Brain mGlu5 is linked to cognition and cigarette smoking but does not differ from control in early abstinence from chronic methamphetamine use.

BACKGROUND: The group-I metabotropic glutamate receptor subtype five (mGlu5) has been implicated in methamphetamine exposure in animals, and in human cognition. Because people with Methamphetamine Use Disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total volume of distribution (VT) of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least two weeks, n = 14) and a control group (n = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs. smoking participants (main effect, p = 0.0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task (RAVLT) and the Stroop Test vs. controls (p = 0.08 and p = 0.13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the SCAP (p = 0.015). Across groups, RAVLT performance correlated with VT in the dorsolateral prefrontal cortex (DLPFC) and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dlPFC with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.

Effects of oral contraceptive pills on mood and magnetic resonance imaging measures of prefrontal cortical thickness.

Gonadal hormones influence neuronal organization and plasticity. Yet the consequences of altering their concentrations by administering contraceptive agents, which are used by most reproductive-age women in the United States, are unclear. Cross-sectional studies have found both larger and smaller cortical regions alongside a variety of mood alterations in women who use oral contraceptive pills (OCPs) compared to naturally-cycling women. The goal of this study, therefore, was to determine whether there is an effect of OCPs on MRI measures of prefrontal cortical brain structure that may influence regulation of mood. We performed a double-blind, placebo-controlled, randomized crossover study comparing effects of OCPs (0.15 mg levonorgestrel + 0.30 µg ethinyl estradiol) vs placebo (N = 26) on MRI measures of prefrontal cortical thickness and on mood, as indicated by self-report on the Daily Record of Severity of Problems, which also includes one item related to somatic symptoms. MRI measures that reflect cortical thickness were smaller bilaterally in the pars triangularis and in the pars opercularis and frontal pole of the right hemisphere during the OCP arm vs. placebo. Only the effect in the right pars triangularis survived multiple comparisons correction. Right pars triangularis MRI measures of cortical thickness were not related to mood symptoms, but negatively correlated across conditions with severity of somatic symptoms on the DSRP. The somatic symptoms and MRI measures may be independently related to the actions of steroid hormones in OCPs, with OCPs simultaneously inducing both more effects on MRI measures of cortical thickness and somatic symptoms.

Cortical thickness and related depressive symptoms in early abstinence from chronic methamphetamine use.

Methamphetamine use is surging globally as a cause of morbidity and mortality. Treatment is typically sought in early abstinence, when craving and depressive symptoms are intense, contributing to relapse and poor outcomes. To advance an understanding of this problem and identify therapeutic targets, we conducted a retrospective analysis of brain structure in 89 adults with Methamphetamine Use Disorder who were in early abstinence and 89 healthy controls. Unlike most prior research, the participants did not significantly differ in age, sex and recent use of alcohol and tobacco (p-values ≥ 0.400). We analysed thickness across the entire cerebral cortex by fitting a general linear model to identify differences between groups. Follow-up regressions were performed to determine whether cortical thickness in regions showing group differences was related to craving, measured on a visual analogue scale, or to the Beck Depression Inventory score. Participants in early methamphetamine abstinence (M ± SD = 22.1 ± 25.6 days) exhibited thinner cortex in clusters within bilateral frontal, parietal, temporal, insular, and right cingulate cortices relative to controls (p-values < 0.001, corrected for multiple comparisons). Unlike craving (ß = 0.007, p = 0.947), depressive symptoms were positively correlated with cortical thickness across clusters (ß = 0.239, p = 0.030) and with thickness in the anterior cingulate cluster (ß = 0.246, p = 0.027) in the methamphetamine-dependent group. Inasmuch as anterior cingulate pathology predicts response to antidepressants for Major Depressive Disorder, cingulate structure may also identify patients with Methamphetamine Use Disorder who can benefit from antidepressant medication.

Sex Differences in the Association of Cigarette Craving With Insula Structure.

