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.

Introduction

Drug addiction is a serious public health problem that manifests as a compulsive drive to take the drug without regard to severe adverse consequences (Volkow and Li, 2005). Neuroimaging studies in drug dependent individuals have revealed significant alterations in brain structure (Franklin et al., 2002, Matochik et al., 2003), neurotransmitters (Goldstein and Volkow, 2002), metabolism (Volkow et al., 1993), functional activity (Kalivas & Volkow, 2005, Kaufman et al., 2003), and biochemistry (Li et al., 1999, Yang et al., 2009), notably in regions generally considered to be part of the brain's mesocorticolimbic (MCL) reward circuitry. These MCL components include the ventral tegmental area (VTA) and nucleus accumbens (NAcc), involved in responding to rewarding stimuli; the amygdala and hippocampus, involved in memory functions, especially related to learning cue and context associations; mediodorsal thalamus, an intermediary node linking midbrain and prefrontal cortex, and a key component of thalamo–cortico–basal ganglia circuits implicated in aberrant habit learning disorders; and prefrontal/orbitofrontal cortex (PFC/OFC) and anterior cingulate cortex (ACC), involved in emotional regulation, cognition and executive function, especially inhibitory control processes (Everitt and Robbins, 2005).

Cellular and molecular studies in animal models of drug dependence show enduring glutamatergic neuroadaptations in the PFC of rats following chronic cocaine administration, and such alterations appear to play a critical role in drug addiction and subsequent relapse to drug-seeking behavior (Baker et al., 2003). Electrophysiological recordings in rats trained to self-administer cocaine demonstrate significant decreases in the baseline, tonic firing of neurons in the NAcc (Hollander & Carelli, 2007, Peoples & Cavanaugh, 2003). While these and other studies have shown changes within individual MCL components following chronic drug administration, little is known about the consequences of these regional alterations on dynamic, functional interactions among and between MCL components and their projections in human chronic cocaine users. Noninvasive neuroimaging offers an important tool to investigate potential circuit level alterations in this disease.

Intrinsic, dynamic interactions between brain regions can be investigated using synchronized spontaneous fluctuations in the resting-state blood-oxygenation-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signal (Biswal et al., 1995). Brain functional connectivity maps in the absence of external stimulation have been observed, in awake humans and anesthetized monkeys and rodents, in specific brain circuits, including sensorimotor, visual, auditory, and the “default mode” system (Fox et al., 2005, Greicius et al., 2003, Lowe et al., 1998, Lu et al., 2007, Vincent et al., 2007, Xiong et al., 1999). Altered resting-state functional connectivity (rsFC) has been previously demonstrated in several brain disorders, including Alzheimer's disease (Li et al., 2002), schizophrenia (Liang et al., 2006), major depression (Greicius et al., 2007), epilepsy (Waites et al., 2006), and attention deficit hyperactivity disorder (Cao et al., 2009). Addiction related rsFC changes have recently been reported. Hong et al. (2009) reported rsFC between dorsal ACC and striatal regions that correlated negatively with severity of nicotine addiction. Ma et al. (2010) reported rsFC from MCL seeds in methadone maintained opiate addicts that indicated stronger connectivity in circuits involved in identifying salient stimuli and weaker connectivity in circuits involved in executive functioning.

While rsFC by definition does not involve task related activation, numerous studies have indicated a relationship between rsFC strength and activation during tasks involving that circuit (Hampson et al., 2006a,Hampson et al., 2006b, Kelly et al., 2008, Seeley et al., 2007). Based upon such a relationship, prominent theories of drug addiction suggest several testable rsFC hypotheses.

Koob and Le Moal (1997) propose that repeated drug use results in a shift in hedonic set point such that natural rewards are no longer sufficiently rewarding to motivate behavior and hyper-physiological drug-induced rewards are sought to provide sufficient stimulation to motivate behavior. Based on this theory, reduced rsFC from salience identifying and processing regions including VTA, NAcc, rACC, amygdala and hippocampus might be expected. However, Robinson and Berridge (1993) suggest that responses to drug-related stimuli become uniquely sensitized, implying that circuits involved in responding to cues, i.e., those involving VTA, NAcc, amygdala and rACC would show increased rsFC, although it is possible that the relatively limited number of cues that are sensitized, compared to the large number of cues for various non-drug rewards that confront people daily, might be insufficient to result in increased rsFC. More recent theories emphasizing over-learned habit formation (Di Chiara, 1999, Everitt & Robbins, 2005) would predict increases in circuits involving thalamo–cortico–basal ganglia loops. In addition, hypo-functioning in cognitive control regions, as posited by Jentsch & Taylor, 1999, Goldstein & Volkow, 2002 would predict decreased rsFC between prefrontal control regions such as ACC, dorsolateral PFC and medial PFC and areas involved in responding to drug cues such as VTA, NAcc, amygdala and rACC.

Based on the above, we hypothesized specific rsFC circuits related to the MCL system would be altered in chronic cocaine dependence and, as these changes are thought to relate to repeated exposure to cocaine and cocaine cues and to underlie addictive behaviors, we hypothesized that one or more of these circuits will be related to duration of use and/or intensity of use.