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1.  Decision Making and Drug Abuse Among HIV+ Men Who Have Sex with Men: A Preliminary Report from the Chicago Multicenter AIDS Cohort Study 
HIV+ substance dependent individuals (SDIs) make significantly poorer decisions compared with HIV− SDIs, but the neurocognitive mechanisms underlying this impairment have not been identified. We administered the Iowa Gambling Task, a measure of decision making under uncertain risk, and the Cups Task, a measure of decision making under specified risk, to a group of 56 HIV+ and 23 HIV− men who have sex with men (MSMs) with a history of substance dependence enrolled in the Multicenter AIDS Cohort Study. The IGT provides no explicit information regarding the contingencies for each possible choice, and the probability of each outcome remains ambiguous at least for the early trials; in contrast, the Cups Task provides explicit information about the probability of each outcome. The HIV+ group made significantly poorer decisions on the IGT compared with the HIV− group. Cups Task performance did not differ significantly between HIV− and HIV+ groups. Exploratory analyses of the IGT data suggested that HIV+ subjects tended to perform more poorly during the early learning phase when uncertainty about specific outcomes was greatest. Additionally, performance on the final two trial blocks was significantly correlated with Stroop Interference scores, suggesting IGT performance is driven increasingly by executive control during the later portion of the task. Potential cognitive mechanisms to be explored in later studies are discussed, including impairment in implicit learning processing
PMCID: PMC3700610  PMID: 23701366
HIV; drug abuse; decision making; executive function; AIDS; neurocognition
2.  Effects of Cannabis on Neurocognitive Functioning: Recent Advances, Neurodevelopmental Influences, and Sex Differences 
Neuropsychology review  2012;23(2):117-137.
Decades of research have examined the effects of cannabis on neurocognition. Recent advances in this field provide us with a better understanding of how cannabis use influences neurocognition both acutely (during intoxication) and non-acutely (after acute effects subside). Evidence of problems with episodic memory is one of the most consistent findings reported; however, several other neurocognitive domains appear to be adversely affected by cannabis use under various conditions. There is significant variability in findings across studies, thus a discussion of potential moderators is increasingly relevant. The purpose of this review was to 1) provide an update on research of cannabis’ acute and non-acute effects on neurocognition, with a focus on findings since 2007 and 2) suggest and discuss how neurodevelopmental issues and sex differences may influence cannabis effects on neurocognition. Finally we discuss how future investigations may lead to better understanding of the complex interplay among cannabis, stages of neurodevelopment, and sex on neurocognitive functioning.
PMCID: PMC3593817  PMID: 23129391
cannabis; cognition; marijuana; neuropsychology; sex differences; THC
3.  Preliminary Evidence for a Sex-Specific Relationship between Amount of Cannabis Use and Neurocognitive Performance in Young Adult Cannabis Users 
Accumulating evidence suggests neuropsychological deficits from cannabis use, with a burgeoning area of preclinical research indicating possible sex-differences. However, few studies have examined how cannabis use may differentially impact neurocognition in male and female cannabis users. As such, we examined potential sex-differences in associations between amount of cannabis use (across several time-frames) and neurocognitive performance among young adult regular cannabis users. Consistent with previous studies, more cannabis use was generally associated with poorer episodic memory and decision-making, but not other measures of inhibitory control. However, patterns of results suggested sex-specific dissociations. In particular, more cannabis use was more consistently associated with poorer episodic memory performance in females than males. Conversely, more cannabis use was associated with poorer decision-making performance for males, but not females. These results provide further evidence for residual cannabis-associated neurocognitive deficits and suggest the importance of examining the impact of cannabis on neurocognition separately for males and females.
