José Miguel Martínez-González

Comparison of impulsivity and working memory in cocaine addiction and pathological gambling : implications for cocaine-induced neurotoxicity

BACKGROUND The aim of this study was to compare the cognitive performance of cocaine dependent individuals (CDI) with that of pathological gamblers (PG). Cocaine dependence and pathological gambling share neurobiological vulnerabilities related to addiction, but PG are relatively free of the toxic consequences, such that any additional deficits observed in CDI may be interpreted as pertaining to specific drug effects. METHODS We used a case-control observational design contrasting multiple measures of impulsivity (UPPS-P trait impulsivity, delay discounting) and executive measures of response inhibition (Stroop) and working memory performance (N-back) between groups of CDI (n=29), PG (n=23), and healthy controls (n=20). We conducted one-way ANOVAs, followed by planned pairwise tests and calculations of Cohens d to estimate significant differences between the groups. RESULTS CDI, as compared to PG, had elevated scores on UPPS-P Negative Urgency and poorer performance on working memory (2-back). PG had steeper delay-discounting rates. Both groups had elevated Positive Urgency and poorer Stroop inhibition compared to controls. Peak amount of cocaine use was negatively correlated with working memory and response inhibition performance. CONCLUSION We found cocaine-related specific elevations in Negative Urgency and working memory deficits, putatively identified as cocaine neurotoxicity effects. Other aspects of impulsivity (Positive Urgency, Stroop inhibition) were increased across CDI and PG groups and may reflect vulnerability factors for addiction.

Re-appraisal of negative emotions in cocaine dependence: dysfunctional corticolimbic activation and connectivity.

Cocaine dependence is associated with pronounced elevations of negative affect and deficient regulation of negative emotions. We aimed to investigate the neural substrates of negative emotion regulation in cocaine‐dependent individuals (CDI), as compared to non‐drug‐using controls, using functional magnetic resonance imaging (fMRI) during a re‐appraisal task. Seventeen CDI abstinent for at least 15 days and without other psychiatric co‐morbidities and 18 intelligence quotient‐matched non‐drug‐using controls participated in the study. Participants performed the re‐appraisal task during fMRI scanning: they were exposed to 24 blocks of negative affective or neutral pictures that they should Observe (neutral pictures), Maintain (sustain the emotion elicited by negative pictures) or Suppress (regulate the emotion elicited by negative pictures through previously trained re‐appraisal techniques). Task‐related activations during two conditions of interest (Maintain>Observe and Suppress>Maintain) were analyzed using the general linear model in SPM8 software. We also performed psychophysiological interaction (PPI) seed‐based analyses based on one region from each condition: the dorsolateral prefrontal cortex (dlPFC—Maintain>Observe) and the inferior frontal gyrus (IFG—Suppress>Maintain). Results showed that cocaine users had increased right dlPFC and bilateral temporoparietal junction activations during Maintain>Observe, whereas they showed decreased right IFG, posterior cingulate cortex, insula and fusiform gyrus activations during Suppress>Maintain. PPI analyses showed that cocaine users had increased functional coupling between the dlPFC and emotion‐related regions during Maintain>Observe, whereas they showed decreased functional coupling between the right IFG and the amygdala during Suppress>Maintain. These findings indicate that CDI have dysfunctional corticolimbic activation and connectivity during negative emotion experience and re‐appraisal.

Negative urgency, disinhibition and reduced temporal pole gray matter characterize the comorbidity of cocaine dependence and personality disorders ☆

