Developmental changes in brain function linked with addiction-like social media use two years later.

Addiction-like social media use (ASMU) is widely reported among adolescents and is associated with depression and other negative health outcomes. We aimed to identify developmental trajectories of neural social feedback processing that are linked to higher levels of ASMU in later adolescence. Within a longitudinal design, 103 adolescents completed a social incentive delay task during 1-3 fMRI scans (6-9th grade), and a 4th self-report assessment of ASMU and depressive symptoms ∼2 years later (10-11th grade). We assessed ASMU effects on brain responsivity to positive social feedback across puberty and relationships between brain responsivity development, ASMU symptoms, and depressive symptoms while considering gender effects. Findings demonstrate decreasing responsivity, across puberty, in the ventral media prefrontal cortex, medial prefrontal cortex, posterior cingulate cortex, and right inferior frontal gyrus associated with higher ASMU symptoms over 2 years later. Significant moderated mediation models suggest that these pubertal decreases in brain responsivity are associated with increased ASMU symptoms which, among adolescent girls (but not boys), is in turn associated with increased depressive symptoms. Results suggest initial hyperresponsivity to positive social feedback, before puberty onset, and decreases in this response across development, may be risk factors for ASMU in later adolescence.

Acculturative Orientations Among Hispanic/Latinx Caregivers in the ABCD Study: Associations With Caregiver and Youth Mental Health and Youth Brain Function.

Background: Population-based neuroscience offers opportunities to examine important but understudied sociocultural factors such as acculturation. Acculturation refers to the extent to which an individual retains their cultural heritage and/or adopts the receiving society's culture and is particularly salient among Hispanic/Latinx immigrants. Specific acculturative orientations have been linked to vulnerability to substance use, depression, and suicide and are known to influence family dynamics between caregivers and their children. Methods: Using data from first- and second-generation Hispanic/Latinx caregivers in the Adolescent Brain Cognitive Development (ABCD) Study (N = 1057), we examined how caregivers' acculturative orientation affects their mental health, as well as the mental health and brain function of their children. Neuroimaging analyses focused on regions associated with self- and affiliation-based social processing (ventromedial prefrontal cortex, insula, and temporoparietal junction). Results: We identified 2 profiles of caregiver acculturation: bicultural (retains heritage culture while adopting U.S. culture) and detached (discards heritage culture and rejects U.S. culture). Bicultural caregivers exhibited fewer internalizing and externalizing problems than detached caregivers; furthermore, youth exhibited similar internalizing effects across caregiver profiles. In addition, youth with bicultural caregivers displayed increased resting-state brain activity (i.e., fractional amplitude of low-frequency fluctuations and regional homogeneity) in the left insula, which has been linked to psychopathology; however, differences in long-range functional connectivity were not significant. Conclusions: Caregiver acculturation is an important familial factor that has been linked to significant differences in youth mental health and insula activity. Future work should examine sociocultural and neurodevelopmental changes across adolescence to assess health outcomes and determine whether localized, corticolimbic brain effects are ultimately translated into long-range connectivity differences.

Methods for decoding cortical gradients of functional connectivity.

Macroscale gradients have emerged as a central principle for understanding functional brain organization. Previous studies have demonstrated that a principal gradient of connectivity in the human brain exists, with unimodal primary sensorimotor regions situated at one end and transmodal regions associated with the default mode network and representative of abstract functioning at the other. The functional significance and interpretation of macroscale gradients remains a central topic of discussion in the neuroimaging community, with some studies demonstrating that gradients may be described using meta-analytic functional decoding techniques. However, additional methodological development is necessary to fully leverage available meta-analytic methods and resources and quantitatively evaluate their relative performance. Here, we conducted a comprehensive series of analyses to investigate and improve the framework of data-driven, meta-analytic methods, thereby establishing a principled approach for gradient segmentation and functional decoding. We found that a two-segment solution determined by a k-means segmentation approach and an LDA-based meta-analysis combined with the NeuroQuery database was the optimal combination of methods for decoding functional connectivity gradients. Finally, we proposed a method for decoding additional components of the gradient decomposition. The current work aims to provide recommendations on best practices and flexible methods for gradient-based functional decoding of fMRI data.

Cascading bidirectional influences of digital media use and mental health in adolescence.

