Associative learning and extinction of conditioned threat predictors across sensory modalities

Abstract

The formation and persistence of negative pain-related expectations by classical conditioning remain incompletely understood. We elucidated behavioural and neural correlates involved in the acquisition and extinction of negative expectations towards different threats across sensory modalities. In two complementary functional magnetic resonance imaging studies in healthy humans, differential conditioning paradigms combined interoceptive visceral pain with somatic pain (study 1) and aversive tone (study 2) as exteroceptive threats. Conditioned responses to interoceptive threat predictors were enhanced in both studies, consistently involving the insula and cingulate cortex. Interoceptive threats had a greater impact on extinction efficacy, resulting in disruption of ongoing extinction (study 1), and selective resurgence of interoceptive CS-US associations after complete extinction (study 2). In the face of multiple threats, we preferentially learn, store, and remember interoceptive danger signals. As key mediators of nocebo effects, conditioned responses may be particularly relevant to clinical conditions involving disturbed interoception and chronic visceral pain.

Altered Brain Structure in Chronic Visceral Pain: Specific Differences in Gray Matter Volume and Associations With Visceral Symptoms and Chronic Stress

“…Results revealed a differential association of chronic stress with GMV in patients with IBS and healthy volunteers, encompassing numerous brain regions involved in networks relevant to the psychological modulation of visceral pain ( 20 ). In addition to regions of the sensorimotor network, central executive network, and default mode network (in which associations with symptom severity were also observed), the relation of chronic stress and GMV in regions of the salience network was significantly altered in patients with IBS, which is interesting given recent evidence indicating the unique salience of pain arising from the visceral modality ( 4 , 5 ). Supplemental partial correlational analyses accomplished within each group, pointed to consistently negative associations within the group of IBS patients but not the control group, suggesting that higher chronic stress was associated with lower regional brain volumes exclusively within patients.…”

“…Bearing the critical considerations described above in mind, it is nevertheless interesting to discuss our findings suggesting possibly reduced GMV in the anterior insula and the middle frontal cortex in UC. The anterior insula is part of the salience network, which is highly relevant to pain anticipation and pain modulation in acute and chronic visceral pain [e.g., ( 4 , 20 , 23 )]. Interestingly, in IBD with and without abdominal pain, resting state functional MRI revealed differences in the insula, and correlations with daily pain scores ( 55 ).…”

“…Work in visceral pain is also called for in light of increasing knowledge about the specificity of visceral pain both in terms of psychological as well as central mechanisms. In contrast to somatic pain, visceral pain is perceived as more diffuse and more unpleasant, provokes more pain-related fear, may be more sensitive to stress ( 1 – 4 ), and, importantly, engages partly distinct functional brain responses, at least during acute experimental pain ( 2 , 5 ). Finally, the clinical relevance of chronic visceral pain is enormous, with a prevalence that likely surpasses even that of chronic low back and neck-shoulder pain.…”

The Good, the Bad, and the Ugly—Chances, Challenges, and Clinical Implications of Avoidance Research in Psychosomatic Medicine

“…Emerging research has started to tackle this challenge with multifaceted translational approaches. Innovative examples range from the implementation of clinically-relevant, interoceptive visceral pain during associative learning (20,(109)(110)(111), over the use of immersive and interactive exposure techniques through virtual reality in phobias, anxiety disorders, and PTSD (112,113), to a variation of the effort required to avoid movements using a robotic arm to address pain-related avoidance (114-116).…”

“…Finally, approaches in experimental and clinical research alike should aim at bridging the gap between models applied in laboratory settings and patients' clinical reality and to more closely integrate the concepts of the FAM into the broad field of psychosomatic medicine. To achieve this goal, clinically-relevant and phenomenologically valid models are needed, capturing different facets as well as the specificity of fear and avoidance in psychosomatic disease, as first innovative attempts in the fields of muscoskeletal (115,(135)(136)(137)163) and interoceptive visceral pain (20,110,111,164,165) have previously demonstrated. These experimental settings provide an ideal opportunity to overcome some common limitations of avoidance research, and to operationalize and assess the complex phenomenon of avoidance in its multiple facets, incorporating behavioral, cognitive, but also neural levels (39).…”