐order cognitive functions

Sleep inertia, sleep homeostatic and circadian processes modulate cognition, including reaction time, memory, mood and alertness. How these processes influence higher‐order cognitive functions is not well known. Six participants completed a 73‐day‐long study that included two 14‐day‐long 28‐h forced desynchrony protocols to examine separate and interacting influences of sleep inertia, sleep homeostasis and circadian phase on higher‐order cognitive functions of inhibitory control and selective visual attention. Cognitive performance for most measures was impaired immediately after scheduled awakening and improved during the first ~2–4 h of wakefulness (decreasing sleep inertia); worsened thereafter until scheduled bedtime (increasing sleep homeostasis); and was worst at ~60° and best at ~240° (circadian modulation, with worst and best phases corresponding to ~09:00 and ~21:00 hours, respectively, in individuals with a habitual wake time of 07:00 hours). The relative influences of sleep inertia, sleep homeostasis and circadian phase depended on the specific higher‐order cognitive function task examined. Inhibitory control appeared to be modulated most strongly by circadian phase, whereas selective visual attention for a spatial‐configuration search task was modulated most strongly by sleep inertia. These findings demonstrate that some higher‐order cognitive processes are differentially sensitive to different sleep–wake regulatory processes. Differential modulation of cognitive functions by different sleep–wake regulatory processes has important implications for understanding mechanisms contributing to performance impairments during adverse circadian phases, sleep deprivation and/or upon awakening from sleep.     

Near‐infrared spectroscopy reveals link between chronic physical activity and anterior frontal oxygenated hemoglobin in healthy young women

Cerebrovascular and cognitive functioning peak developmentally in young adults, yet recent evidence indicates they may benefit on these fronts from regular engagement in physical activity. In light of epidemiological trends for increasingly sedentary lifestyles and the importance of optimal cerebrovascular and cognitive functioning, here we investigated relationships between physical activity levels, anterior frontal hemodynamics, and cognitive performance in 52 healthy young women. Analyses positively linked chronic physical activity level (CPAL) with anterior frontal oxygenated hemoglobin and cognitive inhibitory control, indicating regular physical activity may lead to hemodynamic and cognitive benefits, even in a cohort at developmental peak. In addition, higher anterior frontal oxygenated hemoglobin was linked to better performance for the most difficult cognitive task. Given the importance of oxygen availability for cognitive functioning, the current discovery of a relationship with CPAL may provide important insight toward understanding exercise‐cognition links.     

Machine Learning EEG to Predict Cognitive Functioning and Processing Speed Over a 2-Year Period in Multiple Sclerosis Patients and Controls

Event-related potentials (ERPs) show promise to be objective indicators of cognitive functioning. The aim of the study was to examine if ERPs recorded during an oddball task would predict cognitive functioning and information processing speed in Multiple Sclerosis (MS) patients and controls at the individual level. Seventy-eight participants (35 MS patients, 43 healthy age-matched controls) completed visual and auditory 2- and 3-stimulus oddball tasks with 128-channel EEG, and a neuropsychological battery, at baseline (month 0) and at Months 13 and 26. ERPs from 0 to 700 ms and across the whole scalp were transformed into 1728 individual spatio-temporal datapoints per participant. A machine learning method that included penalized linear regression used the entire spatio-temporal ERP to predict composite scores of both cognitive functioning and processing speed at baseline (month 0), and months 13 and 26. The results showed ERPs during the visual oddball tasks could predict cognitive functioning and information processing speed at baseline and a year later in a sample of MS patients and healthy controls. In contrast, ERPs during auditory tasks were not predictive of cognitive performance. These objective neurophysiological indicators of cognitive functioning and processing speed, and machine learning methods that can interrogate high-dimensional data, show promise in outcome prediction.     

Exposure to bright light and darkness to treat physiologic maladaptation to night work

Working at night results in a misalignment between the sleep-wake cycle and the output of the hypothalamic pacemaker that regulates the circadian rhythms of certain physiologic and behavioral variables. We evaluated whether such physiologic maladaptation to nighttime work could be prevented effectively by a treatment regimen of exposure to bright light during the night and darkness during the day. We assessed the functioning of the circadian pacemaker in five control and five treatment studies in order to assess the extent of adaptation in eight normal young men to a week of night work. In the control studies, on the sixth consecutive night of sedentary work in ordinary light (approximately 150 lux), the mean (+/- SEM) nadir of the endogenous temperature cycle continued to occur during the night (at 3:31 +/- 0:56 hours), indicating a lack of circadian adaptation to the nighttime work schedule. In contrast, the subjects in the treatment studies were exposed to bright light (7000 to 12,000 lux) at night and to nearly complete darkness during the day, and the temperature nadir shifted after four days of treatment to a significantly later, midafternoon hour (14:53 +/- 0:32; P less than 0.0001), indicating a successful circadian adaptation to daytime sleep and nighttime work. There were concomitant shifts in the 24-hour patterns of plasma cortisol concentration, urinary excretion rate, subjective assessment of alertness, and cognitive performance in the treatment studies. These shifts resulted in a significant improvement in both alertness and cognitive performance in the treatment group during the night-shift hours. We conclude that maladaptation of the human circadian system to night work, with its associated decline in alertness, performance, and quality of daytime sleep, can be treated effectively with scheduled exposure to bright light at night and darkness during the day.     

