Depression is associated with enhanced aversive Pavlovian control over instrumental behaviour.

The dynamic modulation of instrumental behaviour by conditioned Pavlovian cues is an important process in decision-making. Patients with major depressive disorder (MDD) are known to exhibit mood-congruent biases in information processing, which may occur due to Pavlovian influences, but this hypothesis has never been tested directly in an unmedicated sample. To address this we tested unmedicated MDD patients and healthy volunteers on a computerized Pavlovian-Instrumental Transfer (PIT) task designed to separately examine instrumental approach and withdrawal actions in the context of Pavlovian appetitive and aversive cues. This design allowed us to directly measure the degree to which Pavlovian cues influence instrumental responding. Depressed patients were profoundly influenced by aversive Pavlovian stimuli, to a significantly greater degree than healthy volunteers. This was the case for instrumental behaviour both in the approach condition (in which aversive Pavlovian cues inhibited 'go' responses), and in the withdrawal condition (in which aversive Pavlovian cues facilitated 'go' responses). Exaggerated aversive PIT provides a potential cognitive mechanism for biased emotion processing in major depression. This finding also has wider significance for the understanding of disrupted motivational processing in neuropsychiatric disorders.This work was supported by a Medical Research Council project grant (G0901275) and supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre

Pawlowsch-Instrumentelle Transfer bei Alkoholabhängigkeit: Verbindungen mit OPRM1-Polymorphismus, Alkohol-Annäherungsbias und „Cognitive bias modification“

