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REVIEW ARTICLE
J Korean Sleep Res Soc 2013;10:1-6
Imaging the Sleep Deprived Brain: A Brief Review
Michael WL Chee, MBBS, FRCP (Edin)
Neuroscience and Behavioral Disorders Program, Duke-NUS Graduate Medical School, Singapore
Key Words: fMRI, Cognitive tasks, Attention, Default mode network, Sleep deprivation.
the subject may have been asleep.8 The evaluation of functional connectivity, conducted by as- Functional magnetic resonance imaging (fMRI) is a highly sessing signal covariation in pairs of regions, or by determin- versatile tool used to study neurobehavioral alterations asso- ing the extent to which signal in a ‘target' region interacts with ciated with sleep deprivation (SD). Task-related fMRI is the that of a ‘seed' region according to state/task context provides most widely used technique and an impressive list of cogni- additional characterization of altered physiology. The latter tive domains has been evaluated using this technique (Table method, known as psychophysiological Interaction-PPI has 1).1-40 fMRI measures relative change in blood oxygenation been applied in studies evaluating selective attention,12,45,46 the level dependant (BOLD) signal in capil aries and venules ad- processing of emotional pictures as wel as executive func- jacent to neuronal clusters whose firing rate and consequ- ently, synaptic potentials are modulated by task performance. In addition to fMRI studies designed to evaluate signal An increase in MR signal occurs as a result of a relatively dis- changes in response to task performance, it may be informa- proportionate elevation in blood flow relative to oxygen con- tive to evaluate ‘resting-state' activity or intrinsic functional sumption in response to sensory stimulation and/or task per- connectivity.47,48 This refers to the identification of regions sh- formance. In addition to task-related activation, the evaluation owing synchronous low frequency oscil ations (0.1-0.01 Hz) of task-related deactivation where signal changes fal below in BOLD signal that are not time locked to task performance baseline levels can be evaluated.1,18,25,30,41 or sensory stimulation. Studies of this type in sleeping indivi- Blood oxygenation level dependant imaging measures rel- duals have shown changes in connectivity within the default ative changes in blood flow, but does not ascertain absolute mode network (DMN) al uded to earlier.49,50 The first study blood flow. Quantification of blood flow may occasional y be evaluating resting state networks in the setting of SD found useful, for example, to study time-on-task effects,42 and other selective reductions in DMN functional connectivity and re- phenomena whose observation requires signal stability over duced anti-correlation with low frequency oscil ations in the several minutes as opposed to several seconds. Such measure- ‘task-positive' network (Fig. 1).18 Analyses of resting state ments can be obtained using a variety of arterial spin labeling data hold promise of being informative of alterations in brain (ASL) techniques that have different levels of precision.43,44 A function without requiring motivated performance on the part disadvantage of ASL is its inferior signal to noise ratio rela- of a participant.51 Related to functional connectivity, MRI in tive to BOLD imaging. Additional y, the requirement for bl- the form of diffusion tensor imaging (DTI) can be used to ock sampling also makes it impossible to perform event-re- evaluate white matter connectivity. Strangely, only one study lated designs that are important in separating out trials where to date has used DTI to study sleep deprived individuals.52 Combining electroencephalography (EEG) and fMRI in SD Received June 12, 2013
Revised June 18, 2013
or sleep related studies is primarily motivated by the need to Accepted June 18, 2013
monitor sleep stage although the high temporal resolution of Address for correspondence
EEG is also wel suited to study transient phenomena like Michael WL Chee, MBBS, FRCP (Edin) Neuroscience and Behavioral Disorders Program, Duke-NUS Graduate Med- lapsing.53 The neural correlates of spindles and slow waves have ical School, 8 College Rd, #06-18, Singapore 169857, Singapore been studied using this technique.54-56 In addition, fMRI guid- Tel: +65 65164916, Fax: +65 62218625 ed repetitive transcranial magnetic stimulation has been used Copyright 2013 Korean Sleep Research Society 1
Imaging the Sleep Deprived Brain Table 1. fMRI studies involving sleep deprivation
Cognitive domain
Bel -McGinty et al.22 Habeck et al.57Chee and Choo1 Choo et al.2Caldwel et al.24 Mu et al.27Chee et al.4 Thomas and Kwong39Lim et al.6 No main effect of state Vandewal e et al.35 Attention (sustained or divided) Sig. main effect of state on functional Drummond et al.25Chee et al.8 Fig. 1. Main ef ect of state on default mode network (DMN) func-
tional connectivity. Schematic showing a significant main ef ect of state on DMN functional connectivity between 3 node pairs using a Attention (selective) seed based analysis; left inferior parietal lobe (LIPL) and dorsal medial prefrontal cortex (dMPFC), LIPL and ventromedial prefron- tal cortex (vMPFC), and LIPL and posterior cingulate cortex (PCC; Bonferroni corrected p<0.05/21=0.002). Adapted from De Havas JA, Parimal S, Soon CS, Chee MW. Neuroimage 2012;59:1745- 1751.18 LLTC: left lateral temporal cortex, RLTC: right lateral tem- poral cortex, RIPL: right inferior parietal lobe.