BACKGROUND: Cigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person's sex influences these associations. METHODS: The research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day. RESULTS: Women reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P < .001). A 3-way interaction of sex, smoking condition, and right anterior circular insular sulcus thickness on craving (P = .033) reflected a negative association of cortical thickness with pre-smoking craving in women only (P = .012). No effects of cortical thickness in the left anterior circular insular sulcus were detected. Nicotine dependence was positively associated with craving (P < .001) across groups and sessions, with no sex differences in this association. CONCLUSIONS: A negative association of right anterior insula thickness with craving in women only suggests that this region may be a relevant therapeutic target for brain-based smoking cessation interventions in women.

The development of race effects in face processing from childhood through adulthood: Neural and behavioral evidence.

Most adults are better at recognizing recently encountered faces of their own race, relative to faces of other races. In adults, this race effect in face recognition is associated with differential neural representations of own- and other-race faces in the fusiform face area (FFA), a high-level visual region involved in face recognition. Previous research has linked these differential face representations in adults to viewers' implicit racial associations. However, despite the fact that the FFA undergoes a gradual development which continues well into adulthood, little is known about the developmental time-course of the race effect in FFA responses. Also unclear is how this race effect might relate to the development of face recognition or implicit associations with own- or other-races during childhood and adolescence. To examine the developmental trajectory of these race effects, in a cross-sectional study of European American (EA) children (ages 7-11), adolescents (ages 12-16) and adults (ages 18-35), we evaluated responses to adult African American (AA) and EA face stimuli, using functional magnetic resonance imaging and separate behavioral measures outside the scanner. We found that FFA responses to AA and EA faces differentiated during development from childhood into adulthood; meanwhile, the magnitudes of race effects increased in behavioral measures of face-recognition and implicit racial associations. These three race effects were positively correlated, even after controlling for age. These findings suggest that social and perceptual experiences shape a protracted development of the race effect in face processing that continues well into adulthood.

The relationship between duration of abstinence and gray-matter brain structure in chronic methamphetamine users.

Background: Brain structural findings in chronic methamphetamine users have been inconsistent. Identifying contributing influences (e.g., sex, abstinence duration) can help clarify the clinical course of recovery.Objectives: We studied the effects of long-term methamphetamine abstinence on gray-matter volume. Our hypothesis was that smaller volume early in abstinence would precede long-term recovery.Methods: Individuals who used methamphetamine (≥100 g lifetime use, mandated to residential treatment for methamphetamine-positive urine; 40 men, 21 women), undergoing supervised abstinence (men: 12-400 days; women: 130-594 days), were compared to healthy controls (49 men, 36 women) using T1-weighted MRI. Volumes of orbitofrontal, anterior cingulate and parietal cortex, hippocampus, and striatum were measured using Freesurfer software. Associations of volumes with abstinence duration were tested in males and females separately because their abstinence times differed (121.5 ± 124.5 vs. 348.0 ± 128.6 days, p < 0.001); only males were studied in early abstinence. The General Linear Model was used to test effects of abstinence duration and group (methamphetamine users vs. controls).Results: In males, duration of abstinence was multivariate significant for gray-matter volumes (p = 0.017). Abstinence duration was associated with increases in volumes of the orbitofrontal and parietal cortices (ps = 0.031, 0.016) and hippocampi (ps = 0.044). Irrespective of abstinence, male methamphetamine users had smaller hippocampi than male controls (p = 0.008). Females showed no significant effects of group or abstinence.Conclusions: In males, abstinence from methamphetamine appears to result in volumetric increases in regions important for cognitive function, which may affect recovery during the course of treatment. Data from the period of early abstinence are required to evaluate volumetric changes in females.

Neural Basis of Smoking-Related Difficulties in Emotion Regulation.