PMCID: PMC3895398  PMID: 23962414
cannabis; cognition; marijuana; neuropsychology; sex differences; THC
4.  A comparison of delay discounting among substance users with and without suicide attempt history 
Although substance use disorders are associated with overall increased suicide risk, there is considerable variability in suicide risk among substance dependent individuals (SDIs). Impairment in impulse control is common among SDIs and may contribute to vulnerability to suicidal behavior. The present study examined the relation between one specific aspect of impulsivity, delay discounting, and suicide attempt history in a sample of SDIs. An interaction was observed between suicide attempt history and discounting rates across delayed reward size. Specifically, SDIs with no history of attempted suicide, devalued small relative to large delayed rewards. In contrast, SDIs with a history of suicide attempts appeared comparatively indifferent to delayed reward size, discounting both small and large delayed rewards at essentially identical rates. These findings provide evidence that, despite the view that SDIs are characterized by marked difficulties in impulsivity, significant variability nevertheless exists within this group in delay discounting tendencies. Furthermore, these differences provide preliminary evidence that specific aspects of impulsivity may help to identify those most at risk for suicidal behavior in this population. The potential implications of our findings for suicide prevention efforts are discussed.
PMCID: PMC3369019  PMID: 22369220
Delay Discounting; Impulsivity; Substance Use Disorders; Suicide
5.  Performance of Young Adult Cannabis Users on Neurocognitive Measures of Impulsive Behavior and their Relationship to Symptoms of Cannabis Use Disorders 
Recent studies suggest that abstinent cannabis users show deficits on neurocognitive laboratory tasks of impulsive behavior. But results are mixed and less is known on the performance of non-treatment seeking, young adult cannabis users. Importantly, relationships between performance on measures of impulsive behavior and symptoms of cannabis addiction remain relatively unexplored. We compared young adult current cannabis users (CU, n = 65) and non-using controls (NU, n = 65) on several laboratory measures of impulsive behavior, as well as on a measure of episodic memory commonly impacted by cannabis use. The CU group performed more poorly than the NU group on the Hopkins Verbal Learning Test-Revised Total Immediate Recall and Delayed Recall. No significant differences were observed on the measures of impulsive behavior (i.e., Iowa Gambling Task [IGT], Go-Stop Task, Monetary Choice Questionnaire, Balloon Analogue Risk Task). We examined relationships between neurocognitive performance and symptoms of cannabis use disorder symptoms (DSM-IV CUD) among the CU group, which revealed that poorer IGT performance was associated with more symptoms of DSM-IV CUD. Our results show poorer memory performance among young adult cannabis users relative to healthy controls, but no differences on measures of impulsive behavior. However, performance on a specific type of impulsive behavior (i.e., poorer decision-making) was associated with more cannabis use disorder symptoms. These results provide preliminary evidence to suggest that decision-making deficits may be more strongly associated with problems experienced from cannabis use, rather than solely being a consequence of cannabis use, per se.
PMCID: PMC3488122  PMID: 22882144
cannabis; addiction; decision-making; neuropsychology; memory; cognitive effects
6.  Correction: Computational Modeling Reveals Distinct Effects of HIV and History of Drug Use on Decision-Making Processes in Women 
PLoS ONE  2013;8(9):10.1371/annotation/5a8e6fe0-623c-4d17-8781-9a0eadf67a43.
PMCID: PMC3770829  PMID: 24039690
7.  Substance Abuse, Hepatitis C, and Aging in HIV: Common Cofactors that Contribute to Neurobehavioral Disturbances 
Neurobehavioral HIV medicine  2012;2012(4):15-34.
Although the prevalence of neurocognitive disturbances among individuals with HIV has decreased in recent years, rates of impairment still remain high. This review presents findings from comorbid conditions that may contribute to further neurocognitive impairments in this already vulnerable population. We will focus on three co-factors that have received substantial attention in the neuroAIDS literature: drug use, hepatitis C co-infection (HCV), and aging. All three conditions commonly co-occur with HIV and likely interact with HIV in complex ways. Collectively, the extant literature suggests that drug use, HCV, and aging serve to worsen the neurocognitive profile of HIV through several overlapping mechanisms. A better understanding of how specific comorbidities interact with HIV may reveal specific phenotypes of HIV-associated neurocognitive disorder that may aid in the development of more targeted behavioral and pharmacological treatment efforts.
