Computational approaches to modeling gambling behaviour: Opportunities for understanding disordered gambling.

Computational modeling has become an important tool in neuroscience and psychiatry research to provide insight into the cognitive processes underlying normal and pathological behavior. There are two modeling frameworks, reinforcement learning (RL) and drift diffusion modeling (DDM), that are well-developed in cognitive science, and have begun to be applied to Gambling Disorder. RL models focus on explaining how an agent uses reward to learn about the environment and make decisions based on outcomes. The DDM is a binary choice framework that breaks down decision making into psychologically meaningful components based on choice reaction time analyses. Both approaches have begun to yield insight into aspects of cognition that are important for, but not unique to, gambling, and thus relevant to the development of Gambling Disorder. However, these approaches also oversimplify or neglect various aspects of decision making seen in real-world gambling behavior. Gambling Disorder presents an opportunity for 'bespoke' modeling approaches to consider these neglected components. In this review, we discuss studies that have used RL and DDM frameworks to investigate some of the key cognitive components in gambling and Gambling Disorder. We also include an overview of Bayesian models, a methodology that could be useful for more tailored modeling approaches. We highlight areas in which computational modeling could enable progression in the investigation of the cognitive mechanisms relevant to gambling.

The ß-adrenoceptor blocker propranolol ameliorates compulsive-like gambling behaviour in a rodent slot machine task: implications for iatrogenic gambling disorder.

Previous work has shown that chronic administration of the dopamine D2/3 receptor agonist ropinirole invigorates performance on a rodent slot machine task (rSMT). This behavioural change appears superficially similar to the iatrogenic gambling disorder (GD) observed in a sub-set of patients with Parkinson's disease (PD), and has been associated with increased activation of the intra-cellular signalling proteins GSK3ß and CREB in the striatum. Here, we wanted to determine whether this response to ropinirole could be attenuated by targeting these signalling proteins, and if the loss of dopaminergic innervation characteristic of PD would alter ropinirole's effects on the rSMT. Male Long Evans rats were trained on the rSMT. Dopaminergic terminals innervating the dorsolateral striatum were then lesioned bilaterally using the neurotoxin 6-hydroxydopamine hydrochloride (6-OHDA). Subsequently animals were implanted with osmotic mini-pumps delivering ropinirole. Lastly, animals were given dietary lithium (Li+ ), to inhibit the activation of GSK3ß, or injections of the ß-adrenoceptor antagonist propranolol, which potently inhibits CREB as a secondary mechanism of action, and any changes in ropinirole-induced increases in compulsive-like engagement in the rSMT evaluated. Chronic ropinirole increased the number of trials animals completed, reproducing our original finding. This increase in task engagement was not altered in animals with 6-OHDA lesions, a putative model of early PD. In addition, the effects of ropinirole were not attenuated by administration of Li+ , but were ameliorated by propranolol. These data suggest that propranolol may represent a potential pharmacotherapy for the treatment of iatrogenic gambling.

Adverse obstetric history is not a risk factor for poor outcome after ventral rectopexy for obstructive defaecation syndrome.

AIM: Ventral rectopexy (VR) has gained popularity in the management of obstructive defaecation syndrome (ODS) due to a symptomatic rectocele ± intussusception. Data on the efficacy and safety of VR are variable and there are few predictors of successful outcome. This study aimed to examine whether or not an adverse obstetric history influenced the functional outcome following VR for ODS. METHOD: This was a retrospective study of a cohort of 76 consecutive patients who had undergone VR for ODS at a tertiary referral centre between 2012 and 2015. Patients were followed up by telephone questionnaire. The obstetric history and pre- and postoperative symptoms of ODS and faecal incontinence (FI) were obtained from telephone interviews. RESULTS: In this cohort, symptoms of ODS were significantly improved by surgery, with 56% of patients showing a reduction of symptoms of 50% or more (P < 0.001). Subgroup analysis demonstrated that a lower body mass index (BMI; 24.4 vs 27.3 kg/m2 ; P < 0.05) and shorter duration of symptoms (7 vs 10 years; P < 0.05) led to a better outcome. VR had no effect on FI. Obstetric factors such as foetal weight, instrumental delivery, episiotomy, perineal tear and total number of deliveries did not influence outcomes. CONCLUSION: Patients with a less straightforward obstetric history can be reassured that this should not adversely influence the functional outcome after VR for ODS. Colorectal surgeons who offer this surgery should warn patients with an elevated BMI or with longstanding symptoms that the operation may be less successful than for those with a lower BMI or shorter duration of symptoms.

