[Show abstract][Hide abstract] ABSTRACT: Although osmotic minipumps are a reliable method for inducing nicotine dependence in rodents, continuous nicotine administration does not accurately model the intermittent pattern of nicotine intake in cigarette smokers. Our objectives, therefore, were to investigate whether intermittent nicotine delivery via osmotic minipumps could induce dependence in rats, and to compare the magnitude and duration of withdrawal following forced abstinence from intermittent nicotine to that induced by continuous nicotine administration. In order to administer nicotine intermittently, rats were surgically implanted with saline-filled osmotic minipumps attached to polyethylene tubing that contained hourly unit doses of nicotine alternating with mineral oil to mimic "injections". Three doses of nicotine (1.2, 2.4, and 4.8mg/kg/day) and saline were administered for 14days using this method. In order to compare our intermittent delivery method with the more traditional continuous nicotine delivery, a second group of rats were implanted with minipumps attached to tubing that delivered continuous nicotine for 14days. Rats were administered a 1.5mg/kg subcutaneous (SC) mecamylamine challenge and observed for somatic signs of withdrawal on days 7, 14, 21, and 28 following minipump implantation. Fifteen somatic withdrawal signs were summed within a 50-min observation period to obtain a composite Dependence Score. A generalized linear mixed-effects model revealed a significant Day × Dose × Method interaction. Amongst continuously-treated rats, only 4.8mg/kg/d nicotine resulted in dependence scores significantly greater than those of controls at 14days of exposure. In contrast, all intermittent nicotine groups showed significantly higher scores beginning at 7days of exposure and persisting beyond 7days of abstinence. In general, intermittent delivery produced a more robust withdrawal syndrome than continuous delivery, and did so at a lower dose threshold and with greater persistence after forced abstinence.
Full-text · Article · Jan 2016 · Pharmacology Biochemistry and Behavior
[Show abstract][Hide abstract] ABSTRACT: Voxel-based morphometry (VBM) studies have revealed gray matter alterations in smokers, but this type of analysis has poor predictive value for individual cases, which limits its applicability in clinical diagnoses and treatment. A predictive model would essentially embody a complex biomarker that could be used to evaluate treatment efficacy. In this study, we applied VBM along 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 on an independent testing set that consisted of 28 smokers and 28 nonsmokers, yielding a 64.04% accuracy level (binomial P = 0.01). Following classification, exploratory post hoc regression analyses were performed, which 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. These results not only indicate that smoking related gray matter alterations can provide predictive power for group membership, but also suggest that machine learning techniques can reveal underlying smoking-related neurobiology. Hum Brain Mapp, 2015. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
No preview · Article · Oct 2015 · Human Brain Mapping
[Show abstract][Hide abstract] ABSTRACT: 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. While 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 down regulation 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.Neuropsychopharmacology accepted article preview online, 06 March 2015. doi:10.1038/npp.2015.54.
Full-text · Article · Mar 2015 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Attenuated activity in performance-monitoring brain regions following erroneous actions may contribute to the repetition of maladaptive behaviors such as continued drug use. Externalizing is a broad personality construct characterized by deficient impulse control, vulnerability to addiction and reduced neurobiological indices of error processing. The insula and dorsal anterior cingulate cortex (dACC) are regions critically linked with error processing as well as the perpetuation of cigarette smoking. As such, we examined the interrelations between externalizing tendencies, erroneous task performance, and error-related insula and dACC activity in overnight-deprived smokers (n=24) and non-smokers (n=20). Participants completed a self-report measure assessing externalizing tendencies (Externalizing Spectrum Inventory) and a speeded Flanker task during functional magnetic resonance imaging scanning. We observed that higher externalizing tendencies correlated with the occurrence of more performance errors among smokers but not non-smokers. Suggesting a neurobiological contribution to such suboptimal performance among smokers, higher externalizing also predicted less recruitment of the right insula and dACC following error commission. Critically, this error-related activity fully mediated the relationship between externalizing traits and error rates. That is, higher externalizing scores predicted less error-related right insula and dACC activity and, in turn, less error-related activity predicted more errors. Relating such regional activity with a clinically relevant construct, less error-related right insula and dACC responses correlated with higher tobacco craving during abstinence. Given that inadequate error-related neuronal responses may contribute to continued drug use despite negative consequences, these results suggest that externalizing tendencies and/or compromised error processing among subsets of smokers may be relevant factors for smoking cessation success.
