Increasing Task Difficulty Facilitates the Cerebral Compensatory Response to
Total Sleep Deprivation
Sean P.A. Drummond, PhD1,2; Gregory G. Brown, PhD1,3,4; Jennifer S. Salamat, BS3; J. Christian Gillin, MD1,2
1Department
4Mental
of Psychiatry, University of California San Diego; 2Psychiatry and 3Psychology Services, Veterans Affairs San Diego Healthcare System;
Illness Research Education and Clinical Center, VISN-22
Study Objectives: To test the role of task difficulty in the cerebral compensatory response after total sleep deprivation (TSD).
Design: Subjects performed a modified version of Baddeley’s logical reasoning task while undergoing functional magnetic resonance imaging
twice: once after normal sleep and once following 35 hours of TSD. The
task was modified to parametrically manipulate task difficulty.
Setting: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center.
Patients or Participants: 16 young adults (7 women; mean age, 27.6 ±
6.1 years; education, 15.4 ± 1.8 years) were included in the final analyses.
Interventions: None
Measurements and Results: Behaviorally, subjects performed the same
after TSD as while well rested. Neuroimaging data revealed a linear
increase in cerebral response with a linear increase in task demands in
INTRODUCTION
RESEARCHERS HAVE LONG NOTED THAT PERFORMANCE ON
SOME COGNITIVE TASKS IS MORE VULNERABLE TO SLEEP
LOSS THAN IS PERFORMANCE ON OTHER TASKS. There is evidence from behavioral studies that task-related demands may affect this
vulnerability. While the authors have not always explicitly stated such,
evidence can been seen for this notion, for example, in tasks varying on
processing speed,1 test length,2 subject- versus experimenter-paced timing,3 and, more recently, cognitive domain assessed by the test.4
Functional neuroimaging techniques allow researchers to examine the
brain regions underlying performance of a cognitive task and ask if the
patterns of brain responses to various task demands change with sleep
loss.
While no published neuroimaging studies have investigated the vulnerability of neurocognitive function to sleep deprivation by systematically manipulating task demands within a given task, one can find evidence for task demand-related effects of sleep deprivation across tasks
and across studies. For example, Thomas et al5 found decreased glucose
metabolism following 24 hours of total sleep deprivation (TSD) during
performance of a difficult arithmetic working-memory task that required
sustained attention of about 30 minutes. On the other hand, Portas et al6
reported increased thalamic responses, as measured with functional
Disclosure Statement
This work was made possible by a grant from the American Sleep Medicine
Foundation, a foundation of the American Academy of Sleep Medicine, and
grants NIH GCRC RR00827 and NIMH T32 18399. There was no off-label or
investigational drug use in this study.
Submitted for publication July 2003
Accepted for publication December 2003
Address correspondence to: Sean P.A. Drummond, PhD, Department of
Psychiatry, 9116A UCSD / VASDHS, 3350 La Jolla Village DR, San Diego,
California 92161; Tel: (858) 642-1274; Fax: (858) 458-4201;
E-mail: [email protected]
SLEEP, Vol. 27, No. 3, 2004
several brain regions after normal sleep. Even stronger linear responses
were found after TSD in several brain regions, including bilateral inferior
parietal lobes, bilateral temporal cortex, and left inferior and dorsolateral
prefrontal cortex.
Conclusions: Task difficulty facilitates the cerebral compensatory
response observed following TSD. Compensation manifests as both new
regions that did not show significant responses to task demands in the
well-rested condition, as well as stronger responses within regions typically underlying task performance. The possible significance of these 2
types of responses should be explored further, as should the importance
of the parietal lobes for cognitive performance after TSD.
Citation: Drummond SPA; Brown GG; Salamat JS; Gillin JC. Increasing
task difficulty facilitates the cerebral compensatory response to total sleep
deprivation. SLEEP 2004;27(3):445-51.
magnetic resonance imaging (fMRI), during a much shorter attention
task following 24 hours of TSD. We recently reported the results from a
study utilizing fMRI to study the effects of 35 hours of TSD on brain
responses during performance of verbal-learning7 and arithmetic working-memory8 tasks. The verbal-learning task showed significantly
increased cerebral responses bilaterally in both the prefrontal cortex and
the parietal lobes following TSD. Arithmetic working memory, on the
other hand, was associated with decreased activation bilaterally in the
prefrontal cortex and parietal lobes after TSD.
Thus, it appears that the brain does not react uniformly to cognitive
demands following TSD. We have proposed a cognitive demand-specific hypothesis underlying the behavioral and cerebral responses to cognitive performance following TSD to help explain these differential
responses.9 This hypothesis suggests that specific demands associated
with a given cognitive task influence the cerebral response to that task
following TSD. Under certain cognitive demands, the brain may adaptively recruit additional resources not used in the normally rested state
to perform some cognitive tasks. This adaptation, or compensation, can
manifest either as spatially larger responses in brain regions activated in
the normally rested state or as recruitment of new brain regions not normally responsive to task performance.9 While it remains unclear which
specific task demands facilitate or inhibit increased cerebral responses
following TSD and where the functional limits of cerebral compensation
lie, the studies cited above suggest some possibilities. For example, one
task demand that may mediate differential results in the attention studies
reviewed above is time on task: the task that required long periods of
attention showed decreased thalamic activation and behavioral performance, while the shorter task showed increased thalamic activation and
intact performance.