Dietary influences on cognition.

Obesity is a world-wide crisis with profound healthcare and socio-economic implications and it is now clear that the central nervous system (CNS) is a target for the complications of metabolic disorders like obesity. In addition to decreases in physical activity and sedentary lifestyles, diet is proposed to be an important contributor to the etiology and progression of obesity. Unfortunately, there are gaps in our knowledge base related to how dietary choices impact the structural and functional integrity of the CNS. For example, while chronic consumption of hypercaloric diets (increased sugars and fat) contribute to increases in body weight and adiposity characteristic of metabolic disorders, the mechanistic basis for neurocognitive deficits in obesity remains to be determined. In addition, studies indicate that acute consumption of hypercaloric diets impairs performance in a wide variety of cognitive domains, even in normal non-obese control subjects. These results from the clinical and basic science literature indicate that diet can have rapid, as well as long lasting effects on cognitive function. This review summarizes our symposium at the 2017 Society for the Study of Ingestive Behavior (SSIB) meeting that discussed these effects of diet on cognition. Collectively, this review highlights the need for integrated and comprehensive approaches to more fully determine how diet impacts behavior and cognition under physiological conditions and in metabolic disorders like type 2 diabetes mellitus (T2DM) and obesity.

Inactivation of the orbitofrontal cortex reduces irrational choice on a rodent Betting Task.

Cognitive biases may play a significant role in disorders of decision making such as pathological gambling and addiction. Understanding the neurobiology of these biases could lead to more effective pharmacological and therapeutic treatments for disorders in which aberrant decision making is prominent. The rodent Betting Task (rBT) was designed to measure one commonly observed decision-making heuristic in rodents, namely "escalation of commitment" in which subjects become more risk averse as the stakes increase, even if the odds of success remain constant. In the rodent task, the animal is presented with a choice between two options of equivalent expected value, such that reward on one option is guaranteed while the other has a 50% chance of double the prize or nothing. Past work has shown that a subset of animals (termed wager sensitive) adopt an irrationally risk-averse choice preference in which they shift their choice away from the uncertain option as the bet size grows larger. In the current study, the orbitofrontal (OFC), prelimbic (PrL), and infralimbic cortex (IL) were inactivated to evaluate the contributions made by these regions to choice behavior on the rBT. Inactivation of the OFC (but not the IL or the PrL) selectively ameliorated the risk-averse choice pattern characteristic of wager-sensitive animals. This finding suggests that the OFC may have a relatively unique role in promoting this type of non-normative decision-making under uncertainty, an effect that is potentially related to its role in representing the subjective value of reinforcing outcomes.

The agranular and granular insula differentially contribute to gambling-like behavior on a rat slot machine task: effects of inactivation and local infusion of a dopamine D4 agonist on reward expectancy.

RATIONALE: Rats, like humans, are susceptible to the reinforcing effects of reward-related stimuli presented within a compound stimulus array, putatively analogous to the so-called near-miss effect. We have previously demonstrated using a rodent slot machine task (rSMT) that the reward expectancy these stimuli elicit is critically mediated by the dopamine D4 receptor. D4 receptors are principally located in prefrontal regions activated during slot machine play in humans, such as the insular cortex. The insula has recently attracted considerable interest as it appears to play a crucial role in substance and behavioral addictions. However, the insula is a heterogeneous area, and the relative contributions of subregions to addictive behaviors are unclear. METHODS: Male Long Evans rats were trained to perform the rSMT, and then bilateral cannula targeting either the granular or agranular insula were implanted. The effects of inactivation and local administration of a D4 agonist were investigated. RESULTS: Temporary inactivation of the agranular, but not the granular insula impaired performance on the rSMT. In contrast, local infusion of the D4 agonist PD168077 into the agranular insula had no effect on task performance, but when administered into the granular insula, it improved animals' ability to differentiate winning from non-winning trials. The agranular insula may therefore modulate decision making when conflicting stimuli are present, potentially due to its role in generating a cohesive emotional percept based on both externally and internally generated signals, whereas the granular insular is not critical for this process. Nevertheless, D4 receptors within the granular insula may amplify the incentive salience of aversive environmental stimuli. DISCUSSION: These data provide insight into the neurobiological mechanism underpinning maladaptive reward expectancy during gambling and provide further evidence that D4 receptors represent a potential target for developing pharmacotherapies for problem gambling.

