The principal computerized test found useful for determining nicotine effects on cognitive function in adults with ADHD is the Conners continuous performance test (CPT).5,6 To characterize possible effects on other aspects of neurobehavioral function, components of the Automated Neuropsychological Assessment Metrics (ANAM) battery have also been used: simple reaction time, spatial mental rotation, and delayed matching to sample.3435
The Conners CPT has been validated as an assessment tool for diagnosing ADHD and is sensitive to stimulant therapy;5,6 it has previously been shown to be sensitive to the effects of acute nicotine treatment in adults with ADHD.726 This is a 14-minute test in which the subject is instructed to respond as quickly as possible to a target stimulus, but to refrain from responding to a more rarely occurring nontarget stimulus. This differentiates the Conners CPT from other CPTs in which the subject must respond to rarely occurring stimuli and makes it sensitive to problems individuals may have in withholding inappropriate responses. Reaction time and variability in reaction time were measured over trial blocks during the course of the session and over different interstimulus intervals (ISI) of 1, 2, and 4 seconds. On the Conners CPT, response time variability typically increases over the course of the session and with longer ISIs. The hypothesis was that drug treatments would attenuate this degradation of performance. Errors of omission and commission were assessed, as was the composite measure of attentiveness (d'), which includes a weighted formula of response scores found to be sensitive to ADHD in adults12 and the positive effects of therapeutic treatments including nicotine.7 25 26
In the acute study,26 nicotine-induced improvement in attentiveness was discernible in terms of performance consistency on the Conners CPT. Smokers showed a significant reduction invariability of reaction time over blocks of the test session, while nonsmokers had a nearly significant reduction in variability of reaction time across different interstimulus intervals. In the chronic study,25 there was a robust (p<0.05) nicotine-induced attenuation of the rise in CPT hit-reaction-time standard error (SE) over blocks of the session. This measure provides an index of the shift in response time variability over the course of the session. The untreated control group showed a consistent rise in variability of response time over the course of the session. Significant nicotine-induced improvements were seen during the acute (p<0.05) and chronic (p<0.025) phases of treatment. The nicotine effects on the CPT appeared to be relatively specific inasmuch as no significant effects were seen on the ANAM tests of simple reaction time, spatial mental rotation, and delayed matching to sample.
Nicotinic treatment holds promise for treating attentional deficits seen in other disorders as well. In Alzheimer's disease patients, attentional performance has been found to be significantly improved by nicotine.224041 Recently, it was found that chronic nicotine patches with short-term administration — after 4 weeks of nicotine administration — nicotine caused a significant reduction in errors of omission in the Conners CPT, an attentional task.25 Supporting a nicotine-induced improvement in attention, this reduction in errors of omission was not at the expense of increased errors of commission. Thus the nicotine effect did not seem to be a mere increase in response rate; rather, a true increase in response accuracy seemed to be caused by nicotine treatment. The consistency of attention seemed to be improved by nicotine as well. In Alzheimer's patients, nicotine caused a significant reduction in variability of response speed on the CPT.
Nicotine-induced attentional improvement has been found in schizophrenics.24 Regardless of the haloperidol dose, nicotine caused a significant dose-related reduction in variability in response time on the Conners CPT. This contrasted with nicotine-induced improvements in short-term memory and mental processing speed, which were only seen as attenuation of deficits caused by moderate or high doses of haloperidol.
Nicotinic agonist-induced improvement in attention has been less evident in rat models than in humans. Sarter and co-workers did not find attentional improvements with either nicotine43 or the nicotinic agonist ABT-418,42 but did find an attentional deficit with the nicotinic antagonist mecamylamine. Bushnell also did not find any evidence of nicotine-induced improvement.4 In contrast, nicotine-induced attentional improvements in aged rats has been found recently, using a two-choice discrimination task.17 In this task, correct responses were signaled by the position of a light; signal duration was individually tritrated so that rats were performing with a baseline accuracy between 75 to 87% correct (mean light duration = 1.8 sec). Similarly, nicotine was found to enhance performance of a five-choice "tracking" task in which lights signaled the correct choice among five possibilities.13 It appears, then, that some of the problems in demonstrating a nicotine-induced attentional improvement in rats may be because of the structure of the task. Nicotine has been shown to increase adverse effects of proactive interference.11 With repeated trials and alternative response sites in the tasks typically used for assessing attention in rats, nicotine's effects on proactive interference may overshadow its effects on attention.
There is clear evidence showing the attentional improvements produced by nicotine in adults with ADHD. Similar effects were seen in normal nonsmoking subjects as well as those with attentional deficits associated with Alzheimer's disease and schizophrenia. Nicotine administered via a skin patch appears to be safer than smoking inasmuch as it does not contain the components of tar and the gas phase of a cigarette. The dependence liability for the nicotine skin patch appears to be lower than for smoking. Since nicotine skin patches are currently only approved for use to aid in smoking cessation, additional evaluation is needed to demonstrate safety and efficacy for other indications, including attentional impairment. The research thus far is promising: nicotine skin patches may prove to be useful as a treatment for attentional deficits. Other novel nicotinic agonists in development may be even better, with lower side-effect profiles.
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