Refinement of animal studies on emesis by defining human biomarkers of nausea

The 2007 NC3Rs workshop on nausea and emesis concluded that studying the human brain processing of nausea via neurophysiological biomarkers i.e. brain imaging (fMRI) is the single most effective method to refine, reduce and replace animals in this research area. Despite nausea being common little is known about its neurophysiological basis in humans due to technical issues related to adapting nausea induction methods for fMRI and other biomarkers (e.g. autonomic reactivity (ANS), electrogastrography reactivity (EGG), neuroendocrine responses (NES), psychometrics).

Recent developments pioneered by the applicants have now made this possible. Prime question: Can a biomarker of nausea susceptibility be reliably identified that is suitable for reverse translation back to animals? Study 1 aims: To identify individuals with a reliable & reproducible sensitivity to a nausea-inducing stimulus. By inducing nausea with a novel visual nausea induction method and observing the psychophysiological response (ANS, EGG, NES, psychometrics), 100 subjects will be studied to identify those subjects that are susceptible and resistant to nausea. Reproducibility studies will be performed in 20 most resistant and 20 most susceptible subjects. Study 2 aims: To determine whether an individual’s physiological phenotype & nausea responsiveness predicts their brain processing of nausea. 15 most nausea susceptible and 15 most nausea resistant subjects from study 1 will be investigated using fMRI. For both studies, all volunteers will attend two sessions in a random order comprising of a nausea induction and a control condition. Study 3 aims: To further define the biomarker of nausea by examining the susceptibility to treatment by a commonly used motion sickness drug. 30 subjects using ANS, EGG, NES, psychometrics biomarkers will be studied, and from that 15 subjects who show pharmacological modulation with Hyoscine with nausea being significantly improved will be investigated via fMRI. All subjects will attend twice (taking Hyoscine once and placebo once) in a double blinded and a random order with nausea stimulus in both visits. Thus, this study will identify a reliable biomarker that allows replacement of animals with suitable human models for studying nausea physiology and nausea drug discovery. In addition, accurate monitoring for nausea will reduce animal suffering in ongoing experiments.