BACKGROUND: Negative emotional states contribute to cigarette smoking, and difficulties in regulating these states can hinder smoking cessation. Understanding the neural bases of these difficulties in smokers may facilitate development of novel therapies for Tobacco Use Disorder. METHODS: Thirty-seven participants (18 smokers, 19 nonsmokers; 16-21 years old) completed the Difficulties in Emotion Regulation Scale (DERS), which is comprised of 6 subscales (lack of emotional clarity, lack of emotional awareness, limited access to emotion regulation strategies, nonacceptance of emotional responses, difficulties engaging in goal-directed behaviors, and impulse control difficulties) that combine to provide a total score. Participants also underwent functional magnetic resonance imaging to determine resting-state functional connectivity of the amygdala. Separate ANOVAs were used to determine group differences in self-reports on the DERS. Voxel-wise linear mixed models were performed to determine whether group influenced relationships between whole-brain functional connectivity of the amygdala and scores on the DERS. RESULTS: Compared with nonsmokers, smokers reported greater difficulties in emotion regulation, denoted by higher total scores on the DERS. Group differences were observed on a subscale of lack of emotional clarity, but no other subscale differences on the DERS were observed. Nonsmokers exhibited a greater negative correlation than smokers between lack of emotional clarity scores and connectivity of the amygdala with the left inferior frontal gyrus. Finally, this amygdala-to-left inferior frontal gyrus connectivity was weaker in smokers than in nonsmokers. CONCLUSIONS: These findings suggest that difficulties in emotion regulation in smokers are at least partially due to lack of emotional clarity. Given the role of the inferior frontal gyrus in understanding emotional states, strengthening connectivity between the amygdala and the inferior frontal gyrus may improve emotional clarity to help smokers regulate their negative emotions, thereby improving their ability to quit smoking.

Neural basis of smoking-induced relief of craving and negative affect: Contribution of nicotine.

Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal.

Functional Connectivity of the Raphe Nuclei: Link to Tobacco Withdrawal in Smokers.

Background: Although nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies. Methods: Functional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers. Results: Connectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal. Conclusions: Relief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking.

Brain activation during emotion regulation in women with premenstrual dysphoric disorder.

BACKGROUND: Difficulties in regulating emotions are linked to the core symptoms of premenstrual dysphoric disorder (PMDD). We therefore investigated the neural substrates of emotion-regulation problems in women with PMDD. METHODS: On the basis of self-evaluations over 2 months on the Daily Record of Severity of Problems, eligible participants were assigned to two groups: PMDD and control (18 per group). Functional magnetic resonance imaging (fMRI) and a well-validated task were used to assess brain function during emotion regulation. Participants were tested twice, once during the follicular (asymptomatic) and once in the late luteal (symptomatic) phase of the menstrual cycle. RESULTS: Women with PMDD gave higher ratings of negative affect in the luteal phase than in the follicular phase, and compared with healthy control participants during the luteal phase. A region-of-interest fMRI analysis indicated that during the late luteal phase, women with PMDD had hypoactivation in right dorsolateral prefrontal cortex (dlPFC) during all conditions of the emotion-regulation task, not only in the contrast that isolated emotion regulation. An exploratory whole-brain, voxel-wise analysis showed that women with PMDD had less activation in the precentral gyrus during the luteal phase than the follicular phase, and less activation in the postcentral gyrus compared with control participants. CONCLUSIONS: During the luteal phase of the menstrual cycle, women with PMDD experience difficulty regulating emotions. Hypoactivation in the right dlPFC may contribute to this problem, but may be related more generally to other affective symptoms of PMDD. Hypofunction in the right pre- and postcentral gyri warrants additional study.

Development, Initial Testing and Challenges of an Ecologically Valid Reward Prediction Error FMRI Task for Alcoholism.