Background: Alcohol dependence (AD) is a prevalent problem characterized by a high relapse risk. The “incentive salience sensitization" theory of addiction proposes that alcohol exposure progressively sensitizes the brain circuitry related to attributing incentive salience to reward-predicting stimuli, which manifests in cue-triggered behavior. The Pavlovian-to-instrumental transfer (PIT) and the approach bias (ApB) to alcohol are two widely investigated cue-related effects in AD. Both effects have been linked to the development, maintenance, and relapse in AD. The studies in my dissertation investigated: (1) whether the opioid system, which has been associated with the alcohol ApB, interacts with the PIT effect; (2) whether the alcohol ApB is associated with PIT; and (3) whether the cognitive bias modification (CBM) training targeting on the alcohol ApB impacts on PIT effects. Methods: Patients with AD (n = 186), young healthy subjects (n = 161), and middle-aged healthy subjects (n = 105) conducted a PIT task in study 1 of this dissertation. Genotyping was performed on whole blood samples to assess the A118G (rs1799971) polymorphism of the opioid receptor mu-1 (OPRM1) gene, which has been shown to influence the affinity of the mu-opioid receptor. In study 2 of this dissertation, 100 patients with AD who performed both the alcohol approach/avoidance task and the PIT were examined. In study 3, patients with AD (n = 95) completed the CBM or placebo training and performed PIT tasks (n = 81) as well as the alcohol approach/avoidance task (n = 88) before and after training. Results: OPRM1 G-allele carriers compared to non-G-allele carriers showed a stronger PIT effect in all three groups. Interestingly, this gene-behavior association was present in prospectively relapsing but not in abstaining patients with AD. The alcohol ApB was associated with both behavioral and neural PIT effects in patients with AD. Moreover, this behavioral association was associated with the severity of AD and trait impulsivity. The CBM training did not significantly affect the PIT effects nor the alcohol ApB. Conclusion: Findings of this dissertation highlight the role of the opioid system in Pavlovian mechanisms in humans that manifests in the PIT effect, which has implications for the treatment of AD. Furthermore, the results indicate an association between PIT, impulsive decision making, and a bias towards alcohol approach. However, the CBM intervention did not interact with mechanisms assessed by our PIT paradigms and may thus not be useful to target Pavlovian mechanisms in human alcohol addiction.Hintergrund: Alkoholabhängigkeit ist durch ein hohes Rückfallrisiko gekennzeichnet. Die „Incentive Salience Sensitization Theorie” der Sucht geht davon aus, dass chronischer Alkoholkonsum jene Schaltkreise im Gehirn, die mit der Zuschreibung von Bedeutsamkeit belohnungsrelevanter Reize zusammenhängen, für Alkoholreize sensibilisiert. Der Pawlowsch-Instrumentelle Transfer (PIT) Effekt sowie ein Alkohol- Annäherungsbias sind zwei in der Literatur beschriebene Effekte, die Folgen einer solchen Sensibilisierung gegenüber Suchtreizen sein können. Beide Effekte wurden mit der Entwicklung, Aufrechterhaltung und dem Rückfall bei Alkoholabhängigkeit assoziiert. In dieser Dissertation untersuchte ich, (1) ob das Opioidsystem, das mit dem Alkohol-Annäherungsbias in Verbindung gebracht wurde, auch an PIT Effekten beteiligt ist, (2) ob der Alkohol-Annäherungsbias mit dem PIT-Effekt in Verbindung steht, und (3) ob ein Training zur Modifikation der kognitiven Verzerrung (CBM), welches auf eine Reduktion des Alkohol-Annäherungsbias, auch den PIT-Effekt beeinflusst. Methoden: Patienten mit Alkohoholabhängigkeit (n = 186), junge gesunde Probanden (n = 161) und gesunde Probanden mittleren Alters (n = 105) führten in Studie 1 dieser Dissertation eine PIT-Aufgabe durch. Es wurde ein OPRM1-Polymorphismus genotypisiert, der die Affinität des mu-Opioidrezeptors beeinflusst. In Studie 2 wurden 100 Patienten mit Alkoholabhängigkeit untersucht, die sowohl die Alkohol- Annäherungs-/Vermeidungsaufgabe als auch die PIT-Aufgabe durchführten. In Studie 3 absolvierten Patienten mit Alkoholabhängigkeit (n = 95) ein CBM- oder Placebo- Training und führten vor und nach dem Training die PIT-Aufgabe (n = 81) sowie die Alkohol-Annäherungs-/Vermeidungs-Aufgabe (n = 88) durch. Ergebnisse: Studie 1: OPRM1 G+ Träger zeigten im Vergleich zu G- Trägern einen stärkeren PIT-Effekt. Diese Gen-Verhaltens-Assoziation war bei Patienten, die prospektiv rückfällig wurden, nicht aber bei abstinenten alkoholabhängigen Patienten zu beobachten. Studie 2: Bei Patienten wurde der Alkohol-Annäherungsbias sowohl mit dem verhaltensbezogenen als auch mit dem neuronalen PIT-Effekt in Verbindung gebracht. Darüber hinaus war diese Verhaltensassoziation mit dem Schweregrad der Erkrankung und der Impulsivität assoziiert. Studie 3: Das CBM-Training wirkte sich weder auf den PIT-Effekt noch auf dem Alkohol-Annäherungsbias aus. Schlussfolgerung: Die Ergebnisse dieser Dissertation unterstreichen die Rolle des Opioidsystems für den Einfluss Pawlowscher Reize auf das menschliche Verhalten, der sich im PIT-Effekt manifestiert. Darüber hinaus zeigen die Ergebnisse einen signifikanten Zusammenhang zwischen impulsiver Entscheidungsfindung, der Alkohol-Annäherungsbias und den Veränderungen der Reaktivität auf Pawlowsche Anreize hin. Die CBM-Intervention interagierte dagegen nicht mit den Mechanismen, die in dem von uns genutzten PIT-Paradigma untersucht wurden

The Association of Non–Drug-Related Pavlovian-to-Instrumental Transfer Effect in Nucleus Accumbens With Relapse in Alcohol Dependence: A Replication