Elucidating the role of D4 receptors in mediating attributions of salience to incentive stimuli on Pavlovian conditioned approach and conditioned reinforcement paradigms.

The power of drug-associated cues to instigate drug 'wanting' and consequently promote drug seeking is a corner stone of contemporary theories of addiction. Gambling disorder has recently been added to the pantheon of addictive disorders due to the phenomenological similarities between the diseases. However, the neurobiological mechanism that may mediate increased sensitivity towards conditioned stimuli in addictive disorders is unclear. We have previously demonstrated using a rodent analogue of a simple slot machine that the dopamine D4 receptor is critically engaged in controlling animals' attribution of salience to stimuli associated with reward in this paradigm, and consequently may represent a target for the treatment of gambling disorder. Here, we investigated the role of acute administration of a D4 receptor agonist on animals' responsivity to conditioned stimuli on both a Pavlovian conditioned approach (autoshaping) and a conditioned reinforcement paradigm. Following training on one of the two tasks, separate cohorts of rats (male and female) were administered a dose of PD168077 shown to be maximally effective at precipitating errors in reward expectancy on the rat slot machine task (10mg/kg). However, augmenting the activity of the D4 receptors in this manner did not alter behaviour on either task. These data therefore provide novel evidence that the D4 receptor does not alter incentive motivation in response to cues on simple behavioural tasks.

Activation of dopamine D4 receptors within the anterior cingulate cortex enhances the erroneous expectation of reward on a rat slot machine task.

Using a rodent slot machine task (rSMT), we have previously shown that rats, like humans, are susceptible to the reinforcing effects of winning signals presented within a compound stimulus array, even when the pattern generated predicts a negative rather than a positive outcome such as during a "near-miss". The dopamine D4 receptor critically mediates the erroneous reward expectancy generated on such trials. D4 receptors are particularly enriched within frontal and limbic areas activated during slot machine play, such as the anterior cingulate cortex (ACC). We therefore selectively inactivated the ACC to confirm involvement of this region in rSMT performance, and subsequently examined the specific contribution of local D4 receptors. ACC inactivations generally impaired animals' ability to optimally differentiate winning from losing outcomes. Local administration of the D4 agonist PD168077 had a qualitatively similar effect, but increased reward expectancy was only evident on archetypal "near-miss" trials i.e. when the first two of three stimuli in the array were concordant with a rewarding outcome, and only the last stimulus critically signalled a non-win. These data indicate that the ACC is critically involved in parsing the appropriate response when competing stimulus-outcome associations are activated, and that signalling via D4 receptors may play a particularly important role in gating the temporal and spatial summation of salient events. Such findings provide novel insights into the mechanism underlying the erroneous expectations of reward generated when playing slot machines, and suggest a mechanism by which D4 receptor antagonists may be effective in treating gambling disorder.

Irrational beliefs, biases and gambling: exploring the role of animal models in elucidating vulnerabilities for the development of pathological gambling.

Gambling is a heterogeneous and complex disorder. Multiple factors may lead to problem gambling, yet one of the most important appears to be the increased presence of cognitive biases or distortions. These biases are thought to precipitate gambling as they can lead to dysfunctional decision making under risk or ambiguity. Modelling these cognitive perturbations in animals can improve our understanding of their neurobiological bases, and potentially stimulate novel treatment options. The first aim of this review is to give a broad overview of some of the cognitive biases that are most commonly associated with gambling. Secondly, we will discuss several animal models that we have developed in which rodent decision-making appears hallmarked by the same cognitive inconsistencies as human choice. In particular, we will discuss two tasks that capture elements of risk and loss averse decision making, and another in which rats appear susceptible to the 'near-miss' effect. To date, findings from both human and non-human studies suggest that these different biases are neuropharmacologically and neurostructurally dissociable, and that dopamine plays a key role in their expression. Lastly, we will briefly discuss areas in both human and animal research where limitations within the field may be hampering a more complete understanding of pathological gambling as a disorder.

