Here we show that the midbrain's positive functional connectivity with MDTHA, cerebellum (culmen), and rACC was significantly lower for cocaine subjects than for controls. In parallel and in absence of performance differences, cocaine subjects had lower activation in MDTHA and cerebellum and higher deactivation in rACC than controls, which is consistent with our previous findings in cocaine subjects tested with working memory 
and visual attention tasks 
Using the DW task we recently showed that drug words, but not neutral words, activated the midbrain in cocaine subjects but not in controls 
. In the current work we evaluated the functional connectivity of this midbrain region (Talairach coordinates xyz
[−6, −15, −18] mm) with the rest of the brain using a different sample and a simplified version of the stimulation paradigm. Since the midbrain is relatively small and the imaging smoothing was larger than 12-mm is all directions, the functional responses in the selected seed region are representative of those in the entire midbrain. The midbrain (mesencephalon) is the origin of the main dopamine (DA) projections to the forebrain, and cocaine addicts have lower dopaminergic function than controls 
. Since cocaine binds to norepinephrine (NE) and DA transporters 
, thereby increasing extracellular NE and DA 
, chronic cocaine exposure could be additionally associated with disrupted neurotransmission in noradrenergic pathways including those into the thalamus. Indeed recent imaging studies have provided evidence of noradrenergic abnormalities in the thalamus (including medial dorsal nuclei) of cocaine abusers when compared with controls 
. Because midbrain also includes the upper portion of the locus coeruleus, the main norepinephrinergic nucleus in the brain, and the upper part of the rostral raphe, which is the main source of serotonergic innervation to cerebellum and forebrain, and considering that the spatial resolution of fMRI is limited to few mm 
, altered functional connectivity of the midbrain with MDTHA, cerebellum, and rACC could reflect not just neuroadaptations in dopaminergic but also in norepinephrinergic and/or serotonergic neurotransmission with chronic cocaine exposure.
The MDTHA had lower CM and lower BOLD signals for cocaine abusers than for control subjects. These results are consistent with previous studies that documented reduced DA release 
and reduced activation 
in the MDTHA for cocaine abusers compared to control subjects. The MDTHA is innervated by norepinephrinergic and dopaminergic neurons 
. Our current findings may therefore reflect a dysfunctional norepinephrinergic and dopaminergic regulation of the MDTHA in cocaine addicts. This interpretation is further supported by the negative correlation between the thalamic CM signals and the years of cocaine use, which suggests that functional connectivity could be a better marker than BOLD responses for the precise characterization of drug-related neuroadaptations. The positive correlation of thalamic BOLD and CM signals in control subjects and the lack of similar correlations in cocaine subjects further supports this conclusion.
This study also shows an association between hypo-activation and lower CM in the cerebellum for cocaine subjects compared to controls. The locus coeruleus, a homeostatic gray matter nucleus in the brainstem (lower midbrain/pons), is the main source of norepinephrinergic innervation to the thalamus and cerebellum 
and is closely located to our midbrain seed (22 mm; 7 imaging voxels apart from midbrain; ). These results are therefore consistent with altered norepinephrinergic regulation in cocaine addiction. Since most cocaine subjects had a positive urine for cocaine on the day of the study, the cocaine subjects' lower cerebellar BOLD and CM signals may reflect in part activation of norepinephrinergic pathways during short-term/acute withdrawal 
. However, it could also reflect serotonergic dysfunction since there is increasing evidence of serotonergic regulation of cerebellar activity 
The negative BOLD responses in the rACC were higher and the CM signals in rACC were lower for cocaine abusers than for control subjects. The rACC, which is innervated by DA, noradrenergic 
and serotonergic 
neurons has been implicated in generation or regulation of spontaneous internal thoughts, emotions, anxiety and in internal conflict resolution 
. Indeed, the rACC activates during emotional tasks and deactivates during cognitive tasks 
. Taking into account that compared to controls cocaine subjects showed rACC hypoactivation during this 
and other 
fMRI paradigms, the higher negative BOLD responses and the lower CM signals in rACC may reflect lower DA-mediated suppression of task-irrelevant emotional responses during fMRI in cocaine abusers.
We did not exclude smokers as from our experience around 75% of cocaine subjects smoke cigarettes (vs. around 25% of controls). Fifteen cocaine subjects and five control subjects were smokers, and the group difference was statistically significant. Subjects were allowed to smoke regularly to minimize withdrawal symptoms. Previous studies have shown that nicotine can induce a dose-dependent increase in neuronal activity in a distributed system of brain regions, including the nucleus accumbens, amygdala, cingulate, and frontal lobes 
. Therefore, the blunted responses of the cocaine smokers could have been even more suppressed if they would have been abstinent for nicotine prior the study. Taking into account that the average elimination half-life for plasma nicotine is 2 hours in humans 
, and given that none of the controls subjects and only two cocaine subjects smoked within the 2-hours period before the study, none of them smoked during the study, and there was no difference between groups in time since last cigarette, the potentially circulating nicotine levels should have been low and the differential effects of nicotine on brain activation should be minimal. Note that contrasting with our previous study 
, we did not observe drug vs. neutral word activation differences in midbrain in the present study, probably reflecting the lack of monetary incentive conditions and the lower statistical power associated to the simplified version of the DW paradigm.
Summary: Using high-field (4 Tesla) fMRI, here we show that during processing of drug and matched neutral words cocaine abusers have similar accuracy and reaction times to matched controls, but lower BOLD and CM signals in the dorsal medial nucleus of the thalamus, cerebellum, and rostral anterior cingulate cortex. These findings suggest that lower recruitment of subcortical resources and impaired inhibition of cortical resources may be mediated by abnormal functional connectivity of catecholamine (dopamine, norepinephrine and serotonin) pathways in cocaine abusers. The negative correlation of the thalamic CM (and the lack of correlation with BOLD responses in the thalamus) with years of cocaine use suggests that functional connectivity might be more sensitive than standard fMRI activation techniques for the detection of subtle functional neuroadaptations associated with drug addiction.