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

“courses from grey matter voxels following segmentation using FSL (Smith et al., 2004) and using restricted maximum likelihood to account for autocorrelation.”

“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.”

“Component 2 was consistent with the default mode network (Raichle et al., 2001).”

“Image preprocessing followed standard steps and was completed using AFNI (Cox, 1996) software.”

“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 (Ar…”

“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.”

“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, 2009).”

“Indeed, a substantive body of research links the insular cortex with cognitive control processes (Medford and Critchley, 2010; Menon and Uddin, 2010).”

“Networks identified during resting-state scans correspond to both task-related patterns of activations (Smith et al., 2009) and structural connectivity pathways (van den Heuvel et al.”

“We implemented the infomax algorithm for ICA within the widely used Group Independent Component Analyses for fMRI Toolbox (GIFT (Calhoun et al., 2001)).”

“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 (Ar…”

“Prevailing theories posit that two processes are largely responsible for mediating drug use disorders: heightened motivational/incentive salience of drug cues and decreased cognitive control ability to modulate response tendencies elicited by drug cues (Garavan and Hester, 2007; Goldstein and Volkow, 2002; Robinson an…”

“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).”

“Thus, resting-state functional connectivity is theorized to indicate intrinsic functional connectivity pathways (Deco et al., 2011) and is ideally suited for testing hypotheses about altered intrinsic (i.”

“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 (Cr…”

“Drug dependence is associated with conditioned incentive salience of drug-related cues, a process believed to be mediated by druginduced sensitization of mesocorticolimbic systems (Robinson and Berridge, 2000, 2003, 2008).”

“Drug dependence is associated with conditioned incentive salience of drug-related cues, a process believed to be mediated by druginduced sensitization of mesocorticolimbic systems (Robinson and Berridge, 2000, 2003, 2008).”

“, 2004), the inferior frontal gyrus (IFG), dorsal medial PFC and subthalamic nucleus are commonly implicated in response inhibition (Aron et al., 2003, 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 e…”

“This interpretation is consistent with the disruption of nicotine dependence in individuals following insula damage (Naqvi et al., 2007).”

“Independent Component Analysis (ICA) is a blind source separation technique (Calhoun et al., 2009) first applied to neuroimaging by and McKeown 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 selfreferential processing (Benoit et al., 2010; Etkin et al., 2006; Johnstone et al., 2007; Sajonz et al., 2010).”

“These lesion effect findings are consistent with prior imaging studies demonstrating insular cortex activation among individuals with substance use disorders in drug cue-induced craving studies (Garavan et al., 2000; Kilts et al., 2004).”

“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).”

“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).”

“Prior investigations of the insular cortex functional connectivity among healthy populations demonstrated that both the anterior insular cortex (including both ventral and dorsal anterior insula) were connected with cognitive control regions, including dorsal ACC and lateral PFC (Taylor et al., 2009; Cauda et al., 201…”

“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).”

“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).”

“That is, the insular cortex is functionally heterogeneous (Craig, 2002, 2009; Deen et al., 2011; Jonides et al., 1998), and the observed diminished functional connectivity of the anterior/mid-insula with the dorsal posterior insula suggests poorer ability to integrate information between different regions of the insul…”

“Prior investigations of the insular cortex functional connectivity among healthy populations demonstrated that both the anterior insular cortex (including both ventral and dorsal anterior insula) were connected with cognitive control regions, including dorsal ACC and lateral PFC (Taylor et al., 2009; Cauda et al., 201…”

“Indeed, a substantive body of research links the insular cortex with cognitive control processes (Medford and Critchley, 2010; Menon and Uddin, 2010).”

“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, 2010; Naqvi et al., 2007).”

“That is, the insular cortex is functionally heterogeneous (Craig, 2002, 2009; Deen et al., 2011; Jonides et al., 1998), and the observed diminished functional connectivity of the anterior/mid-insula with the dorsal posterior insula suggests poorer ability to integrate information between different regions of the insul…”

“, 2004), the inferior frontal gyrus (IFG), dorsal medial PFC and subthalamic nucleus are commonly implicated in response inhibition (Aron et al., 2003, 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 e…”

“Prevailing theories posit that two processes are largely responsible for mediating drug use disorders: heightened motivational/incentive salience of drug cues and decreased cognitive control ability to modulate response tendencies elicited by drug cues (Garavan and Hester, 2007; Goldstein and Volkow, 2002; Robinson an…”

“, 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.”

“These lesion effect findings are consistent with prior imaging studies demonstrating insular cortex activation among individuals with substance use disorders in drug cue-induced craving studies (Garavan et al., 2000; Kilts et al., 2004).”

“, 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.”

“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.”

“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).”

“, 2010), while regions within medial and ventral medial PFC (rostral and subgenual cingulate, medial PFC) are implicated in emotional control, salience attribution, and selfreferential processing (Benoit et al., 2010; Etkin et al., 2006; Johnstone et al., 2007; Sajonz et al., 2010).”

“, 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.”

“, 2003, 2004) and cognitive conflict/error monitoring (Botvinick et al., 2001; Kerns et al., 2004; Modirrousta and Fellows, 2008).”

“, 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.”

“, 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.”

“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 (Cr…”

“, 2007) and the automatic nature of the attentional bias effect for drug use reminders in individuals with cocaine use disorders (Liu et al., 2011).”

“Individuals with cocaine dependence show a greater connectivity between insula and the frontal control network (Cisler et al., 2013) and less connectivity to the salience network (Albein-Urios et al., 2013).”

“Orexins in the mPFC: role in ethanol seeking and stress-induced relapse The mPFC has been known to regulate seeking behaviour for most drugs of abuse including cocaine (Pietro et al., 2008; Pentkowski et al., 2010; Chen et al., 2013a; Cisler et al., 2013) and ethanol (George et al.”

“, 2003) and connectivity (Cisler et al., 2013; McHugh et al., 2013; Wisner et al., 2013) in CD are common in the literature.”

“…is anatomically connected to ACC (Deen et al. 2011; Naqvi et al. 2014), centrally situated in the salience network (Menon 2011), a circuit critical for switching between DMN and ECN acti- vation in the decision whether to maintain ongoing behavior (Sutherland et al. 2012; Cisler et al. 2013).”

“Age (median, range) 35 (22–61) 36 (20–59) 35 (22–57) 35 (20–61) Race White 56 (76) 37 (80) 47 (70) 140 (75) Mixed race 7 (9) 4 (9) 8 (12) 19 (10) African American 5 (7) 0 4 (6) 9 (5) Other (filled in ethnicity) 2 (3) 1 (2) 6 (9) 9 (5) Native American 3 (4) 3 (7) 2 (3) 8 (4) Asian 1 (1) 1 (2) 0 2 (1) Ethnicity: Hispani…”

“Given the observed arousal dysregulation in neonates with PCE, we hypothesized that PCE-related alterations in brain connectivity would also be present, particularly between the areas of the amygdala/insula and prefrontal cortex (PFC; Cisler et al., 2013; Li et al., 2013).”

“network (Camchong et al., 2011; Cisler et al., 2013; Wisner et al., 2013) and striatal-frontal circuits (Hu et al.”

“The patterns of increased interconnectivity between dlPFC and other prefrontal regions, particularly ACC, are strikingly similar to those found in cocaine-dependent adults (Camchong et al., 2011; Cisler et al., 2013).”

“Cocaine users show aberrant rsFC of key regions in the salience network with other cortical regions involved in decision making compared to controls (Cisler et al., 2013).”

“…differences in fronto-striatal regions in PG have also been found in executive function tasks and been commonly interpreted as reflecting impairments in cognitive control and inhibitory functions (Potenza et al., 2003) which contribute to maladaptive decision making in PG, comparable to…”

“In contrast, the present study, and the one other study demonstrating insula and striatal abnormalities in cocaine users (63) employed ICA to derive networks across voxels, and then a priori selection of networks for analysis.”

“To explore the effects of frontopolar multifocal anodal tDCS on inter‐network connectivity, we conducted independent component analysis (ICA) of resting‐state data using published methods (Supplemental Materials) (Calhoun et al., 2001; Cisler et al., 2013, 2019).”

“…studies have provided evidence for significant changes in neural activity across brain regions in cocaine users (Li et al., 2000; Gu et al., 2010; Ma et al., 2010, 2011; Kelly et al., 2011; Cisler et al., 2013; Konova et al., 2013; McHugh et al., 2013, 2014; Camchong et al., 2014; Hu et al., 2015).”

“Our findings add to mounting evidence that the insula plays a central role in addictive behavior (Cisler et al., 2013; Goldstein et al., 2009; McHugh et al., 2013; Naqvi et al., 2014; Noel et al., 2013a; Sutherland et al., 2012; Viswanath et al., 2015; Volkow and Baler, 2015; Wisner et al., 2013; Zhang et al., 2015),…”

“The insula would appear to intervene in the conscious urge to take drugs, due to its role in integrating homeostatic feelings and conscious decision-making (Cisler et al., 2013; Naqvi et al., 2014).”

“This is consistentwith theproposal that the IC is a key brain area modulating the disrupting nature of interoceptive cues on choice processes involved in drug use and relapse (Cisler et al., 2013; Naqvi and Bechara, 2009, 2010; Volkow and Baler, 2014).”

“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).”

“[27] 41 CDs and 19 CTLs ICA and CCA with R ventral anterior insula, R mid-insula as seeds ● CDs had greater rsFC between R ventral anterior insula and R IFG and dorsomedial PFC.”

“2019), and in substance use disorders (Cisler et al. 2013; Ma et al. 2018).”

“Together, these and many other studies highlighted changes in functional connectivity during resting or task challenges in cocaine misuse (Adinoff et al., 2015; Albein-Urios et al., 2014; BarrosLoscertales et al., 2011; Caldwell et al., 2015; Cisler et al., 2013; Hu et al., 2015c; Konova et al., 2015; Ma et al., 2014;…”

“, 2020) and other studies (Cisler et al., 2013; Jung et al., 2019), the required number of ICs that could best explain the total variance of the fMRI data was estimated with a minimum description length (MDL) criterion (Li et al.”

“Some studies (Cisler et al. 2013; Han et al. 2015a; Zhang et al. 2015) showed increased functional connectivity of insula-based network in IGD or cocaine addiction, The present and some other studies (McHugh et al.”

“A handful of resting state cocaine studies have also examined functional connectivity between frontal and limbic brain areas (Cisler et al., 2013; Gu et al., 2010; Verdejo-Garcia et al., 2012; Wilcox et al., 2011) as cocaine addiction is characterized by persistent decision-making deficits, which…”

“These deficits might be related to altered connectivity of the right insula to the dorsomedial PFC, inferior frontal gyrus, and DLPFC in cocaine-dependent subjects (55).”

“, 1999), and RSFC of the right insula with prefrontal networks is greater in cocaine addicts than controls (Cisler et al., 2013).”

“Some of the most significant hyperconnections included connections between FPC and VAN as well as between VIS and DAN.”

“Furthermore, recent work showed altered functional and effective connectivity of prefrontal, cingulate and subcortical structures during cognitive challenges in cocaine abusers (Cisler et al., 2013; Ma et al., 2015; Zhang et al., 2014).”

“We characterized six task-related networks with independent component analysis of fMRI data of a stop signal task and employed MVPA to distinguish CD from HC on the basis of voxel-wise thalamic connectivity to the six independent components.”

“Functional MRI studies have established that reduction in neural connectivity of the PFC is associated with maladaptive decision making (107) and cognitive control (108).”

