Neural correlates of drinking reduction during a clinical trial of cognitive behavioral therapy for alcohol use disorder.

BACKGROUND: Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a region implicated in cognitive control and goal-directed behavior, plays a role in behavior change during CBT by facilitating the regulation of craving (ROC). METHODS: Treatment-seeking participants with AUD (N = 22) underwent functional magnetic resonance imaging (fMRI) scanning both before and after a 12-week, single-arm trial of CBT, using an ROC task that was previously shown to engage the DLPFC. RESULTS: We found that both the percentage of heavy drinking days (PHDD) and the overall self-reported alcohol craving measured during the ROC task were significantly reduced from pre- to post-CBT. However, we did not find significant changes over time in either the ability to regulate craving or regulation-related activity in any brain region. We found a significant 3-way interaction between the effects of cue-induced craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on PHDD in the left DLPFC. Follow-up analysis showed that cue-induced craving was associated with cue-induced activity in the left DLPFC among participants who ceased heavy drinking during CBT, both at pre-CBT and post-CBT timepoints. No such associations were present at either timepoint among participants who continued to drink heavily. CONCLUSIONS: These results suggest that patients in whom DLPFC functioning is more strongly related to cue-induced craving may preferentially respond to CBT.

Open label trial of lofexidine-assisted non-opioid induction onto naltrexone extended-release injection for opioid use disorder.

Background: Opioid use disorder (OUD) continues to be major public health problem in the US and innovative medication strategies are needed. The extended-release injectable formulation of naltrexone (ER-NTX), an opioid receptor antagonist, is an effective treatment for OUD, but the need for an opioid-free period during the induction phase of treatment is a barrier to treatment success, particularly in the outpatient setting. Lofexidine, an alpha-2-adrenergic agonist, is an effective treatment for opioid withdrawal.Objectives: To evaluate the feasibility, safety, and tolerability of lofexidine for facilitating induction onto ER-NTX in the management of OUD.Methods: In an open-label, uncontrolled, 10-week outpatient clinical trial, 20 adults (four women) with OUD were treated with a fixed-flexible dosing strategy (maximum 0.54 mg 4×/daily) of lofexidine for up to 10 days to manage opioid withdrawal prior to receiving ER-NTX. The COVID-19 pandemic resulted in a modification of the study methods after enrolling 10 participants who attended all visits in person. The second group of 10 participants attended most induction period visits remotely.Results: Overall, 10 of the 20 participants (50%) achieved the primary outcome by receiving the first ER-NTX injection. Rates of induction success did not differ by the presence of fentanyl or remote visit attendance, although the small sample size provided limited statistical power. Six out of 20 participants (30%) initiated on lofexidine required dose adjustments. There were no study-related serious adverse events.Conclusions: This study provides preliminary evidence supporting the feasibility of inducting individuals with OUD onto ER-NTX using lofexidine.

Neural correlates of drinking reduction during cognitive behavioral therapy for alcohol use disorder.

Cognitive behavioral therapy (CBT) is an effective treatment for alcohol use disorder (AUD). We hypothesized that the dorsolateral prefrontal cortex (DLPFC), a brain region implicated in cognitive control and goal-directed behavior, plays a role behavior change during CBT by facilitating regulation of craving. To examine this, treatment-seeking participants with AUD (N=22) underwent functional MRI scanning both before and after a 12-week single-arm trial of CBT, using a regulation of craving (ROC) fMRI task designed to measure an individual's ability to control alcohol craving and previously shown to engage the DLPFC. We found that both the number of heavy drinking days (NHDD, the primary clinical outcome) and the self-reported alcohol craving measured during the ROC paradigm were significantly reduced from pre- to post-CBT [NHDD: t=15.69, p<0.0001; alcohol craving: (F(1,21)=16.16; p=0.0006)]. Contrary to our hypothesis, there was no change in regulation effects on self-reported craving over time (F(1,21)=0.072; p=0.79), nor was there was a significant change in regulation effects over time on activity in any parcel. Searching the whole brain for neural correlates of reductions in drinking and craving after CBT, we found a significant 3-way interaction between the effects of cue-induced alcohol craving, cue-induced brain activity and timepoint of assessment (pre- or post-CBT) on NHDD in a parcel corresponding to area 46 of the right DLPFC (ß=-0.37, p=0.046, FDR corrected). Follow-up analyses showed that reductions in cue-induced alcohol craving from pre- to post-CBT were linearly related to reductions in alcohol cue-induced activity in area 46 only among participants who ceased heavy drinking during CBT (r=0.81, p=0.005) but not among those who continued to drink heavily (r=0.28, p=0.38). These results are consistent with a model in which CBT impacts heavy drinking by increasing the engagement of the DLPFC during cue-induced craving.