AIMS: To advance translational studies of the role of reward prediction error (PE) in alcohol use disorder, the present study sought to develop and conduct an initial test of an alcohol-specific PE task paradigm using functional magnetic resonance imaging in humans. METHODS: Alcohol dependent or social drinkers received small tastes of their preferred alcohol beverage or control beverage, with preceding visual cues indicating whether alcohol (or water) would be delivered. To assess both positive and negative PE signals, expectancies were systematically violated in both positive (i.e. expecting water and receiving alcohol) and negative (i.e. expecting alcohol and receiving water) directions. Exploratory trial-by-trial analyses were conducted to explore temporal fluctuations of activation within a priori-defined regions of interest that have been implicated in cue reactivity and PE processing. RESULTS: Across the entire sample of participants, positive PE-related brain activation was found in a large cluster comprised of frontal lobe regions, as well as insular cortex, and motor/sensory cortices. Compared to social drinking subjects, alcohol dependent subjects had greater positive PE-related brain activity in left superior parietal lobule, lateral occipital cortex and postcentral gyrus. Exploratory trial-by-trial analyses indicated differences in activation specific to type of taste, mostly at earlier trials. CONCLUSIONS: This task-development oriented pilot study found that PE signaling may not be detected in expected brain regions when image analyses average across all PE trials of the task. Rather, a trial-by-trial analysis approach may help detect sparse, temporally distinct PE signaling in expected reward processing regions. SHORT SUMMARY: This fMRI study of reward prediction error found greater positive prediction error-related activity (i.e. expecting water taste, receiving alcohol taste) in alcohol dependent individuals relative to social drinkers in parietal and occipital cortices. Trial-by-trial analyses may be able to better detect sparse prediction error signaling in expected reward processing regions.

Striatal D1- and D2-type dopamine receptors are linked to motor response inhibition in human subjects.

Motor response inhibition is mediated by neural circuits involving dopaminergic transmission; however, the relative contributions of dopaminergic signaling via D1- and D2-type receptors are unclear. Although evidence supports dissociable contributions of D1- and D2-type receptors to response inhibition in rats and associations of D2-type receptors to response inhibition in humans, the relationship between D1-type receptors and response inhibition has not been evaluated in humans. Here, we tested whether individual differences in striatal D1- and D2-type receptors are related to response inhibition in human subjects, possibly in opposing ways. Thirty-one volunteers participated. Response inhibition was indexed by stop-signal reaction time on the stop-signal task and commission errors on the continuous performance task, and tested for association with striatal D1- and D2-type receptor availability [binding potential referred to nondisplaceable uptake (BPND)], measured using positron emission tomography with [(11)C]NNC-112 and [(18)F]fallypride, respectively. Stop-signal reaction time was negatively correlated with D1- and D2-type BPND in whole striatum, with significant relationships involving the dorsal striatum, but not the ventral striatum, and no significant correlations involving the continuous performance task. The results indicate that dopamine D1- and D2-type receptors are associated with response inhibition, and identify the dorsal striatum as an important locus of dopaminergic control in stopping. Moreover, the similar contribution of both receptor subtypes suggests the importance of a relative balance between phasic and tonic dopaminergic activity subserved by D1- and D2-type receptors, respectively, in support of response inhibition. The results also suggest that the stop-signal task and the continuous performance task use different neurochemical mechanisms subserving motor response inhibition.

Relationship of Alexithymia Ratings to Dopamine D2-type Receptors in Anterior Cingulate and Insula of Healthy Control Subjects but Not Methamphetamine-Dependent Individuals.