“ur finding of heightened insula reactivity among adolescents ith PCE who experiment with drugs-of-abuse raise the possiility that neurodevelopmental factors might contribute to the nsular cortex alterations observed in adults with cocaine dependnce (Potenza et al., 2012; Cisler et al., 2013; McHugh et al., 2013; atel…”

“Functional connectivity has been examined in cocaine users in resting-state (Gu et al., 2010; Wilcox et al., 2011; Cisler et al., 2013; Ray et al., 2015a) and also when they performed tasks (a finger-tapping and an attention task; Tomasi et al., 2010; Hanlon et al., 2011).”

“Correlations in spontaneous resting state activity between specific regions of the cortex and limbic subcortical areas are impacted by drug abuse and are altered in volunteers dependent on alcohol, cocaine, cannabis or heroin [22].”

“…healthy adults [Cocchi et al., 2013; Ham et al., 2013], tracks with development across adolescence and early adulthood [Vink et al., 2014], in children with autism [Lesh et al., 2013; Ambrosino et al., 2014], among individuals with substance use disorders [Cisler et al., 2013; Mitchell et al., FIG.”

“…the insula, increased connectivity between the insula and frontal cortical regions is also associated with cocaine dependence, suggesting that the Ins can convey interoceptive information to influence cognitive control and decision-making processes presumably mediated by prefrontal networks (61).”

“Apart from the reward circuitry, users of cocaine demonstrated altered FC between vital regions in the salience network and cortical regions (involved in decision making) (33); and within cortical brain areas involved with executive control (such as the cognitive control and attentional salience networks) (30, 33).”

“Furthermore, insula (Naqvi & Bechara, 2009) and dPFC (Cisler et al., 2013) disruption is also implicated in addiction.”

“These systems include: (a) the impulsive system, which is implicated in rewards and learned associations; it includes temporal cortex lesions involving the amygdala and basal ganglia lesions specifically involving the ventral striatum; (b) the reflective system, which is implicated in decision making; it includes the…”

“Research has established that altered functional interactions of the aINS with prefrontal networks can result in elevated substance use (Cisler et al., 2013).”

“26 Moreover, altered functional connectivity of the IC has been observed in cocaine-dependent patients 27 and during opioid withdrawal, 28 providing additional evidence for a correlation between drug cravings and alterations in the neural circuits of the IC.”

“…et al., 2006; Martinez et al., 2007; Volkow et al., 2011) and described altered VS and DS activation during cognitive challenges in individuals with drug addiction, including cocaine addiction (Cisler et al., 2013; Ding and Lee, 2013; Konova et al., 2013; Vaquero et al., 2017; Zhang and Li, 2018).”

“In this sense, one possible methodological approach able to capture alterations in cognitive control networks is independent component analysis (ICA), which has been used in the past to identify and evaluate networks mainly involving frontal regions [15].”

“, 1997), and which are well-established to impart long-lasting changes to neural integrity (e.g. Barrós-Loscertales et al., 2011; Cisler et al., 2013; Ma et al., 2015; Beard et al., 2019).”

“Subsequent studies have repeatedly demonstrated reduced grey matter volume and functional alterations in the bilateral insula and especially the right AIC in acute and prolonged cocaine use (Cisler et al., 2013; Garavan et al., 2008; Geng et al., 2017).”

“This is supported by a growing number of neuroimaging studies which show that neural communication between distant regions is impaired in conditions such as a mental health disorders or neurodegenerative diseases [14], [38], or due to aging processes [7], [41].”

“Similar to prior studies that employed ICA [26, 56, 69, 71], the optimal number of ICs that could accurately account for the total variance of the fMRI data was determined using the minimum description length criterion [77].”

“Using seed-based RSFC, we showed that ATSAs had altered functional connectivity between the posterior insular and medial prefrontal cortex, in line with the hypothesis that cocaine dependence is related to an altered functional interaction of the insular cortex with prefrontal networks [78].”

“Functional connectivity has been examined in current cocaine users in the resting state [25-28] as well as while they performed a finger-tapping and an attention task [22,29].”