Drug cue reactivity involves hierarchical instrumental learning: evidence from a biconditional Pavlovian to instrumental transfer task

This is the final version of the article. Available from Springer Verlag via the DOI in this record.RATIONALE: Drug cue reactivity plays a crucial role in addiction, yet the underlying mechanisms are poorly understood. According to the binary associative account, drug stimuli retrieve an expectation of the drug outcome, which, in turn, elicits the associated drug-seeking response (S-O-R). By contrast, according to the hierarchical account, drug stimuli retrieve an expectation that the contingency between the drug-seeking response and the drug outcome is currently more effective, promoting performance of the drug-seeking response (S:R-O). METHODS: The current study discriminated between these two accounts using a biconditional Pavlovian-to-instrumental transfer (PIT) task with 128 alcohol drinkers. A biconditional discrimination was first trained in which two responses produced alcohol and food outcomes, respectively, and these response-outcome contingencies were reversed across two discriminative stimuli (SDs). In the PIT test, alcohol and food cues were compounded with the two SDs to examine their impact on percent alcohol choice in extinction. RESULTS: It was found that alcohol and food cues selectively primed choice of the response that earned that outcome in each SD (p < .001), and this effect was associated with participants' belief that cues signalled greater effectiveness of that response (p < .0001). CONCLUSIONS: The alcohol stimulus could not have selectively primed the alcohol-seeking response through binary S-O-R associations because the drug outcome was equally associated with both responses. Rather, the alcohol stimulus must have retrieved an expectation that the response-alcohol contingency available in the current context was more likely to be effective (S:R-O), which primed performance of the alcohol-seeking response.The work was supported by an ESRC PhD scholarship to Lorna Hardy

Automaticity and cognitive control: Effects of cognitive load on cue-controlled reward choice

This is the author accepted manuscript. The final version is available from SAGE Publications via the DOI in this recordThe extent to which human outcome-response (O-R) priming effects are automatic or under cognitive control is currently unclear. Two experiments tested the effect of cognitive load on O-R priming to shed further light on the debate. In Experiment 1, two instrumental responses earned beer and chocolate points in an instrumental training phase. Instrumental response choice was then tested in the presence of beer, chocolate, and neutral stimuli. On test, a Reversal instruction group was told that the stimuli signalled which response would not be rewarded. The transfer test was also conducted under either minimal (No Load) or considerable (Load) cognitive load. The Non-Reversal groups showed O-R priming effects, where the reward cues increased the instrumental responses that had previously produced those outcomes, relative to the neutral stimulus. This effect was observed even under cognitive load. The Reversal No Load group demonstrated a reversed effect, where response choice was biased towards the response that was most likely to be rewarded according to the instruction. Most importantly, response choice was at chance in the Reversal Load condition. In Experiment 2, cognitive load abolished the sensitivity to outcome devaluation that was otherwise seen when multiple outcomes and responses were cued on test. Collectively, the results demonstrate that complex O-R priming effects are sensitive to cognitive load, whereas the very simple, standard O-R priming effect is more robust

Goal-directed control in Pavlovian-instrumental transfer

The current article concerns human outcome - selective Pavlovian - instrumental transfer (PIT), where Pavlovian cues selectively invigorate instrumental responses that predict common rewarding outcomes. Several recent experiments have observed PIT effects that were insensitive to outcome devaluation manipulations, which has been taken as evidence of an automatic “associative” mechanism. Other similar studies observed PIT effects that were sensitive to devaluation, which suggest s a more controlled, goal - directed process. Studies supporting the automatic approach have been criticised for using a biased baseline, while studies supporting the goal - directed approach have been criticised for priming multiple outcomes attest. The current experiment addressed both of these issues. Participants first learned to perform two instrumental responses to earn two outcomes each (R1 - O1/ O3, R2 - O2/ O4), before four Pavlovian stimuli (S1 - S4) were trained to predict each outcome. One outcome that was paired with each instrumental response (O3 and O4) was then devalued, so that baseline response choice at test would be balanced. Instrumental responding was then assessed in the presence of each individual Pavlovian stimulus, so that only one outcome was primed per trial. PIT effect s were observed for the valued outcomes , t s > 3.99, p s < .001, but not for the devalued outcomes , F < 1 , BF 10 = 0.29. Hence, when baseline response choice was equated and only one outcome was primed per test trial, PIT was sensitive to outcome devaluation. The data therefore support goal - directed models of PIT

Bis(tetra­phenyl­phospho­nium) bis­[N-(2,5-dichloro­phenyl­sulfon­yl)dithio­carbimato(2−)-κ2 S,S′]platinate(II)