One cognitive demand that may have mediated the differential brain
responses in our previous reports is task difficulty. Specifically, it may
be that the arithmetic task was sufficiently difficult to overwhelm the
adaptive compensatory process of the brain, while the verbal learning
task was not. It is tenuous to compare difficulty across different types of
cognitive tasks, though, because difficulty is confounded with differences in cognitive processes. A more appropriate way to examine diffi445 Cerebral Compensatory Response to Total Sleep Deprivation—Drummond et al
culty is to manipulate it within a single task. We do that here with
Baddeley’s Grammatical Transformations (also called logical reasoning)
task.10
This study examines brain responses and cognitive performance after
a normal night of sleep and following 35 hours of TSD using a modified
grammatical transformation task where we have parametrically manipulated task demands, and thus task difficulty, to produce 3 levels of the
task.11 To our knowledge, this study represents the first test of the limits
of cerebral compensation during TSD and the first to use functional neuroimaging techniques to test the interaction between the effect of TSD
and the effect of manipulating task demands within a single task (as
opposed to across tasks). Because our previous verbal learning and arithmetic working-memory tasks suggested that task difficulty may play a
role in the cerebral compensatory response, we directly test the role of
task difficulty here. Specifically, we tested 2 alternative hypotheses
regarding the role of task difficulty in the cerebral response following
TSD. First, there may be an upper limit to the brain’s ability to recruit
additional resources during TSD. That implies that the easier levels of
task difficulty here should elicit an increased response after TSD, while
the hardest level should inhibit a compensatory response. This would
manifest as an initial increase in activation, as task demands increase
slightly, followed by decreased activation at the hardest level of the task
(ie, a negative quadratic response). Alternatively, the compensatory
response may continue to increase as task difficulty increases. This
would be quantified as a regionally stronger linear response to increasing task demands following TSD compared to after normal sleep. The
main goal of this study, then, is to better understand the influence of task
difficulty in cerebral responses to TSD, thereby refining the cognitive
demand-specific hypothesis and, ultimately, to contribute to its ability to
predict cerebral and behavioral responses to sleep loss.
METHODS
Subjects and Conditions
A total of 21 right-handed subjects participated after providing written informed consent. One subject was dropped from the analysis due to
falling asleep in the MRI scanner during the TSD session, 1 subject did
not complete the task on 1 night because of technical difficulties, and 3
subjects are not included here because they were significantly older than
the remaining subjects and therefore may have introduced significant
variance in the data without providing the power necessary to examine
age effects. This report, then, includes 16 subjects (7 women; mean age:
27.6 ± 6.1 years; education: 15.4 ± 1.8 years). Subjects were healthy, as
established with a physical examination, routine laboratory tests, and
interviews covering medical and psychiatric histories. They all habitually maintained normal sleep schedules, obtaining 7 to 9 hours of sleep
each night sometime between the hours of 10:00 PM and 8:00 AM, and
followed their regular schedules during the study. Participants were studied with fMRI while performing a modified Baddeley’s Grammatical
Transformation Task at 2 time points: once approximately 12 hours after
awakening from a normal night of sleep and once at the same time of day
following 35.2 ± 0.7 hours of TSD. The order of the 2 nights was counterbalanced across subjects, and the nights were separated by 2 weeks.
Data from the normal sleep night of 14 subjects reported here were also
used in our previous report of cerebral responses to this task in the normally rested condition.11 Thus, this report focuses on sleep-deprivation
effects.
Task
This grammatical transformation task (also called logical reasoning)
is widely used in its original form in sleep and sleep-deprivation studies.
Traditionally, participants see a sentence describing the order of 2 letters
(eg, A precedes B) along with a letter pair (eg, AB) and judge the veracity of the sentence based on the letter pairs. We modified this task to (a)
adapt it to the fMRI environment and (b) parametrically manipulate the
SLEEP, Vol. 27, No. 3, 2004
difficulty of the task.11 Participants viewed a sentence describing the
order of 2, 3 (eg, A does not precede B does not follow C), or 4 letters
(eg, A precedes B follows C precedes D) (2LTR, 3LTR, & 4LTR) followed by a set of 2, 3 (eg, BCA), or 4 letters (eg, CABD), respectively.
Sentences and letter sets appeared separately. Subjects were instructed to
determine the proper order of the letters and respond either yes or no (via
a button box) during presentation of the letter set, depending on whether
the sentence correctly described the order of the letters. The probability
of any given sentence being correct was 0.50. The sentences used for
each difficulty level were matched for syntactic structure (eg, positive/negative, active/passive, precedes/follows) and veracity (true/false).
