Network meta-analysis of CAR T-Cell therapy for the treatment of 3L+ R/R LBCL after using published comparative studies.

INTRODUCTION: Studies have compared chimeric antigen receptor (CAR) T-cell therapies and salvage chemotherapy in relapsed/refractory large B-cell lymphoma (LBCL) patients, but further evidence of their relative effectiveness is warranted. METHODS: Our systematic review identified studies comparing efficacy and safety outcomes of axicabtagene ciloleucel (axi-cel), lisocabtagene maraleucel (liso-cel) and tisagenlecleucel (tisa-cel) trials to salvage chemotherapy cohorts in LBCL patients with ≥2 prior lines of treatment; and an extended evidence network included indirect comparisons comparing CAR T-cell therapies. We conducted network meta-analyzes using Bayesian hierarchical modeling. RESULTS: Three studies comparing ZUMA-1 (axi-cel), TRANSCEND (liso-cel) and JULIET (tisa-cel) trials to salvage chemotherapy within the SCHOLAR-1 cohort were identified. Axi-cel (odds ratio [OR]:5.63; 95% credible interval [CrI]:2.66-12.42) and liso-cel (OR:4.26; 95%CrI:2.33-7.93) showed a significant increased overall response rate compared to tisa-cel, but not to one-another. Axi-cel demonstrated significant improvements in overall survival relative to liso-cel (hazard ratio [HR]:0.54; 95%CrI:0.37-0.79) and tisa-cel (HR:0.47; 95%CrI:0.26-0.88). Higher rates of grade ≥3 neurological events were observed with axi-cel than with tisa-cel and liso-cel. CONCLUSIONS: We highlight important differences in clinical outcomes between CAR T-cell therapies. Axi-cel demonstrated improved overall survival compared to tisa-cel and liso-cel, and both axi-cel and liso-cel showed higher response rates compared to tisa-cel.

A Comparison of 3-Year Follow-up of ZUMA-5 (Axicabtagene Ciloleucel) With SCHOLAR-5 in Relapsed/Refractory Follicular Lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory follicular lymphoma patients. SCHOLAR-5 is an external control cohort designed to act as a comparator to ZUMA-5. Here, we present an updated comparative analysis of ZUMA-5 and SCHOLAR-5, using the 36-month follow-up data and the intent-to-treat population of ZUMA-5. Using propensity-score methods, 127 patients in ZUMA-5 were compared to 129 patients in SCHOLAR-5. At this extended follow-up, axi-cel continues to demonstrate clinically meaningful benefits in survival compared to historically available treatments in this population.

Real-World Outcomes with Chimeric Antigen Receptor T Cell Therapies in Large B Cell Lymphoma: A Systematic Review and Meta-Analysis.

Chimeric antigen receptor T cell (CAR-T) therapies, including axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel), are innovative treatments for patients with relapsed or refractory (r/r) large B cell lymphoma (LBCL). Following initial regulatory approvals, real-world evidence (RWE) of clinical outcomes with these therapies has been accumulating rapidly. Notably, several large registry studies have been published recently. Here we comprehensively describe clinical outcomes with approved CAR-T therapies in patients with r/r LBCL using available RWE. We systematically searched Embase, MEDLINE, and 15 conference proceedings to identify studies published between 2017 and July 2022 that included ≥10 patients with r/r LBCL treated with commercially available CAR-T therapies. Eligible study designs were retrospective or prospective observational studies. Key outcomes of interest were objective response rate (ORR), complete response (CR) rate, overall survival (OS), progression-free survival (PFS), cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). Random-effects meta-analyses were used to compare real-world outcomes with those of pivotal clinical trials and to compare clinical outcomes associated with axi-cel and tisa-cel. Study cohort mapping was conducted to avoid including patients more than once. Of 76 cohorts we identified, 46 reported patients treated specifically with either axi-cel or tisa-cel, with 39 cohorts (n = 2754 patients) including axi-cel and 20 (n = 1649) including tisa-cel. No studies of liso-cel that met the inclusion criteria were identified during the search period. One-half of the tisa-cel cohorts were European, compared with 33% of the axi-cel cohorts. Among studies with available data, axi-cel had a significantly shorter median time from apheresis to CAR-T infusion than tisa-cel. Despite including broader patient populations, real-world effectiveness and safety of both axi-cel and tisa-cel were consistent with data from the pivotal clinical trials. Comparative meta-analysis of axi-cel versus tisa-cel demonstrated adjusted hazard ratios for OS and PFS of .60 (95% confidence interval [CI], .47 to .77) and .67 (95% CI, .57 to .78), respectively, both in favor of axi-cel. Odds ratios (ORs) for ORR and CR rate, both favoring axi-cel over tisa-cel, were 2.05 (95% CI, 1.76 to 2.40) and 1.70 (95% CI, 1.46 to 1.96), respectively. The probability of grade ≥3 CRS was comparable with axi-cel and tisa-cel, whereas axi-cel was associated with a higher incidence of grade ≥3 ICANS (OR, 3.95; 95% CI, 3.05 to 5.11). Our meta-analysis indicates that CAR-T therapies have manageable safety profiles and are effective in a wide range of patients with r/r LBCL, and that axi-cel is associated with improved OS and PFS and increased risk of grade ≥3 ICANS compared with tisa-cel. Limitations of this study include nonrandomized treatments, potential unknown prognostic factors, and the lack of available real-world data for liso-cel.

