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    The Impact of Moderate Sleep Loss on Neurophysiologic Signals ... The Impact of Moderate Sleep Loss on Neurophysiologic Signals ... Document Transcript

    • VARIATIONS IN SLEEP AND PERFORMANCE The Impact of Moderate Sleep Loss on Neurophysiologic Signals during Working- Memory Task Performance Michael E. Smith, PhD; Linda K. McEvoy, PhD; Alan Gevins, D.Sc San Francisco Brain Research Institute and SAM Technology, San Francisco, California Study Objectives: This study examined how sleep loss affects neuro- mance throughout the late-night tests. Despite such continued effort, physiologic signals related to attention and working memory. responses became slower, more variable, and more error prone within 1 Design: Subjective sleepiness, resting-state electroencephalogram, and hour after participants’ normal time of sleep onset. This behavior failure behavior and electroencephalogram during performance of working-mem- was accompanied by significant degradation of event-related brain poten- ory tasks were recorded in a within-subject, repeated-measures design. tials related to the transient focusing of attention. Setting: Data collection occurred in a computerized laboratory setting. Conclusions: Moderate sleep loss compromises the function of neural Participants: Sixteen healthy adults (mean age, 26 years; 8 female) circuits critical to subsecond attention allocation during working-memory Interventions: Data from alert daytime baseline tests were compared tasks, even when an effort is made to maintain wakefulness and perfor- with data from tests during a late-night, extended-wakefulness session mance. Multivariate analyses indicate that combinations of working-mem- that spanned up to 21 hours of sleep deprivation. ory-related behavior and neurophysiologic measures can be sensitive Measurements and Results: Alertness measured both subjectively and enough to permit reliable detection of such effects of sleep loss in individ- electrophysiologically decreased monotonically with increasing sleep uals. Similar methods might prove useful for assessment of functional deprivation. A lack of alertness-related changes in electroencephalo- alertness in patients with sleep disorders. graphic measures of the overall mental effort exerted during task execu- Key Words: Fatigue, alertness, cognition, attention, working memory, tion indicated that participants attempted to maintain high levels of perfor- electroencephalogram, event-related potentials INTRODUCTION resentation in the face of distracting influences.10,11 This ability plays an important role in comprehension, reasoning, planning, and learning.12 THIS PAPER EXAMINES THE IMPACT OF MODERATE SLEEP Indeed, the use of active mental representations to guide performance LOSS ON BEHAVIOR AND NEUROPHYSIOLOGIC MEASURES appears critical to behavior flexibility,13,14 and measures of this ability RELATED TO WORKING-MEMORY TASK PERFORMANCE. In tend to be positively correlated with performance on psychometric tests children and adolescents, sleep loss tends to be associated with impaired of cognitive ability and other indexes of scholastic aptitude.15-17 performance on neuropsychologic tests and lower levels of scholastic Metabolic studies suggest that working memory and the neural mech- achievement.1-3 Equivalent patterns of degraded performance on the job anisms of attention control involve cortical circuits linking regions of or on controlled tests have been observed in working adults experienc- prefrontal cortex with posterior association cortexes.18-22 Activation of ing interruption of normal sleep patterns.4-7 Not surprisingly then, sleep these circuits also occurs during reasoning and problem solving.23-25 loss is frequently implicated in major workplace accidents.8,9 Many such Such activation can be detected in measurements of neuroelectric activ- accidents likely result from the fact that, although rote activities might ity recorded at the scalp. More specifically, a sustained-task-imposed be performed adequately even after moderate sleep loss, subtle changes change in working-memory requirements tends to produce characteris- in a drowsy individual’s cognitive ability might nonetheless diminish his tic tonic changes in the amplitude of attention-related spectral features or her capacity to respond optimally when circumstances arise that of the ongoing electroencephalogram (EEG)26-28 that are punctuated by require rapid evaluation and thoughtful action. more phasic changes in components of the stimulus-locked, transient The ability to perform competently in such attention-demanding cir- event-related potentials (ERP).29-31 cumstances depends in part on the integrity of working memory. Work- Under normal conditions, neurophysiologic signals modulated by ing memory refers to the limited capacity to hold and manipulate infor- task-imposed variations in working-memory demands tend to be very mation in mind for several seconds in the context of cognitive activity. stable. For example, in a recent study in which the test-retest reliability In a sense, working memory is an outcome of the ability to control and of task-related EEG spectral features was examined in well-practiced sustain attention and to strategically focus it on a particular mental rep- subjects, correlations of r > .9 were found between two test sessions with a 1-week lag.32 Despite this apparent stability when other factors are held constant, there is evidence that task-related neurophysiologic sig- Disclosure Statement nals are highly sensitive to stressors that impose some form of mild, This research was sponsored by the National Aeronautics and Space transient cognitive impairment. For example, recent studies have Administration, the National Institute of Mental Health, the National demonstrated that working-memory-sensitive neurophysiologic signals Institute of Neurological Disorders and Stroke, and The Air Force Office vary in conjunction with low doses of alcohol33-35; diphenhydramine34; of Scientific Research. marijuana36; and prescription medications frequently used to treat neu- rologic37 and psychiatric38 disorders. Submitted for publication February 2002 Results of this type suggest that the cortical networks responsible for Accepted for publication June 2002 generating working-memory-sensitive neurophysiologic signals might Address correspondence to: Michael E. Smith, Ph.D., SFBRI , 425 Bush Street, also be disrupted in conjunction with moderate sleep loss. To evaluate 5th Floor, San Francisco, CA 94108; Tel: 415. 837.1699; Fax: 415. 274.9574; this possibility, the current study examined the impact of extended E-mail: Michael@eeg.com SLEEP, Vol. 25, No. 7, 2002 56 Sleep Loss and Working Memory—Smith et al
