Search

How does craving bias decisions to pursue drugs over other valuable, and healthier, alternatives in addiction? To address this question, we measured the in-the-moment economic decisions of people with opioid use disorder as they experienced craving, shortly after receiving their scheduled opioid maintenance medication and ~24 h later. We found that higher cravers had higher drug-related valuation, and that moments of higher craving within-person also led to higher drug-related valuation. When experiencing increased opioid craving, participants were willing to pay more for personalized consumer items and foods more closely related to their drug use, but not for alternative “nondrug-related” but equally desirable options. This selective increase in value with craving was greater when the drug-related options were offered in higher quantities and was separable from the effects of other fluctuating psychological states like negative mood. These findings suggest that craving narrows and focuses economic motivation toward the object of craving by selectively and multiplicatively amplifying perceived value along a “drug relatedness” dimension.

BACKGROUND Impulsivity has been defined by acting rashly during positive mood states (positive urgency; PU) or negative mood states (negative urgency; NU) and by excessive de-valuation of deferred rewards. These behaviors reflect a "live in the now" mentality that is not only characteristic of many individuals with severe substance use disorder (SUD) but also impedes medical treatment compliance and could result in repeated hospitalizations or other poor health outcomes. Purpose/objectives: We sought preliminary evidence that impulsivity may relate to adverse health outcomes in the veteran population. Impulsivity measured in 90 veterans receiving inpatient or outpatient SUD care at a Veterans Affairs Medical Center was related to histories of inpatient/residential care costs, based on VA Health Economics Resource Center data. Results: We found that positive urgency, lack of persistence and lack of premeditation, but not sensation-seeking or preference for immediate or risky rewards, were significantly higher in veterans with a history of one or more admissions for VA-based inpatient or residential health care that either included (n = 30) or did not include (n = 29) an admission for SUD care. Among veterans with a history of inpatient/residential care for SUD, NU and PU, but not decision-making behavior, correlated with SUD care-related costs. Conclusions/Importance: In veterans receiving SUD care, questionnaire-assessed trait impulsivity (but not decision-making) related to greater care utilization within the VA system. This suggests that veterans with high impulsivity are at greater risk for adverse health outcomes, such that expansion of cognitive interventions to reduce impulsivity may improve their health.

los enfoques neuroeconomicos ofrecen un marco prometedor para el modelado algoritmico de la toma de decisiones alterada en la adiccion. Concluimos que la dinamica en el tratamiento de estos parametros neuroeconomicos puede contribuir, junto con otros factores demograficos, de personalidad y de comorbilidad psiquiatrica, a la construccion de un fenotipo de recaida que podria ayudar en la seleccion de intervencion dirigida para la atencion individualizada.