Early Treatment with Pegylated Interferon Lambda for Covid-19.

BACKGROUND: The efficacy of a single dose of pegylated interferon lambda in preventing clinical events among outpatients with acute symptomatic coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a randomized, controlled, adaptive platform trial involving predominantly vaccinated adults with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Brazil and Canada. Outpatients who presented with an acute clinical condition consistent with Covid-19 within 7 days after the onset of symptoms received either pegylated interferon lambda (single subcutaneous injection, 180 µg) or placebo (single injection or oral). The primary composite outcome was hospitalization (or transfer to a tertiary hospital) or an emergency department visit (observation for >6 hours) due to Covid-19 within 28 days after randomization. RESULTS: A total of 933 patients were assigned to receive pegylated interferon lambda (2 were subsequently excluded owing to protocol deviations) and 1018 were assigned to receive placebo. Overall, 83% of the patients had been vaccinated, and during the trial, multiple SARS-CoV-2 variants had emerged. A total of 25 of 931 patients (2.7%) in the interferon group had a primary-outcome event, as compared with 57 of 1018 (5.6%) in the placebo group, a difference of 51% (relative risk, 0.49; 95% Bayesian credible interval, 0.30 to 0.76; posterior probability of superiority to placebo, >99.9%). Results were generally consistent in analyses of secondary outcomes, including time to hospitalization for Covid-19 (hazard ratio, 0.57; 95% Bayesian credible interval, 0.33 to 0.95) and Covid-19-related hospitalization or death (hazard ratio, 0.59; 95% Bayesian credible interval, 0.35 to 0.97). The effects were consistent across dominant variants and independent of vaccination status. Among patients with a high viral load at baseline, those who received pegylated interferon lambda had lower viral loads by day 7 than those who received placebo. The incidence of adverse events was similar in the two groups. CONCLUSIONS: Among predominantly vaccinated outpatients with Covid-19, the incidence of hospitalization or an emergency department visit (observation for >6 hours) was significantly lower among those who received a single dose of pegylated interferon lambda than among those who received placebo. (Funded by FastGrants and others; TOGETHER ClinicalTrials.gov number, NCT04727424.).

A 24-month updated analysis of the comparative effectiveness of ZUMA-5 (axi-cel) vs. SCHOLAR-5 external control in relapsed/refractory follicular lymphoma.