    • wakefulness on behavior and neurophysiologic measures made during liseconds once every 4.5 seconds on a computer monitor. At 1.3 seconds performance of well-practiced working-memory tasks. Data from a sam- prior to stimulus onset, a warning cue (a small x) appeared in the center ple of healthy young adult subjects were compared between an average of the screen for 200 milliseconds. The letter stimulus occurred 1.3 sec- alert daytime baseline test interval and 5 nighttime test intervals that onds after the cue in 1 of 12 possible locations on the monitor. The iden- occurred over the course of an extended-wakefulness session in which tity of the letter and its spatial position varied randomly from trial to the participants performed tasks throughout a night of sleep deprivation. trial. A small fixation dot was continuously present at the center of the screen. METHODS In an easy, low-working-memory-load version of the task, subjects were required to match the position of the current stimulus with the posi- Subjects tion of the very first stimulus in the block. In a difficult, high-working- memory-load version of the task, participants compared the current stim- Sixteen healthy adults (21-32 years; mean age, 26 years; 8 females) ulus with that presented two trials previously. In this version, they were participated. Most were full-time college students and as such they tend- required to remember two positions (and their sequential order) for the ed to maintain fairly irregular sleep-wake schedules. All were non-smok- duration of 2 trials (9 seconds) and to update that information on each ers, social drinkers (1-10 drinks per week), and mild to moderate caf- subsequent trial. In both versions of the task, stimuli were presented in feine consumers (1-3 cups of coffee per day). None were taking any cen- blocks of 53 trials (the first 3 trials were warm-up trials and were dis- trally acting medications during the course of the study, and none had carded from analysis). Matches occurred randomly on 50% of the trials. been previously diagnosed with any psychiatric or neurologic problems Participants were instructed to respond as quickly and as accurately as or sleep disorders. All participation was fully informed and voluntary possible. and conformed to all institution and government guidelines for the pro- tection of human subjects. Participants were remunerated on an hourly basis for their efforts. To minimize attrition, a significant bonus was also Procedures awarded to all participants upon completion of all test sessions. Finally, Each subject participated in a total of 6 experimental sessions. The to increase motivation to task performance, extra bonus payments were first session was a practice session in which subjects learned to perform awarded in a competitive fashion to the two participants who had the the working-memory tasks to an asymptotic level. All subjects then par- best overall accuracy across all test sessions. ticipated in 5 subsequent sessions, separated by at least 1 week. Four ses- sions involved recording from participants before and after they had Tasks ingested alcohol, caffeine, antihistamine, or placebo. These sessions occurred in a counter-balanced order, and the data concerning drug The focus of the present paper is on the effects of sleep deprivation effects are described in a separate report.34 A fifth experimental session during working-memory tasks. Participants performed two difficulty was an extended-wakefulness manipulation that began in the evening levels of a continuous performance, n-back–style working-memory-task and lasted until 6:00 AM the following morning. This extended-wakeful- versions of which we have employed in prior EEG studies.17,26-30,32-34 ness session is the focus of the current report. However, since each of the Similar n-back tasks have been adopted in many other laboratories as a four drug sessions involved a baseline recording prior to drug adminis- means to activate functional networks of working memory in a con- tration (around 12:00 PM on each day), the average of these alert, day- trolled fashion. Such applications have spanned conventional behavior time, baseline sessions was used as a comparison point for the data col- studies,39 other electrophysiologic studies,40,41 studies of the effects of lected in the extended-wakefulness session. In the week prior to the magnetic fields on cognitive function,42,43 and functional neuroimaging extended-wakefulness session, participants were required to keep a sleep studies employing positron emission tomography or functional magnet- diary indicating (among other things) the time on each day they went to ic imaging methods.44-48 sleep and the time they awoke. In the versions of this task employed in the present study (Figure 1), In the overnight extended-wakefulness session, subjects arrived at the participants were required to compare the spatial location of the current laboratory at approximately 8:30 PM, were given a warm-up block of the stimulus with that of one presented previously. Briefly, single capital-let- working-memory task and other tasks, and were prepared for the EEG ter stimuli, drawn randomly from a set of 12, were presented for 200 mil- recording. They then participated in five 40-minute recording intervals spaced throughout the night. The first interval occurred on average at 11:00 PM, the second at 12:30 AM, the third at 1:30 AM, the fourth at 3:30 AM, and the fifth at 5:00 AM. The internal structure of each interval was the same as that used during the daytime baseline sessions. Within each interval, participants completed the Karolinska49 Subjective Sleepiness Rating Scale and had their EEG recorded while they performed two blocks each of the easy and difficult versions of the working-memory task. At each interval, EEG data were also recorded while the partici- pants rested quietly for 90 seconds with their eyes open and closed. Such resting-state data were analyzed in order to obtain objective neurophys- iologic measures of changes in alertness. The resting conditions, the subjective measures, and the four blocks of the working-memory task took approximately 20 minutes to complete during each testing interval. In the periods between these recording blocks, the participants performed other repetitive computer tasks to ensure continued wakefulness and to help induce mental fatigue. Thus, at each of the test intervals, participants also performed a 10-minute ver- Figure 1—Schematic diagram of the low memory load and high memory load versions of the n-back sion of the Psychomotor Vigilance Task, which is a simple reaction-time working-memory task. Every 4.5 seconds, one of 12 possible capital-letter stimuli appeared in one of task that has been frequently used in sleep deprivation studies,50-52 and a 12 possible locations on a computer monitor. In the easy version of the task, subjects compared the location of the current stimulus, regardless of its identity as a letter, with the location of the very first stim- 5-minute version of the Multi-Attribute Task Battery,53 which is a com- ulus in the block of 50 trials. In the difficult version of the task, subjects compared the location of the cur- puter-based multitasking environment that simulates some of the activi- rent stimulus with the location of the stimulus presented two trials previously. ties a pilot might be required to perform and that has often been SLEEP, Vol. 25, No. 7, 2002 57 Sleep Loss and Working Memory—Smith et al
