Results of COVID-minimal Surgical Pathway During Surge-phase of COVID-19 Pandemic.

OBJECTIVE: The outcomes of patients treated on the COVID-minimal pathway were evaluated during a period of surging COVID-19 hospital admissions, to determine the safety of continuing to perform urgent operations during the pandemic. SUMMARY OF BACKGROUND DATA: Crucial treatments were delayed for many patients during the COVID-19 pandemic, over concerns for hospital-acquired COVID-19 infections. To protect cancer patients whose survival depended on timely surgery, a "COVID-minimal pathway" was created. METHODS: Patients who underwent a surgical procedure on the pathway between April and May 2020 were evaluated. The "COVID-minimal surgical pathway" consisted of: (A) evolving best-practices in COVID-19 transmission-reduction, (B) screening patients and staff, (C) preoperative COVID-19 patient testing, (D) isolating pathway patients from COVID-19 patients. Patient status through 2 weeks from discharge was determined as a reflection of hospital-acquired COVID-19 infections. RESULTS: After implementation, pathway screening processes excluded 7 COVID-19-positive people from interacting with pathway (4 staff and 3 patients). Overall, 122 patients underwent 125 procedures on pathway, yielding 83 admissions (42 outpatient procedures). The median age was 64 (56-79) and 57% of patients were female. The most common surgical indications were cancer affecting the uterus, genitourinary tract, colon, lung or head and neck. The median length of admission was 3 days (1-6). Repeat COVID-19 testing performed on 27 patients (all negative), including 9 patients evaluated in an emergency room and 8 readmitted patients. In the postoperative period, no patient developed a COVID-19 infection. CONCLUSIONS: A COVID-minimal pathway comprised of physical space modifications and operational changes may allow urgent cancer treatment to safely continue during the COVID-19 pandemic, even during the surge-phase.

Monoaminergic modulation of decision-making under risk of punishment in a rat model.

The ability to decide advantageously among options that vary in both their risks and rewards is critical for survival and well-being. Previous work shows that some forms of risky decision-making are robustly modulated by monoamine signaling, but it is less clear how monoamine signaling modulates decision-making under risk of explicit punishment. The goal of these experiments was to determine how this form of decision-making is modulated by dopamine, serotonin, and norepinephrine signaling, using a task in which rats choose between a small, 'safe' food reward and a large food reward associated with variable risks of punishment. Preference for the large, risky reward (risk-taking) was reduced by administration of a D2/3 dopamine receptor agonist (bromocriptine) and a selective D2 agonist (sumanirole). The selective D3 agonist PD128907 appeared to attenuate reward discrimination abilities but did not affect risk-taking per se. In contrast, drugs targeting serotonergic and noradrenergic signaling had few if any effects on choice behavior. These data suggest that in contrast to other forms of risky decision-making, decision-making under risk of punishment is selectively modulated by dopamine signaling, predominantly through D2 receptors.

Affective and cognitive mechanisms of risky decision making.

The ability to make advantageous decisions under circumstances in which there is a risk of adverse consequences is an important component of adaptive behavior; however, extremes in risk taking (either high or low) can be maladaptive and are characteristic of a number of neuropsychiatric disorders. To better understand the contributions of various affective and cognitive factors to risky decision making, cohorts of male Long-Evans rats were trained in a "Risky Decision making Task" (RDT), in which they made discrete trial choices between a small, "safe" food reward and a large, "risky" food reward accompanied by varying probabilities of footshock. Experiment 1 evaluated the relative contributions of the affective stimuli (i.e., punishment vs. reward) to RDT performance by parametrically varying the magnitudes of the footshock and large reward. Varying the shock magnitude had a significant impact on choice of the large, "risky" reward, such that greater magnitudes were associated with reduced choice of the large reward. In contrast, varying the large, "risky" reward magnitude had minimal influence on reward choice. Experiment 2 compared individual variability in RDT performance with performance in an attentional set shifting task (assessing cognitive flexibility), a delayed response task (assessing working memory), and a delay discounting task (assessing impulsive choice). Rats characterized as risk averse in the RDT made more perseverative errors on the set shifting task than did their risk taking counterparts, whereas RDT performance was not related to working memory abilities or impulsive choice. In addition, rats that showed greater delay discounting (greater impulsive choice) showed corresponding poorer performance in the working memory task. Together, these results suggest that reward-related decision making under risk of punishment is more strongly influenced by the punishment than by the reward, and that risky and impulsive decision making are associated with distinct components of executive function.

