Abstract

INTRODUCTION

The importance of adequate sleep duration is often overlooked, especially in countries with busy 24/7 schedules. In a meta-analysis by Knutson et al.,¹ the trend of shorter sleep periods among individuals in the USA for the time period of 1975-2006 was documented. Short sleepers were defined as those reporting < 6 h of sleep in their sleep diary. They found an increase in the number of short sleepers from 7.6% in 1975 to 9.3% in 2006 among full-time workers. Another meta-analysis on 1,382,999 participants from 8 different countries (USA, Japan, UK, Spain, Sweden, Finland, Israel, and Taiwan) showed that both short and long duration of sleep are associated with increased mortality risk.⁵

Studies have shown that restricting sleep to ≤ 6 h in healthy individuals can produce a significant decline in vigilance reaction time, increase objective daytime sleepiness to pathological levels, and produce impairments in memory.^6–8 However, it is unclear whether impairments of neuronal processing of auditory information are present in individuals who regularly restrict habitual time in bed (TIB) to ≤ 6 hours.

It is also unknown if deficiency in neuronal processing can be reversed following sleep extension. Sleep extension in college students has been shown to improve daytime alertness vigilance and mood.⁹ Roehrs and colleagues¹⁰ showed that habitually sleepy individuals (multiple sleep latency test [MSLT] < 6 min) did improve their sleepiness after 6 consecutive nights of extended TIB (10 h) to near fully alert levels (MSLT = 10 min).

In a recent sleep restriction-extension study,¹¹ the authors showed that one week of sleep extension (TIB 10 h) improved resilience during subsequent sleep restriction and facilitated task related performance during recovery in normal subjects. A 2-week sleep extension study showed full recovery of alertness after 2 weeks.¹² These data suggest that increasing time in bed in habitual short sleepers may also provide benefits for specific aspects of cognitive function. However, it remains unknown if extending time in bed to levels typical of the general population would have benefits on cognitive processing.

Neurocognitive changes associated with sleep loss have been studied in both clinic and research subjects. Among methods used for this assessment are event-related brain potentials (ERPs). ERPs are one of the most informative and dynamic methods of monitoring the information stream in the brain. The voltage deflections comprising the ERP reflect the reception and processing of sensory information, as well as higher-level processing involving selective attention, memory updating, and other types of cognitive activity. ERPs are linked in time with a physical or mental event, and typically extracted from the scalp-recorded electroencephalogram (EEG) by means of signal averaging.

Due to its high sensitivity to variables related to information processing (e.g., auditory discrimination), the ERP may complement traditional and limited performance measures, such as the accuracy and speed of behavioral responses. Monitoring changes in ERPs may also be used to assess the effects of sleep restriction and extension on early stages of information processing (e.g., occurring in tens of milliseconds). The cognitive operations reflected in ERP components are supported by specific brain systems, which in some cases have been well defined.^13–15

As the human brain does not have a sufficient capacity to enable our consciousness to simultaneously detect all sensory information entering our sensory system, our cognitive processes involve an “automatic” mode as well as an “attentional” mode to process all of the incoming information. Therefore, following an initial phase (sensory input), only part of the incoming information gains access to consciousness.¹⁶ In the current theory of human attention-control, there is an assumption that the relatively large-capacity system performs the initial processing of sensory information, and the subsequent limited-capacity system takes over for task-related evaluation and decision-making processes.^17,18 Thus, the entry of information to the limited-capacity system is controlled by two types of processes: focused attention and breakthrough of the unattended information (or passive attention).¹⁹ The balance between these two neuronal processes is very important for attention control. For example, lack of flexibility between the two processes may lead to either insufficient attention to potentially relevant events or easy distraction by irrelevant events. In laboratory studies, these two processes have been found to be greatly affected by sleep loss.^20–22