BACKGROUND Individuals with cocaine dependence and co-occurring personality disorders are more likely to have increased impulsivity, dysfunctional beliefs, executive dysfunction and brain structural abnormalities by virtue of the conjoint impact of both pathologies. METHODS We recruited 32 cocaine dependent patients with comorbid Cluster B personality disorders, 44 cocaine dependent patients without comorbidities and 34 non-drug-using controls. They completed the UPPS-P impulsivity scale, the Personality Belief Questionnaire, and executive function tests of working memory, attention/response inhibition and shifting. A subsample (n=61) was also scanned using Magnetic Resonance Imaging. We used univariate ANOVAs for group comparisons, and tested the association between impulsivity, executive control and personality dysfunction and diagnoses using correlation and multivariate logistic regression analyses. RESULTS Cocaine dependent patients with personality disorders had elevated negative urgency and borderline beliefs, decreased inhibition and attention regulation, and reduced temporal pole gray matter with respect to the rest of the sample. Trait and cognitive measures correctly classified 73% of comorbid patients (60% sensitivity and 82% specificity). CONCLUSION The co-occurrence of cocaine dependence and personality disorders is associated with negative-mood impulsivity and beliefs, executive dysfunction and temporal pole attrition.

Neural substrates of cognitive flexibility in cocaine and gambling addictions

BACKGROUND Individuals with cocaine and gambling addictions exhibit cognitive flexibility deficits that may underlie persistence of harmful behaviours. AIMS We investigated the neural substrates of cognitive inflexibility in cocaine users v. pathological gamblers, aiming to disambiguate common mechanisms v. cocaine effects. METHOD Eighteen cocaine users, 18 pathological gamblers and 18 controls performed a probabilistic reversal learning task during functional magnetic resonance imaging, and were genotyped for the DRD2/ANKK Taq1A polymorphism. RESULTS Cocaine users and pathological gamblers exhibited reduced ventrolateral prefrontal cortex (PFC) signal during reversal shifting. Cocaine users further showed increased dorsomedial PFC (dmPFC) activation relative to pathological gamblers during perseveration, and decreased dorsolateral PFC activation relative to pathological gamblers and controls during shifting. Preliminary genetic findings indicated that cocaine users carrying the DRD2/ANKK Taq1A1+ genotype may derive unique stimulatory effects on shifting-related ventrolateral PFC signal. CONCLUSIONS Reduced ventrolateral PFC activation during shifting may constitute a common neural marker across gambling and cocaine addictions. Additional cocaine-related effects relate to a wider pattern of task-related dysregulation, reflected in signal abnormalities in dorsolateral and dmPFC.

Cocaine use severity and cerebellar gray matter are associated with reversal learning deficits in cocaine-dependent individuals.

Cocaine addiction involves persistent deficits to unlearn previously rewarded response options, potentially due to neuroadaptations in learning‐sensitive regions. Cocaine‐targeted prefrontal systems have been consistently associated with reinforcement learning and reversal deficits, but more recent interspecies research has raised awareness about the contribution of the cerebellum to cocaine addiction and reversal. We aimed at investigating the link between cocaine use, reversal learning and prefrontal, insula and cerebellar gray matter in cocaine‐dependent individuals (CDIs) varying on levels of cocaine exposure in comparison with healthy controls (HCs). Twenty CDIs and 21 HCs performed a probabilistic reversal learning task (PRLT) and were subsequently scanned in a 3‐Tesla magnetic resonance imaging scanner. In the PRLT, subjects progressively learn to respond to one predominantly reinforced stimulus, and then must learn to respond according to the opposite, previously irrelevant, stimulus‐reward pairing. Performance measures were errors after reversal (reversal cost), and probability of maintaining response after errors. Voxel‐based morphometry was conducted to investigate the association between gray matter volume in the regions of interest and cocaine use and PRLT performance. Severity of cocaine use correlated with gray matter volume reduction in the left cerebellum (lobule VIII), while greater reversal cost was correlated with gray matter volume reduction in a partially overlapping cluster (lobules VIIb and VIII). Right insula/inferior frontal gyrus correlated with probability of maintaining response after errors. Severity of cocaine use detrimentally impacted reversal learning and cerebellar gray matter.

Increased corticolimbic connectivity in cocaine dependence versus pathological gambling is associated with drug severity and emotion-related impulsivity.

