Target Audience

This talk is directed towards scientists interested in using fMRI data for the assessment of nicotine effects on the brain.

Objectives

This talk will introduce the participants to the effects that nicotine and concurrent use with alcohol and nicotine have in the functional connectivity of the brain.

Purpose

Concurrent use of substances of abuse is very common (Cook, 1987). These substances may share common biochemical pathways of action in the brain that may end in addictive behavior (Nestler, 2005). Thus, nicotine effects cohabit with repercussions caused by the presence other substances in the brain. This work exploited fMRI data to identify functional connectivity changes due to nicotine and the effects due to comorbid substance consumption.

Methods

Disentangling nicotine effects from other substances and their concurrent use requires a dissociation of nicotine consumption from any other substance. Since a sample of subjects with “pure” nicotine addiction is difficult to find, we lessen the restriction to subjects with a very low level of alcohol use based on the Alcohol Use Disorder Identification Test (AUDIT) (Saunders, et al., 1993) and strict abstinence of other substances. Given that the three most commonly used substances are nicotine, alcohol and cannabis (Winstock, 2014), we created sample groups for single alcohol addiction, single cannabis consumption and groups representing all combinations of comorbid use. Functional connectivity on the brain of each subject was assessed using fMRI data collected from a resting state protocol. The fMRI data register brain activation as it evolves with time. Functional connectivity was assessed by measuring the coactivation of separate brain areas. The level of coactivation was estimated using the Pearson correlation coefficient (Vergara, et al., 2017). In addition, we track connectivity dynamics describing effects that might appear at short lapses of time (Vergara, et al., 2018).

Results

Pure smokers exhibited a general increased functional connectivity within the default mode network, specifically between the left angular gyrus and the precuneus. A decrease in functional connectivity between thalamus and the dorsal striatum (putamen) was also observed. In addition, a reduction in dynamic connectivity was observed between dorsal striatum and supplementary motor area (SMA) occurring in average 12% of the time and consistent with all other subjects that consumed nicotine disregarding of the comorbid substance. These effects were attributed to nicotine with little relationship with other substances. The major effect of combined alcohol and nicotine was a generalized reduction of functional connectivity between sensorimotor and primary visual areas. Nicotine and cannabis effects could not be pinpointed to specific brain areas. However, comorbid cannabis and nicotine alternated between higher and lower whole brain connectivity observed in dynamic functional connectivity.

Discussion

The exclusive effect of nicotine in the dorsal striatum can be added to a list of previous findings. Different from the ventral striatum, morphological alterations in the dorsal striatum have been associated with nicotine craving (Janes, et al., 2015). As time progress, changes in the dorsal striatum get involved in the transition from voluntary to habitual nicotine seeking behavior (Everitt and Robbins, 2005). The involvement of supplemental motor area (SMA), striatum and thalamic areas suggest a deleterious effect in a cortico-thalamic-striatal circuit where the key dysfunction may be surrounding the striatum. At the same time, increased connectivity in the default mode network (angular to precuneus connection) was predicted by the network model of nicotine addiction (Sutherland, et al., 2012). This lack of restraint in the default mode is thought to be a mechanism of abstinence (posterior to nicotine administration) that interfere with normal executive functions of the brain (Janes, et al., 2016; Wilcox, et al., 2017). Combined effects of alcohol and nicotine consistently reduced connectivity between visual and sensorimotor areas for both of the functional connectivity methods considered (Vergara, et al., 2017; Vergara, et al., 2018). Different from the smoking and drinking subjects, it was found that connectivity reduction in drinkers included high visual areas (Vergara, et al., 2017). This effect is thought to be related to the activation enhancement of high visual areas produced by nicotine (Lawrence, et al., 2002).

Conclusion

Nicotine alters resting state functional connectivity of the brain in several aspects. It causes changes in a cortico-thalamic-striatal circuit involving the SMA, but with the putamen as the main dysfunctional node in the circuit. It also diminishes default mode network restraints which translate into an increased connectivity. This lack of restraint affects the healthy relationships with other areas of the brain including those related to executive control and saliency.

Acknowledgements

This work was supported by grants from the National Institutes of Health grant numbers 2R01EB005846, R01REB020407, and P20GM103472; and the National Science Foundation (NSF) grants 1539067/1631819 to VDC.

References

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