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

Lead Research Organisation: Queen Mary, University of London
Department Name: Blizard Institute of Cell and Molecular

Abstract

Nausea, a very common human experience, is influenced by stressful and painful events. Even though
nausea is well studied, little is known about what happens in our mind and body when we experience
nausea. This poses a dilemma to doctors as different individuals have different thresholds for nausea and
respond very differently to the same drugs used for treatment. Thus, a good human model is needed to
study the bodily functions and areas of the brain involved in nausea to help identify factors predicting
nausea. Our research group has pioneered methods to study nausea that can be used in the brain imaging environment to discover how the brain processes nausea.
Our study aims to discover what happens in a person??a??a??s body and which areas of the brain are
activated in nausea using latest technology and new methods specially designed by our team of researchers.
100 volunteers will watch a specially designed video that may cause nausea and another that doesn??a??a??t,
and we will observe their response. Measures to be observed include their state of mind, hormonal changes,
electrical activity of nerves automatically controlling internal organs and electrical activity of the gut. On 20
subjects complaining of nausea and another 20 subjects who don??a??a??t complain of nausea in the first study will
repeat the study to confirm the results. Using the same method, 45 volunteers (15 highly, 15 moderate and
15 not complaining of nausea) are observed for their brain activity. All will undergo two conditions, one in
which they experience nausea and the other in which they won??a??a??t. The study might then shed some light on
predicting who??a??a??s prone to nausea.
The human model developed will then be used to discover how established nausea treatment act in 30
subjects using the same methods as study 1, following that 15 subjects who complain less of nausea with
the treatment will be investigated for the change in their brain activity.
The model for observing the areas of the brain activated and how the body responds to nausea may
develop tools to determine nausea susceptibility. Furthermore, this model may be used for studying nausea
treatment drugs to discover which drugs work better in which individuals.

Technical Summary

The 2007 National Centre for the Replacement, Refinement & Reduction (3Rs) of Animals in Research 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 individuala??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. CONCLUSION Thus, this study will identify a reliable biomarker that allows replacement of animals with suitable human models for studying nausea physiology & nausea drug discovery. In addition, accurate monitoring for nausea will reduce animal suffering in ongoing experiments. Current animal models can be refined by removing unproven predictors of nausea (if their use is justified) via reverse engineering.

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