Addicted to green: priming effect of menthol cigarette packaging on brain response to smoking cues.

INTRODUCTION: Mentholated tobacco cigarettes are believed to be more addictive than non-menthol ones. Packaging of most menthol cigarette brands includes distinctive green hues, which may act as conditioned stimuli (ie, cues) and promote menthol smoking. To examine the cue properties of menthol cigarette packaging, we used a priming paradigm to assess the effect of packaging on the neural substrates of smoking cue reactivity. We hypothesised that menthol packaging will exert a specific priming effect potentiating smoking cue reactivity in menthol compared with non-menthol smokers. METHODS: Forty-two menthol and 33 non-menthol smokers underwent functional MRI while viewing smoking and neutral cues. The cues were preceded (ie, primed) by briefly presented images of menthol or non-menthol cigarette packages. Participants reported craving for cigarettes in response to each cue. RESULTS: Menthol packaging induced greater frontostriatal and occipital smoking cue reactivity in menthol smokers than in non-menthol smokers. Menthol packaging also enhanced the mediation by neural activity of the relationship between cue exposure and cigarette craving in menthol but not non-menthol smokers. Dynamic causal modelling showed stronger frontostriatal-occipital connectivity in response to menthol packaging in menthol compared with non-menthol smokers. The effects of non-menthol packaging did not differ between categories of smokers. CONCLUSIONS: Our findings demonstrate heightened motivational and perceptual salience of the green-hued menthol cigarette packaging that may exacerbate menthol smokers' susceptibility to smoking cues. These effects could contribute to the greater addiction severity among menthol smokers and could be considered in the development of science-based regulation and legal review of tobacco product marketing practices.

The role of withdrawal in mesocorticolimbic drug cue reactivity in opioid use disorder.

Opioid use disorder (OUD) is characterized by heightened cognitive, physiological, and neural responses to opioid-related cues that are mediated by mesocorticolimbic brain pathways. Craving and withdrawal are key symptoms of addiction that persist during physiological abstinence. The present study evaluated the relationship between the brain response to drug cues in OUD and baseline levels of craving and withdrawal. We used functional magnetic resonance imaging (fMRI) to examine brain responses to opioid-related pictures and control pictures in 29 OUD patients. Baseline measures of drug use severity, opioid craving, and withdrawal symptoms were assessed prior to cue exposure and correlated with subsequent brain responses to drug cues. Mediation analysis was conducted to test the indirect effect of drug use severity on brain cue reactivity through craving and withdrawal symptoms. We found that baseline drug use severity and opioid withdrawal symptoms, but not craving, were positively associated with the neural response to drug cues in the nucleus accumbens, orbitofrontal cortex, and amygdala. Withdrawal, but not craving, mediated the effect of drug use severity on the nucleus accumbens' response to drug cues. We did not find similar effects for the neural responses to stimuli unrelated to drugs. Our findings emphasize the central role of withdrawal symptoms as the mediator between the clinical severity of OUD and the brain correlates of sensitization to opioid-related cues. They suggest that in OUD, baseline withdrawal symptoms signal a high vulnerability to drug cues.

Behavioral and Accumbal Responses During an Affective Go/No-Go Task Predict Adherence to Injectable Naltrexone Treatment in Opioid Use Disorder.

Adherence is a major factor in the effectiveness of the injectable extended-release naltrexone as a relapse prevention treatment in opioid use disorder. We examined the value of a variant of the Go/No-go paradigm in predicting extended-release naltrexone adherence in 27 detoxified opioid use disorder patients who were offered up to 3 monthly extended-release naltrexone injections. Before extended-release naltrexone, participants performed a Go/No-go task that comprised positively valenced Go trials and negatively valenced No-go trials during a functional magnetic resonance imaging scan. Errors of commission and neural responses to the No-go vs Go trials were independent variables. Adherence, operationalized as the completion of all 3 extended-release naltrexone injections, was the outcome variable. Fewer errors of commission and greater left accumbal response during the No-go vs Go trials predicted better adherence. These findings support the clinical potential of the behavioral and neurophysiological correlates of response inhibition in the prediction of extended-release naltrexone treatment outcomes in opioid use disorder.

