| 1. |
- Chye, Yann, et al.
(författare)
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Subcortical surface morphometry in substance dependence : An ENIGMA addiction working group study
- 2020
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Ingår i: Addiction Biology. - : WILEY. - 1355-6215 .- 1369-1600. ; 25:6
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Tidskriftsartikel (refereegranskat)abstract
- While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.
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| 2. |
- Cortes, Carlos R., et al.
(författare)
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Insula Sensitivity to Unfairness in Alcohol Use Disorder
- 2018
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Ingår i: Alcohol and Alcoholism. - : OXFORD UNIV PRESS. - 0735-0414 .- 1464-3502. ; 53:3, s. 201-208
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Tidskriftsartikel (refereegranskat)abstract
- Aims: Social decision making has recently been evaluated in alcohol use disorder (AUD) using the ultimatum game (UG) task, suggesting a possible deficit in aversive emotion regulation elicited by the unfairness during this task. Despite the relevance to relapse of this possible faulty regulation, the brain correlates of the UG in AUD are unknown. Methods: In total, 23 AUD and 27 healthy controls (HC) played three consecutive fMRI runs of the UG, while behavioral and brain responses were recorded. Results: Overall, acceptance rate of unfair offers did not differ between groups, but there was a difference in the rate of behavioral change across runs. We found significant anterior insula (aINS) activation in both groups for both fair and unfair conditions, but only HC showed a trend towards increased activation during unfair vs. fair offers. There were not overall whole-brain between-group significant differences. We found a trend of signal attenuation, instead of an increase, in the aINS for AUD when compared to HC during the third run, which is consistent with our recent findings of selective insula atrophy in AUD. Conclusion: We found differential group temporal dynamics of behavioral response in the UG. The HC group had a low acceptance rate for unfair offers in the first two runs that increased markedly for the third run; whereas the AUD group was consistent in their rejection of unfair offers across the three runs. We found a strong significant decrease in neural response across runs for both groups. Short summary: This fMRI study of UG in alcohol use disorder found behavioral group differences in acceptance rate across runs, which together with significant BOLD-signal decrease across runs in UG-related regions in both groups, highlights the impairment of strategy in AUD and the effect of repetitive exposure to unfairness in this task.
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| 3. |
- Gowin, Joshua L., et al.
(författare)
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The Effect of Varenicline on the Neural Processing of Fearful Faces and the Subjective Effects of Alcohol in Heavy Drinkers
- 2016
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Ingår i: Alcoholism. - : WILEY-BLACKWELL. - 0145-6008 .- 1530-0277. ; 40:5, s. 979-987
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pharmacotherapies for alcohol use disorder have been shown to reduce hazardous drinking and improve overall health. The effect sizes for the effectiveness of these medications, however, are small, underscoring the need to expand the range of therapeutics and develop personalized treatment approaches. Recent studies have suggested that varenicline, an 42-nicotinic partial agonist widely used for smoking cessation, can help alcoholics reduce drinking, but the neurocognitive underpinnings of its effectiveness remain largely unexplored. Methods: In this double-blind study, 32 heavy drinkers were randomized to receive varenicline (2 mg/d) or placebo. After 2 weeks of dosing, participants underwent functional MRI scans, during which they viewed images of faces with either neutral or fearful expressions at baseline and following an intravenous alcohol infusion to a target breath alcohol concentration of 80 mg%. Blood oxygen level-dependent (BOLD) response was analyzed with Analysis of Functional Neuroimaging software. Linear mixed-effects models were used to examine the effects of facial expression (fearful vs. neutral) and medication (placebo vs. varenicline) on BOLD response. The effect of medication on measures of subjective response to alcohol was also examined. Results: Results indicated a significant facial expression-by-medication interaction in the left amygdala. The groups showed equivalent activation to neutral faces, but, whereas the placebo group showed increased activation to fearful faces, the varenicline group showed no change in activation. Amygdala activation to fearful faces correlated with number of drinks in the previous 90 days and Obsessive Compulsive Drinking Scale scores. There was no effect of varenicline on subjective response to alcohol. Conclusions: Our results indicate that varenicline may disrupt amygdala response to fearful faces in heavy drinkers. Further, amygdala activation correlated with alcohol consumption, suggesting that the effects of varenicline may be related to aspects of drinking behavior. These results suggest that amygdala response to fearful faces may be developed as a biomarker of the effectiveness of medications being developed for the treatment of alcohol use disorder.
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| 4. |
- Grodin, Erica N., et al.
(författare)
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Neural Correlates of Compulsive Alcohol Seeking in Heavy Drinkers
- 2018
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Ingår i: Biological Psychiatry. - : Elsevier. - 2451-9022. ; 3:12, s. 1022-1031
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Tidskriftsartikel (refereegranskat)abstract
- Compulsive alcohol use, the tendency to continue alcohol seeking and taking despite negative consequences, is a hallmark of alcohol use disorder. Preclinical rodent studies have suggested a role for the medial prefrontal cortex, anterior insula, and nucleus accumbens in compulsive alcohol seeking. It is presently unknown whether these findings translate to humans. We used a novel functional magnetic resonance imaging paradigm and tested the hypothesis that heavy drinkers would compulsively seek alcohol despite the risk of an aversive consequence, and that this behavior would be associated with the activity of frontostriatal circuitry.
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| 5. |
- Kwako, Laura E., et al.
