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Title: Motivational salience, the clinical high-risk state for psychosis and acute modulation by cannabidiol
Author: Wilson, Robin
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2020
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Functional psychosis is a severe mental illness with often devastating consequences for individuals and a high cost to society. One leading aetiopathological hypothesis is the ‘aberrant salience theory’ whereby abnormal salience is attributed to stimuli leading to psychotic symptoms mediated by striatal dopamine. Reward processing is also thought to be mediated by striatal dopamine and is disrupted in psychosis. One aspect of reward processing is motivational salience, whereby perception of an incentivising stimulus leads to approach behaviour in an organism. Accumulating data points to a role for the endocannabinoid system in both psychosis and reward processing. In particular, the phytocannabinoid cannabidiol (CBD) is a promising candidate as a novel antipsychotic. At the core of this thesis are two published articles using functional magnetic resonance imaging (fMRI) to investigate the neural substrate of motivational salience in health, how it is affected in psychosis and the neurocognitive effects of CBD. The first article is an international meta-analysis of fifteen original fMRI group maps sourced from healthy adult participants (n=346) undertaking the Monetary Incentive Delay Task (MIDT). We analysed the anticipation of monetary reward and loss contrasted with the neutral condition. In both contrasts there was consistent activation of the striatum and salience network, with more complex patterns of activation and deactivation in the central executive network, default network and cerebellum. We subsequently compared the anticipation of reward with loss and found significantly greater relative deactivation in the left inferior frontal gyrus. The second publication reports a randomised double-blind placebo-controlled study using the MIDT in which thirty-three participants at clinical high risk for psychosis (CHR) were administered either 600mg oral CBD or placebo and compared with nineteen healthy controls (HC). CHR subjects represent a population of help-seeking individuals who have experienced psychotic-like symptoms or have significant genetic risk of developing a psychotic illness, but they remain antipsychotic-naïve. Reward and loss anticipation conditions were combined to create a condition of motivational salience, subsequently contrasted with neutral. Region-of-interest analysis was confined to two masks consisting of striatum/midbrain/hippocampus and the core salience network (anterior cingulate/insula). Differences were detected between CHR-placebo and HC groups and CHR-placebo and CHR-CBD groups within the core salience network but not within the mask containing the striatum. There was increased activation in a region of posterior left insula/parietal operculum in CHRplacebo compared to HC. Activation in this area in the CHR-placebo group positively correlated with psychotic symptoms and negatively correlated with salience perception, as indexed by reaction time difference between salient and neutral stimuli. Thus, psychopathology and aberrant salience were 8 linked to increased activation in the same region of brain in CHR. Increased activation in the left insula/parietal operculum in CHR was attenuated by CBD. In conclusion, this thesis establishes that the salience network is activated in motivational salience, and that the neurocognitive dysfunction associated with reward processing in psychosis may be based in the salience network, in particular insula/operculum regions. Moreover, the effect of CBD in attenuating activity in the insula/operculum suggests a potential antipsychotic mechanism-of-action by normalising aberrant motivational salience.
Supervisor: Bhattacharyya, Sagnik Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available