domain engaged and task difficulty might affect neural resp- onse to SD.21 This motivated subsequent studies probing wo- rking memory to examine the effect of manipulating task dif- Visual short-term memory ficulty and/or item load.1,2,57 Although the specific areas most affected by SD differ somewhat across these studies, a com- Logical reasoning Drummond et al.23 mon set of findings concerns the decrease in higher visual cor- Inhibition (Go/No-Go) tex and fronto-parietal activation when performance declined Risky decision making Venkatraman et al.7 during SD. In contrast, activation is relatively preserved when Venkatraman et al.17 performance is maintained. The notion that increased task Emotional Processing difficulty might elicit ‘compensatory' frontal activation was Sterpenich et al.61 then independently demonstrated in a study evaluating logical As experience in fMRI cumulated with studies that recruit- Drummond et al.20 ed at least 20 subjects, it became evident that inter-individual Verbal episodic memory differences in response to SD could be identified reliably using imaging. A few studies suggested that a single imaging study Default mode/Resting state conducted in the rested state might predict vulnerability to De Havas et al.18 performance decline in the tested domain whereas later stud- ies found that a shift in activation across state may be more to evaluate the therapeutic potential of transcranial magnetic reliable as a marker of inter-individual differences in perfor- stimulation in al eviating SD.28 mance when sleep deprived.4,9,11,24,26 A wealth of behavioral data col ected on behavior in sleep Effects of Task Difficulty, Cognitive Domain
deprived persons suggests the loss of vigilance or sustained at- Tested and Inter-Individual Differences
tention to be the most prominent deficit encountered in SD.14 The failure of attention and the possible maladaptive conse- The results of behavioral studies suggested that cognitive quences of endogenous efforts to sustain wakefulness in the face of mounting sleep pressure has been a central idea. A cog- higher or lower than during rested wakefulness depending ent il ustration of the vital role played by at ention in support- on whether the sleep deprived volunteer is performing adequ- ing cognitive performance comes from an experiment origi- ately or lapsing.8,37 nal y designed to evaluate visual working memory capacity in SD.5 Participants in this study were briefly shown an array of colored squares and seconds later had to verify if the test item was of a color shown in the array. The number of differ- A majority of persons show decline in cognitive perform- ently colored squares shown varied from 1 to 8 squares. The ance after 24 h of SD. fMRI has been used to track the efficacy key finding was that during SD, even when memory capacity of countermeasures against, for example, to evaluate the effect and perceptual load were not taxed, task-related activation in of modafinil,39 and donepezil.9,10 In these studies, the effect of brain regions mediating top-down control of at ention and vi- drug in the wel -rested state was negligible but was evident in sual perception in extrastriate visual cortex was significantly the sleep-deprived state in some volunteers. In the donepezil diminished (Fig. 2). trials, improvement was positively correlated with the magni- This indicated that a more global curtailment of process- tude of performance decline when undergoing SD on placebo ing resources rather than storage limitation was problematic. in both short-term memory and episodic memory experi- As both working memory and attention are intertwined pro- ments in the same subjects. The smal er trial involving mo- cesses and engage similar cortical and subcortical areas,58,59 dafanil evidenced increases in both cortical and subcortical the parametric variation of visual memory and visual item activation in volunteers sleep deprived on modafanil. load across multiple levels in two paral el sets of scans were Repetitive transcranial magnetic stimulation has been re- instrumental in proving the point. ported to improve verbal working memory in sleep deprived Other studies probing the effects of SD on selective atten- volunteers when applied to the right ‘upper middle occipital' tion used visual tracking or visual picture selection paradi- region that was part of the network associated with SD in- gms.12,37,46 They arrived at convergent observations regarding duced performance impairment.28 Improvement correlated the at enuation of top-down control of at ention together with with the extent to which performance declined during SD in diminished engagement of the visual extrastriate cortex. To- sham stimulations. In contrast no benefit was observed when gether with deficits in responding to stimuli, attenuated acti- stimulating the midline parietal region, part of a network of vation of fronto-parietal and visual extrastriate cortex also areas showing reduced task-related activation in SD, or when occurs in the preparatory period prior to stimulus appearance.15 the lower left middle occipital gyrus which was not part this In comparison to its effects on cortical activation the effects network.
