HUMAN PSYCHOPHARMACOLOGY

Hum[ Psychopharmacol[ Clin[ Exp[ 04\ 060066 "1999#

The E}ect of Sleep Deprivation on Memory and Psychomotor Function in Healthy Volunteers
N[ QUIGLEY0\ J[ F[ GREEN1\ D[ MORGAN2\ C[ IDZIKOWSKI3 and D[ J[ KING2
Department of Psychiatry\ La`an Valley Hospital\ Lisburn\ County Antrim\ UK Mental Health Unit\ Ards Hospital\ Newtownards\ County Down\ UK 2 Department of Therapeutics and Pharmacolo`y\ The Queen|s University of Belfast\ Whitla Medical Buildin`\ 86 Lisburn Road\ Belfast\ UK 3 Sleep Assessment and Advisory Service\ PO Box 10\ Lisburn\ County Antrim\ UK
1 0

Benzodiazepines and other psychotropic drugs have been implicated in the production of memory de_cits[ The mechanism is unclear\ but both a distinct pharmacological action and a non!speci_c sedative e}ect have been suggested as being causal or contributory[ These two postulated mechanisms of action may be examined separately by using sleep deprivation as a method of non!pharmacological sedation[ We measured psychomotor and memory functions in eight sleep!deprived healthy volunteers and eight controls[ There was both subjective and objective evidence of sedation\ but memory function was not a}ected[ These _ndings support the view that the e}ect on memory of psychotropic drugs is principally caused by a direct amnestic e}ect rather than by drug!induced sedation[ Copyright 1999 John Wiley + Sons\ Ltd[
KEY WORDS

* sleep deprivation^ memory^ saccadic eye movements^ psychomotor performance^ healthy volunteers

INTRODUCTION Psychotropic drugs have been implicated in the production of memory de_cits\ however\ the distinction between drugs which have a direct amnestic e}ect\ and those which cause non!speci_c decreased arousal with secondary memory dys! function\ is not easily made[ Anticholinergic drugs have been realiably shown to cause memory dys! function * in our hands 4 mg of benzhexol has caused short term memory de_cits\ evident in both word recall and word recognition tests "Quigley et al[\ 0885#[ Benzodiazepines have well!known amnestic e}ects\ and antipsychotic drugs may have some lesser e}ects on speci_c aspects of memory function "Danion et al[\ 0881^ Green et al[\ 0885#[ One way to separate non!speci_c sedative e}ects from direct amnestic e}ects is to use sleep depri! vation techniques to examine the e}ect of non! pharmacological sedation on tests of memory and psychomotor function[

Correspondence to] Professor D[ J[ King\ Department of Therapeutics and Pharmacology\ The Queen|s University of Belfast\ Whitla Medical Building\ 86 Lisburn Road\ Belfast BT8 6BL\ Northern Ireland[ Tel] 90121!224660[ Fax] 90121!327235[

The e}ects of sleep deprivation on performance have been assessed both by examination of par! ticular working situations and by measurement of task performance in healthy research subjects[ The review of Leung and Becker "0881# identi_es 03 studies examining job performance after sleep deprivation] seven found an adverse e}ect on performance\ six found no e}ect\ and one found an improvement in cognitive performance after decreased sleep[ The length of sleep deprivation is thought to be crucial\ with decrements in per! formance being more easily demonstrable after continuous sleep deprivation for 37 h[ Performance on tasks which are interesting is less sensitive to sleep deprivation^ this is also true for sensitivity to the e}ects of psychotropic drugs[ Sleep deprivation may have deleterious e}ects not just on arousal levels "seen in its negative e}ects on vigilance tasks#\ but also on activation "Kowslowsky and Babko}\ 0881^ Linde and Bergstrom\ 0881#[ Van Steveninck et al "0888# demonstrated deterioration after one night of sleep deprivation in a range of psycho! motor measures[ Peak saccadic velocity\ visual analogue rating scales\ adaptive tracking and body sway signi_cantly deteriorated^ attempts to demonstrate worsening function through the