Importance: Opioid addiction is a major public health problem. Despite availability of evidence-based treatments, relapse and dropout are common outcomes. Efforts aimed at identifying reuse risk and gaining more precise understanding of the mechanisms conferring reuse vulnerability are needed. Objective: To use tools from computational psychiatry and decision neuroscience to identify changes in decision-making processes preceding opioid reuse. Design, Setting, and Participants: A cohort of individuals with opioid use disorder were studied longitudinally at a community-based treatment setting for up to 7 months (1-15 sessions per person). At each session, patients completed a risky decision-making task amenable to computational modeling and standard clinical assessments. Time-lagged mixed-effects logistic regression analyses were used to assess the likelihood of opioid use between sessions (t to t + 1; within the subsequent 1-4 weeks) from data acquired at the current session (t). A cohort of control participants completed similar procedures (1-5 sessions per person), serving both as a baseline comparison group and an independent sample in which to assess measurement test-retest reliability. Data were analyzed between January 1, 2018, and September 5, 2019. Main Outcomes and Measures: Two individual model-based behavioral markers were derived from the task completed at each session, capturing a participant's current tolerance of known risks and ambiguity (partially unknown risks). Current anxiety, craving, withdrawal, and nonadherence were assessed via interview and clinic records. Opioid use was ascertained from random urine toxicology tests and self-reports. Results: Seventy patients (mean [SE] age, 44.7 [1.3] years; 12 women and 58 men [82.9% male]) and 55 control participants (mean [SE] age, 42.4 [1.5] years; 13 women and 42 men [76.4% male]) were included. Of the 552 sessions completed with patients (mean [SE], 7.89 [0.59] sessions per person), 252 (45.7%) directly preceded opioid use events (mean [SE], 3.60 [0.44] sessions per person). From the task parameters, only ambiguity tolerance was significantly associated with increased odds of prospective opioid use (adjusted odds ratio, 1.37 [95% CI, 1.07-1.76]), indicating patients were more tolerant specifically of ambiguous risks prior to these use events. The association of ambiguity tolerance with prospective use was independent of established clinical factors (adjusted odds ratio, 1.29 [95% CI, 1.01-1.65]; P =.04), such that a model combining these factors explained more variance in reuse risk. No significant differences in ambiguity tolerance were observed between patients and control participants, who completed 197 sessions (mean [SE], 3.58 [0.21] sessions per person); however, patients were more tolerant of known risks (B = 0.56 [95% CI, 0.05-1.07]). Conclusions and Relevance: Computational approaches can provide mechanistic insights about the cognitive factors underlying opioid reuse vulnerability and may hold promise for clinical use. © 2019 American Medical Association. All rights reserved.

Measuring temporal discounting through the use of intertemporal choice tasks is now the gold standard method for quantifying human choice impulsivity (impatience) in neuroscience, psychology, behavioral economics, public health and computational psychiatry. A recent area of growing interest is individual differences in discounting levels, as these may predispose to (or protect from) mental health disorders, addictive behaviors, and other diseases. At the same time, more and more studies have been dedicated to the quantification of individual attitudes towards risk, which have been measured in many clinical and non-clinical populations using closely related techniques. Economists have pointed to interactions between measurements of time preferences and risk preferences that may distort estimations of the discount rate. However, although becoming standard practice in economics, discount rates and risk preferences are rarely measured simultaneously in the same subjects in other fields, and the magnitude of the imposed distortion is unknown in the assessment of individual differences. Here, we show that standard models of temporal discounting -such as a hyperbolic discounting model widely present in the literature which fails to account for risk attitudes in the estimation of discount rates- result in a large and systematic pattern of bias in estimated discounting parameters. This can lead to the spurious attribution of differences in impulsivity between individuals when in fact differences in risk attitudes account for observed behavioral differences. We advance a model which, when applied to standard choice tasks typically used in psychology and neuroscience, provides both a better fit to the data and successfully de-correlates risk and impulsivity parameters. This results in measures that are more accurate and thus of greater utility to the many fields interested in individual differences in impulsivity.

High mobility group (HMG) proteins are a family of architectural transcription factors, with HMGA1 playing a role in the regulation of genes involved in promoting systemic inflammatory responses. We speculated that blocking HMGA1-mediated pathways might improve outcomes from sepsis. To investigate HMGA1 further, we developed genetically modified mice expressing a dominant negative (dn) form of HMGA1 targeted to the vasculature. In dnHMGA1 transgenic (Tg) mice, endogenous HMGA1 is present, but its function is decreased due to the mutant transgene. These mice allowed us to specifically study the importance of HMGA1 not only during a purely pro-inflammatory insult of endotoxemia, but also during microbial sepsis induced by implantation of a bacterial-laden fibrin clot into the peritoneum. We found that the dnHMGA1 transgene was only present in Tg and not wild-type (WT) littermate mice, and the mutant transgene was able to interact with transcription factors (such as NF-κB), but was not able to bind DNA. Tg mice exhibited a blunted hypotensive response to endotoxemia, and less mortality in microbial sepsis. Moreover, Tg mice had a reduced inflammatory response during sepsis, with decreased macrophage and neutrophil infiltration into tissues, which was associated with reduced expression of monocyte chemotactic protein-1 and macrophage inflammatory protein-2. Collectively, these data suggest that targeted expression of a dnHMGA1 transgene is able to improve outcomes in models of endotoxin exposure and microbial sepsis, in part by modulating the immune response and suggest a novel modifiable pathway to target therapeutics in sepsis. High mobility group A1 is a modifiable pathway for therapeutics in sepsis, using a dominant negative approach to regulate the immune response.