BACKGROUND: The Pavlovian-to-instrumental transfer (PIT) paradigm measures the effects of Pavlovian conditioned cues on instrumental behavior in the laboratory. A previous study conducted by our research group observed activity in the left nucleus accumbens (NAcc) elicited by a non–drug-related PIT task across patients with alcohol dependence (AD) and healthy control subjects, and the left NAcc PIT effect differentiated patients who subsequently relapsed from those who remained abstinent. In this study, we aimed to examine whether such effects were present in a larger sample collected at a later date. METHODS: A total of 129 recently detoxified patients with AD (21 females) and 74 healthy, age- and gender-matched control subjects (12 females) performing a PIT task during functional magnetic resonance imaging were examined. After task assessments, patients were followed for 6 months. Forty-seven patients relapsed and 37 remained abstinent. RESULTS: We found a significant behavioral non–drug-related PIT effect and PIT-related activity in the NAcc across all participants. Moreover, subsequent relapsers showed stronger behavioral and left NAcc PIT effects than abstainers. These findings are consistent with our previous findings. CONCLUSIONS: Behavioral non–drug-related PIT and neural PIT correlates are associated with prospective relapse risk in AD. This study replicated previous findings and provides evidence for the clinical relevance of PIT mechanisms to treatment outcome in AD. The observed difference between prospective relapsers and abstainers in the NAcc PIT effect in our study is small overall. Future studies are needed to further elucidate the mechanisms and the possible modulators of neural PIT in relapse in AD

Biasing actions by incentive valence in an approach/avoidance task

The present study investigates interactions between incentive valence and action, which mirror wellknown valence-action biases in the emotional domain. In three joystick experiments, incentive valence (win/loss) and action type (approach/avoid) were signaled by distinct orthogonal stimulus features. By combining several design aspects, i.e., the use of bi-directional joystick movements, the inclusion of no-incentive baseline trials, and cue-locked versus target-locked valence and action signals, we tried to bridge between paradigms used in the emotional and motivational domain, and to understand previous, partly inconsistent results. In the first task variant (Experiment 1), we observed performance benefits for compatible mappings (win-approach; loss-avoid) relative to incompatible ones (loss-approach; win-avoid) when valence and action signals were target-locked, consistent with a fairly automatic response activation that can benefit or impair task performance. In contrast, cue-locked valence signals led to response facilitation (relative to a no-incentive baseline) more or less independent of actual valence (win/loss) and action type (approach/avoid), which is reminiscent of general facilitation effects of incentive cues across diverse cognitive tasks. Slight design variations did not change this main result pattern, indicating that it was neither driven by the close proximity between target and performance feedback (Experiment 2), nor by mere temporal coincidence of valence and action signals (Experiment 3), but rather by differences between preparatory (cued) and immediate (non-cued) effects of incentive valence. The present study provides novel insights regarding the nature of valence-action biases in the motivational domain and helps to integrate previous, partly inconsistent findings across domain

Reduced Affective Biasing of Instrumental Action With tDCS Over the Prefrontal Cortex

AbstractBackgroundInstrumental action is well known to be vulnerable to affective value. Excessive transfer of affective value to instrumental action is thought to contribute to psychiatric disorders. The brain region most commonly implicated in overriding such affective biasing of instrumental action is the prefrontal cortex.ObjectiveThe aim of the present study was to reduce affective biasing of instrumental action using transcranial direct current stimulation (tDCS) in young healthy human volunteers.MethodsIn a double-blind, randomized between-group design, 120 participants received anodal, cathodal and sham tDCS while at the same time (online) performing a task that assessed affective biasing of instrumental action. We placed tDCS electrodes over the anterior part of the prefrontal cortex based on evidence from brain stimulation work demonstrating the role of this brain region in controlling affective biasing of instrumental action.ResultsWe showed that prefrontal tDCS reduced affective biasing of instrumental action. Specifically, prefrontal tDCS reduced the degree to which aversive (versus appetitive) cues potentiated instrumental avoidance and suppressed instrumental approach. Contrary to our hypothesis, this effect was seen for cathodal tDCS rather than anodal tDCS.ConclusionThe results demonstrate the potential utility of prefrontal tDCS as a tool for reducing affective biasing of instrumental behavior, thus opening avenues for interventional research on psychiatric disorders that implicate excessive transfer of affective value

