Elevated Cue Reactivity Research Articles

Medial Prefrontal Cortex Theta Burst Stimulation Improves Treatment Outcomes in Alcohol Use Disorder: A Double-Blind, Sham-Controlled Neuroimaging Study

BackgroundAlcohol use disorder (AUD) is associated with elevated brain response to cues. Recent studies have suggested that theta burst stimulation (TBS) to the medial prefrontal cortex (MPFC) can decrease reactivity to cues in a transdiagnostic manner. The goal of this clinical trial was to evaluate the effect of continuous TBS as a tool to decrease drinking behavior and brain reactivity to alcohol cues among individuals with AUD. MethodsA total of 50 individuals with AUD were recruited from an intensive outpatient treatment program. Using a randomized, double-blind, sham-controlled design, participants received 10 sessions of continuous TBS (left frontal pole, 1 session/10 days, 110% resting motor threshold, 3600 pulse/session, cue provocation before and during session). Brain reactivity to alcohol cues was acquired at four time points: at baseline and after all TBS sessions (1 month, 2 months, and 3 months). ResultsOverall, 80% of the participants completed all TBS sessions. Individuals who received real TBS were 2.71 times more likely to remain enrolled in the study after 3 months and 3.09 times more likely to remain sober 3 months after treatment initiation. Real TBS also led to a significantly greater reduction in brain reactivity to alcohol cues, specifically a reduction in MPFC-striatum and MPFC-insula connectivity 2 and 3 months after TBS treatment. ConclusionsTen days of MPFC TBS is well tolerated, reduces drinking, and decreases brain reactivity to alcohol cues for up to 3 months after treatment initiation. These results pave a critical next step in the path toward developing transcranial magnetic stimulation as an intervention for AUD and disorders associated with elevated cue reactivity.

Suppressing images of desire: Neural correlates of chocolate-related thoughts in high and low trait chocolate cravers

Chocolate is the most often craved food in Western societies and many individuals try to resist its temptation due to weight concerns. Suppressing chocolate-related thoughts might, however, lead to paradoxical enhancements of these thoughts and this effect might be more pronounced in individuals with frequent chocolate cravings. In the current study, neural and cognitive correlates of chocolate thought suppression were investigated as a function of trait chocolate craving. Specifically, 20 high and 20 low trait chocolate cravers followed suppression vs. free thinking instructions after being exposed to chocolate and neutral images. Enhanced cue reactivity was evident in high trait chocolate cravers in that they reported more chocolate-related thoughts selectively after chocolate images compared to their low trait craving counterparts. This cue reactivity was mirrored neurally by higher activation in the ventral and dorsal striatum, demonstrating enhanced reward system activity. Unexpectedly, high trait chocolate cravers successfully reduced their elevated chocolate thoughts in the suppression condition. This lends support for the use of thought suppression as a means of regulating unwanted thoughts, cravings and imagery. Whether this thought manipulation is able to curb the elevated cue reactivity and the underlying reward sensitivity in chocolate cravers in applied settings remains to be shown.

Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.

Altered Brain Reactivity to Game Cues After Gaming Experience.

Individuals who play Internet games excessively show elevated brain reactivity to game-related cues. This study attempted to test whether this elevated cue reactivity observed in game players is a result of repeated exposure to Internet games. Healthy young adults without a history of excessively playing Internet games were recruited, and they were instructed to play an online Internet game for 2 hours/day for five consecutive weekdays. Two control groups were used: the drama group, which viewed a fantasy TV drama, and the no-exposure group, which received no systematic exposure. All participants performed a cue reactivity task with game, drama, and neutral cues in the brain scanner, both before and after the exposure sessions. The game group showed an increased reactivity to game cues in the right ventrolateral prefrontal cortex (VLPFC). The degree of VLPFC activation increase was positively correlated with the self-reported increase in desire for the game. The drama group showed an increased cue reactivity in response to the presentation of drama cues in the caudate, posterior cingulate, and precuneus. The results indicate that exposure to either Internet games or TV dramas elevates the reactivity to visual cues associated with the particular exposure. The exact elevation patterns, however, appear to differ depending on the type of media experienced. How changes in each of the regions contribute to the progression to pathological craving warrants a future longitudinal study.

