title: A Neural Mechanism for Nonconscious Activation of Conditioned Placebo and Nocebo Responses.
abstract: Fundamental aspects of human behavior operate outside of conscious awareness. Yet, theories of conditioned responses in humans, such as placebo and nocebo effects on pain, have a strong emphasis on conscious recognition of contextual cues that trigger the response. Here, we investigated the neural pathways involved in nonconscious activation of conditioned pain responses, using functional magnetic resonance imaging in healthy participants. Nonconscious compared with conscious activation of conditioned placebo analgesia was associated with increased activation of the orbitofrontal cortex, a structure with direct connections to affective brain regions and basic reward processing. During nonconscious nocebo, there was increased activation of the thalamus, amygdala, and hippocampus. In contrast to previous assumptions about conditioning in humans, our results show that conditioned pain responses can be elicited independently of conscious awareness and our results suggest a hierarchical activation of neural pathways for nonconscious and conscious conditioned responses. Demonstrating that the human brain has a nonconscious mechanism for responding to conditioned cues has major implications for the role of associative learning in behavioral medicine and psychiatry. Our results may also open up for novel approaches to translational animal-to-human research since human consciousness and animal cognition is an inherent paradox in all behavioral science.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Karin B
authors.initials: KB
authors.lastname: Jensen
authors.affiliation: Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Ted J
authors.initials: TJ
authors.lastname: Kaptchuk
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Chen
authors.affiliation: Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, USA School of Psychology, Plymouth University, Plymouth PL4 8AA, UK.
authors.forename: Irving
authors.initials: I
authors.lastname: Kirsch
authors.affiliation: Department of Clinical Neuroscience, Karolinska Institutet, Stockholm 17176, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Ingvar
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Gollub
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA 02129, USA Program in Placebo Studies, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Kong
mesh_terms: D000328:Adult; D000679:Amygdala / Q000502:physiology; D001364:Awareness / Q000502:physiology; D001921:Brain / Q000502:physiology*; D001931:Brain Mapping; D003214:Conditioning, Classical / Q000502:physiology*; D003243:Consciousness / Q000502:physiology*; D003463:Cues; D005260:Female; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D064786:Nocebo Effect; D010147:Pain Measurement; D058748:Pain Perception / Q000502:physiology*; D010470:Perceptual Masking / Q000502:physiology; D015990:Placebo Effect; D017397:Prefrontal Cortex / Q000502:physiology; D013360:Subliminal Stimulation; D013788:Thalamus / Q000502:physiology; D055815:Young Adult
keywords: amygdala; conditioning; nocebo effect; placebo effect; subliminal perception