BACKGROUND: In the ZUMA-5 trial (Clinical trials identification: NCT03105336), axicabtagene ciloleucel (axi-cel; a chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients and clear superiority relative to the SCHOLAR-5 external control cohort. We update this comparison using the ZUMA-5 24-month data. RESEARCH DESIGN AND METHODS: The SCHOLAR-5 cohort is comprised of r/r FL patients who initiated ≥3rd line of therapy after July 2014 and meeting ZUMA-5 eligibility criteria. Groups were balanced for patient characteristics through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. The overall response rate was compared using a weighted logistic regression. Time-to-event outcomes were evaluated using a Cox regression. RESULTS: For SCHOLAR-5, the sum of weights for the 143 patients was 85 after SMR weighting, versus 86 patients in ZUMA-5. The median follow-up was 29.4 months and 25.4 months for ZUMA-5 and SCHOLAR-5, respectively. The hazard ratios for overall survival and progression-free survival were 0.52 (95% confidence interval (CI): 0.28-0.95) and 0.28 (95% CI: 0.17-0.45), favoring axi-cel. CONCLUSION: This updated analysis, using a longer minimum follow-up than a previously published analysis, shows that the improved efficacy of axi-cel, relative to available therapies, in r/r FL is durable. .

Clinical outcomes in patients relapsed/refractory after ≥2 prior lines of therapy for follicular lymphoma: a systematic literature review and meta-analysis.

BACKGROUND: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review. METHODS: Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis. RESULTS: The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval [CI]: 51.13-65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02-24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8-68.78) and median PFS was 9.78 months (95% CI: 9.01-10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%). CONCLUSIONS: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe.

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study.

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.

Do pupillary responses during authentic slot machine use reflect arousal or screen luminance fluctuations? A proof-of-concept study.

Modern slot machines are among the more harmful forms of gambling. Psychophysiological measures may provide a window into mental processes that underpin these harms. Here we investigated pupil dilation derived from eye tracking as a means of capturing changes in sympathetic nervous system arousal following outcomes on a real slot machine. We hypothesized that positively reinforcing slot machine outcomes would be associated with increases in arousal, reflected in larger pupil diameter. We further examined the contribution of game luminance fluctuations on pupil diameter. In Experiment 1A, experienced slot machine gamblers (N = 53) played a commercially-available slot machine in a laboratory for 20 minutes while wearing mobile eye tracking glasses. Analyses differentiated loss outcomes, wins, losses-disguised-as-wins, and (free-spin) bonus features. Bonus features were associated with rapid increases in pupil diameter following the onset of outcome-related audiovisual feedback, relative to losses. In Experiment 1B, luminance data were extracted from captured screen videos (derived from Experiment 1A) to characterize on-screen luminance changes that could modulate pupil diameter. Bonus features and wins were associated with pronounced and complex fluctuations in screen luminance (≈50 L and ≈25L, respectively). However, the pupil dilation that was observed to bonus features in Experiment 1A coincided temporally with only negligible changes in screen luminance, providing partial evidence that the pupil dilation to bonus features may be due to arousal. In Experiment 2, 12 participants viewed pairs of stimuli (scrambled slot machine images) at luminance difference thresholds of ≈25L, ≈50L, and ≈100L. Scrambled images presented at luminance differences of ≈25L and greater were sufficient to cause pupillary responses. Overall, pupillometry may detect event-related changes in sympathetic nervous system arousal following gambling outcomes, but researchers must pay careful attention to substantial in-game luminance changes that may confound arousal-based interpretations.

Gambling disorder is associated with reduced sensitivity to expected value during risky choice.

BACKGROUND AND AIMS: Individuals with gambling disorder display increased levels of risk-taking, but it is not known if it is associated with an altered subjective valuation of gains and/or losses, perception of their probabilities, or integration of these sources of information into expected value. METHODS: Participants with gambling disorder (n = 48) were compared with a healthy comparison group (n = 35) on a two-choice lottery task that involved either gains-only or losses-only gambles. On each trial, two lotteries were displayed, showing the associated probability and magnitude of the possible outcome for each. On each trial, participants chose one of the two lotteries, and the outcome was revealed. RESULTS: Choice behaviour was highly sensitive to the expected value of the two gambles in both the gain and loss domains. This sensitivity to expected value was attenuated in the group with gambling disorder. The group with gambling disorder used both probability and magnitude information less, and this impairment was greater for probability information. By contrast, they used prior feedback (win vs loss) to inform their next choice, despite the independence of each trial. Within the gambling disorder group, problem gambling severity and trait gambling-related cognitions independently predicted reduced sensitivity to expected value. The majority of observed effects were consistent across both gain and loss domains. DISCUSSION AND CONCLUSIONS: Our results provide a thorough characterization of decision processes in gain and loss domains in gambling disorder, and place these problems in the context of theoretical constructs from behavioural economics.