A preliminary investigation of Stroop-related intrinsic connectivity in cocaine dependence: associations with treatment outcomes.

BACKGROUND: Cocaine-dependent individuals demonstrate neural and behavioral differences compared to healthy comparison subjects when performing the Stroop color-word interference test. Stroop measures also relate to treatment outcome for cocaine dependence. Intrinsic connectivity analyses assess the extent to which task-related regional brain activations are related to each other in the absence of defining a priori regions of interest. OBJECTIVE: This study examined 1) the extent to which cocaine-dependent and non-addicted individuals differed on measures of intrinsic connectivity during fMRI Stroop performance; and 2) the relationships between fMRI Stroop intrinsic connectivity and treatment outcome in cocaine dependence. METHODS: Sixteen treatment-seeking cocaine-dependent patients and matched non-addicted comparison subjects completed an fMRI Stroop task. Between-group differences in intrinsic connectivity were assessed and related to self-reported and urine-toxicology-based cocaine-abstinence measures. RESULTS: Cocaine-dependent patients vs. comparison subjects showed less intrinsic connectivity in cortical and subcortical regions. When adjusting for individual degree of intrinsic connectivity, cocaine-dependent vs. comparison subjects showed relatively greater intrinsic connectivity in the ventral striatum, putamen, inferior frontal gyrus, anterior insula, thalamus and substantia nigra. Non-mean-adjusted intrinsic-connectivity measures in the midbrain, thalamus, ventral striatum, substantia nigra, insula and hippocampus negatively correlated with measures of cocaine abstinence. CONCLUSION: The diminished intrinsic connectivity in cocaine-dependent vs. comparison subjects suggests poorer communication across brain regions during cognitive-control processes. In mean-adjusted analyses, the cocaine-dependent group displayed relatively greater Stroop-related connectivity in regions implicated in motivational processes in addictions. The relationships between treatment outcomes and connectivity in the midbrain and basal ganglia suggest that connectivity represents a potential treatment target.

Dopaminergic modulation of risky decision-making.

Many psychiatric disorders are characterized by abnormal risky decision-making and dysregulated dopamine receptor expression. The current study was designed to determine how different dopamine receptor subtypes modulate risk-taking in young adult rats, using a "Risky Decision-making Task" that involves choices between small "safe" rewards and large "risky" rewards accompanied by adverse consequences. Rats showed considerable, stable individual differences in risk preference in the task, which were not related to multiple measures of reward motivation, anxiety, or pain sensitivity. Systemic activation of D2-like receptors robustly attenuated risk-taking, whereas drugs acting on D1-like receptors had no effect. Systemic amphetamine also reduced risk-taking, an effect which was attenuated by D2-like (but not D1-like) receptor blockade. Dopamine receptor mRNA expression was evaluated in a separate cohort of drug-naive rats characterized in the task. D1 mRNA expression in both nucleus accumbens shell and insular cortex was positively associated with risk-taking, while D2 mRNA expression in orbitofrontal and medial prefrontal cortex predicted risk preference in opposing nonlinear patterns. Additionally, lower levels of D2 mRNA in dorsal striatum were associated with greater risk-taking. These data strongly implicate dopamine signaling in prefrontal cortical-striatal circuitry in modulating decision-making processes involving integration of reward information with risks of adverse consequences.

Effects of developmental nicotine exposure in rats on decision-making in adulthood.

Exposure to tobacco smoke during pregnancy is associated with a range of adverse outcomes in offspring, including cognitive deficits and increased incidence of attention deficit-hyperactivity disorder, but there is a considerable controversy with regard to the causal role of tobacco smoke in these outcomes. To determine whether developmental exposure to the primary psychoactive ingredient in tobacco smoke, nicotine, may cause long-lasting behavioral alterations analogous to those in attention deficit-hyperactivity disorder, male Sprague-Dawley rats underwent a chronic neonatal nicotine administration regimen, which models third-trimester human exposure. Male rat pups were administered nicotine (6 mg/kg/day) by oral gastric intubation on postnatal days 1-7. In adulthood, rats were tested in two decision-making tasks (risky decision-making and delay discounting) as well as in free-operant responding for food reward and the elevated plus maze. Chronic neonatal nicotine attenuated weight gain during nicotine exposure, but there were no effects on performance in the decision-making task, and only a modest decrease in arm entries in the elevated plus maze in one subgroup of rats. These data are consistent with previous findings that developmental nicotine exposure has no effect on delay discounting, and they extend these findings to risky decision-making as well. They further suggest that at least some neurocognitive alterations associated with prenatal tobacco smoke exposure in humans may be due to genetic or other environmental factors, including non-nicotine components of tobacco smoke.