Pavlovian-to-Instrumental Transfer in Alcohol Dependence: A Pilot Study

This publication is with permission of the rights owner freely accessible due to an alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Background: Pavlovian processes are thought to play an important role in the development, maintenance and relapse of alcohol dependence, possibly by influencing and usurping ongoing thought and behavior. The influence of pavlovian stimuli on ongoing behavior is paradigmatically measured by pavlovian-to-instrumental transfer (PIT) tasks. These involve multiple stages and are complex. Whether increased PIT is involved in human alcohol dependence is uncertain. We therefore aimed to establish and validate a modified PIT paradigm that would be robust, consistent and tolerated by healthy controls as well as by patients suffering from alcohol dependence, and to explore whether alcohol dependence is associated with enhanced PIT. Methods: Thirty-two recently detoxified alcohol-dependent patients and 32 age- and gender-matched healthy controls performed a PIT task with instrumental go/no-go approach behaviors. The task involved both pavlovian stimuli associated with monetary rewards and losses, and images of drinks. Results: Both patients and healthy controls showed a robust and temporally stable PIT effect. Strengths of PIT effects to drug-related and monetary conditioned stimuli were highly correlated. Patients more frequently showed a PIT effect, and the effect was stronger in response to aversively conditioned CSs (conditioned suppression), but there was no group difference in response to appetitive CSs. Conclusion: The implementation of PIT has favorably robust properties in chronic alcohol-dependent patients and in healthy controls. It shows internal consistency between monetary and drug-related cues. The findings support an association of alcohol dependence with an increased propensity towards PIT.Peer Reviewe

An Adaptation of Pavlovian-to-Instrumental Transfer (PIT) Methodology to Examine the Energizing Effects of Reward-Predicting Cues on Behavior in Young Adults

There is growing recognition that much of human behavior is governed by the presence of classically conditioned cues. The Pavlovian-to-Instrumental Transfer (PIT) paradigm offers a way to measure the effects of classically conditioned stimuli on behavior. In the current study, a novel behavioral task, an adaptation of the PIT framework, was developed for use in conjunction with an fMRI classical conditioning task. Twenty-four healthy young adults completed (1) instrumental training, (2) Pavlovian conditioning, and (3) a Transfer test. During instrumental training, participants learned to apply force to a handgrip to win money from slot machines pictured on a computer screen. During Pavlovian conditioning, slot machines appeared with one of two abstract symbols (cues), one symbol was predictive of monetary reward. During the Transfer test, participants again applied force to a handgrip to win money. This time, the slot machines were presented with the Pavlovian cues, but with the outcomes hidden. The results indicated increased effort on the instrumental task, i.e. higher response frequency and greater force, in the presence of the reward-predicting cue. Our findings add to the growing number of studies demonstrating PIT effects in humans. This new paradigm is effective in measuring the effects of a conditioned stimulus on behavioral activation

Learning in anticipation of reward and punishment: perspectives across the human lifespan

Learning to act to receive reward and to withhold to avoid punishment has been found to be easier than learning the opposite contingencies in young adults. To what extent this type of behavioral adaptation might develop during childhood and adolescence and differ during aging remains unclear. We therefore tested 247 healthy individuals across the human life span (7-80 years) with an orthogonalized valenced go/no-go learning task. Computational modeling revealed that peak performance in young adults was attributable to greater sensitivity to both reward and punishment. However, in children and adolescents, we observed an increased bias toward action but not reward sensitivity. By contrast, reduced learning in midlife and older adults was accompanied by decreased reward sensitivity and especially punishment sensitivity along with an age-related increase in the Pavlovian bias. These findings reveal distinct motivation-dependent learning capabilities across the human life span, which cannot be probed using conventional go/reward no-go/punishment style paradigms that have important implications in lifelong education