1. Hippocampal Basal Regional Cerebral Blood Flow (rCBF) and Functional Connectivity Predicts Cocaine Relapse. More than 70% of those treated for cocaine addiction will relapse and return to regular cocaine use within a few weeks of treatment. Identification of individual differences predicting relapse or remission will provide a more rational targeting of mechanisms associated with relapse risk. We utilized rCBF to identify neuronal activity alterations as a function of relapse status. We then used this alteration to identify those functional circuits driven by this local change in activity with the hypothesis that such circuits may serve as relapse predictors. CD participants who relapsed within 30 days following treatment showed increased resting rCBF in posterior hippocampus (pHp) and increased rsFC strength between pHp and posterior cingulate cortex (PCC). Both predicted days to relapse over a six-month period;the prediction power was strengthened when the two measures were considered concurrently. The identification of both pHp activity and pHp-PCC rsFC as independent predictors of relapse, coupled with the extant literature, support exploration of the interaction between contextual cravings and the DMN upon relapse. 2. Resting state functional connectivity of striatal network in cocaine users. Converging evidence has identified both impulsivity and compulsivity as key psychological constructs in drug addiction. We tested the hypothesis that cocaine addiction is associated with disturbances in striatal-cortical communication as captured by rsFC. We also explored the relationships between striatal rsFC, impulsivity and compulsivity in cocaine addiction. Increased rsFC strength was observed predominantly in striatal-frontal circuits while decreased rsFC was found in striatal-cingulate, striatum, -temporal, -hippocampus and -insula circuits in the CU group compared with the HCs. Increased striatal- dorsal lateral prefrontal cortex connectivity strength was positively correlated with recent cocaine use and elevated impulsivity in the CUs while the balance between striatal- dACC and striatal- inferior prefrontal cortex circuits was significantly associated with cocaine compulsive behaviors. 3. Beyond functional localization: Advancing the understanding of addiction-related processes by examining brain connectivity. In this review we discuss methodological considerations and limitations of using rsFC to advance understanding of addiction. Using nicotine addiction as an exemplar, we present evidence consistent with the hypothesis that distinct brain network dynamics represent: (1) a state-like marker of nicotine withdrawal, and (2) a trait-like marker of nicotine addiction. Specifically, aberrant inter- and intra-network functioning of the SN, DMN, and ECN may reflect the state of nicotine withdrawal as such network dynamics are modulated by pharmacological cessation aids (e.g., nicotine replacement, varenicline), correlate with self-reported withdrawal symptoms, and are linked with impairments in behavioral performance. In contrast, the inter-network coupling between the SN and striatum may reflect the trait of nicotine addiction as such coupling is inversely related to a clinical measure of addiction severity, not impacted by acute nicotine administration, and appears modulated by nAChR genetics. Taken together, the results of these initial studies suggest the intriguing possibility that alterations in dissociable neurocircuitry may provide network-level biomarkers of addiction-related processes. 4. Contribution of striatal circuits to impulsivity and relapse: Dysregulated striatal functioning coupled with executive control deficits arising from abnormal frontal cortical function are key mechanisms in the development and maintenance of cocaine addiction. The same features are thought to underlie high trait impulsivity observed in cocaine-addicted populations. Relative to a group of healthy controls, individuals in treatment for cocaine-addiction evidenced reduced positive connectivity between the putamen and posterior insula and postcentral gyrus. This reduction was most pronounced among individuals who relapsed within 30 days. Scores on the Barratt Impulsiveness Scale were higher in cocaine-addicted participants, an effect that was partially mediated by reduced putamen- insula connectivity. Cocaine addiction, relapse risk and impulsivity were associated with reduced connectivity in putamen- insula/postcentral gyrus circuits implicated in temporal discounting and habitual responding. Findings provide new insight into the neurobiological mechanisms underlying impulsivity and relapse in cocaine addiction. 5. Cortico-amygdala circuits and relapse to cocaine use: The amygdala has been implicated in multiple relapse-related processes including craving, anxiety and reactivity to stress following both acute and protracted withdrawal from cocaine. We examined rsFC within amygdala circuits among cocaine-addicted individuals during the final week of treatment. Relapse during the first 30 days post-treatment was associated with reduced connectivity between the corticomedial amygdala and ventromedial prefrontal cortex/rostral anterior cingulate cortex. Individuals who didnt relapse during the first 30 days also evidenced suppressed connectivity between the basolateral amygdala and visual processing regions. Findings suggest that probing functional connectivity within neural circuits implicated in preclinical models of relapse to cocaine-seeking provide a promising tool for assessing relapse risk in cocaine-addiction. 6. Disrupted network interactions in chronic cocaine dependents as revealed by modular network analysis. Neuroimaging studies on cocaine dependents revealed their impairments in various brain circuits, including the striatum (ST), medial temporal lobe (MTL), and ECN. In addition, two other brain networks, the DMN and SN, have also shown addiction-related impairments. We used modularity analysis to identify the modules of interest. On the modular level, CDs exhibited decreased inter-module connectivity between the DMN and SN modules, and between the DMN and MTL modules. On the nodal level, CDs showed decreased PC in insula and rostral anterior cingulate cortex. Finally, we found that the intra-module connectivity within SN module showed significantly negative correlation with a sub-scale score of TAS-20. These results demonstrate that cocaine addiction is associated with disruptions of network-level interactions. 7. Temporal difference error prediction signal dysregulation in cocaine-dependence (CD). Despite known effects on reward processing for drug-related reinforcers, the influence of CD on non-drug reward processing is unclear. Subjects were scanned twice in sessions that were identical, except that CD participants received cocaine or saline before task onset. CD engendered increased responsiveness to unexpected negative outcomes (i.e. omission of an expected reward) and reduced sensitivity to positive events (i.e. expected or unexpected rewards) in dopaminergic reward pathway regions. Group differences in reward-related activity were predicted by the time since last self-administered cocaine use but not influenced by acute cocaine. These effects likely have implications for the high cocaine use recidivism rates by contributing to the drive to consume cocaine, perhaps via influence on dopamine-related reward computations. That they do not acquiesce to acute cocaine administration might factor in binge-related escalated consumption.
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