Neural and neurocognitive markers of vulnerability to gambling disorder: a study of unaffected siblings.

Psychological and neurobiological markers in individuals with gambling disorder (GD) could reflect transdiagnostic vulnerability to addiction or neuroadaptive consequences of long-term gambling. Using an endophenotypic approach to identify vulnerability markers, we tested the biological relatives of cases with GD. Male participants seeking treatment for GD (n = 20) were compared with a male control group (n = 18). Biological siblings of cases with GD (n = 17, unrelated to the current GD group) were compared with a separate control group (n = 19) that overlapped partially with the GD control group. Participants completed a comprehensive assessment of clinical scales, neurocognitive functioning, and fMRI of unexpected financial reward. The GD group displayed elevated levels of self-report impulsivity and delay discounting, and increased risk-taking on the Cambridge Gamble Task. We did not observe impaired motor impulsivity on the stop-signal task. Siblings of GD showed some overlapping effects; namely, elevated impulsivity (negative urgency) and increased risk-taking on the Cambridge Gamble Task. We did not observe any differences in the neural response to win outcomes, either in the GD or sibling analysis compared with their control group. Within the GD group, activity in the thalamus and caudate correlated negatively with gambling severity. Increased impulsivity and risk-taking in GD are present in biological relatives of cases with GD, suggesting these markers may represent pre-existing vulnerability to GD.

The effects of alcohol on sequential decision-making biases during gambling.

RATIONALE: Gambling and alcohol use are recreational behaviours that share substantial commonalities at a phenomenological, clinical and neurobiological level. Past studies have shown that alcohol can have a disinhibiting effect on gambling behaviour, in terms of bet size and persistence. OBJECTIVES: This study was conducted in order to characterise how alcohol affects biases in judgment and decision-making that occur during gambling, with a focus on sequential decision-making including the gambler's fallacy. METHODS: Sequential biases were elicited via a roulette-based gambling task. Using a standard between-groups alcohol challenge procedure, male participants played the roulette task 20 min after receiving an alcoholic (0.8 g/kg; n = 22) or placebo (n = 16) beverage. The task measured colour choice decisions (red/black) and bet size, in response to varying lengths of colour runs and winning/losing feedback streaks. RESULTS: Across both groups, a number of established sequential biases were observed. On colour choice, there was an effect of run length in line with the gambler's fallacy, which further varied by previous feedback (wins vs losses). Bet size increased with feedback streaks, especially for losing streaks. Compared to placebo, the alcohol group placed higher bets following losses compared to wins. CONCLUSIONS: Increased bet size after losses following alcohol consumption may reflect increased loss chasing that may amplify gambling harms. Our results do not fit a simple pattern of enhanced gambling distortions or reward sensitivity, but help contextualise the effects of alcohol on gambling to research on decision-making biases.

Zoned in or zoned out? Investigating immersion in slot machine gambling using mobile eye-tracking.

BACKGROUND AND AIMS: Immersion during slot machine gambling has been linked to disordered gambling. Current conceptualizations of immersion (namely dissociation, flow and the machine zone) make contrasting predictions as to whether gamblers are captivated by the game per se ('zoned in') or motivated by the escape that immersion provides ('zoned out'). We examined whether selected eye-movement metrics can distinguish between these predictions. DESIGN AND SETTING: Pre-registered, correlational analysis in a laboratory setting. Participants gambled on a genuine slot machine for 20 minutes while wearing eye-tracking glasses. PARTICIPANTS: Fifty-three adult slot machine gamblers who were not high-risk problem gamblers. MEASUREMENTS: We examined self-reported immersion during the gambling session and eye movements at different areas of the slot machine screen (the reels, the credit window, etc.). We further explored these variables' relationships with saccade count and amplitude. FINDINGS: The ratio of dwell time on the game's credit window relative to the game's reels was positively associated with immersion (t(51)  = 1.68, P = 0.049 one-tailed, R2  = 0.05). Follow-up analyses described event-related changes in these patterns following different spin outcomes. CONCLUSIONS: Immersion while gambling on a slot machine appears to be associated with active scanning of the game and a focus on the game's credit window. These results are more consistent with a 'zoned in' account of immersion aligned with flow theory than a 'zoned out' account based on escape.

