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Specific impairments in visuospatial working and short-term memoryfollowing low-dose scopolamine challenge in healthy older adults
Elizabeth Thomasa, Peter J. Snyderb,c, Robert H. Pietrzakd,e, Colleen E. Jacksonf,Martin Bednarg, Paul Maruffe,h,∗
a Department of Psychology, University of Melbourne, Australiab Department of Clinical Neurosciences, Warren Alpert Medical School of Brown University, Providence, RI, USAc Child Study Center, Yale University School of Medicine, New Haven, CT, USAd Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA
e CogState Ltd., Melbourne, Australiaf Department of Psychology, University of Connecticut, Storrs, CT, USAg Pfizer Global Research and Development, Groton, CT, USAh Centre for Neuroscience, University of Melbourne, Australia
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Article history:Received 31 August 2007Received in revised form 15 April 2008Accepted 16 April 2008Available online 22 April 2008
Keywords:ScopolamineDonepezil cognitive functionSpatial working memory
a b s t r a c t
Scopolamine-induced defimals and humans, althouThis study examined theing memory using the Grlearning test that yields mmemory, and visuomotorolder adults were adminidonepezil (5 mg oral), scolamine led to performancewere observed in errors r
rule-break errors d = −2.49) anfor scopolamine-related slowinrated scopolamine-related impthan short-term memory. By itfunction. These results suggestperformance monitoring, in co
1. Introduction
The role of the dopaminergic (DA) system in frontal cortex activ-ity and working memory functions associated with the frontalcortex has been widely investigated. Animal experiments andrecent pharmacological research in humans also suggests a roleof the cholinergic system in working memory (Hasselmo & Stern,2006). In humans, cholinergic neurotransmission has been widelyimplicated in sensory processing, attention, and memory encodingfunctions (Giocomo & Hasselmo, 2007). Although working memoryand short-term memory impairments have been observed fol-
n cognitive and motor processes have been widely demonstrated in ani-e role of acetylcholine in working memory is not as well understood.f acetylcholine neurotransmission in visuospatial short term and work-Maze Learning Test (GMLT). The GMLT is a computerized hidden mazeres of component cognitive processes such as spatial memory, working
ion, as well as their integration in trial-and-error problem solving. Healthyd scopolamine (0.3 mg subcutaneous), the acetlycholinesterase inhibitor
ine with donepezil, or placebo. Compared to placebo, low-dose scopo-its on all measures of the GMLT. The greatest scopolamine-induced deficitsing working memory processes (e.g., perseverative errors d = −2.98, and
d these impairments remained robust when statistical models accountedg in visuomotor speed. Co-administration of donepezil partially amelio-airments and this effect was greatest for measures of working memoryself, donepezil was associated with a small improvement in visuomotor
that scopolamine disrupts processes required for rule maintenance and
lowing administration of cholinergic antagonists in humans, thishas been demonstrated mainly within the verbal domain (Curran,Schifano, & Lader, 1991; Ebert, Siepman, Oertel, Wesnes, & Kirch,1998; Eddington & Rusted, 2003; Ellis et al., 2006; Mintzer &Griffiths, 2003; Tariot, Patel, Cox, & Henderson, 1996). It is not clearfrom these studies the degree to which working memory impair-ments produced by cholinergic antagonists are a consequence ofattentional, sensory, or short-term memory impairments, and areconsistent with spatial working memory deficits observed in ani-mal studies. This study was designed to investigate the changesin short-term learning and memory, and working memory asso-ciated with modulation of central nervous system acetylcholinetransmission in healthy older adults. We expected that administra-tion of a muscarinic acetylcholine agonist (donepezil), antagonist(scopolamine), their co-administration, or placebo would producedifferent, but well-ordered performance profiles on a computerized
version of a hidden pathway maze learning task designed to assessmultiple aspects of change in different cognate abilities.
Executive function is often defined as a cognitive systemthat supports the integration of memory, planning, monitoringand motor functions towards goal-directed actions in a flexiblemanner (Baddeley, 1996; Goldman-Rakic, 1996; Levy & Goldman-Rakic, 2000; Postle, 2006). The maintenance of information inimmediate memory, or short-term memory is distinguished fromworking memory, which requires the transformation, or manipu-lation of information above simple storage and retrieval (Baddely,2003). Working memory may be regarded as a blanket termthat encompasses operations such as memory updating, perfor-mance monitoring, inhibition of prepotent responses, and mentalset-shifting, all of which support the optimal functioning of exec-utive control (Lehto, Juujarvi, Kooistra, & Pulkkinen, 2003; Miyake,Friedman, Emerson, Witzki, & Howerter, 2000 but see Salthouse,Atkinson, & Berish, 2003 for a more ‘unitary’ account of execu-tive function; and Koechlin & Summerfield, 2007 for a theory offunctional hierarchical organization of the prefrontal cortex). Whilepsychopharmacological investigations of working memory havefocused on the role of dopaminergic neurotransmission (e.g., Ellis& Nathan, 2001; Gruber, Dayan, Gutkin, & Solla, 2006; Iversen &Iversen, 2007; Li, Sham, Owen, & He, 2006; Robbins, 2000), there isa growing body of evidence showing the necessary involvement ofacetylcholine (i.e. cholinergic neurotransmission) in working mem-ory functions (Giocomo & Hasselmo, 2007; Hasselmo & Stern, 2006;Mameli-Engvall et al., 2006).
