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.

Published by Elsevier Inc.

Figures

Figure 1

Functional connectivity maps of six MCL seeds for healthy controls (yellow) and cocaine users (red) under resting state (pcorrected < 0.001, with t(38) > 3.8 and a cluster size of 38 voxels). Maps were overlaid together for display purpose. Orange color indicates overlapped areas for both groups.

Figure 2

Significant differences in functional connectivity in cocaine addicts as compared to matched control subjects (pcorrected < 0.05 with t(76) > 2.4 and a cluster size of 43 – 81 voxels), when seed regions were located in the (a) VTA; (b) amygdala; (c) hippocampus; (d) MD thalamus; and (e) rostral ACC (BA24). For further details, see Table 3.

Figure 3

Schematic representation of regions showing decreased functional connectivity (indicated by the colored lines) in cocaine users compared with matched healthy controls. The lines match the color of the seed regions where the decreased connectivity was associated. Amygdala and rACC, as well as the hippocampus and rACC, each showed a reduction when the other was the seed region. VTA showed reduced connectivity to much of the thalamus, including the MD thalamus seed region. VTA: ventral tegmental area; NAcc: nucleus accumbens; Amy: amygdala; Hip: hippocampus; Thal: thalamus; rACC: rostral anterior cingulate cortex; mPFC: medial prefrontal cortex; Ins: insula; LN: lentiform nucleus.

Figure 4

Multiple regression analysis (pcorrected < 0.05) shows negative correlation between rsFC strength (indicated by average z value) and the number of years of cocaine use in the VTA – thalamus/leniform nucleus/NAcc circuit (R = −0.47, puncorrected = 0.004). The box plot on the left summarizes the connectivity strength from the HC group in the corresponding ROI, with the open symbols representing the outliers in the HC group.