BACKGROUND: Individuals with substance-use disorders exhibit emotional problems, including deficits in emotion recognition and processing, and this class of disorders also has been linked to deficits in dopaminergic markers in the brain. Because associations between these phenomena have not been explored, we compared a group of recently abstinent methamphetamine-dependent individuals (n=23) with a healthy-control group (n=17) on dopamine D2-type receptor availability, measured using positron emission tomography with [(18)F]fallypride. METHODS: The anterior cingulate and anterior insular cortices were selected as the brain regions of interest, because they receive dopaminergic innervation and are thought to be involved in emotion awareness and processing. The Toronto Alexithymia Scale, which includes items that assess difficulty in identifying and describing feelings as well as externally oriented thinking, was administered, and the scores were tested for association with D2-type receptor availability. RESULTS: Relative to controls, methamphetamine-dependent individuals showed higher alexithymia scores, reporting difficulty in identifying feelings. The groups did not differ in D2-type receptor availability in the anterior cingulate or anterior insular cortices, but a significant interaction between group and D2-type receptor availability in both regions, on self-report score, reflected significant positive correlations in the control group (higher receptor availability linked to higher alexithymia) but nonsignificant, negative correlations (lower receptor availability linked to higher alexithymia) in methamphetamine-dependent subjects. CONCLUSIONS: The results suggest that neurotransmission through D2-type receptors in the anterior cingulate and anterior insular cortices influences capacity of emotion processing in healthy people but that this association is absent in individuals with methamphetamine dependence.

Risk-taking behavior: dopamine D2/D3 receptors, feedback, and frontolimbic activity.

Decision-making involves frontolimbic and dopaminergic brain regions, but how prior choice outcomes, dopamine neurotransmission, and frontostriatal activity are integrated to affect choices is unclear. We tested 60 healthy volunteers using the Balloon Analogue Risk Task (BART) during functional magnetic resonance imaging. In the BART, participants can pump virtual balloons to increase potential monetary reward or cash out to receive accumulated reward; each pump presents greater risk and potential reward (represented by the pump number). In a separate session, we measured striatal D2/D3 dopamine receptor binding potential (BPND) with positron emission tomography in 13 of the participants. Losses were followed by fewer risky choices than wins; and during risk-taking after loss, amygdala and hippocampal activation exhibited greater modulation by pump number than after a cash-out event. Striatal D2/D3 BPND was positively related to the modulation of ventral striatal activation when participants decided to cash out and negatively to the number of pumps in the subsequent trial; but negatively related to the modulation of prefrontal cortical activation by pump number when participants took risk, and to overall earnings. These findings provide in vivo evidence for a potential mechanism by which dopaminergic neurotransmission may modulate risk-taking behavior through an interactive system of frontal and striatal activity.

Emotion regulation in women with premenstrual dysphoric disorder.

Premenstrual dysphoric disorder (PMDD) is a psychiatric disorder that causes serious impairments in the functioning and quality of life of affected women. Until recently, research efforts were somewhat hampered by the lack of formal diagnostic criteria, which have now been codified as a category in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Better characterization of deficits in socioemotional functioning caused by PMDD may aid in improving treatment efforts. In this investigation, prospective symptom ratings, based on DSM-5 criteria, were used to measure PMDD symptoms in 36 women (18 with PMDD and 18 healthy controls). Two self-report inventories, the Emotion Regulation Questionnaire and the Difficulties in Emotion Regulation Scale, were used to measure ability to regulate emotions, and socioemotional functioning was measured by inventories of social connectedness, perceived stress, and affect. Potential relationships between ability to regulate emotion and PMDD symptom severity, as well as other measures of socioemotional functioning and affective state, were tested. Women with PMDD reported significantly more behavioral impulsivity and greater difficulties in regulating emotion and in socioemotional functioning. Cognitive or behavioral strategies to improve these problems may benefit women with PMDD and help to alleviate distress caused by this disorder.

The effect of alcohol priming on neural markers of alcohol cue-reactivity.