There are auditory ERP components that can be used as a tool for assessing pre-attentive, attention-dependent, and memory-dependent brain mechanisms involved in attention control. Mismatch negativity (MMN) is an ERP component with a frontocentral scalp topographical distribution, elicited by infrequent stimuli presented among frequent stimuli. The MMN has been described as an “automatic” brain response occurring at a latency around 150 ms from deviance onset to any change in the acoustical environment and is relatively independent of the listener's perception of the sound or behavioral response to the sound.²³ Thus, the MMN (amplitude and latency) reflects the outcome of a deviance-detection process associated with infrequent sound that is based on the memory of regularities in the auditory input formed by frequent sound.^23–25 Because the MMN is elicited when an incoming sound does not “match” the series of previous stimuli, even when these stimuli occur outside of the subject's attention, it might be that the MMN-generating process (frontal counterpart of the MMN) could be involved in both the “passive” and “active” directing of attention.^26,26,27 Therefore, in our study we used the MMN in passive and active tasks to evaluate the frontal lobe function in direction of attention to the novelty associated with automatic change-detection processes.

Another ERP component, the P3a (or novelty P3) is elicited by novel or deviant sounds during an “ignore” or “attend” task condition. The P3a is associated with involuntary attention switching (irrelevant to the task) to salient sounds.^28,27 The P3a has latency at around 200-300 ms from deviance onset and a frontocentral scalp distribution. ERP studies in humans with frontal lobe lesions have found that such patients produce a clear diminution of the P3a from a distracting stimulus.²⁹ Frontal lobe engagement is therefore necessary for P3a generation and mechanisms of attention control.³⁰ It has been demonstrated that 36 hours of total sleep deprivation affects frontal neuronal processes involved in novelty detection as measured by P3a (or novelty P3).²⁰ In this study, authors demonstrated the sensitivity of P3a amplitude to sleep deprivation (8.7 μV in control subjects vs. 3.5 μV following 36 h of total sleep deprivation). Following recovery sleep (TIB 10 hours), the P3a increased from 3.5 μV to 6.2 μV at frontal sites.²⁰ Based on these previous studies, we expected that novel sounds would elicit the MMN and P3a complex with attenuated amplitudes in short sleepers with respect to these ERPs in normal-sleeping individuals.

Unlike the P3a, another ERP component termed “P3b” is task relevant and associated with target detection. It is elicited when a subject's attention is focused on a stimulus.³¹ The P3b is associated with the process of memory comparison in the context of the previous stimuli, generating a brain potential with a parietal scalp distribution. The initial processing of a new stimulus engages the switching of attention that underlies P3a production, whereas the subsequent memory comparison engages the operations associated with P3b production.^32,33 According to previous research showing the effect of sleep deprivation on the amplitude and latency of the P3b,^20,33 attenuation of amplitude and prolonged latency of the P3b are expected in habitually short sleepers compared to normal sleepers.

In the current study, we utilized “to-be-ignored” vs. “attend” novelty oddball tasks to evaluate the effect of habitual short sleep on brain function underlying attention control process measured by the MMN (index of pre-attentive stage), P3a (attention-dependent), and P3b (memory-dependent) ERP components (Study I). Extended time in bed was used to evaluate the possible reversal of the impairments of these processes in habitual short sleepers (Study II).

We expected novel sounds to elicit ERP components with predominantly frontal scalp distribution (MMN and P3a) in normal sleeping individuals, whereas in habitually short sleeping individuals these ERPs show amplitude attenuation over frontal areas due to the impact of habitual short sleep time on reducing markers of frontal lobe activity.^20,41 We also hypothesized that attention load in the attend condition would contribute to the attenuation of the MMN, P3a, and P3b amplitudes with respect to the ERPs in normal-sleeping individuals. For the extended sleep condition, we hypothesized that longer time in bed would increase total sleep time, which subsequently would improve frontal activity in short sleeping individuals.

METHODS

RESULTS

DISCUSSION

The main findings of the present study show that habitually short sleeping individuals have deficiency in activity of the MMN and P3a brain responses over frontal areas as compared to normal sleeping subjects. The P3b amplitude increased over frontal areas and decreased over parietal with respect to the control group. Furthermore, one week of sleep extension was enough to partially normalize frontal counterpart of the MMN brain response in habitually short sleeping individuals, while attention-dependent brain responses (P3a and P3b) did not recover after one week of sleep extension.