A substantial portion of critical adolescent development is occurring within digital environments. However, certain individual differences may lead adolescents to use digital media in diverse ways. In this chapter we suggest that the way teens use digital media influences how digital media affects their mental health. Further, we propose a model in which these influences, in the context of ongoing development, may have feedback effects on how digital media is subsequently used, thus resulting in a self-perpetuating cycle. Our model suggests that certain developmental risk/protective factors and maladaptive/adaptive digital media behaviors likely perpetuate each other in a cyclical manner each serving to maintain and/or escalate the other. We discuss existing evidence of these processes in psychosocial, identity, incentive processing, and physical health development. Future research focusing on individual differences and self-reinforcing digital media behaviors that manifest these feedback loops may portray a more complete picture of cascading digital media influences across adolescent development.

Developmental Changes in Habenular and Striatal Social Reinforcement Responsivity Across Adolescence Linked With Substance Use.

BACKGROUND: Habenula (HB) function is implicated in substance use disorders and is involved in inhibiting dopamine release in the ventral striatum (VS). While blunted VS reward responsivity is implicated in risk for later substance use, links between HB reinforcement processing and progression of use have not, to our knowledge, been examined among adolescents. In the present study, we longitudinally assessed HB and VS responsivity to social rewards and punishments across adolescence and examined associations with substance use. METHODS: Within a longitudinal design, 170 adolescents (53.5% female) completed 1 to 3 functional magnetic resonance imaging scans across 6th to 9th grade and reported yearly substance use across 6th to 11th grade. We examined VS and HB responsivity to social reinforcement during a social incentive delay task in which adolescents received social rewards (smiling faces) and punishments (scowling faces). RESULTS: We observed increased VS responsivity to social rewards (vs. reward omissions) and increased VS, but decreased HB, responsivity to social punishment avoidance versus receipt. However, contrary to hypotheses, the HB displayed increased responsivity to social rewards (vs. reward omissions). Further, adolescents reporting regular substance use displayed longitudinally declining HB responsivity to social rewards (vs. reward omissions), whereas adolescents reporting no substance use displayed longitudinally increasing HB responsivity. In contrast, whereas VS responsivity to punishment avoidance versus receipt increased longitudinally among regular substance users, it stayed relatively stable among nonusers. CONCLUSIONS: These results suggest that differential HB and VS social reinforcement processing trajectories across adolescence are associated with substance use.

The Link Between Neuroticism and Everyday Cognitive Failures is Mediated by Self-Reported Mindfulness Among College Students.

Neuroticism has been linked to an increased likelihood of cognitive failures, including episodes of inattentiveness, forgetfulness, or accidents causing difficulties in successfully executing everyday tasks and impacting health and quality of life. Cognitive failures associated with trait neuroticism can prompt some negative psychological outcomes and risky behaviors. Accumulating evidence shows that augmenting mindfulness can benefit cognitive health and general well-being. However, little is known regarding potential cognitive-behavioral pathways through which individual differences in trait neuroticism could influence the propensity to cognitive failures. Using a sample of 1003 undergraduate college students (females: n = 779) consisting of self-reported questionnaire data, we conducted correlational and mediational analyses to investigate the interrelationship between neuroticism, mindfulness, and cognitive failures. Higher neuroticism scores (females: r = -0.388, males: r = -0.390) and higher cognitive failures scores (females: r = -0.339, males: r = -0.407, p < .001) were significantly correlated with lower self-reported mindfulness scores. Mindfulness significantly mediated the relationship between neuroticism and cognitive failures (ß = 0.50, 95%, CI: 0.37, 0.65). These findings indicate that higher mindfulness may help ameliorate negative effects of neuroticism on everyday cognitive failures. Future research will determine how college students may benefit from positive impact of mindfulness to improve their psychological and physical health.

Convergent gray matter alterations across drugs of abuse and network-level implications: A meta-analysis of structural MRI studies.