Interoception and respiratory sinus arrhythmia in gambling disorder.

Gambling has longstanding links with excitement and physiological arousal, but prior research has not considered (a) gamblers' ability to detect internal physiological signals, or (b) markers of parasympathetic functioning. The present study measured interoception in individuals with gambling disorder, using self-report measures and a heartbeat counting task administered at rest. Resting state respiratory sinus arrhythmia (RSA), an index of heart rate variability, was measured as a proxy for parasympathetic control and emotional regulation capacity. In a case-control design, 50 individuals with gambling disorder were compared against 35 controls without gambling problems. Participants completed two self-report measures of bodily awareness and a behavioral test of heartbeat counting. A resting state electrocardiogram (5 min) was used to calculate RSA. There were no significant differences on the self-report or behavioral interoception probes. The group with gambling disorder displayed significantly reduced RSA, which at face value is consistent with reduced parasympathetic control. However, the group difference in RSA did not survive controlling for age and smoking status, as established predictors of heart rate variability. Our findings do not support any changes in interoceptive processing in people with gambling disorder, at least under resting conditions. Our observation that group differences in RSA are partly explained by smoking behavior highlights the importance of controlling for nicotine use in future research characterizing physiological functioning and emotional regulation in disordered gambling.

Financial gain- and loss-related BOLD signals in the human ventral tegmental area and substantia nigra pars compacta.

Neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) play central roles in reward-related behaviours. Nonhuman animal studies suggest that these neurons also process aversive events. However, our understanding of how the human VTA and SNC responds to such events is limited and has been hindered by the technical challenge of using functional magnetic resonance imaging (fMRI) to investigate a small structure where the signal is particularly vulnerable to physiological noise. Here we show, using methods optimized specifically for the midbrain (including high-resolution imaging, a novel registration protocol, and physiological noise modelling), a BOLD (blood-oxygen-level dependent) signal to both financial gain and loss in the VTA and SNC, along with a response to nil outcomes that are better or worse than expected in the VTA. Taken together, these findings suggest that the human VTA and SNC are involved in the processing of both appetitive and aversive financial outcomes in humans.

Let me take the wheel: Illusory control and sense of agency.

Illusory control refers to an effect in games of chance where features associated with skilful situations increase expectancies of success. Past work has operationalized illusory control in terms of subjective ratings or behaviour, with limited consideration of the relationship between these definitions, or the broader construct of agency. This study used a novel card-guessing task in 78 participants to investigate the relationship between subjective and behavioural illusory control. We compared trials in which participants (a) had no opportunity to exercise illusory control, (b) could exercise illusory control for free, or (c) could pay to exercise illusory control. Contingency Judgment and Intentional Binding tasks assessed explicit and implicit sense of agency, respectively. On the card-guessing task, confidence was higher when participants exerted control than in the baseline condition. In a complementary model, participants were more likely to exercise control when their confidence was high, and this effect was accentuated in the pay condition relative to the free condition. Decisions to pay were positively correlated with control ratings on the Contingency Judgment task, but were not significantly related to Intentional Binding. These results establish an association between subjective and behavioural illusory control and locate the construct within the cognitive literature on agency.

'Put Your Money Where Your Mouth Is!': Effects of Streaks on Confidence and Betting in a Binary Choice Task.

Human choice under uncertainty is influenced by erroneous beliefs about randomness. In simple binary choice tasks, such as red/black predictions in roulette, long outcome runs (e.g. red, red, red) typically increase the tendency to predict the other outcome (i.e. black), an effect labeled the "gambler's fallacy." In these settings, participants may also attend to streaks in their predictive performance. Winning and losing streaks are thought to affect decision confidence, although prior work indicates conflicting directions. Over three laboratory experiments involving red/black predictions in a sequential roulette task, we sought to identify the effects of outcome runs and winning/losing streaks upon color predictions, decision confidence and betting behavior. Experiments 1 (n = 40) and 3 (n = 40) obtained trial-by-trial confidence ratings, with a win/no win payoff and a no loss/loss payoff, respectively. Experiment 2 (n = 39) obtained a trial-by-trial bet amount on an equivalent scale. In each experiment, the gambler's fallacy was observed on choice behavior after color runs and, in experiment 2, on betting behavior after color runs. Feedback streaks exerted no reliable influence on confidence ratings, in either payoff condition. Betting behavior, on the other hand, increased as a function of losing streaks. The increase in betting on losing streaks is interpreted as a manifestation of loss chasing; these data help clarify the psychological mechanisms underlying loss chasing and caution against the use of betting measures ("post-decision wagering") as a straightforward index of decision confidence. © 2014 The Authors. Journal of Behavioral Decision Making published by John Wiley & Sons Ltd.