We developed 2 matched versions of the task and randomly assigned, for
each individual subject, the order in which the versions were administered. Pilot studies showed practice effects resolved, while preserving
the differential difficulty of sentence levels, after 4 administrations.
Therefore, each subject practiced the task 4 times prior to scanning.
These practice sessions each consisted of 1 administration of the task,
exactly as it was to be administered during the experimental sessions
(with the exception of the subjects sitting in a chair rather than lying on
an MRI table). Thus, subjects practiced both versions of the task twice
prior to the first experimental session with no additional practice
between experimental sessions. Subjects performed 1 of the task versions after normal sleep and the other after TSD, with the order counterbalanced.
fMRI Data Acquisition
All images were acquired with a Siemens 1.5T scanner. Functional
images consisted of 171 gradient echo EPI images (TR: 2.5s, TE: 35ms,
FOV: 256mm, 4 mm x 4 mm in-plane resolution) of 30 4-mm axial slices
covering the whole brain. Functional data were aligned with high-resolution anatomic images (MPRAGE: 1-mm3 resolution). The task alternated in a fixed format so that blocks of each sentence level (2LTR,
3LTR, 4LTR) were presented once every 3 blocks. Four blocks of each
sentence level were presented, for a total of 12 blocks. Each sentence
was presented for 8 seconds and each letter set for 2 seconds. Blocks
contained 3 sentences and so lasted for a total of 30 seconds.
Additionally, three 20-second fixation blocks were interspersed to allow
comparison of the 2-letter sentences to a baseline. With instructions, the
task lasted 427.5 seconds. Immediately following completion of the task,
while still in the fMRI scanner, subjects were administered the Stanford
and Karolinska Sleepiness Scales and 10-point Likert scale questions
assessing the following subjective aspects: task difficulty, ability to concentrate, effort required by the task, effort put into the task, and motivation to perform the task well.
Data Analysis
Accuracy across sentence levels was compared with repeated-measures analysis of variance (ANOVA)(with terms for night, task level, and
the interaction) and follow-up t tests with Bonferroni corrections to correct for the number of posthoc t tests. fMRI data were processed and
analyzed with AFNI12 in a 2-step procedure: individual time-course analysis followed by group statistical analysis. After motion coregistration,
individual time-course blood oxygen level-dependent (BOLD) signal
data were fit to a design matrix using the general linear model (GLM).
Parameters estimated from the design matrix represented the constant,
linear drift, 6 motion-correction parameters derived from the motioncoregistration step (3 relational and 3 translational movement directions), and the expected time course based on the behavioral paradigm
(ie, the reference functions). Two reference functions of interest were
included. One coded a positive linear association between sentence
level, excluding the baseline, and cerebral responses. The second coded
a negative quadratic brain response predicting increases in responses
between 2LTR and 3LTR but decreased responses between 3LTR and
4LTR. To account for the known delay in the hemodynamic response,
the reference function parameters included time shifts of 0.0, 2.5, and
446 Cerebral Compensatory Response to Total Sleep Deprivation—Drummond et al
5.0 seconds. The final parameters of interest for each reference function
were the BOLD response associated with the average of these 3 time
shifts.13 While the main questions of interest in this study concern brain
regions where activity is modulated by increasing task demands, this
task is typically only administered in its original 2LTR form. Therefore,
we conducted a separate time-series analysis comparing just BOLD
responses to the 2LTR sentences with BOLD responses to the baseline
fixation condition. This allows us to report the effects of TSD on cerebral responses to the more commonly used 2LTR sentences, although
these findings are not discussed extensively.
Prior to group analyses, individual data sets were then spatially
smoothed using a Gaussian filter of 4.0-mm, full-width, half-maximum
and transformed to standard atlas coordinates.14 To test the alternate
hypotheses regarding the role of task difficulty in the cerebral compensatory response, the main group-level analysis was a mixed-effects
ANOVA with Night (normal vs TSD) and Contrast (linear vs. quadratic)
as fixed effects and Subjects as a random effect. We previously reported
that, under well-rested conditions, the brain shows a significant linear
response to increasing difficulty of this task in a number of regions.11
Thus, if difficulty level facilitates cerebral compensation, we would
expect regionally stronger linear responses following TSD, while an
inhibition of compensation would result in areas showing a linear
response to task demands in the well-rested condition and a negative
quadratic response following TSD. A significant Night by Contrast interaction would suggest the latter. In brain regions not showing an interaction, we tested the main effect of TSD on the linear and quadratic
responses separately.
