Metabolic brain network mediating the placebo response in Parkinson's disease

Objectives Recently, the general practice of sham surgery as a placebo-control condition for surgical trials has been challenged reasoning unethical for patients’ right to receive the best available care and high probability of rejecting efficient treatment due to the potent placebo effects. While consensus alternatives for research strategy have been lacking, we propose a novel approach to use an imaging-based biomarker for placebo effect which expresses distinctive feature from the real treatment effect.

Methods We have investigated 23 sham-surgery-treated Parkinson’s disease (PD) patients who underwent FDG-PET scans at pre-surgery (baseline) and 6 months after. 16 patients showed clinical improvement measured by UPDRS-III. Among those improved, 8 patients were selected and analyzed with Ordinal Trends/Canonical Variates Analysis, which identified the brain metabolic pattern that is increased 6 months after the surgery compared to the baseline. Then, we prospectively computed this placebo-related pattern (PlcRP) expression in another set of patients who benefited (#1) and not benefited (#2) from sham surgery, patients who benefited from the real gene therapy (#3), and patients who received open-label levodopa (#4).

Results The resulting PlcRP was consisted of increased FDG uptake in the subgenual anterior cingulate cortex, cerebellar vermis and other limbic regions. The pattern expression was significantly different between the improved (#1) and non-improved (#2) patients (p=0.031). In addition, the increase in PlcRP expression was positively correlated with improved clinical output (p<0.001). This was not found in patients who received real treatment (#3 & #4, p>0.05).

Conclusions This result suggests that one can prove that the underlying mechanisms of the real treatment effect is distinct from placebo treatment effect, even if the clinical outcome (e.g., UPDRS motor scores) are only marginally different.