GABAergic polygenic risk for cocaine use disorder is negatively correlated with precuneus activity during cognitive control in African American individuals
Introduction
Impaired control has been proposed as a central component in models of addiction (Brand et al., 2019, Goldstein and Volkow, 2011, Noël et al., 2013). The Stroop task assesses cognitive control (Botvinick & Cohen, 2014). Neural underpinnings of cognitive-control impairment in cocaine use disorder (CUD) and other substance use disorders (SUDs) have been suggested in Stroop-related fMRI studies (Garavan & Hester, 2007). Poor cognitive control may facilitate the development and progression of CUD, contribute to relapse (Garavan & Hester, 2007), and relate to poorer treatment outcomes (Streeter et al., 2008).
During Stroop performance, regional cognitive-control-related activations in cortical (e.g., ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC)), and subcortical (striatum, thalamus) have been linked to treatment outcomes in CUD (Brewer et al., 2008, DeVito, et al., 2017). With treatment, Stroop-related cortico-striatal activations become less pronounced in individuals with SUDs, including CUD, suggesting possible improved neural efficiency after treatment (DeVito et al., 2019, DeVito et al., 2012). Furthermore, cognitive impairment in CUD relating to Stroop performance may vary according to individual characteristics. For example, among CUD subjects with impaired insight, lower error-induced rostral anterior cingulate cortex (rACC) activity has been associated with more frequent cocaine use and lower levels of emotional awareness (Moeller et al., 2014).
Stroop-related circuits have also been linked to CUD and CUD-related treatment outcomes. CUD patients showed differences in Stroop-related network recruitment, with a fronto-cingular network associated with treatment retention and subcortical and ventral prefrontal networks related to abstinence during treatment (Worhunsky, 2013). Additionally, a fronto-parietal circuit that included the precuneus was linked to Stroop effects and reaction times differently in CUD and HC subjects (Worhunsky, 2013). More recent work has suggested a cocaine abstinence network initially identified using task-based reward processing data and more recently extended to Stroop data (Yip et al., 2019, Lichenstein, 2019) (Supplemental materials).
Genetic contributions to CUD are well established (Supplementary materials). Cognitive function is also substantially heritable; heritability estimates of cognitive control, inhibitory control, and response inhibition range from 0.38 to 0.60 (Gagne and Saudino, 2010, Macare et al., 2014, Anokhin et al., 2017). However, little is known regarding how CUD genetic risk influences brain activity (Supplemental material). A study investigating genetic influences of a single nucleotide polymorphism (SNP) at proenkephalin gene (PENK) on neural correlates of Stroop performance in CUD and HC subjects found a diagnosis-by-allele interaction that implicated neural responses to errors in the putamen, rACC/OFC, and inferior frontal gyrus, where neural activities were increased in CUD individuals carrying the higher risk allele (Moeller et al., 2015). Thus, genetic factors linked to CUD may influence brain mechanisms underlying poor cognitive control in CUD. However, such genetic factors have rarely been studied and not with respect to polygenic risk scores (PRSs), a potentially powerful new approach for targeting treatment development efforts for complex disorders (Gibson, 2019). This is particularly relevant for CUD, a complex condition for which no medication has a formal indication.
Augmenting GABAergic function has been proposed as a possible therapy for CUD (Johnson et al., 2013) that may ameliorate cognitive-control deficits (Filip et al., 2006, Sofuoglu and Kosten, 2006). GABAergic agents such as topiramate, tiagabine, baclofen, and vigabatrin have shown some promise in CUD treatment (Karila et al., 2008). Several lines of evidence support the development of GABAergic agents in treating CUD via restoring GABA system homeostasis and increasing cognitive control (Huang et al., 2011, Wang et al., 2018). Low GABA levels in PFC have been observed in CUD subjects (Ke et al., 2004). Cocaine may impact GABAergic systems in the PFC and subcortical regions and thus influence sensitization, craving and relapse processes (Hearing, Zink, & Wickman, 2012). Abnormal GABA levels and GABAergic inhibitory circuits have also been linked to impaired cognitive control (Silveri, 2013, van den Wildenberg et al., 2010), and lower GABA levels have been associated with greater impulsivity and poorer response inhibition (Silveri, 2013). GABAergic disruptions may be partially restored using GABAergic medications (Sofuoglu & Kosten, 2005). Taken together, data suggest that abnormal GABAergic function may underlie impaired cognitive control in CUD (Supplemental materials).