In rodents, the relationship between cholinergic neurotransmis-sion and spatial working memory has been studied thoroughlyusing maze learning paradigms such as the Morris Water Maze,Barnes Maze, and the Olton Radial Arm Maze (Douglas & Isaacson,1966; Drew, Miller, & Baugh, 1973; Ennaceur & Meliani, 1992;Komater et al., 2005; Watts, Stevens, & Robinson, 1981). Blockade ofnicotinic or muscarinic acetylcholine receptors causes impairmentin performance on all of these tasks (Blockland, 1996; Gold, 2003;Power, Vazdarjanova, & McGaugh, 2003; Sarter & Bruno, 1997;Sarter, Bruno, & Givens, 2003). Furthermore, co-administration ofcompounds that stimulate the release of acetylcholine or block theenzymatic breakdown of acetylcholine can overcome the impair-ments in visuospatial learning, working memory, and executivefunctions (Friedman, 2004; Padlubnaya, Galizio, Pitts, & Keith,2005; Sahakian et al., 1993; Wezenberg, Verkes, Sabbe, Ruigt, &Hulstijn, 2005).
In humans, the cognitive effects caused by modulation of
cholinergic neurotransmission have also been well studied, mainlythrough blockade of muscarinic receptors with the antagonistscopolamine (Ellis et al., 2006; Wesnes, Simpson, & Kidd, 1988).However, despite the wealth of animal data on the effects of scopo-lamine on spatial working memory, most studies examining theeffects of scopolamine on learning and memory, or working mem-ory in humans have utilized auditory–verbal testing paradigms(e.g., effects on word list learning, paragraph learning, or verbalmemory span; Curran et al., 1991; Ebert et al., 1998; Ellis et al.,2006; Mintzer & Griffiths, 2003; Tariot et al., 1996). When spa-tial cognition or working memory has been challenged in humanswith scopolamine, the tasks chosen (e.g., Trail Making Test Part-B, delayed spatial memory, visual spatial short-term memory anddelayed matching-to-sample) have required only passive storageand retrieval of spatial information (Flicker, Serby, & Ferris, 1990;Koller et al., 2003; Kopelman & Corn, 1988; Robbins et al., 1997;Rusted & Warburton, 1988; Tariot et al., 1996). Thus, while scopo-lamine disrupts auditory–verbal short term and working memory,and spatial short-term memory in humans, the nature or magni-tude of the effect of scopolamine on ‘active’ functions of spatialworking memory is unclear.
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Identification of the effects of cholinergic neurotransmission onattention, short-term memory, and working memory has been dif-ficult to determine using standard neuropsychological tests for anumber of reasons. First, most studies investigating the effects ofcompounds that act on the cholinergic system have been basedon performance across batteries of neuropsychological tests thatmay differ in sensitivity to detect cognitive impairment or change(Collie, Maruff, Faletti, Silbert, & Darby, 2002; Osterberg, Orbaek,Karlson, Bergendorf, & Seger, 2000). Theoretical inferences regard-ing the presence and relative magnitude of impairment in domain,or process-specific functioning may be confounded by the differ-ent psychometric properties of tests used for comparison (Lewis,Maruff, & Silbert, 2005; Lewis, Maruff, Silbert, Evered, & Scott,2006). Second, identifying the underlying processes which leadto impaired performance on complex tests of short-term mem-ory or working memory are difficult to establish from methodsthat produce single outcome measures (such as speed or accu-racy). The disruption to executive processes (e.g., working memory,goal maintenance), supporting functions (e.g., sensory process-ing, attention), or the domain itself (e.g., language, visuospatial ornumerical processing) can produce sub-optimal performance ontests of purported executive functions (Chan, Shum, Toulopoulou,& Chen, 2008; Royall et al., 2002). The problem of inferring process-or domain-specific activity from variably complex tasks has beennoted by many researchers (Burgess, 1997; Conway, Kane, & Engle,2003; Hamilton, Coates, & Heffernan, 2003; Jacoby, 1991; Merian,2005). Of course it is also difficult to dissociate completely verbaland visuospatial executive functions in humans. When faced withdifficult visual tasks, humans generally develop verbal strategies toguide performance on spatial tasks even in the absence of linguisticstimuli, performance rules expressed verbally, or requirements forspoken responses (Gillett, 2007). These issues aside, it is increas-ingly recognized that in complex tasks, it is important to identifythe sources of performance variability within and between groupsand individuals (Leite, Ratcliff, & Hale, 2007; Ratcliffe, Spieler, &McKoon, 2000; Verhagen, Cerella, Semenec, Leo, & Steitz, 2002),and to use appropriate statistical methods for characterizing theparameters of change or impairment (Collie et al., 2002; Maruff etal., 2006). One approach that can accommodate these imperatives isto use tasks that can measure component processes that contributeto performance on the same test, and from which valid comparisonsof relative cognitive impairments can be inferred using appropri-ate statistical methods. Such an approach need not assume that theunderlying processes are independent or organized hierarchically
but can investigate associations between measures of the differentcomponent processes.
