Disrupted functional connectivity with dopaminergic midbrain in cocaine abusers.
- Authors
- Tomasi, Dardo; Volkow, Nora D; Wang, Ruiliang; Carrillo, Jean H; Maloney, Thomas; Alia-Klein, Nelly; Woicik, Patricia A; Telang, Frank; Goldstein, Rita Z
- Year
- 2010
- Journal
- PloS one
- PMID
- 20520835
- DOI
- 10.1371/journal.pone.0010815
- PMCID
- PMC2876035
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.
Drug-word fMRI paradigm.
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: βWordβ 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.
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.
Brain activation.Statistical maps of BOLD-fMRI signals during the DW task across word conditions (βDrugβ and βNeutralβ) 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.
Brain activation and functional connectivity of midbrain.A: Statistical map of BOLD-fMRI signals during the DW task across word conditions (conjunctive analysis βDrugβ + βNeutralβ 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 βDrugβ + βNeutralβ 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.
Functional connectivity of midbrain.Statistical maps of normalized CM coefficients during task epochs of the DW task across word conditions (βDrugβ and βNeutralβ) 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.
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.
| Name | Type |
|---|---|
| accuracy | phenotype |
| acute withdrawal | phenotype |
| age | phenotype |
| alcohol | phenotype |
| alcohol abuse | phenotype |
| alcohol dependence | phenotype |
| Altered functional connectivity local | phenotype |
| amygdala | anatomy |
| anterior cingulate cortex | anatomy |
| autoimmune diseases | phenotype |
| barbiturates | drug |
| benzodiazepines | drug |
| BOLD local | drug |
| BOLD contrast maps local | phenotype |
| BOLD signal | phenotype |
| BOLD signals local | phenotype |
| brain | anatomy |
| brain activation local | phenotype |
| Brain activation local | phenotype |
| brain activation clusters local | anatomy |
| brain regions modulated by dopamine local | anatomy |
| brainstem | anatomy |
| cannabis dependence | phenotype |
| cannabis use | phenotype |
| cardiovascular disease | phenotype |
| Catecholamine pathways local | drug |
| catecholamines | drug |
| caudate nucleus | anatomy |
| cerebellar activity local | phenotype |
| cerebellum | anatomy |
| cerebellum (culmen) local | anatomy |
| chronic cocaine abusers | phenotype |
| Chronic cocaine exposure local | phenotype |
| cigarettes | phenotype |
| cingulate cortex | anatomy |
| CM local | drug |
| CM signal local | phenotype |
| cocaine | phenotype |
| cocaine group | cohort |
| control group | cohort |
| controls | cohort |
| control subjects | cohort |
| DA | drug |
| depression | phenotype |
| Disrupted noradrenergic neurotransmission local | phenotype |
| dopamine | drug |
| dopaminergic function local | phenotype |
| dopaminergic neurons | anatomy |
| Dorsal medial nucleus of thalamus local | anatomy |
| dorsal striatum | anatomy |
| drug | drug |
| drug-cue related activation local | phenotype |
| education | phenotype |
| Endocrinological disease local | phenotype |
| epilepsy | phenotype |
| executive cognitive dysfunction local | phenotype |
| forebrain | anatomy |
| frontal cortex | anatomy |
| GABA | phenotype |
| glutamatergic system local | phenotype |
| gross brain morphological abnormalities local | phenotype |
| group | cohort |
| Head injury | phenotype |
| healthy controls | cohort |
| higher negative BOLD responses in rACC local | phenotype |
| hypo-activation | phenotype |
| inferior frontal gyrus | anatomy |
| inhalants | drug |
| insula | anatomy |
| locus coeruleus | anatomy |
| lower CM local | phenotype |
| lower CM signals in rACC local | phenotype |
| lower dopaminergic function local | phenotype |
| matched controls | cohort |
| MDTHA local | anatomy |
| medial dorsal nuclei local | anatomy |
| Medial dorsal nuclei local | anatomy |
| medial dorsal nuclei of the thalamus local | anatomy |
| Medial dorsal thalamus local | anatomy |
| midbrain | anatomy |
| middle frontal gyrus | anatomy |
| Neurological disease of central origin local | phenotype |
| nicotine | drug |
| nicotine dependence | phenotype |
| noradrenaline | drug |
| noradrenergic abnormalities local | phenotype |
| Noradrenergic abnormalities local | phenotype |
| norepinephrine | drug |
| Norepinephrinergic neurons local | phenotype |
| nucleus accumbens | anatomy |
| Number of years of cocaine use local | phenotype |
| occipital cortex | anatomy |
| Oncological disease local | phenotype |
| opiates | drug |
| orbitofrontal cortex | anatomy |
| parahippocampal gyrus | anatomy |
| parietal cortex | anatomy |
| phencyclidine | drug |
| physical abuse | phenotype |
| pons | anatomy |
| posterior insula local | anatomy |
| precuneus | anatomy |
| prefrontal cortex | anatomy |
| psychiatric disorders | phenotype |
| putamen | anatomy |
| rACC hypoactivation local | phenotype |
| reaction time | phenotype |
| region-of-interest local | anatomy |
| reward sensitivity | phenotype |
| Rostral raphe local | anatomy |
| Self-reported time since last use of cocaine local | phenotype |
| serotonin | drug |
| sex | phenotype |
| smoking | phenotype |
| smoking frequency | phenotype |
| smoking status | phenotype |
| stress response | phenotype |
| subjects | cohort |
| substance abuse | phenotype |
| substantia nigra | anatomy |
| temporal cortex | anatomy |
| thalamus | anatomy |
| time since last cigarette local | phenotype |
| urine results local | phenotype |
| ventral precuneus local | anatomy |
| verbal IQ local | phenotype |
| word type local | phenotype |
| Years of cocaine use local | phenotype |
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