Assessment of the effects of nicotine on human performance involves careful selection of appropriate cognitive, behavioral, and/or imaging measures. Increasingly, measures are combined in studies of nicotinic agents in humans in an attempt to draw correlations between cognitive and behavioral effects and neuroanatomical or neurophysiologic mechanisms.
Cognitive measures generally focus on learning, memory, and attention. Whether nicotine enhances cognitive function apart from its ability to relieve nicotine withdrawal has motivated the search for cognitive measures that would be independent of or not influenced by withdrawal. Studies of the cognitive effects of nicotine using cigarette smokers have been confounded by withdrawal effects that have obscured the effects of nicotinic stimulation alone.5859 Studies of nonimpaired humans and patients with a variety of disorders have suggested that nicotinic stimulation improves certain types of attentional processes, learning, and memory under conditions of significant cognitive load.60
Tasks that measure sustained or continuous attention performance appear to show the most robust nicotinic effects. Tasks such as the rapid visual information processing task or the Connor's continuous performance test have shown sensitivity to nicotinic stimulation in normal volunteers,60,61 patients with ADHD, and patients with Alzheimer's disease.6263 Measures of selective attention have produced more mixed results. For example, the Stroop task is a measure of conflict between verbal and color processing. While some studies have demonstrated a reduction in the Stroop effect with cigarettes or nicotinic stimulation64 others have shown inconsistent results60 or results suggesting that nicotine enhances the Stroop effect.23 Measures which examine attentional performance over very long periods of time have shown positive effects of nicotine,65 especially in preventing performance decrements. Nic-otinic stimulation has been shone to improve attentional performance in primates, particularly when distraction is present,66 while little improvement was seen without the distraction. This paradigm should probably be used more frequently in studies of attentional effects of nicotinic stimulation in humans.
Within continuous or sustained performance tests, it is possible for the effects of nicotine or nicotinic stimulation to be manifest in some but not all aspects of the task. For example, in a study of adults with ADHD, nicotine patch administration reduced errors of omission but did not have any significant effect on errors of commission,67 suggesting an effect on sustained attention without a general increase in responding or a shift in response strategy. A reduction in attentional performance errors is an effect seen in a variety of different paradigms with different populations, such as patients with Alzheimer's disease68 and schizophrenia,69 and suggests that error reduction in cognitive tasks is a measure which may prove particularly sensitive to nicotinic effects. This is further supported by studies of the effects of nicotinic antagonists. Newhouse and colleagues70 showed that the nicotinic antagonist mecamylamine produced a dose-related increase in errors on a nonverbal learning task (the repeat acquisition task) that required significant and sustained attention to a computer screen. Nicotine administration improved error performance on this task in a group of Alzheimer's disease patients.71
In tasks which have examined divided attention, nicotine administration has shown improvement of performance on naturalistic telephone directory search task with concomitant tone counting60 in normals. However, in this laboratory, nicotine administration appeared to produce a reduction in overall performance on verbalvisual divided attention tasks involving number string retrieval and maze completion in a group of patients with Parkinson's disease (Newhouse et al., unpublished). In a study examining the effects of nicotine on intensity and selectivity features of attention, Mancuso and colleagues61 showed that nicotine appeared to have no effect on attentional switching or selectivity but did appear to improve intensity features of attention, suggesting a general increase in processing resources.
Measures of learning and memory have generally been focused on variants of serial learning such as words, numbers, etc. Rusted and colleagues have suggested that learning and memory tasks that involve effortful processing (as opposed to automatic processing) are more likely to demonstrate nicotinic effects or improvements. This may be due to the ability of nicotinic stimulation to enhance cognitive resources overall.72 In addition, attentional improvement during encoding may also be responsible for an improvement in the amount of information placed in working memory. There is also evidence for nicotinic effects on memory consolidation as well.52 72 73 An example of a useful measure in studies of learning with nicotinic stimulation with a significant effortful component is the selective reminding task (SRT). This measure involves serial list learning of unrelated words with the caveat that, from trial to trial, the only words repeated are words not recalled from the previous trial. In a study of the effects of the novel nicotinic agonist ABT-418 in Alzheimer's disease patients, significant positive effects were found on the SRT task on measures of word recall and recall failure;17 both of these measures reflect processes of working memory. Additionally, studies of the effects of the nicotinic antagonist mecamylamine have shown that the learning rate on this task (the amount learned/the amount remaining to be learned) can be measured accurately and may be a more meaningful measure of cognitive capability.25 Measures of verbal recall (which demand significant effort demanding) are generally used in preference to verbal recognition (presumed to be less demanding). However, Rusted and colleagues have shown significant effects of nicotine administration on recognition of Chinese characters.73 The test subjects' lack of familiarity with these characters may have contributed to the effort required to preserve recognition of them and may have increased the effort demanded of this task. Another type of memory task that appears to show nicotinic responsivity is match-to-sample tasks, particularly in primates.74 In these tasks, a sample item is demonstrated for a brief period of time, then a variable delay interval ensues followed by the appearance of a probe item. The subject must determine whether the probe matches the original sample. Such tasks have only occasionally been used in studies of cognitive enhancement in humans,75 probably due to concerns about having enough unique test items and interference effects, but this task may be a useful task for nicotinic assessment, particularly when long delay intervals occur between sample and probe items. Verbal and nonverbal versions could be constructed as long as the task is made sufficiently difficult.