Effects of d-cycloserine on extinction of mesolimbic cue reactivity in alcoholism: a randomized placebo-controlled trial

Mesocorticolimbic reactivity to alcohol-associated cues has been shown to be associated with relapse to renewed drinking and to be decreased by cue-exposure-based extinction training (CET). Evidence from preclinical studies suggests that the extinction of conditioned alcohol-seeking behavior might be facilitated by drugs increasing N-methyl-D-aspartate (NMDA) receptor-associated memory consolidation. In this study, we assessed the efficacy of CET treatment supplemented with the partial NMDA-receptor agonist D-cycloserine (DCS) at reducing mesolimbic cue reactivity (CR), craving, and relapse risk in alcoholism. In a randomized, placebo-controlled, double-blind study, we recruited 76 recently detoxified abstinent alcohol-dependent patients. Thirty-two (16 DCS, 16 placebo) patients showed cue-induced ventral-striatal activation measured with functional magnetic resonance imaging (fMRI) prior to treatment and were thus included in the efficacy analyses. After inpatient detoxification, patients underwent nine sessions of CET spaced over 3weeks, receiving either 50mg DCS or placebo 1h prior to each CET session. FMRI was conducted before treatment and 3weeks after treatment onset. Following treatment with CET plus DCS, cue-induced brain activation in the ventral and dorsal striatum was decreased compared to treatment with CET plus placebo. Elevated posttreatment ventral striatal CR and increased craving (assessed using the Obsessive Compulsive Drinking Scale) were associated with increased relapse risk. DCS was shown to augment the effect of CET for alcohol-dependent subjects. The interaction between craving and ventral-striatal CR on treatment outcome suggests that CET might be especially effective in patients exhibiting both high craving and elevated CR.

Lower Serotonin 2C receptor (5-HT2CR) expression in the ventral tegmental area (VTA) associates with elevated cue reactivity following extended forced abstinence from cocaine-taking

Lower Serotonin 2C receptor (5-HT2CR) expression in the ventral tegmental area (VTA) associates with elevated cue reactivity following extended forced abstinence from cocaine-taking

A systematic review of studies exploring craving, its moderators, and the link with substance use in daily life using Ecological Momentary Assessment (EMA)

s / Drug and Alcohol Dependence 140 (2014) e169–e251 e221 nence. While it is unclear whether these differences were due to improved attention, these results suggest that IB may help to improve cognitive function in early MA withdrawal. Data provide some support for developing MA treatments that reduce cognitive impairment. Financial support: National Institute on Drug Abuse (1R01DA029804; S. Shoptaw); National Center for Advancing Translational Sciences (UL1TR000124; S. Dubinett). http://dx.doi.org/10.1016/j.drugalcdep.2014.02.612 A systematic review of studies exploring craving, its moderators, and the link with substance use in daily life using Ecological Momentary Assessment (EMA) J. Swendsen2, F. Serre1,3, M. Fatseas1,3, Marc Auriacombe1,3 1 Addiction Psychiatry, University Bordeaux/CNRS USR 3413, Bordeaux, France 2 CNRS UMR 5287 INCIA, University Bordeaux, Bordeaux, France 3 CH Ch. Perrens et CHU Bordeaux, Bordeaux, France Aims: Studies examining the link between craving and substance use have often revealed contradictory results. Ecological MomentaryAssessment (EMA) is amethodparticularlywell-suited to assess subjective variables and episodic events in daily life, and it offers a new opportunity to examine questions concerning craving with high ecological validity. The objective of this systematic review was to examine all published studies using EMA to: (1) examine the temporal link between craving and substance use, and (2) identify relevant moderators of craving intensity among substance users. Methods: The literature searchusedMedlineup to July31, 2012, and was based on a systematic review methodology. Results: Fifty-seven studies were selected, of which most concerned tobacco or alcohol. The majority of studies (91%) reported a positive relationship between craving and substance use, both concurrently and prospectively, within preand post-quit periods, among users with different levels of use, and for both legal and illegal substances. EMA data also confirmed the influence of intra-individual variables (negative affects, social contexts, other substance use) and inter-individual variables (age, level of use) in daily life craving reports Conclusions: This review of EMA investigations demonstrates a strong link between craving and substance use, and underscores the importance of taking into account temporal and contextual considerations in the assessment of this relationship. Financial support: PHRC 2006, MILDT 2010, CRA 2009, PRACNRS-CHU 2008, CNRS ATIP. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.613 Lower Serotonin 2C receptor (5-HT2CR) expression in the ventral tegmental area (VTA) associates with elevated cue reactivity following extended forced abstinence from cocaine-taking Sarah E. Swinford, Noelle C. Anastasio, R.G. Fox, S.J. Stutz, K.A. Cunningham Ctr Addiction Res, UTMB, Galveston, TX, United

