Faculty Bibliography

PURPOSE: To evaluate the clinical results of the use of biodegradable oesophageal stents in malignant strictures. METHODS: Eleven patients were included in this prospective analysis in which a woven polydioxanone biodegradable oesophageal stent was used. The inclusion criterion was that the patient underwent neoadjuvant treatment or radical radiotherapy after the stent insertion. Primary end points were dysphagia score at discharge, stent patency, and complication rate. Secondary end points were overall survival and surgical outcome of surgery. RESULTS: There was a 100% procedure technical success rate. Early complications occurred in three patients resulting in failure to restore oral nutrition. In the remaining eight patients, dysphagia was significantly improved at discharge. Mean stent patency rate in this group was 71.5 days. Stent dysfunction occurred in five of eight patients (62.5%); in two of five patients this was due to local inflammatory reaction, and in three of five patients it was due to tumour growth after a mean time of 97.8 days, and a new metallic stent was consequently placed in four of five patients. One patient was successfully treated with esophagectomy. At the end of follow-up (mean time 102.1 days), three of eight stents were patent. The overall patient survival rate was 81.8%. CONCLUSION: Although short-term dysphagia scores improved, biodegradable stents do not appear to offer a clear beneficial effect in most cases of malignant strictures, particularly due to a local inflammatory reaction that may be induced. Technical improvement of the device and delineation of the patient group that would benefit from its use is necessary if further studies are to be conducted in the future.

Hepatocyte-specific contrast agents have been made available in the last 15 years for magnetic resonance imaging of the liver. These agents are differentially taken up by functioning hepatocytes and excreted in the biliary system. They can help distinguish focal liver lesions of hepatocellular origin from lesions of nonhepatocellular origin, and can also be used in the evaluation of the biliary tree. The purpose of this review is to summarize the different types of hepatocyte-specific contrast agents presently available, their use in the characterization of focal liver lesions, their role in the evaluation of biliary pathology, and their potential future applications.

Rewards in real life are rarely received without incurring costs and successful reward harvesting often involves weighing and minimizing different types of costs. In the natural environment, such costs often include the physical effort required to obtain rewards and potential risks attached to them. Costs may also include potential risks. In this study, we applied fMRI to explore the neural coding of physical effort costs as opposed to costs associated with risky rewards. Using an incentive-compatible valuation mechanism, we separately measured the subjective costs associated with effortful and risky options. As expected, subjective costs of options increased with both increasing effort and increasing risk. Despite the similar nature of behavioral discounting of effort and risk, distinct regions of the brain coded these two cost types separately, with anterior insula primarily processing risk costs and midcingulate and supplementary motor area (SMA) processing effort costs. To investigate integration of the two cost types, we also presented participants with options that combined effortful and risky elements. We found that the frontal pole integrates effort and risk costs through functional coupling with the SMA and insula. The degree to which the latter two regions influenced frontal pole activity correlated with participant-specific behavioral sensitivity to effort and risk costs. These data support the notion that, although physical effort costs may appear to be behaviorally similar to other types of costs, such as risk, they are treated separately at the neural level and are integrated only if there is a need to do so.

Dopamine is synonymous with reward and motivation in mammals. However, only recently has dopamine been linked to motivated behaviour and rewarding reinforcement in fruitflies. Instead, octopamine has historically been considered to be the signal for reward in insects. Here we show, using temporal control of neural function in Drosophila, that only short-term appetitive memory is reinforced by octopamine. Moreover, octopamine-dependent memory formation requires signalling through dopamine neurons. Part of the octopamine signal requires the α-adrenergic-like OAMB receptor in an identified subset of mushroom-body-targeted dopamine neurons. Octopamine triggers an increase in intracellular calcium in these dopamine neurons, and their direct activation can substitute for sugar to form appetitive memory, even in flies lacking octopamine. Analysis of the β-adrenergic-like OCTβ2R receptor reveals that octopamine-dependent reinforcement also requires an interaction with dopamine neurons that control appetitive motivation. These data indicate that sweet taste engages a distributed octopamine signal that reinforces memory through discrete subsets of mushroom-body-targeted dopamine neurons. In addition, they reconcile previous findings with octopamine and dopamine and suggest that reinforcement systems in flies are more similar to mammals than previously thought.

Optimal choices benefit from previous learning. However, it is not clear how previously learned stimuli influence behavior to novel but similar stimuli. One possibility is to generalize based on the similarity between learned and current stimuli. Here, we use neuroscientific methods and a novel computational model to inform the question of how stimulus generalization is implemented in the human brain. Behavioral responses during an intradimensional discrimination task showed similarity-dependent generalization. Moreover, a peak shift occurred, i.e., the peak of the behavioral generalization gradient was displaced from the rewarded conditioned stimulus in the direction away from the unrewarded conditioned stimulus. To account for the behavioral responses, we designed a similarity-based reinforcement learning model wherein prediction errors generalize across similar stimuli and update their value. We show that this model predicts a similarity-dependent neural generalization gradient in the striatum as well as changes in responding during extinction. Moreover, across subjects, the width of generalization was negatively correlated with functional connectivity between the striatum and the hippocampus. This result suggests that hippocampus-striatal connections contribute to stimulus-specific value updating by controlling the width of generalization. In summary, our results shed light onto the neurobiology of a fundamental, similarity-dependent learning principle that allows learning the value of stimuli that have never been encountered.

Rewards in the natural environment are rarely predicted with complete certainty. Uncertainty relating to future rewards has typically been defined as the variance of the potential outcomes. However, the asymmetry of predicted reward distributions, known as skewness, constitutes a distinct but neuroscientifically underexplored risk term that may also have an impact on preference. By changing only reward magnitudes, we study skewness processing in equiprobable ternary lotteries involving only gains and constant probabilities, thus excluding probability distortion or loss aversion as mechanisms for skewness preference formation. We show that individual preferences are sensitive to not only the mean and variance but also to the skewness of predicted reward distributions. Using neuroimaging, we show that the insula, a structure previously implicated in the processing of reward-related uncertainty, responds to the skewness of predicted reward distributions. Some insula responses increased in a monotonic fashion with skewness (irrespective of individual skewness preferences), whereas others were similarly elevated to both negative and positive as opposed to no reward skew. These data support the notion that the asymmetry of reward distributions is processed in the brain and, taken together with replicated findings of mean coding in the striatum and variance coding in the cingulate, suggest that the brain codes distinct aspects of reward distributions in a distributed fashion.