The aberrant salience hypothesis of psychosis¹ postulates that hyperdopaminergia in the mesostriatal pathway leads to aberrant assignment of salience to everyday experiences and stimuli, which in turn result in psychotic symptoms. Elevated presynaptic dopamine function in the striatum is established in psychotic disorders² and in subjects at clinical high risk for psychosis (CHR)^3,4, and an understanding of the relationship between dopamine, aberrant salience and psychotic symptoms, particularly delusions, is emerging⁵. It has been suggested that mesostriatal dopaminergic overactivity may be driven by glutamatergic dysfunction in the medial temporal lobe (MTL)⁶, and both increased hippocampal blood flow⁷ and metabolism⁸ have been reported in CHR subjects and established psychosis.

Dopamine signalling is fundamental to reward processing⁹ which is dysfunctional in psychosis¹⁰. Reward processing includes the attribution of ‘motivational salience’, whereby the anticipation of a rewarding stimulus or incentive prepares an individual for ‘approach behaviour’ towards eventual consumption. Neuroimaging studies have demonstrated abnormal brain activity during cognitive tasks capturing ‘motivational salience’ in CHR and psychosis. Compared to healthy controls, CHR subjects have been found to have hypoactivation in the ventral striatum (VS) and midbrain¹¹ and right inferior parietal lobule¹², with VS activity to ‘aberrant’ or non-salient stimuli correlating with severity of positive psychotic symptoms¹³. Others have shown increased activation in the posterior cingulate cortex (PCC), middle and superior frontal gyri (MFG, SFG)¹⁴ and ventral pallidum and midbrain¹⁵. In the VS, activity while processing both non-salient¹³ and salient stimuli¹⁵ have been correlated with positive psychotic symptoms, as has activity in the right anterior insula during salient stimuli¹⁵. In established psychosis, meta-analysis suggests hypoactivation of the VS¹⁶, and individual studies have reported reduced activation in the cingulate and ventral tegmentum in unmedicated patients^12,17, and in the right insula in medicated patients¹² while processing motivational salience.

While the aberrant salience hypothesis of psychosis generally focuses on midbrain and striatal function, emerging evidence points towards a key role for other brain regions. In particular, the ‘salience network’ (SN), anchored in the anterior cingulate (ACC) and insular cortex (IC), may play a role in selecting relevant internal and externally generated signals for higher order processing^18,19. Altered volume, activation and dysconnectivity of components of the SN have been observed both in established psychotic disorders^12,20–22 and in CHR^23–26 prior to the onset of psychosis, with evidence of association between symptoms and both the extent of volume loss²⁷ and altered activation^12,28,29 of the insula. This has led to the hypothesis that psychotic symptoms arise as a result of insular dysfunction within the salience network³⁰.

There is evidence from healthy volunteer studies that cannabidiol (CBD), a non-psychoactive substance in cannabis, opposes the psychotomimetic effects of Δ9-tetrahydrocannabinol (Δ9-THC)^31,32, its main psychoactive ingredient. This is complemented by evidence of efficacy as an antipsychotic in some^33,34, though not all³⁵, clinical trials. We have recently shown that CBD may normalise MTL, midbrain and striatal dysfunction in CHR patients³⁶, but the precise neurocognitive mechanism of any antipsychotic effect remains unclear. Whether CBD modulates aberrant motivational salience, and whether this is linked to any antipsychotic effect remains untested.

Therefore, in this study we investigated whether there is a pattern of abnormal activation in CHR compared to healthy controls during the processing of motivationally salient stimuli, and whether a single dose of CBD attenuates this abnormal function in CHR. We selected CHR subjects, because they are antipsychotic-naïve and at risk of developing psychosis³⁷, thus avoiding confounding effects of dopamine antagonism. Furthermore, they are more stable than people with established psychosis and can better tolerate the demands of complex neuroimaging investigations.

We employed the monetary incentive delay task (MIDT), a reward processing task adapted for fMRI³⁸. The MIDT allows reward processing to be parsed into at least two distinct components: ‘anticipation’ and ‘feedback’. We focused on the anticipation condition, as VS activity in this condition has been linked to dopamine release³⁹, and the SN is robustly activated in both anticipation of reward and loss⁴⁰. Hence, we did not limit anticipation to one specific valence (e.g. reward or loss), but combined all motivationally salient conditions, as previously reported^17,41. Existing research in CHR using the MIDT has found abnormal activation in the PCC, MFG and SFG in reward anticipation¹⁵, though abnormal striatal activity hasn’t been detected^15,42.

Our primary hypothesis was that CHR participants would display altered activation in the core SN (IC and ACC) relative to healthy controls, and a single dose of CBD would have an opposite effect in these regions. Our secondary hypothesis was that CHR participants would display altered activation in the midbrain, striatum and hippocampus, and again CBD would have an opposite effect in these regions.