Neuroimaging Placebo Effects: New Tools Generate New Questions

Abstract

Placebos were historically defined as inert substances (e.g., sugar or bread pills) that cause symptom improvement but are now characterized more broadly to include contextual aspects of both active and inactive treatments that contribute to symptom improvement in therapeutic settings. These contexts may be associated with the environment, including the size and color of a pill, a doctor's demeanor, or the invasiveness and cost of a treatment. The context may also be generated by the patient's prior experience or expectations about the efficacy of a treatment. Placebo effects are cognitive, behavioral, or biological responses to these contextual aspects of treatment.Although placebo effects may be a nuisance for clinical trials, they remain an important tool for clinicians and often prove beneficial for patients. Despite their efficacy, the scientific community has tended to regard placebo effects as noise rather than a potential topic of research. However, a major paradigm shift has generated renewed interest in investigating neurocognitive and neurochemical mechanisms that drive placebo effects. The timing of this renewed interest overlaps with increasing access to neuroimaging tools, allowing for investigation of these underlying mechanisms that cannot be readily assessed via self-report or observation alone. Neuroimaging as a tool to identify mechanisms driving placebo effectsLike all mammals, humans are well equipped with endogenous mechanisms designed to maintain homeostasis in the face of a perturbation. When these systems are engaged, the body uses its own resources to promote healing and relief from distress. Placebos have the capacity to activate these endogenous mechanisms, but how do they do so?Most studies investigating placebo effects have focused on measuring extent of symptom improvement following administration of an inert placebo. Although these studies inform our understanding of the magnitude, frequency, and pervasiveness of placebo effects, they have done relatively little to clarify the underlying mechanisms of these effects. Using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), investigators can gain insight into the neurobiological mechanisms driving placebo effects by relating this neurobiological activity to symptom improvement. By applying knowledge

A Phase I Study of Low-Pressure Hyperbaric Oxygen Therapy for Blast-Induced Post-Concussion Syndrome and Post-Traumatic Stress Disorder

“…Placebo effects on many of the cognitive measures in our study have been reported to be smaller than the changes we found with HBOT for FSIQ and WMS Visual Immediate and Delayed Memory (Doraiswamy et al, 2007), for Stroop Reaction Time (Calabrese et al, 2008), and for Stroop Color/ Word raw score ( Jorge et al, 2010). The placebo effects reported on SPECT in psychiatric disease, in healthy individuals, and in neurological disease have shown focal changes in regional cerebral blood flow (Beauregard, 2009), most commonly in the inferior frontal gyrus, striatum, and rostral anterior cingulate cortex ( Jarcho et al, 2009). The global diffuse changes we measured have not been reported.…”

Pharmacology of the New Treatments for Lower Gastrointestinal Motility Disorders and Irritable Bowel Syndrome

“…The selective CRH 1 receptor antagonist GW876008 attenuated psychological stress‐induced rectal hypersensitivity in nine patients with IBS 156 . However, a multicenter, randomized, double‐blind, placebo‐controlled, two‐period, crossover clinical trial of 19 weeks duration with the same agent showed no significant difference from placebo in the global improvement scale, daily IBS pain/discomfort, or individual lower GI symptoms 157 …”

“…156 However, a multicenter, randomized, double-blind, placebo-controlled, two-period, crossover clinical trial of 19 weeks duration with the same agent showed no significant difference from placebo in the global improvement scale, daily IBS pain/discomfort, or individual lower GI symptoms. 157 β3 aDrenerGic aGonist Solabegron was proposed as a treatment for IBS, based on the finding of functional β3 adrenergic receptors on enteric neurons. 158 However, solabegron failed to show any significant effect on human GI or colonic transit.…”

Brain and Disease: The Long Path to Discovery and Treatment

“…In depression, placebo can imitate the effects of antidepressants in the brain, and in Parkinson's patients, placebo may stimulate dopaminergic pathways. The Macroscopy by Jarcho et al 15 focuses on the neuroimaging of placebo responses. In addition to their obviously intriguing aspects and their potential for therapeutic development, placebo effects may also complicate the interpretation of clinical trials.…”

“…In depression, placebo can imitate the effects of antidepressants in the brain, and in Parkinson's patients, placebo may stimulate dopaminergic pathways. The Macroscopy by Jarcho et al 15 . focuses on the neuroimaging of placebo responses.…”