On the neural computation of utility

The rewarding effect produced by electrical stimulation of the lateral hypothalamus can compete and summate with gustatory rewards. However, physiological manipulations, such as sodium depletion and the accumulation of an energy-rich solution in the gut, can alter the rewarding impact of the gustatory stimuli without producing substantial changes in the rewarding effect of the electrical stimulation. On the basis of their competition and summation, it is argued that the artificial and natural rewards are evaluated in a common currency, represented in an aggregate firing-rate code. Such a code would make it possible for the synchronous, spatially contiguous pattern of neural firing induced by the electrode to simulate a signal normally produced by asynchronous, spatially distributed activity. It is suggested that a unidimensional code of this sort is employed to represent the utility of a goal object. In order for physiological feedback to alter the utility of one natural reward, such as sucrose, without changing the utility of a second natural reward, such as a salt solution, the physiological feedback signals must enter into the computation of utility at a stage of processing in which the representations of the two natural rewards are distinct. However, orderly choice between such rewards implies that their utilities are expressed ultimately in a common neural currency. That physiological feedback alters the rewarding effects of the gustatory stimuli suggests that the physiological feedback signals modulate the value of such natural stimuli at a stage of processing prior to their translation into a common currency. In contrast, physiological feedback would fail to alter the rewarding effect of the electrical stimulation if the electrically evoked signal is injected at a later stage processing, a stage in which different rewards are represented in a common currency. In this view, the signal injected by the electrical stimulation mimics the utility of a natural stimulus but not its sensory quality

A new view of the effect of dopamine receptor antagonism on operant performance for rewarding brain stimulation in the rat

RATIONALE:Previous studies of neuroleptic challenges to intracranial self-stimulation (ICSS) employed two-dimensional (2D) measurements (curve shifts). Results so obtained are ambiguous with regard to the stage of neural processing at which the drug produces its performance-altering effect. We substituted a three-dimensional (3D) method that measures reward-seeking as a function of both the strength and cost of reward. This method reveals whether changes in reward seeking are due to drug action prior to the output of the circuitry that performs spatiotemporal integration of the stimulation-induced neural activity. OBJECTIVES:The aim of this study was to obtain new information about the stage of neural processing at which pimozide acts to alter pursuit of brain stimulation reward (BSR). METHODS:Following treatment with pimozide (0.1 mg/kg) or its vehicle, the proportion of trial time allocated to working for BSR was measured as a function of pulse frequency and opportunity cost. A surface defined by Shizgal's reward-mountain model was fitted to the drug and vehicle data. RESULTS:Pimozide lowered the cost required to decrease performance for a maximal BSR to half its maximal level but did not alter the pulse-frequency required to produce a reward of half-maximal intensity. CONCLUSIONS:Like indirect dopamine agonists, pimozide does not alter the sensitivity of brain reward circuity but changes reward-syste

Role of dopamine tone in the pursuit of brain stimulation reward

Dopaminergic neurons contribute to intracranial self-stimulation (ICSS) and other reward-seeking behaviors, but it is not yet known where dopaminergic neurons intervene in the neural circuitry underlying reward pursuit or which psychological processes are involved. In rats working for electrical stimulation of the medial forebrain bundle, we assessed the effect of GBR-12909, a specific blocker of the dopamine transporter. Operant performance was measured as a function of the strength and cost of electrical stimulation. GBR-12909 increased the opportunity cost most subjects were willing to pay for a reward of a given intensity. However, this effect was smaller than that produced by a regimen of cocaine administration that drove similar increases in nucleus accumbens (NAc) dopamine levels in unstimulated rats. Delivery of rewarding stimulation to drug-treated rats caused an additional increase in dopamine concentration in the NAc shell in cocaine-treated, but not GBR-treated, rats. These behavioral and neurochemical differences may reflect blockade of the norepinephrine transporter by cocaine but not by GBR-12909. Whereas the effect of psychomotor stimulants on ICSS has long been attributed to dopaminergic action at early stages of the reward pathway, the results reported here imply that increased dopamine tone boosts reward pursuit by acting at or beyond the output of the circuitry that temporally and spatially summates the output of the directly stimulated neurons underlying ICSS. The observed enhancement of reward seeking could be due to a decrease in the value of competing behaviors, a decrease in subjective effort costs, or an increase in reward-system gain. Video: The video reveals a fundamental source of ambiguity in two-dimensional measurements of operant performance for reward, such as those obtained in the curveshift and progressive-ratio paradigms. We show how the three-dimensional portrayal provided by the reward-mountain model resolves this ambiguity. The reward-mountain model is derived, described, discussed, and applied in the following papers: • Arvanitogiannis A, & Shizgal P (2008). The reinforcement mountain: allocation of behavior as a function of the rate and intensity of rewarding brain stimulation. Behav Neurosci 122:1126-1138. doi: 10.1037/a0012679 http://psycnet.apa.org/journals/bne/122/5/1126/ • Hernandez G, Breton YA, Conover K, & Shizgal P (2010). At what stage of neural processing does cocaine act to boost pursuit of rewards? PLoS One 5:e15081. doi: 10.1371/journal.pone.0015081 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015081 • Shizgal, P, & Hernandez, G (2010). Intracranial Self-Stimulation. Encyclopedia of Psychopharmacology, 653–660. doi:10.1007/978-3-540-68706-1_66 http://www.springerlink.com/content/w37074k2586301j6/?MUD=MP • Trujillo-Pisanty I, Hernandez G, Moreau-Debord I, Cossette MP, Conover K, Cheer JF, & Shizgal P (2011). Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation. J Neurosci 31:5426-5435. http://www.jneurosci.org/content/31/14/5426.long • Shizgal, P. (2012). Scarce means with alternative uses: Robbins' definition of economics and its extension to the behavioral and neurobiological study of animal decision making. Frontiers in Neuroscience, 6, 20. doi:10.3389/fnins.2012.00020 http://www.frontiersin.org/Decision_Neuroscience/10.3389/fnins.2012.00020/abstract • Hernandez, G., Trujillo-Pisanty, I., Cossette, M-P., Conover, K., & Shizgal, P. (2012). Role of dopamine tone in the pursuit of brain stimulation reward. Journal of Neuroscience, 2012, in press