BACKGROUND: Neuroimaging studies often consider brain alterations linked with substance abuse within the context of individual drugs (e.g., nicotine), while neurobiological theories of addiction emphasize common brain network-level alterations across drug classes. Using emergent meta-analytic techniques, we identified common structural brain alterations across drugs and characterized the functionally-connected networks with which such structurally altered regions interact. METHODS: We identified 82 articles characterizing gray matter (GM) volume differences for substance users vs. controls. Using the anatomical likelihood estimation algorithm, we identified convergent GM reductions across drug classes. Next, we performed resting-state and meta-analytic functional connectivity analyses using each structurally altered region as a seed and computed whole-brain functional connectivity profiles as the union of both maps. We characterized an "extended network" by identifying brain areas demonstrating the highest degree of functional coupling with structurally impacted regions. Finally, hierarchical clustering was performed leveraging extended network nodes' functional connectivity profiles to delineate subnetworks. RESULTS: Across drug classes, we identified medial frontal/ventromedial prefrontal, and multiple regions in anterior cingulate (ACC) and insula as regions displaying convergent GM reductions among users. Overlap of these regions' functional connectivity profiles identified ACC, inferior frontal, PCC, insula, superior temporal, and putamen as regions of an impacted extended network. Hierarchical clustering revealed 3 subnetworks closely corresponding to default mode (PCC, angular), salience (dACC, caudate), and executive control networks (dlPFC and parietal). CONCLUSIONS: These outcomes suggest that substance-related structural brain alterations likely have implications for the functioning of canonical large-scale networks and the perpetuation of substance use and neurocognitive alterations.

The association of amygdala-insula functional connectivity and adolescent e-cigarette use via sleep problems and depressive symptoms.

BACKGROUND: Adolescent electronic cigarette (e-cigarette) use remains high. Elucidating contributing factors may enhance prevention strategies. Neurobiologically, amygdala-insula resting-state functional connectivity (rsFC) has been linked with aspects of sleep, affect, and substance use (SU). As such, we hypothesized that amygdala's rsFC with the insula would be associated with e-cigarette use via sleep problems and/or depression levels. METHODS: An adolescent sample (N = 146) completed a rs-fMRI scan at time 1 and self-reports at time 2 (∼15 months later). Given consistent associations between mental health outcomes and the rsFC of the laterobasal amygdala (lbAMY) with the anterior insula, we utilized a seed region (lbAMY) to region of interest (ROI) analysis approach to characterize brain-behavior relationships. Two serial mediation models tested the interrelations between amygdala's rsFC with distinct anterior insula subregions (i.e., ventral insula [vI], dorsal insula [dI]), sleep problems, depression levels, and days of e-cigarette use. RESULTS: An indirect effect was observed when considering the lbAMY's rsFC with the vI. Greater rsFC predicted more sleep problems, more sleep problems were linked with greater depressive symptoms, and greater depressive symptoms were associated with more e-cigarette use (indirect effect = 0.08, CI [0.01,0.21]). Indicative of a neurobiological dissociation, a similar indirect effect linking these variables was not observed when considering the lbAMY's rsFC with the dI (indirect effect = 0.03, CI [-0.001,0.10]). CONCLUSIONS: These outcomes highlight functional interactions between the amygdala and insula as a neurobiological contributor to sleep problems, depressive symptoms, and ultimately SU thereby suggesting potential intervention points to reduce teen e-cigarette use.

Risky decision-making strategies mediate the relationship between amygdala activity and real-world financial savings among individuals from lower income households: A pilot study.

Lower financial savings among individuals experiencing adverse social determinants of health (SDoH) increases vulnerabilities during times of crisis. SDoH including low socioeconomic status (low-SES) influence cognitive abilities as well as health and life outcomes that may perpetuate poverty and disparities. Despite evidence suggesting a role for financial growth in minimizing SDoH-related disparities and vulnerabilities, neurobiological mechanisms linked with financial behavior remain to be elucidated. As such, we examined the relationships between brain activity during decision-making (DM), laboratory-based task performance, and money savings behavior. Participants (N = 24, 14 females) from low-SES households (income<$20,000/year) underwent fMRI scanning while performing the Balloon Analogue Risk Task (BART), a DM paradigm probing risky- and strategic-DM processes. Participants also completed self-report instruments characterizing relevant personality characteristics and then engaged in a community outreach financial program where amount of money saved was tracked over a 6-month period. Regarding BART-related brain activity, we observed expected activity in regions implicated in reward and emotional processing including the amygdala. Regarding brain-behavior relationships, we found that laboratory-based BART performance mediated the impact of amygdala activity on real-world behavior. That is, elevated amygdala activity was linked with BART strategic-DM which, in turn, was linked with more money saved after 6 months. In exploratory analyses, this mediation was moderated by emotion-related personality characteristics such that, only individuals reporting lower alexithymia demonstrated a relationship between amygdala activity and savings. These outcomes suggest that DM-related amygdala activity and/or emotion-related personality characteristics may provide utility as an endophenotypic marker of individual's financial savings behavior.