of SD on subcortical activation are more complex. For exam- ple, the thalamus, which plays an important role in mediat- Affective Aspects of Behavior-Emotional
ing arousal and attention, shows decreased glucose metabo- Processing and Decision-Making
lism during SD if measurement is averaged over several mi- nutes.60 However, for individual events, activation can either be Most of the tasks used in experimental studies engage a fr- Visual short term memory task Item load control Number of items to be remembered Fig. 2. Deficits in at ention underlie functional imaging changes when visual short-term memory is tested in the sleep-deprived state. Task-
related activation of the intraparietal sulcus increases with memory load--but not visual item load when memory is not engaged--in both rest- ed wakefulness (RW) and sleep deprivation (SD). In the sleep-deprived state, even when visual short-term memory is not taxed (e.g., low test item load or no load on memory), decrements in activation are observed. This implicates a fundamental deficit in at ention rather than one of storage capacity or memory. Adapted from Chee MW, Chuah YM. Proc Natl Acad Sci U S A 2007;104:9487-9492.5 www.sleepnet.or.kr 3
Imaging the Sleep Deprived Brain signal change 0.2 Neutral Emotional Corrected recognition (SD-RW) Fig. 3. Right amygdala activity was elevated in response to emotional distracters relative to neutral distracters at rested wakefulness (RW).
A state (rested wakefulness, sleep deprivation) by Condition (Neutral, Emotional) repeated-measures ANOVA conducted on averaged acti- vation within this region of interest indicated marginal decreases in amygdala activation fol owing sleep deprivation. Critical y, state-related change in amygdala activation correlated with the corresponding alteration of emotional distractibility while no paral el ef ect was present for neutral distracters. Adapted from Chuah LY, Dolcos F, Chen AK, Zheng H, Parimal S, Chee MW. Sleep 2010;33:1305-1313.13 BOLD: blood oxygenation level dependant.
onto-parietal network involved in the control of at ention and related to enhanced hippocampal to medial frontal and hip- do not evaluate affective changes that constitute an important pocampal to orbitofrontal connectivity in the SD state. aspect of behavioral alteration in SD. Brain structures involved in affective processing include the amygdala, striatum, ven- Opportunities for Research
tromedial prefrontal cortex and the insula. These structures can be expected to show altered activation if a state-related ch- A critical gap in our current knowledge of the mechanisms ange in affect is present.