To protect against Type I error and correct for multiple comparisons
across voxels, cluster thresholding was used to determine significantly
activated regions.15 For the interaction and main-effects analyses, we
accepted only clusters consisting of at least 9 contiguous voxels (576
mm3), each of which was significant at the P = .01 level (1-sided
because our hypotheses concern specific directional changes). This
threshold protects the whole-brain α level such that the clusters we
report are equal to or larger than the single largest cluster of activation
expected anywhere in the brain by chance at α = 0.01. Follow-up tests
protected whole-brain α with Bonferroni corrections. Anatomic labels
listed for activated regions are based on the Talairach coordinate system.14
Finally, we were interested in exploring the relationship between
changes in brain responses and accuracy on the task. To explore this
issue, we determined for each subject the most difficult level of the task
on which he or she was at least 83% accurate (ie, at least 10 of 12 sentences correct) after TSD. Then, for each of the brain regions showing a
significant response to TSD (see Table 3), we correlated the magnitude
of the increased response after TSD with the highest task level completed with at least 83% accuracy. The reason for equating subjects on performance was to remove the effects of differential performance on brain
responses and ask whether any brain regions were related to the ability
to accurately perform more difficult versions of the task.16
RESULTS
Behavioral Results
For accuracy scores, there was not a night-by-task-level interaction
(F2,30 = 1.16, P = .327), nor a main effect of night (F1,15 = 0.053, P =
.821). There was a main effect of task level (F2,30 = 37.68, P < .001). The
task-level effect contained significant and orthogonal linear and quadratic components. Subjects performed progressively worse as sentences
became more complex, and the drop from 3LTR to 4LTR was greater
than the drop from 2LTR to 3LTR, but this pattern did not change with
TSD. Accuracy scores averaged across nights were (mean ± SD) 2LTR:
93.0% ± 10%; 3LTR: 85.7% ± 10.8%; and 4LTR: 68.2% ± 14.4%.
Subjective measures showed that subjects reported feeling more sleepy
following TSD but did not rate task demands differently on the 2 nights
(Table 1).
SLEEP, Vol. 27, No. 3, 2004
Imaging Results Following Normal Sleep
We have previously reported brain regions underlying performance of
this task in the well-rested state,11 and, not surprisingly, the findings here
from the normal sleep night are essentially identical (see Table 2). The
original 2LTR version of this task, the version commonly used in sleep
research studies, elicits activation primarily in bilateral posterior visualspatial working-memory and visual-processing regions and in rehearsal
and language-processing regions of the left hemisphere but not workingmemory regions in the prefrontal cortex. Parametrically increasing task
difficulty by increasing the complexity of the sentences engages several
subregions within the prefrontal cortex, as well as monotonically
increasing brain responses in the same regions responsive to 2LTR.
Table 1—Subjective Assessments of Task Performance
Question
Stanford Sleepiness Scale score*
Karolinska Sleepiness Scale score†
Ability to Concentrate (1-10)
Effort Required (1-10)
Effort Put In (1-10)
Task Difficulty (1-10)
Motivation to Perform Well (1-10)
Normal Sleep
Sleep Deprivation
2.4 ± 1.2
3.1 ± 1.8
7.4 ± 2.2
7.6 ± 1.9
8.1 ± 1.5
6.9 ± 2.0
8.1 ± 1.8
3.9 ± 1.4
6.1 ± 2.0
6.2 ± 1.6
7.2 ± 1.7
7.4 ± 1.8
6.4 ± 1.9
7.8 ± 1.8
Data are presented as mean ± SD
*P < .05
†P <.001
Table 2—Brain Regions Underlying Logical Reasoning Performance
after Normal Sleep Night
Anatomic Location
Frontal Operculum / Premotor Area
Medial Frontal Gyrus
Precentral Gyrus
Anterior Insula / Claustrum
Superior/Middle Temporal Gyri
Inferior/Superior Parietal Lobes
Inferior/Middle Occipital Gyri
Inferior Occipital Gyrus
2-Letter Sentences
Brodmann’s
Centorid
Area
Coordinates
L 44/45/6
M6
L 4/6
L 13
L 22/21
L 40/7
R 40/7
L 18/19
R 18/19
R 19
46L 2A 35S
3L 5P 52S
30L 10P 58S
29L 19A 8S
58L 33P 4S
39L 48P 44S
30R 54P 44S
33L 83P 4I
24R 90P 3S
38R 73P 5I
Linear Increase with Increasing Sentence Complexity
Anatomic Location
Middle Frontal Gyrus
Inferior Frontal Gyrus/Middle
Frontal Gyrus/Premotor Area
Brodmann’s
Area
Centorid
Coordinates
L 46
43L 40A 17S
L 44/45/46/9/6
R 45/46/9/6
M 32/6 (R>L)
R 44
R6
L 1/2
L 37/20
38L 3A 40S
43R 11A 30S
0R 14A 44S
41R 12A 12S
26R 3P 55S
56L 19P 32S
45L 43P 8I
Anterior Cingulate/Medial Frontal Gyrus
Inferior Frontal Gyrus
Premotor Area
Postcentral Gyrus
Inferior Temporal Gyrus
Superior Parietal Lobe/Inferior Parietal
Lobe/Precuneus/Superior Occipital Gyrus/
Middle Occipital Gyrus/Inferior Occipital
Gyrus/Lingual Gyrus
B 7/39/40/18/19
(covers all areas in both hemispheres)
Caudate / medial Putamen
R
Ventral Thalamic Nuclei
Overlapping with Putamen
L
Overlapping with Pulvinar N
R
1L 72P 20S
15R 4A 9S
16L 2P 10S
7R 22P 3S
Clusters shown survived our cluster threshold α protection procedure.