Altered large-scale brain network interactions associated with HIV infection and error processing.

Altered activity within and between large-scale brain networks has been implicated across various neuropsychiatric conditions. However, patterns of network dysregulation associated with human immunodeficiency virus (HIV), and further impacted by cannabis (CB) use, remain to be delineated. We examined the impact of HIV and CB on resting-state functional connectivity (rsFC) between brain networks and associations with error awareness and error-related network responsivity. Participants (N = 106), stratified into four groups (HIV+/CB+, HIV+/CB-, HIV-/CB+, HIV-/CB-), underwent fMRI scanning while completing a resting-state scan and a modified Go/NoGo paradigm assessing brain responsivity to errors and explicit error awareness. We examined separate and interactive effects of HIV and CB on resource allocation indexes (RAIs), a measure quantifying rsFC strength between the default mode network (DMN), central executive network (CEN), and salience network (SN). We observed reduced RAIs among HIV+ (vs. HIV-) participants, which was driven by increased SN-DMN rsFC. No group differences were detected for SN-CEN rsFC. Increased SN-DMN rsFC correlated with diminished error awareness, but not with error-related network responsivity. These outcomes highlight altered network interactions among participants with HIV and suggest such rsFC dysregulation may persist during task performance, reflecting an inability to disengage irrelevant mental operations, ultimately hindering error processing.

Interactive Effects of HIV Infection and Cannabis Use on Insula Subregion Functional Connectivity.

Chronic inflammation in the central nervous system is one mechanism through which human immunodeficiency virus (HIV) may lead to progressive cognitive decline. Given cannabis's (CB's) anti-inflammatory properties, use prevalence among people living with HIV (PLWH), and evidence implicating the insula in both, we examined independent and interactive effects of HIV and CB on insular circuitry, cognition, and immune function. We assessed resting-state functional connectivity (rsFC) of three insula subregions among 106 participants across four groups (co-occurring: HIV+/CB+; HIV-only: HIV+/CB-; CB-only: HIV-/CB+; controls: HIV-/CB-). Participants completed a neurocognitive battery assessing functioning across multiple domains and self-reported somatic complaints. Blood samples quantified immune function (T-cell counts) and inflammation (tumor necrosis factor alpha [TNF-α]). We observed interactive HIV × CB effects on rsFC strength between two anterior insula (aI) subregions and sensorimotor cortices such that, CB appeared to normalize altered rsFC among non-using PLWH. Specifically, compared to controls, HIV-only and CB-only groups displayed decreased dorsal anterior insula (DI) - postcentral gyrus rsFC and increased ventral anterior insula (VI) - supplementary motor area rsFC, whereas the co-occurring group displayed DI and VI rsFC more akin to that of controls. Altered DI - postcentral rsFC correlated with decreased processing speed and somatic complaints, but did not significantly correlate with inflammation (TNF-α). These outcomes implicate insula - sensorimotor neurocircuitries in HIV and CB and are consistent with prior work suggesting that CB use may normalize insula functioning among PLWH.

The cue-reactivity paradigm: An ensemble of networks driving attention and cognition when viewing drug and natural reward-related stimuli.

The cue-reactivity paradigm is a widely adopted neuroimaging probe engendering brain activity linked with attentional, affective, and reward processes following presentation of appetitive stimuli. Given the multiple mental operations invoked, we sought to decompose cue-related brain activity into constituent components employing emergent meta-analytic techniques when considering drug and natural reward-related cues. We conducted coordinate-based meta-analyses delineating common and distinct brain activity convergence across cue-reactivity studies (N = 196 articles) involving drug (n = 133) or natural (n = 63) visual stimuli. Across all studies, convergence was observed in limbic, cingulate, insula, and fronto-parieto-occipital regions. Drug-distinct convergence was observed in posterior cingulate, dorsolateral prefrontal, and temporo-parietal regions, whereas distinct-natural convergence was observed in thalamic, insular, orbitofrontal, and occipital regions. We characterized connectivity profiles of identified regions by leveraging task-independent and task-dependent MRI datasets, grouped these profiles into subnetworks, and linked each with putative mental operations. Outcomes suggest multifaceted brain activity during cue-reactivity can be decomposed into elemental processes and indicate that while drugs of abuse usurp the brain's natural-reward-processing system, some regions appear distinct to drug cue-reactivity.

