Ventral striatal dysfunction in cocaine dependence - difference mapping for subregional resting state functional connectivity

Abstract

Research of dopaminergic deficits has focused on the ventral striatum (VS) with many studies elucidating altered resting state functional connectivity (rsFC) in individuals with cocaine dependence (CD). The VS comprises functional subregions and delineation of subregional changes in rsFC requires careful consideration of the differences between addicted and healthy populations. In the current study, we parcellated the VS using whole-brain rsFC differences between CD and non-drug-using controls (HC). Voxels with similar rsFC changes formed functional clusters. The results showed that the VS was divided into 3 subclusters, in the area of the dorsal-anterior VS (daVS), dorsal posterior VS (dpVS), and ventral VS (vVS), each in association with different patterns of rsFC. The three subregions shared reduced rsFC with bilateral hippocampal/parahippocampal gyri (HG/PHG) but also showed distinct changes, including reduced vVS rsFC with ventromedial prefrontal cortex (vmPFC) and increased daVS rsFC with visual cortex in CD as compared to HC. Across CD, daVS visual cortical connectivity was positively correlated with amount of prior-month cocaine use and cocaine craving, and vVS vmPFC connectivity was negatively correlated with the extent of depression and anxiety. These findings suggest a distinct pattern of altered VS subregional rsFC in cocaine dependence, and some of the changes have eluded analyses using the whole VS as a seed region. The findings may provide new insight to delineating VS circuit deficits in cocaine dependence and provide an alternative analytical framework to address functional dysconnectivity in other mental illnesses.

Fig. 1. Data analytic procedures and subregions of the ventral striatum.

(a) A flow chart of data analysis. (b) Seed region: the ventral striatum (VS). (c) K-means clustering segments the VS based on connectivity differences between CD and HC of individual voxels within the region. Three subclusters were represented with different colors as dorsal-anterior VS (daVS), dorsal posterior VS (dpVS), and ventral VS (vVS)

Fig. 2. Ventral striatum subregional connectivity.

One-sample t test results of functional connectivity maps of the dorsal anterior VS (daVS), dorsal posterior VS (dpVS), and ventral VS (vVS) each for (a) CD and (b) HC. p < 0.05, corrected for familywise error of multiple comparisons

Fig. 3. Altered functional connectivity in CD compared to HC is shown for each of the three subclusters of the VS.

Warm color: CD > HC; cool color: HC > CD. Details can be found in Supplementary Table 2. LNG: Lingual gyrus; biHG: bilateral hippocampus; biPHG: bilateral parahippocampus; PCu: precuneus; IFC: inferior frontal cortex; MFG: middle frontal gyrus; SMA: supplementary motor area; preSMA: pre-supplementary motor area; biITG: bilateral inferior temporal gyrus; vmPFC: ventromedial prefrontal gyrus; HT: hypothalamus

Fig. 4. Correlation of VS connectivity with clinical measures.

Dorsal anterior VS (daVS) connectivity with the lingual gyrus (LNG) was positively correlated with (a) the average monthly use of cocaine (grams) in the prior year and with (b) craving score as assessed by the Cocaine Craving Questionnaire (CCQ). Ventral VS (vVS) connectivity with the ventromedial prefrontal cortex (vmPFC) was negatively correlated with (c) depression score, as assessed by the Beck Depression Inventory (BDI) and with (d) trait anxiety score, as assessed by the Spielberger State Trait Anxiety Inventory (STAI). Correlations in (b) and (d) were significant only at a trend level, with correction for multiple comparisons

Fig. 5. Ventral striatum connectivity in CD and HC.

One sample t test of whole-brain functional connectivity with the entire VS as the seed each in (a) CD and (b) HC, p < 0.05 FWE; as well as (c) the two-sample t test results of CD vs. HC, p < 0.005 uncorrected