Drinking reduction during cognitive behavioral therapy for alcohol use disorder is associated with a reduction in anterior insula-bed nucleus of the stria terminalis resting-state functional connectivity.

BACKGROUND: Connectivity between the anterior insula (AI) and the bed nucleus of the stria terminalis (BNST) may play a role in negative emotions that drive compulsive drinking in patients with alcohol use disorder (AUD). We hypothesized that reductions in drinking during cognitive behavioral therapy (CBT), an effective treatment that teaches regulation (coping) skills for managing negative emotions during abstinence, would be associated with reductions in resting-state functional connectivity (RSFC) between the AI and the BNST. METHODS: We included 18 patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of AUD who were (1) seeking treatment and (2) drinking heavily at baseline. We measured RSFC as Pearson's correlation between the BNST and multiple regions of interest in the insula at baseline and after completion of 12 weeks of a single-arm clinical trial of outpatient CBT. We also assessed the number of heavy drinking days over the previous 28 days (NHDD) at both time points. We used 1-sample t-tests to evaluate AI-BNST RSFC at baseline, paired t-tests to evaluate changes in AI-BNST RSFC from pre-CBT to post-CBT, and linear regression to evaluate the relationship between changes in AI-BNST RSFC and NHDD. RESULTS: We found a significant positive RSFC between the AI and the BNST at baseline (p = 0.0015). While there were no significant changes in AI-BNST RSFC from pre- to post-CBT at the group level (p = 0.42), we found that individual differences in reductions in AI-BNST RSFC from pre- to post-CBT were directly related to reductions in NHDD from pre- to post-CBT (r = 0.73, p = 0.0008). CONCLUSIONS: These findings provide preliminary evidence that reduced AI-BNST RSFC may be a mechanism of drinking reduction in AUD and that AI-BNST RSFC may be a target for CBT and possibly other treatments.

Open-label trial of a single-day induction onto buprenorphine extended-release injection for users of heroin and fentanyl.

BACKGROUND AND OBJECTIVES: Fentanyl and other highly potent synthetic opioids are the leading cause of opioid overdose deaths in the United States. METHODS: This study was an open-label, uncontrolled 12-week outpatient clinical trial to test the feasibility of a single-day induction onto extended-release buprenorphine (BXR) injection treatment for five adults (N = 5) with opioid use disorder using heroin-containing fentanyl. Participants were planned to receive three monthly BXR injections (300, 300, and 100 mg). RESULTS: After receiving 24 mg sublingual buprenorphine (SL-BUP), all five participants received the BXR 300 mg injection on the first day of induction. All five participants were retained for the full 3-month study period postinduction and received all three scheduled BXR injections. DISCUSSION AND CONCLUSION: This study provides preliminary evidence supporting the feasibility of inducting users of heroin-containing fentanyl onto BXR 300 mg in a single day. SCIENTIFIC SIGNIFICANCE: The ability to administer a long-acting injection of BXR that assures therapeutic serum levels for a month on the first day of treatment contact is a promising development for the treatment of OUD.

Case Series: Rapid Induction Onto Long Acting Buprenorphine Injection for High Potency Synthetic Opioid Users.

BACKGROUND AND OBJECTIVES: Highly potent synthetic opioids (HPSO) are increasingly responsible for opioid overdose deaths in the United States. METHODS: In an open-label, uncontrolled trial to test the feasibility of extended-release buprenorphine (BXR) injection treatment of heroin-using individuals with opioid use disorder testing positive for HPSO, participants were enrolled and began an induction with sublingual BXR (n = 5). During the induction, ancillary medications (clonidine, clonazepam, zolpidem, and prochlorperazine) were provided for breakthrough opioid withdrawal symptoms. RESULTS: Two participants received the BXR injection on the second day of the induction and three participants on the third day. DISCUSSION AND CONCLUSION: All five participants were retained at least 1-month postinduction. SCIENTIFIC SIGNIFICANCE: It may be feasible to provide BXR treatment to HPSO-positive heroin users rapidly to achieve clinical stabilization. (Am J Addict 2020;00:00-00).

Cognitive Neuroscience Approaches to Understanding Behavior Change in Alcohol Use Disorder Treatments.