underpinning altered behavior in SD lies in the piecemeal In one study, where participants graded the emotionality of use of functional imaging in this state whereby a single cogni- faces, SD enhanced amygdala responses to negative pictures.29 tive domain is tested at a time. Behavioral studies show that Accompanying this change was reduced functional connec- SD may affect performance unevenly across different cognitive tivity between the medial prefrontal cortex and amygdala (Fig. domains.62,63 It remains a open chal enge to execute within- 3). In a second study,13 volunteers remembered neutral faces subject studies involving multiple, sensitive, short-duration, over a brief interval during which distracter pictures were pre- tasks that probe dissociable cognitive domains.64 sented. The distractors could be neutral, negative emotional While total SD is convenient to study in a laboratory set ing, or noise patterns. Amygdala activation during the mainten- most persons encounter the effects of sleep loss through ch- ance period was higher for emotional distracters than neutral ronic sleep restriction and sleep fragmentation.65 Partial SD distracters in both states although maintenance activity was studies where sleep is restricted to between 3-6 hours of time overal , lower in the SD state for both conditions (Fig. 3). Face in bed per night suggest that the relationship between hours of memoranda were less wel maintained in working memory sleep and cognition is not linear.66,67 The rate of build up of to the extent that SD reduced functional connectivity between slow wave activity during sustained wakefulness and its dis- ventromedial and dorsolateral frontal areas and the amygda- sipation fol owing recovery sleep also does not correspond wel la.13 Responses to emotional stimuli during SD can thus be with behavioral performance alteration suggesting that dif- perturbed by disrupting the transmission of top-down control ferent measures provide independent information regarding signals from regions involved in valuation and/or cognitive changes occurring in SD. It remains of interest to study how control. In one experiment, negative stimuli were better rec- functional imaging changes evolve during partial SD-such ognized after SD than neutral or positive stimuli. The recol- studies can provide new understanding of compensatory brain lection of negative and positive stimuli was correlated with network dynamics during the process of chronic partial sleep greater functional connectivity between medial frontal re- gions and the hippocampus when subjects had a normal night Imaging genomics seeks to identify genes that influence of sleep compared to when they were sleep-deprived.61 brain, cognition and risk for disease. For example, the candi- In another experiment, the bias towards processing emo- date gene approach was applied to study the effect of Per 35/5 tional stimuli over neutral ones was extended to positive sti- on n-back task performance in subjects undergoing total SD. muli. SD also caused volunteers to increase the number of Widespread relative reductions in task related activation were neutral pictures that were rated positively.32 This finding was found in frontal, parietal and occipital regions in this vulner- able group when they were sleep deprived.35 The intriguing effects on object-selective attention. Neuroimage 2010;49:1903-1910.
behavioral results were not replicated when a different set of 13. Chuah LY, Dolcos F, Chen AK, Zheng H, Parimal S, Chee MW. Sleep deprivation and interference by emotional distracters. Sleep 2010;33: sleep restricted (not total SD) subjects were studied leaving room for future studies to clarify.68 14. Lim J, Dinges DF. A meta-analysis of the impact of short-term sleep Sleep deprivation provides a unique opportunity to perturb deprivation on cognitive variables. Psychol Bul 2010;136:375-389.
brain networks of healthy individuals in a manner that degr- 15. Chee MW, Goh CS, Namburi P, Parimal S, Seidl KN, Kastner S. Effects of sleep deprivation on cortical activation during directed at ention in the ades performance in a reversible manner. Several similarities absence and presence of visual stimuli. Neuroimage 2011;58:595-604.
between the behavioral deficits in SD and cognitive aging have 16. Kong D, Soon CS, Chee MW. Reduced visual processing capacity in been highlighted.69,70 There are also functional imaging paral- sleep deprived persons. Neuroimage 2011;55:629-634.
17. Venkatraman V, Huettel SA, Chuah LY, Payne JW, Chee MW. Sleep lels that remain to be exploited in future studies.1,71 The at rac- deprivation biases the neural mechanisms underlying economic pref- tion of this approach is that it may al ow conspecific evaluation erences. J Neurosci 2011;31:3712-3718.
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Characterising patients and controls with brain graphs constructed from fMRI data September 28, 2012 Systems Biology DTC University of Oxford Network science is a novel method of investigating the structure and function of the brain. We used network analysis in an attempt to distinguish between braingraphs constructed from fMRI data from patients and controls. The nodes in thebrain graphs are spatial regions of interest and the strength of their connectionis the correlation of the blood oxygen level-dependent (BOLD) signal of pairs ofnodes. The first data set contained little temporal information, so we performeda spectral clustering method on the communicability networks generated fromthe data. We found that there was some distinction between healthy and brain-damaged individuals. The second data set contained time-series data, whichallowed us to construct time-dependent adjacency matrices. The patients werediagnosed with schizophrenia, and the data was taken with the patients andcontrols taking the drugs Aripiprazole, Sulpiride, or a placebo. We performedtime-dependent community detection on the multilayer networks and the meanflexibility of the network was found. We found that for all drugs, the controlshad a higher mean network flexibility than the patients.

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HALDOL® NAME OF THE MEDICINAL PRODUCT 2 mg/ml and 10 mg/ml oral solution Clear, colourless solution. 5 mg/ml injectable solution Clear, colourless solution, free from visible foreign International Non-Proprietary Name (INN) QUALITATIVE AND QUANTITATIVE The tablets contain either 1 mg, 2 mg, 5 mg, 10 mg As a neuroleptic agent in: