Specific impairments in visuospatial working and short-term memory following low-dose scopolamine challenge in healthy older adults
Introduction
The role of the dopaminergic (DA) system in frontal cortex activity and working memory functions associated with the frontal cortex has been widely investigated. Animal experiments and recent pharmacological research in humans also suggests a role of the cholinergic system in working memory (Hasselmo & Stern, 2006). In humans, cholinergic neurotransmission has been widely implicated in sensory processing, attention, and memory encoding functions (Giocomo & Hasselmo, 2007). Although working memory and short-term memory impairments have been observed following administration of cholinergic antagonists in humans, this has 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 clear from these studies the degree to which working memory impairments produced by cholinergic antagonists are a consequence of attentional, sensory, or short-term memory impairments, and are consistent with spatial working memory deficits observed in animal studies. This study was designed to investigate the changes in short-term learning and memory, and working memory associated with modulation of central nervous system acetylcholine transmission in healthy older adults. We expected that administration of a muscarinic acetylcholine agonist (donepezil), antagonist (scopolamine), their co-administration, or placebo would produce different, but well-ordered performance profiles on a computerized version of a hidden pathway maze learning task designed to assess multiple aspects of change in different cognate abilities.
Executive function is often defined as a cognitive system that supports the integration of memory, planning, monitoring and motor functions towards goal-directed actions in a flexible manner (Baddeley, 1996, Goldman-Rakic, 1996; Levy & Goldman-Rakic, 2000; Postle, 2006). The maintenance of information in immediate memory, or short-term memory is distinguished from working memory, which requires the transformation, or manipulation of information above simple storage and retrieval (Baddely, 2003). Working memory may be regarded as a blanket term that encompasses operations such as memory updating, performance monitoring, inhibition of prepotent responses, and mental set-shifting, all of which support the optimal functioning of executive control (Lehto, Juujarvi, Kooistra, & Pulkkinen, 2003; Miyake, Friedman, Emerson, Witzki, & Howerter, 2000 but see Salthouse, Atkinson, & Berish, 2003 for a more ‘unitary’ account of executive function; and Koechlin & Summerfield, 2007 for a theory of functional hierarchical organization of the prefrontal cortex). While psychopharmacological investigations of working memory have focused 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 is a growing body of evidence showing the necessary involvement of acetylcholine (i.e. cholinergic neurotransmission) in working memory functions (Giocomo & Hasselmo, 2007; Hasselmo & Stern, 2006; Mameli-Engvall et al., 2006).
In rodents, the relationship between cholinergic neurotransmission and spatial working memory has been studied thoroughly using 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 of nicotinic or muscarinic acetylcholine receptors causes impairment in performance on all of these tasks (Blockland, 1996, Gold, 2003; Power, Vazdarjanova, & McGaugh, 2003; Sarter & Bruno, 1997; Sarter, Bruno, & Givens, 2003). Furthermore, co-administration of compounds that stimulate the release of acetylcholine or block the enzymatic breakdown of acetylcholine can overcome the impairments in visuospatial learning, working memory, and executive functions (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, mainly through blockade of muscarinic receptors with the antagonist scopolamine (Ellis et al., 2006; Wesnes, Simpson, & Kidd, 1988). However, despite the wealth of animal data on the effects of scopolamine on spatial working memory, most studies examining the effects of scopolamine on learning and memory, or working memory in humans have utilized auditory–verbal testing paradigms (e.g., effects on word list learning, paragraph learning, or verbal memory span; Curran et al., 1991; Ebert et al., 1998; Ellis et al., 2006; Mintzer & Griffiths, 2003; Tariot et al., 1996). When spatial cognition or working memory has been challenged in humans with scopolamine, the tasks chosen (e.g., Trail Making Test Part-B, delayed spatial memory, visual spatial short-term memory and delayed matching-to-sample) have required only passive storage and 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 scopolamine disrupts auditory–verbal short term and working memory, and spatial short-term memory in humans, the nature or magnitude of the effect of scopolamine on ‘active’ functions of spatial working memory is unclear.
Identification of the effects of cholinergic neurotransmission on attention, short-term memory, and working memory has been difficult to determine using standard neuropsychological tests for a number of reasons. First, most studies investigating the effects of compounds that act on the cholinergic system have been based on performance across batteries of neuropsychological tests that may differ in sensitivity to detect cognitive impairment or change (Collie, Maruff, Faletti, Silbert, & Darby, 2002; Osterberg, Orbaek, Karlson, Bergendorf, & Seger, 2000). Theoretical inferences regarding the presence and relative magnitude of impairment in domain, or process-specific functioning may be confounded by the different psychometric properties of tests used for comparison (Lewis, Maruff, & Silbert, 2005; Lewis, Maruff, Silbert, Evered, & Scott, 2006). Second, identifying the underlying processes which lead to impaired performance on complex tests of short-term memory or working memory are difficult to establish from methods that produce single outcome measures (such as speed or accuracy). The disruption to executive processes (e.g., working memory, goal maintenance), supporting functions (e.g., sensory processing, attention), or the domain itself (e.g., language, visuospatial or numerical processing) can produce sub-optimal performance on tests 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 been noted 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 verbal and visuospatial executive functions in humans. When faced with difficult visual tasks, humans generally develop verbal strategies to guide performance on spatial tasks even in the absence of linguistic stimuli, performance rules expressed verbally, or requirements for spoken responses (Gillett, 2007). These issues aside, it is increasingly recognized that in complex tasks, it is important to identify the sources of performance variability within and between groups and individuals (Leite, Ratcliff, & Hale, 2007; Ratcliffe, Spieler, & McKoon, 2000; Verhagen, Cerella, Semenec, Leo, & Steitz, 2002), and to use appropriate statistical methods for characterizing the parameters of change or impairment (Collie et al., 2002, Maruff et al., 2006). One approach that can accommodate these imperatives is to use tasks that can measure component processes that contribute to performance on the same test, and from which valid comparisons of relative cognitive impairments can be inferred using appropriate statistical methods. Such an approach need not assume that the underlying processes are independent or organized hierarchically but can investigate associations between measures of the different component processes.