Early drop-out: An indication of treatment success or difficulties?

s / Drug and Alcohol Dependence 140 (2014) e2–e85 e5 Results: High impulsive rats exhibit a higher 5-HT2AR0:5HT2CR protein ratio in synaptosomes frommPFC vs. low impulsive rats (p<0.05). Rats with a knockdown of 5-HT2CR in the mPFC expressed significantly elevated impulsive action relative to control rats (p<0.05) and enhancedpotency of the 5-HT2AR antagonist M100907 to suppress impulsive action (p<0.05). In rats trained to SA cocaine (0.75mg/kg/inf; FR5; 14 days) and then assessed for cue reactivity on FADay 1 or FADay 30, we observed elevated cue reactivity and a late-forming increase in the 5-HT2AR:5-HT2CR mPFC synaptosomal protein ratio at FA Day 30 (p<0.05). Conclusions: These data indicate that there is a reciprocal or interactive relationship between 5-HT2AR and 5-HT2CR, notably in mPFC, that is key in expression of these phenotypes, and that a 5-HT2AR:5-HT2CR imbalance may be a functionally-relevant mechanism underlying impulsivity and cue reactivity. Financial support: DA06511, DA024157, DA000403. http://dx.doi.org/10.1016/j.drugalcdep.2014.02.034 Novel association of amgydala prodynorphin with addiction and negative affect-related neurocircuitry Sarah Ann R. Anderson1, M. Michaelides1, J. Neumaier2, M. Bannon3, Yasmin L. Hurd1 1 Pharmacology, MSSM, New York, NY, United States 2 Psychiatry, University of Washington, Seattle, WA, United States 3 Pharmacology, Wayne State University, Detroit, MI,

Epigenetic and pharmacological regulation of 5HT3 receptors controls compulsive ethanol seeking in mice.

Factors underlying individual vulnerability to develop alcoholism are largely unknown. In humans, the risk for alcoholism is associated with elevated cue reactivity. Recent evidence suggests that in animal models, reactivity to reward-paired cues is predictive of addictive behaviors. To model cue reactivity in mice, we used a Pavlovian approach (PA) paradigm in which mice were trained to associate a cue with delivery of a food reinforcer. We then investigated the relationship between PA status with habitual and compulsive-like ethanol seeking. After training mice to respond for 10% ethanol, habitual behavior was investigated using both an outcome devaluation paradigm, in which ethanol was devalued via association with lithium chloride-induced malaise, and a contingency degradation paradigm in which the relationship between action and outcome was disrupted. Compulsive-like behavior was investigated in a modified conditioned place preference paradigm in which footshock was paired with the reward-paired chamber. PA was found to be predictive of habitual and compulsive-like ethanol seeking. Additionally, innate risk status was related to epigenetic changes in the gene encoding the requisite subunit of the 5HT3 receptor, Htr3a, as well as 5HT3A protein expression in the amygdala. We then used pharmacological tools to demonstrate that risk status determines the ability of a 5HT3 antagonist to reduce compulsive ethanol seeking. These data indicate that risk status can be identified prior to any alcohol exposure by assessment of cue reactivity, and further that this endophenotype may be predictive of response to pharmacological treatment for components of alcoholism.