Full-text · Article · Mar 2015 · Addiction Biology
[Show abstract][Hide abstract] ABSTRACT: Previous preclinical studies have emphasized that drugs of abuse, via actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of naturally rewarding stimuli. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward goal-directed behaviour, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period previously shown to induce behavioral self administration (SA) plasticity. A third group of sedentary animals served as a negative control group for general handling effects. We examined low frequency spontaneous fluctuations in the fMRI signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic cortex (PrL) and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts and suggest potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross sectional human studies may reflect the consequence of rather than a predispositional predecessor to their dependence.
[Show abstract][Hide abstract] ABSTRACT: Machine learning-based approaches are now able to examine functional magnetic resonance imaging data in a multivariate manner and extract features predictive of group membership. We applied support vector machine (SVM)-based classification to resting state functional connectivity (rsFC) data from nicotine-dependent smokers and healthy controls to identify brain-based features predictive of nicotine dependence. By employing a network-centered approach, we observed that within-network functional connectivity measures offered maximal information for predicting smoking status, as opposed to between-network connectivity, or the representativeness of each individual node with respect to its parent network. Further, our analysis suggests that connectivity measures within the executive control and frontoparietal networks are particularly informative in predicting smoking status. Our findings suggest that machine learning-based approaches to classifying rsFC data offer a valuable alternative technique to understanding large-scale differences in addiction-related neurobiology.
Full-text · Article · Jun 2014 · Frontiers in Human Neuroscience
[Show abstract][Hide abstract] ABSTRACT: Cocaine dependence impacts drug-related, dopamine-dependent reward processing, yet its influence on non-drug reward processing is unclear. Here, we investigated cocaine-mediated effects on reward learning using a natural food reinforcer. Cocaine-dependent subjects (N=14) and healthy controls (N=14) learned to associate a visual cue with a juice reward. In subsequent functional imaging sessions they were exposed to trials where juice was received as learned, withheld (negative temporal difference error (NTDE)), or received unexpectedly (positive temporal difference error (PTDE)). Subjects were scanned twice in sessions that were identical, except that cocaine-dependent participants received cocaine or saline 10 min before task onset. In the insula, precentral and postcentral gyri NTDE signals were greater, and PTDE-related function was reduced in cocaine-dependent subjects. Compared with healthy controls, in the cocaine-dependent group PTDE signals were also reduced in medial frontal gyrus and reward-related function, irrespective of predictability, was reduced in the putamen. Group differences in error-related activity were predicted by the time as last self-administered cocaine use, but TDE function was not influenced by acute cocaine. Thus, cocaine dependence seems to engender increased responsiveness to unexpected negative outcomes and reduced sensitivity to positive events in dopaminergic reward regions. Although it remains to be established if these effects are a consequence of or antecedent to cocaine dependence, they likely have implications for the high-cocaine use recidivism rates by contributing to the drive to consume cocaine, perhaps via influence on dopamine-related reward computations. The fact that these effects do not acquiesce to acute cocaine administration might factor in binge-related escalated consumption.Neuropsychopharmacology advance online publication, 26 February 2014; doi:10.1038/npp.2014.21.
Full-text · Article · Jan 2014 · Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Unlabelled:
The neural correlates of response to psychosocial stress and gender differences therein are difficult to model experimentally as this type of stressor is difficult to induce in a brain imaging environment. The Trier Social Stress Test (TSST), a behavioral paradigm that reliably induces moderate levels of stress was thus modified for the MRI environment. To determine the neurobehavioral basis of gender differences in response to observing oneself under social evaluative stress, 26 subjects (14 females) performed the TSST while being videotaped. During fMRI scanning, subjects were shown alternating video clips of two
SELF or a same-sex OTHER performing the TSST. Subjects rated their stress level immediately after the video clips. GENDER differences in the [SELF-OTHER] contrast were analyzed. There was a GENDER×CONDITION interaction such that only women reported increased subjective stress during video feedback of their TSST session. A whole brain analysis (SELF vs. OTHER) showed activation in the bilateral insula, inferior, middle and superior frontal gyri. Greater recruitment was seen among males in some of these same areas in the context of significantly lower stress ratings. Activation of areas involved in inhibitory control and sensory awareness might contribute to the significantly lower stress ratings in males. Understanding these gender differences is relevant to disorders of stress and self-concept.
