Enhancing Clinical Trials Through Synergistic Gamma Power Analysis

Abstract

While the etiology of many neuropsychiatric disorders remains unknown, increasing evidence suggests that aberrant sensory processing plays a central role. For this class of disorders, which are characterized by affective, cognitive, and behavioral symptoms, electroencephalography remains the dominant tool for providing insight into the physiological and molecular underpinnings of the disease state and predicting the effectiveness of investigational new drugs. Within the spectrum of electrical activity present in the CNS, high-frequency oscillations in the gamma band are frequently altered in these patient populations. Measurement of gamma oscillation can be further classified into baseline and evoked, each of which offers a specific commentary on disease state. Baseline gamma analysis provides a surrogate of pharmacodynamics and predicting the time course effects of clinical candidate drugs, while alterations in evoked (time-locked) gamma power may serve as a disease biomarker and have utility in assessing patient response to new drugs. Together, these techniques offer complimentary methods of analysis for discrete realms of clinical and translational medicine. In terms of drug development, comprehensive analysis containing aspects of both baseline and evoked gamma oscillations may prove more useful in establishing better workflow and more accurate criteria for the testing of investigational new drugs.

Keywords: Auditory Steady State Response (ASSR); autism spectrum disorder (ASD); baseline gamma; bipolar disorder; electroencephalography (EEG); evoked gamma; schizophrenia.

Figure 1

Proposed workflow of gamma oscillation analysis in future clinical trials. Phase 1a PK/PD analysis of investigational drugs targeting E/I imbalance. In the proposed trial design, baseline gamma alterations are tracked against investigational drugs concentrations in plasma, receptor occupancy, etc., in healthy volunteers. These results are confirmed in the patient population prior to stage-up. Phase 1b also includes patient population stratification, achieved in part by identification of blunted evoked gamma in ASSR testing. Phase 2 trial design is informed on dosing and time course insights gained in Phase 1a/b PK/PD testing, while candidate patient populations are defined (Phase 1b) before therapeutic response is evaluated using evoked gamma ASSR and other clinical endpoints in Phase 2.