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night demonstrated entirely consistent but non! signi_cant trends\ probably due to the small size of the test population[ These results contrasted with the lack of change of smooth pursuit eye move! ments measures\ digit symbol substitution and electroencephalogram "EEG# amplitudes following sleep deprivation[ Studies on the e}ects of sleep deprivation on memory have been just as equivocal[ Many workers have long held the view that sleep helps the reten! tion of previously learned material "e[g[ Jenkins and Dallenbach\ 0813#^ its absence\ therefore\ should give the opposite e}ect[ The literature however gives con~icting results[ Some studies show a detrimental e}ect of sleep deprivation on short! term memory "STM# "e[g[ Webb and Levy\ 0873#^ some do not identify any e}ect "e[g[ England et al[\ 0874#^ and\ paradoxically\ an improvement in STM is occasionally noted "Cutler and Cohen\ 0868#[ Animal studies show similar results] McGrath and Cohen "0867# reviewed experiments on sleep deprived rats in which _ve experiments found a decrease in learning ability\ four had no e}ect\ and one demonstrated an improvement[ The aim of this study was to examine and com! pare the e}ects of sleep deprivation on a wide range of psychomotor and memory tests[ The psycho! motor tests in this battery have been extensively used to evaluate the central e}ects of psychoactive drugs "see King\ 0882^ Mannion et al[\ 0883#[ We have shown that saccade function is a}ected by lorazepam 01 mg "Green et al[\ 0885#\ chlor! promazine 49099 mg "Green and King\ 0887# and haloperidol 35 mg "Lynch et al[\ 0886#[ The ability of saccades to detect the presence of barbiturates\ clonidine\ histamine ligands\ anticholinergic drugs\ ca}eine and carbamazepine is reviewed by Glue "0880#[ There appears to be an association between a drug|s potential to cause sedation and its ability to decrease peak saccadic velocity and saccade acceleration[ The memory test battery is designed to examine several di}erent aspects of memory function] the articulatory loop and central executive processor of STM\ or working memory^ and the semantic\ procedural\ and face memory com! ponents of long!term memory "LTM#[ This concept of human memory as a complex of modular systems has been extensively reviewed by Allain et al "0882#[ MATERIALS AND METHODS Eight male and eight female healthy volunteers\ aged 0711 years "mean 08=4\ SD 0=1#\ weighing
Copyright 1999 John Wiley + Sons\ Ltd[

42014 kg "mean 69\ SD 06=2# were recruited[ They drank between 9 and 19 units of alcohol per week and _ve volunteers smoked "in four\ this was less than _ve cigarettes:day#[ A full history\ physical examination\ electrocardiogram\ full blood picture and block serum analysis were performed to exclude volunteers with physical ill!health[ Volun! teers were excluded if there was a history or evi! dence of any of the following] cardiovascular\ respiratory\ hepatic or renal disease\ psychiatric or neurological disease\ drug abuse\ or drug ingestion within 03 days of the study|s commencement[ Smoking was not permitted on study days and volunteers were asked to abstain from alcohol! and ca}eine!containing compounds 13 h before each study day and from smoking for 7 h before each study day[ Subjects completed two practice sessions in the week preceding their testing\ allowing fam! iliarisation with and training on the tasks in the battery of tests[ There were two consecutive test days[ At the end of the _rst "baseline# day\ volunteers were randomly allocated to one of two sex!matched groups "sleep deprived or control#[ Investigators were blind to the allocation throughout the study[ The sleep deprived group were kept in the department overnight\ supervised by a monitor who was not an inves! tigator[ They were permitted to play board games\ watch television\ or study[ The following day both groups repeated the battery of tests[ The tests were performed at the same time on successive mornings\ to exclude any e}ects of diurnal variation of per! formance[ Each test battery took approximately 64 min to perform[ Sleep diaries\ completed by the volunteers\ con_rmed that each had had a normal "5 h duration of sleep before the baseline session\ and for the control group\ for the night between the two sessions[ Memory tests Di`it span tests A standard digit span test\ in which a sequence of digits are presented sequentially on a visual display unit "VDU# at a rate of one per second\ was used[ The volunteer was asked to repeat the sequence\ typing his sequence on a keyboard[ The number of digits presented increased by one with each correctly completed sequence[ The subject|s score was one less than the sequence length he failed to repeat on two successive trials[ A second test was then performed\ in which the subject is asked to re!order the list in ascending numerical order\ with subsequent presentation and scoring as
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before[ The re!ordering component of this second trial is thought to use the STM central executive processor[ Baddeley|s lo`ical reasonin` test This test has been considered a measure of central executive function "Baddeley\ 0857^ Rusted and Warburton\ 0877#[ A series of statements are presented\ such as {A| is preceded by B [ [ [ AB|[ Subjects respond by marking the statements true or false[ Sixteen trials were presented[ Word recall This test is designed to measure use of the articulatory loop of working memory[ Sixteen words were presented consecutively on a VDU\ at one second intervals and volunteers were then asked to recall them verbally[ Each of the words was derived from a 149 word database compiled from the monograph of Paivio et al[ "0857# listing 814 nouns[ The words occurred at a similar frequency\ and within each list varied by less than a quarter of a standard deviation from each other on scales of concreteness\ imagery and meaningfulness[ Di`it symbol substitution test "DSST# This test\ derived from the Wechsler Adult Intelligence Scale "Wechsler\ 0847# uses the central executive portion of working memory and possibly involves the visuo! spatial scratch pad "Warburton and Rusted\ 0878#[ Volunteers were provided with a code relating a symbol to a number between 9 and 8[ They were then given 89 s to translate a page containing eight rows of symbols\ each row having 04 symbols[ They were scored according to the number of symbols translated\ regardless of accuracy[ A di}erent version of the test was used on each occasion[ Implicit memory test Sixteen words\ each with a unique three!letter stem\ were presented con! secutively[ The volunteer was asked to ascribe pleasant or unpleasant connotations to each word by tapping one of two marked keys on a keyboard[ The volunteers were later presented with the 05 three!letter stems of the original words\ sequentially on the VDU[ They were asked to type a word which completes the stem[ The volunteer|s score was the number of stems he completed by using the words originally presented[ The words used were also derived from the monograph of Paivio et al[ "0857# as described previously[ Prose recall This involved prose passages based on the version in the Rivermead Behavioural Memory
Copyright 1999 John Wiley + Sons\ Ltd[