[Show abstract][Hide abstract] ABSTRACT: Background:
Although the amygdala and insula are regarded as critical neural substrates perpetuating cigarette smoking, little is known about their circuit-level interactions with interconnected regions during nicotine withdrawal or following pharmacotherapy administration. To elucidate neurocircuitry associated with early smoking abstinence, we examined the impact of varenicline and nicotine, two modestly efficacious pharmacologic cessation aids, on amygdala- and insula-centered circuits using resting-state functional connectivity (rsFC).
In a functional magnetic resonance imaging study employing a two-drug, placebo-controlled design, 24 overnight-abstinent smokers and 20 nonsmokers underwent ∼17 days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. We examined the impact of varenicline and nicotine (both alone and in combination) on amygdala- and insula-centered rsFC using seed-based assessments.
Beginning with a functionally defined amygdala seed, we observed that rsFC strength in an amygdala-insula circuit was down-regulated by varenicline and nicotine in abstinent smokers. Using this identified insula region as a new seed, both drugs similarly decreased rsFC between the insula and constituents of the canonical default-mode network (posterior cingulate cortex, ventromedial/dorsomedial prefrontal cortex, parahippocampus). Drug-induced rsFC modulations were critically linked with nicotine withdrawal, as similar effects were not detected in nonsmokers.
These results suggest that nicotine withdrawal is associated with elevated amygdala-insula and insula-default-mode network interactions. As these potentiated interactions were down-regulated by two pharmacotherapies, this effect may be a characteristic shared by pharmacologic agents promoting smoking cessation. Decreased rsFC in these circuits may contribute to amelioration of subjective withdrawal symptoms.
Full-text · Article · Mar 2013 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: Rationale
Alexithymia is a personality trait characterized by difficulty indentifying and describing subjective emotional experiences. Decreased aptitude in the perception, evaluation, and communication of affectively laden mental states has been associated with reduced emotion regulation, more severe drug craving in addicts, and structural/functional alterations in insula and anterior cingulate cortex (ACC). The insula and ACC represent sites of convergence between the putative neural substrates of alexithymia and those perpetuating cigarette smoking.
We examined the interrelations between alexithymia, tobacco craving, and insula/ACC neurocircuitry using resting-state functional connectivity (rsFC).
Overnight-deprived smokers (n = 24) and nonsmokers (n = 20) completed six neuroimaging assessments on different days both in the absence of, and following, varenicline and/or nicotine administration. In this secondary analysis of data from a larger study, we assessed trait alexithymia and state tobacco craving using self-reports and examined the rsFC of bilateral insular subregions (anterior, middle, posterior) and dorsal ACC.
Higher alexithymia in smokers predicted reduced rsFC strength between the right anterior insula (aI) and ventromedial prefrontal cortex (vmPFC). Higher alexithymia also predicted more severe tobacco craving during nicotine withdrawal. Critically, the identified aI–vmPFC circuit fully mediated this alexithymia–craving relation. That is, elevated alexithymia predicted decreased aI–vmPFC rsFC and, in turn, decreased aI–vmPFC rsFC predicted increased craving during withdrawal. A moderated mediation analysis indicated that this aI–vmPFC mediational effect was not observed following drug administration.
These results suggest that a weakened right aI–vmPFC functional circuit confers increased liability for tobacco craving during smoking abstinence. Individual differences in alexithymia and/or aI–vmPFC functional coupling may be relevant factors for smoking cessation success.