    • employed in studies of mental workload. At three occasions over the RESULTS extended-wakefulness testing session, participants also performed a 20- minute version of a simple visual “oddball” discriminative judgment The sleep-diary data indicated that over the week prior to the extend- vigilance task. During periods when the participants were not actively ed-wakefulness session, the participants typically fell asleep between involved in one of the formal tasks, they were allowed to read, play 11:30 PM and 1:00 AM and received about 7 hours (range, 6-9 hours) of video games, or surf the Internet, but no napping was permitted. sleep on an average night. On the day of the extended-wakefulness ses- sion, participants reported awakening between 6:00 AM and 10:30 AM EEG Recording and Preprocessing (average, 8:00 AM) after having obtained an average of 7 hours of sleep. Thus, the first test (11:00 PM) during the extended-wakefulness session The EEG was continuously recorded from 28 scalp electrodes using a occurred, on average, after 15 hours of wakefulness, and the final test linked-mastoids reference. The electrooculogram was recorded from session at 5:00 AM took place after about 21 hours (range, 19.5 to 23 electrodes placed above and below one eye and at the outer canthus of hours) of wakefulness. each eye. Physiologic signals were band-pass filtered at 0.01 hertz to 100 No caffeinated beverages were consumed during the extended-wake- hertz and sampled at 256 hertz. Data were digitally filtered offline with fulness session itself. Twelve of the participants consumed no caffeine a zero-phase-shift, 0.5 hertz, high-pass IIR filter. Automated artifact after noon of the day of the extended-wakefulness session. The other 4 detection was followed by application of adaptive eye-contaminant participants had last consumed caffeinated beverages in the late after- removal filters.54 The data were then visually inspected, and data seg- noon. None consumed a total of more than three caffeinated beverages ments containing possible residual artifacts were eliminated from subse- on the day of the extended-wakefulness session. quent analyses. To obtain power spectral estimates, Fast Fourier trans- forms were applied, and periodograms were computed on 50% over- Impact of Extended Wakefulness on Subjective and EEG Measures of lapped, 512-sample Hanning windows for all artifact-free trials and Sleepiness averaged over all data within a condition. Average spectra were convert- ed to dB power by normalizing them with a log10 transform. The ERP Subjectively, participants reported that they felt most alert in the 12:00 were computed by averaging together all of the artifact-free epochs of PM baseline interval and progressively less alert at later test intervals, the stimulus-locked EEG for correctly classified trials within each con- with minimal alertness usually reached during the final test at about 5:00 dition for each subject. These epochs began 0.2 seconds before stimulus AM (Figure 2). This change was reflected in a significant main effect of onset and extended to 1.0 second afterward. The ERP were low-pass fil- test interval (F(5,75) = 23.31; P < .001). Posthoc pair-wise comparisons tered at 20 hertz prior to subsequent analyses. indicated that although there was no significant difference between the 11:00 PM interval and the 12:00 PM baseline, subjects had become sig- Analyses nificantly sleepy (P < .01) by the 12:30 AM interval. Eye-movement activity and EEG spectra recorded while the partici- To examine how individual behavior and physiologic features varied pants rested quietly displayed classic signs of sleepiness, providing con- over the extended test session, univariate repeated measures analyses of vergent evidence that alertness decreased approximately linearly over variance were used to compare data from the 12:00 PM baseline to data the course of the extended-wakefulness session. For example, past recorded across the different test intervals of the extended-wakefulness research has indicated that horizontal slow eye movements tend to session. The experiment-related sources of variance in each of the indi- increase as individuals become increasingly sleepy.49,55,56 To measure vidually measured parameters were assessed in univariate task (easy vs. difficult) or resting condition (eyes-open vs. eyes-closed) by test interval repeated measures ANOVA. Changes in mental function related to extended wakefulness would thus be expected to manifest as a main effect of test interval or as an interaction involving test interval. The Greenhouse-Geisser correction to degrees-of-freedom was employed to correct for any violations of the sphericity assumption in analyses involving repeated measures. In such cases, the reported p values corre- spond to the corrected degrees of freedom. Figure 2—Average (±SEM) subjective sleepiness ratings assessed with the Karolinska Sleepiness Figure 3—Average electroencephalographic power recorded from a midline occipital electrode in the Scale. Sleepiness did not differ significantly between the 12:00 PM alert baseline and the 11:00 PM test resting eyes-closed (top) and eyes-open (bottom) conditions during the 12:00 PM baseline and during interval. It increased in an approximately linear fashion from the 11:00 PM test interval to the 5:00 AM test the 5 AM test interval. In both conditions, electroencephalographic power below the alpha band was rel- interval. atively higher at the 5 AM test interval. In contrast, alpha-band power was relatively attenuated at 5 AM in the eyes-closed condition. SLEEP, Vol. 25, No. 7, 2002 58 Sleep Loss and Working Memory—Smith et al
    • changes in the incidence of slow eye movements, a bipolar derivation characterized in terms of the ability to detect match trials as character- was computed between a pair of electrodes placed at the outer canthi of ized by d’62. Reaction times were measured in milliseconds and then log the eyes, and average power in a 0.5-hertz to 1.0-hertz band was extract- normalized prior to statistical analyses. Across test intervals, subjects ed from this derivation prior to removal of eye-movement contaminants. responded more accurately (F(1,15) = 38.22; P < .001) and faster By this measure, slow eye movements increased significantly over the (F(1,15) = 53.58; P < .001) in the low-load task than in the high-load test session (F(5,75) = 10.52; P < .001). task (Figure 4). These effects of task load did not interact with test inter- Past studies have also consistently demonstrated a drowsiness-related val. Classification accuracy was approximately 15% lower late at night pattern of changes in the spectral composition of the resting state EEG.57- than during the 12:00 PM baseline (F(5,75) = 4.90; P < .02), and reaction 61 In general, particularly during eyes-closed resting conditions over times were slowed on average by about 100 milliseconds (F(5,75) = parietooccipital electrode locations, spectral power in the delta and theta 6.53; P < .001). Independently of the overall slowing, reaction times also bands tends to increase during sleepy states, whereas alpha-band power became relatively more variable over test intervals. That is, there was a tends to decrease. These effects were observed