Pandemic Recovery Using a COVID-Minimal Cancer Surgery Pathway.

The coronavirus disease 2019 (COVID-19) pandemic has created unprecedented disruption in health care delivery around the world. In an effort to prevent hospital-acquired COVID-19 infections, most hospitals have severely curtailed elective surgery, performing only surgeries if the patient's survival or permanent function would be compromised by a delay in surgery. As hospitals emerge from the pandemic, it will be necessary to progressively increase surgical activity at a time when hospitals continue to care for COVID-19 patients. In an attempt to mitigate the risk of nosocomial infection, we have created a patient care pathway designed to minimize risk of exposure of patients coming into the hospital for scheduled procedures. The COVID-minimal surgery pathway is a predetermined patient flow, which dictates the locations, personnel, and materials that come in contact with our cancer surgery population, designed to minimize risk for virus transmission. We outline the approach that allowed a large academic medical center to create a COVID-minimal cancer surgery pathway within 7 days of initiating discussions. Although the pathway represents a combination of recommended practices, there are no data to support its efficacy. We share the pathway concept and our experience so that others wishing to similarly align staff and resources toward the protection of patients may have an easier time navigating the process.

Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models.

Drug-addicted individuals show high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decade has shown that chronic drug administration in animal models can cause increases in impulsive choice, suggesting that a similar causal relationship may exist in human drug users. This article reviews this literature, with a particular focus on the effects of chronic cocaine administration, which have been most thoroughly characterized. The potential mechanisms of these effects are described in terms of drug-induced neural alterations in ventral striatal and prefrontal cortical brain systems. Some implications of this research for pharmacological treatment of drug-induced increases in impulsive choice are discussed, along with suggestions for future research in this area.

Endocannabinoid-Enhanced "Liking" in Nucleus Accumbens Shell Hedonic Hotspot Requires Endogenous Opioid Signals.

Introduction: Stimulating either endogenous cannabinoids or opioids within a restricted dorsomedial "hedonic hotspot" in nucleus accumbens (NAc) shell enhances hedonic impact, or "liking" reactions to sweet tastes. In this study, we probed within this hotspot the relationship between endocannabinoid and opioid signals in hedonic enhancement. Materials and Methods: Specifically, we asked whether enhancement of sucrose "liking" by intra-NAc microinjections of the endocannabinoid anandamide requires concurrent endogenous opioid signaling. Results: Co-administration of the opioid antagonist naloxone in the same NAc microinjections with anandamide prevented the endocannabinoid from enhancing orofacial "liking" reactions to sucrose. Since intra-NAc hotspot naloxone injection alone failed to affect hedonics, reversal of anandamide-induced "liking" by opioid blockade reveals an interdependence of opioid and cannabinoid signaling in enhancing taste hedonic impact. Conclusions: These results elaborate our understanding of the mechanisms of hedonic processing of food rewards, and may also carry implications more generally for how opioid and cannabinoid drugs interact to generate natural pleasures, or drug-induced euphoria.

Effects of nucleus accumbens amphetamine administration on performance in a delay discounting task.

Chronic administration of cocaine can cause pronounced and enduring cognitive alterations such as increases in impulsive choice. Chronic cocaine can also result in enhanced dopamine (DA) release in the nucleus accumbens (NAc) in response to reward-related cues. It is possible that this enhanced DA release in the NAc is a mechanism by which cocaine increases impulsive choice. To date, however, the specific role of DA in the NAc in impulsive choice is unclear. To begin to address this, rats received acute microinjections of the indirect DA agonist amphetamine directly into the NAc prior to testing in a delay discounting task in which rats chose between a small, immediate and a large, delayed food reward. When delays to the large reward increased within test sessions, amphetamine increased choice of the large reward. When delays decreased within test sessions, however, amphetamine decreased choice of the large reward. These findings suggest that, rather than specifically mediating impulsive choice, DA neurotransmission in the NAc is necessary for flexible adaptation of choice strategies in the presence of shifting reward contingencies. These results further indicate that enhancements in NAc DA release likely do not account for lasting increases in impulsive choice caused by chronic cocaine.

Choice impulsivity: Definitions, measurement issues, and clinical implications.