Full-text · Article · Feb 2013 · Psychopharmacology
[Show abstract][Hide abstract] ABSTRACT: Patients with schizophrenia (SZ) show deficits on tasks of rapid reinforcement learning, like probabilistic reversal learning (PRL), but the neural bases for those impairments are not known. Recent evidence of relatively intact sensitivity to negative outcomes in the ventral striatum (VS) in many SZ patients suggests that PRL deficits may be largely attributable to processes downstream from feedback processing, involving both the activation of executive control task regions and deactivation of default mode network (DMN) components. We analyzed data from 29 chronic SZ patients and 21 matched normal controls (NCs) performing a PRL task in an MRI scanner. Subjects were presented with eight pairs of fractal stimuli, for 50 trials each. For each pair, subjects learned to choose the more frequently-rewarded (better) stimulus. Each time a criterion was reached, the better stimulus became the worse one, and the worse became the better. Responses to feedback events were assessed through whole-brain and regions-of-interest (ROI) analyses in DMN. We also assessed correlations between BOLD signal contrasts and clinical measures in SZs. Relative to NCs, SZ patients showed comparable deactivation of VS in response to negative feedback, but reduced deactivation of DMN components including medial prefrontal cortex (mPFC). The magnitudes of patients' punishment-evoked deactivations in VS and ventromedial PFC correlated significantly with clinical ratings for avolition/anhedonia. These findings suggest that schizophrenia is associated with a reduced ability to deactivate components of default mode networks, following the presentation of informative feedback and that motivational deficits in SZ relate closely to feedback-evoked activity in reward circuit components. These results also confirm a role for ventrolateral and dorsomedial PFC in the execution of response-set shifts.
[Show abstract][Hide abstract] ABSTRACT: Nicotine and tonic DA levels (as inferred by COMT Val158Met genotype) interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine x COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine x COMT genotype interaction for BOLD signal during performance feedback in corticostriatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, areas associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, nevertheless, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy.
Full-text · Article · Feb 2013 · Genes Brain and Behavior
[Show abstract][Hide abstract] ABSTRACT: Individuals addicted to most chemical substances present with hypoactive dopaminergic systems as well as altered prefrontal white matter structure. Prefrontal dopaminergic tone is under genetic control and is influenced by and modulates descending cortico-striatal glutamatergic pathways that in turn, regulate striatal dopamine release. The catechol-O-methyltransferase (COMT) gene contains an evolutionarily recent and common functional variant at codon 108/158 (rs4680) that plays an important role in modulating prefrontal dopaminergic tone. To determine if the COMT val158met genotype influences white matter integrity (i.e., fractional anisotropy (FA)) in substance users, 126 healthy controls and 146 substance users underwent genotyping and magnetic resonance imaging. A general linear model with two between-subjects factors (COMT genotype and addiction status) was performed using whole brain diffusion tensor imaging (DTI) to assess FA. A significant Genotype x Drug Use status interaction was found in the left prefrontal cortex. Post-hoc analysis showed reduced prefrontal FA only in Met/Met homozygotes who were also drug users. These data suggest that Met/Met homozygous individuals, in the context of addiction, have increased susceptibility to white matter structural alterations, which might contribute to previously identified structural and functional prefrontal cortical deficits in addiction.
[Show abstract][Hide abstract] ABSTRACT: Hyperactive amygdala functioning may underlie emotional dysregulation during smoking abstinence and represents one neurobiological target for pharmacological cessation aids. Available pharmacotherapies (e.g., nicotine replacement and varenicline) aid only a subset of individuals with smoking cessation and therefore elucidating the neurobiological impact of these medications is critical to expedite improved interventions. In a fMRI study employing a within-subject, double-blind, placebo-controlled design, we assessed task performance and amygdala functioning during an emotional face matching paradigm following administration of nicotine and varenicline to 24 abstinent smokers and 20 nonsmokers. All participants underwent ~17days of varenicline and placebo pill administration and were scanned, on different days under each condition, wearing a transdermal nicotine or placebo patch. During the amygdala reactivity paradigm, nicotinic acetylcholine receptor (nAChR) stimulation by nicotine and varenicline decreased reaction time (RT) in abstinent smokers but not in nonsmokers. When considering all smokers as a single homogenous group, no drug-induced effects on amygdala reactivity were detected. However, in an exploratory analysis we parsed participants into subgroups according to individual differences in the propensity to demonstrate stable performance augmentation following nAChR stimulation (stable RT-improvers [SI] vs. variable RT-improvers [VI]). Using this exploratory approach, drugs appeared to modulate amygdala reactivity in only one smoker subgroup but not in either nonsmoker subgroup. Specifically, in the SI-smoker cohort abstinence-induced elevated amygdala reactivity was down-regulated by nAChR stimulation. In contrast, varenicline and nicotine did not modulate amygdala functioning in the VI-smoker cohort who displayed moderate levels of amygdala reactivity in the absence of drug administration. These results suggest that pharmacotherapies most robustly dampened amygdala functioning in smokers appearing susceptible to abstinence-induced effects. Such findings provide a step towards fractionating the smoker phenotype by discrete neurobiological characteristics.