PMCID: PMC3763847  PMID: 24014165
HIV; Substance Use; Hepatitis C; Aging; Neurocognition; HIV Co-Factors
8.  Computational Modeling Reveals Distinct Effects of HIV and History of Drug Use on Decision-Making Processes in Women 
PLoS ONE  2013;8(8):e68962.
Drug users and HIV-seropositive individuals often show deficits in decision-making; however the nature of these deficits is not well understood. Recent studies have employed computational modeling approaches to disentangle the psychological processes involved in decision-making. Although such approaches have been used successfully with a number of clinical groups including drug users, no study to date has used computational modeling to examine the effects of HIV on decision-making. In this study, we use this approach to investigate the effects of HIV and drug use on decision-making processes in women, who remain a relatively understudied population.
Fifty-seven women enrolled in the Women's Interagency HIV Study (WIHS) were classified into one of four groups based on their HIV status and history of crack cocaine and/or heroin drug use (DU): HIV+/DU+ (n = 14); HIV+/DU− (n = 17); HIV−/DU+ (n = 14); and HIV−/DU− (n = 12). We measured decision-making with the Iowa Gambling Task (IGT) and examined behavioral performance and model parameters derived from the best-fitting computational model of the IGT.
Although groups showed similar behavioral performance, HIV and DU exhibited differential relationship to model parameters. Specifically, DU was associated with compromised learning/memory and reduced loss aversion, whereas HIV was associated with reduced loss aversion, but was not related to other model parameters.
Results reveal that HIV and DU have differential associations with distinct decision-making processes in women. This study contributes to a growing line of literature which shows that different psychological processes may underlie similar behavioral performance in various clinical groups and may be associated with distinct functional outcomes.
PMCID: PMC3737214  PMID: 23950880
9.  The Influence of Inhibitory Control and Episodic Memory on the Risky Sexual Behavior of Young Adult Cannabis Users 
Cannabis use is associated with risky sexual behavior (RSB) and sex-related negative health consequences. This investigation examined the role of inhibitory control and episodic memory in predicting RSB and sex-related negative consequences among current cannabis users. Findings indicated that the relationships between cannabis, neurocognition and sexual-risk varied according to the dimension of neurocognition and the parameter of RSB in question. Specifically, more risk-taking was associated with more RSB. Furthermore, amount of recent cannabis use was associated with more RSB and sex-related negative consequences, but only among those with worse performances on a measure of decision-making and of risk-taking. Contrary to hypotheses, worse episodic memory also significantly predicted higher overall sexual-risk and decreased safe-sex practices. Results indicate that worse neurocognitive performance in the areas of risk-taking, decision-making, and episodic memory may influence the degree to which cannabis users engage in RSB and experience negative health consequences as a result.
PMCID: PMC3677559  PMID: 22676889
Cannabis; Risky Sex; Young Adults; Cognition; Inhibitory Control; Episodic Memory
10.  Neurocognitive performance in drug dependent males and females with PTSD symptoms 
Sex differences in neurobiological mechanisms of substance dependence are well documented but studies of sex differences in associated neurocognitive deficits have produced inconsistent results. PTSD is comorbid with substance dependence and frequently affects neurocognition. Thus, we investigated the effects of sex and PTSD symptoms on sustained attention and inhibition abilities among 126 female and 297 male substance dependent individuals (SDIs) using the Immediate Memory Test (IMT). Females with significant PTSD (PTSD+) symptoms demonstrated significantly impaired IMT performance relative to other participants. These results represent progress in efforts to delineate sex-specific risk factors for neurocognitive deficits among SDIs.
