APOE e4 polymorphism in young adults is associated with improved attention and indexed by distinct neural signatures.

The APOE e4 allele, which confers an increased risk of developing dementia in older adulthood, has been associated with enhanced cognitive performance in younger adults. An objective of the current study was to compare task-related behavioural and neural signatures for e4 carriers (e4+) and non-e4 carriers (e4-) to help elucidate potential mechanisms behind such cognitive differences. On two measures of attention, we recorded clear behavioural advantages in young adult e4+ relative to e4-, suggesting that e4+ performed these tasks with a wider field of attention. Behavioural advantages were associated with increased task-related brain activations detected by fMRI (BOLD). In addition, behavioural measures correlated with structural measures derived from a former DTI analysis of white matter integrity in our cohort. These data provide clear support for an antagonistic pleiotropy hypothesis--that the e4 allele confers some cognitive advantage in early life despite adverse consequences in old age. The data implicate differences in both structural and functional signatures as complementary mediators of the behavioural advantage.

A role for glutamate in subjective response to smoking and its action on inhibitory control.

RATIONALE: Our previous study using memantine in smokers suggests that there may be a differential role for N-methyl-D-aspartate (NMDA) receptors in the subjective and cognitive effects of smoking. OBJECTIVES: This study was designed to investigate if D-cycloserine (DCS) would modulate the subjective and cognitive effects of limited smoking. METHODS: Forty-eight habitual smokers abstinent for a minimum of 2 h were randomly allocated to receive either placebo or 50 mg DCS (double-blind) and were subsequently required either to smoke half of one cigarette or to remain abstinent. Subjective and physiological effects of DCS were measured at baseline, 90 min postcapsule, and again after the partial-smoking manipulation, while the effects on sustained attention (rapid visual information processing test--RVIP) and cognitive flexibility (intra-extra dimensional set-shift test--IED) were evaluated only after the partial-smoking manipulation. RESULTS: DCS alone did not produce significant subjective effects other than an increase in ratings of "Stimulated". In combination with partial smoking, however, DCS blocked the smoking-induced increase in "Stimulated" and the decrease in "Relaxed" ratings. Furthermore, in combination with smoking, DCS reduced the number of false alarms during the RVIP test (an index of inhibitory control) and produced a small increase in diastolic blood pressure. DCS failed to modulate IED performance. CONCLUSIONS: These findings provide further evidence of a role for glutamate release in the subjective effects of smoking but not the effects on attention and cognitive flexibility. Furthermore, our results indicate that glutamate release may also be involved in the effect of smoking on inhibitory control.

Positive effects of nicotine on cognition: the deployment of attention for prospective memory.

RATIONALE: Human and animal studies over the last two decades report that nicotine can improve cognitive performance. Prospective memory (PM), the retrieval and implementation of a previously encoded intention, is also improved by pre-administration of nicotine. As with other nicotine effects, however, predicting precisely how and when nicotine improves the processes engaged by PM has proved less straightforward. OBJECTIVE: We present two studies that explore the source of nicotine's enhancement of PM. Experiment 1 tests for effects of nicotine on preparatory attention (PA) for PM target detection. Experiment 2 asks whether nicotine enhances processing of the perceptual attributes of the PM targets. MATERIALS AND METHODS: Young adult non-smokers matched on baseline performance measures received either 1 mg nicotine or matched placebo via nasal spray. Volunteers completed novel PM tasks at 15 min post-administration. RESULTS: Experiment 1 confirmed that pre-administration of nicotine to non-smokers improved detection rate for prospective memory targets presented during an attention-demanding ongoing task. There was no relationship between PM performance and measures of preparatory attention. In experiment 2, salient targets were more likely to be detected than non-salient targets, but nicotine did not confer any additional advantage to salient targets. CONCLUSION: The present study suggests that nicotinic stimulation does not work to enhance perceptual salience of target stimuli (experiment 2), nor does it work through better deployment of preparatory working attention (experiment 1). An alternative explanation that nicotine promotes PM detection by facilitating disengagement from the ongoing task is suggested as a future line of investigation.

Nicotine effects on retrieval-induced forgetting are not attributable to changes in arousal.

BACKGROUND: There is emerging evidence from behavioural studies in humans for nicotinic modulation of inhibitory control. Administration of nicotine, however, also increases general arousal, and this may be responsible for the cognitive enhancing effects of nicotine. DISCUSSION: To test an arousal explanation of nicotine's effects on cognitive inhibition, this study compared the separate and combined effects of an acute dose of nicotine and an arousal manipulation on inhibitory processes associated with the retrieval-induced forgetting (RIF) paradigm. RESULTS: In a double blind placebo controlled design, 1.0 mg of nicotine delivered via nasal spray to non-smoking healthy young adults significantly increased the retrieval-induced forgetting observed in episodic list learning, relative to the placebo condition. In contrast, negative arousal evoked by an unsolvable anagram task had no effect either separately or in combination with nicotine. CONCLUSION: This result argues against the attribution of nicotine-induced changes in RIF performance to non-specific arousal effects. It suggests, furthermore, that pharmacological manipulation of the RIF produces effects that are qualitatively distinct from mood-induced effects. We consider these changes to relate to the direct modulation of information processing by nicotine.

Non-cholinergic modulation of antisaccade performance: a modafinil-nicotine comparison.

INTRODUCTION: The antisaccade task provides a powerful tool with which to investigate the cognitive and neural systems underlying goal-directed behaviour, particularly in situations when the correct behavioural response requires the suppression of a prepotent response. Antisaccade errors (failures to suppress reflexive prosaccades towards sudden-onset targets) are increased in patients with damage to the dorsolateral prefrontal cortex, and in patients with schizophrenia. Nicotine has been found to improve antisaccade performance in patients with schizophrenia and healthy controls. This performance enhancing effect may be due to direct effects on the cholinergic system, but there has been no test of this hypothesis. MATERIALS AND METHODS: In a double blind, double dummy, placebo-controlled design, we compared the effect of nicotine and modafinil, a putative indirect noradrenergic agonist, on antisaccade performance in healthy non-smokers. RESULTS AND DISCUSSION: Both compounds reduced latency for correct antisaccades, although neither reduced antisaccade errors. These findings are discussed with reference to the pharmacological route of performance enhancement on the antisaccade task and current models of antisaccade performance.

Nicotine improves memory for delayed intentions.

RATIONALE: The present paper asked first whether the cholinergic agonist nicotine improves memory for delayed intentions (prospective memory, ProM) and second whether pharmacological dissociation would support the psychological distinction that is made between strategic (effortful) and automatic (non-effortful) intention activation in prospective memory. OBJECTIVES: To use nicotine as a pharmacological tool with which to examine the neurochemical bases of prospective memory and to dissociate strategic from automatic components of ProM retrieval. METHODS: In three experiments, minimally deprived (2 h) smokers either smoked or abstained prior to completing a standard prospective memory study. This involved participants in the simultaneous processing of a ProM task and a cover task (ongoing between the setting and the recall of the intention). Here, the ongoing task involved lexical decision (LDT), while the ProM task required a response to pre-specified target items occurring within the LDT stimuli. Variations in task instructions were used to manipulate the processing requirements of the ProM task, the attention allocated to the ProM task and the balance of importance assigned to the ongoing and ProM tasks. RESULTS: In experiment 1, where the ProM processing was automatic, nicotine did not improve ProM accuracy. In experiment 2, where the ProM task involved strategic processing, positive effects of nicotine were observed. In experiment 3, we covaried ProM task instructions, assigned task importance and nicotine conditions. We observed a main effect of nicotine on ProM accuracy, a main effect of task on ProM accuracy and a main effect of assigned task importance on ProM accuracy. There were no interactions between the factors. CONCLUSIONS: Employing both direct and indirect manipulations of strategic engagement, we demonstrated nicotine-induced enhancement of performance on the ProM task. The results are consistent with the view that relatively small changes in instruction and in task variables engage strategic processing in a ProM task and that when these conditions stretch cognitive resources, nicotine may significantly improve performance.

Verbal fluency facilitated by the cholinergic blocker, scopolamine.

This study was designed to explore putative facilitatory effects of low doses of scopolamine (SP) on phonemic (letter) and semantic (category) verbal fluency. A double-blind, parallel-group design was used with 36 subjects who completed a test battery before and 2 h after 0.6 mg or 1.2 mg of SP or placebo. Fluency measures included total number of words generated, clustering (the production of words within semantic or phonemic subcategories) and switching (the ability to shift efficiently to new subcategories). Low doses of scopolamine increased phonemic fluency, as has been shown previously. Semantic fluency was not increased by SP, although subjects treated with 1.2 mg of SP generated higher-frequency words. SP did not affect clustering or switching. It is suggested that phonemic and semantic fluency reflect distinct cognitive processes.

Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease.