Optimal indolence: a normative microscopic approach to work and leisure

Dividing limited time between work and leisure when both have their attractions is a common everyday decision. We provide a normative control theoretic treatment of this decision that bridges economic and psychological accounts. We show how our framework applies to free-operant behavioural experiments in which subjects are required to work (depressing a lever) for sufficient total time (called the price) to receive a reward. When the microscopic benefit-of-leisure increases nonlinearly with duration, the model generates behaviour that qualitatively matches various microfeatures of subjects’ choices, including the distribution of leisure bout durations as a function of the payoff. We relate our model to traditional accounts by deriving macroscopic, molar, quantities from microscopic choices

Cannabinoid receptor blockade reduces the opportunity cost at which rats maintain operant performance for rewarding brain stimulation

There is ample evidence that blockade of CB1 receptors reduces reward seeking. However, the reported effects of CB1 blockade on performance for rewarding electrical brain stimulation stand out as an exception. By applying a novel method for conceptualizing and measuring reward seeking, we show that AM-251, a CB1 receptor antagonist, does indeed decrease performance for rewarding electrical stimulation of the medial forebrain bundle in rats. Reward-seeking depends on multiple sets of variables, including the intensity of the reward, its cost, and the value of competing rewards. In turn, reward intensity depends both on the sensitivity and gain of brain reward circuitry. We show that drug-induced changes in sensitivity cannot account for the suppressive effect of AM-251 on reward seeking. Therefore, the role of CB1 receptors must be sought among the remaining determinants of performance. Our analysis provides an explanation of the inconsistencies between prior reports, which likely arose from: a) the averaging of data across subjects showing heterogeneous effects and b) the use of methods that cannot distinguish between the different determinants of reward pursuit. By means of microdialysis, we demonstrate that blockade of CB1 receptors attenuates nucleus accumbens dopamine release in response to rewarding medial forebrain bundle stimulation, and we propose that this action is responsible for the ability of the drug to decrease performance for the electrical reward

Asymptotic behaviour and optimal word size for exact and approximate word matches between random sequences

BACKGROUND: The number of k-words shared between two sequences is a simple and effcient alignment-free sequence comparison method. This statistic, D(2), has been used for the clustering of EST sequences. Sequence comparison based on D(2 )is extremely fast, its runtime is proportional to the size of the sequences under scrutiny, whereas alignment-based comparisons have a worst-case run time proportional to the square of the size. Recent studies have tackled the rigorous study of the statistical distribution of D(2), and asymptotic regimes have been derived. The distribution of approximate k-word matches has also been studied. RESULTS: We have computed the D(2 )optimal word size for various sequence lengths, and for both perfect and approximate word matches. Kolmogorov-Smirnov tests show D(2 )to have a compound Poisson distribution at the optimal word size for small sequence lengths (below 400 letters) and a normal distribution at the optimal word size for large sequence lengths (above 1600 letters). We find that the D(2 )statistic outperforms BLAST in the comparison of artificially evolved sequences, and performs similarly to other methods based on exact word matches. These results obtained with randomly generated sequences are also valid for sequences derived from human genomic DNA. CONCLUSION: We have characterized the distribution of the D(2 )statistic at optimal word sizes. We find that the best trade-off between computational efficiency and accuracy is obtained with exact word matches. Given that our numerical tests have not included sequence shuffling, transposition or splicing, the improvements over existing methods reported here underestimate that expected in real sequences. Because of the linear run time and of the known normal asymptotic behavior, D(2)-based methods are most appropriate for large genomic sequences