Objectives: Rheumatoid arthritis (RA) is associated with an increased prevalence of cardiovascular disease (CVD). Since atherosclerosis development is a gradual process of damage inside the artery wall, and the phenotype –genotype correlation of complex diseases may vary depending on ethnicity, we sought to investigate the influence of clinical features, routine inflammatory markers, and the genetic component of RA on different stages of atherosclerosis in northwestern Colombian patients with RA. Methods: A group of 140 patients with RA were enrolled in this study. All patients underwent a noninvasive evaluation of endothelial function by flow-mediated vasodilation (FMV) and an assessment of carotid intima-media thickness (IMT) by high-resolution B-mode ultrasonography. The patients were classified into 3 categories: endothelial dysfunction (FMV 5%), increased IMT (0.91-1.29 mm), and plaque (IMT 1.30 mm). The risk of being in each category was assessed by investigating traditional and nontraditional cardiovascular risk factors. For each stage of atherosclerosis development, we searched for nontraditional risk factors that were significantly associated with the stage after adjusting for traditional risk factors and current age. Results: Rheumatoid factor seropositivity was significantly associated with endothelial dysfunction (adjusted odds ratio, AOR 3.0). A duration of RA 10 years (AOR 29.0) and being a carrier of an HLA-DRB1 shared epitope allele (AOR 4.8) were associated with atherosclerotic plaque. No association of extra-articular manifestations, anticyclic citrullinated peptide (anti-CCP3) antibodies, and tumor necrosis factor 308 polymorphism with CVD was found. Conclusions: Our results reveal the presence of RA-related risk factors for CVD which act independently of traditional risk factors. These factors can be used by clinicians to predict CVD in RA patients, and this data should assist in the development of public health policies in our population for the improvement of patient outcomes.

BackgroundThe architectural transcription factor High Mobility Group-A1 (HMGA1) binds to the minor groove of AT-rich DNA and forms transcription factor complexes ("enhanceosomes") that upregulate expression of select genes within the inflammatory cascade during critical illness syndromes such as acute lung injury (ALI). AT-rich regions of DNA surround transcription factor binding sites in genes critical for the inflammatory response. Minor groove binding drugs (MGBs), such as Distamycin A (Dist A), interfere with AT-rich region DNA binding in a sequence and conformation-specific manner, and HMGA1 is one of the few transcription factors whose binding is inhibited by MGBs.ObjectivesTo determine whether MGBs exert beneficial effects during endotoxemia through attenuating tissue inflammation via interfering with HMGA1-DNA binding and modulating expression of adhesion molecules.Methodology/principal findingsAdministration of Dist A significantly decreased lung and liver inflammation during murine endotoxemia. In intravital microscopy studies, Dist A attenuated neutrophil-endothelial interactions in vivo following an inflammatory stimulus. Endotoxin induction of P-selectin expression in lung and liver tissue and promoter activity in endothelial cells was significantly reduced by Dist A, while E-selectin induction was not significantly affected. Moreover, Dist A disrupted formation of an inducible complex containing NF-kappaB that binds an AT-rich region of the P-selectin promoter. Transfection studies demonstrated a critical role for HMGA1 in facilitating cytokine and NF-kappaB induction of P-selectin promoter activity, and Dist A inhibited binding of HMGA1 to this AT-rich region of the P-selectin promoter in vivo.Conclusions/significanceWe describe a novel targeted approach in modulating lung and liver inflammation in vivo during murine endotoxemia through decreasing binding of HMGA1 to a distinct AT-rich region of the P-selectin promoter. These studies highlight the ability of MGBs to function as molecular tools for dissecting transcriptional mechanisms in vivo and suggest alternative treatment approaches for critical illness.