Anatomic locations and Brodmann’s areas list every region covered by a given cluster. This
does not imply all portions of a listed region were covered.
Brodmann’s Area: L refers to left; R, right; M, medial; B, bilateral (1 cluster covered
regions within both hemispheres)
447 Cerebral Compensatory Response to Total Sleep Deprivation—Drummond et al
Quadratic Versus Linear Brain Response Following TSD
During performance of the 2LTR sentences, TSD elicited increased
activation (relative to the well-rested condition) within the left-hemisphere semantic (inferior frontal gyrus) and auditory-processing (superior temporal gyrus) and the posterior visual-processing regions (left
fusiform gyrus, precuneus, and medial visual cortex). The only “executive function” region showing increased activation following TSD was a
small portion of the inferior frontal gyrus overlapping with Brodmann’s
area 46.
The main analyses of interest in this report, however, are those that
identify changes in the brain’s response to task demands following TSD.
The initial analysis of these TSD effects aimed to identify if any brain
region showing a linear response to task demands in the well-rested state
showed a negative quadratic response following TSD. This did not occur
for any region reported in Table 2. Moreover, in a whole-brain analysis
not restricted to the regions activated after the normal-sleep night, no
area in the brain showed the negative quadratic response hypothesized to
provide evidence for task difficulty inhibiting the cerebral compensatory response.
On the other hand, a number of regions showed a stronger linear
response to increasing task difficulty following TSD compared to their
responses following normal sleep (Figure 2), providing evidence that
task difficulty facilitates the cerebral compensatory response. As with
previous reports on different cognitive tasks,7,17 we found both new
regions responding to task demands following TSD, as well as stronger
responses in the same regions that responded in the well-rested state
(Table 3). Specifically, following TSD, increasing task demands elicited
new responses in regions, including the left anterior cingulate, bilateral
temporal cortex, and bilaterally at the junction of the superior temporal
gyrus and inferior parietal lobes (ie, Wernicke’s area and its right-hemisphere homologue). These regions were not significantly responsive to
Table 3—Regions Showing a Stronger Linear Response to Increasing
Task Demands Following Total Sleep Deprivation Compared to After
Normal Sleep
Anatomic Location
Inferior Frontal Gyrus
Middle Frontal Gyrus
Brodmann’s
Area
Centorid
Coordinates
Maximum
Effect Size
(Cohen’s d)
Number
of voxels
L 44
L 46
L 46
52L 11A 14S
28L 45A 7S
39L 40A 7S
0.80
0.92
1.04
9
9
12
8L 33A 34S
0.98
27
40R 16A 2I
15L 14A 48S
14L 5A 20S
29L 11A 4S
27R 14A 4S
0.77
0.93
1.13
0.82
0.76
20
9
63
14
12
56L 33P 2I
50R 29P 4S
49R 17P 39S
19L 18P 47S
0.83
0.99
0.88
1.19
20
9
10
16
50L 52P 22S
43R 44P 30S
46L 49P 40S
38R 47P 43S
54R 36P 46S
1.05
0.99
1.24
0.98
1.11
28
45
61
9
13
Anterior Cingulate /
Superior Frontal Gyrus
L 32/8
Anterior Insula /
Inferior Frontal Gyrus
R 13/47
Medial/Superior Frontal Gyri
L6
Caudate / Putamen
L
Claustrum / Lateral Putamen
L
R
Superior/Middle
Temporal Gyri
L 22/21
R 22/21
Postcentral Lobule
R
Posterior Cingulate
L 31
Inferior Parietal /
Superior Temporal Lobes
L 39/40/22
R 40/22
Inferior Parietal Lobe
L 40
R 40
R 40
Clusters shown survived our cluster threshold α protection procedure.
Anatomic locations and Brodmann’s areas list every region covered by a given cluster. This
does not imply all portions of a listed region were covered.
Brodmann’s Area: L refers to left; R, right.
Cohen’s d can be interpreted here as it is in behavioral studies. Specifically, it represents
the magnitude of the difference between the response on the total sleep deprivation (TSD)
night and that on the normal night, scaled by the variability of that difference across subjects.
Bold = New activations after TSD. These regions did not show a significant response to
increasing task demands following a normal night of sleep but did show a significant
response following TSD. All other regions did show a significant response to increasing
task demands following a normal night of sleep, and an even stronger response after TSD.
SLEEP, Vol. 27, No. 3, 2004
increasing task demands in the well-rested state. Among the regions that
did show a significant response to task demands after normal sleep and
an even stronger response following TSD were the bilateral inferior parietal lobes, left inferior frontal gyrus, and left dorsolateral prefrontal cortex.
