1. Genetic imaging consortium for addiction medicine. Since the sample size of a typical neuroimaging study lacks sufficient statistical power to explore unknown genomic associations with brain phenotypes, several international genetic imaging consortia have been organized in recent years to pool data across sites. The challenges and achievements of these consortia are considered here with the goal of leveraging these resources to study addiction. The authors of this review have joined together to form an Addiction working group within the framework of the ENIGMA project, a meta-analytic approach to multisite genetic imaging data. Collectively, the Addiction working group possesses neuroimaging and genomic data obtained from over 10,000 subjects. The deadline for contributing data to the first round of analyses occurred at the beginning of May 2015. The studies performed on this data should significantly impact our understanding of the genetic and neurobiological basis of addiction. 2. Posterior hippocampal regional cerebral blood flow predicts cocaine relapse: The posterior hippocampus (pHp) plays a major role in the processing and storage of drug-related cues and is linked to striatal-limbic brain circuits involved with craving and drug salience. We have recently reported that increased basal regional cerebral blood flow (rCBF) in a pHp loci, as measured by pseudo-continuous arterial spin labeling magnetic resonance imaging, predicted days to cocaine relapse following residential treatment. In this secondary analysis, we explored whether rCBF in this same pHp region would successfully predict 30-day point prevalence abstinence 60days following residential treatment in an independent group of previously studied participants with cocaine dependence. rCBF was assessed with single photon emission computerized tomography during a saline infusion in 21 cocaine dependence and 22 healthy control participants. pHp rCBF was significantly higher in those endorsing substance use (n=10) relative to both abstinent (n=11) (p<0.001) and control (p<0.05) participants. There were no significant differences in measured demographic or clinical variables between the actively using and non-using participants. This replicative finding suggests that heightened pHp activation is a significant predictor of substance use in cocaine-dependent individuals, possibly reflecting a neural susceptibility to continued drug cues. 3. Distress tolerance among substance users associated with connectivity between the prefrontal regions during a distress tolerance task. Defined as the ability to persist in goal directed behavior while experiencing affective distress, DT is implicated in the development and maintenance of substance use disorders. While theory and evidence indicate that cortico-limbic neural dysfunction may account for deficits in goal directed behavior while experiencing distress, the neurobiological mechanisms of DT have yet to be examined. We modified a computerized DT task for use in functional magnetic resonance imaging (fMRI), the Paced Auditory Serial Addition Task (PASAT-M), and examined the neural correlates and functional connectivity of DT among a cohort of substance users (n=21; regular cocaine and nicotine users) and healthy controls (n=25). In response to distress during the PASAT-M, we found greater activation in a priori cortico-limbic network ROIs, namely the right insula, anterior cingulate cortex (ACC), bilateral medial frontal gyrus (MFG), right inferior frontal gyrus (IFG) and right ventromedial prefrontal cortex (vmPFC) significantly predicted higher DT among substance users, but not healthy controls. In addition, greater task-specific functional connectivity during distress between the right MFG and bilateral vmPFC/sgACC was associated with higher DT among substance users, but not healthy controls. The observed positive relationship between DT and neural activation in cortico-limbic structures, as well as functional connectivity between the rMFG and vmPFC/sgACC, is in line with theory and research suggesting the importance of these structures for persisting in goal directed behavior while experiencing affective distress. 4. The relative impact of chronic vs. acute cocaine on dependence-related variability in reward processing in cocaine-dependent individuals (CD) is not well understood, despite the relevance of such effects to long-term outcomes. To dissociate these effects, CD (N=15) and healthy controls (HC; N=15) underwent MRI twice while performing a monetary incentive delay (MID) task. Both scans were identical across subjects/groups except that, in a single-blind, counter-balanced design, CD received intravenous cocaine (30mg/70kg) prior to one session (CD+cocaine) and saline in another (CD+saline). Imaging analyses focused on activity related to anticipatory valence (gain/loss), anticipatory magnitude (small/medium/large), and reinforcing outcomes (successful/unsuccessful). Drug condition (cocaine vs. saline) and group (HC vs. CD+cocaine or CD+saline) did not influence valence-related activity. However, compared to HC, magnitude-related activity for gains was reduced in CD in the left cingulate gyrus post-cocaine and in the left putamen in the abstinence/saline condition. In contrast, magnitude-dependent activity for losses increased in CD vs. HC the right inferior parietal lobe post-cocaine and the left superior frontal gyrus post-saline. Across outcomes (i.e., successful and unsuccessful) activity in the right habenula decreased in CD in the abstinence/saline condition vs. acute cocaine and HC. Cocaine-dependent variability in outcome- and loss-magnitude activity correlated negatively with ratings of cocaine craving and positively with how high subjects felt during the scanning session. Collectively, these data suggest dissociable effects of acute cocaine on non-drug reward processes, with cocaine consumption partially ameliorating dependence-related insensitivity to reinforcing outcomes/liking, but having no discernible effect on dependence-related alterations in incentive salience/wanting. The relationship of drug-related affective sequelae to non-drug reward processing suggests that CD experience a general alteration of reward function and may be motivated to continue using cocaine for reasons beyond desired drug-related effects. This may have implications for individual differences in treatment efficacy for approaches that rely on reinforcement strategies (e.g., contingency management) and for the long-term success of treatment. 5. Resting state functional connectivity (rsFC) analysis for addiction medicine: from individual loci to complex networks. rsFC has provided a new and valuable tool for investigating network-level dysfunction in addiction. Following the recent development of a framework of large scale network disruptions, we have been able to arrive at unique insights into craving-related aspects of addiction using rsFC. However, such network-level advancement has thus far eluded our understanding of mesocorticolimbic involvement in addiction. Given the importance of this system in vulnerability and resilience to addiction, understanding mesocorticolimbic dynamics to the same extent could provide critical insights into the disease. To this end, we reviewed recent studies on addiction that employ rsfC and suggest a new approach, one that combines a novel model for addiction with new experimental techniques as well as participant groups, to accelerate progress in this arena.

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