Rosipal R., Trejo L.J., Wallerius J., Apparies R., Cimrova B, Miller J.

We are developingWhole Brain Time-Frequency (WBTF) analysis as a new physiological biomarker for clinical trials of pharmacodynamics of novel drugs. WBTF analysis expands the power of event-related potential (ERP) assessment by using wavelets to measure both evoked (phase-locked) and induced (non-phase-locked) activity. Unlike traditional ERP measures, which are indexed by specific electrodes and peak latencies, WBTF analysis measures integrated change in brain responses across time, frequency and space to infer whether a drug has a significant effect. WBTF analysis also uses permutation tests and multiple comparison corrections to identify important within-subject changes between conditions and rule out differences arising from recording noise, artifacts or random variability.

The specific aim of this study was to assess the sensitivity and specificity of WBTF analysis to drug effects that are typically measured with ERP amplitudes and latencies. We simulated effects of dose-related changes in N1-P2-P3 ERP components and 40-Hz induced gamma bursts at 24 electrodes. Simulations included a range of amplitude effects, latency effects and signal-to-noise ratios, serving to define the sensitivity and specificity of WBTF analysis to ERP differences. 

The simulations allowed us to optimize parameters for WBTF analysis, including choice of analyzing wavelets, energy normalization, baseline correction, measures of evoked and induced activity, and method of testing significant differences. We found that WBTF analysis reliably detects small differences in evoked activity (on the order of 10%) in realistic noise and background EEG conditions. We found similar detectability of small differences in induced 40-Hz gamma bursts.

It is the goal of the further studies to investigate the clinical relevance of these observed differences using WBTF analysis, and to relate the evoked and induced components ERP differences to mechanisms of drug action. Currently we are applying WBTF analysis to data from three Phase 1 clinical trials of novel compounds for schizophrenia in both healthy controls and schizophrenia patients.