In the title salt, (C24H20P)2[Pt(C7H3Cl2NO2S3)2], the PtII ion (site symmetry ) is coordinated by two S,S′-bidentate N-(2,5-dichloro­phenyl­sulfon­yl)dithio­carbimate ligands, resulting in a slightly distorted PtS4 square-planar geometry. In the crystal, a C—H⋯O inter­action is observed, as well as electrostatic attraction between the oppositely charged ions

Langmuir-Blodgett films of polyethylene

The possibility to obtain surface layers on water and prepare solid multilayer Langmuir–Blodgett films of medium-density polyethylene is shown. The polymer film on water is stable, demonstrates a reversible surface pressure-area isotherm up to 15 mN/m, and can be deposited onto a substrate using the Langmuir–Blodgett technique in a wide range of surface pressures. The thickness of a single deposited layer is 5.1 nm on average. The dielectric and optical constants of multilayer films are near their bulk values. The films exhibit high dielectric strength of at least 200 MV/m

Electrophysiological correlates of associative learning in smokers: a higher-order conditioning experiment

Background: Classical conditioning has been suggested to play an important role in the development, maintenance, and relapse of tobacco smoking. Several studies have shown that initially neutral stimuli that are directly paired with smoking are able to elicit conditioned responses. However, there have been few human studies that demonstrate the contribution of higher-order conditioning to smoking addiction, although it is assumed that higher-order conditioning predominates learning in the outside world. In the present study a higher-order conditioning task was designed in which brain responses of smokers and non-smokers were conditioned by pairing smoking-related and neutral stimuli (CS1smokeand CS1neutral) with two geometrical figures (CS2smokeand CS2neutral). ERPs were recorded to all CSs.Results: Data showed that the geometrical figure that was paired with smoking stimuli elicited significantly larger P2 and P3 waves than the geometrical figure that was paired with neutral stimuli. During the first half of the experiment this effect was only present in smokers whereas non-smokers displayed no significant differences between both stimuli, indicating that neutral cues paired with motivationally relevant smoking-related stimuli gain more motivational significance even though they were never paired directly with smoking. These conclusions are underscored by self-reported evidence of enhanced second-order conditioning in smokers.Conclusions: It can be concluded that smokers show associative learning for higher-order smoking-related stimuli. The present study directly shows the contribution of higher-order conditioning to smoking addiction and is the first to reveal its electrophysiological correlates. Although results are preliminary, they may help in understanding the etiology of smoking addiction and its persistence

Immunomodulation of inflammatory leukocyte markers during intravenous immunoglobulin treatment associated with clinical efficacy in chronic inflammatory demyelinating polyradiculoneuropathy

© 2016 The Authors. Brain and Behavior published by Wiley Periodicals, Inc. Objective: The objective of the study was to profile leukocyte markers modulated during intravenous immunoglobulin (IVIg) treatment, and to identify markers and immune pathways associated with clinical efficacy of IVIg for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with potential for monitoring treatment efficacy. Methods: Response to IVIg treatment in newly diagnosed IVIg-naïve and established IVIg-experienced patients was assessed by changes in expression of inflammatory leukocyte markers by flow cytometry. The adjusted INCAT disability and Medical Research Council sum scores defined clinical response. Results: Intravenous immunoglobulin modulated immunopathogenic pathways associated with inflammatory disease in CIDP. Leukocyte markers of clinical efficacy included reduced CD185 + follicular helper T cells, increased regulatory markers (CD23 and CD72) on B cells, and reduction in the circulating inflammatory CD16 + myeloid dendritic cell (mDC) population and concomitant increase in CD62L and CD195 defining a less inflammatory lymphoid homing mDC phenotype. A decline in inflammatory CD16 + dendritic cells was associated with clinical improvement or stability, and correlated with magnitude of improvement in neurological assessment scores, but did not predict relapse. IVIg also induced a nonspecific improvement in regulatory and reduced inflammatory markers not associated with clinical response. Conclusions: Clinically effective IVIg modulated inflammatory and regulatory pathways associated with ongoing control or resolution of CIDP disease. Some of these markers have potential for monitoring outcome

Evidence for Habitual and Goal-Directed Behavior Following Devaluation of Cocaine: A Multifaceted Interpretation of Relapse

BACKGROUND:Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug's consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue-induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit. METHODOLOGY/PRINCIPAL FINDINGS:We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self-administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal-directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine. CONCLUSIONS/SIGNIFICANCE:Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus-nearly perfectly correlated with the infusion-likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse