Response inhibition and fronto-striatal-thalamic circuit dysfunction in cocaine addiction

Highlights

• Response inhibition is compromised in cocaine dependent people (CD).

• CD showed prolonged stop signal reaction time (SSRT), compared to controls (HC).

• ICA showed diminished engagement of the fronto-striatal-thalamic network in CD.

• The network engagement is associated with response inhibition in HC but not CD.

Abstract

Background

Many studies have investigated how cognitive control may be compromised in cocaine addiction. Here, we extend this literature by employing spatial Independent Component Analysis (ICA) to describe circuit dysfunction in relation to impairment in response inhibition in cocaine addiction.

Methods

Fifty-five cocaine-dependent (CD) and 55 age- and sex-matched non-drug-using healthy control individuals (HC) participated in the study. Task-relatedness of 40 independent components (ICs) was assessed using multiple regression analyses of component time courses with the modeled time courses of hemodynamic activity convolved with go success (GS), stop success (SS) and stop error (SE). This procedure produced beta-weights that represented the degree to which each IC was temporally associated with, or ‘engaged’, by each task event.

Results

Behaviorally, CD participants showed prolonged stop signal reaction times (SSRTs) as compared to HC participants (p < 0.01). ICA identified two networks that showed differences in engagement related to SS between CD and HC (p < 0.05, FDR-corrected). The activity of the fronto-striatal-thalamic network was negatively correlated with SSRTs in HC but not in CD, suggesting a specific role of this network in mediating deficits of response inhibition in CD individuals. In contrast, the engagement of the fronto-parietal-temporal network did not relate to SSRTs, was similarly less engaged for both SS and SE trials, and may reflect attentional dysfunction in cocaine addiction.

Conclusions

This study highlights the utility of ICA in identifying neural circuitry engagement related to SST performance and suggests that specific networks may represent important targets in remedying executive-control impairment in cocaine addiction.

Introduction

Cocaine addiction is a debilitating and relapsing disorder (McLellan et al., 2000; Yuferov et al., 2005). Previous work has suggested deficits in cognitive control as an etiological process of habitual drug use in cocaine addiction (Ersche et al., 2011; Garavan and Hester, 2007; Goldstein and Volkow, 2011). Cortical and subcortical dysfunction has been suggested in brain imaging studies of addiction to cocaine or other stimulants (Aron and Paulus, 2007; Goldstein and Volkow, 2011; Hanlon et al., 2009, 2011; Hester and Garavan, 2004; Kaufman et al., 2003; Moeller et al., 2005; Peters et al., 2016; Wesley et al., 2011; Zhang et al., 2018). The medial and lateral frontal cortical regions, in particular, have been repeatedly implicated in deficits of response inhibition in association with cocaine misuse (Connolly et al., 2012; Hester et al., 2013; Hester and Garavan, 2004; Lundqvist, 2010). For example, attenuated responses in executive-cortical regions during Go-NoGo task performance was observed in cocaine users (Kaufman et al., 2003). Striatal activation during performance of the Stroop color-word interference task was correlated with the drug-free rate of urine screen and longer duration of self-reported abstinence (Brewer et al., 2008). Combining Bayesian model of stop-signal-task (SST) performance and functional magnetic resonance imaging (fMRI), we highlighted a distinct role of the frontal-subcortical structures in Bayesian learning for goal-directed control and deficits in learning in cocaine dependent (CD) individuals (Hu et al., 2015a; Ide et al., 2014). Among individuals without and with addiction including to cocaine, impulsivity has been associated with smaller volumes in the hippocampus, amygdala, and insula (Yip et al., 2018). Deficits in goal-directed action control, particularly in situations that involve uncertain outcomes (Mirabella, 2014), represent a prominent feature of drug addiction. Together, these studies support structural and functional differences in cortical and subcortical regions in association with deficits in cognitive control and related constructs in cocaine addiction. Along with incentivized salient responses to drug cues (Berridge and O’Doherty, 2014; Berridge and Robinson, 2016; Chow et al., 2016; Hickey and Peelen, 2015; Mirabella et al., 2007), cognitive control dysfunction may perpetuate habitual drug use in cocaine-addicted individuals.

Functional connectivity analyses have identified regional interactions associated with cognitive dysfunction in neuropsychiatric populations. Cocaine dependence was related to altered functional interactions of the insula with the prefrontal cortex, suggesting the influence of interoceptive information on cognitive-control and decision-making processes (Cisler et al., 2013). Compulsive cocaine use was associated with decreased cortico-striatal and increased limbic-striatal resting-state functional connectivity (rsFC) (Hu et al., 2015b). Disrupted connectivity dynamics, as reflected by power spectrum scale invariance (PSSI) of cerebral blood oxygenation-level dependent (BOLD) signal, in fronto-parietal-temporal areas was related to compromised post-signal behavioral adjustment in CD individuals (Ide et al., 2016). Interhemispheric coupling of executive-control networks was weakened during early abstinence of cocaine use (McCarthy et al., 2017). Our recent study of dynamic functional connectivity study described a decrease in temporal flexibility of executive networks in CD as compared to non-drug-using control (HC) participants (Zhang et al., 2018). These studies suggest the importance of characterizing the functional network organization of cerebral activity in support of cognitive control and how these network activities are disrupted in cocaine addiction.

Independent component analysis (ICA) represents a useful tool to investigate functional network activity. A data-driven method, ICA uncovers hidden factors from a set of measurements such that the sources of the observed data are maximally independent (Calhoun and Adali, 2006; Calhoun et al., 2001a, 2002; Lange et al., 1999; McKeown et al., 2003, 1998). Applied to fMRI data, ICA is capable of identifying functionally integrated brain regions, or functional networks, through a decomposition of the BOLD signal into maximally independent systems displaying temporally synchronous activity. In contrast to the general linear modeling of BOLD signals, ICA demonstrates the advantage of uncovering task-related regions with concurrent but opposite changes in response to task events (Xu et al., 2015, 2016). ICA has been widely used to describe the cerebral functional organization. For instance, we recently employed ICA to understand how the thalamus is functionally parcellated according to connectivities with identified components (Zhang and Li, 2017). In previous studies, we applied ICA to fMRI data of the SST and characterized the component networks in response to go success, stop success and stop error trials (Zhang and Li, 2012) and how motor network activities may contribute to individual variation in the stop-signal-reaction time (SSRT) (Zhang et al., 2015b). We have also used ICA to identify networks linked to Stroop performance, cocaine addiction and its treatment (Worhunsky et al., 2013), reward and loss processing in cocaine addiction (Worhunsky et al., 2017), and Go-NoGo performance and drinking behaviors among college students (Worhunsky et al., 2016).

In this study, we used ICA to identify network engagement related to response inhibition during SST performance and aimed to characterize how CD and HC individuals may differ in circuitry recruitment. During SST performance, participants must override a prepotent motor response, monitor errors, and adjust the speed of responding after encountering an error (Duann et al., 2009; Hu et al., 2015a; Ide et al., 2013; Li et al., 2006b; Zhang and Li, 2012). The capacity of response inhibition is quantified by the SSRT, the time it requires for subjects to successfully inhibit a response half of the time, with a longer SSRT reflecting impairment in response inhibition. We examined the temporal profiles of the activity during different trial types and how CD and HC participants differed in engaging these component activities. Following our previous work on regional responses relating to stop-signal inhibition (Duann et al., 2009; Li et al., 2008), we hypothesized that a network involving fronto-parietal-subcortical circuits, including the thalamus and subthalamic nucleus, may be specifically engaged during stop success (SS) trials. In particular, as compared to HC individuals, CD individuals would display reduced SS-related engagement of this functional network.