Emotional salience of the image component facilitates recall of the text of cigarette warning labels.

Background: Graphic warning labels (GWLs) on cigarette packages, that combine textual warnings with emotionally salient images depicting the adverse health consequences of smoking, have been adopted in most European countries. In the US, the courts deemed the evidence justifying the inclusion of emotionally salient images in GWLs insufficient and put the implementation on hold. We conducted a controlled experimental study examining the effect of emotional salience of GWL's images on the recall of their text component. Methods: Seventy-three non-treatment-seeking daily smokers received cigarette packs carrying GWLs for a period of 4 weeks. Participants were randomly assigned to receive packs with GWLs previously rated as eliciting high or low level of emotional reaction (ER). The two conditions differed in respect to images but used the same textual warning statements. Participants' recognition of GWL images and statements were tested separately at baseline and again after the 4-week repetitive exposure. Results: Textual warning statements were recognized more accurately when paired with high ER images than when paired with low ER images, both at baseline and after daily exposure to GWLs over a 4-week period. Conclusion: The results suggest that emotional salience of GWLs facilitates cognitive processing of the textual warnings, resulting in better remembering of the information about the health hazards of smoking. Thus, high emotional salience of the pictorial component of GWLs is essential for their overall effectiveness.

Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder.

BACKGROUND: Heightened response to drug-related cues is a hallmark of addiction. Extended-release naltrexone (XR-NTX) is a US Food and Drug Administration-approved pharmacotherapy for relapse prevention in patients with opioid use disorder (OUD). In these patients, XR-NTX has been shown to reduce brain responses to opioid-related visual stimuli. To assess the biomarker potential of this phenomenon, it is necessary to determine whether this effect is limited to opioid-related stimuli and whether it is associated with key OUD symptoms. METHODS: Using functional MRI (fMRI), we measured the brain responses to opioid-related and control (i.e., sexual and aversive) images in detoxified patients with OUD before, during and after XR-NTX treatment. Craving and withdrawal severity were evaluated using clinician- and self-administered instruments during each session. RESULTS: We included 24 patients with OUD in our analysis. During XR-NTX treatment, we found reduced responses to opioid-related stimuli in the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). The reduction in mOFC response was specific to the opioid-related stimuli. The reduced NAcc and mOFC opioid cue reactivity was correlated with reduction in clinician-assessed and self-reported withdrawal symptoms, respectively. LIMITATIONS: The study was not placebo-controlled owing to ethical, safety and feasibility concerns. CONCLUSION: Extended-release naltrexone reduces the NAcc and mOFC cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only. The reduction in neural response to opioid-related stimuli is more robust in patients with greater decline in withdrawal severity. Our results support the clinical utility of mesocorticolimbic cue reactivity in monitoring the XR-NTX treatment outcomes and highlight the link between opioid withdrawal symptomatology and neural opioid cue reactivity.

Effects of extended-release naltrexone on the brain response to drug-related stimuli in patients with opioid use disorder.

BACKGROUND: Heightened response to drug-related cues is a hallmark of addiction. Extended-release naltrexone (XR-NTX) is a US Food and Drug Administration-approved pharmacotherapy for relapse prevention in patients with opioid use disorder (OUD). In these patients, XR-NTX has been shown to reduce brain responses to opioid-related visual stimuli. To assess the biomarker potential of this phenomenon, it is necessary to determine whether this effect is limited to opioid-related stimuli and whether it is associated with key OUD symptoms. METHODS: Using functional MRI (fMRI), we measured the brain responses to opioid-related and control (i.e., sexual and aversive) images in detoxified patients with OUD before, during and after XR-NTX treatment. Craving and withdrawal severity were evaluated using clinician- and self-administered instruments during each session. RESULTS: We included 24 patients with OUD in our analysis. During XR-NTX treatment, we found reduced responses to opioid-related stimuli in the nucleus accumbens (NAcc) and medial orbitofrontal cortex (mOFC). The reduction in mOFC response was specific to the opioid-related stimuli. The reduced NAcc and mOFC opioid cue reactivity was correlated with reduction in clinician-assessed and self-reported withdrawal symptoms, respectively. LIMITATIONS: The study was not placebo-controlled owing to ethical, safety and feasibility concerns. CONCLUSION: Extended-release naltrexone reduces the NAcc and mOFC cue reactivity in patients with OUD. This effect is specific to opioid-related stimuli in the mOFC only. The reduction in neural response to opioid-related stimuli is more robust in patients with greater decline in withdrawal severity. Our results support the clinical utility of mesocorticolimbic cue reactivity in monitoring the XR-NTX treatment outcomes and highlight the link between opioid withdrawal symptomatology and neural opioid cue reactivity.