Nicotinic systems play an important role in the neural basis of working memory and attention. Recent progress in understanding of the structure, function, and distribution of central nervous system (CNS) nicotinic receptors and their pharmacology has opened up new possibilities for novel CNS therapeutics with nicotinic agents. In this paper, we review the theoretical justification and the experimental evidence supporting these developments. We focus on the applications of nicotinic agonists in CNS disorders that are degenerative in nature, namely Parkinson's disease and Alzheimer's disease. We suggest that there is considerable potential for therapeutic applications in the near future. Clinically, two major issues remain: (a) the selectivity of effects, that is, developing compounds which are selective in producing improvement in cognition, motor function, attention, or pain without significant side-effects; and (b) the realistic likelihood of long-term improvements in everyday functioning in people who have degenerative diseases.

Moving out of the laboratory: does nicotine improve everyday attention?

The most robust demonstrations of the nicotine-related performance effects on human cognitive processes are seen in tasks that measure attention. If nicotine does have some potential for enhancing attention, the obvious question to ask is whether the effects demonstrated in the laboratory hold any significance for real-life performance. This paper describes three studies that compare the effects in smokers of a single own brand cigarette on laboratory tests of attention and on everyday analogues of these laboratory tasks. In the laboratory measures of sustained attention and in the everyday analogue, performance advantages were registered in the smoking condition. These benefits were observed in smokers who abstained for a self-determined period of not less than 2 h. The studies were unable to replicate previous research reporting positive effects of smoking on a laboratory task of selective attention, the Stroop task. Small but significant improvements in performance were registered in the everyday analogues, which involved sustaining attention in a dual task situation, a telephone directory search task and a map search task. In addition, smokers showed a significant colour-naming decrement for smoking-related stimuli in the Stroop task. This attentional bias towards smoking-related words occurred independent of whether they had abstained or recently smoked an own brand cigarette. The effect is discussed in terms of the two-component model of processing bias for emotionally valenced stimuli.

Effortful processing is a requirement for nicotine-induced improvements in memory.

We report two studies examining the effects of nicotine on memory in minimally deprived smokers. In experiment 1, semantically related words were recalled significantly better than unrelated words following nicotine, even when volunteers were explicitly instructed to target the unrelated word set for recall. Experiment 2 examined the effect of nicotine on two different types of lexical association: association by joint category membership (semantically related items), and association by derived meaning ("encapsulated" word pairs). Nicotine-induced improvements in recall were observed only for category associates and not for encapsulated word pairs. This implies that explicit, effortful processing of material in the presence of nicotine is necessary for improved recall performance to be observed.

Deprivation state but not nicotine content of the cigarette affects responding by smokers on a progressive ratio task.

In two experiments, we used a progressive ratio schedule to explore factors associated with smoking motivation. In study 1, smokers who had abstained for more than 8 h bar-pressed for longer to obtain puffs on a cigarette than did non-deprived smokers. Neither group, however, showed nicotine-induced improvements in performance on an attention-demanding task. In the second study, two groups of minimally deprived smokers worked on the progressive ratio task for puffs of either a standard or an ultralow nicotine cigarette. The amount of work expended for puffs was the same for both cigarettes. The groups were also indistinguishable in terms of their subjective experience of the impact of smoking. These results suggest that the addition of nicotine to the cigarette may not have an immediate impact on the effort expended for a puff on that cigarette, and that short term changes in craving may be observed independent of satiety effects associated with nicotine ingestion. We conclude that the progressive ratio task is a useful and sensitive measure of desire to smoke, although the two experiments highlight the complexity of the relationship between subjective, objective and behavioural measures of smoking and nicotine ingestion in humans.

Perspectives on cognitive psychopharmacology research.

This article discusses new perspectives in the psychopharmacology of cognition and analyses the advantages and disadvantages of using drugs as tools to study the mechanisms underlying memory functions. The use of 'stages' in the processing of information as a means for the analysis of cognitive operations is critically discussed as a rigid approach which can only partially accommodate different cognitive functions. Theoretical models of memory 'systems' and allocation of attentional resources are presented alongside findings from the two types of more commonly used drugs in cognitive psychopharmacology: the benzodiazepines (BZ) and the anticholinergics. In a post-hoc analysis of the effects of BZ and scopolamine on memory and attention, it has become clear that these newer theoretical models can accommodate most, but not all, of the effects of BZ and scopolamine on cognition. It is suggested that the development of cognitive tasks on the basis of these models and the execution of prospective studies with drugs as tools taking in to account the 'systems' approach to interpretation of data may be more useful for understanding cognitive functions.

Methodological considerations in nicotine research: the use of "denicotinised" cigarettes as the control condition in smoking studies.