Comparison of real time diagnostic chemistries to detect Pseudomonas aeruginosa in respiratory samples from cystic fibrosis patients.

BACKGROUND: Early eradication therapy is key to keeping the airways Pseudomonas aeruginosa infection-free and rapid identification is essential. METHODS: We used rapid DNA extraction and qPCR assays to detect bacterial, P. aeruginosa and strain-specific targets in samples using two qPCR chemistries. Using 459 respiratory samples from adult and children CF patients, we compared two qPCR methods to culture-based methods in terms of sensitivity and time to result. RESULTS: For adult samples, there was 100% concordance between methods. There was no clear pattern in fluctuations in P. aeruginosa number during exacerbation. In child samples, qPCR methods identified additional P. aeruginosa positive samples. The time-to-result was reduced by over 24h and copy number and colony forming unit could differ dramatically in some samples. CONCLUSION: If adopted, these methods could significantly improve early P. aeruginosa detection in diagnostic laboratories and therefore play a pivotal role in prolonging infection-free airways in CF patients.

Increasing resistance of the Liverpool Epidemic Strain (LES) of Pseudomonas aeruginosa (Psa) to antibiotics in cystic fibrosis (CF)--a cause for concern?

BACKGROUND: Transmissible Pseudomonas aeruginosa (Psa) strains such as the Liverpool Epidemic Strain (LES) are now widespread throughout UK CF clinics: their susceptibility to antibiotics is therefore important. To study this, we compared antibiogram patterns of Psa strains in our CF clinic over 5 years, looking at differences in resistance patterns between strains and changes to these over time. METHODS: The antibiograms of sputum samples between 2004 and 2008 from patients attending our centre were included. We compared Psa isolate antibiotic resistance (to six anti-pseudomonal antibiotics) patterns for patients infected with LES with those infected with other Psa strains, both in the total population in 2004 (125 patients) and 2008 (166 patients) and also longitudinally from annual review samples 2004 to 2008 in matched and unmatched patient groups. RESULTS: LES exhibited significantly more resistant isolates in 2004 (p<0.0001). There was an increase in antibiotic resistance in both LES and other Psa strains over time (p<0.001). Cox proportional hazards analysis of both unmatched (n=125) and matched (n=56) patients in 2004 revealed that LES infected patients were more likely to develop antibiotic resistant isolates over time (hazard ratio 8.1, p<0.001). Fewer LES isolates were classed as fully sensitive in both matched and unmatched groups at the end of study period (p<0.001). CONCLUSION: This study shows a worrying trend in antibiotic resistance in the Psa isolates amongst patients chronically infected with LES. This highlights the need to prevent cross infection through segregation and also the need to develop new strategies to treat these organisms.

Contributions of serotonin in addiction vulnerability.

The serotonin (5-hydroxytryptamine; 5-HT) system has long been associated with mood and its dysregulation implicated in the pathophysiology of mood and anxiety disorders. While modulation of 5-HT neurotransmission by drugs of abuse is also recognized, its role in drug addiction and vulnerability to drug relapse is a more recent focus of investigation. First, we review preclinical data supporting the serotonergic raphe nuclei and their forebrain projections as targets of drugs of abuse, with emphasis on the effects of psychostimulants, opioids and ethanol. Next, we examine the role of 5-HT receptors in impulsivity, a core behavior that contributes to the vulnerability to addiction and relapse. Finally, we discuss evidence for serotonergic dysregulation in comorbid mood and addictive disorders and suggest novel serotonergic targets for the treatment of addiction and the prevention of drug relapse.

Comparison of Arcobacter isolation methods, and diversity of Arcobacter spp. in Cheshire, United Kingdom.

The aims of this study were, firstly, to compare five published methods for the isolation of Arcobacter spp. from animal feces in order to determine the most sensitive and specific method. Second, we analyzed the resulting isolates by multilocus sequence typing (MLST) in order to investigate the diversity of the isolates recovered. Third, we investigated the ability to recover Arcobacter spp. from frozen fecal samples. Seventy-seven fecal samples from cattle, sheep, and badgers were subjected to five isolation methods, based on published methods for the isolation of Arcobacter and Campylobacter spp. Thirty-nine Arcobacter butzleri isolates were analyzed using a multilocus sequence typing scheme. The survival of Arcobacter spp. in frozen samples was investigated by freezing the fecal samples at -80°C for 7 days and then applying the same five isolation methods. The most sensitive and specific method used an Arcobacter-specific broth in conjunction with modified charcoal cefoperazone deoxycholate agar (mCCDA) with added antibiotics. Freezing of fecal samples led to a reduction in the recovery of Arcobacter spp. by approximately 50%. The 39 allelic profiles obtained by MLST could be divided into 11 sequence types (STs). We have identified the most sensitive and specific method for the isolation of Arcobacter spp. from animal feces and demonstrated that the freezing of fecal samples prior to isolation reduces arcobacter recovery. MLST analysis of the isolates revealed a high level of diversity.

Isolation of a novel Campylobacter jejuni clone associated with the bank vole, Myodes glareolus.

Campylobacter jejuni can be isolated from different animal hosts. Various studies have used multilocus sequence typing to look for associations between particular clones of C. jejuni and specific hosts. Here, we describe the isolation of a novel clone (sequence type 3704 [ST-3704]) of C. jejuni associated with the bank vole (Myodes glareolus).

Transmission of Pseudomonas aeruginosa epidemic strain from a patient with cystic fibrosis to a pet cat.

Chronic infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) and certain strains are more transmissible and virulent than others. Of these, the Liverpool Epidemic Strain (LES) is highly transmissible and cross infection has been reported between patients with CF and healthy non-CF relatives. However, the risk of transmission from humans to animals is unknown. The first report of interspecies transmission of the LES strain of P aeruginosa from an adult patient with CF to a pet cat is described. This development further complicates the issue of infection control policies required to prevent the spread of this organism.

Characterization of a spirochaete isolated from a case of bovine digital dermatitis.

AIMS: The aim of the study was to characterize a spirochaete isolated from the lesions of a cow with digital dermatitis (DD). METHODS AND RESULTS: The characterization was on the basis of its light and electron microscopic appearance, enzymic profile and DNA sequence analysis of its flagellin and 16S rRNA genes. The spirochaete was 6-8-microm long and 0.2-0.3 microm in diameter, and possessed seven to eight periplasmic flagella, with three to five helical turns. The enzymic profile of the bacterium resembles, but is not identical to that of Treponema brennaborense. Its flagellin gene sequence was identical to that of Treponema phagedenis but distinct from that of an ovine spirochaete. Analysis of a 1477-bp region of the 16S rRNA genes indicated that this is a Treponema species and that it is indistinguishable from some isolates made from cases of bovine DD in the United States. Finally, electron microscopy revealed the presence of myovirus-like bacteriophage particles in all cultures of the treponeme examined. CONCLUSIONS: The spirochaete isolate was identified as a Treponema species closely related to some isolates from the United States (by 16S rDNA) and to T. phagedenis (by flagellin gene sequence) and is associated with bacteriophage particles. SIGNIFICANCE AND IMPACT OF THE STUDY: The fact that the isolates with the same or very similar 16S rDNA sequences have been obtained from cases of bovine DD in cattle in different countries at different times, lends further support to the hypothesis that treponemes play a role in the pathogenesis of this disease.

Environmental contamination with an epidemic strain of Pseudomonas aeruginosa in a Liverpool cystic fibrosis centre, and study of its survival on dry surfaces.

