1. Multivariate classification of smokers from nonsmokers using SVM-RFE on brain gray matter density. Voxel-based morphometry (VBM) studies have revealed gray matter alterations in smokers, but this type of analysis has poor predictive value for individual cases, limiting applicability in clinical diagnoses and treatment. A predictive model would essentially embody a complex biomarker that could be used to evaluate treatment efficacy. We applied VBM with a multivariate classification method consisting of a support vector machine with recursive feature elimination to discriminate smokers from nonsmokers using their structural MRI data. Mean gray matter volumes in 1,024 cerebral cortical regions of interest created using a subparcellated version of the Automated Anatomical Labeling template were calculated from 60 smokers and 60 nonsmokers, and served as input features to the classification procedure. The classifier achieved the highest accuracy of 69.6% when taking the 139 highest ranked features via 10-fold cross-validation. Critically, these features were later validated yielding a 64.04% accuracy level (binomial P = 0.01). Following classification, exploratory post hoc regression analyses revealed that gray matter volumes in the putamen, hippocampus, prefrontal cortex, cingulate cortex, caudate, thalamus, pre-/postcentral gyrus, precuneus, and the parahippocampal gyrus, were inversely related to smoking behavioral characteristics, indicating that smoking related gray matter alterations can provide predictive power for group membership. It also suggests that machine learning techniques can reveal underlying smoking-related neurobiology. 2. Insula demonstrates a non-linear response to varying demands for cognitive control and weaker resting connectivity with the executive control network in smokers. In a sample of 35 smokers and 21 non-smokers, we used a previously validated parametric flanker task to characterize addiction-related alterations in response to high, intermediate, and low demands for cognitive control. This approach yields a demand-response curve that aims to characterize potential non-linear responses to increased demand for control, including insensitivities or lags in fully activating the cognitive control network. We further used task-based differences in activation between groups as seeds for resting-state analysis of network dysfunction in an effort to more closely link prior inconsistencies in task-related activation with evidence of impaired network connectivity in smokers. For both smokers and non-smokers, fMRI results showed similar increases in activation in brain areas associated with cognitive control. However, reduced activation in right insula was seen only in smokers and only when processing intermediate demand for cognitive control. Further, in smokers, this task-modulated right insula showed weaker functional connectivity with the superior frontal gyrus, a component of the task-positive executive control network. These results demonstrate that the neural instantiation of salience attribution in smokers is both more effortful to fully activate and has more difficulty communicating with the exogenous, task-positive, executive control network. Together, these findings further articulate the cognitive control dysfunction associated with smoking and illustrate a specific brain circuit potentially responsible. 3. Chronic cigarette smoking is linked with structural alterations in brain regions showing acute nicotinic drug-induced functional modulations. Whereas acute nicotine administration alters brain function which may, in turn, contribute to enhanced attention and performance, chronic cigarette smoking is linked with regional brain atrophy and poorer cognition. However, results from structural MRI studies comparing smokers versus nonsmokers have been inconsistent and measures of gray matter possess limited ability to inform functional relations or behavioral implications. The purpose of this study was to address these interpretational challenges through meta-analytic techniques in the service of clarifying the impact of chronic smoking on gray matter integrity and more fully contextualizing such structural alterations. We first conducted a coordinate-based meta-analysis of structural MRI studies to identify consistent structural alterations associated with chronic smoking. Subsequently, we conducted two additional meta-analytic assessments to enhance insight into potential functional and behavioral relations. Specifically, we performed a multimodal meta-analytic assessment to test the structuralfunctional hypothesis that smoking-related structural alterations overlapped those same regions showing acute nicotinic drug-induced functional modulations. Finally, we employed database driven tools to identify pairs of structurally impacted regions that were also functionally related via meta-analytic connectivity modeling, and then delineated behavioral phenomena associated with such functional interactions via behavioral decoding. Results showed that smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structuralfunctional relation, we observed that smoking-related gray matter decreases overlapped with the acute functional effects of nicotinic agonist administration in the left insula, ventromedial PFC, and mediodorsal thalamus. Suggesting structural-behavioral implications, we observed that the left insulas task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellums interactions with other regions were associated with overt body movements, interactions between the parahippocampus and thalamus were linked with memory processes, and interactions between medial PFC regions were associated with face processing. Collectively, these findings emphasize that the ventromedial PFC, insula, and thalamus are critically linked with smoking, suggest neuroimaging paradigms warranting additional consideration among smokers (e.g., pain processing), and highlight regions in need of further elucidation in addiction (e.g., cerebellum). 4. Resting State Functional Connectivity and Nicotine Addiction: Prospects for Biomarker Development. Given conceptual frameworks of addiction as a disease of intercommunicating brain networks, examinations of network interactions may provide a holistic characterization of addiction-related dysfunction. One approach is the examination of resting-state functional connectivity, which quantifies correlations in low-frequency fluctuations of the blood oxygen level-dependent MRI signal between disparate brain regions in the absence of task performance. We found evidence of differentiated effects of chronic nicotine exposure, which reduces the efficiency of network communication across the brain, and acute nicotine exposure, which increases connectivity within specific limbic circuits. Several large-scale resting networks, including the salience, default, and executive control networks, have also been implicated in nicotine addiction. The dynamics of connectivity changes among and between these large-scale networks during nicotine withdrawal and satiety provide a heuristic framework with which to characterize the neurobiological mechanism of addiction. The ability to simultaneously quantify effects of both chronic (trait) and acute (state) nicotine exposure provides a platform to develop a neuroimaging-based addiction biomarker. While such development remains in its early stages, evidence of coherent modulations in resting-state functional connectivity at various stages of nicotine addiction suggests potential network interactions on which to focus future addiction biomarker development.
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