Baroreflex sensitivity during rest and executive functioning in attention-deficit/hyperactivity disorder. The TRAILS study

Children with attention-deficit/hyperactivity disorder (ADHD) often show executive function (EF) problems and neurophysiological hypoarousal. Baroreceptor activation, as part of the baroreflex short-term blood pressure regulatory mechanism, has been linked to cortical inhibition and attenuated cognitive-attentional functioning. We investigated the hypothesis that higher resting baroreflex sensitivity (BRS) predicts poorer EF performance in children with ADHD. EF measures of speed and accuracy were regressed upon resting BRS in 10-12-year-old children with ADHD from a clinic-referred sample (n=181) and healthy (n=194) and clinic-referred (n=260) comparison samples. Resting BRS was positively associated with poorer EF performance (e.g., response variability, working memory, response inhibition), especially in ADHD combined type, boys, and unmedicated children. Comparison samples partly suggested negative associations. We conclude that higher resting BRS is related to poorer cognitive performance in children with ADHD. Findings suggest afferent influences of the body's visceral state on higher-order cognitive functioning and imply energetic state dysregulation in ADHD.     

Chronic insomnia and cognitive functioning among older adults

Chronic insomnia and cognitive impairment are both common complaints among older adults. This study explores the association between chronic insomnia and changes in cognitive functioning among older adults. The study population comprised two groups: 64 older adults without insomnia and 35 older adult insomniacs. The cognitive capacity of each participant was tested at the participant's home using the computerized “MindFit” test (CogniFit, Inc.). In five categories of cognitive functioning, older adult insomniacs displayed impaired performance compared to older adult good sleepers. Specifically, significant differences were found between insomniacs and good sleepers on memory span, allocating attention to a target, time estimation, executive functioning, and integration of two dimensions (visual and semantic) tests. The findings imply that insomnia may have detrimental effects on some cognitive functions in healthy older adults.     

Cognitive and social functioning in recovery from depression: results from a population-based three-year follow-up

BACKGROUND: This study prospectively examined cognitive and social functioning in recovery from depression using participants sampled from the general population. METHOD: Seventy-six depressed persons fulfilling (n=41) and not fulfilling (n=35) the criteria for DSM-IV depression at a three-year follow-up were compared with respect to episodic memory performance and social functioning at baseline (T1), at follow-up (T2) and change across time. RESULTS: The groups did not differ in episodic memory performance either at T1, T2 or in residual change. However, the groups differed in social functioning at T2 and in residual change indicating improved social functioning in the recovered group. LIMITATION: The absence of a healthy control group at follow-up. CONCLUSION: Despite the symptomatic improvement and improved social functioning, cognitive functioning does not follow this general recovery trend, at least not in the three-year interval examined.     

Neurocognitive basis of impaired empathy in schizophrenia

Patients with schizophrenia show impaired emotional and social behavior, such as lack of theory of mind and misinterpretation of social situations. However, there is a paucity of work focusing on the empathic abilities of these patients. The present study was designed to examine the degree of impairment in cognitive and affective empathy in schizophrenia and to evaluate the contribution of executive prefrontal functions to empathy in these patients. To explore the neurocognitive processes that underlie the empathic ability in schizophrenic patients, the relationship between empathy scores and the performance on a cognitive flexibility task that assesses dorsolateral and orbitofrontal functioning (set shifting and reversal, respectively) was examined in 26 patients with schizophrenia and 31 healthy control subjects. Results indicated that patients with schizophrenia were significantly impaired in both cognitive and affective empathy compared with healthy control subjects. The degree of impaired empathy related to the severity of negative symptoms. In addition, patients showed impaired performance on measures of both shifting and reversal. However, while cognitive empathy was particularly related to measurements of orbitofrontal (rather than dorsolateral) functioning, affective empathy was related to measures of social functioning.     

Cognitive and motor features in elderly people with bipolar disorder

BACKGROUND: Although elderly people will represent one third of the bipolar population in a few years, data about cognitive and motor features in these patients are very scarce. The aim of this study was to compare the cognitive and motor functioning between elderly euthymic patients with bipolar disorder (BD) and healthy controls, as well as to determine the degree of correlation with psychosocial functioning. METHODS: Euthymic older adults with BD (n=20) and healthy controls (n=20) were evaluated with traditional clinical instruments and measures of exposure to psychotropic drugs and extrapyramidal symptoms. All subjects completed an extensive neuropsychological battery. RESULTS: Patients with BD had more extrapyramidal symptoms and worse performance than healthy controls in psychomotor speed, verbal memory, and executive functions even after controlling sub-clinical symptomatology. These findings were not associated with age at onset or length of illness or with current pharmacological exposure. Psychosocial functioning correlated negatively with performance in psychomotor speed and executive function, and with extrapyramidal symptoms. LIMITATIONS: The small sample size and cross-sectional design. CONCLUSIONS: Older adult patients with BD in a euthymic state could have a similar cognitive and motor profile to that described in younger euthymic bipolar patients. Cognitive-motor disturbances may help to explain impairments in daily functioning among elderly patients with bipolar disorder during remission.