BACKGROUND: Priming doses of alcohol are associated with increased desire to drink and disinhibitory effects on subsequent control over drinking. Despite the importance of alcohol priming in the cue-reactivity literature, the effects of priming on brain responses to alcohol cues remains unclear. Furthermore, evidence suggests this relationship may be moderated by OPRM1 genotype. METHODS: Twenty individuals with alcohol dependence (six females; 90% Caucasian; mean age = 29.4) who were prospectively genotyped on the OPRM1 gene underwent two functional magnetic resonance imaging (fMRI) sessions, before and after a priming dose of alcohol, each including a gustatory alcohol cue reactivity paradigm and self-reported craving measures. RESULTS: Self-reported alcohol craving generally increased and remained higher for alcohol versus water cue presentations across pre- and post-priming scans. Compared to alcohol cues delivered during the post-priming scan, alcohol cues delivered pre-priming were associated with greater activation in regions including the hippocampus, amygdala, inferior frontal gyrus, temporal cortex, and occipital cortex. Controlling for alcoholism severity increased statistical significance of activation in these regions. Follow-up analyses revealed a positive correlation between alcoholism severity and pre- versus post-priming alcohol cue-reactivity primarily in frontal regions. OPRM1 genotype was also found to moderate alcohol cue-reactivity across scans. CONCLUSION: This study provides initial evidence of alcohol cue-elicited habituation in fronto-temporal regions, despite continued craving, following a priming dose of alcohol. Further, it provides preliminary evidence for moderating roles of alcoholism severity and OPRM1 genotype on priming-related changes in cue-reactivity, adding to our understanding of the function of alcohol priming in alcohol dependence.

Varenicline, naltrexone, and their combination for heavy-drinking smokers: preliminary neuroimaging findings.

RATIONALE: Heavy drinking smokers constitute a sizeable and hard-to-treat subgroup of smokers, for whom tailored smoking cessation therapies are not yet available. OBJECTIVE: The present study used a double-blind, randomized, 2 × 2 medication design, testing varenicline alone (VAR; 1 mg twice daily), naltrexone alone (NTX; 25 mg once daily), varenicline plus naltrexone, and placebo for effects on neural activation to cigarette cues in a sample (n = 40) of heavy drinking daily smokers (≥10 cigarettes/day). METHODS: All participants were tested after a 10-12-day titration period designed to reach steady state on the target medication. Participants underwent functional neuroimaging (fMRI) for examination of brain responses to visual smoking-related (vs. neutral) cues. RESULTS: Region of interest (ROI) analyses of brain responses to Cigarette vs. Neutral Cues indicated that the combination of VAR + NTX was associated with reduced activation of the bilateral anterior cingulate cortex as compared to placebo and to NTX alone. Exploratory whole-brain analyses also indicated significant differences in brain activation during cigarette cues in the active medications versus placebo condition. All medications suppressed left nucleus accumbens activation relative to placebo, suggesting the possibility that both medications, either alone or in combination, reduce neural signals associated with appetitive behavior. CONCLUSIONS: Although preliminary, these neuroimaging findings indicate that clinical studies of the combination of VAR + NTX for heavy drinkers trying to quit smoking may be warranted.

Initial evidence that OPRM1 genotype moderates ventral and dorsal striatum functional connectivity during alcohol cues.

BACKGROUND: Endogenous opioids and striatal dopamine have been implicated in cue-induced alcohol craving and have been hypothesized to play a role in goal-directed, as opposed to habitual, alcohol use. This initial study examines dorsal and ventral striatal functional connectivity during alcohol-cue processing as a function of the A118G single-nucleotide polymorphism of the mu-opioid receptor (OPRM1) gene. METHODS: Seventeen individuals with alcohol dependence (6 females; 90% Caucasian; mean age = 29.4) underwent blood oxygen level-dependent functional magnetic resonance imaging, while performing an alcohol taste-cues task. Psychophysiological interaction analyses investigated associations of the OPRM1 genotype with ventral and dorsal striatum functional connectivity, using the ventral striatum and the caudate as the seed region, respectively. RESULTS: Compared to A-allele homozygotes, G-allele carriers of the OPRM1 gene showed (i) greater activation of the insula and orbitofrontal cortex and (ii) stronger negative fronto-striatal functional connectivity for both ventral and dorsal striatal seed regions during processing of alcohol versus water cues. CONCLUSIONS: These preliminary findings suggest that, relative to A-allele homozygotes, G-allele carriers show unstable frontal regulation over reward and/or habit-driven inputs from the striatum resulting from greater reward sensitivity combined with limited self-control resources.