Effects of emotional arousal on the neural impact and behavioral efficacy of cigarette graphic warning labels.

BACKGROUND AND AIMS: Graphic warning labels (GWLs) on cigarette packs have been adopted by many jurisdictions world-wide. In the United States, the introduction of GWLs has been delayed by claims that their high level of negative emotional arousal unnecessarily infringed upon the tobacco manufacturers' free speech. This study aimed to provide experimental data on the contribution of emotional arousal to GWL efficacy. DESIGN: Observational study using long-term naturalistic exposure and functional magnetic resonance imaging. SETTING: Research university in Philadelphia, PA, USA. PARTICIPANTS: A total of 168 adult smokers. MEASUREMENTS: For 4 weeks, participants received cigarettes in packs that carried either high-arousal or low-arousal GWLs (n = 84 versus 84). Smoking behavior, quitting-related cognitions and GWL-induced brain response were measured before and after the 4-week exposure. The amygdala and medial prefrontal cortex served as regions of interest. FINDINGS: Compared with the high-arousal group, the low-arousal group smoked fewer cigarettes [log10 -transformed, 1.076 versus 1.019; difference = 0.056, 95% confidence interval (CI) = 0.027, 0.085, χ2 (1)  = 14.21, P < 0.001] and showed stronger intention to quit (2.527 versus 2.810; difference = -0.283, 95% CI = -0.468, -0.098, χ2 (1) = 8.921, P = 0.007) and endorsement of the GWLs' textual component (4.805 versus 5.503; difference = -0.698, 95% CI = -1.016, -0.380, χ2 (1) = 18.47, P < 0.001). High-arousal GWLs induced greater amygdala response than low-arousal GWLs (0.157 versus 0.052; difference = 0.105, 95% CI = 0.049, 0.161, χ2 (1) = 23.52, P < 0.001), although the response to high-arousal GWLs declined over time (slope = -0.087 versus 0.016; difference = -0.103, 95% CI = -0.198, -0.009, χ2 (1) = 6.370, P = 0.046). Greater baseline amygdala response was associated with more smoking at 4 weeks in the high-arousal group, but less smoking in the low-arousal group (slope = 0.179 versus -0.122; difference = 0.287, 95% CI = 0.076, 0.498, χ2 (1) = 7.086, P = 0.008). Medial prefrontal response did not differ significantly between groups. CONCLUSIONS: High-arousal cigarette graphic warning labels (GWLs) appear to be less efficacious than low-arousal GWLs. The high emotional reaction that high-arousal GWLs elicit wanes over time. Baseline amygdala response negatively predicts efficacy of high-arousal GWLs and positively predicts efficacy of low-arousal GWLs. High emotional arousal may not be required for sustained GWL efficacy.

Brain Responses to Anti-Smoking Health Warnings In Youth.

PURPOSE OF THE REVIEW: Adolescents and young adults are a critical target for smoking prevention efforts. Health education is a key approach to these efforts, yet little is known about how adolescents and young adults process health information. One novel approach to understanding the neurobiological mechanisms of cognitive processing of public health communications is to use neuroimaging techniques to map the brain regions involved and make inferences about the neural systems engaged in the processing of health information. We reviewed recent studies that employed functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) to examine the brain responses of adolescents and young adults to anti-smoking health messages and videos. FINDINGS: This narrative literature review found that the medial prefrontal cortex, amygdala, and hippocampus were the brain regions most commonly engaged in response to health warnings. Developmental factors modulate the relationship between brain regions, regulated emotional reaction, and frontal regions that are responsible for decision making. SUMMARY: Research that integrates neurophysiology and behavior to study adolescent and young adult neurocognitive responses to health messaging is an important tool for identifying optimal methods to communicate the health hazards of smoking to this vulnerable population.