In a recent study, we used performance on a hidden path-way maze learning task (the Groton Maze Learning Test; GMLT)to investigate pharmacodynamic response to acute doses of scopo-lamine and donepezil, alone and together in healthy older people(Snyder, Bednar, Cromer, & Maruff, 2005). Older participants wererecruited because of the known decline in cholinergic function withaging, hence the sensitivity of this population to compounds whichenhance or impair the cholinergic system (Ellis & Nathan, 2001).The GMLT was chosen for this study because of its demonstratedsensitivity to drug effects, and its demonstrated neuroscientificvalidity, brevity, repeatability, and utility across groups accordingto age, clinical, or cultural status (e.g., Maruff et al., 2006; Pietrzak,Cohen, & Snyder, 2007; Schroder, Snyder, Seilski, & Mayes, 2004;Snyder, Maruff, Pietrzak, Cromer, & Snyder, 2008). The GMLT isadapted from the Milner “stepping stone” maze (Milner, 1965) andthe Austin maze (Morrison & Gates, 1988). The GMLT is admin-istered via touchscreen computer monitor, and individuals arerequired to identify, one step at a time, a pathway that is hidden ina 10 × 10 matrix. There are four rules of the task, which aid the dis-
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Fig. 1. The Groton Maze Learning Test. Participants must find a 28-step hidden path-way concealed within the tile grid accord with the following rules: do not movediagonally, backward, or more than one tile at a time. Return to the last correct loca-tion after an unsuccessful search. Each search begins in the top left corner. The mazeappears in color, although the image presented is in black and white. The currentlocation (in black) appears in blue, the background tiles appear in grey, and each‘search’ result is signalled by a green tick on a white background for a correct move,or a red cross on a white background for an incorrect move.
covery of the pathway by reducing the possible number of correctlocations at each decision point to a maximum of three possibil-ities. That is, subjects are instructed not to move diagonally, notto go backwards on the path unless they make an error, not to‘jump’ tiles, and to return to the last correct location after an error(see Fig. 1 for an image of the appearance of the task to a sub-ject). The GMLT software measures the latency of each responseand classifies it as correct or incorrect according to error type. Thepathway is never revealed in its entirety, and the subject sees onlythe current correct location. Once the subject has worked their waythrough to the end of the pathway they must return to the start andfind the same pathway again. Successful performance on the GMLT
requires the individual to hold the task rules in working mem-ory and use this information to guide trial-and-error learning inaccordance with moment-to-moment performance feedback andthe developing representation in memory of the actual pathwaylocation.
Analysis of the responses made in learning the maze can indicatethe integrity of different cognitive operations after pharmacologi-cal challenge (Snyder et al., in press). For example, assuming thatsubjects adhere to the task rules, errors made in finding the path-way (i.e. exploratory errors) reflect the ability to build a short-termspatial representation of the pathway in memory. The number ofrule-break errors provides an index of the ability of individuals tohold and use the general rules in working memory, and to mon-itor ongoing performance. Perseverative errors (or the same errormade in succession) provide an index of the individual’s tendency toautomatically repeat errors they have already made. Hence, whileexploratory errors reflect spatial working memory processes, thecombined measures of perseverative and rule-break errors providea measure of working memory functions such as error/performancemonitoring (Pietrzak et al., 2007; Pietrzak, Maruff, Mayes, Roman,Sosa, & Snyder, in press). The number of correct speeded responses
gia 46 (2008) 2476–2484
made on a simple reaction time version of the maze (Chase test)can provide an index of visuomotor function. This can be used toestablish the extent to which changes in working memory dueto modulation of cholinergic neurotransmission are an indirectconsequence of the reduced alertness, sedation, and changes insensory processing that can occur with muscarinic antagonists (e.g.,Callaway, Halliday, Naylor, & Schechter, 1985; Cohen, Gross, Semple,Nordahl, & Sunderland, 1994; Curran et al., 1991; Eddington &Rusted, 2003; Robbins et al., 1997; Sipos, Burchnell, & Galbicka,1999; Wesnes & Warburton, 1984).
In a previous paper, we reported that scopolamine (0.3 mg s.c.)induced deficits in processing speed and learning efficiency thatwere greatest 2.5 h after scopolamine administration (Snyder etal., 2005). Administration of donepezil (5 mg oral) 3 h prior toscopolamine ameliorated these deleterious effects. Interestingly,administration of donepezil by itself actually improved perfor-mance on the GMLT above baseline levels. However, the originalstudy was designed to use the maze to measure the pharma-codynamic effects of scopolamine and donepezil administeredalone and together. Consequently, only summary measures of mazeperformance were analyzed. There was no investigation of theinteraction between the measures of the different cognitive oper-ations necessary for optimal problem solving on the maze. Thus,while the earlier findings provide prima facie evidence that workingmemory is affected by modulation of cholinergic neurotransmis-sion, we believe that a more detailed analysis is required to identifythe associations between different cognitive operations pertainingto working and short-term memory on the GMLT.
The current paper presents that analysis, with the goal ofdecomposing performance on the hidden maze learning taskinto the component operations of spatial and working memoryand examining how these operations are modulated by acetyl-choline neurotransmission. We hypothesized that scopolaminewould interfere with all of the component cognitive processes nec-essary for maze learning and that scopolamine-related impairmentwould be ameliorated by donepezil. We investigated the extentto which modulation of acetylcholine affected visuomotor speed,short term and working memory components of maze learning.These relationships were examined by computing standardizedmeasures of change for the different outcome measures and com-paring these between treatment conditions.