PMCID: PMC3337707  PMID: 22385364
11.  Impact of HIV and a history of marijuana dependence on procedural learning among individuals with a history of substance dependence 
Marijuana (MJ) use and HIV infection are both associated with neurocognitive deficits, yet there is little research to date examining their interactions, specifically how they pertain to procedural learning (PL). We examined a sample of 86 individuals with a history of dependence for multiple substances who underwent a comprehensive evaluation including measures of mental health, substance use history, and three measures of PL: the photoelectric Rotary Pursuit Task (RPT), the Star Mirror Tracing Task (SMT), and the Weather Prediction Task (WPT). We found that a positive HIV serostatus and a history of marijuana dependence were both independently associated with overall poorer performance on the SMT and RPT in this sample of individuals with a history of dependence for multiple substances. Rate of improvement across trial blocks did not differ as a function of HIV serostatus or history of marijuana dependence. Although we found no significant HIV × MJ interaction for any of the PL tasks, we did observe evidence of additive negative effects from HIV and a history of marijuana dependence on overall performance on the SMT and RPT, but not the WPT. The findings suggest that complex motor skills are adversely affected among abstinent polysubstance users with a history of marijuana dependence and that such deficits are compounded by HIV.
PMCID: PMC3633561  PMID: 21480022
HIV; Cannabis; Nondeclarative memory; Striatum; Motor skills
12.  Psychopathic Heroin Addicts are not Uniformly Impaired across Neurocognitive Domains of Impulsivity 
Drug and alcohol dependence  2010;114(2-3):194-200.
Impulsivity is a hallmark characteristic of drug addiction and a prominent feature of externalizing disorders such as psychopathy that are commonly comorbid with drug addiction. In a previous study (Vassileva et al., 2007) we have shown that psychopathic heroin addicts evidence more impulsive decision-making on the Iowa Gambling Task relative to non-psychopathic heroin addicts. The goal of the current study was to investigate whether the observed impulse-control deficits in psychopathic heroin addicts would generalize to other neurocognitive domains of impulsivity, such as delay discounting and behavioral inhibition among a group of relatively “pure” heroin addicts in Bulgaria who participated in our previous study.
We tested 92 currently abstinent male heroin addicts, classified as psychopathic or non-psychopathic based on the Hare Psychopathy Checklist – Revised (PCL-R). We administered two neurocognitive tasks of impulsivity: (1) Delayed Rewards Discounting Task, a measure of temporal discounting of rewards; and (2) Passive Avoidance Learning Task, a measure of behavioral inhibition.
Psychopathic heroin addicts were not impaired relative to non-psychopathic heroin addicts on the Delayed Rewards Discounting Task and the Passive Avoidance Learning Task, on the latter of which they showed better attentional capacity.
These results indicate that psychopathic heroin users are not uniformly impaired across neurocognitive domains of impulsivity. Combined with our previous findings, these results suggest that the presence of psychopathy may exacerbate decision-making deficits in psychopathic heroin addicts, but it may not have significant effect on other neurocognitive domains of impulsivity in this population.
PMCID: PMC3062675  PMID: 21112701
impulsivity; heroin addiction; psychopathy; decision-making; delay discounting; behavioral inhibition
13.  HIV+ Men and Women Show Different Performance Patterns on Procedural Learning Tasks 
The literature suggests that nondeclarative, or nonconscious, learning might be impaired among HIV+ individuals compared with HIV− matched control groups, but these studies have included relatively few women. We administered measures of motor skill and probabilistic learning, tasks with a nondeclarative or procedural learning component that are dependent on integrity of prefrontal-striatal systems, to well-matched groups of 148 men and 65 women with a history of substance dependence that included 45 men and 30 women seropositive for HIV. All participants were abstinent at testing. Compared to HIV− women, HIV+ women performed significantly more poorly on both tasks, but HIV+ men’s performance did not differ significantly compared to HIV− men on either task. These different patterns of performance indicate that features of HIV-associated neurocognitive disorder (HAND) can not always be generalized from men to women. Additional studies are needed to address directly the possibility of sex differences in HIV-associated neurocognitive disorder (HAND) and the possibility that women might be more vulnerable to the effects of HIV and substance dependence on some neurocognitive functions.