Measures of nonverbal learning have only rarely been used in the assessment of nicotinic drug effects. Measures of memory for spatial location have shown some positive effects in a study of the nicotinic agonist ABT-418 in Alzheimer's disease patients. Nonverbal serial learning was used in studies of the nicotinic agonist mecamylamine utilizing the repeated acquisition task,70,76 in which subjects learn a sequence (chain) of button pushes on a key pad or button box. The subject learns a sequence prior to the beginning of the experiment and is periodically asked to reproduce that chain or sequence after drug administration. In addition, during the experiment, the subject is periodically asked to learn a new chain of button pushes. This enables the assessment of both long-term memory and retrieval as well as the acquisition of new nonverbal information and shape of the acquisition curve. Mecamylamine not only produces an increase in errors of acquisition of new information on this task but also appears to decrease the ability of working memory to hold information. By contrast, retrieval of previously learned information (original chain) was not affected. The length of the chain can be adjusted to the cognitive abilities of the subject, which makes this task widely applicable to subject groups with varying cognitive abilities. Measures of visual memory that do not involve location have not been used frequently in studies of nicotinic effects, perhaps because of concerns about lack of sufficient forms for repeated measures designs.
Neuroimaging is rapidly becoming a new area for nicotinic investigation. The availability of ligands for PET and SPECT imaging of nicotinic receptors and nicotinic receptor function has opened up the possibility of functional assessment of the effects of nicotinic drugs. Initial neuroimaging studies were directed at documenting the involvement of nicotinic cholinergic systems in AD. Nordberg12 showed a significant correlation between the change in temporal cortex labeling of 11C-nicotine and cognitive function scores in AD patients using positron emission tomography (PET). Significant correlations were shown between cognitive dysfunction and the loss of nicotinic receptor binding in temporal and frontal cortices and hippocampus in patients using PET. Nordberg77 also examined the effects of treatment with the anticholinesterase tacrine in AD patients using PET and showed that brain nicotinic receptor binding of 11C-nicotine increased along with cerebral blood flow after three weeks of treatment. Extensive development of novel nicotinic ligands for PET and SPECT in the past several years offers additional opportunities for functional imaging including studies where functional activation patterns in the brain during memory tasks are measured by cerebral blood flow changes with PET.78 In addition to measuring nicotinic receptor function directly using these ligands, it may be useful to measure extracellular neurotransmitter levels such as dopamine that may be released with nicotinic stimulation. PET ligands are now available to estimate these levels. Pharmacokinetics, distribution, and pharmaco-dynamics of nicotinic agents at nicotinic receptors are parameters that can now be assessed with currently available or soon-to-be available PET ligands. Nicotinic SPECT ligands79 are currently in human trials and will shortly become available. The potential advantages of SPECT imaging are the longer half-life of the isotopes and smaller technical requirements for administration and imaging. Functional magnetic resonance imaging (fMRI) of the brain has become the most widely used method for real-time assessment of cognitive-anatomical relationships and assessment of the effects of cognitive operations on cerebral activity. However applications to examine the effects of nicotinic agents on cognitive performance and dribble activity using fMRI have been minimal. The utilization of this technology may have been limited in studies of nicotinic agents because of concerns that nicotinic stimulation or blockade may directly affect cerebral blood vessels,78 thereby confusing the effects of nicotinic stimulation or blockade on cognitive performance if blood flow becomes the proxy measure of activity (as it often is in fMRI).
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