2. Methods
2.1. Subjects
The subject group consisted of 32 healthy older (mean age = 71 years,range = 65–90 years) men (N = 12) and women (N = 20). All individuals satisfied rig-orous inclusion and exclusion criteria (summarized below), and were both willingand able to provide written informed consent. All subjects had normal or correctedto normal visual and auditory acuity, were in good general health or without anyclinically significant abnormalities, had a normal ECG, and a Mini-Mental StateExam Score ≥28/30. Women were required to be at least 2 years post-menopausal.Exclusion criteria included a history of major depression or other Axis I psychi-atric disorders (as described in DSM-IV) within the past 2 years, psychotic features,agitation or behavioral problems within the last 3 months, a history of alcohol orsubstance abuse or dependence within the past 2 years (DSM-IV criteria), a his-tory of schizophrenia (DSM-IV criteria) and significant systemic illness or unstablemedical condition which could lead to difficulty complying with the protocol. Suchmedical conditions included: cancer, cardiovascular disease or angina, obstructivepulmonary disease or asthma, clinically significant and unstable gastrointestinaldisorder such as ulcer disease or a history of active or occult gastrointestinal bleed-ing within 2 years, clinically significant laboratory test abnormalities (hematology,prothrombin time, chemistry, urinalysis), Insulin-requiring diabetes or uncontrolleddiabetes mellitus, uncontrolled hypertension (systolic BP > 170 or diastolic BP > 100),a history of clinically significant liver disease, coagulopathy, or vitamin K deficiencywithin the past 2 years, narrow-angle glaucoma, or clinically significant obstructiveuropathy.
Vitamin supplements (including vitamin E) were allowed and individuals takingany prescribed medication were required to have been stable on that medication and
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learn the pathway was also computed. All measures of the GMLT were reported assummed totals across the five trials.
2.4. Study protocol
Prior to beginning the study, all subjects completed two practice assessmentsduring which they completed the GMLT. Donepezil (5 mg, oral administration) orplacebo was given prior to a single baseline session before each day of treatment.All subjects received either scopolamine (0.3 mg s.c.) or placebo 3 h after the baselineassessment on each visit. Further testing was conducted at 2.5, 4, 5.5, 7 and 9 h afterbaseline. As stated earlier, the 5.5-h assessment is reported in this paper because theadministration of the two drugs were staggered so that the Cmax of each drug, aloneand in combination, would coincide at this time. See Snyder et al. (2005) (Figs. 1–4)for the analyses that confirm this general observation.
2.5. Data analysis
The data analysis proceeded in four stages. First, the presence of carry overeffects was determined by submitting data from the two baseline assessments toa series of treatment-order × time ANOVAs and inspecting main effects and inter-actions that included the time factor. None of these were significant (see Table 1).The within-subject standard deviation (WSD) for each measure was also derivedfrom the residual error term in these comparisons between baselines (see Bland &Altman, 1995, 1996; Maruff et al., 2006). For each outcome measure, performancewas averaged to provide a baseline for each treatment condition. Performance at
Fig. 2. Effect size of change from baseline scores (Cohen’s d) at 5.5 h after baselinefor placebo, 5 mg donepezil orally, 0.3 mg scopolamine s.c, and scopolamine (0.3 mg)with donepezil (5 mg) on Groton Maze Learning Test outcome measures (n = 15 ineach group).
dose for at least 1 month prior to screening. Individuals were excluded if they weretaking centrally active beta-blockers, narcotics, methyldopa and clonidine within4 weeks prior to screening, dopamine agonists or l-DOPA medications within 2months prior to screening, neuroleptics or narcotic analgesics within 4 weeks priorto screening, long-acting benzodiazepines or barbiturates within 4 weeks priorto screening, short-acting anxiolytics or sedative-hypnotics more frequently thantwo times per week within 4 weeks prior to screening, initiation or change indose of an antidepressant lacking significant cholinergic side effects within the 4weeks prior to screening (use of stable doses of antidepressants for at least 4 weeksprior to screening was acceptable), systemic corticosteroids within 3 months priorto screening, any medications with significant cholinergic or anticholinergic sideeffects (e.g., pyridostigmine, tricyclic antidepressants, meclizine, and oxybutynin)within 4 weeks prior to screening, anti-convulsants (e.g., phenytoin, phenobarbital,carbamazepine) within 2 months prior to screening, warfarin (coumadin) within4 weeks prior to screening, or prior use of any FDA approved medications for thetreatment of Alzheimer’s disease. Subjects with a positive urine drug screen (e.g., forbenzodiazepines or narcotics) were also excluded, as were subjects with a knownhypersensitivity to scopolamine or agents of this class of drugs, or hypersensitivityto donepezil hydrochloride or piperidine derivatives.
2.2. Design
This study utilized a parallel-group, double-blind, placebo-controlled, crossoverdesign to assess the ameliorating effect of donepezil on scopolamine-induced cog-nitive decline. Subjects were tested over two study days, 21 days apart. On the firstday, individuals were assigned randomly to receive scopolamine or placebo. Withineach of these groups, all subjects also received a single dose of donepezil or placebo.The order of drug administration was randomized between all subjects and the twostudy conditions. This combination gave rise to four treatment groups; scopolamine
plus donepezil, scopolamine plus placebo, placebo plus donepezil or placebo plusplacebo.
Although performance was assessed across the entire study day, the currentstudy investigated performance at the assessment conducted 5.5 h after baseline tocoincide with the maximum concentration (Cmax) of scopolamine (Ebert et al., 1998)and donepezil. This point corresponds to the 5.5 h assessment in Figs. 1–4 shown inSnyder et al. (2005).