PMCID: PMC2990780  PMID: 20694870
HIV; neurocognition; substance use disorders; addiction; sex differences; procedural learning
14.  Influence of Procedural Learning on Iowa Gambling Task Performance Among HIV+ Individuals with History of Substance Dependence 
HIV+ individuals have been shown to demonstrate deficits on the Iowa Gambling Task (IGT), a complex measure of “decision-making.” Little remains known about what other neurocognitive processes may account for variability in IGT performance among HIV+ samples or the role of procedural learning (PL) in IGT performance. A sample of 49 HIV+ individuals with a history of substance use disorders was examined to explore the relationship between IGT performance and three measures of PL: The Rotary Pursuit, Mirror Star Tracing, and Weather Prediction tasks. We found no statistically significant relationships between IGT performance and any of the PL tasks, despite finding significant correlations among the PL tasks. This pattern of results persisted when analyzing IGT performance in various ways (e.g., performance on earlier trial blocks or impairment classifications). Although other nondeclarative processes (e.g., somatic markers) may be important for IGT performance, these findings do not support PL as an important component neurocognitive process for the IGT. Similarly, these results suggest that differences in PL performance does not account for the decision-making deficits or variability in performances observed on the IGT among HIV+ individuals with a history of substance dependence.
PMCID: PMC2809553  PMID: 19939850
HIV; Substance use disorders; Nondeclarative memory; Implicit memory; Decision-making; Basal ganglia; Orbitofrontal cortex; Executive functions
15.  Deficits in complex motor functions, despite no evidence of procedural learning deficits, among HIV+ individuals with history of substance dependence 
Neuropsychology  2008;22(6):776-786.
HIV and drugs of abuse affect common neural systems underlying procedural memory, including the striatum. We compared performance of 48 HIV seropositive (HIV+) and 48 HIV seronegative (HIV−) participants with history of cocaine and/or heroin dependence across multiple Trial Blocks of three procedural learning (PL) tasks: Rotary Pursuit (RPT), Mirror Star Tracing (MST), and Weather Prediction (WPT). Groups were well matched on demographic, psychiatric, and substance use parameters, and all participants were verified abstinent from drugs. Mixed model ANOVAs revealed that the HIV+ group performed more poorly across all tasks, with a significant main effect of HIV serostatus observed on the MST and a trend toward significance obtained for the RPT. No significant differences were observed on the WPT. Both groups demonstrated significant improvements in performance across all three PL tasks. Importantly, no significant Serostatus X Trial Block interactions were observed on any task. Thus, the HIV+ group tended to perform worse than the HIV− group across all trial blocks of PL tasks with motor demands, but showed no differences in their rate of improvement across all tasks. These findings are consistent with HIV-associated deficits in complex motor skills, but not in procedural learning.
PMCID: PMC2630709  PMID: 18999351
HIV; substance use disorders; basal ganglia; procedural memory; nondeclarative memory; neuropsychology
16.  Archaeosomes made of Halorubrum tebenquichense total polar lipids: a new source of adjuvancy 
BMC Biotechnology  2009;9:71.
Archaeosomes (ARC), vesicles prepared from total polar lipids (TPL) extracted from selected genera and species from the Archaea domain, elicit both antibody and cell-mediated immunity to the entrapped antigen, as well as efficient cross priming of exogenous antigens, evoking a profound memory response. Screening for unexplored Archaea genus as new sources of adjuvancy, here we report the presence of two new Halorubrum tebenquichense strains isolated from grey crystals (GC) and black mood (BM) strata from a littoral Argentinean Patagonia salt flat. Cytotoxicity, intracellular transit and immune response induced by two subcutaneous (sc) administrations (days 0 and 21) with BSA entrapped in ARC made of TPL either form BM (ARC-BM) and from GC (ARC-GC) at 2% w/w (BSA/lipids), to C3H/HeN mice (25 μg BSA, 1.3 mg of archaeal lipids per mouse) and boosted on day 180 with 25 μg of bare BSA, were determined.