in the present data (Fig- significant increase in the “coefficient of variability” (computed for each ure 3). Specifically, across resting conditions, delta activity measured as subject as the ratio of the standard deviation of reaction times over trials the average power between 2 hertz and 4 hertz at electrode Pz increased within a block of trials to the average of reaction times within the block) over test intervals (F(5,75) = 3.87, P = .01), as did posterior theta mea- over test intervals (F(5,75)=4.28, P < .007). There were no significant sured as the average power between 4 hertz and 6 hertz at the same site interactions obtained between task load and interval for accuracy, reac- (F(5,75) = 4.3, P = .01). In contrast, occipital alpha measured as the tion time, or reaction-time variability. Across tasks, none of these mea- average power in a 1-hertz band around the peak frequency in the 8-hertz sures significantly differed between the 12:00 PM baseline and the 11:00 and 12-hertz range at Oz was significantly attenuated by extended wake- PM test interval. Marginal impairment in performance could be observed fulness in the eyes-closed resting condition but not in the eyes-open rest- by the 12:30 AM test interval, and performance reached a nadir by the ing condition (F(5,75) = 4.61 P < .01). For both slow eye movements 1:30 AM test interval. That is, performance in both the low-memory-load and EEG spectral measures during resting conditions, the observed and high-memory-load tasks had become significantly impaired by a rel- changes paralleled those observed in the subjective ratings, with no sig- atively early stage of the extended-wakefulness session. Performance nificant differences obtained between the 11:00 PM interval and the remained at that degraded level through the remaining test intervals, 12:00 PM baseline, a significant difference from baseline occurring by with no further decrement between 1:30 AM and 5:00 AM. the 12:30 AM interval, an approximately monotonic increase (or decrease To more carefully evaluate the pattern of errors observed during the in the case of the alpha rhythm during the eyes-closed condition) over course of the extended-wakefulness session, the rate of false match the course of the extended-wakefulness session, and a maximum differ- responses (1.8% overall) was compared with the rate of false nonmatch ence from baseline during the 5:00 AM test interval. responses. Although there was a slightly higher incidence of false non- match response on average (2.2% overall), this difference did not reach Impact of Sleep Loss on Behavior Measures during Task Performance significance (F(1,15) =3.0, P = .10), nor was there any interaction between type of false response made and test interval. Furthermore, To examine changes in task performance over the course of the there was no significant difference between the rate of errors of com- extended-wakefulness session, stimulus classification accuracy was mission (false-positive match and nonmatch responses, 4% of all trials) and errors of omission (failures to respond in the time allowable, 5.2% of all trials) nor was there any interaction between these two types of errors and test interval (both Fs < 1). Finally, there was a high positive Figure 5—Grand average power spectra for task-related electroencephalography in the low-load and Figure 4—Average (±SEM) reaction time (top) and accuracy (bottom) in the easy and difficult levels of high-load levels of the working-memory task over frontal and parietal midline sites. Over frontal areas, the working-memory task over test intervals. In both task levels, accuracy decreased significantly and power in the frontal midline theta band (6-7 hertz) was larger in the high-load task than in the low-load reaction time increased significantly with time; performance decrements reached an asymptotic trough task. Over parietal areas, alpha power, in both the slow (8-10 hertz) and fast (10-12 hertz) alpha bands at about 1:30 AM, remaining at that level throughout the rest of the test session. was larger in the low-load task than in the high-load task. SLEEP, Vol. 25, No. 7, 2002 59 Sleep Loss and Working Memory—Smith et al
    • correlation between these two error types over participants and test with attenuation of power in the alpha band at parietal sites (F(1,15) intervals (Spearman rho = 0.69, P < .001). =47.25, P < .001). Neither of these signals displayed a test interval by task load interaction (both P values > 0.1), indicating that the magnitude Impact of Sleep Loss on EEG Spectral Measures during Task Performance of the task load effect on EEG spectral parameters did not significantly differ over the course of the test session. Figure 5 compares average power spectra in the low-load and high- Despite the lack of any interaction with task load, both the frontal load working-memory tasks. As noted in the introduction, past studies midline theta measure (F(5,75) = 7.59, P < .001) and the parietal alpha indicate that regional power spectral measures in the theta and alpha measure (F(5,75) = 3.24, P < .04) displayed overall main effects of test bands are sensitive to variations in the working-memory load imposed interval. As can be seen in Figure 6, the absolute power of both signals by continuous performance tasks like those employed herein. In partic- was lower at the 11:00 PM test interval of the extended-wakefulness-test ular, the theta rhythm at frontal midline sites tends to be enhanced with session than it was at either the 12:00 PM daytime baseline or at the late- higher working-memory loads, whereas the alpha rhythm tends to be night test intervals. Since this effect does not appear to be related in any attenuated, particularly at parietal sites.17,26,27,30,32-34 Such tonic differ- consistent fashion to either the subjective or objective measures of ences in EEG spectral composition between tasks that differ continu- sleepiness described above, or to the observed pattern of changes in the ously in working-memory requirements might be expected to reflect the task-related behavior measures, it is unlikely that the transient signal integrity of attention-control mechanisms. That is, they would appear to attenuation at approximately 11:00 PM is related to the same factors index differences in the effort that subjects willfully make and sustain responsible for those other changes. An alternative possibility is that the over the course of several minutes in response to variations in the demands of the task environment. To quantify these phenomena for statistical analyses, the spectral power of the working-memory-load–sensitive frontal theta rhythm was measured at the peak frequency in a 5-hertz to 7-hertz band at frontal midline electrode site AFz. The power of the alpha rhythm was original- ly measured in both an 8-hertz to 10-hertz band and a 10-hertz to 12- hertz band at electrode site Pz. Preliminary analyses indicated no impor- tant differences between these two alpha-band measures in response to sleep loss, so they were collapsed into a single task-related parietal alpha measure. Mean spectral power for frontal midline theta and parietal alpha rhythms at