Researchers have begun to apply cognitive neuroscience concepts and methods to study behavior change mechanisms in alcohol use disorder (AUD) treatments. This review begins with an examination of the current state of treatment mechanisms research using clinical and social psychological approaches. It then summarizes what is currently understood about the pathophysiology of addiction from a cognitive neuroscience perspective. Finally, it reviews recent efforts to use cognitive neuroscience approaches to understand the neural mechanisms of behavior change in AUD, including studies that use neural functioning to predict relapse and abstinence; studies examining neural mechanisms that operate in current evidence-based behavioral interventions for AUD; as well as research on novel behavioral interventions that are being derived from our emerging understanding of the neural and cognitive mechanisms of behavior change in AUD. The article highlights how the regulation of subcortical regions involved in alcohol incentive motivation by prefrontal cortical regions involved in cognitive control may be a core mechanism that plays a role in these varied forms of behavior change in AUD. We also lay out a multilevel framework for integrating cognitive neuroscience approaches with more traditional methods for examining AUD treatment mechanisms.

Cognitive regulation of craving in alcohol-dependent and social drinkers.

BACKGROUND: Helping alcohol-dependent individuals to cope with, or regulate, cue-induced craving using cognitive strategies is a therapeutic goal of cognitive behavioral therapy (CBT) for alcohol dependence. An assumption that underlies this approach is that alcohol dependence is associated with deficits in such cognitive regulation abilities. To date, however, the ability to utilize such strategies for regulation of craving has never been tested in a laboratory setting. METHODS: Here we compared 19 non-treatment-seeking, alcohol-dependent drinkers (AD) to 21 social drinkers (SD), using a laboratory task that measured the ability to reduce cue-induced alcohol craving by thinking about long-term negative consequences of drinking, which is a specific cognitive regulation strategy that is taught in CBT. The task also assessed the ability to reduce food craving elicited by high-calorie food cues using a similar strategy. RESULTS: The reduction in craving when using this cognitive regulation strategy was approximately double in SD, compared to AD, for both alcohol and food cues. Furthermore, in SD but not AD, the ability to regulate cue-induced alcohol craving was correlated with the ability to regulate food craving. There were no significant correlations found between the ability to regulate cue-induced alcohol craving and a number of self-report measures related to severity of alcohol dependence, baseline craving, impulsivity, and general self-regulation ability, for either AD or SD. CONCLUSIONS: The results suggest that alcohol dependence is associated with deficits in cognitive regulation of cue-induced craving and that these deficits are not specific to the regulation of alcohol craving, but generalize to the regulation of other appetitive states, such as food craving. Future studies may use similar procedures to address the neural and cognitive processes that underlie such regulation deficits, as well as the effects of treatments such as CBT on these processes.

The insula: a critical neural substrate for craving and drug seeking under conflict and risk.

Drug addiction is characterized by the inability to control drug use when it results in negative consequences or conflicts with more adaptive goals. Our previous work showed that damage to the insula disrupted addiction to cigarette smoking-the first time that the insula was shown to be a critical neural substrate for addiction. Here, we review those findings, as well as more recent studies that corroborate and extend them, demonstrating the role of the insula in (1) incentive motivational processes that drive addictive behavior, (2) control processes that moderate or inhibit addictive behavior, and (3) interoceptive processes that represent bodily states associated with drug use. We then describe a theoretical framework that attempts to integrate these seemingly disparate findings. In this framework, the insula functions in the recall of interoceptive drug effects during craving and drug seeking under specific conditions where drug taking is perceived as risky and/or where there is conflict between drug taking and more adaptive goals. We describe this framework in an evolutionary context and discuss its implications for understanding the mechanisms of behavior change in addiction treatments.

The contributions of cognitive neuroscience and neuroimaging to understanding mechanisms of behavior change in addiction.

In the last decade, there has been an upsurge of interest in understanding the mechanisms of behavior change (MOBC) and effective behavioral interventions as a strategy to improve addiction-treatment efficacy. However, there remains considerable uncertainty about how treatment research should proceed to address the MOBC issue. In this article, we argue that limitations in the underlying models of addiction that inform behavioral treatment pose an obstacle to elucidating MOBC. We consider how advances in the cognitive neuroscience of addiction offer an alternative conceptual and methodological approach to studying the psychological processes that characterize addiction, and how such advances could inform treatment process research. In addition, we review neuroimaging studies that have tested aspects of neurocognitive theories as a strategy to inform addiction therapies and discuss future directions for transdisciplinary collaborations across cognitive neuroscience and MOBC research.

The insula and drug addiction: an interoceptive view of pleasure, urges, and decision-making.