In a recent study, we used performance on a hidden pathway maze learning task (the Groton Maze Learning Test; GMLT) to investigate pharmacodynamic response to acute doses of scopolamine and donepezil, alone and together in healthy older people (Snyder, Bednar, Cromer, & Maruff, 2005). Older participants were recruited because of the known decline in cholinergic function with aging, hence the sensitivity of this population to compounds which enhance or impair the cholinergic system (Ellis & Nathan, 2001). The GMLT was chosen for this study because of its demonstrated sensitivity to drug effects, and its demonstrated neuroscientific validity, brevity, repeatability, and utility across groups according to 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 is adapted from the Milner “stepping stone” maze (Milner, 1965) and the Austin maze (Morrison & Gates, 1988). The GMLT is administered via touchscreen computer monitor, and individuals are required to identify, one step at a time, a pathway that is hidden in a 10 × 10 matrix. There are four rules of the task, which aid the discovery of the pathway by reducing the possible number of correct locations at each decision point to a maximum of three possibilities. That is, subjects are instructed not to move diagonally, not to 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 subject). The GMLT software measures the latency of each response and classifies it as correct or incorrect according to error type. The pathway is never revealed in its entirety, and the subject sees only the current correct location. Once the subject has worked their way through to the end of the pathway they must return to the start and find the same pathway again. Successful performance on the GMLT requires the individual to hold the task rules in working memory and use this information to guide trial-and-error learning in accordance with moment-to-moment performance feedback and the developing representation in memory of the actual pathway location.
Analysis of the responses made in learning the maze can indicate the integrity of different cognitive operations after pharmacological challenge (Snyder et al., in press). For example, assuming that subjects adhere to the task rules, errors made in finding the pathway (i.e. exploratory errors) reflect the ability to build a short-term spatial representation of the pathway in memory. The number of rule-break errors provides an index of the ability of individuals to hold and use the general rules in working memory, and to monitor ongoing performance. Perseverative errors (or the same error made in succession) provide an index of the individual's tendency to automatically repeat errors they have already made. Hence, while exploratory errors reflect spatial working memory processes, the combined measures of perseverative and rule-break errors provide a measure of working memory functions such as error/performance monitoring (Pietrzak et al., 2007; Pietrzak, Maruff, Mayes, Roman, Sosa, & Snyder, in press). The number of correct speeded responses made on a simple reaction time version of the maze (Chase test) can provide an index of visuomotor function. This can be used to establish the extent to which changes in working memory due to modulation of cholinergic neurotransmission are an indirect consequence of the reduced alertness, sedation, and changes in sensory 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 that were greatest 2.5 h after scopolamine administration (Snyder et al., 2005). Administration of donepezil (5 mg oral) 3 h prior to scopolamine ameliorated these deleterious effects. Interestingly, administration of donepezil by itself actually improved performance on the GMLT above baseline levels. However, the original study was designed to use the maze to measure the pharmacodynamic effects of scopolamine and donepezil administered alone and together. Consequently, only summary measures of maze performance were analyzed. There was no investigation of the interaction between the measures of the different cognitive operations necessary for optimal problem solving on the maze. Thus, while the earlier findings provide prima facie evidence that working memory is affected by modulation of cholinergic neurotransmission, we believe that a more detailed analysis is required to identify the associations between different cognitive operations pertaining to working and short-term memory on the GMLT.
The current paper presents that analysis, with the goal of decomposing performance on the hidden maze learning task into the component operations of spatial and working memory and examining how these operations are modulated by acetylcholine neurotransmission. We hypothesized that scopolamine would interfere with all of the component cognitive processes necessary for maze learning and that scopolamine-related impairment would be ameliorated by donepezil. We investigated the extent to which modulation of acetylcholine affected visuomotor speed, short term and working memory components of maze learning. These relationships were examined by computing standardized measures of change for the different outcome measures and comparing these between treatment conditions.
Section snippets
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 rigorous inclusion and exclusion criteria (summarized below), and were both willing and able to provide written informed consent. All subjects had normal or corrected to normal visual and auditory acuity, were in good general health or without any clinically significant abnormalities, had a normal ECG, and a Mini-Mental State Exam Score ≥28/30. Women were
Results
Two subjects were excluded from analysis due to missing data, resulting in 15 subjects in each treatment group. Group means and standard deviations for each of the GMLT outcome measures at baseline and 5.5 h after baseline under each treatment condition are shown in Table 1. The group means for the standardized changes from baseline scores are shown in Fig. 2 for each of the maze outcome measures. Fig. 2 indicates that, relative to baseline, the placebo group showed subtle improvement from
Discussion
The current study examined the extent to which modulation of cholinergic neurotransmission altered the different component cognitive processes of visuospatial executive function in older adults. As observed previously, blockage of muscarinic receptors with scopolamine induced large impairments in all aspects of performance on the hidden pathway maze learning task (Snyder et al., 2005). However, the magnitude of this deleterious effect was greater for working memory processes (i.e. rule-break
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