Fronto-striatal dysregulation in drug addiction and pathological gambling: Consistent inconsistencies?

Alterations in appetitive processing are central to the major psychological theories of addiction, with differential predictions made by the reward deficiency, incentive salience, and impulsivity hypotheses. Functional MRI has become the chief means of testing these predictions, with experiments reliably highlighting disturbances at the level of the striatum, medial prefrontal cortex, and affiliated regions. However, demonstrations of hypo-reactivity and hyper-reactivity of this circuitry in drug addicted groups are reported in approximately equal measure. Similar findings are echoed in the emergent neuroimaging literature on pathological gambling, which has recently witnessed a coming of age. The first aim of this article is to consider some of the methodological aspects of these experiments that could influence the observed direction of group-level effects, including the baseline condition, trial structure and timing, and the nature of the appetitive cues (drug-related, monetary, or primary rewards). The second aim is to highlight the conceptual traction that is offered by pathological gambling, as a model of a 'toxicity free' addiction and an illness where tasks of monetary reinforcement afford a more direct mapping to the abused commodity. Our conclusion is that relatively subtle decisions in task design appear capable of driving group differences in fronto-striatal circuitry in entirely opposing directions, even with tasks and task variants that look ostensibly similar. Differentiation between the psychological theories of addiction will require a greater breadth of experimental designs, with more research needed on processing of primary appetitive cues, aversive processing, and in vulnerable/at-risk groups.

Disordered gambling: a behavioral addiction.

Developments in psychiatry have ratified the existence of behavioral addictions, that certain activities such as gambling or video-game play may be considered addictive in the absence of exogenous (i.e. drug-induced) stimulation of brain reinforcement circuitry. This article describes recent advances in understanding the neurobiological basis of behavioral addiction, with a focus on pathological gambling as the prototypical disorder. We describe positron emission tomography (PET) studies characterizing dopaminergic transmission, and functional imaging studies of reward processing and gambling-related cognitive distortions. The current evidence not only indicates changes in pathological gamblers in core circuitry implicated in drug addiction, but also highlights some subtle differences. Behavioral addictions can also provide experimental traction on distinguishing vulnerability markers for addictions from the active detrimental effects of chronic drug use.

Identification and characterisation of midbrain nuclei using optimised functional magnetic resonance imaging.

Localising activity in the human midbrain with conventional functional MRI (fMRI) is challenging because the midbrain nuclei are small and located in an area that is prone to physiological artefacts. Here we present a replicable and automated method to improve the detection and localisation of midbrain fMRI signals. We designed a visual fMRI task that was predicted would activate the superior colliculi (SC) bilaterally. A limited number of coronal slices were scanned, orientated along the long axis of the brainstem, whilst simultaneously recording cardiac and respiratory traces. A novel anatomical registration pathway was used to optimise the localisation of the small midbrain nuclei in stereotactic space. Two additional structural scans were used to improve registration between functional and structural T1-weighted images: an echo-planar image (EPI) that matched the functional data but had whole-brain coverage, and a whole-brain T2-weighted image. This pathway was compared to conventional registration pathways, and was shown to significantly improve midbrain registration. To reduce the physiological artefacts in the functional data, we estimated and removed structured noise using a modified version of a previously described physiological noise model (PNM). Whereas a conventional analysis revealed only unilateral SC activity, the PNM analysis revealed the predicted bilateral activity. We demonstrate that these methods improve the measurement of a biologically plausible fMRI signal. Moreover they could be used to investigate the function of other midbrain nuclei.