2.3. Task protocol and apparatus
The GMLT was administered on a touchscreen tablet PC. The GMLT consists of a10 × 10 grid of tiles that conceals a 28-step hidden pathway. Subjects are required tofind the path from the top left-hand corner to the bottom right-hand corner by trial-and-error learning in conjunction with the test rules. Participants were instructedthat (1) they must find the pathway one step at a time beginning in the top left-handcorner of the maze; (2) the next step in the pathway is always in a location imme-diately adjacent to their current location; (3) this location is never diagonal to theircurrent location; and (4) return to the last correct location after each incorrect move.The end point was indicated for the duration of the test. Correct moves were indictedby a green ‘tick’ on the selected tile, whereas incorrect moves were indicted by a red‘cross’. Only one tile was illuminated at a time so that the identified pathway andhistory of moves remained hidden. In each testing session, subjects were requiredto find the same pathway on five consecutive trials. The GMLT was preceded by atest of visuomotor speed (‘Chase’ test) in which the subject was instructed to fol-low a signal around the grid moving by adjacent tiles. Performance measures of the
Fig. 3. Mean number of exploratory errors (dotted lines and filled symbols),and working memory errors (rule-break plus perseverative: continuous lines andunfilled symbols), on trials 1–5 at 5.5 h after baseline for placebo (triangles), 5 mgdonepezil orally (squares), 0.3 mg scopolamine s.c. (diamonds), and scopolamine(0.3 mg) with donepezil (5 mg) (circles).
Chase test were the total number of correct moves in 30 s. The main outcome mea-sures from the GMLT were analyzed according to the number of rule-break errors,perseverative, and exploratory errors. In addition to this, the total time required to
Fig. 4. Effect size of change from baseline (Cohen’s d) at 5.5 h after baseline forplacebo, 5 mg donepezil orally, 0.3 mg scopolamine s.c, and scopolamine (0.3 mg)with donepezil (5 mg) on Groton Maze Learning Test outcome measures, statisticallycontrolling for the effect of psychomotor speed (chase test) on outcome measures(n = 15 in each group).
2480 E. Thomas et al. / Neuropsychologia 46 (2008) 2476–2484
Table 1Groton Maze Learning Test performance according to order of treatmentbetween study days 1 and 2 for donepezil/placebo (n = 8), placebo/donepezil(n = 7), scopolamine/donepezil plus scopolamine (n = 8), and donepezil plusscopolamine/scopolamine (n = 7) groups (means and standard deviations (S.D.)),within-subject deviations (WSD), and at baseline on each study day and at the 5.5 hassessment after baseline
Outcome measure Order of treatment Baseline 1 Baseline 2 5.5 h WSD
Maze values are summed totals across the five learning trials.a Scopolamine administered with donepezil.
b Scopolamine.
the average baseline was then subtracted from performance at the 5.5-h assess-ment for each outcome measure for each subject to yield a change from baselinescore. The signs of these scores were altered so that positive values indicated per-formance improvement from baseline and negative scores indicated decline frombaseline. To allow comparison between the changes in performance on the differentoutcome measures, each change score was standardized using the relevant WSD.Standardized change from baseline scores were then submitted to a series of threeplanned comparisons within a repeated measures ANOVA (i.e. the signed values ofchange scores were used). These comparisons were (1) change from baseline underscopolamine versus change from baseline under placebo; (2) change from baselineunder scopolamine versus change from baseline under scopolamine plus donepezil;and (3) change from baseline under donepezil versus change from baseline underplacebo. Effect sizes (Cohen’s d) were also computed to reflect these comparisons(Cohen, 1988).
The second stage of the analysis aimed to determine the extent to which changefrom baseline scores on GMLT outcome measures was due to change in visuomotorspeed (i.e. performance on the Chase task). Here the analyses comparing treatmentconditions for each standardized change from baseline score was repeated with thestandardized change from baseline scores on the Chase task treated as a covariate.Group mean standardized change scores adjusted for change in visuomotor speedwere shown graphically as measures of effect size to reflect the main recomputedcomparisons.
verative errors), and S.D. on trials 1–5 on the GMLT at the 5.5 h assessment (n = 15in each group)
a Scopolamine.b Scopolamine administered with donepezil.
The third stage of the analysis was examine and compare the accumulation of dif-ferent error types across successive learning trials, trend analyses were conductedon exploratory errors and working memory errors (perseverative plus rule-breakerrors). These analyses indicated that logarithmic functions described best (i.e. pro-vided the best fit) the relationship between number of exploratory errors and trialwhile logarithmic functions also described best the relationship between trial num-ber and working memory errors (Table 2). Therefore, these different functions werefitted to the data for exploratory and working memory errors from individual partic-ipants. Estimates of slope (and log slope) and intercept were computed for each errortype for each participant and these were compared between treatment conditionsusing one-way analysis of variance.
The fourth stage of analysis aimed to determine the extent to which impairmentin working memory function was related to short-term memory processes. To exam-ine this, the total perseverative and rule-break errors were summed for each subjectat the baseline and 5.5 h post-baseline assessment. The WSD was computed for thismeasure and a standardized change from the two baseline scores was computed foreach subject. The standardized change from baseline score for exploratory errorswas compared between conditions using the three planned comparisons within aone-way ANOVA. In this analysis, the change from baseline in working memory func-tions (i.e. perseverative plus rule-break errors) was treated as a covariate. For eachcomparison performed, a measure of effect size was also computed. The final anal-ysis examined change from baseline in working memory errors with exploratoryerrors treated as a covariate.