This study supports the growing literature demonstrating that shortened sleep time negatively affects various aspects of cognitive functioning and performance, including reduced alertness,^6,7 impaired psychomotor performance,^8,36 increased risk-taking,³⁷ and impaired performance in complex cognitive behavioral tasks.³⁸

The present study adds to that literature by demonstrating that habitual short sleep is associated with deficits in frontal neuronal processing of novelty. Our results show that the MMN in the ignore and attend task was significantly reduced in short sleepers compared to controls. However, the greatest reduction of the MMN amplitude was observed during the attend task over frontal electrodes relative to the rest of the brain in the short sleep condition as compared to extended sleep. The MMN is characterized as an index of pre-attentive sensory memory operations in detection of changes in the auditory stream; our results suggest that habitual short sleep reduces the efficiency of this frontal mechanism, especially with regard to tasks that require attention. Extension of time in bed for one week increased total sleep time (from 5.7 h to 7.4 h) and concomitantly MMN amplitude increased from −0.1 μV up to −1.25 μV across frontal electrodes (F3, Fz, and F4). We did not find a significant correlation between increased sleep duration and the MMN response. In control subjects the mean amplitude of the MMN across frontal electrodes was −2.3 μV in the attend task, suggesting that sleep extension did, at least in part, normalize neurophysiological deficits in short sleepers in this attentional task, although a similar additional increase (∼1 μV) would be required for complete normalization of the habitual short sleepers. The lack of complete recovery after sleep extension might be related to the relatively short period of extension, both in terms of number of nights as well as hours per night. Chronic short sleepers may require an additional week of sleep extension for normalization of their neurophysiological impaired processes. In fact, while one week of sleep extension in a previous study did not produce normalization of alertness¹⁰ a subsequent study providing two weeks of sleep extension (TIB = 10 h) did provide evidence of normalization of alertness.¹² Thus, an additional week of sleep extension in the present study may have further improved the MMN deficits to a point where impairments were no longer present. Future studies with longer duration sleep extension are required to test this possibility.

Based on the results of the ignore task of study II, the lack of ERP-differences between extended and habitual short sleep suggest a potential adaptation effect to chronic sleep restriction of neuronal network as compared to ERPs in normal sleeping subjects. Such an interpretation is consistent with a previous sleep restriction study, showing that when sleep is reduced gradually (as with chronic sleep restriction) adaptive processes occur which minimize expected impairments relative to similar amounts of sleep loss experienced rapidly.⁷ However, when the attentional system is challenged in an attend task, the deficits in frontal regions involved in novelty processing are exposed, reflected by a greater reduction of the MMN amplitude in short sleepers. This latter result is consistent with numerous sleep deprivation studies, which show that more complex tasks requiring greater levels of attentional processing are more sensitive to the effects of sleep deprivation.³⁸

In a previous sleep deprivation study,³⁹ it was shown that the degradation of the pre-attentive processes which is reflected by the MMN response may also lead to disruption of the “reflexive shift” of attention to novelty. Our ERP results (illustrated in Figure 5) show this difference in brain activity associated with an attention switch (P3a response) between controls and short sleepers. The sleep extension period did not alter the P3a amplitude in either the ignore or the attend task-conditions. Therefore, our finding suggests that this process is impaired in short sleepers and not recovered after one week of sleep extension. This result is consistent with the study of Salmi et al.,⁴⁰ which also suggests that the involuntary attention switching system (reflected by the P3a) is sensitive to sleep duration reduction, and suggests that some types of tasks may require substantially longer periods for full recovery. Alternatively, such deficits may not fully recover in chronic short sleepers.