HIV infection is linked with reduced error-related default mode network suppression and poorer medication management abilities.

OBJECTIVE: Brain activity linked with error processing has rarely been examined among persons living with HIV (PLWH) despite importance for monitoring and modifying behaviors that could lead to adverse health outcomes (e.g., medication non-adherence, drug use, risky sexual practices). Given that cannabis (CB) use is prevalent among PLWH and impacts error processing, we assessed the influence of HIV serostatus and chronic CB use on error-related brain activity while also considering associated implications for everyday functioning and clinically-relevant disease management behaviors. METHODS: A sample of 109 participants, stratified into four groups by HIV and CB (HIV+/CB+, n = 32; HIV+/CB-, n = 27; HIV-/CB+, n = 28; HIV-/CB-, n = 22), underwent fMRI scanning while completing a modified Go/NoGo paradigm called the Error Awareness Task (EAT). Participants also completed a battery of well-validated instruments including a subjective report of everyday cognitive failures and an objective measure of medication management abilities. RESULTS: Across all participants, we observed expected error-related anterior insula (aI) activation which correlated with better task performance (i.e., less errors) and, among HIV- participants, fewer self-reported cognitive failures. Regarding awareness, greater insula activation as well as greater posterior cingulate cortex (PCC) deactivation were notably linked with aware (vs. unaware) errors. Regarding group effects, unlike HIV- participants, PLWH displayed a lack of error-related deactivation in two default mode network (DMN) regions (i.e., PCC, medial prefrontal cortex [mPFC]). No CB main or interaction effects were detected. Across all participants, reduced error-related PCC deactivation correlated with reduced medication management abilities and PCC deactivation mediated the effect of HIV on such abilities. More lifetime CB use was linked with reduced error-related mPFC deactivation among HIV- participants and poorer medication management across CB users. CONCLUSIONS: These results demonstrate that insufficient error-related DMN suppression linked with HIV infection, as well as chronic CB use among HIV- participants, has real-world consequences for medication management behaviors. We speculate that insufficient DMN suppression may reflect an inability to disengage task irrelevant mental operations, ultimately hindering error monitoring and behavior modification.

Common and distinct brain activity associated with risky and ambiguous decision-making.

Two often-studied forms of uncertain decision-making (DM) are risky-DM (outcome probabilities known) and ambiguous-DM (outcome probabilities unknown). While DM in general is associated with activation of several brain regions, previous neuroimaging efforts suggest a dissociation between activity linked with risky and ambiguous choices. However, the common and distinct neurobiological correlates associated with risky- and ambiguous-DM, as well as their specificity when compared to perceptual-DM (as a 'control condition'), remains to be clarified. We conducted multiple meta-analyses on neuroimaging results from 151 studies to characterize common and domain-specific brain activity during risky-, ambiguous-, and perceptual-DM. When considering all DM tasks, convergent activity was observed in brain regions considered to be consituents of the canonical salience, valuation, and executive control networks. When considering subgroups of studies, risky-DM (vs. perceptual-DM) was linked with convergent activity in the striatum and anterior cingulate cortex (ACC), regions associated with reward-related processes (determined by objective functional decoding). When considering ambiguous-DM (vs. perceptual-DM), activity convergence was observed in the lateral prefrontal cortex and insula, regions implicated in affectively-neutral mental processes (e.g., cognitive control and behavioral responding; determined by functional decoding). An exploratory meta-analysis comparing brain activity between substance users and non-users during risky-DM identified reduced convergent activity among users in the striatum, cingulate, and thalamus. Taken together, these findings suggest a dissociation of brain regions linked with risky- and ambiguous-DM reflecting possible differential functionality and highlight brain alterations potentially contributing to poor decision-making in the context of substance use disorders.

Meta-analytic clustering dissociates brain activity and behavior profiles across reward processing paradigms.