Leukocytes Are Recruited through the Bronchial Circulation to the Lung in a Spontaneously Hypertensive Rat Model of COPD

Chronic obstructive pulmonary disease (COPD) kills approximately 2.8 million people each year, and more than 80% of COPD cases can be attributed to smoking. Leukocytes recruited to the lung contribute to COPD pathology by releasing reactive oxygen metabolites and proteolytic enzymes. In this work, we investigated where leukocytes enter the lung in the early stages of COPD in order to better understand their effect as a contributor to the development of COPD. We simultaneously evaluated the parenchyma and airways for neutrophil accumulation, as well as increases in the adhesion molecules and chemokines that cause leukocyte recruitment in the early stages of tobacco smoke induced lung disease. We found neutrophil accumulation and increased expression of adhesion molecules and chemokines in the bronchial blood vessels that correlated with the accumulation of leukocytes recovered from the lung. The expression of adhesion molecules and chemokines in other vascular beds did not correlate with leukocytes recovered in bronchoalveolar lavage fluid (BALF). These data strongly suggest leukocytes are recruited in large measure through the bronchial circulation in response to tobacco smoke. Our findings have important implications for understanding the etiology of COPD and suggest that pharmaceuticals designed to reduce leukocyte recruitment through the bronchial circulation may be a potential therapy to treat COPD

At What Stage of Neural Processing Does Cocaine Act to Boost Pursuit of Rewards?

Dopamine-containing neurons have been implicated in reward and decision making. One element of the supporting evidence is that cocaine, like other drugs that increase dopaminergic neurotransmission, powerfully potentiates reward seeking. We analyze this phenomenon from a novel perspective, introducing a new conceptual framework and new methodology for determining the stage(s) of neural processing at which drugs, lesions and physiological manipulations act to influence reward-seeking behavior. Cocaine strongly boosts the proclivity of rats to work for rewarding electrical brain stimulation. We show that the conventional conceptual framework and methods do not distinguish between three conflicting accounts of how the drug produces this effect: increased sensitivity of brain reward circuitry, increased gain, or decreased subjective reward costs. Sensitivity determines the stimulation strength required to produce a reward of a given intensity (a measure analogous to the KM of an enzyme) whereas gain determines the maximum intensity attainable (a measure analogous to the vmax of an enzyme-catalyzed reaction). To distinguish sensitivity changes from the other determinants, we measured and modeled reward seeking as a function of both stimulation strength and opportunity cost. The principal effect of cocaine was a two-fourfold increase in willingness to pay for the electrical reward, an effect consistent with increased gain or decreased subjective cost. This finding challenges the long-standing view that cocaine increases the sensitivity of brain reward circuitry. We discuss the implications of the results and the analytic approach for theories of how dopaminergic neurons and other diffuse modulatory brain systems contribute to reward pursuit, and we explore the implications of the conceptual framework for the study of natural rewards, drug reward, and mood

Risk of hydroxychloroquine alone and in combination with azithromycin in the treatment of rheumatoid arthritis: a multinational, retrospective study

Background: Hydroxychloroquine, a drug commonly used in the treatment of rheumatoid arthritis, has received much negative publicity for adverse events associated with its authorisation for emergency use to treat patients with COVID-19 pneumonia. We studied the safety of hydroxychloroquine, alone and in combination with azithromycin, to determine the risk associated with its use in routine care in patients with rheumatoid arthritis. Methods: In this multinational, retrospective study, new user cohort studies in patients with rheumatoid arthritis aged 18 years or older and initiating hydroxychloroquine were compared with those initiating sulfasalazine and followed up over 30 days, with 16 severe adverse events studied. Self-controlled case series were done to further establish safety in wider populations, and included all users of hydroxychloroquine regardless of rheumatoid arthritis status or indication. Separately, severe adverse events associated with hydroxychloroquine plus azithromycin (compared with hydroxychloroquine plus amoxicillin) were studied. Data comprised 14 sources of claims data or electronic medical records from Germany, Japan, the Netherlands, Spain, the UK, and the USA. Propensity score stratification and calibration using negative control outcomes were used to address confounding. Cox models were fitted to estimate calibrated hazard ratios (HRs) according to drug use. Estimates were pooled where the I2 value was less than 0·4. Findings: The study included 956 374 users of hydroxychloroquine, 310 350 users of sulfasalazine, 323 122 users of hydroxychloroquine plus azithromycin, and 351 956 users of hydroxychloroquine plus amoxicillin. No excess risk of severe adverse events was identified when 30-day hydroxychloroquine and sulfasalazine use were compared. Self-controlled case series confirmed these findings. However, long-term use of hydroxychloroquine appeared to be associated with increased cardiovascular mortality (calibrated HR 1·65 [95% CI 1·12–2·44]). Addition of azithromycin appeared to be associated with an increased risk of 30-day cardiovascular mortality (calibrated HR 2·19 [95% CI 1·22–3·95]), chest pain or angina (1·15 [1·05–1·26]), and hear