Neural biomarkers for the active detrimental effects of cocaine dependence (CD) are lacking. Direct comparisons of brain connectivity in cocaine‐targeted networks between CD and behavioural addictions (i.e. pathological gambling, PG) may be informative. This study therefore contrasted the resting‐state functional connectivity networks of 20 individuals with CD, 19 individuals with PG and 21 healthy individuals (controls). Study groups were assessed to rule out psychiatric co‐morbidities (except alcohol abuse and nicotine dependence) and current substance use or gambling (except PG). We first examined global connectivity differences in the corticolimbic reward network and then utilized seed‐based analyses to characterize the connectivity of regions displaying between‐group differences. We examined the relationships between seed‐based connectivity and trait impulsivity and cocaine severity. CD compared with PG displayed increased global functional connectivity in a large‐scale ventral corticostriatal network involving the orbitofrontal cortex, caudate, thalamus and amygdala. Seed‐based analyses showed that CD compared with PG exhibited enhanced connectivity between the orbitofrontal and subgenual cingulate cortices and between caudate and lateral prefrontal cortex, which are involved in representing the value of decision‐making feedback. CD and PG compared with controls showed overlapping connectivity changes between the orbitofrontal and dorsomedial prefrontal cortices and between amygdala and insula, which are involved in stimulus–outcome learning. Orbitofrontal–subgenual cingulate cortical connectivity correlated with impulsivity and caudate/amygdala connectivity correlated with cocaine severity. We conclude that CD is linked to enhanced connectivity in a large‐scale ventral corticostriatal–amygdala network that is relevant to decision making and likely to reflect an active cocaine detrimental effect.

Cocaine‐specific neuroplasticity in the ventral striatum network is linked to delay discounting and drug relapse

AIMS To contrast functional connectivity on ventral and dorsal striatum networks in cocaine dependence relative to pathological gambling, via a resting-state functional connectivity approach; and to determine the association between cocaine dependence-related neuroadaptations indexed by functional connectivity and impulsivity, compulsivity and drug relapse. DESIGN Cross-sectional study of 20 individuals with cocaine dependence (CD), 19 individuals with pathological gambling (PG) and 21 healthy controls (HC), and a prospective cohort study of 20 CD followed-up for 12 weeks to measure drug relapse. SETTING AND PARTICIPANTS CD and PG were recruited through consecutive admissions to a public clinic specialized in substance addiction treatment (Centro Provincial de Drogodependencias) and a public clinic specialized in gambling treatment (AGRAJER), respectively; HC were recruited through community advertisement in the same area in Granada (Spain). MEASUREMENTS Seed-based functional connectivity in the ventral striatum (ventral caudate and ventral putamen) and dorsal striatum (dorsal caudate and dorsal putamen), the Kirby delay-discounting questionnaire, the reversal-learning task and a dichotomous measure of cocaine relapse indicated with self-report and urine tests. FINDINGS CD relative to PG exhibit enhanced connectivity between the ventral caudate seed and subgenual anterior cingulate cortex, the ventral putamen seed and dorsomedial pre-frontal cortex and the dorsal putamen seed and insula (P≤0.001, kE=108). Connectivity between the ventral caudate seed and subgenual anterior cingulate cortex is associated with steeper delay discounting (P≤0.001, kE=108) and cocaine relapse (P≤0.005, kE=34). CONCLUSIONS Cocaine dependence-related neuroadaptations in the ventral striatum of the brain network are associated with increased impulsivity and higher rate of cocaine relapse.

Cocaine users with comorbid Cluster B personality disorders show dysfunctional brain activation and connectivity in the emotional regulation networks during negative emotion maintenance and reappraisal