We conducted an environmental survey in the Liverpool adult cystic fibrosis (CF) centre in order to determine the extent of environmental contamination with an epidemic strain of Pseudomonas aeruginosa that colonizes most CF patients in Liverpool, and to identify possible reservoirs and routes of cross-infection. In addition, we studied the survival of this strain on dry surfaces, compared with that of other CF P. aeruginosa strains, to explore factors that might contribute to its high transmissibility. Samples were collected from staff, patients and the environment (drains, bath tubs, showers, dry surfaces, respiratory equipment and air) in the inpatient ward and outpatient clinic. P. aeruginosa strains were tested using a new polymerase chain reaction amplification assay specific for the Liverpool epidemic strain (LES). LES was isolated from patients' hands, clothes and bed linen. Environmental contamination with LES was only detected in close proximity to colonized patients (external surfaces of their respiratory equipment, and spirometry machine tubing and chair) and was short-lived. No persistent environmental reservoirs were found. LES was detected in the majority of air samples from inside patients' rooms, the ward corridor and the outpatient clinic. Survival of LES on dry surfaces was significantly longer than that for some other strains tested, but not compared with other strains shown not to be transmissible. Improved environmental survival on its own, therefore, cannot explain the high transmissibility of this epidemic strain. Our study suggests that airborne dissemination plays a significant role in patient-to-patient spread of LES, and confirms the need to segregate those patients colonized by epidemic P. aeruginosa strains from all other CF patients.

Increased morbidity associated with chronic infection by an epidemic Pseudomonas aeruginosa strain in CF patients.

BACKGROUND: Chronic pulmonary infection with transmissible Pseudomonas aeruginosa strains in individuals with cystic fibrosis (CF) has been reported, raising issues of cross infection and patient segregation. The first such strain to be described (the Liverpool epidemic strain, LES) is now widespread in many UK CF centres. However, whether such infection carries a worse prognosis is unknown. To address this, the clinical course of a group of CF patients chronically infected by LES was compared with that in patients harbouring unique strains. METHODS: Using P aeruginosa strain genotyping, two cohorts of CF patients attending the Liverpool CF service were identified who were LES positive or negative in 1998 and remained so until 2002. From these, two groups of 12 patients were matched in 1998 for age, spirometric parameters, and nutritional state and their clinical course was followed for 5 years. Patients chronically infected with Burkholderia cepacia were excluded. RESULTS: Patients chronically infected with LES had a greater annual loss of lung function than those not chronically infected by LES (mean difference between groups -4.4% (95% CI -8.1 to -0.9; p<0.02)), and by 2002 their percentage predicted forced expiratory volume in 1 second (FEV1) was worse (mean 65.0% v 82.6%, p<0.03). Their nutritional state also deteriorated over the study period (mean difference between groups in body mass index -0.7 (95% CI -1.2 to -0.2; p<0.01)), such that by 2002 they were malnourished compared with LES negative patients (mean BMI 19.4 v 22.7, p<0.02). CONCLUSIONS: Chronic infection with the Liverpool epidemic P aeruginosa strain in CF patients confers a worse prognosis than infection with unique strains alone, confirming the need for patient segregation. Since this strain is common in many CF units, strain identification in all CF centres is essential. This can only be carried out using genomic typing methods.

Molecular characterization and distribution of virulence-associated genes amongst Aeromonas isolates from Libya.

AIMS: The aim of the study was to type 52 Aeromonas spp. isolates from chicken carcasses, children with diarrhoea and a hospital environment in Libya, and to determine the distribution of putative virulence genes amongst them. METHODS AND RESULTS: Macrorestriction analysis using pulsed-field gel electrophoresis (PFGE) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of 16S rRNA and aroA genes were used to type the isolates. Whereas 30 of 32 chicken isolates were identified as Aeromonas veronii, eight of 12 environmental isolates were Aer. caviae. Three species were identified amongst the eight isolates from children. Aeromonas veronii and Aer. caviae isolates could be divided into eight and five PFGE types, respectively. All species could be further subtyped into one of 21 aroA PCR-RFLP groups. Aerolysin-like haemolysin or enterotoxin gene sequences were detected in all the isolates. Overall carriage rates for hlyA and alt were 77 and 75%, respectively. CONCLUSIONS: Seven of eight isolates from children were of different subtypes, indicating a lack of any common source of acquisition. Isolates of common molecular type did not share identical distributions of putative virulence genes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the effectiveness of using molecular typing to identify and study genetic variation amongst Aeromonas isolates.