Test "Wilson et al[\ 0874#[ All the passages con! tained 10 idea units and between 39 and 59 words[ Each volunteer on Day 0 was presented with a prose passage on a pre!recorded audio cassette\ and was asked to recall it\ the response itself also being recorded[ They were not warned that they would be asked to recall this passage again on Day 1\ as well as a further prose passage as before[ The taped responses were marked by one investigator "NQ# who gave one mark for each correctly remembered idea unit\ and half a mark for each partially remem! bered unit[ Sentence processin` This is a test derived from the Speed and Capacity of Language Processing "SCOLP# battery "Baddeley et al[\ 0881#\ containing a series of 05 statements which are obviously true or false[ The statements were presented sequentially on a VDU and subjects were asked to press the {true| or {false| key on a keyboard[ Cate`ories test Volunteers were presented with 19 pairs of words consecutively[ If the words were thought to belong to the same category "e[g[ orange and apple#\ the volunteer responded {true|^ if not\ he responded {false| "Battig and Montague\ 0858#[ Spot the word In this test volunteers were presented with two words\ one on either side of a VDU screen[ Only one of these words was a real word * the other was a nonsense word[ The subject identi_ed the real word by pressing a key under the appro! priate word[ Word reco`nition Sixteen words\ previously pre! sented to the volunteers in the spot the word test\ were presented consecutively\ each alongside three words not seen earlier[ The volunteer|s task was to identify the words seen before[ Mill Hill vocabulary test This was a pencil and paper test of crystallised semantic memory\ in which 19 words were presented\ each alongside four alter! native words\ only one of which is a synonym for the presented word[ The score was the number of correctly identi_ed synonyms[ The Mill Hill test has been extensively validated[ Each volunteer acted as his own control because di}erences from baseline were analysed^ inter!individual variations ability should therefore not be relevant[ Procedural memory In this test\ volunteers were shown slides of words written backwards\ and
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asked to call out the word[ They were timed over a presentation of _ve words\ then practised on 04 words\ then timed again over a further _ve words[ The di}erence in the times is a measure of the acqui! sition and use of a skill "in this case\ reading reversed script# which utilises procedural memory[ For obvious reasons\ this was not included in the practice battery[ The words were drawn from the database described above^ each set contained a similar number of four\ _ve\ and six letter words\ and the number of syllables did not vary between sets[ Face memory Volunteers were shown 19 con! secutive slides of faces at 1 s intervals[ After a 1 min pause\ the slides were re!presented\ mixed with 19 slides of faces not seen previously[ The volunteer|s score was the number of slides correctly identi_ed as having been previously seen or not[ The faces were all European\ without marked expression\ and taken against a blank background[ Saccadic and smooth pursuit eye movements and psychomotor tests Saccadic eye movements and smooth pursuit eye movements were measured using an electro! oculogram in accordance with the Cardi} Saccade Generation and Analysis System "CSGAAS# "Gri.ths et al[\ 0873#[ The following eight parameters are derived from this version of the system] peak acceleration\ peak deceleration\ latency\ saccadic duration\ peak saccadic velocity "PSV#\ undershoot\ acceleration:deceleration ratio\ average velocity of acceleration\ average velocity of deceleration and error[ The primary measure is PSV which\ in our hands\ has a coe.cient of variation ranging from 1=77 to 3=21 per cent "Mannion et al[\ 0883#\ and has proved a sensitive means of detecting drug e}ects "King\ 0882#[ In addition\ Critical Flicker Fusion Threshold "CFFT# and Choice Reaction Time "CRT# were measured using the Leeds Psychomotor Tester "Hindmarch\ 0864#[ CFFT score was taken as the mean of six runs\ three with ascending and three with descending ~icker frequency[ The CRT was the mean of 14 trials taken after _ve practice trials on each occasion[ Visual analo`ue ratin` scales "VARS# Subjective feelings and moods were assessed using 05 VARS "Norris\ 0860#\ which measured three dimensions] alertness\ contentedness and calmness "Bond and Lader\ 0863#[
Copyright 1999 John Wiley + Sons\ Ltd[

