Dissociable Learning Processes Underlie Human Pain Conditioning

Abstract

Pavlovian conditioning underlies many aspects of pain behavior, including fear and threat detection [1LeDoux J.E. Coming to terms with fear.Proc. Natl. Acad. Sci. USA. 2014; 111: 2871-2878Crossref PubMed Scopus (510) Google Scholar], escape and avoidance learning [2Gerber B. Yarali A. Diegelmann S. Wotjak C.T. Pauli P. Fendt M. Pain-relief learning in flies, rats, and man: basic research and applied perspectives.Learn. Mem. 2014; 21: 232-252Crossref PubMed Scopus (98) Google Scholar], and endogenous analgesia [3Wager T.D. Atlas L.Y. The neuroscience of placebo effects: connecting context, learning and health.Nat. Rev. Neurosci. 2015; 16: 403-418Crossref PubMed Scopus (398) Google Scholar]. Although a central role for the amygdala is well established [4Phelps E.A. LeDoux J.E. Contributions of the amygdala to emotion processing: from animal models to human behavior.Neuron. 2005; 48: 175-187Abstract Full Text Full Text PDF PubMed Scopus (2257) Google Scholar], both human and animal studies implicate other brain regions in learning, notably ventral striatum and cerebellum [5Seymour B. O’Doherty J.P. Dayan P. Koltzenburg M. Jones A.K. Dolan R.J. Friston K.J. Frackowiak R.S. Temporal difference models describe higher-order learning in humans.Nature. 2004; 429: 664-667Crossref PubMed Scopus (472) Google Scholar]. It remains unclear whether these regions make different contributions to a single aversive learning process or represent independent learning mechanisms that interact to generate the expression of pain-related behavior. We designed a human parallel aversive conditioning paradigm in which different Pavlovian visual cues probabilistically predicted thermal pain primarily to either the left or right arm and studied the acquisition of conditioned Pavlovian responses using combined physiological recordings and fMRI. Using computational modeling based on reinforcement learning theory, we found that conditioning involves two distinct types of learning process. First, a non-specific “preparatory” system learns aversive facial expressions and autonomic responses such as skin conductance. The associated learning signals—the learned associability and prediction error—were correlated with fMRI brain responses in amygdala-striatal regions, corresponding to the classic aversive (fear) learning circuit. Second, a specific lateralized system learns “consummatory” limb-withdrawal responses, detectable with electromyography of the arm to which pain is predicted. Its related learned associability was correlated with responses in ipsilateral cerebellar cortex, suggesting a novel computational role for the cerebellum in pain. In conclusion, our results show that the overall phenotype of conditioned pain behavior depends on two dissociable reinforcement learning circuits.