Impulsivity critically relates to many psychiatric disorders. Given the multifaceted construct that impulsivity represents, defining core aspects of impulsivity is vital for the assessment and understanding of clinical conditions. Choice impulsivity (CI), involving the preferential selection of smaller sooner rewards over larger later rewards, represents one important type of impulsivity. The International Society for Research on Impulsivity (InSRI) convened to discuss the definition and assessment of CI and provide recommendations regarding measurement across species. Commonly used preclinical and clinical CI behavioral tasks are described, and considerations for each task are provided to guide CI task selection. Differences in assessment of CI (self-report, behavioral) and calculating CI indices (e.g., area-under-the-curve, indifference point, and steepness of discounting curve) are discussed along with properties of specific behavioral tasks used in preclinical and clinical settings. The InSRI group recommends inclusion of measures of CI in human studies examining impulsivity. Animal studies examining impulsivity should also include assessments of CI and these measures should be harmonized in accordance with human studies of the disorders being modeled in the preclinical investigations. The choice of specific CI measures to be included should be based on the goals of the study and existing preclinical and clinical literature using established CI measures.

Recent Insights into the Neurobiology of Impulsivity.

Impulsivity is associated with various psychopathologies, and elevated impulsivity is typically disadvantageous. This manuscript reviews recent investigations into the neurobiology of impulsivity using human imaging techniques and animal models. Both human imaging and preclinical pharmacological manipulations have yielded important insights into the neurobiological underpinnings of impulsivity. A more thorough understanding of the complex neurobiology underlying aspects of impulsivity may provide insight into new treatment options that target elevated impulsivity and psychopathologies such as addictions.

Addictions and Personality Traits: Impulsivity and Related Constructs.

Behavioral tendencies that might be captured through self-report measures may provide insight into personality features that are associated with substance addictions. Recently, impulsivity and related constructs, such as sensation-seeking, have been examined to help better understand their relationships with addictions. Here, we review recent findings that show links over developmental epochs between addictive behaviors and impulsivity, sensation-seeking, and other constructs that are theoretically linked. These findings have significant implications for generating improved treatments and interventions aimed at preventing the development of addictive disorders.

Adolescent risk taking, cocaine self-administration, and striatal dopamine signaling.

Poor decision making and elevated risk taking, particularly during adolescence, have been strongly linked to drug use; however the causal relationships among these factors are not well understood. To address these relationships, a rat model (the Risky Decision-making Task; RDT) was used to determine whether individual differences in risk taking during adolescence predict later propensity for cocaine self-administration and/or whether cocaine self-administration causes alterations in risk taking. In addition, the RDT was used to determine how risk taking is modulated by dopamine signaling, particularly in the striatum. Results from these experiments indicated that greater risk taking during adolescence predicted greater intake of cocaine during acquisition of self-administration in adulthood, and that adult cocaine self-administration in turn caused elevated risk taking that was present following 6 weeks of abstinence. Greater adolescent risk taking was associated with lower striatal D2 receptor mRNA expression, and pharmacological activation of D2/3 receptors in the ventral, but not dorsal, striatum induced a decrease in risk taking. These findings indicate that the relationship between elevated risk taking and cocaine self-administration is bi-directional, and that low striatal D2 receptor expression may represent a predisposing factor for both maladaptive decision making and cocaine use. Furthermore, these findings suggest that striatal D2 receptors represent a therapeutic target for attenuating maladaptive decision making when choices include risk of adverse consequences.

Intake-dependent effects of cocaine self-administration on impulsive choice in a delay discounting task.

Cocaine use is associated with high levels of impulsive choice (greater discounting of delayed rewards) in humans, but the cause/effect relationships between cocaine use and impulsive choice are not fully understood. In previous work, we found that both experimenter- and self-administration of fixed quantities of cocaine caused lasting increases in impulsive choice in rats. The present study extended these findings by taking into account baseline impulsive choice prior to self-administration and by allowing rats free access to cocaine. Male Long-Evans rats were trained in a delay discounting task in which they made discrete-trial choices between small immediate and large delayed food rewards. Half of the rats were then implanted with intravenous catheters and, following recovery, allowed to self-administer cocaine HCl (1.0 mg/kg/infusion) in 6-hr sessions over 14 days. Control rats orally self-administered a sucrose solution under similar conditions. Upon completion of self-administration, rats remained abstinent for 3 weeks before retesting in the delay discounting task. Cocaine and control groups did not differ prior to self-administration, but afterward, the cocaine group showed greater impulsive choice (fewer choices of large, delayed rewards) than controls. Additional analyses revealed that the effects of cocaine on impulsive choice were intake-dependent; rats classified as "low intake" did not differ from controls, whereas rats classified as "high intake" were significantly more impulsive than both controls and their precocaine baseline. These findings are consistent with the idea that cocaine-induced, pharmacologically based neural adaptations promote the development of impulsive decision making.