Statistical analysis Analysis of variance for a mixed design was used to determine signi_cance between conditions and days for each dependent variable[ A least squares means procedure was then used to determine sig! ni_cance for pre!de_ned individual comparisons[ RESULTS Memory tests None of the memory tests was signi_cantly a}ected by 13 h of sleep deprivation "Table 0#[ Results are included for the procedural memory test\ although it should be noted that technical di.culties arose during the study\ resulting in low sensitivity for this particular measure[ Psychomotor tests Results are presented in Table 1[ Saccadic eye movements were a}ected by sleep deprivation^ both peak saccadic velocity " p 9=94# and acceleration " p 9=90# were signi_cantly decreased[ Smooth pursuit eye movements were una}ected[ There was no other statistical di}erence in the psychomotor tests between groups\ although the sleep deprived group showed a non!signi_cant trend towards a lengthened recognition reaction time compared to the control group " p 9=96#[ VARS The sleep deprived group showed a signi_cant decline in self!rated alertness compared with control "Table 1#[ The other two dimensions examined "contentedness and calmness# were una}ected[ DISCUSSION We have shown that non!pharmacological sedation induced by 13 h of sleep deprivation does not pro! duce an e}ect on a large battery of memory tests\ but does a}ect saccadic eye movement components and VARS[ The duration of sleep deprivation may be an important factor in determining the extent of e}ects on memory performance[ Baddeley|s logical reasoning test\ for instance\ has been reliably shown to detect sleep deprivation of 37 h duration "Webb and Levy\ 0871\ 0873^ Angus and Haslegrave\ 0874#^ it appears to be more di.cult to detect
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Table 0[ Memory tests[ All results are expressed as mean values[ There are no statistically signi_cant di}erences Control Baseline Digit span "no recalled# Digit span re!ordered "no re!ordered# Logical reasoning reaction time "sec# Word recall "no correct# Word recognition reaction time "sec# Digit Symbol Substitution Test "no translated# Sentence processing reaction time "sec# Categories test reaction time "sec# Spot the word Vocabulary test "no correct# Prose recall "idea units:10# Procedural memory Face recall "no correct:39# Implicit memory 5=3 6=8 1=6 8=2 2=5 44=2 0=63 0=42 01=6 19=2 02=0 0=88 22=2 13 h 6=3 7=0 2=9 8=4 1=7 44=5 0=49 0=21 02=3 07=8 7=8 0=43 22=7 6=6 Sleep deprivation Baseline 4=8 7=3 1=5 09=9 2=9 43=9 0=43 0=55 01=2 07=7 02=5 0=08 21=9 13 h 5=2 7=8 1=6 8=4 1=7 47=5 0=45 0=53 02 06=7 8=9 1=4 23=7 8=9

Table 1[ Psychomotor function and subjective alertness[ All results are expressed as mean value "SEM#[ p 9=94^ p 9=90 Control Baseline Peak saccadic velocity "deg:s# Acceleration "deg:s1# CFFT "Hz# CRT "ms# VARS "alertness# 379 "11# 59[4 "2=4# 12=1 "0=9# 224 "07# 42 "5=5# 13 h 365 "11# 48[8 "2[1# 12=4 "9=8# 223 "02# 58 "6=0# Sleep deprivation Baseline 357 "06# 44[3 "1[7# 12=2 "0=9# 214 "09# 55 "4=2# 13 h 318 "11# 40[9 "2[4# 12=2 "9=7# 235 "09# 31 "6=4#