Relationship Between Changes in Brain Responses and Performance
Two brain regions showing a significant response to TSD also significantly correlated with the ability to accurately perform more difficult
versions of the task. These areas were both within the right inferior parietal lobe (r = 0.573, P = .02 for the more anterior cluster and r = 0.541,
P = .03 for the more posterior cluster).
DISCUSSION
Here we report the effects of task difficulty on the cerebral compensatory response following 35 hours of TSD. Task difficulty was manipulated by parametrically increasing the demands of a grammatical transformation task, often called logical reasoning. We tested whether task
difficulty inhibits or facilitates recruitment of additional cognitive
resources following TSD. Results showed that increasing task demands
facilitate the brain’s BOLD response following TSD. As the task became
more difficult, the associated BOLD response following TSD became
stronger. Thus, this study extends previous findings by showing that one
cognitive demand interacting with the cerebral response to TSD is task
difficulty. Furthermore, it suggests that the hardest versions of a task,
more so than the easiest versions, are the ones that elicit a cerebral compensatory response.
As with previous reports,7,17 the cerebral compensation found here
occurred within regions that normally underlie task performance, as well
as new brain regions not typically used during performance in the normally rested state. For example, cerebral responses within the bilateral
inferior parietal lobes and the language region of left inferior frontal
gyrus were modulated by task difficulty in the normally rested state and
Figure 1—Potential Cerebral Responses Contrasted in the fMRI Analyses. This figure
depicts idealized forms of the 2 potential cerebral responses to increasing task demands that
we contrasted in the main functional magnetic resonance imaging (fMRI) analysis. In the
linear response, a given brain region would show greater activation in tasks requiring 3 letters (3LTR) compared to 2 letters (2LTR) and in tasks with 4 letters (4 LTR) compared to
3LTR. In the negative quadratic response, a given brain region would show greater activation in 3LTR compared to 2LTR, but activation would decrease again during 4LTR. If a
region shows a steeper linear slope (ie, a significantly larger parameter estimate in the fMRI
time-series analysis) after total sleep deprivation (TSD) compared to after normal sleep, that
is evidence for difficulty facilitating a cerebral compensatory response. If a region shows a
linear response after normal sleep but a negative quadratic response after TSD, that would
suggest that difficulty inhibits a cerebral compensatory response after TSD.
448 Cerebral Compensatory Response to Total Sleep Deprivation—Drummond et al
showed an even stronger modulation following TSD. Language-processing regions within left temporal lobes and their right-hemisphere
homologues, on the other hand, only responded to increasing task difficulty after TSD. Stern16 recently proposed a tentative model distinguishing between cognitive reserve and compensation that, while focusing on
brain damage and Alzheimer disease, may provide a useful framework
for understanding the brain’s reaction to TSD. In that model, greater
responses on the part of patients within brain regions normally underlying task performance were characterized as reflecting cognitive reserve.
The term compensation is then specifically applied to the use of alternative cerebral networks by patients, compared to healthy adults, when
performing the same task. Under such a schema, regions showing a pattern of response as seen in Figure 3a-b would reflect cognitive reserve.
That is, while these regions increase their activation in response to task
difficulty after normal sleep, individuals use them efficiently enough
that there are more resources left to draw upon following TSD. Those
regions showing a pattern more like Figure 3c-d would then reflect cerebral compensation. That is, these regions are not typically used by wellrested subjects but are recruited to aid performance only during a cognitive stress such as TSD. The entries in boldface type in Table 3 show the
latter pattern while those entries in normal type show the former. This
possible distinction in the brain’s response to cognitive challenges following TSD should be studied further, though.
Performance on each level of this task did not change with TSD. This
suggests that the compensatory responses reported here (whether reflecting “cognitive reserve” or “cerebral compensation”) allowed subjects to
maintain normal performance despite having not slept for 35 hours.
While average performances did not change with TSD, we did find, as
would be expected, individual variability in the response to TSD, particularly on the harder versions of the task. Given this and the fact that,
overall, task difficulty seems to facilitate a compensatory response, it is
reasonable to ask if modulation within any specific brain region or
regions after TSD is associated with the ability to accurately solve the
more difficult versions of this task. We found that subjects who were
able to successfully complete the hardest level of the task (ie, 4LTR) had
stronger compensatory responses in both right inferior parietal lobe clusters than did subjects who could only accurately complete easier versions of the task. This suggests that the ability to modulate activity within these spatial-processing regions after TSD to match increasing task
difficulty is important for success on this task. A correlation between
post-TSD performance and responses within the parietal lobes is also
consistent with 2 of our previous reports on tasks unrelated to the 1
reported here.7,17 Thus, while much debate has focused on the vulnerability or lack thereof of frontal regions to TSD,9,18-21 our data suggest that
more focus should be placed on the parietal lobes and their role in overcoming the detrimental effects of sleep loss.
