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Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity.

ABSTRACT: Preclinical models have consistently demonstrated the importance of the mesocorticolimbic (MCL) brain reward system in drug dependence, with critical molecular and cellular neuroadaptations identified within these structures following chronic cocaine administration. Cocaine dependent individuals manifest alterations in reward functioning that may relate to changes induced by cocaine or to pre-existing differences related to vulnerability to addiction. The circuit level manifestations of these drug-induced plastic changes and predispositions to drug dependence are poorly understood in preclinical models and virtually unknown in human drug dependence. Using whole-brain resting-state fMRI connectivity analysis with 'seed voxels' placed within individual nodes of the MCL system, we report network-specific functional connectivity strength decreases in cocaine users within distinct circuits of the system, including between ventral tegmental area (VTA) and a region encompassing thalamus/lentiform nucleus/nucleus accumbens, between amygdala and medial prefrontal cortex (mPFC), and between hippocampus and dorsal mPFC. Further, regression analysis on regions showing significant functional connectivity decrease in chronic cocaine users revealed that the circuit strength between VTA and thalamus/lentiform nucleus/nucleus accumbens was negatively correlated with years of cocaine use. This is the first evidence of circuit-related changes in human cocaine dependence and is consistent with the range of cognitive and behavioral disruptions seen in cocaine dependence. As potential circuit level biomarkers of cocaine dependence, these circuit alterations may be usefully applied in treatment development and monitoring treatment outcome.

SUBMITTER: Gu H

PROVIDER: S-EPMC2930044 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity.

Gu Hong H Salmeron Betty Jo BJ Ross Thomas J TJ Geng Xiujuan X Zhan Wang W Stein Elliot A EA Yang Yihong Y

NeuroImage 20100711 2

Preclinical models have consistently demonstrated the importance of the mesocorticolimbic (MCL) brain reward system in drug dependence, with critical molecular and cellular neuroadaptations identified within these structures following chronic cocaine administration. Cocaine dependent individuals manifest alterations in reward functioning that may relate to changes induced by cocaine or to pre-existing differences related to vulnerability to addiction. The circuit level manifestations of these dr ...[more]

PMID: 20603217

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Project description:Cocaine addiction is associated with altered resting-state functional connectivity among regions of the mesocorticolimbic dopamine pathways. Methylphenidate hydrochloride, an indirect dopamine agonist, normalizes task-related regional brain activity and associated behavior in cocaine users; however, the neural systems-level effects of methylphenidate in this population have not yet been described.To use resting-state functional magnetic resonance imaging to examine changes in mesocorticolimbic connectivity with methylphenidate and how connectivity of affected pathways relates to severity of cocaine addiction.Randomized, placebo-controlled, before-after, crossover study.Clinical research center.Eighteen nonabstaining individuals with cocaine use disorders.Single doses of oral methylphenidate (20 mg) or placebo were administered at each of 2 study sessions. At each session, resting scans were acquired twice: immediately after drug administration (before the onset of effects [baseline]) and 120 minutes later (within the window of peak effects).Functional connectivity strength was evaluated using a seed voxel correlation approach. Changes in this measure were examined to characterize the neural systems-level effects of methylphenidate; severity of cocaine addiction was assessed by interview and questionnaire.Short-term methylphenidate administration reduced an abnormally strong connectivity of the ventral striatum with the dorsal striatum (putamen/globus pallidus), and lower connectivity between these regions during placebo administration uniquely correlated with less severe addiction. In contrast, methylphenidate strengthened several corticolimbic and corticocortical connections.These findings help elucidate the neural systems-level effects of methylphenidate and suggest that short-term methylphenidate can, at least transiently, remodel abnormal circuitry relevant to the pathophysiologic characteristics of cocaine addiction. In particular, the effects of methylphenidate within striatal and cortical pathways constitute a potentially viable mechanism by which methylphenidate could facilitate control of behavior in cocaine addiction.

Project description:Lapses in inhibitory control have been linked to relapse in human drug addiction. Evidence suggests differences in inhibitory control depending on abstinence duration, but the underlying neural mechanisms remain unknown. We hypothesized that early abstinence (2-5 days) would be characterized by the strongest impairments of inhibitory control and most wide-spread deviations in resting-state functional connectivity of brain networks, while longer-term abstinence (>30 days) would be characterized by weaker impairments as compared to healthy controls. In this laboratory-based cross-sectional study, we compared individuals with Cocaine Use Disorder (iCUD) during early (cocaine urine-positive: N = 19, iCUD+; 32% female; mean age: 46.8 years) and longer-term abstinence (cocaine urine-negative: N = 29, iCUD-; 15% female; mean age: 46.6 years) to healthy controls (N = 33; 24% female; mean age: 40.9 years). We compared the groups on inhibitory control performance (Stop-Signal Task) and, using a whole-brain graph theory analysis (638 region parcellation) of functional magnetic resonance imaging (fMRI) data, we tested for group differences in resting-state brain function (local/global efficiency). We characterized how resting-state brain function was associated with inhibitory control performance within iCUD. Inhibitory control performance was worst in the early abstinence group, and intermediate in the longer-term abstinence group, as compared to the healthy control group (P < 0.01). More recent use of cocaine (CUD+ > CUD- > healthy controls) was characterized by decreased efficiency in fronto-temporal and subcortical networks (primarily in the salience, semantic, and basal ganglia networks) and increased efficiency in visual networks. Importantly, a similar functional connectivity pattern characterized impaired inhibitory control performance within iCUD (all brain analyses P < 0.05, FWE-corrected). Together, we demonstrated that a similar pattern of systematic and widespread deviations in resting-state brain efficiency, extending beyond the networks commonly investigated in human drug addiction, is linked to both abstinence duration and inhibitory control deficits in iCUD.

Dataset Information

Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity.

Publications

Mesocorticolimbic circuits are impaired in chronic cocaine users as demonstrated by resting-state functional connectivity.

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