Sustained opioid antagonism modulates striatal sensitivity to baby schema in opioid use disorder.

BACKGROUND: Chronic opioid misuse is associated with reduced sensitivity to natural rewards and social motivation deficits that include impaired caregiving. The neurobiological mechanisms underlying these deficits and their response to treatment are not well understood. Baby schema (Kindchenschema) is a set of juvenile physical features, which is perceived as "cute" and triggers motivation for caregiving. Recent studies suggest that the "baby schema effect" is mediated by the brain "reward" network. We studied the impact of opioid antagonist treatment on the baby schema response in patients with opioid use disorder. METHODS: Forty-seven (24 F) recently detoxified patients with opioid use disorder underwent functional magnetic resonance imaging (fMRI) while viewing infant portraits that were parametrically manipulated for baby schema content and rating them for cuteness, at baseline and during treatment with the injectable extended release opioid antagonist naltrexone (XRNTX). The study was not placebo-controlled. RESULTS: The behavioral effect of baby schema, indexed by "cuteness" ratings, was present and unaffected by XRNTX. The brain response to baby schema was absent at baseline, but present in the bilateral ventral striatum after two weeks of XRNTX treatment. The decline in self-reported craving for opioids was positively correlated with the brain fMRI response to baby schema in the bilateral ventral striatum. CONCLUSIONS: Opioid antagonist treatment modulated the brain reward system response to a marker of caregiving motivation in patients with opioid use disorder. Neural response to baby schema may offer a novel probe of social motivation and affiliative behaviors in this population.

Crack Cocaine Use in Adolescents: Clinical Characteristics and Predictors of Early Initiation.

OBJECTIVE: To describe the clinical characteristics of adolescents with crack cocaine dependence and possible predictors of transition from drug experimentation to crack cocaine dependence. METHODS: This cross-sectional study enrolled a consecutive sample of 90 adolescents admitted to a psychiatric inpatient unit in the city of Porto Alegre in southern Brazil for crack cocaine detoxification between May 2011 and November 2012. Comorbid psychological conditions were assessed using the Kiddie-SADS-Present and Lifetime Version, and severity of drug use was assessed using the Teen Addiction Severity Index (T-ASI). Comorbidities were compared with those in a community sample of non-drug using controls (n = 81). RESULTS: Patients' mean age was 15.6 years (85.6% boys, 14.4% girls). Seventy-nine (93.2%) met criteria for cocaine dependence (DSM-IV-TR), while 78 (91.8%) had symptoms consistent with cocaine abuse. All patients had experimented with at least 1 other addictive substance before crack cocaine: 61.4%, tobacco (mean age at first use = 11.61 years); 44.3%, alcohol (age at first use = 12.43 years); and 54.5%, cannabis (age at first use = 12.15 years). Patients had used crack cocaine 23.2 days in the last month, and the mean age at first use of crack cocaine was 13.38 years. The most common psychiatric comorbidity was conduct disorder (81.8%), followed by oppositional defiant disorder (52.3%) and attention-deficit/hyperactivity disorder (44.3%), all of which were more prevalent in the patient population than in controls (P < .001). The T-ASI questionnaire showed severe consequences of drug use in most areas of life assessed. The mean time between onset of drug experimentation and crack cocaine dependence was 2.53 (SD = 1.96) years. When Cox regression models were applied, we found that predictors of earlier progression to using crack cocaine were age at first use of any drug (hazard ratio [HR] = 0.79 [95% CI, 0.71-0.88]; P < .001) and age at admission (HR = 0.7 [95% CI, 0.57-0.87]; P = .001). CONCLUSIONS: Patients were found to have a multitude of comorbid conditions, which supports the idea of treatment by a multidisciplinary health care team. For each year of delay in the age at first drug use, the chance of crack cocaine initiation is reduced by 18%. Prevention programs aimed at delaying experimentation with addictive substances, especially "gateway" drugs, could delay the progression to crack cocaine dependence.