Reward learning is a ubiquitous cognitive mechanism guiding adaptive choices and behaviors, and when impaired, can lead to considerable mental health consequences. Reward-related functional neuroimaging studies have begun to implicate networks of brain regions essential for processing various peripheral influences (e.g., risk, subjective preference, delay, social context) involved in the multifaceted reward processing construct. To provide a more complete neurocognitive perspective on reward processing that synthesizes findings across the literature while also appreciating these peripheral influences, we used emerging meta-analytic techniques to elucidate brain regions, and in turn networks, consistently engaged in distinct aspects of reward processing. Using a data-driven, meta-analytic, k-means clustering approach, we dissociated seven meta-analytic groupings (MAGs) of neuroimaging results (i.e., brain activity maps) from 749 experimental contrasts across 176 reward processing studies involving 13,358 healthy participants. We then performed an exploratory functional decoding approach to gain insight into the putative functions associated with each MAG. We identified a seven-MAG clustering solution that represented dissociable patterns of convergent brain activity across reward processing tasks. Additionally, our functional decoding analyses revealed that each of these MAGs mapped onto discrete behavior profiles that suggested specialized roles in predicting value (MAG-1 & MAG-2) and processing a variety of emotional (MAG-3), external (MAG-4 & MAG-5), and internal (MAG-6 & MAG-7) influences across reward processing paradigms. These findings support and extend aspects of well-accepted reward learning theories and highlight large-scale brain network activity associated with distinct aspects of reward processing.

Habenular and striatal activity during performance feedback are differentially linked with state-like and trait-like aspects of tobacco use disorder.

The habenula, an epithalamic nucleus involved in reward and aversive processing, may contribute to negative reinforcement mechanisms maintaining nicotine use. We used a performance feedback task that differentially activates the striatum and habenula and administered nicotine and varenicline (versus placebos) to overnight-abstinent smokers and nonsmokers to delineate feedback-related functional brain alterations both as a function of smoking trait (smokers versus nonsmokers) and drug administration state (drug versus placebo). Smokers showed less striatal responsivity to positive feedback, an alteration not mitigated by drug administration, but rather correlated with trait-level addiction severity. Conversely, nicotine administration reduced habenula activity following both positive and negative feedback among abstinent smokers, but not nonsmokers, and increased habenula activity among smokers correlated with elevated state-level tobacco cravings. These outcomes highlight a dissociation between neurobiological processes linked with the dependence severity trait and the nicotine withdrawal state. Interventions simultaneously targeting both aspects may improve currently poor cessation outcomes.

Cooperating yet distinct brain networks engaged during naturalistic paradigms: A meta-analysis of functional MRI results.

Cognitive processes do not occur by pure insertion and instead depend on the full complement of co-occurring mental processes, including perceptual and motor functions. As such, there is limited ecological validity to human neuroimaging experiments that use highly controlled tasks to isolate mental processes of interest. However, a growing literature shows how dynamic, interactive tasks have allowed researchers to study cognition as it more naturally occurs. Collective analysis across such neuroimaging experiments may answer broader questions regarding how naturalistic cognition is biologically distributed throughout the brain. We applied an unbiased, data-driven, meta-analytic approach that uses k-means clustering to identify core brain networks engaged across the naturalistic functional neuroimaging literature. Functional decoding allowed us to, then, delineate how information is distributed between these networks throughout the execution of dynamical cognition in realistic settings. This analysis revealed six recurrent patterns of brain activation, representing sensory, domain-specific, and attentional neural networks that support the cognitive demands of naturalistic paradigms. Although gaps in the literature remain, these results suggest that naturalistic fMRI paradigms recruit a common set of networks that allow both separate processing of different streams of information and integration of relevant information to enable flexible cognition and complex behavior.

Chronic cigarette smoking is linked with structural alterations in brain regions showing acute nicotinic drug-induced functional modulations.

BACKGROUND: 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 magnetic resonance imaging (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. METHODS: 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 structural-functional 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: Across studies, smoking was associated with convergent structural decreases in the left insula, right cerebellum, parahippocampus, multiple prefrontal cortex (PFC) regions, and the thalamus. Indicating a structural-functional 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 insula's task-based, functional interactions with multiple other structurally impacted regions were linked with pain perception, the right cerebellum's 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. CONCLUSIONS: Collectively, these findings emphasize brain regions (e.g., ventromedial PFC, insula, thalamus) critically linked with cigarette 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).