Not all smokers are alike: the hidden cost of sustained attention during nicotine abstinence.

Nicotine Withdrawal Syndrome (NWS)-associated cognitive deficits are notably heterogeneous, suggesting underlying endophenotypic variance. However, parsing this variance in smokers has remained challenging. In this study, we identified smoker subgroups based on response accuracy during a Parametric Flanker Task (PFT) and then characterized distinct neuroimaging endophenotypes using a nicotine state manipulation. Smokers completed the PFT in two fMRI sessions (nicotine sated, abstinent). Based on response accuracy in the stressful, high cognitive demand PFT condition, smokers split into high (HTP, n = 21) and low task performer (LTP, n = 24) subgroups. Behaviorally, HTPs showed greater response accuracy (88.68% ± 5.19 SD) vs. LTPs (51.04% ± 4.72 SD), independent of nicotine state, and greater vulnerability to abstinence-induced errors of omission (EOm, p = 0.01). Neurobiologically, HTPs showed greater BOLD responses in attentional control brain regions, including bilateral insula, dorsal ACC, and frontoparietal Cx for the [correct responses (-) errors of commission] PFT contrast in both states. A whole-brain functional connectivity (FC) analysis with these subgroup-derived regions as seeds identified two circuits: Precentral Cx↔Insula and Insula↔Occipital Cx, with abstinence-induced FC strength increases seen only in HTPs. Finally, abstinence-induced FC and behavior (EOm) differences were positively correlated for HTPs in a Precentral Cx↔Orbitofrontal cortical circuit. In sum, only the HTP subgroup demonstrated sustained attention deficits following 48-hr nicotine abstinence, a stressor in dependent smokers. Unpacking underlying smoker heterogeneity with this 'dual (task and abstinence) stressor' approach revealed discrete smoker subgroups with differential attentional deficits to withdrawal that could be novel pharmacological/behavioral targets for therapeutic interventions to improve cessation outcomes.

Affective Neural Mechanisms of a Parenting-Focused Mindfulness Intervention.

OBJECTIVES: Behavioral evidence suggests that parenting-focused mindfulness interventions can improve parenting practices and enhance family wellbeing, potentially operating through altered emotional processing in parents. However, the mechanisms through which parent mindfulness interventions achieve their positive benefits have not yet been empirically tested, knowledge which is key to refine and maximize intervention effects. Thus, as part of a randomized controlled trial, the present study examined the affective mechanisms of an 8-week parenting-focused mindfulness intervention, the Parenting Mindfully (PM) intervention, versus a minimal-intervention parent education control. METHODS: Twenty highly stressed mothers of adolescents completed pre- and post-intervention behavioral and fMRI sessions, in which mothers completed a parent-adolescent conflict interaction, fMRI emotion task, and fMRI resting state scan. Mothers reported on their mindful parenting, and maternal emotional reactivity to the parent-adolescent conflict task was assessed via observed emotion expression, self-reported negative emotion, and salivary cortisol reactivity. RESULTS: Results indicated that the PM intervention increased brain responsivity in left posterior insula in response to negative affective stimuli, and altered resting state functional connectivity in regions involved in self-reference, behavioral regulation, and social-emotional processing. Changes in mothers' brain function and connectivity were associated with increased mindful parenting and decreased emotional reactivity to the parent-adolescent conflict task. CONCLUSIONS: Findings suggest that mindfulness-based changes in maternal emotional awareness at the neurobiological level are associated with decreased emotional reactivity in parenting interactions, illuminating potential neurobiological targets for future parent-focused intervention.

Time-Varying Functional Connectivity Decreases as a Function of Acute Nicotine Abstinence.

BACKGROUND: The nicotine withdrawal syndrome (NWS) includes affective and cognitive disruptions whose incidence and severity vary across time during acute abstinence. However, most network-level neuroimaging uses static measures of resting-state functional connectivity and assumes time-invariance and is thus unable to capture dynamic brain-behavior relationships. Recent advances in resting-state functional connectivity signal processing allow characterization of time-varying functional connectivity (TVFC), which characterizes network communication between networks that reconfigure over the course of data collection. Therefore, TVFC may more fully describe network dysfunction related to the NWS. METHODS: To isolate alterations in the frequency and diversity of communication across network boundaries during acute nicotine abstinence, we scanned 25 cigarette smokers in the nicotine-sated and abstinent states and applied a previously validated method to characterize TVFC at a network and a nodal level within the brain. RESULTS: During abstinence, we found brain-wide decreases in the frequency of interactions between network nodes in different modular communities (i.e., temporal flexibility). In addition, within a subset of the networks examined, the variability of these interactions across community boundaries (i.e., spatiotemporal diversity) also decreased. Finally, within 2 of these networks, the decrease in spatiotemporal diversity was significantly related to NWS clinical symptoms. CONCLUSIONS: Using multiple measures of TVFC in a within-subjects design, we characterized a novel set of changes in network communication and linked these changes to specific behavioral symptoms of the NWS. These reductions in TVFC provide a meso-scale network description of the relative inflexibility of specific large-scale brain networks during acute abstinence.