A recent study done by Gosselin et al.²⁰ demonstrated the effects of total sleep deprivation on novelty detection in an attended sound stream. Their finding suggests a “deactivation” of frontal regions associated with total sleep deprivation, as reflected by a reduction of the P3a amplitude. The authors also found the amplitude of the “P300” response (to novelty and to target) increased over parietal areas in sleep deprived subjects as compared to controls. They suggested that these amplitude enhancements might reflect a compensatory process in specific brain areas. A positron emission tomography study by Thomas et al.⁴¹ provided evidence that 24 hours of sleep deprivation produces global decreases in activity across all brain areas, with larger reductions in activity of the thalamus, prefrontal, and posterior parietal cortices involved in attentional and memory functions. Another sleep deprivation (restriction) study demonstrated a differential regional brain response to continuous (one week) sleep restriction by 33% per night.⁴² In this study, there is EEG/ERP evidence of the immediate response (after day one) to sleep restriction by reduced activity in frontal regions, while parietal regions showed maintenance of function until restriction progressed (after fourth day). More studies are needed to investigate this differential brain-regional response to sleep deprivation and chronic sleep restriction conditions.

In the attend task condition, in addition to a reduction of neuronal activity underlying the MMN and P3a responses in short sleeping individuals, we found increased amplitude and latency prolonged for the P3b response over frontal brain regions in short sleepers compared to controls. In fMRI studies on normal healthy subjects using a novelty task found that the P3a response appears related to the neural changes in the anterior cingulate when incoming stimuli replace the contents of working memory. Communication of this representational change is transmitted to infero-temporal lobe representation maintenance mechanisms.^43,44

The P3b response results from memory storage operations that are initiated in the hippocampal formation with the updated output transmitted to parietal cortex.⁴⁵ Thus, P3a is produced when a demanding stimulus commands frontal lobe attention; P3b is produced when attention resources are allocated for memory updating in association cortex. It is possible that acute total sleep deprivation impacts anterior cingulate and hippocampal formation differently from the impact associated with chronic sleep restriction. The increased amplitude of the P3b at the frontal electrode in the present study might be related to a compensatory mechanism for impaired frontal attention involved in the memory updating processes and occurs with chronic restriction of sleep but not acute sleep loss. Previous neuroimaging (fMRI) investigations have found that some verbal learning tasks are associated with a compensatory brain response (stronger linear responses) in several brain regions, including bilateral temporal, parietal lobes, and prefrontal cortex to short duration and more difficult tasks.⁴⁶ These regions are highly significant for attention and memory. The prolonged wakefulness produces a decrease in metabolic rates in widespread cortical and subcortical areas, specifically in the thalamus, hypothalamus, and brainstem reticular formation.^41,47 The reduction of the P3b amplitude in habitual short sleepers over parietal areas might be explained by the reduction of activity in parietal cortex in response to the prolonged wakefulness.

In our previous study,²² we found hyperactivation in novelty processing in shift work disorder subjects known to experience chronic sleep loss. Thus, the increased frontal brain activity underlying late ERP components at a latency of ∼250-320 ms in auditory processing may be associated with reduced sleep. In fact, insomnia patients show an increased N1 ERP component to rare (or deviant) auditory stimuli during the sleep initiation process⁴⁸ and upon morning awakening⁴⁹ as a result of possible cortical hyperarousal.⁵⁰ However, an ERP study on P300 brain response, done by Devoto et al.⁵¹ suggested that cortical hyperarousal is not a “stable individual characteristic” of insomnia, but rather is associated directly with the poor quality of patient's nocturnal sleep of the prior night. Thus, sleep loss may differently affect the brain regions involved in attention and memory, and importantly, the compensation of the network also may contribute to the reduction of the MMN and P3a and increasing P3b responses to chronic sleep restriction. Finally, in a clinical fMRI study in primary insomnia, the authors demonstrated the recovery effect of the prefrontal brain region after 6 weeks of intensive behavioral therapy.⁵² In our study, we found that the neuronal process associated with automatic change detection function may recover after one week of sleep extension, whereas attention-dependent neural processes do not normalize after this period of time in habitually short sleeping individuals and may require longer recovery periods. Further studies are required to confirm this possibility and to understand more about compensatory mechanisms of the neuronal network involved in the response to sleep loss and chronic sleep restriction.