[Show abstract][Hide abstract] ABSTRACT: Background:
Dopaminergic activity plays a role in mediating the rewarding aspects of abused drugs, including nicotine. Nicotine modulates the reinforcing properties of other motivational stimuli, yet the mechanisms of this interaction are poorly understood. This study aimed to ascertain the impact of nicotine exposure on neuronal activity associated with reinforcing outcomes in dependent smokers.
Smokers (n = 28) and control subjects (n = 28) underwent functional imaging during performance of a monetary incentive delay task. Using a randomized, counterbalanced design, smokers completed scanning after placement of a nicotine or placebo patch; nonsmokers were scanned twice without nicotine manipulation. In regions along dopaminergic pathway trajectories, we considered event-related activity for valence (reward/gain vs. punishment/loss), magnitude (small, medium, large), and outcome (successful vs. unsuccessful).
Both nicotine and placebo patch conditions were associated with reduced activity in regions supporting anticipatory valence, including ventral striatum. In contrast, relative to controls, acute nicotine increased activity in dorsal striatum for anticipated magnitude. Across conditions, anticipatory valence-related activity in the striatum was negatively associated with plasma nicotine concentration, whereas the number of cigarettes daily correlated negatively with loss anticipation activity in the medial prefrontal cortex only during abstinence.
These data suggest a partial dissociation in the state- and trait-specific effects of smoking and nicotine exposure on magnitude- and valence-dependent anticipatory activity within discrete reward processing brain regions. Such variability may help explain, in part, nicotine's impact on the reinforcing properties of nondrug stimuli and speak to the continued motivation to smoke and cessation difficulty.
Full-text · Article · Aug 2012 · Biological psychiatry
[Show abstract][Hide abstract] ABSTRACT: Repeated cocaine exposure induces long-lasting neuroadaptations that alter subsequent responsiveness to the drug. However, systems-level investigation of these neuroplastic consequences is limited. We employed a rodent model of drug addiction to investigate neuroadaptations associated with prolonged forced abstinence after long-term cocaine self-administration (SA). Since natural rewards also activate the mesolimbic reward system in a partially overlapping fashion as cocaine, our design also included a sucrose SA group. Rats were trained to self-administer cocaine or sucrose using a fixed-ratio one, long-access schedule (6 h/day for 20 days). A third group of naïve, sedentary rats served as a negative control. After 30 days of abstinence, the reactivity of the reward system was assessed with functional magnetic resonance imaging (fMRI) following an intravenous cocaine injection challenge. A strong positive fMRI response, as measured by fractional cerebral blood volume changes relative to baseline (CBV%), was seen in the sedentary control group in such cortico-limbic regions as medial prefrontal cortex and anterior cingulate cortex. In contrast, both the cocaine and sucrose SA groups demonstrated a very similar initial negative fMRI response followed by an attenuated positive response. The magnitude of the mPFC response was significantly correlated with the total amount of reinforcer intake during the training sessions for the cocaine SA but not for the sucrose SA group. Given that the two SA groups had identical histories of operant training and handling, this region-specific group difference revealed by regression analysis may reflect the development of neuroadaptive mechanisms specifically related to the emergence of addiction-like behavior that occurs only in cocaine SA animals.