Cocaine dependence often co-occurs with Cluster B personality disorders. Since both disorders are characterized by emotion regulation deficits, we predicted that cocaine comorbid patients would exhibit dysfunctional patterns of brain activation and connectivity during reappraisal of negative emotions. We recruited 18 cocaine users with comorbid Cluster B personality disorders, 17 cocaine users without comorbidities and 21 controls to be scanned using functional magnetic resonance imaging (fMRI) during performance on a reappraisal task in which they had to maintain or suppress the emotions induced by negative affective stimuli. We followed region of interest (ROI) and whole-brain approaches to investigate brain activations and connectivity associated with negative emotion experience and reappraisal. Results showed that cocaine users with comorbid personality disorders had reduced activation of the subgenual anterior cingulate cortex during negative emotion maintenance and increased activation of the lateral orbitofrontal cortex and the amygdala during reappraisal. Amygdala activation correlated with impulsivity and antisocial beliefs in the comorbid group. Connectivity analyses showed that in the cocaine comorbid group the subgenual cingulate was less efficiently connected with the amygdala and the fusiform gyri and more efficiently connected with the anterior insula during maintenance, whereas during reappraisal the left orbitofrontal cortex was more efficiently connected with the amygdala and the right orbitofrontal cortex was less efficiently connected with the dorsal striatum. We conclude that cocaine users with comorbid Cluster B personality disorders have distinctive patterns of brain activation and connectivity during maintenance and reappraisal of negative emotions, which correlate with impulsivity and dysfunctional beliefs.

Executive functions in cocaine-dependent patients with cluster B and cluster C personality disorders

OBJECTIVE Cocaine dependence often co-occurs with personality disorders from Clusters B and C, which are inherently associated with some of the executive dysfunctions found in addiction. We address the question of whether the comorbidity between cocaine dependence and different types of personality disorders is associated with differential profiles of executive deficits compatible with their personality dysfunction. We predicted that the comorbidity with Cluster B disorders would be associated with inhibition and shifting deficits, whereas the comorbidity with Cluster C disorders would be associated with working memory deficits. METHOD We tested 107 participants (22 cocaine users with Cluster B disorders, 15 cocaine users with Cluster C disorders, 36 cocaine users without comorbidities, and 34 controls) using tests of working memory, attention, inhibition, and shifting. Groups were statistically matched on IQ and had no Axis I comorbidities (other than substance-related). Based on the performance of the control group, we obtained z-score composite measures of working memory, attention/inhibition, shifting, and global executive impairment. We tested group differences in these composite measures using univariate analyses of variance and Sidak tests corrected for multiple comparisons. RESULTS Cocaine users with Cluster B disorders had poorer attention/inhibition, whereas cocaine users with comorbid Cluster C disorders had poorer working memory. Cluster B and noncomorbid cocaine users (but not Cluster C users) differed from controls on the global executive impairment measure. CONCLUSION The comorbidity between cocaine dependence and personality disorders from Clusters B and C is associated with executive function deficits that are compatible with their respective personality dysfunctions.

Prefrontal Gray Matter and Motivation for Treatment in Cocaine-Dependent Individuals with and without Personality Disorders

Addiction treatment is a long-term goal and therefore prefrontal–striatal regions regulating goal-directed behavior are to be associated with individual differences on treatment motivation. We aimed at examining the association between gray matter volumes in prefrontal cortices and striatum and readiness to change at treatment onset in cocaine users with and without personality disorders. Participants included 17 cocaine users without psychiatric comorbidities, 17 cocaine users with Cluster B disorders, and 12 cocaine users with Cluster C disorders. They completed the University of Rhode Island Change Assessment Scale, which measures four stages of treatment change (precontemplation, contemplation, action, and maintenance) and overall readiness to change, and were scanned in a 3 T MRI scanner. We defined three regions of interest (ROIs): the ventromedial prefrontal cortex (including medial orbitofrontal cortex and subgenual and rostral anterior cingulate cortex), the dorsomedial prefrontal cortex (i.e., superior medial frontal cortex), and the neostriatum (caudate and putamen). We found that readiness to change correlated with different aspects of ventromedial prefrontal gray matter as a function of diagnosis. In cocaine users with Cluster C comorbidities, readiness to change positively correlated with gyrus rectus gray matter, whereas in cocaine users without comorbidities it negatively correlated with rostral anterior cingulate cortex gray matter. Moreover, maintenance scores positively correlated with dorsomedial prefrontal gray matter in cocaine users with Cluster C comorbidities, but negatively correlated with this region in cocaine users with Cluster B and cocaine users without comorbidities. Maintenance scores also negatively correlated with dorsal striatum gray matter in cocaine users with Cluster C comorbidities. We conclude that the link between prefrontal–striatal gray matter and treatment motivation is modulated by co-existence of personality disorders.