Structural indices of brain aging in methamphetamine use disorder.

BACKGROUND: Methamphetamine use is surging globally. It has been linked to premature stroke, Parkinsonism, and dementia, suggesting that it may accelerate brain aging. METHODS: We performed a retrospective study to determine if structural indices of brain aging were more prevalent prior to old age (26 - 54 years) in individuals with Methamphetamine Use Disorder (MUD), who were in early abstinence (M ± SD = 22.1 ± 25.6 days) than in healthy control (HC) participants. We compared T1-weighted MRI brain scans in age- and sex-matched groups (n = 89/group) on three structural features of brain aging: the brain volume/cerebrospinal fluid (BV/CSF) index, volume of white matter hypointensities/lesions, and choroid plexus volume. RESULTS: The MUD group had a lower mean BV/CSF index and larger volumes of white matter hypointensities and choroid plexus (p-values < 0.01). Regression analyses showed significant age-by-group effects, indicating different age trajectories of the BV/CSF index and choroid plexus volume, consistent with abnormal global brain atrophy and choroid plexus pathology in the MUD group. Significant age and group main effects reflected a larger volume of white matter hypointensities for older participants across groups and for the MUD group irrespective of age. None of the three measures of brain aging correlated significantly with recent use or duration of recent abstinence from methamphetamine. CONCLUSIONS: Premature brain pathology, which may reflect cerebrovascular damage and dysfunction of the choroid plexus, occurs in people with MUD. Such pathology may affect cognition and thereby efficacy of behavioral treatments for MUD.

Parameter Space and Potential for Biomarker Development in 25 Years of fMRI Drug Cue Reactivity: A Systematic Review.

Importance: In the last 25 years, functional magnetic resonance imaging drug cue reactivity (FDCR) studies have characterized some core aspects in the neurobiology of drug addiction. However, no FDCR-derived biomarkers have been approved for treatment development or clinical adoption. Traversing this translational gap requires a systematic assessment of the FDCR literature evidence, its heterogeneity, and an evaluation of possible clinical uses of FDCR-derived biomarkers. Objective: To summarize the state of the field of FDCR, assess their potential for biomarker development, and outline a clear process for biomarker qualification to guide future research and validation efforts. Evidence Review: The PubMed and Medline databases were searched for every original FDCR investigation published from database inception until December 2022. Collected data covered study design, participant characteristics, FDCR task design, and whether each study provided evidence that might potentially help develop susceptibility, diagnostic, response, prognostic, predictive, or severity biomarkers for 1 or more addictive disorders. Findings: There were 415 FDCR studies published between 1998 and 2022. Most focused on nicotine (122 [29.6%]), alcohol (120 [29.2%]), or cocaine (46 [11.1%]), and most used visual cues (354 [85.3%]). Together, these studies recruited 19 311 participants, including 13 812 individuals with past or current substance use disorders. Most studies could potentially support biomarker development, including diagnostic (143 [32.7%]), treatment response (141 [32.3%]), severity (84 [19.2%]), prognostic (30 [6.9%]), predictive (25 [5.7%]), monitoring (12 [2.7%]), and susceptibility (2 [0.5%]) biomarkers. A total of 155 interventional studies used FDCR, mostly to investigate pharmacological (67 [43.2%]) or cognitive/behavioral (51 [32.9%]) interventions; 141 studies used FDCR as a response measure, of which 125 (88.7%) reported significant interventional FDCR alterations; and 25 studies used FDCR as an intervention outcome predictor, with 24 (96%) finding significant associations between FDCR markers and treatment outcomes. Conclusions and Relevance: Based on this systematic review and the proposed biomarker development framework, there is a pathway for the development and regulatory qualification of FDCR-based biomarkers of addiction and recovery. Further validation could support the use of FDCR-derived measures, potentially accelerating treatment development and improving diagnostic, prognostic, and predictive clinical judgments.