Transcranial electrical and magnetic stimulation (tES and TMS) for addiction medicine: A consensus paper on the present state of the science and the road ahead.

There is growing interest in non-invasive brain stimulation (NIBS) as a novel treatment option for substance-use disorders (SUDs). Recent momentum stems from a foundation of preclinical neuroscience demonstrating links between neural circuits and drug consuming behavior, as well as recent FDA-approval of NIBS treatments for mental health disorders that share overlapping pathology with SUDs. As with any emerging field, enthusiasm must be tempered by reason; lessons learned from the past should be prudently applied to future therapies. Here, an international ensemble of experts provides an overview of the state of transcranial-electrical (tES) and transcranial-magnetic (TMS) stimulation applied in SUDs. This consensus paper provides a systematic literature review on published data - emphasizing the heterogeneity of methods and outcome measures while suggesting strategies to help bridge knowledge gaps. The goal of this effort is to provide the community with guidelines for best practices in tES/TMS SUD research. We hope this will accelerate the speed at which the community translates basic neuroscience into advanced neuromodulation tools for clinical practice in addiction medicine.

Learning From the Slips of Others: Neural Correlates of Trust in Automated Agents.

With the rise of increasingly complex artificial intelligence (AI), there is a need to design new methods to monitor AI in a transparent, human-aware manner. Decades of research have demonstrated that people, who are not aware of the exact performance levels of automated algorithms, often experience a mismatch in expectations. Consequently, they will often provide either too little or too much trust in an algorithm. Detecting such a mismatch in expectations, or trust calibration, remains a fundamental challenge in research investigating the use of automation. Due to the context-dependent nature of trust, universal measures of trust have not been established. Trust is a difficult construct to investigate because even the act of reflecting on how much a person trusts a certain agent can change the perception of that agent. We hypothesized that electroencephalograms (EEGs) would be able to provide such a universal index of trust without the need of self-report. In this work, EEGs were recorded for 21 participants (mean age = 22.1; 13 females) while they observed a series of algorithms perform a modified version of a flanker task. Each algorithm's degree of credibility and reliability were manipulated. We hypothesized that neural markers of action monitoring, such as the observational error-related negativity (oERN) and observational error positivity (oPe), are potential candidates for monitoring computer algorithm performance. Our findings demonstrate that (1) it is possible to reliably elicit both the oERN and oPe while participants monitored these computer algorithms, (2) the oPe, as opposed to the oERN, significantly distinguished between high and low reliability algorithms, and (3) the oPe significantly correlated with subjective measures of trust. This work provides the first evidence for the utility of neural correlates of error monitoring for examining trust in computer algorithms.

Nicotine Abstinence Influences the Calculation of Salience in Discrete Insular Circuits.

BACKGROUND: Insular subdivisions show distinct patterns of resting-state functional connectivity (rsFC) with specific brain regions, each with different functional significance. Seeds in these subdivisions are employed to characterize the effects of acute nicotine abstinence on rsFC between insula subdivisions and brain networks implicated in addiction and attentional control. METHODS: In a within-subjects design, resting-state blood oxygen level-dependent data were collected from treatment-seeking smokers (N= 20) following smoking satiety and again following 48 hours of nicotine abstinence. Three right hemisphere insular regions of interest (dorsal, ventral, and posterior) served as seeds for analyses. Indices of both static and dynamic rsFC were obtained and correlated with indices of subjective withdrawal and behavioral performance. RESULTS: Abstinence-induced physiological, subjective, and cognitive differences were observed. Overall dynamic rsFC was reduced during abstinence, and circuits containing each insular seed showed changes in rsFC as a function of nicotine abstinence. Specifically, dorsal and posterior insular connections to the default mode and salience networks were enhanced, while a previously undescribed ventral insular connection to the executive control network was reduced. Further, static rsFC was significantly correlated with subjective ratings of aversive affect and withdrawal in the modified ventral and posterior insular-seeded circuits. CONCLUSIONS: As predicted, divergent connections between insula subdivisions and anticorrelated resting brain networks were observed during abstinence. These changes reflect an attentional bias toward aversive affective processing and not directly away from exogenous cognitive processing, suggesting a coordinated modulation of circuits associated with interoceptive and affective processing that instantiates an aversive state during nicotine abstinence.

Insula Demonstrates a Non-Linear Response to Varying Demand for Cognitive Control and Weaker Resting Connectivity With the Executive Control Network in Smokers.