One may speculate that the effect of acute TSD is to simply make any
given level of this (or any other) task harder, essentially equivalent to
performing a more difficult version while well rested. For example, this
argument would say that after TSD, 2LTR sentences were simply equal
in cognitive demand to the 3LTR sentences after normal sleep, and that
is why we saw increased activation following TSD. We do not believe
this is the case. First, the areas reported here are those that showed
greater and greater responses as the task became harder and harder (ie,
we tested the slope of the regression). If the difficulty “starting point” of
the task (ie, the intercept of the regression) simply increased after TSD,
but the relationship among task levels (ie, the slope) was the same, our
analyses would not have revealed changes with TSD. Second, subjects
did not report an increase in subjective task difficulty or effort associated with the task following TSD. Third, as discussed above, average performance did not change significantly for any task level following TSD.
It is also not likely the case that the task simply required more attentional
resources following TSD. We did not find significantly increased
responses in right-hemisphere sustained-attention regions of the superior parietal lobes and prefrontal cortex or within arousal-related regions
of the thalamus following TSD.
What cognitive processes, then, may account for increased cerebral
responses after TSD? Increases were found in a left temporal lobe language-processing region as well as the right-hemisphere homologue of
this region. Subjects all reported using “repetition” as a strategy on both
Figure 2—Brain Regions Showing Increased Linear Responses to Task Demands Following Total Sleep Deprivation. Picture depicts the anatomic image averaged across all subjects as an
underlay and the results of the main effect of total sleep deprivation (TSD) on the linear response to increasing task demands as the overlay. Functional data are color-coded per voxel by the
effect size, Cohen’s d, associated with the increased linear response following TSD compared to normal sleep. Only those voxels surviving our cluster threshold α protection method are
shown. Each 3-dimensional brain image has 2 slices removed. Left image: 53 mm left and 45 mm superior of the anterior commisure-posterior commisure line (AC-PC). Right image: 44
mm right and 32 mm superior of the AC-PC line.
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449 Cerebral Compensatory Response to Total Sleep Deprivation—Drummond et al
nights to hold onto answers between solving the sentences and needing
to respond. These increased temporal responses, along with stronger
responses in left inferior frontal gyrus, suggest that this rehearsal may
have required more resources after TSD. A second process that may have
influenced post-TSD responses is cognitive slowing.2 Due to the design
of the experiment, we only collected response times during the “answer”
portion of the task. Given that this represents only 20% of each trial
length, our ability to fully evaluate cognitive slowing is limited.
Nonetheless, examination of those data may suggest possibilities. TSD
did not lead to a significant increase in response times for any individual sentence level (all P > .05). However, a trend analysis (parallel to the
analysis done with the fMRI data) revealed that while subjects had progressively slower reaction times with increasing sentence complexity on
both nights, the slope of this change was greater after TSD (P = .023).
Additionally, there was an increase in the number of nonresponses to the
4LTR sentences after TSD (P = .005), raising the possibility that some
of these responses may have actually occurred during presentation of the
subsequent sentence. Bilateral inferior parietal lobe regions, similar to
those showing stronger responses after TSD here, have been reported to
correlate with increased response times on a working-memory task.22
Therefore, it is possible that some of the increased parietal activation we
observed after TSD was related to an increase in processing time, particularly of the more complex sentences. Other parietal responses may
have related to the spatial nature of this task.11 A final set of interesting
regions to show significantly increased responses following TSD are the
junctions of the superior temporal and inferior parietal lobes in both
hemispheres. These regions are heteromodal association regions23 and
may have been involved in integrating language-based and spatial-based
processing after TSD.
Thus, it does not appear to us that cognitive tasks simply become
harder or require more attention after TSD. Rather, there seems to be a
more complex process whereby cerebral mechanisms recruited to perform a task are altered by TSD. The data presented here allow us to
extend our previous reports to suggest now that cerebral compensation
is elicited by at least 1 specific cognitive demand: increasing task difficulty. This fact suggests the reason we previously reported a compensatory response for a verbal-learning task, but not an arithmetic workingmemory task, was not because the latter was harder than the former.
Thus, that difference must be related to another task demand. We should
note, though, that even though we did not find a negative quadratic brain
response in these data, there may still exist some extreme level of task
difficulty that would indeed inhibit brain responses. At the very least,
one might expect an eventual leveling off of brain responses as the limit
for cognitive-resource recruitment is reached. Additionally, it is worth
noting that the interaction we report can be interpreted in the opposite
direction than what we emphasize here. Rather than concluding that task
Figure 3—Two Patterns of Increased Response after Total Sleep Deprivation. These graphs show examples of the 2 basic patterns observed within brain regions showing a greater response
to increasing task demands following total sleep deprivation (TSD) compared to after normal sleep. Each graph depicts one of the clusters reported in Table 3. Values are mean ± SEM. For
3a and 3b, each functional region showed a significant linear response to task demands after normal sleep. For 3a, this region showed a spatially larger response following TSD, such that the
voxels contained in the functional subregion depicted were not among those showing a significant linear response with normal sleep. Rather, voxels neighboring those shown here were significantly activated after both normal sleep and TSD. However, the region activated after TSD was spatially larger, and the voxels graphed here are those that represent this increased spatial
extent. For 3b, this region showed a stronger (ie, greater magnitude) linear response after TSD within the same voxels that showed a significant response after normal sleep. Graphs 3a and
3b may be characterized as reflecting cognitive reserve. The functional regions depicted in 3c and 3d did not show a significant response to increasing difficulty after normal sleep but did
show a significant linear response after TSD. This type of response may be characterized as reflecting cerebral compensation. 2LTR refers to the 2-letter task; 3LTR, the 3-letter task; 4LTR,
the 4-letter task.