3. Results
Two subjects were excluded from analysis due to missing data,resulting in 15 subjects in each treatment group. Group meansand standard deviations for each of the GMLT outcome measuresat baseline and 5.5 h after baseline under each treatment condi-tion are shown in Table 1. The group means for the standardizedchanges from baseline scores are shown in Fig. 2 for each of themaze outcome measures. Fig. 2 indicates that, relative to baseline,the placebo group showed subtle improvement from baseline onthe Chase test only. Donepezil improved performance from base-line levels for most outcome measures although the magnitude ofthis improvement was small for all measures except the Chase test.Scopolamine induced a decline in performance from baseline forall GMLT measures, with the magnitude of this decline being great-est for perseverative, and rule-break errors. Co-administration ofdonepezil with scopolamine reduced the severity of scopolamine-related decline for all outcome measures except the Chase test.
Planned comparisons indicated that the deterioration frombaseline observed with scopolamine treatment was significantlygreater than change from baseline under the placebo for all out-come measures: Chase test (F = 3.53, p = 0.04, d = 1.02), completion
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Table 3Trend line function (linear and logarithmic), with intercept and r2 values for explgroup
Working memory errors Scopolamine 0.04Scop + donb −0.15Placebo −0.16Donepezil −0.18
a Proportion of variance accounted for by the model.b Scopolamine administered with donepezil.
time (F = 2.88, p = 0.03, d = 1.64), exploratory errors (F = 5.14, p = 0.01,d = 1.59), perseverative errors (F = 8.47, p = 0.000, d = 3.19), andrule-break errors (F = 8.13, p < 0.001, d = 2.69). Co-administrationof donepezil with scopolamine ameliorated scopolamine-relateddecline, although significant differences from placebo remainedonly for perseverative errors (F = 2.59, p = 0.04, d = 1.75) and rule-break errors (F = 2.55, p = 0.04 d = 1.49). Although this trend wasevident for all of the other maze outcome measures (d’s rangedfrom 0.07 to 1.01), no other planned comparisons were signifi-cant. Administration of donepezil improved performance over thatobserved for placebo for all measures, although none of the plannedcomparisons reached significance (d’s ranged from 0.12 to 0.87).
Table 2 and Fig. 3 display the means and standard deviationsfor exploratory and working memory errors from trials 1–5 ineach treatment group. For exploratory errors, all treatment groupsshowed a reduction across trials that was best described by a log-arithmic function (Table 3). For working memory errors, slopeswere marginally positive for the scopolamine group and shallow,but negative for all other groups; this was best described overallby a logarithmic function (although the r2 values were small). Forexploratory errors, no differences were observed between groupsfor intercept (F = 1.45, p = 0.24) or slope (F = 1.35, p = 0.27). Differ-ences between groups for intercept of working memory errorswere observed between placebo and scopolamine (mean diff = 3.30,p < 0.001), donepezil and scopolamine (mean diff = 2.71, p = 0.01),and placebo and scopolamine plus donepezil (mean diff = 2.48,p = 0.02). No differences were observed between groups for loga-rithmic slope of working memory errors (F = 0.25, p = 0.86).
Fig. 4 shows the change from baseline scores for each GMLT
outcome measure adjusted statistically for change in visuomotorspeed, as measured by the Chase test. Re-analysis of the differ-ence between treatment conditions indicated that deteriorationfrom baseline observed with scopolamine treatment remained sig-nificantly greater than that for placebo for perseverative errors(F = 5.71, p = 0.02, d = 2.77), and rule-break errors (F = 5.16, p < 0.03,d = 2.24). Although differences between treatment conditions forthe other adjusted change from baseline scores became non-significant with the adjustment for change in visuomotor speed,the magnitudes of the differences remained large (completiontime, d = 1.13; exploratory errors, d = 1.14). Statistical adjustmentfor changes in visuomotor speed rendered the differences betweenscopolamine and scopolamine plus donepezil non-significant forall of the outcome measures. However, the magnitude of thisdifference remained large for maze completion time (d = 1.06), per-severative errors (d = 1.79), and rule-break errors (d = 1.53), but notfor exploratory errors (d = 0.86). Statistical adjustment for changein visuomotor speed resulted in the elimination of statistically sig-nificant differences between change from baseline under donepeziland placebo, with small-to-medium effect sizes for each of thesecomparisons (d’s ranged from 0.04 to 0.79).
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y and working memory errors (rule-break plus perseverative) for each treatment
ercept r2a Log function Intercept r2a
.48 0.66 −1.90 15.06 0.69
.49 0.91 −3.97 15.51 0.91
.88 0.89 −4.32 15.00 0.97
.72 0.93 −3.47 12.90 0.93
.13 0.03 0.13 5.13 0.05
.36 0.11 −0.50 3.38 0.19
.53 0.44 −0.33 1.36 0.30
.43 0.51 −0.53 1.40 0.71
The final analysis aimed to determine the extent to whichchanges in errors of executive function (i.e. rule-break plus per-severative errors) were related to changes in errors of short-termmemory (i.e. exploratory errors). Results from this analysis indi-cated that, with changes in rule-break plus perseverative errorscontrolled statistically, the difference in change from baselinein the number of exploratory errors between with scopolamineand placebo treatment was no longer significant (F = 0.003,p = 0.96, d = 0.03), nor were the differences between placebo anddonepezil treatments (F = 3.95, p = 0.06, d = 0.81), and scopolamineand the scopolamine plus donepezil treatments (F = 0.07, p = 0.72,d = 0.14). Changes in exploratory errors, with working memoryerrors statistically controlled for revealed the same pattern asabove, with differences in change from baseline in the numberof exploratory errors no longer significant between the scopo-lamine and placebo groups (F = 2.65, p = 0.12, d = 1.10), placebo anddonepezil groups (F = 0.84, p = 0.37, d = 0.32), or between scopo-lamine and scopolamine plus donepezil groups (F = 1.41, p = 0.25,d = 0.78). Correlations between change from baseline in exploratoryerrors and working memory errors were significant for placebo(r = 0.67, p = 0.007), donepezil (r = 0.61, p = 0.02), and scopolaminewith donepezil (r = 0.77, p = 0.001), but not scopolamine (r = 0.43,p = 0.11).