each test interval is presented in Figure 6. As in prior studies, the power of the frontal midline theta rhythm was observed to be greater in the high-load task than in the low-load task (F(1,15) = 7.08, P < .02). In contrast, increasing working-memory load was associated Figure 7—Grand average (N,16), stimulus-locked, event-related potentials over the right parietooccipi- tal area. Data are collapsed over low-load and high-load versions of the working-memory task and over matching and nonmatching stimulus categories. The amplitude of the N170 peak was reduced by the 1:30 AM test period relative to the 12:00 PM baseline period. Data were bandpass filtered at 2 hertz to 20 hertz. Figure 8—Grand average (N,16), stimulus-locked, event-related potentials over central and parietal Figure 6—Average (±SEM) EEG power, in decibels, for the anterior frontal midline theta band (6-7 midline sites. Data are collapsed over low-load and high-load versions of the working-memory task and hertz) (top) and the parietal alpha band (8-12 hertz) (bottom). The impact of increasing working-memo- over matching and nonmatching stimulus categories. The amplitudes of the P215 and late positive com- ry task load on these spectral parameters of the EEG remained relatively constant across test intervals. ponent (LPC) peaks were reduced by the 1:30 AM test period relative to the 12:00 PM baseline period. In This suggests that although performance degraded over the night, the subjects continued to allocate contrast, the reduction in the slow wave (SW) peak that followed the LPC did not reach significance. greater neural resources and make a greater effort to perform the more difficult task throughout the Data were averaged over all intervals, and low-pass filtered at 7 hertz. night. SLEEP, Vol. 25, No. 7, 2002 60 Sleep Loss and Working Memory—Smith et al
    • effect reflects some type of transient beginning-of-session difference in ponents of the ERP tend to be affected by sleepiness. Several compo- the overall state of arousal. To evaluate this possibility, the measure- nents of the ERP response in the current study appear to be associated ments of the task-related EEG were recomputed as difference scores with attention and decision making in that they varied systematically from corresponding measurements made in the eye-open resting condi- between correctly classified matching versus nonmatching stimuli, tion (under the presumption that an overall state difference would have between task loads, or between stimuli and task loads. These compo- similar effects on both the resting and the task-related EEG). In ANOVA nents included: 1) an N170 recorded over parietooccipital regions (Fig- performed on these difference scores, the effects of task-load observed ure 7); 2) a central P215; 3) a “P300” or late positive component (LPC); above were still obtained for both the frontal midline theta signal and for and 4) a positive slow wave recorded over central and parietal regions parietal alpha signal, but no main effects of test interval or test interval (Figure 8). To quantify these phenomena for statistical analyses, ERP by task load interactions were observed for either signal. component peak latencies were measured with respect to the time of stimulus onset, and amplitudes were measured with respect to the aver- Impact of Sleep Loss on Stimulus-Locked ERPs age amplitude 200-millisecond prestimulus onset. The amplitude of the N170 (as measured at lateral parietooccipital Studies of extended wakefulness,63-67 and of medication use that alters electrode P8) had complex task correlates, displaying a significant task- alertness,68,69 have found that attention-related and decision-related com- load-by-stimulus-type interaction (F(1,15) = 11.07, P < .005). This inter- action resulted from a lack of difference in N170 amplitude between the two task types for nonmatch stimuli, whereas for match stimuli the N170 was much larger in amplitude in the low-load task than in the high-load task. The amplitude of the N170 (Figure 9, top) was attenuated over test intervals (F(5,75) = 6.33, P < .001). This attenuation did not interact with stimulus type or task-load factors. Similarly, the peak latency of the N170 was observed to increase over test intervals (F(5,75) = 7.46, P < .001), with a total increase of about 10 milliseconds between the 12:00 PM baseline measure and the 5:00 AM test interval. For both the ampli- tude and the latency measures, posthoc analyses revealed significant (P < .01) effects by the 1:30 AM test interval, with no further significant change over the remaining test intervals. Peak amplitude of the P215 was larger for correctly classified non- match stimuli than for match stimuli (F(1,15)=8.26, P < .02), indepen- dent of task load. A significant main effect of test interval (Figure 9, mid- dle) was also obtained (F(5,75)=4.09, P < .01). There were no interac- tions between test interval and the other factors. As with the N170, rela- tive to the 12:00 PM baseline, there was a significant (P < .01) reduction in P215 amplitude by the 1:30 AM test interval. This attenuation in ampli- tude persisted throughout the remainder of the session, though the P215 displayed a trend toward recovery at the 3:30 AM and 5:00 AM test inter- vals. No significant effects were observed for the peak latency of the P215. Amplitude of the LPC (measured as the average amplitude in a 50- millisecond window around peak latency at parietal midline electrode Pz) did not display significant main effects of task load or stimulus type. There was, however, a significant interaction between these factors (F(1,15)=9.01, P < .01); in the low-load task, the LPC amplitude did not differ between match and nonmatch stimuli, whereas in the high-load task, the amplitude of this potential was much smaller to match stimuli than to nonmatch stimuli. A significant effect of test interval (Figure 9, bottom) was also obtained (F(5,75)=5.58, P < .04). As with the other ERP measures, posthoc analyses revealed that by the 1:30 AM test-inter- val amplitude of the LPC was significantly (P < .01) attenuated, and this attenuation persisted at approximately the same level throughout the remaining test intervals. Peak latency for the LPC did not significantly differ as a function of task load or of test interval. The positive slow-wave component occurring at approximately 500 milliseconds to 600 milliseconds following stimulus onset (measured as the average amplitude in a 100-millisecond window around peak ampli- tude at parietal electrode Pz) was larger to correctly identified nonmatch stimuli than to match stimuli (F(1,15) = 22.68; P < .001), but it did not differ significantly over test intervals. The behavior data reviewed above indicated that accuracy decreased Figure 9—Average (±SEM) amplitude for the N170 (top), P215 (middle), and LPC (bottom) peaks of the and that reaction times increased and became more variable on a trial- stimulus-locked ERP collapsed across stimulus type and task-load conditions. The data were normal- by-trial basis (as measured by the coefficient of variability) in the late- ized across test intervals within each subject for each