Effects of acute administration of nicotine, amphetamine, diazepam, morphine, and ethanol on risky decision-making in rats.

RATIONALE: Most individuals can accurately assess the risks and rewards associated with choice alternatives and decide accordingly; however, drug users often display maladaptive decision-making, such that choices are biased toward excessively risky options. OBJECTIVE: The purpose of this study was to investigate the effects of a range of drugs of abuse on risky decision-making. METHODS: Male Long-Evans rats were trained in the Risky Decision-Making Task, in which they chose between two levers, one which produced a small, "safe" food reward and the other which produced a large, "risky" food reward. The large reward was accompanied by the risk of a mild footshock, the probability of which increased over the course of each test session (0%, 25%, 50%, 75%, and 100%). RESULTS: Nicotine (0.6 mg/kg) and amphetamine (1.5 mg/kg) caused a significant decrease in choice of the large risky reward (decreased risk taking). Diazepam (1.0 mg/kg) caused a significant increase in choice of the large risky reward (increased risk taking), whereas morphine (3.0 mg/kg) caused only a trend toward increased choice of the large risky reward. Ethanol had no effect on choice behavior. CONCLUSIONS: These results show that acute administration of drugs of abuse can modulate risk taking in a drug-specific manner, either increasing or decreasing preference for highly rewarding, but risky, options.

Risk, reward, and decision-making in a rodent model of cognitive aging.

Impaired decision-making in aging can directly impact factors (financial security, health care) that are critical to maintaining quality of life and independence at advanced ages. Naturalistic rodent models mimic human aging in other cognitive domains, and afford the opportunity to parse the effects of age on discrete aspects of decision-making in a manner relatively uncontaminated by experiential factors. Young adult (5-7 months) and aged (23-25 months) male F344 rats were trained on a probability discounting task in which they made discrete-trial choices between a small certain reward (one food pellet) and a large but uncertain reward (two food pellets with varying probabilities of delivery ranging from 100 to 0%). Young rats chose the large reward when it was associated with a high probability of delivery and shifted to the small but certain reward as probability of the large reward decreased. As a group, aged rats performed comparably to young, but there was significantly greater variance among aged rats. One subgroup of aged rats showed strong preference for the small certain reward. This preference was maintained under conditions in which large reward delivery was also certain, suggesting decreased sensitivity to reward magnitude. In contrast, another subgroup of aged rats showed strong preference for the large reward at low probabilities of delivery. Interestingly, this subgroup also showed elevated preference for probabilistic rewards when reward magnitudes were equalized. Previous findings using this same aged study population described strongly attenuated discounting of delayed rewards with age, together suggesting that a subgroup of aged rats may have deficits associated with accounting for reward costs (i.e., delay or probability). These deficits in cost-accounting were dissociable from the age-related differences in sensitivity to reward magnitude, suggesting that aging influences multiple, distinct mechanisms that can impact cost-benefit decision-making.

Self-administered cocaine causes long-lasting increases in impulsive choice in a delay discounting task.

Cocaine use is associated with high levels of impulsive choice (preference for immediate over delayed rewards), but it is not clear whether cocaine use causes elevated impulsive choice, or whether elevated impulsive choice is solely a predisposing factor for cocaine use. This study examined the effects of prior cocaine self-administration on rats performing a delay discounting task commonly used to measure impulsive choice. Male Long-Evans rats were implanted with intravenous catheters, and following recovery, were trained to self-administer 30 mg/kg/day cocaine HCl (approx. 0.5 mg/kg/infusion) for 14 consecutive days (a control group received yoked intravenous saline infusions). Following three weeks of withdrawal, all rats were food-restricted and began training on the delay discounting task in standard operant chambers. On each trial, rats were given a choice between two levers. A press on one lever delivered a small food reward immediately, and a press on the other delivered a large food reward after a variable delay period. Rats that self-administered cocaine displayed greater impulsive choice (enhanced preference for the small immediate over the large delayed reward, as reflected by shorter indifference points) compared to controls, but were no different from controls on a "probabilistic discounting" task in which they chose between small certain and large uncertain rewards. These data suggest that self-administered cocaine can cause lasting elevations in impulsive choice, and that the high levels of impulsive choice observed in human cocaine users may be due in part to long-term effects of cocaine on brain function.