We have recently shown that damage to the insula leads to a profound disruption of addiction to cigarette smoking (Naqvi et al., Science 315:531-534, 2007). Yet, there is little understanding of why the insula should play such an important role in an addictive behavior. A broad literature (much of it reviewed in this issue) has addressed the role of the insula in processes related to conscious interoception, emotional experience, and decision-making. Here, we review evidence for the role of the insula in drug addiction, and propose a novel theoretical framework for addiction in which the insula represents the interoceptive effects of drug taking, making this information available to conscious awareness, memory and executive functions. A central theme of this framework is that a primary goal for the addicted individual is to obtain the effects of the drug use ritual upon the body, and representations of this goal in interoceptive terms by the insula contribute to how addicted individuals feel, remember, and decide about taking drugs. This makes drug addiction like naturally motivated behaviors, such as eating and sex, for which an embodied ritual is the primary goal.

The hidden island of addiction: the insula.

Most prior research on the neurobiology of addiction has focused on the role of subcortical systems, such as the amygdala, the ventral striatum and mesolimbic dopamine system, in promoting the motivation to seek drugs. Recent evidence indicates that a largely overlooked structure, the insula, plays a crucial part in conscious urges to take drugs. The insula has been highlighted as a region that integrates interoceptive (i.e. bodily) states into conscious feelings and into decision-making processes that involve uncertain risk and reward. Here, we propose a model in which the processing of the interoceptive effects of drug use by the insula contributes to conscious drug urges and to decision-making processes that precipitate relapse.

Damage to the insula disrupts addiction to cigarette smoking.

A number of brain systems have been implicated in addictive behavior, but none have yet been shown to be necessary for maintaining the addiction to cigarette smoking. We found that smokers with brain damage involving the insula, a region implicated in conscious urges, were more likely than smokers with brain damage not involving the insula to undergo a disruption of smoking addiction, characterized by the ability to quit smoking easily, immediately, without relapse, and without persistence of the urge to smoke. This result suggests that the insula is a critical neural substrate in the addiction to smoking.

Skin conductance responses are elicited by the airway sensory effects of puffs from cigarettes.

The airway sensations stimulated by smoking are an important source of hedonic impact (pleasure) for dependent smokers. The learning process by which these sensations become pleasurable is not well understood. The classical conditioning model predicts that airway sensory stimulation will elicit sympathetic arousal that is positively correlated with the hedonic impact that is elicited by airway sensory stimulation. To test this prediction, we measured skin conductance responses (SCRs) and subjective hedonic impact elicited by a series of individual puffs from nicotinized, denicotinized and unlit cigarettes. Nicotinized puffs elicited more subjective hedonic impact than denicotinized and unlit puffs partly as a result of the fact that they provided a greater level of airway sensory stimulation. We found that SCRs were not larger for nicotinized puffs than for denicotinized puffs, but that they were larger for both nicotinized and denicotinized puffs than for unlit puffs. We also found that the average SCR of a subject to denicotinized puffs was positively correlated with the average hedonic impact that a subject obtained from denicotinized puffs. Together, this suggests that SCR magnitude does not reflect within-subject variations in hedonic impact that are due to variations in the level of airway sensory stimulation, but that it does reflect individual differences in the amount of hedonic impact that is derived from a given level of airway sensory stimulation. The results of a post hoc correlation analysis suggest that these individual differences may have been due to variations in the prevailing urge to smoke. The implications of these findings for the classical conditioning model, as well as for other learning models, are discussed.

The airway sensory impact of nicotine contributes to the conditioned reinforcing effects of individual puffs from cigarettes.

Puffs from cigarettes are the fundamental unit of smoking reward. Here, we examined the extent to which reward from puffs can be derived from the airway sensory effect of nicotine, in the absence of a direct central nervous system effect of nicotine. We did this by assessing the self-reported reward obtained from individual puffs from nicotinized, denicotinized and unlit cigarettes within 7 s of inhalation, which is before nicotine had an opportunity to reach the brain. We also assessed the self-reported strength of airway sensations elicited by the puffs. We found that nicotinized puffs were rated as both stronger and more rewarding than denicotinized and unlit puffs. We also found that the extent to which nicotine elicited reward was directly correlated with the extent to which nicotine elicited airway sensations. This indicates that the airway sensory effects of nicotine contribute to the reward from puffs, above and beyond the reward derived from the airway sensory effects of non-nicotine constituents. These findings have implications for the interpretation of studies that use puffs as experimental units to examine nicotine reward. They also have implications for the use of denicotinized and low nicotine cigarettes as aids to smoking cessation.