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450 Cerebral Compensatory Response to Total Sleep Deprivation—Drummond et al
difficulty influences the effects of TSD that we and others have previously reported,6,7,17 one could conclude that TSD influences the previously established effects of increasing task difficulty on cerebral
responses (ie, it facilitates regional cerebral responses to increasing task
demands). This direction of interpretation may hold particular relevance
for cognitive neuroscientists. While it is rarely stated in manuscripts, it
is not uncommon for functional neuroimaging studies to be conducted
during off hours on clinical scanners. While the subjects in these studies
were probably not completely sleep deprived, it is likely that some published studies include some confounds of sleep loss in the results.
Finally, this study illustrates a basic discrepancy in the overall literature on functional neuroimaging of TSD in healthy adults. The only 2
positron emission tomography (PET) studies measuring glucose
metabolism each reported regionally decreased activation after TSD,5,24
while 4 of 5 papers (including the current 1) report regional increases in
BOLD fMRI signal.6-8,17 All of these studies used 24 to 36 hours of TSD,
so length of sleep loss is unlikely to explain the results. It is possible that
differences in cognitive demands associated with the various tasks
employed may play a role in the different results. Long tasks (ie, in the
PET studies) are more likely to show decreased cerebral responses after
TSD than are short tasks (ie, in the fMRI studies). Additionally, working-memory tasks5,8 are more likely to show decreases with TSD than
are tasks with a language-processing component,7,17 while attention
tasks have given mixed results.6,24
Another possibility, however, has to do with the physiologic processes measured by the different technologies. The PET studies both measured glucose metabolism. Consistent with the PET neuroimaging studies, Van Cauter’s group has recently reported several sets of findings
suggesting that glucose metabolism throughout the body is disrupted by
sleep deprivation.25,26 The BOLD fMRI signal is based on cerebral blood
flow, cerebral blood volume, and oxygen utilization but not glucose
metabolism.27-29 Neural activity leads to an increase in cerebral blood
flow and cerebral blood volume but less of an increase in oxygen utilization. The excess oxygen in the venous system produces an increase
in the BOLD signal. Therefore, it is possible that increased neural activity after TSD could lead to an increase in the BOLD signal despite a drop
in glucose metabolism, especially if cells could get the required energy
from glycogen or some other source. At this point, this explanation is
necessarily speculative. What we strongly need in the field are studies
examining cerebral blood flow and oxygen metabolism following TSD,
particularly during cognitive testing. Such studies would tell us whether
the basal levels of the physiologic factors underlying the BOLD signal
are altered by TSD and would thereby provide greater context for interpreting the results of BOLD fMRI studies. These studies have not been
done, to our knowledge.
In summary, this study was an initial test of the limits of the cerebral
compensatory response during TSD. We examined the cerebral response
to parametrically manipulated difficulty levels on Baddeley’s
Grammatical Transformation Task. These data suggest that increasing
task difficulty facilitates the recruitment of additional cognitive
resources following TSD. As with previous reports, stronger responses
within the inferior parietal lobes were associated with increased cognitive performance (here, in the right hemisphere only). It may be useful
to start conceptualizing the cognitive and cerebral response to TSD as
reflecting 2 related phenomena, cognitive reserve and cerebral compensation, although these ideas require further refinement. Finally, it is
worth noting that, as with previous reports,7,17 regions reported here as
showing TSD-related increases in activation occur in homologous
regions in both hemispheres. This is not unlike the compensatory
responses seen in healthy elderly,30,31 as well as in patients with earlystage Alzheimer disease.16 Future studies should examine both the
demands of specific cognitive tasks (eg, spatial vs verbal tasks) and the
characteristics of the individuals performing those tasks (eg, age and
education) to better predict whether and where a compensatory response
will occur with TSD. Specific to this task, future studies could focus on
differences among sentence types (eg, positive vs negative, true vs false,
active vs passive) within a single sentence level (eg, only with 2LTR or
SLEEP, Vol. 27, No. 3, 2004
3LTR). This would perhaps be a more refined way to examine difficulty
levels without necessarily increasing the perceptual-processing requirements or the number of cognitive processes involved, as is done when
one compares across sentence levels.
ACKNOWLEDGEMENTS
We would like to thank Allen Kushinsky and Carina Lopez for invaluable assistance in recruiting, screening, and running the subjects in this
study. We would also like to thank the staff of the UCSD General
Clinical Research Center for their hard work and efforts in conducting
the overnight portions of this study.
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