Deficits in cognitive control processes are a primary characteristic of nicotine addiction. However, while network-based connectivity measures of dysfunction have frequently been observed, empirical evidence of task-based dysfunction in these processes has been inconsistent. Here, in a sample of smokers (n=35) and non-smokers (n=21), a previously validated parametric flanker task is employed to characterize addiction-related alterations in responses to varying (ie, 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, neuroimaging 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.

Uncertainty-dependent activity within the ventral striatum predicts task-related changes in response strategy.

Recent neuroimaging work has demonstrated that the ventral striatum (VS) encodes confidence in perceptual decisions. However, it remains unclear whether perceptual uncertainty can signal the need to adapt behavior (such as by responding more cautiously) and whether such behavioral changes are related to uncertainty-dependent activity within the VS. Changes in response strategy have previously been observed following errors and are associated with both medial frontal cortex (MFC) and VS, two components of the performance-monitoring network. If uncertainty can elicit changes in response strategy (slowing), then one might hypothesize that these changes rely on the performance-monitoring network. In the present study, we investigated the link between perceptual uncertainty and task-related behavioral adaptations (response slowing and accuracy increases), as well as how such behavioral changes relate to uncertainty-dependent activity within MFC and VS. Our participants performed a two-choice perceptual decision-making task in which perceptual uncertainty was reported on each trial while behavioral and event-related functional magnetic resonance imaging data were collected. Analysis of the behavioral data revealed that uncertain (but correct) responses led to slowing on subsequent trials, a phenomenon that was positively correlated with increased accuracy. Critically, post-uncertainty slowing was negatively correlated with the VS activity elicited by uncertain responses. In agreement with previous reports, increases in MFC activation were observed for uncertain responses, although MFC activity was not correlated with post-uncertainty slowing. These results suggest that perceptual uncertainty can serve as a signal to adapt one's response strategy and that such behavioral changes are closely tied to the VS, a key node in the performance-monitoring network.

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 such methodological approach is the examination of resting-state functional connectivity, which quantifies correlations in low-frequency fluctuations of the blood oxygen level-dependent magnetic resonance imaging signal between disparate brain regions in the absence of task performance. Here, 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, is discussed. 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.

Reward Anticipation Is Differentially Modulated by Varenicline and Nicotine in Smokers.

Recidivism rates for cigarette smokers following treatment often exceed 80%. Varenicline is the most efficacious pharmacotherapy currently available with cessation rates of 25-35% following a year of treatment. Although the in vivo binding properties are well known, varenicline's neurobiological mechanisms of action are still poorly understood. Varenicline acts as a nicotinic receptor partial agonist or antagonist depending on the presence or absence of nicotine and has been implicated in the reduction of reward signaling more broadly. The current study probed anticipatory reward processing using a revised monetary incentive delay task during fMRI in cohorts of smokers and non-smokers who completed a two-drug, placebo-controlled, double-blind crossover study. All participants underwent ~17 days of order-balanced varenicline and placebo pill administration and were scanned under each condition wearing a transdermal nicotine or placebo patch. Consistent with nicotine's ability to enhance the rewarding properties of nondrug stimuli, acute nicotine administration enhanced activation in response to reward-predicting monetary cues in both smokers and non-smokers. In contrast, varenicline reduced gain magnitude processing, but did so only in smokers. These results suggest that varenicline's downregulation of anticipatory reward processing in smokers, in addition to its previously demonstrated reduction in the negative affect associated with withdrawal, independently and additively alter distinct brain circuits. These effects likely contribute to varenicline's efficacy as a pharmacotherapy for smoking cessation.

The N2 ERP component as an index of impaired cognitive control in smokers.

Impaired cognitive control has been proposed as a hallmark of nicotine dependence and is thought to arise, in part, from synaptic alterations in anterior cingulate cortex (ACC), a primary component of the dopamine reward pathway. The N2 component of the event-related potential (ERP) appears to index a cognitive control process in paradigms such as the visual go/no-go task. Moreover, as dipole-modeling has suggested that the neural generator of the N2 component can be localized to the ACC, this component may prove useful for investigating impairments of cognitive control in smokers. Given conflicting reports of whether the N2 is reduced in smokers (as compared to non-smoker controls), the current study further examined the suitability of this component as an index for impaired cognitive control in smokers. Smokers and non-smokers performed a visual go/no-go task while electroencephalogram (EEG) was recorded. As predicted, the no-go N2 of smokers was significantly smaller than that of non-smoker controls, while the no-go P3 did not differ between groups. Importantly, behavioral performance (reaction time and accuracy) did not differ between smokers and nonsmokers, which might reflect the low levels of nicotine dependence (assessed by the Fagerstrom test) in our sample. The observed N2 modulation in the absence of behavioral impairments provides evidence for the utility of the N2 component as a sensitive measure of impaired cognitive control in smokers, even in those with low levels of nicotine dependence.