DNA G+C content (59.5 and 61.7% mol BM and GC, respectively), 16S rDNA sequentiation, DNA-DNA hybridization, arbitrarily primed fingerprint assay and biochemical data confirmed that BM and GC isolates were two non-previously described strains of H. tebenquichense. Both multilamellar ARC mean size were 564 ± 22 nm, with -50 mV zeta-potential, and were not cytotoxic on Vero cells up to 1 mg/ml and up to 0.1 mg/ml of lipids on J-774 macrophages (XTT method). ARC inner aqueous content remained inside the phago-lysosomal system of J-774 cells beyond the first incubation hour at 37°C, as revealed by pyranine loaded in ARC. Upon subcutaneous immunization of C3H/HeN mice, BSA entrapped in ARC-BM or ARC-GC elicited a strong and sustained primary antibody response, as well as improved specific humoral immunity after boosting with the bare antigen. Both IgG1 and IgG2a enhanced antibody titers could be demonstrated in long-term (200 days) recall suggesting induction of a mixed Th1/Th2 response.
We herein report the finding of new H. tebenquichense non alkaliphilic strains in Argentinean Patagonia together with the adjuvant properties of ARC after sc administration in mice. Our results indicate that archaeosomes prepared with TPL from these two strains could be successfully used as vaccine delivery vehicles.
PMCID: PMC2739508  PMID: 19678953
17.  Are all Drug Addicts Impulsive? Effects of Antisociality and Extent of Multidrug Use on Cognitive and Motor Impulsivity 
Addictive behaviors  2007;32(12):3071-3076.
The purpose of this investigation was to examine the influence of antisociality and extent of multidrug use on cognitive and motor impulsivity among substance dependent individuals (SDIs) that used primarily cocaine and/or heroin. One hundred currently abstinent male SDIs participated in the study. Extent of multidrug use and degree of antisociality, assessed with the Socialization Scale of the California Psychological Inventory (So-CPI), were used to classify participants into one of four groups: high antisocial/low multidrug use, high antisocial/high multidrug use, low antisocial/low multidrug use, and low antisocial/high multidrug use. All subjects completed the Iowa Gambling Task to assess cognitive impulsivity and the Stroop Task to measure motor impulsivity. Contrary to expectations, antisociality was associated with more advantageous performance on the Iowa Gambling Task, independent of extent of multidrug use. In contrast, greater multidrug use was associated with general psychomotor slowing on the Stroop Task. Results suggest that a subclinical form of antisociality may have a paradoxically facilitating effect on decision-making and cognitive impulsivity among SDIs.
PMCID: PMC2128047  PMID: 17507173
drug addiction; impulsivity; antisocial; polysubstance use; multidrug use; decision-making
18.  Transcriptional and post-transcriptional regulation of retrotransposons IAP and MuERV-L affect pluripotency of mice ES cells 
In the mouse, culture of embryonic stem (ES) cells may decrease their pluripotency and give rise to foetal abnormalities in recipient embryos. These abnormalities are frequently associated with both, chromosome abnormalities or epigenetic alteration of imprinting genes; however, little is known about the epigenetic stability of endogenous retrotransposable elements (REs). In our laboratory, we came across a R1 ES cell line, which at passage 27, lost the ability of germline transmission and started inducing the kinky tail phenotype in all chimeric animals produced with it.
In order to investigate whether this phenotype was associated with chromosome alteration, inadvertent differentiation, or epigenetic modification, we characterized and compared this R1 ES cell line at passage 27 with an early passage and with a second ES cell line C57/CBAF1 generated in our laboratory. We assessed: i) karyotype; ii) expression of pluripotent and differentiation markers, iii) mRNA transcription by qRT-PCR of two REs, intracisternal-A particle (IAP) and murine endogenous-retrovirus-L (MuERV-L), and iv) methylation of IAP and MuERV-L.
The R1 ES cell at passage 27, presented normal morphology, karyotype, and expression of genetic markers characteristic of pluripotent; however, it was detected an altered mRNA transcription of sense and antisense RNA strands of both REs, concomitantly with an altered methylation pattern for the IAP element but not for MuERV-L. These results indicate that besides methylation, other post-transcriptional processes are involved in gene silencing of some REs; and that culture of ES cells may decrease their pluripotency by producing inadvertent alterations in the expression of REs without significantly affecting the morphology, chromosome structure, and expression of pluripotent or differentiation markers.
Inadvertent REs instability may have important consequences for the use of ES cells in transgenesis (chimera formation) or in cell therapy.
PMCID: PMC1636644  PMID: 17090336

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