In conjunction with previous behavioral-ERP studies looking at the relation between function and ERP measures, it is important to emphasize that the three cognitive components measured in our study (MMN, P3a, and P3b) have been utilized in clinical and basic research intensively and have established clinical utility. Moreover, each of these components has been operationally related to neurocognitive processes such as stimulus change-detection, sensory memory formation, novelty detection, orienting attention to new events, target detection, memory updates, and decision making.³² Since our study was carried out on healthy subjects, it would be logical to compare our results to previous literature addressing healthy populations where it was shown that the inter-individual differences or abilities to learn and process information can be measured by behavioral performance and ERPs such as the MMN, P3a, and P3b. Thus, in a fundamental study of the MMN component in regard to development of a memory trace for a complex sound, Näätänen and colleagues⁵³ demonstrated differences between good and poor learners of complex sound discrimination and processing. In that study, it was shown that subjects with a 93% correct response rate showed amplitude of the MMN of −1.4 μV with no further increase, even after intensive training. In contrast, if a participant had 19% hit rate, there was no MMN amplitude elicited to the complex sounds. Further, there were some “middle” learners who improved their behavioral performance and corresponding MMN amplitude with further training from 0.20 μV to −1.12 μV. In a study combining the MMN with psychophysical indexes of perceptual accuracy of the sound duration, Amenedo and Escera⁵⁴ demonstrated how the brain can detect decreasing or increasing changes in the duration of a tone and predict the accuracy of the behavioral detection of these same changes as indicated by MMN amplitude. This combined ERP-behavioral study of distractibility demonstrated the relation between prolonged reaction time due to load of working memory and P3a amplitude attenuation elicited by novel sounds in relation to not loaded working memory condition in healthy subjects.⁵⁵

In relating these simultaneous behavioral-ERP results and our findings, there may be a link that indicates short sleepers have less ability to learn new information, and their attention capacity as well as their memory related function is likely limited compared to normal sleeping subjects. However, new studies need to be conducted to further investigate this link.

The question arises as to whether the short sleepers in the current study exemplify trait short sleepers where sleep need may be less than that typically seen in the general population or rather are state short sleepers where their habitual short sleep habits prevent them from obtaining adequate sleep. Although the initial evaluation could not clearly differentiate these possibilities, the findings from both studies favor the latter interpretation. For example, the ERP data associated with the habitual short sleep condition showed significantly lower MMN, P3a, and P3b amplitudes as compared to the ERP data obtained from normal sleeping individuals (i.e., control group). Further, the extended time in bed significantly increased TST in short sleepers. This finding is in correspondence with previous studies demonstrating that as time in bed increases, both TST and alertness increase.^10,12 Moreover, our ERP results show that short sleepers after extended sleep have enhancement (i.e., towards normalization) of the MMN brain response as compared to the MMN during habitual short sleep. The implications of our findings contribute to the conclusion that our short sleepers correspond to a “state” rather than “trait” group.

DISCLOSURE STATEMENT

This study was partially supported (e.g., subjects compensation) by ZEO Inc. Dr. Roth has received research support from Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, Sanofi-Aventis, Schering Plough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth, XenoPort; has consulted for Abbott, Accadia, Acoglix, Actelion, Alchemers, Alza, Ancil, Arena, AstraZeneca, Aventis, BMS, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hypnion, Johnson and Johnson, King, Ludbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Orginer, Prestwick, Procter and Gamble, Pfizer, Purdue, Resteva, Roche, Sanofi, Schering Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanuchi, and XenoPort and has participated in speaking engagements for Sanofi, Cephalon, and Takeda. Dr. Drake has received research support from Merck, Inc., Cephalon, Zeio, Inc., and Takeda. He has also participated in speaking engagements for Cephalon and Asante Communications. The other authors have indicated no financial conflicts of interest.

ACKNOWLEDGMENTS

REFERENCES