Impaired cognitive control in CUD has been hypothesized to be a consequence of cocaine misuse (Hearing et al., 2012, Cass et al., 2013). However, other studies suggest that impaired cognitive control may precede compulsive drug-seeking and drug-taking and accelerate the progression from experimentation to compulsive use (Belin et al., 2008, Homberg et al., 2014). Findings among discordant sib-pairs with and without stimulant dependence and unrelated healthy control subjects (HCs) suggest that poor cognitive control may run within vulnerable family members and not directly be caused by chronic drug misuse (Ersche et al., 2012, Smith, et al., 2013). Thus, pre-existing or genetic factors prior to substance use may contribute to impaired cognitive control in CUD.
Here, we aimed to identify GABAergic PRSs as related to CUD and apply this information in an independent sample to investigate relationships with neural correlates of cognitive control. We chose to focus on African Americans (AAs) because they are disproportionately impacted by CUD, and genetic predispositions are often population-specific. To identify genes of interest, we selected SNP variants mapped to the genes identified in GABAergic pathways and estimated relative risks of SNP variants with respect to CUD from a reference cohort of AAs in a genome-wide association study (GWAS) of CUD (Gelernter et al., 2014). In an independent AA fMRI case-control sample with genotypes from exome microarrays, we computed CUD-related GABAergic PRSs using the relative risks estimated from the reference cohort (Purcell, 2009). The PRS approach has been used to predict disease risk and facilitate interpretation of the genetic architecture of complex diseases (Evans, Visscher, & Wray, 2009).
We hypothesized that CUD subjects in the fMRI cohort would, on average, have higher GABAergic PRSs and that higher GABAergic PRSs would be related to lower brain activations during cognitive control processing in regions implicated in cognitive control in CUD (e.g., cingulate, frontal and parietal cortices, precuneus, striatum, and thalamus).
Section snippets
Subjects and ethics
Participants were recruited using advertisements and other established methods. The studies were reviewed by ethics committees at the participating universities, written informed consent was obtained after procedures had been fully explained, and procedures were conducted in accordance with the Declaration of Helsinki.
African American cohort for GABA-PRS (Reference Cohort)
The cohort for determining GABA-PRS included 3318 AA participants with SUDs (2482 subjects with cocaine dependence, with relates to moderate to severe CUD in DSM-5), as detailed
GABAergic PRSs
Among the five GABAergic PRSs for the fMRI cohort, only the PRS generated by the p-value threshold of 0.005 significantly distinguished CUD from HC subjects (p = 0.013, Fig. 2A). This PRS, designated as CUD-GABA-PRS, was higher in CUD relative to HC subjects (23.47 ± 0.84 versus 22.93 ± 1.08, p = 0.013). This CUD-GABA-PRS was generated using the relative risks from the association analysis for CUD in the large cohort with 89 SNPs (p-value < 0.005) from the 3309 SNPs identified in the GABAergic
Discussion
We identified among AA individuals elevated GABAergic PRSs linked to CUD using genetic variants extracted from genomewide-genotyped data. These PRSs were inversely associated with precuneus activation in an independent AA CUD sample during fMRI Stroop performance. Further, differential precuneus/PCC connectivity was observed between CUD and HC subjects. Our findings suggest that GABA-related genetic factors may relate to neural underpinnings of cognitive control in CUD. These findings provide a
Conclusions
We demonstrated that GABAergic PRSs relate to Stroop-related precuneus activity and connectivity in CUD by integrating two independent AA cohorts assessed through large-scale genetic screening and brain imaging. The findings extend pre-clinical reports of cocaine-related alterations in GABAergic neural function (Hearing et al., 2012, Kaufling, 2010), demonstrating for the first time GABAergic genetic links to neural correlates of cognitive control for individuals with CUD. Given that neural
Conflict of Interest
The authors report no conflicts of interest with respect to the content of this manuscript. Dr. Potenza has: consulted for and advised the Addiction Policy Forum, Game Day Data, AXA, Idorsia and Opiant/Lakelight Therapeutics; received research support from the Mohegan Sun Casino and the National Center for Responsible Gaming (now the International Center for Responsible Gaming); consulted for legal and gambling entities on issues related to impulse-control and addictive disorders; given
Acknowledgements and disclosures
Funding was provided by NIH grants K01 DA24758, R01 DA019039, R01 DA012849, R01 DA012690, R01 DA018647, R01 DA035058, K12 DA00167, P20 DA027844, R01DA039136, K01 DA042998, a Brain and Behavior Research NARSAD Young Investigator award (BZY), the Connecticut Council on Problem Gambling, and the Connecticut Mental Health Center. The funding agencies did not provide input or comment on the content of the manuscript, and the content of the manuscript reflects the contributions and thoughts of the
References (68)
- et al.
Heritability of brain activity related to response inhibition: A longitudinal genetic study in adolescent twins
International Journal of Psychophysiology
(2017) - et al.
Lower activation in the right frontoparietal network during a counting Stroop task in a cocaine-dependent group
Psychiatry Research: Neuroimaging
(2011) - et al.
The Interaction of Person-Affect-Cognition-Execution (I-PACE) model for addictive behaviors: Update, generalization to addictive behaviors beyond internet-use disorders, and specification of the process character of addictive behaviors
Neuroscience & Biobehavioral Reviews
(2019) - et al.
Pretreatment brain activation during stroop task is associated with outcomes in cocaine-dependent patients
Biological Psychiatry
(2008) - et al.
Developmental disruption of gamma-aminobutyric acid function in the medial prefrontal cortex by noncontingent cocaine exposure during early adolescence
Biological Psychiatry
(2013) - et al.
fMRI Stroop and behavioral treatment for cocaine-dependence: Preliminary findings in methadone-maintained individuals
Addictive Behaviors
(2019) - et al.
A preliminary study of the neural effects of behavioral therapy for substance use disorders
Drug and Alcohol Dependence
(2012) - et al.
Comparing GABA-dependent physiological measures of inhibition with proton magnetic resonance spectroscopy measurement of GABA using ultra-high-field MRI
NeuroImage
(2017) - et al.
Various GABA-mimetic drugs differently affect cocaine-evoked hyperlocomotion and sensitization
European Journal of Pharmacology
(2006) - et al.
Adenosine receptors and brain diseases: Neuroprotection and neurodegeneration
Biochimica et Biophysica Acta (BBA) – Biomembranes
(2011)
Cocaine-induced homeostatic regulation and dysregulation of nucleus accumbens neurons
Behavioural Brain Research
gamma-Aminobutyric acid cells with cocaine-induced DeltaFosB in the ventral tegmental area innervate mesolimbic neurons
Biological Psychiatry
Frontal lobe GABA levels in cocaine dependence: A two-dimensional, J-resolved magnetic resonance spectroscopy study
Psychiatry Research: Neuroimaging
Pharmacogenetic Randomized Trial for Cocaine Abuse: Disulfiram and Dopamine β-Hydroxylase
Biological Psychiatry
Preliminary findings on the heritability of the neural correlates of response inhibition
Biological Psychology
Effects of an opioid (proenkephalin) polymorphism on neural response to errors in health and cocaine use disorder
Behavioural Brain Research
A neurocognitive approach to understanding the neurobiology of addiction
Current Opinion in Neurobiology
Posterior cingulate cortex: Adapting behavior to a changing world
Trends in Cognitive Sciences
PLINK: A tool set for whole-genome association and population-based linkage analyses
American Journal of Human Genetics
Frontal lobe gamma-aminobutyric acid levels during adolescence: Associations with impulsivity and response inhibition
Biological Psychiatry
Fronto-parietal network: Flexible hub of cognitive control
Trends in Cognitive Sciences
Data quality control in genetic case-control association studies
Nature Protocols
High impulsivity predicts the switch to compulsive cocaine-taking
Science
The computational and neural basis of cognitive control: Charted Territory and New Frontiers
Cogn Sci
Complex brain networks: Graph theoretical analysis of structural and functional systems
Nature Reviews Neuroscience
Resting GABA concentration predicts inhibitory control during an auditory Go-Nogo task
Experimental Brain Research
Frontoparietal cortical networks for directing attention and the eye to visual locations: Identical, independent, or overlapping neural systems?
Proceedings of the National Academy of Sciences of the United States of America
Structural and functional connectivity of the precuneus and thalamus to the default mode network: Precuneus-Thalamus Connectivity to the DMN
Human Brain Mapping
Abnormal Brain Structure Implicated in Stimulant Drug Addiction
Science
Assessing the impact of population stratification on genetic association studies
Nature Genetics
Wait For It! A twin study of inhibitory control in early childhood
Behavior Genetics
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