Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers

Abstract

Background: Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task.

Methodology/principal findings: We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and this was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate.

Conclusions/significance: These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.

Figure 1. Drug-word fMRI paradigm.

Figure 2. Functional connectivity analysis of task-related signal fluctuations during the blocked fMRI paradigm.

A: BOLD response elicited by the drug-word paradigm (black curve) and the fitted SPM2 canonic hemodynamic response (red curve). The gray periods identify the plateaus of the model. B: “Word” time series are composed by 37 the time points of plateau 1 (green curve) and the 37 time points of plateau 2 (blue curve). C: Mid-sagittal slice of an MRI structure showing the position of the midbrain seed used for the functional connectivity analysis. D: Mid-saggital slice exemplifying the normalized (z-score) maps reflecting correlations of MRI signals in the brain with those in midbrain. These individual maps were used in group analyses of functional connectivity.

Figure 3. Behavioral data.

Average performance accuracy (A) and reaction times (RT; B) during the drug-word (DW) paradigm for cocaine (N = 20) and control (N = 20) subjects.

Figure 4. Brain activation.

Statistical maps of BOLD-fMRI signals during the DW task across word conditions (“Drug” and “Neutral”) for 20 cocaine abusers (left) and 20 healthy matched control subjects (right). Random-effects analyses (two-way repeated measures ANOVA). Red-yellow and blue-green color bars show the t-score windows for activation and deactivation, respectively.

Figure 5. Brain activation and functional connectivity of midbrain.

A: Statistical map of BOLD-fMRI signals during the DW task across word conditions (conjunctive analysis “Drug” + “Neutral” vs. resting baseline) for controls > cocaine, superimposed on a sagittal view of the human brain. The light-blue squares and labels mark the positions of relevant ROI. The left side bar plots display the average BOLD responses in these regions for the cocaine and control groups (P<0.05). 5B: Statistical map of correlations with midbrain (CM) across word conditions (conjunctive analysis “Drug” + “Neutral” vs. resting baseline) for controls > cocaine, superimposed on a sagittal view of the human brain. The right side bar plots display the average CM signals in these regions for the cocaine and control groups (P<0.05). SPM Model: two-way repeated measures ANOVA. Sample: cocaine (N = 20) and control (N = 20) subjects. MDTHA: medial dorsal nucleus of the thalamus; CER: cerebellum (culmen); rACC: rostral anterior cingulate cortex (BA 32). ROI volume = 27 voxels (0.73 cc). Error bars are standard errors. CER: cerebellum; MDTHA: medial dorsal nucleus of the thalamus; rACC: rostral Anterior cingulate cortex.

Figure 6. Functional connectivity of midbrain.

Statistical maps of normalized CM coefficients during task epochs of the DW task across word conditions (“Drug” and “Neutral”) for 20 cocaine abusers (left) and 20 healthy matched control subjects (right). Random-effects analyses (two-way repeated measures ANOVA). Red-yellow and blue-green color bars show the t-score windows.

Figure 7. Midbrain-thalamus functional connectivity of vs. thalamic activation and cocaine exposure.

Scatter plots of average CM coefficients vs. the average BOLD responses (A) and the duration of cocaine use in the life span (B) for the dorsal medial nucleus of the thalamus. Solid circles: cocaine addicts; open circles: controls. Solid and dashed lines are the corresponding linear fits. ROI volume = 27 voxels (0.73 cc). Error bars are standard errors. MDTHA: medial dorsal nucleus of the thalamus.