Baseline Network Biomarker Predicts Placebo Response: Implications for Neurosurgical Trial Design

Introduction: Placebo effects represent a significant challenge in Parkinson's disease (PD) trials, particularly in neurosurgical interventions, where up to 42% of patients show >50% improvement in motor ratings compared to 16% in medical trials (Goetz et al, 2008). We previously identified a sham surgery-related pattern (SSRP) from FDG-PET data in a trial of subthalamic gene therapy for advanced PD patients (Ko et al, 2014) using Ordinal Trends/Canonical Variates Analysis (OrT/CVA; Habeck et al, 2005, Niethammer et al, 2018). We found that baseline, pre-randomization SSRP expression predicted clinical improvement in the sham surgery arm (n=21, 6-month follow-up), but the generalizability of these results remained unclear.

Methods: We analyzed data from the oral placebo arm (n=14, 30-day follow-up) of a double-blind phase I trial of nicotinamide riboside for de novo drug-naïve PD patients (Brakedal et al, 2022). We calculated SSRP expression in both FDG-PET and resting-state fMRI data using amplitude of low-frequency fluctuations (ALFF). We compared functional connectivity at each timepoint to age- and sex-matched healthy controls (n=15).

Results: Pre-randomization SSRP expression predicted subsequent motor improvement in both cohorts (sham surgery: r=0.46, p=0.036; oral placebo: r=0.58, p=0.030), despite marked differences in intervention type, disease stage, and trial duration. SSRP expression in baseline ALFF maps similarly predicted placebo responses (r=0.54, p=0.045). Under placebo conditions, the SSRP network gained significant functional connections between limbic regions (cingulate, amygdala) and motor areas (putamen, thalamus, cerebellar vermis). Notably, these connectivity changes reverted upon unblinding in the surgical cohort, where post-unblinding scans were taken.

Conclusion : The SSRP represents an intriguing network biomarker that predicts placebo susceptibility across different interventional contexts. Its validation in non-invasive resting-state fMRI suggests potential clinical applicability. Incorporating baseline SSRP assessment into surgical trial design could enable stratification of placebo-susceptible individuals, potentially reducing the number of patients exposed to sham procedures while increasing statistical power.