4. Discussion
The current study examined the extent to which modulationof cholinergic neurotransmission altered the different compo-nent cognitive processes of visuospatial executive function in
older adults. As observed previously, blockage of muscarinicreceptors with scopolamine induced large impairments in allaspects of performance on the hidden pathway maze learningtask (Snyder et al., 2005). However, the magnitude of this dele-terious effect was greater for working memory processes (i.e.rule-break and perseverative errors) than for short-term mem-ory processes (exploratory errors). Simultaneous facilitation ofcholinergic neurotransmission by co-administration of donepezilwith scopolamine reduced the magnitude of scopolamine-relatedimpairment. However, working memory processes and short-termmemory remained impaired when donepezil was co-administeredwith scopolamine, with the magnitude of persistent impair-ment relatively greater for working memory. In addition tochanging working memory processes, scopolamine was alsoassociated with a large impairment in visuomotor function,although changes in visuomotor function could not accountfor the effects of scopolamine, donepezil, or scopolamine anddonepezil on working memory functions. Thus, it is unlikelythat the changes in working memory processes observed inresponse to modulation of cholinergic neurotransmission weresecondary to changes in levels of alertness or sedation. Taken
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together, these data suggest that the visuomotor, short-term mem-ory and working memory processes that subserve visuospatialexecutive function are all dependent on cholinergic neurotransmis-sion.
In this study, rule-break and perseverative errors were classi-fied as errors related to working memory. These occurred whenindividuals choose to look, or re-look, for the next step in thehidden pathway in locations where it would never be located.Importantly, GMLT rules remain constant across trials and assess-ments (including baseline and practice assessments). Furthermore,if any of these rules are broken in the middle of a trial, visual andauditory feedback signals are given to the individual and they areunable to advance to the next correct location until they makethe correct move. With this consistency, it is highly unlikely thatthe scopolamine-related increase in rule-break and perseverativeerrors or the reduction of this effect with donepezil, occurredbecause individuals suddenly forgot or remembered the rules. Amore likely explanation is that modulation of cholinergic neuro-transmission changes the ability of individuals to use the task rulesto guide the acquisition and recall of the maze pathway and/orto monitor and adjust performance according to task feedbackand behavioral goals. Increased perseverative and rule-break errorson the GMLT have been observed in clinical groups with knownimpairments in executive function, including healthy children whohave been exposed to cocaine in utero, adults with schizophrenia,and children with attention-deficit/hyperactivity disorder (Mayes,Snyder, Langlois, & Hunter, 2007; Schroder et al., 2004; Snyder etal., in press; Snyder et al., 2008).
The observation that scopolamine increased errors related toboth short term and working memory functions, and that statisticalcontrol of working memory errors removed the effect of scopo-lamine on short-term memory errors, and the effects of workingmemory were removed when statistical controlling for short-termmemory errors, illustrates the interdependence between shortterm and working memory functions in hidden pathway mazelearning. It is also consistent with neuropsychological evidencethat individuals with primary impairments in either memory (e.g.,patients with temporal lobe injuries) or executive function (e.g.,patients with lesions or neurodegenerative diseases involving thefrontal lobes) have great difficulty performing hidden pathwaymaze learning tasks (Abrahams, Pickering, Polkey, & Morris, 1997;Kessels, De Haan, Jaap Kappelle, & Postma, 2001; Milner, 1965;Petrides & Milner, 1982). It is possible, although very rare, forhealthy individuals to make no rule-break or perseverative errors
when performing the GMLT. In contrast, because individuals donot know the location of the hidden pathway at the beginning ofeach assessment, they must make exploratory errors in order tolocate each step in the pathway. Individuals who adhere to taskinstructions advance through the maze solely on the basis of trial-and-error learning. With repetition over trials, individuals developa representation of the location of the pathway in memory. Theefficiency of short-term memory processes in pathway learningand memory are reflected in the reduction in exploratory errorsover trials. Had the short-term memory component of the mazetask been the only cognitive process dependent on cholinergic neu-rotransmission, we would have expected that the largest effectsizes observed in response to scopolamine alone or scopolamineand donepezil together would have been for exploratory errors,which was not the case. It should be noted, however, that the abil-ity to adhere to the task rules (working memory), and to develop arepresentation of the pathway in memory on the GMLT, are not the-oretically dependant as in typical ‘storage plus manipulation’ testsof short term and working memory, such as digit span forwards andbackwards. In accordance with maze learning paradigms on whichthe GMLT is based, short-term (or reference) memory for between
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trial information and working memory for within trial performancerequired processes which are qualitatively and temporally differ-ent (Olton, 1985). In the context of the GMLT, the ability to utilizetask rules and feedback do not depend on spatial span memory.Although a reduced capacity to use memory-based strategies innegotiating the maze would lead to a greater reliance on trial-and-error strategies, it does not follow that this would also leadto a significant impairment in error monitoring and rule adherence(rule-break and perseverative errors), although the opportunity forsuch errors would be increased. As shown in Fig. 4, working mem-ory errors were greater for the scopolamine group from the firsttrial (when trial and error strategies are used by all groups of neces-sity), and persisted to the fifth trial without decrease in frequency,despite the decrease in exploratory errors related to short-termmemory. This suggests that working memory impairments werenot secondary to short-term memory impairments.
