Placebo treatments can induce clinically significant benefits, compared with no-treatment controls, across a variety of disorders. But placebo treatments themselves are pharmacologically and physically inert: Their benefits result from active brain and psychological responses to the treatment context. Neuroscientific studies have established that placebo treatments influence cortical-subcortical brain pathways and neurochemical systems relevant for expectation, appraisals of personal and social meaning, and value-driven learning. These systems are also related to symptom progression across mental health disorders and several other neurological and substance use disorders. Understanding the brain and psychological mechanisms of placebo effects will help improve psychological and neurological (e.g., neuromodulation-based) treatments across disorders. This R01 renewal funds an ongoing program of research that has made fundamental contributions to this literature. It has also identified several significant gaps that are particularly important for connecting placebo research to mental health. One gap is that our understanding of the brain mechanisms underlying placebo effects comes almost purely from studies of pain. The proposed studies extend previous work to study the brain pathways underlying placebo effects in anxiety and social rejection, negative affective processes directly relevant for multiple mental health disorders. Pattern-recognition (machine learning) analyses identify the most symptom-relevant pathways, and test effects of placebo and other context interventions on these pathways. In Aim 1 (Experiments 1-3), we develop models across multiple affective symptoms, parsing affective pathways into those that are symptom-specific and those that generalize across multiple symptoms and outcomes. We also address the role of endogenous opioids, strongly linked to placebo analgesia, in other negative affective experiences. Another gap is that most previous studies of the context variables that drive strong placebo effects?including social influences, treatment history?have not been studied extensively at the brain level. In Aim 2, we study the brain pathways underlying several promising context interventions that enhance the strength of placebo effects, including social modeling of successful or unsuccessful treatment response, initial experiences of treatment success or failure, and the match between placebo suggestions and a person?s predisposition to be receptive to them.