In this study, we report on the comparability of the subjective experience and smoking style elicited by two commercially available cigarettes which differ in nicotine levels, one containing a 'regular' delivery of 0.7 mg and the other containing minimal (0.1 mg) nicotine. Our findings suggest subtle differences in the smoking of these two cigarettes, with the 'denicotinised' cigarette being smoked for longer and with more puffs taken. While these subtle differences have little significance for studies concerned with the effects of nicotine on cognitive performance measures, they are certainly important for studies concerned with the role of nicotine in maintaining smoking behaviour.

Structuring the acquisition and retrieval environment to facilitate learning in individuals with dementia of the Alzheimer type.

Three experiments using variations of the Subject Performed Task (SPT) paradigm examined whether structuring the learning and retrieval environment would improve learning in individuals with mild to moderate dementia of the Alzheimer type (DAT). Experiment 1 examined the role of enactment at encoding and retrieval, and found that with appropriate retrieval support DAT volunteers do benefit from enactment at encoding. Experiment 2 showed that recall was further enhanced when the list of SPTs formed a cohesive, goal-directed sequence of actions. In Experiment 3, DAT subjects acquired a more complex action-based sequence and maintained it accurately over a short period of time. It is concluded that the provision of contextual support at encoding and at retrieval can enhance residual memory in individuals with DAT.

Cholinergic control of cognitive resources.

In this paper, we describe our approach to the investigation of cholinergic modulation of human information processing. In a continuing series of studies from our laboratories, we have systematically examined the extent to which current psychological models of information processing provide an adequate framework for the interpretation of the modulatory effects of cholinergic agents on cognitive performance measures. We suggest that the data are consistent with the view of attention and memory as processes which operate through a common, limited capacity executive mechanism, rather than separable serial processes described in the traditional modular models of memory.

Patterns of facilitation of memory by nicotine.

A single oral dose of 1.5mg of nicotine was administered to healthy young normal males in a placebo-controlled double-blind study. The nicotine produced a significant improvement in the number of words recalled from a 32 item list. An examination of the individual serial position curves showed that most subjects were recalling either predominantly from the first half of the list or predominantly from the second half of the list. Examination of these groups separately showed that nicotine improved recall for the part of the list that was being recalled better in the placebo condition. These results are consistent with the hypothesis that nicotine was supplying additional processing resources and that deployment of these is under the strategic control of the subject.

A comparison of the attentional and consolidation hypotheses for the facilitation of memory by nicotine.

Studies examining facilitation of human memory by the administration of nicotine have given equivocal results and it has been argued that the positive findings on memory may have resulted indirectly from an effect on attention, rather than from a direct effect on memory storage. This study compared the "attentional" and the "mnemonic" hypotheses directly, by using both immediate and delayed recall tasks in a verbal free recall study, in which volunteers smoked on a fixed regime during presentation of a 32 word list (namely, one puff after each of eight 4-word blocks). The serial position curve for immediate recall demonstrated a significant improvement on the later blocks of the list (an attentional effect) when volunteers smoked a nicotine-containing cigarette. However, improved performance was found for items at the beginning of the list on the delayed recall measure and this improvement was significant on the first block of 4 words. Since nicotine input had been taken after presentation of this information, the results demonstrate post-learning facilitation of memory by nicotine.

Facilitation of memory by post-trial administration of nicotine: evidence for an attentional explanation.

In human studies, reported performance improvements with post-trial administration of nicotine have all involved associative learning (Mangan and Golding 1983; Colrain et al. 1992; Warburton et al. 1992). In this study, post-trial nicotine, obtained through smoking a cigarette, improved free recall of lists of unrelated words under conditions which limited the opportunity for associative learning. However, the nicotine-induced advantage was not observed when volunteers were required to complete a secondary (attention) task during the post-trial period in which they smoked. The results suggest that post-trial effects depend on the opportunity for stimulus processing after input, and that nicotine improves performance by increasing the attentional resources available for such strategic processing.

A comparison of the effects of scopolamine and diazepam on working memory.

Two drug models of memory dysfunction, namely the benzodiazepine and the cholinergic models, have emerged from the considerable number of studies which have examined drug effects on information processing. The reported impairments produced by administration of compounds from these two families appear to be more similar than dissimilar, and to date, direct comparisons on traditional memory tasks have failed to differentiate the models. This study compared the effects of diazepam and scopolamine on tasks associated with separable components of working memory. The results indicate that this model also fails to discriminate between the drug models; both compounds selectively impaired tasks associated with the central executive mechanism and failed to disrupt tasks associated with the articulatory loop or the visuospatial scratchpad.