Although donepezil ameliorated scopolamine-related declineon each of the GMLT performance measures, when given alone itimproved only visuomotor function. These data are consistent withother observations that donepezil increases visuomotor activity inhumans (Seltzer, 2007). Interestingly, unlike the effects observedfor working memory functions, co-administration of donepezilwith scopolamine did not reduce the magnitude of scopolamine-related impairment in visuomotor function. Thus, donepezil andscopolamine may modulate performance on the hidden pathwaymaze learning differently for working memory and visuomotorprocesses. While this is consistent with the different mechanismsof the two compounds in modulating cholinergic neurotransmis-sion, it may also reflect relative differences in the doses of eachcompound used in this study, the sample used, or even the taskitself.
The results of the current study show that working memoryfunctions are dependent upon normal cholinergic neurotrans-mission. Most human psychopharmacological models considercholinergic neurotransmission to be most important for normalmemory encoding functions (Giocomo & Hasselmo, 2007; Gold,2003; Power et al., 2003; Rogers & Kesner, 2003). In this context, thelarger effects of scopolamine and donepezil on working memorythan on short-term memory functions is surprising. However, pre-vious studies have found that scopolamine disrupts integrative orexecutive and working memory processes, including reduced cog-nitive flexibility in rodents (Cabrera, Chavez, Corley, Kitto, & Butt,2006; Ragozzino, 2003; Ragozzino, Jih, & Tzavos, 2002), dual taskperformance in humans (Rusted & Warburton, 1988), and the abil-
ity to maintain performance as task difficulty increases in humans(Kopelman & Corn, 1988; Rusted & Warburton, 1988). A recentpharmacological fMRI study found that scopolamine attenuatedactivation of the prefrontal cortex according to the level of diffi-culty on an object location learning task (Bullmore et al., 2003, seealso Thiel, 2003).
Recent pharmacological evidence also suggests that acetyl-choline can modulate executive functions. It has been proposedthat DA in the basal ganglia performs a gating function to inter-nal noise and external distraction to frontal areas by influencingthe states of the striatum, which provides targeted disinhibition tothe cortex (Gruber et al., 2006). Mameli-Engvall et al. (2006) haveshown in mice that acetylcholine acts hierarchically on DA affer-ents in the basal ganglia, thereby controlling their firing rate andmodulating the responsiveness of the system to external inputs.This mechanism, they hypothesized, facilitates adaptive behav-ioral responses within a noisy environment and against internalnoise. Cragg (2006) has shown recently that the responses of stri-atal DA neurons can be amplified by pauses in the tonic activityof acetylcholine neurons to which they are connected monosy-naptically. Taken together, these studies suggest that acetylcholine
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may modulate DA neurotransmission in the basal ganglia and affectperformance on tasks of executive function such as the GMLT.
The efficiency of different attentional networks has been asso-ciated with specific neurochemical modulators (Ellis & Nathan,2001; Fan, Wu, Fossella, & Posner, 2001). Disruptions to the ori-enting of visual attention have been observed in blockade ofacetylcholine neurotransmission in the intraparietal cortex inmonkeys (Davidson & Marrocco, 2000), and in cholinergic deple-tion in Alzheimer’s disease (Parasuraman, Greenwood, Haxby, &Grady, 1992). Impaired performance on a visual vigilance task hasalso been observed in humans after scopolamine administration(Wesnes & Warburton, 1984). Giocomo and Hasselmo (2007) pro-pose that acetylcholine modulates cortical dynamics by alteringthe dominant influence of afferent inputs for encoding of extrin-sic information (requiring high muscarinic activity), and recall ofintrinsic feedback (associated with low muscarinic activity). Theysuggest the parahippocampal region mediates working memory fornovel stimuli (but not familiar stimuli), which is impaired by cholin-ergic blockade. Effects of acetylcholine blockade on attentionalorienting tasks may be related to a similar mechanism associatedwith attentional deployment to extrinsic novel stimuli (Giocomo& Hasselmo, 2007; Hasselmo & Stern, 2006). Such an effect wouldlikely compound the influence of scopolamine on working mem-ory functions which require visual orienting to novel stimuli (Awh& Jonides, 2001; Bor & Owen, 2006; Cowan & Morey, 2006), such asis required by trial-and-error feedback, and stimulus selection onthe GMLT.
In general, our findings are consistent with the range of effects ofscopolamine on spatial processing observed in previous research.These results are novel in that they suggest that scopolamineaffects multiple cognitive functions required for self-guided searchin novel rule-bound environments that require continuous mon-itoring of performance from task feedback for effective learning.Further, they suggest that cholinergic modulation affects spatialworking memory processes that combine to alter memory encod-ing and recall efficacy. Further studies will be required to determinewhether these effects are specific for individual working mem-ory processes, such as rule maintenance or error monitoring, andwhether multiple within-task requirements additively impair shortterm, and working memory abilities under scopolamine challenge.
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