Altered functional connectivity of the insular cortex across prefrontal networks in cocaine addiction

Abstract

Interoception is theorized to be an important process mediating substance use disorders, and the insular cortex is recognized as a core neural region supporting interoception. The purpose of this study was to compare the integration of the insular cortex into prefrontal-related resting-state networks between individuals with cocaine dependence and healthy controls. Participants comprised 41 patients with cocaine dependence and 19 controls who underwent a resting-state 3-T functional magnetic resonance imaging scan. Individuals with cocaine dependence demonstrated altered functional connectivity of the insular cortex, predominantly the right insular cortex, with all eight prefrontal-related resting-state networks identified through Independent Component Analysis (ICA). A conjunction analysis demonstrated that the right insular cortex was the neural region with the highest number of common group differences across the networks. There was no evidence that insular cortex connectivity commonly differed between groups for non-prefrontal-related networks. Further, seed-based functional connectivity analyses extended the network analyses and indicated that cocaine dependence was associated with greater connectivity of the right insula with the dorsomedial prefrontal cortex, inferior frontal gyrus, and bilateral dorsolateral prefrontal cortex. These data support the hypothesis that cocaine dependence is related to altered functional interactions of the insular cortex with prefrontal networks. The results suggest possible neural mechanisms by which the insular cortex and interoceptive information influence cognitive control and decision-making processes presumably mediated by prefrontal networks in the cocaine dependence process.

Introduction

Cocaine use is associated with high rates of drug dependence, making cocaine dependence among the more prevalent substance use disorders (SAMHSA, 2010, Wagner and Anthony, 2002). Drug dependence is associated with conditioned incentive salience of drug-related cues, a process believed to be mediated by drug-induced sensitization of mesocorticolimbic systems (Robinson and Berridge, 2000, Robinson and Berridge, 2003, Robinson and Berridge, 2008). While incentive sensitization helps explain many aspects of drug dependence, additional core processes including cognitive control, response inhibition, and decision making are altered in drug dependence and theorized to increase the impact of incentive salience on decision making around drug use (Goldstein and Volkow, 2002, Robinson and Berridge, 2003). The combined views of incentive sensitization and cognitive control deficits posit that compulsive drug use results from increased response tendencies elicited by drug cues in tandem with decreased cognitive control ability to modulate these response tendencies. Here, we purposefully use the broad term ‘cognitive control’ to refer to the overarching key functional role of the prefrontal cortex: to control the coordination and biasing of information processing across distributed brain regions based on current context and goals (Miller and Cohen, 2001).

It has recently been proposed that interoception may play a key function in the drug use disorder process that integrates incentive salience with cognitive control and decision making processes (Naqvi and Bechara, 2009, Naqvi and Bechara, 2010, Naqvi et al., 2007). Interoception refers to the neural representation of hedonic bodily states (Craig, 2002), such as internal state changes related to pain, temperature, pleasure, craving, or withdrawal. According to one theory, interoception involves two major processes: neural representation of hedonic bodily states, and conscious/subjective awareness of these bodily states (Craig, 2002, Craig, 2009). These processes can be dissociated at the neural processing level, with the dorsal posterior insular cortex hypothesized to represent the actual changes in bodily states and the anterior insular cortex hypothesized to mediate subjective awareness of the bodily states (Craig, 2002, Craig, 2009, Craig et al., 2000). This hypothesized differential role of the posterior and anterior insular cortex is consistent with anatomical studies showing heterogeneous structural connectivity across the insular cortex (Augustine, 1996) and human neuroimaging studies showing heterogeneous activation and connectivity across the insular cortex (Craig, 2002, Craig, 2009, Deen et al., 2011, Nanetti et al., 2009). These differing patterns of functional and structural connectivity support differential integration of the anterior and posterior insula into large-scale neural networks. The neural substrates mediating interoception can be differentiated from neural substrates mediating the commonly theorized processes involved in drug use disorders: reward/valuation and cognitive control. Reward valuation involves a network of regions including the orbitofrontal cortex (OFC), basolateral amygdala, and ventral striatum (Goldstein and Volkow, 2002, Robinson and Berridge, 2001). Cognitive control is a more heterogeneous construct that involves several spatially and functionally distinct networks including the dorsolateral prefrontal cortex (PFC), ventrolateral PFC, anterior cingulate, and parietal cortex. For example, a network involving the dorsolateral PFC and anterior cingulate is commonly implicated in conflict monitoring and attentional control (Botvinick et al., 2001, Kerns et al., 2004), the inferior frontal gyrus (IFG), dorsal medial PFC and subthalamic nucleus are commonly implicated in response inhibition (Aron et al., 2003, Aron et al., 2004, Hampshire et al., 2010, Sharp et al., 2010), while regions within medial and ventral medial PFC (rostral and subgenual cingulate, medial PFC) are implicated in emotional control, salience attribution, and self-referential processing (Benoit et al., 2010, Etkin et al., 2006, Johnstone et al., 2007, Sajonz et al., 2010).

According to one recent model (Naqvi and Bechara, 2009), interoceptive processes mediate the relationship between incentive/motivational-related bodily changes associated with detecting drug cues and the disruption of on-going behavior in order to engage in drug use. Neurobiologically, the OFC and amygdala appear essential for detecting and processing the motivational significance of drug cues, the posterior insular cortex codes bodily changes associated with changes in motivational states, and the anterior insular cortex mediates subjective awareness of the craving state. This information is transmitted to the anterior cingulate cortex, dorsal lateral PFC, and likely also the IFG, that gate whether to maintain on-going behavior or disrupt it and engage in drug use (Naqvi and Bechara, 2009). From this model, it can be seen how interoceptive processes, either the degree of the representation of changes in craving states or the degree of subjective awareness of the craving state, can influence the subsequent control of behavior. Thus, the model predicts that drug dependence should be associated with altered functional connectivity of the insular cortex within cognitive control processes, and therefore, with prefrontal networks. Indeed, a substantive body of research links the insular cortex with cognitive control processes (Medford and Critchley, 2010, Menon and Uddin, 2010). For example, a prior study suggested that interactions between the right insular cortex and anterior cingulate cortex were critical for switching between default mode and cognitive control networks (Sridharan et al., 2008). Other regions implicate the anterior insula as critical in mediating uncertainty processing and tracking variance in risk (Behrens et al., 2007, Bossaerts, 2010, Preuschoff et al., 2008, Rushworth and Behrens, 2008). Findings such as these are consistent with one hypothesized role of the anterior insula in mediating awareness and salience detection (Craig, 2009) and highlights the integration of the insular cortex into cognitive control processes.

Given the predominant role of the prefrontal cortex in mediating cognitive control processes (Miller and Cohen, 2001), we focus analyses here on resting-state networks with peak loadings in the prefrontal cortex derived from Independent Component Analysis. Though a growing body of research is examining functional connectivity in drug use disorders (Ma et al., 2011), and cocaine dependence in particular (Camchong et al., 2011, Gu et al., 2010, Kelly et al., 2011, Tomasi et al., 2010, Wilcox et al., 2011), there have been no prior studies explicitly testing insular cortex connectivity.