shorter periods "Linde and Bergstrom\ 0881#[ Deterioration in psychomotor performance is also more reliably demonstrated following sleep depri! vation of 37 h "Kowslowsky and Babko}\ 0881#[ Extending the period between testing beyond 13 h does\ however\ introduce the confounding e}ect of circadian rhythm in performance[ Folkard "0864#\ for example\ found that\ between 7=99 am and 1=99 pm speed of performance on the logical reasoning task increased\ but accuracy decreased[ Some workers have suggested that sleep depri! vation may have a paradoxical activating e}ect[ Cutler and Cohen "0868# suggested that their _nd! ing of an improvement in word list recall following one night|s sleep deprivation was a consequence of endogenous activation[ Ford and Wertz "0873# noted an improvement in psychomotor per! formance of physicians following sleep deprivation\
Copyright 1999 John Wiley + Sons\ Ltd[

and postulated that the reticular activating system\ in a compensatory mechanism\ causes stimulation of the cerebrum[ However\ these _ndings are rela! tively uncommon\ and results from most studies suggest that sleep deprivation has a detrimental e}ect both on arousal and activation[ Sleep deprivation of 13 h duration was su.cient in this study to demonstrate objective evidence of sedation\ with an 7=2 per cent decline in PSV[ This is in keeping with results of work by Van Steveninck et al[ "0882\ 0888#\ who detected decreases of 809 per cent in PSV during and following 13 h of sleep deprivation[ The e}ects on psychotropic drugs on saccadic eye movement velocity are drug! and dose! dependent[ Similar percentage decreases in PSV are caused by lorazepam 0 mg "8=8 per cent decrease# "Green et al[\ 0885# and chlorpromazine 49 mg "7=4 per cent decrease# "Green and King\ 0887#[
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PSV is considered a relatively reliable and objec! tive measure\ but some inter!study variability occurs^ Green and King "0887# found a 8=5 per cent decrease in velocity with lorazepam 1 mg\ which is similar to the e}ect of 0 mg of lorazepam found by Green et al[ "0885#[ However\ Green et al[ "0885# used a similar battery of memory tests to this study\ and demonstrated consistent signi_cant decreases in memory test performance with both 0 and 1 mg doses on lorazepam[ There is a clear di}erence between the e}ects on memory of lorazepam in that study and the e}ects of sleep deprivation as measured in this study[ Therefore\ it may be argued that this can be attributed to a direct amnestic e}ect of the drug which is not due to sedation\ since the e}ects on PSV between the studies are roughly comparable[ This argument is strengthened if the VARS are taken into account\ since the VARS and the PSV may be considered as two methodologically dis! similar but mutually supporting measures of sedation[ VARS results from this study and the two studies cited above are entirely consistent with the PSV results[ However\ it is important to note that this study used less subjects per group than Green et al[ "0885# "n 7 as opposed to n 19#\ thus this study may be less likely to detect subtle di}erences in test scores[ Subjects in this study were young and would be expected to be best able to tolerate the adverse e}ects of sleep deprivation[ Older subjects might be expected to have larger and more easily detected memory de_cits\ if these were to occur with sleep deprivation[ Compatible _ndings arise from investigation of other types of psychotropic drugs\ where relatively low sedative potential maybe combined with sig! ni_cant amnestic e}ects[ A dose response relation! ship for the e}ect of benztropine on verbal learning has been demonstrated "McEvoy and Freter\ 0878#\ as has a correlation between anticholinergic drug level and verbal memory dysfunction "Tune et al[\ 0871^ Perlick et al[\ 0875#[ E}ects on memory tests have been demonstrated with benzhexol\ which is not considered a sedative compound and does not decrease PSV "Quigley et al[\ 0885#[ Further support is given to this hypothesis by Green et al[ "0885#\ who showed that the sedative drug chlorpromazine signi_cantly slowed PSV\ but did not have com! parable e}ects on a battery of tests of cognitive function\ including memory[ We conclude that investigation of non!pharma! cological sedation in healthy volunteers gives results that support the _ndings of studies using
Copyright 1999 John Wiley + Sons\ Ltd[

di}erent designs[ The results of investigation of acute e}ects of sedative drugs\ non!sedative drugs and non!pharmacological sedation are all con! sistent in suggesting that the amnestic e}ects of psychotropic drugs "speci_cally benzodiazepines and anticholinergics# are a distinct entity and not simply a consequence of sedation[

ACKNOWLEDGEMENTS We wish to thank Dr M[ F[ Mannion for access to his database of word lists^ Mr Paul Best for tech! nical assistance and expertise^ Dr Karen Trimble for assistance with the testing sessions^ Mr Bernhardt Hasson for maintaining good humoured wakefulness during the night with the sleep deprived subjects^ and Mrs Helen Hunter for invaluable help in preparing test materials[ REFERENCES
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