peak. Values for the negative N170 peak were inverted to make them graphically comparable to the P215 and the LPC. The average amplitudes for night test sessions relative to the alert baseline. To examine whether each peak did not differ between the 12:00 PM baseline and the 11:00 PM test interval. Amplitudes were there was a systematic relationship between these performance changes significantly attenuated between the 11:00 PM and 1:30 AM test intervals. For the N170 and LPC, this and the observed attenuation of ERPs with sleep loss, the change in LPC attenuation reached a nadir at 1:30 AM and displayed little further change over the remaining test inter- vals. For the P215, there was a slight recovery in amplitude at later test periods. These results suggest amplitudes between the daytime baseline measure and the extended- that the ability to efficiently focus attention on transient stimulus events rapidly decayed in response to wakefulness session was calculated for each subject and test interval, a moderate delay in normal sleep-onset time. LPC, late positive component and correlated with the corresponding change in the accuracy, response SLEEP, Vol. 25, No. 7, 2002 61 Sleep Loss and Working Memory—Smith et al
    • latency, and response-variability measures. The participants and test tal Effort intervals that displayed the largest reduction in LPC amplitude also tend- ed to display the largest decrease in response accuracy (Pearson r = 0.48, Electrophysiologic measures obtained from the passive resting condi- P < .001), the largest increase in reaction times (r = -0.42, P < .001), and tions varied in a predictable manner with increased sleepiness and men- the largest increase in response variability (r = -0.48, P < .001) tal fatigue as evidenced by the subjective ratings and overt task perfor- mance. When comparing brain signals recorded over posterior regions DISCUSSION under eyes-closed resting conditions, past studies have demonstrated sleepiness-related increases in the delta and theta EEG bands and The objective of this study was to evaluate whether and how moder- decreases in the alpha band.57-61 Slow eye movements have been shown ate sleep deprivation affects behavior and neurophysiologic measures of to increase with sleepiness.49,55,56 These findings were replicated in the working-memory task performance. The extended-wakefulness manipu- current study, providing convergent objective evidence of the effective- lation induced significant sleepiness as measured with conventional sub- ness of the extended-wakefulness manipulation for inducing sleepiness jective and electrophysiologic criteria. Even moderate levels of sleep in the subjects. These physiologic measures had a timecourse similar to loss were found to impair task performance and to disrupt neurophysio- that of the subjective ratings, showing a relatively continuous and grad- logic signals related to phasic aspects of working-memory task perfor- ual increase in sleepiness from the 11:00 PM test interval until the 5:00 mance. These findings are discussed below. AM test interval. Although both objective and subjective measures of alertness thus Effects of Sleep Loss on Overt Task Performance suggested that sleepiness increased in an approximately linear fashion over the intervals of the extended-wakefulness session, as noted above, Some recent research has suggested that 1 night of sleep deprivation the corresponding change in behavior was more sigmoidal in nature, is not enough to impair performance on tasks designed to assess higher showing a rapid asymptotic decline in accuracy and response speed cognitive functions.70 However, most studies have found that modest between the 11:00 PM and 1:30 AM test intervals. One possibility that amounts of sleep loss can significantly degrade performance on tests that might account for this dissociation is that once subjects started to explicitly incorporate a working-memory component or that otherwise become sleepy, they rapidly became less motivated to make the sus- are thought to require contributions from prefrontal cortical regions.71-74 tained mental effort required by the continuous performance tasks, Such deficits are consistent with the impairments in working memory resulting in a corresponding rapid decline in performance. However, in and other executive functions that have been observed to accompany the order to mitigate such motivational lapses, this study employed a com- sleep fragmentation and hypoxia associated with obstructive sleep petitive, performance-related reimbursement scheme that rewarded con- apnea.75-77 The effects of sleep loss on behavior measures in the current sistently high levels of effort. Furthermore, other investigators who have study appear to be entirely consistent with such findings. studied behavior impairments in simple reaction-time sustained-atten- The observed effects of the working-memory-load manipulations on tion tasks during sleep deprivation have suggested that motivation issues behavior data were in good agreement with previous find- are unlikely to be the major cause of performance decrements. In partic- ings17,26,27,29,30,32,33; accuracy was lower and reaction times were slower ular, past results indicate that increases in errors of omission (failures to in the high-memory-load task than in the low-memory-load task. Of respond) in such contexts tend to be highly positively correlated with more interest to the current context, behavior began to degrade by the increases in errors of commission (inappropriate key presses), which 12:30 AM test interval relative to the 12:00 PM alert baseline level. The suggests that participants in such studies often actively try to compen- beginning of this decline in overt performance was in good agreement sate for any sleepiness-related performance failures that might occur.80 with subjective measures of sleepiness. However, behavior reached a Though error rates in the current study were fairly low, the pattern of significant, asymptotic level of impairment by the 1:30 AM test interval. errors observed was consistent with this view. This rapid decline to an asymptotic level of functional impairment is in Measures of ongoing EEG during task performance in the current contrast to subjective sleepiness and to objective measures of alertness study were also consistent with this view, suggesting that participants in obtained from resting EEG data, which suggested that drowsiness con- the extended-wakefulness session continued to exert mental effort tinued to increase between the 1:30 AM and 5:00 AM test intervals. toward task performance even at the late-night test intervals. As noted Successful performance of the working-memory tasks demanded par- above, past research with n-back working-memory tasks has demon- ticipants to sustain mental effort over several minutes, to strategically strated that the theta rhythm at frontal midline sites is enhanced with control and quickly focus their attention in order to accurately register higher working-memory loads, whereas the alpha rhythm is attenuat- transient stimulus events, and to rapidly compare incoming information ed.17,26,27,30,32-34 Given that the perceptual and motor requirements of the to that maintained in working memory. The behavior data demonstrate different versions of the task are identical, such tonic working-memory that some critical aspect of this ability was significantly impaired when -load-related differences in the EEG can be interpreted as indexes of the wakefulness was extended just an hour past the normal time of sleep participants’ deliberate differential allocation of mental resources in onset. This result is consistent with the notion that even moderate response to increased demands in the task environment. The data from amounts of sleep loss might increase the likelihood of performance the current study replicated the previously described changes in spectral errors in real-world activities—especially those that require sustained EEG characteristics in response to increased working-memory load, attention and working memory.9 Indeed, the magnitude of the behavior indicating that throughout the session participants dedicated a greater impairment observed herein when subjects were performing tasks just a proportion of their available mental resources to task performance in the few hours after their normal time of sleep onset exceeded that observed high-load condition than in the low-load condition. Furthermore, there following a legally intoxicating dose of alcohol in these same subjects,34 did not appear to be any systematic changes across test intervals in EEG and in other groups of subjects performing the same tasks.33,35 This correlates of the subjects’ tonic mental effort. Thus, performance was observation is consistent with other reports that have compared the impaired despite evidence that participants made a relatively constant effects of sleep deprivation and alcohol on performance.66,78,79 In con- effort throughout the night to commit neural resources to task perfor- trast, the magnitude of the behavior impairment associated with moder- mance. Such results are in sharp contrast to those observed in response ate sleep loss was not as great as that observed following a single stan- to the sedating benzodiazepine alprazolam, the acute effects of which dard 50-milligram dose of the over-the-counter antihistamine diphenhy- have been found to both dramatically degrade performance and elimi- dramine in the same subjects.34 nate the differences in EEG spectral characteristics otherwise observed to occur in response to variations in working-memory load in tasks sim- ilar to those employed herein38. Tonic Modulation of the Ongoing EEG by Sleepiness and Sustained Men- SLEEP, Vol. 25, No. 7, 2002 62 Sleep Loss and Working Memory—Smith et al
    • Like the change in behavior measures, the overall average timecourse The Impact of Extended Wakefulness on the Phasic ERP of the ERP changes also showed a rapid decline to an asymptotic floor between the 11:00 PM and 1:30 AM test intervals. Furthermore, correla- Careful analyses of behavior measures during sleep deprivation have tion analyses indicated that there was a tight coupling between the size led some researchers to posit that sleep loss produces an unstable men- of the ERP amplitude attenuation observed in individual participants and tal state that is characterized by momentary lapses in attention and alert- test intervals over the course of the extended-wakefulness session and ness. Such lapses lead to performance errors and an increase in the vari- the magnitude of the performance impairments observed in those same ability of response times that is disproportional to what might be expect- participants and test intervals. Other investigators have observed similar ed from overall behavior slowing.51,80-82 In the current study, evidence of correlations between the magnitude of ERP attenuation and the behavior such “state instability”80 was provided by the observation of decreased impairments that are associated with sleep deprivation.65 accuracy on even the low-load version of the working-memory task, as The amplitude of an averaged stimulus-locked ERP might decrease well as a significant increase in the coefficient of variability measure of either as a result of the latency of the neural response to the stimulus reaction times over the course of the extended-wakefulness session. becoming more variable across individual task trials or as a result of a Such drowsiness-related increases in error rate and response variability decrease in the average absolute magnitude of the neural response pro- have been reported to be associated with a decrease in the transient elec- duced across trials. The observed negative correlation between the ERP trodermal orienting response, an autonomic measure of the degree to amplitude reduction and the increase in variability in reaction-time mea- which a stimulus is successful at capturing an individual’s attention.82 sures provides some indirect evidence that the former mechanism might Measures of the spectral power of the continuous EEG over a set of be at least partly responsible for ERP-amplitude attenuation in response task trials—such as those described in the previous section—reflect the to sleep loss. However, this does not exclude the second possibility from relative commitment of attention and working-memory resources to task also being a contributing factor, and other considerations are consistent performance over the course of several minutes. While adequate for with the notion that sleep loss is associated with a decrease in the mag- characterizing tonic states and for differentiating the overall resource nitude of transient cortical responses. For example, in primate models, demands of tasks that vary in terms of the effortful attention required for noradrenergic locus coerulus neurons have been shown to display con- their performance, such measures are likely to be poor indexes of subtle tinuous moderately irregular activity during the alert waking state, punc- changes in more phasic aspects of attention, such as those required for tuated by phasic enhancements of firing in the first 200 milliseconds fol- perceptually analyzing a transient stimulus and for working-memory lowing a task-relevant or attention-capturing stimulus. While the magni- encoding and updating. In contrast, subsecond neurophysiologic mea- tude of locus coerulus background activity might be associated with the sures such as stimulus-locked ERPs can be highly sensitive to any animal’s general state or level of wakefulness, the phasic enhancement changes in the manner in which attention is transiently captured and is thought to provide a brief, stimulus-specific modulating input to cor- focused in response to a stimulus event. Past research has demonstrated tical networks and to produce a transient attention-related increase in the that such measures are affected by sleep deprivation and mental amplitude of the cortically generated ERP that follows task-relevant fatigue,63,83,84 and the ERP results from the present study are consistent stimuli.88 Simulation studies suggest that this phasic cortical input from with the notion that even moderate sleep loss can compromise more pha- the locus coerulus is also a critical factor in the