A meta-analysis of human psychopharmacological studies in smokers and nonsmokers suggests that nicotine improves accuracy in episodic memory only with short delays between encoding and recall. Working memory accuracy does not appear to be significantly modulated, however reaction times have been shown to be significantly improved under nicotine [1
]. Although there are a few imaging studies which investigate the role of the cholinergic system on episodic memory [33
], the role of the nicotinic cholinergic system has mainly been investigated with respect to working memory. As for the above mentioned studies on nicotinic modulation of attention, results may depend upon whether nonsmokers or smokers serve as subjects [35
]. Kumari and colleagues [36
] used an n-back working memory task with numerals as stimuli. The n-back task is an attentionally demanding parametrically variable working memory task with loads varying from minimal (matching) to high (matching to item that occurs three items back). Nonsmokers received 12μg/kg subcutaneous nicotine and the results yielded a nicotine-induced increase in fronto-parietal activity which was strongest in the 1-back condition. In line with the studies mentioned above [13
] nicotine also induced a reduction in posterior cingulate activity under rest. The activity pattern resembles the findings of Lawrence et al. [9
] using the rapid visual information processing task. Indeed, rapid visual information processing and n-back tasks bear several similarities in that both measure aspects of sustained attention and working memory (though to a different extent). Increases in dorsolateral and medial frontal cortex were also found in a region of interest analysis with the α4β2 partial agonist varenicline, however only in the most difficult 3-back condition [37
]. Additionally a whole brain analysis revealed nicotine induced decreases of neural activity in inferior and superior frontal gyrus, posterior cingulate cortex and the parahippocampal gyrus among others. In contrast to the study of Kumari et al. [36
], which showed strongest effects in the 1-back condition, deprived smokers served as subjects and the stimuli used for the n-back paradigm were complex geometric figures. A smoking-induced increase in dorsolateral prefrontal activity in deprived smokers that was specific to the most difficult 3-back condition was also reported by Xu and colleagues [38
]. Notably, non-deprived smokers showed smoking-induced increases in the 1-back condition only, indicating that the status of deprivation is critical. The role of nicotine on switching between items in verbal working memory was investigated in a study by Sutherland et al. [39
] who administered 21 mg transdermal nicotine to mildly deprived smokers. Even though nicotine yielded behavioral effects, no effects on neural activity related to task performance or switching were observed – one of the rare examples where neuroimaging was not found to be more sensitive than behavioral data. In summary, nicotinic stimulation during tasks of working memory seem to affect similar systems as those involved in sustained attention.
In two studies, Dumas and colleagues [40
] examined the effects of nicotinic blockade with 20 mg mecamylamine on brain activation during working memory and episodic memory tasks in healthy postmenopausal women not taking estrogen therapy. Nicotinic blockade with mecamylamine did not impair working memory performance on the n-back task, but did reduce frontal activation relative to placebo [40
]. These findings are in line with the increases in frontal activation after nicotinic receptor stimulation with the administration of nicotine. Mecamylamine similarly did not impair recognition memory performance but did modulate brain regions involved in episodic memory using a continuous recognition memory task. Mecamylamine compared to placebo increased frontal and hippocampal activation during the encoding of new information into memory. Nicotinic blockade also resulted in decreased occipital activity compared to placebo during encoding [41
]. During the retrieval phase of this task, nicotinic blockade resulted in increased activation in the inferior temporal gyrus, anterior hippocampus, occipital cortex, and the uncus (). The use of a continuous recognition memory task allowed for the dissociation of encoding and retrieval processes during nicotinic system manipulation. Future studies should utilize tasks where the cognitive components of memory processes can be dissociated to more fully understand the role of nicotinic modulation.
Figure 3 The effect of the nicotinic antagonist mecamylamine compared to placebo for retrieved words compared to encoded words in a sample (n = 6) of postmenopausal women not on estrogen (p < .01). Increased activation for mecamylamine compared to placebo (more ...)
Thus, the pattern of brain activation produced by nicotinic stimulation or blockade is dependent upon the task requirements, age, gender, and presumably the amount of engagement of nicotinic systems. Interestingly, only one of the nicotinic drug studies reviewed above used an approach that would have enabled dissociation of encoding, maintenance, or retrieval of working or episodic memory [41
]. A study using the cholinesterase inhibitor physostigmine was able to show that cholinergic stimulation increases neural activity during encoding in sensory cortices and subsequently reduces retrieval demands in prefrontal cortices. Again, such approaches are especially valuable since they can dissociate cognitive processes which cannot be segregated behaviorally. The nicotinic antagonist mecamylamine produced reduced activation in frontal, parietal and occipital regions generally compared to placebo in attention and working memory tasks. However, a frontal and hippocampal increase was observed during the episodic memory task. Additional work is needed to disentangle the role of nicotinic systems in memory-related cognitive processes and more specifically the role of α4β2 as well as α7 receptors.