The neural bases of placebo effects and their relation to regulatory processes

Placebo treatments can induce clinically significant benefits across a variety of disorders. These benefits are not due to the treatment itself, which is pharmacologically and physically inert, but to the effects of the interpersonal context and treatment cues on the patient’s brain. This R01 renewal funds an ongoing program of research that has made fundamental contributions to the neuroscience of placebo effects. Neuroscientific studies from our group and others have established that placebo treatments influence cortical-subcortical brain pathways and neurochemical systems related to the endogenous control of pain, threat, and other affective responses. Placebo treatments influence internal conceptual models of the situation and its impact on the self, interacting with learning systems to create stable patterns of affective reactivity. These systems are also central to symptom progression across mental health, substance use, and other brain disorders. Understanding placebo effects will thus help improve psychological and neurological treatments across disorders. Our previous work identifies several significant gaps important for connecting placebo research to mental health. First, not all placebo treatments influence affective brain processes in fundamental ways, and it is critical to identify the factors that underlie deep and durable influences. A key may lie in the nature of the interpersonal interactions involved. In spite of their critical importance, few neuroscientific studies investigate the qualities of the care provider and the provider-recipient match that lead to powerful therapeutic effects. Second, treatments must be studied at a computational level, incorporating models of the dynamic learning processes that create robust and durable effects. Third is a need to investigate brain pathways across multiple types of affect relevant for mental health. In Aim 1 (Studies 1-3), we develop an interpersonal placebo paradigm that allows for the study of provider-recipient resonance. We probe placebo effects across multiple types of affect, including pain, fear, and cognitive performance under threat using fMRI (Study 1), autonomic responses (Studies 1 and 2), and some of the first direct neural recordings of interpersonal influence in humans (Study 3). In Aim 2, we extend this work to consider interactions with the recipient’s mental state. We use fMRI to compare and study the interaction between placebo suggestions and mindful acceptance (Study 4), testing the hypothesis that a state of relaxed, mindful awareness will increase receptivity to placebo suggestions and potentiate placebo effects. Across studies, computational models test whether placebo treatments, and their enhancement by interpersonal processes, influence learning dynamics in a way that creates self-reinforcing effects resistant to extinction.