(författare)
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The Corticotropin Releasing Hormone-1 (CRH1) Receptor Antagonist Pexacerfont in Alcohol Dependence: A Randomized Controlled Experimental Medicine Study
- 2015
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 40:5, s. 1053-1063
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Tidskriftsartikel (refereegranskat)abstract
- Extensive preclinical data implicate corticotropin-releasing hormone (CRH), acting through its CRH1 receptor, in stress- and dependence-induced alcohol seeking. We evaluated pexacerfont, an orally available, brain penetrant CRH1 antagonist for its ability to suppress stress-induced alcohol craving and brain responses in treatment seeking alcohol-dependent patients in early abstinence. Fifty-four anxious alcohol-dependent participants were admitted to an inpatient unit at the NIH Clinical Center, completed withdrawal treatment, and were enrolled in a double-blind, randomized, placebo-controlled study with pexacerfont (300 mg/day for 7 days, followed by I 00 mg/day for 23 days). After reaching steady state, participants were assessed for alcohol craving in response to stressful or alcohol-related cues, neuroendocrine responses to these stimuli, and functional magnetic resonance imaging (fMRI) responses to alcohol-related stimuli or stimuli with positive or negative emotional valence. A separate group of 10 patients received open-label pexacerfont following the same dosing regimen and had cerebrospinal fluid sampled to estimate central nervous system exposure. Pexacerfont treatment had no effect on alcohol craving, emotional responses, or anxiety. There was no effect of pexacerfont on neural responses to alcohol-related or affective stimuli. These results were obtained despite drug levels in cerebrospinal fluid (CSF) that predict close to 90% central CRH1 receptor occupancy. CRH1 antagonists have been grouped based on their receptor dissociation kinetics, with pexacerfont falling in a category characterized by fast dissociation. Our results may indicate that antagonists with slow offset are required for therapeutic efficacy. Alternatively, the extensive preclinical data on CRH1 antagonism as a mechanism to suppress alcohol seeking may not translate to humans.
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| 6. |
- Lee, Mary R., et al.
(författare)
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Corticotropin-Releasing Factor receptor 1 (CRF1) antagonism in patients with alcohol use disorder and high anxiety levels: effect on neural response during Trier Social Stress Test video feedback
- 2023
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Ingår i: Neuropsychopharmacology. - : SPRINGERNATURE. - 0893-133X .- 1740-634X. ; 48:5, s. 816-820
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Tidskriftsartikel (refereegranskat)abstract
- In preclinical models of alcohol use disorder, the corticotropin-releasing factor (CRF) receptor is upregulated, particularly in the extended amygdala. This upregulation is thought to play a role in stress-induced relapse to drinking by a mechanism that is independent of the hypothalamic-pituitary-adrenal axis. As part of a double-blind, placebo-controlled clinical study with pexacerfont, a selective, orally available, and brain-penetrant CRF1 receptor antagonist which has anti-anxiety effects in preclinical studies, we examined the effect of pexacerfont on the neural response to a social stress task adapted to fMRI. Subjects were 39 individuals (4 women) with high trait anxiety and moderate to severe alcohol use disorder randomized to receive pexacerfont or placebo. The task involved feedback of videoclips of an individual performing the Trier Social Stress Test. Pexacerfont had no effect on the neural response to self-observation under stress. The neural response to viewing oneself under stress vs an unknown other under stress activated prefrontal brain regions including insula, inferior frontal gyrus as well as medial, superior frontal gyri. These regions of activation overlap with those found in studies using similar paradigms. Potential applications of this task to probe neurocircuitry that is disrupted in addiction is discussed.
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| 7. |
- Mayo, Leah M, et al.
(författare)
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Conditioned Preference to a Methamphetamine-Associated Contextual Cue in Humans
- 2013
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group: Open Access Hybrid Model Option A. - 0893-133X .- 1740-634X. ; 38:6, s. 921-929
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Tidskriftsartikel (refereegranskat)abstract
- Classical conditioning is widely used to study motivational properties of addictive drugs in animals, but has rarely been used in humans. We established a procedure suitable for studying the neurobiology and individual determinants of classical conditioning in humans. Healthy volunteers were randomly assigned to four groups that received methamphetamine or placebo in the presence of distinctive environmental cues under paired or unpaired conditions. During each session, subjects performed tasks known to activate the ventral striatum. Tasks were performed in the presence of a distinctive context, consisting of a screen background image of a beach or mountains, accompanied by corresponding sounds. Separate groups of subjects carried out the tasks under high ($35-50) or low ($5-20) reward conditions. Within each of the two reward conditions, one group (paired) received methamphetamine (20 mg, oral) or placebo consistently associated with one of the contexts, while the other (unpaired) received drug or placebo unrelated to context. A fifth group (paired) performed the tasks with contextual cues but in the absence of monetary incentives. Before and after conditioning, participants carried out a series of forced choice tasks for the contextual cues, and change of preference over time was analyzed. All paired groups showed a significant increase in preference for the drug-associated context, with a linear trend for increase across the levels of reward. Preference was unrelated to subjective drug effects, and did not change in the unpaired group. These data support the translational utility of our conditioning procedure for studies of reward mechanisms in humans.
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| 8. |
- Muench, Christine, et al.
(författare)
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Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity
- 2021
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Ingår i: Addiction Biology. - : WILEY. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohens d = .89, P-(FWE) = .037) and in the left amygdala during fear renewal (Cohens d = .68, P-(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P-(Bonferroni) = .009), depressive symptoms (r = .37, P-(Bonferroni) = .015), trait anxiety (r = .41, P-(Bonferroni) = .006), and perceived stress (r = .45, P-(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.
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| 9. |
- Schwandt, Melanie L., et al.
(författare)
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The CRFI Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects
- 2016
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 41:12, s. 2818-2829
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Tidskriftsartikel (refereegranskat)abstract
- Blockade of corticotropin-releasing factor receptor I (CRFI) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRFI antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n = 39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRFI antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRFI antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRFI blockade in stress-induced alcohol craving and relapse.
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