animal’s ability to make sic aspects of attention. fast and accurate responses.89 Drowsiness and decreased vigilance tend For example, the N170 of the visual ERP has frequently been shown to be accompanied by a reduction in stimulus-related phasic enhance- to be modulated by the strategic transient focusing of attention.85-87 That ment of locus coerulus neuronal activity and a contemporaneous deteri- is, it is enhanced when stimuli are presented at a target location to which oration of task related behavior.90 Such reduction of phasic noradrener- subjects are directing their attention and is attenuated when stimuli are gic input to the cortex might have played a central role in both the presented away from the target location. Although the task used here dif- degraded behavioral performance and the reduced ERP amplitudes that fers from the classic visual attention task in which attention is manipu- were observed to occur in response to sleep loss in the current study. lated by cues prior to each stimulus, the N170 in the current study also appeared to be enhanced by the strategic phasic focusing of attention. In Detecting Changes in Functional Alertness with Multivariate Methods that particular, in the tasks employed here, subjects were required to compare Combine Behavior and EEG Measures stimuli to a target location indicated on a previous trial; this requirement produced an enhancement of the N170 response to stimuli that then As noted above, the data described here were collected as part of a occurred at the anticipated location, a result that replicates similar find- larger study in which the same subjects also participated in four separate ings from other studies employing these tasks.30,37 With extended wake- daytime test sessions in which they performed the same tasks before and fulness, the N170 latency increased and N170 amplitude was signifi- after ingesting alcohol, caffeine, an antihistamine, or placebo. The aver- cantly reduced. Thus, moderate sleep loss appeared to rapidly degrade a age of the data from the premedication period for each of those sessions neural signal related to the selective focusing of attention onto particular comprised the 12:00 PM baseline reference period for the sleep-depriva- stimulus attributes. tion manipulation. In analyses of the drug-effects data, multivariate Similarly, past research has also indicated that ERP components cor- methods (in particular, stepwise linear discriminant analysis) were responding to the P215 and the LPC are sensitive to the attention and applied to combinations of behavior and EEG variables to detect and working-memory requirements of a task.17,29,30 In the current study, these quantify the neurocognitive effects of the drugs and to track their phar- potentials also differed between stimuli that matched or failed to match macodynamics. Inclusion of EEG variables in discriminant functions led the target stimulus in working memory, and, in the case of the LPC, this to more sensitive detection of drug effects than that which could be match sensitivity interacted with working-memory load. Extended accomplished when only behavior performance variables were used.34 wakefulness had a similar impact on the amplitude of these potentials as To begin to determine whether such methods could be extended to the it did on the N170: both rapidly declined in amplitude when task perfor- problem of detecting changes in cognitive function associated with sleep mance was required after the participants’ normal time of sleep onset. deprivation, stepwise linear discriminant analyses were performed in These effects contrast with the lack of a significant attenuation for the which functions were derived (either from behavior measures alone, parietal slow wave that followed the LPC. The lack of a slow wave effect electrophysiologic measures alone, or from combinations of behavior suggests that extended wakefulness had its primary impact on compo- and electrophysiologic measures) to discriminate each testing interval nents of the stimulus-locked neural response that are primed by selective during the extended-wakefulness session from the 12:00 PM alert base- attention to stimulus processing rather than ERP components related to line data. A leave-out-one resampling procedure91 was used for cross- subsequent operations. validation. In this approach, functions are iteratively developed on N-1 of SLEEP, Vol. 25, No. 7, 2002 63 Sleep Loss and Working Memory—Smith et al
    • the participants and then tested by application to the remaining participant. during attention and working-memory tasks,92-95 and extend these find- Figure 10 summarizes the results of the cross-validation analysis, ings by providing information about the likely relative timing and pha- illustrating the percentage of individuals (out of 16 total) detected as dif- sic nature of such changes. Given the disruption to executive functions ferent from the alert baseline test interval at each night-time test interval sometimes reported in patients with obstructive sleep apnea,75,76 the high for each of the three analysis strategies. Consistent with the univariate sensitivity of neurophysiologic signals of attention and working-memo- analyses, none of the three analysis strategies significantly discriminat- ry task performance to moderate degrees of sleep loss suggests that these ed data recorded at the 11:00 PM interval from the 12:00 PM baseline. By types of measures might prove useful in assessing functional alertness in 12:30 AM, the behavior changes could be significantly detected (binomi- such patients. al P < .01), but analyses based on behavior alone did not yield a stable . pattern of results when viewed over subsequent test intervals. Electro- ACKNOWLEDGMENTS physiologic changes from baseline could be detected in 100% of the par- ticipants by the 1:30 AM test session (P < .0001); however, as with We thank Jennifer Barber, Gail Chang, Arati Karnik, Caroline Pri- behavior, analyses based on electrophysiologic measures alone provided oleau, and Georgia Rush for assistance with data collection and analysis. a mixed picture when viewed across test intervals. In contrast, analyses The National Aeronautics and Space Administration, the National Insti- that incorporated both behavior and electrophysiologic measures dis- tute of Mental Health, the National Institute of Neurological Disorders played a monotonic increase in discriminability from baseline, with the and Stroke, and The Air Force Office of Scientific Research sponsored largest increase occurring between the 12:30 AM and 1:30 AM test inter- this research. vals. By the 5:00 AM test interval, 94% of the data samples in the com- bined analysis could be accurately discriminated from baseline (binomi- REFERENCES al P < 0.0005), versus only 69% when behavior measures alone were 1. Owens J, Opipari L, Nobile C, Spirito A. Sleep and daytime behav- used (P < .10). Such results indicate that the fairly modest amounts of ior in children with obstructive sleep apnea and behavioral sleep sleep loss incurred in the current study were sufficient to induce neu- disorders. 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