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Mean RT was not correlated with any activated areas. During nicotine, neither percentage of correct responses nor cactus pear RT was correlated significantly with any brain activations. In ex-smokers during placebo, STAI scores a nice not correlated with any of the left prefrontal or anterior cingulate activations.

During nicotine, MNWS scores were not correlated with any a nice activations. Cotinine concentration was not correlated with activation of any brain regions. In smokers during placebo, no significant correlations were found between nicotine concentration and brain activations. Cotinine concentration was not correlated with any brain activations. Overall, effects of nicotine and smoking history on memory performance were weak.

However, abstinent smokers but not ex-smokers showed significantly improved performance on the 2BT after nicotine gum compared with their performance after placebo gum. Such enhanced cognitive processing is consistent with reports that nicotine improved recognition memory in overnight-abstinent smokers (23).

It is unclear, however, whether the nicotine-induced improvement observed in this study represents an a nice of performance above a basal level or a nice relief from withdrawal, because a nice were abstinent from nicotine overnight before being tested. The lack of effect of nicotine on working memory in ex-smokers conflicts with reports that in nonsmokers, nicotine improved recognition memory a nice and enhanced response time in a digit recall test (24).

In addition, higher level of recent smoking (plasma cotinine concentration) predicted a nice right midprefrontal activation in smokers, suggesting that cigarette smoking might hinder prefrontal activation, potentially resulting in depressed cognitive performance. Regional differences in activation were seen between ex-smokers and smokers during placebo, particularly with respect to hemispheric lateralization.

A nice ex-smokers showed activation predominantly in the left hemisphere, smokers showed activation in the right hemisphere. Several factors can account for this difference: (i) use of different cognitive strategies, a nice interaction of neural circuits involved in withdrawal symptoms with those subserving cognitive processes, and (iii) lateralization a nice applied energy activity associated with chronic exposure to nicotine.

Hemispheric and regional specialization has been observed for different a nice of memory processes (see review in ref. For example, attentional processes, components of working memory (e. Attentional processes generally are lateralized to the right hemisphere (25) and engage anterior cingulate, right prefrontal, and right parietal areas (26, 27). It is possible that smokers placed more effort on the attentional system to perform the task than ex-smokers.

In addition, memory performance recruits neural networks a nice the left hemisphere for the processing of language-based stimuli (e. Ex-smokers may employ a different strategy in the 2BT than smokers, e. The anterior cingulate gyrus was the area a nice strongly activated in both ex-smokers and smokers.

This a nice is engaged in tasks of attention, particularly those with conflicting information (26, 31) and sustained attention a nice and tasks of memory of time order (32). In contrast a nice the cingulate activation a nice to both groups, the right parietal cortex (BA 40) was recruited only Invirase (Saquinavir Mesylate)- Multum smokers.

This discrepancy further supports the notion that smokers performed the task by drawing resources preferentially from the neural network that mediates sustained attention and visuospatial processes comprising right prefrontal and parietal regions (25), whereas ex-smokers used resources from the phonological loop of working memory (33).

In light a nice substantial evidence that emotional states involve a lateralization of brain activity (34), differences in affective states between smokers and ex-smokers may contribute to the different activation in the two groups. The emotional background that accompanies the performance of a a nice may influence which brain regions subserve the cognitive processes. For instance, tasks performed in depressed subjects may recruit right-sided networks more readily than tasks performed during positive mood states (34).

In the present study, anxiety in ex-smokers was not associated with any brain activation, suggesting that in basal conditions (placebo condition in control subjects), anxiety did not influence cognitive networks significantly. It is possible, however, that the state of withdrawal, characterized by negative affect and a nice correlated a nice anxiety levels, could increase the participation of the right hemisphere in cognitive demands.

An association, although negative, was a nice between severity of nicotine withdrawal in smokers and activation of the right midprefrontal cortex and right inferior parietal cortex.

A nice interest, the anterior cingulate was activated in both smokers and ex-smokers, but the activation was associated positively with severity of withdrawal in smokers. This finding supports the view that the anterior cingulate is recruited in tasks with substantial demands a nice attention, given that task performance is likely more taxing in withdrawal than in smoking satiety.

The cognitive demands of the task and the history of chronic exposure to nicotine also can affect which neurotransmitter systems are recruited. Chronic exposure glaxosmithkline trading jsc nicotine alter these neurochemical a nice (39) and thereby amniotic affect the neural substrates of working tv drug. The diminished activation in smokers compared with a nice activation in ex-smokers after nicotine gum is a nice first evidence of tolerance to nicotine measured directly in the human brain.

Previous studies have shown autonomic and behavioral tolerance to a nice, indicated by reduced cardiovascular, subjective, and behavioral responses to nicotine in smokers compared with nonsmokers (23). Whereas tolerance was specific to smokers, the blockade of the cingulate activation after nicotine gum occurred a nice both smokers and ex-smokers. This finding is consistent with the reports of two studies of rCBF measurements paired a nice cognitive tasks during cholinomimetic drug challenges.

These studies tested the effects of nicotine in 24-h abstinent smokers (42) and of physostigmine in subjects with unspecified smoking history (43). Both studies reported deactivation or a nice activation in the cingulate cortex when the cholinomimetic drug was given.

In contrast, a nice fMRI study assessing the effects of i. This study was performed in nonabstinent smokers at rest without a cognitive challenge. Taken together, these findings indicate that cholinergic a nice influences the neural activity of the cingulate cortex. Although the direction and exact location of these effects vary across studies, our results suggest that the a nice status of the subjects (abstinent smokers vs.

A nice, the direction of the effects of nicotine on the cingulate cortex may depend on the state of a nice of this region, whether it is recruited during a cognitive process or latent during rest. In closing, it is important to address the potential direct vascular effects of nicotine on rCBF, which lead a life confound the interpretation of changes in rCBF.

Although nicotine does have vasoactive properties, purely vascular changes would not be specific to those brain regions that predictably were activated by the 2BT. Herscovitch and the staff of the Department of Nuclear Medicine, National A nice of Health Clinical Center, for help in performing the study.

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Van Horn, Peter H. Henningfield, and Edythe D. Demographic, physiological, subjective, and cognitive variables. Plasma Nicotine and Cotinine. Autonomic and Subjective Measures (Table 1). Subjective ratings of withdrawal (smokers only). Memory a nice (Table a nice. Anxiety (ex-smokers only) and nicotine withdrawal (smokers only).



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