Volume 26, Issue 3

The glucocorticoid cortisol, a major player in the development of stress-related psychopathology, can also be used for the augmentation of extinction-based psychotherapies (e.g., exposure therapy). Substantial evidence supports its beneficial effects in the treatment of post-traumatic stress disorder and specific phobias. In this review, we first present the role of stress and cortisol in the development of maladaptive emotional memories. Then, we describe the mechanisms that may account for the cortisol-induced augmentation of exposure, namely, the enhancement of extinction memory consolidation and the reduction of the contextual dependency of the extinction memory. Finally, we discuss several considerations and limitations for the use of cortisol in psychotherapy, focusing on the possible adverse effects of cortisol in a reconsolidation-based (as opposed to extinction-based) intervention.

Anxiety disorders (ADs) are characterized by increased chronicity and comorbidity with other ADs. Although exposure is the most effective therapy option for ADs, some patients show poor treatment response and a heightened vulnerability for relapse after treatment completion. Hence, significant research effort needs to be devoted to improve the long-term effectiveness of exposure effects. Recent attempts to increase exposure therapy efficacy use strategies aimed at promoting the acquisition and retrieval of extinction memories. The present review illustrates the value and limitations of such extinction-based therapy approaches. We present and discuss recent findings from translational studies using cortisol and self-efficacy enhancement as an add-on to exposure therapy. We illustrate how the integration of findings from experimental research on fear extinction learning and self-efficacy could advance the development of more optimized treatments for ADs.

The role of pain-related fear learning and memory processes, conceptually embedded within the fear-avoidance model of chronic pain, is increasingly recognized. The unique biological salience of interoceptive, visceral pain with its cognitive, emotional, and motivational facets fosters associative learning. Conditioned fear is in principle adaptive but may turn maladaptive and contribute to hypervigilance and hyperalgesia in chronic pain. This review summarizes current knowledge on the formation, extinction, and return of pain-related memories with a focus on visceral pain. It provides a conceptual background, describes experimental approaches, and summarizes findings on behavioral and neural mechanisms in healthy humans and patients with chronic pain. Future directions underscore the potential of refining knowledge on the role of associative learning in the pathophysiology and treatment of chronic visceral pain in disorders of gut–brain interactions such as irritable bowel syndrome.

This review outlines behavioral and neurobiological aspects of extinction learning, with a focus on nonaversive experience. The extinction of acquired behavior is crucial for readaptation to our environment and plays a central role in therapeutic interventions. However, behavior that has been extinguished can reappear owing to context changes. In the first part of the article, we examine experimental strategies aimed at reducing behavioral recovery after extinction of nonaversive experience, focusing on extinction learning in multiple contexts, reminder cues, and the informational value of contexts. In the second part, we report findings from human imaging studies and studies with rodents on the neural correlates of extinction and response recovery in nonaversive learning, with a focus on ventromedial prefrontal cortex, hippocampus, and neurotransmitter systems.

Extinction learning modifies the dynamics of brain circuits such that a previously learned conditioned response is no longer generated. The majority of extinction studies use fear conditioning in rodents and identified the prefrontal cortex, the hippocampus, and the amygdala as core regions of the extinction circuit. We sought to find answers to two questions: First, do we find a similar functional brain circuit in birds, which underwent a 300-million-year separate evolution from mammals? Second, do we have to incorporate the cerebellum as a key component of the central extinction circuit? We indeed show that the avian extinction pathways are not identical but highly similar to those of mammals. In addition, we reveal that the human cerebellum processes prediction errors, a key element driving extinction of learned fear responses, and contributes to context-related effects of extinction.

Experimental studies in rodents and humans have convincingly demonstrated that immune functions can be modulated by associative learning processes. We have established a conditioned taste avoidance (CTA) paradigm in rats by pairing a novel taste (conditioned stimulus, CS) with an injection of the immunosuppressive drug cyclosporine A (CsA; unconditioned stimulus, US). Re-exposure to the CS results in a pronounced CTA and, more importantly, in a selective suppression of specific T-cell functions, mimicking the drugs’ effects. To provide a basis for using learned immunosuppressive strategies in clinical situations, we are currently investigating the neurobiological mechanisms underlying the extinction of conditioned immunosuppressive responses and the generalizability of our findings to other immunomodulatory drugs.