Prestimulus oscillations in the alpha band of the EEG are modulated by the difficulty of feature discrimination and predict activation of a sensory discrimination process.

Recent work has demonstrated that the occipital-temporal N1 component of the ERP is sensitive to the difficulty of visual discrimination, in a manner that cannot be explained by simple differences in low-level visual features, arousal, or time on task. These observations provide evidence that the occipital-temporal N1 component is modulated by the application of top-down control. However, the timing of this control process remains unclear. Previous work has demonstrated proactive, top-down modulation of cortical excitability for cued spatial attention or feature selection tasks. Here, the possibility that a similar top-down process facilitates performance of a difficult stimulus discrimination task is explored. Participants performed an oddball task at two levels of discrimination difficulty, with difficulty manipulated by modulating the similarity between target and nontarget stimuli. Discrimination processes and cortical excitability were assessed via the amplitude of the occipital-temporal N1 component and prestimulus alpha oscillation of the EEG, respectively. For correct discriminations, prestimulus alpha power was reduced, and the occipital-temporal N1 was enhanced in the hard relative to the easy condition. Furthermore, within the hard condition, prestimulus alpha power was reduced, and the occipital-temporal N1 was enhanced for correct relative to incorrect discriminations. The generation of ERPs contingent on relative prestimulus alpha power additionally suggests that diminished alpha power preceding stimulus onset is related to enhancement of the occipital-temporal N1. As in spatial attention, proactive control appears to enhance cortical excitability and facilitate discrimination performance in tasks requiring nonspatial, feature-based attention, even in the absence of competing stimulus features.

Representation of response alternatives in human presupplementary motor area: multi-voxel pattern analysis in a go/no-go task.

A debate exists as to the role of the presupplementary motor area (preSMA) in cognitive control. Recent findings suggest that preSMA plays a central role in conflict resolution and encodes response alternatives as opposed to simply the presence of conflict. Evidence of neuronal heterogeneity within preSMA of non-human primates suggests that univariate analysis of functional MRI data may not provide adequate resolution to fully characterize cognitive control-related responses. Here, multi-voxel pattern analysis (MVPA) is employed to examine the distributed patterns of activity in preSMA associated with both successful go responses and no-go inhibitions. In a go/no-go task, univariate analysis showed undifferentiated activation of preSMA in response to both go and no-go stimuli. However, when an anatomically-defined preSMA ROI was subjected to MVPA, a significant difference in the activation pattern encoded by go as compared to no-go stimuli was observed. These differences in preSMA activation are consistent with the ongoing maintenance and manipulation of stimulus-action representations.

Contextual task difficulty modulates stimulus discrimination: electrophysiological evidence for interaction between sensory and executive processes.

The occipital-temporal N1 component of the event-related potential (ERP) has previously been shown to index a stimulus discrimination process. However, the N1 has not consistently been shown to be sensitive to the difficulty of stimulus discrimination. Here, we manipulated the difficulty of stimulus discrimination by modulating the similarity between serially presented targets and nontargets. The same target stimulus was employed in both easy and difficult discrimination contexts, and these physically identical target stimuli elicited a larger N1 and smaller P3b in the difficult task context. Moreover, when targets were incorrectly categorized, N1 amplitude was diminished and a P3b was not elicited. These findings provide evidence that the N1 component reflects a sensory discrimination process that is modulated by executive control, and that this component can index discrimination errors when stimulus discrimination is difficult.

Dissociation of visual C1 and P1 components as a function of attentional load: an event-related potential study.

The earliest cortical location at which attention influences visual processing is controversial. To address this issue, the C1 and P1 components of cue-elicited ERPs were examined in a spatially-cued task under high and low levels of attentional load (active vs. passive viewing). Cues were presented either to the left or to the right visual field in separate trials (unilateral presentation), or to both visual fields simultaneously (bilateral presentation). For the unilateral presentation, C1 (peak latency approximately 80 ms) was not modulated by attentional load, whereas P1 (peak latency approximately 120-140 ms) was larger for high-relative to low-load condition. Bilateral presentation of the stimuli enhanced the amplitude of the C1 component relative to unilateral presentation; however, the increase of signal/noise ratio of C1 revealed no attentional load effect on C1. Results show that attentional load modulates visual processing in the P1, but not in the C1 time range, regardless of the increased signal/noise ratio by bilateral presentation. While it remains unclear about the conditions under which a C1 attentional effect is reliably elicited, the present results suggest that the direct manipulation of attentional load under a voluntary attention task seems not crucial for eliciting C1 attentional effect.