Abstract/Summary

Animal studies have shown that the striatal cholinergic system plays a role in reversal learning, but there has been no attempt to study this in humans due to a lack of appropriate non-invasive techniques. This body of work aimed to address the gap in the literature concerning the role of the human striatal cholinergic system and its thalamic inputs in cognitive flexibility in vivo. To do this, we used a combination of proton magnetic resonance spectroscopy ('H-MRS) and high-resolution functional magnetic resonance imaging (fMRI), together with a reversal learning task and computational modelling to investigate the relationship between cholinergic function and cognitive flexibility. First, we measured individual levels of choline (CHO) at rest in both the dorsal and ventral striatum using 'H-MRS, and examined their relationship with performance on a reversal learning task. We found that average levels of CHO in the human dorsal striatum (DS) are associated with performance during reversal, but not during initial learning. Specifically, lower levels of CHO in the dorsal striatum were associated with faster perseveration. Moreover, choline levels explained variance in the number of perseverative trials over and above that explained by learning rates from negative prediction errors. Second, we used functional-'H-MRS (fMRS) to measure changes in CHO levels in the DS during performance on the reversal learning task. We found a task-dependent decrease in CHO levels in the human DS specifically during reversal learning. We interpret this to reflect an increase in ACh levels, which is in line with findings from the animal literature. Lastly, we used fMRI along with a combination of parametric modulation and psychophysiological interaction (PPI) analysis to investigate the role of the DS and thalamostriatal interactions during human reversal learning. Parametric modulation revealed a performance-dependent dynamic increase in activation in the dorsal striatum. Additionally, PPI analysis revealed task-dependent changes in connectivity between the DS and the centromedial parafascicular complex, which is the main input to the cholinergic system . Moreover, the strength of connectivity correlated with the ability to flexibly alter behaviour. Taken together, these three experiments provide multimodal in vivo evidence to demonstrate a role for the human cholinergic system in the DS in behavioural flexibility as measured using a reversal learning paradigm. Additionally, this body of work demonstrates that it is possible to use in-vivo 'H-MRS, both at rest and as a functional measure to investigate the human striatal cholinergic system. This method not only helps to bridge the gap between animal and human studies, but importantly may provide a novel method of studying disorders that comprise cholinergic dysfunction in humans in vivo (e.g. Parkinson's Disease, Alzheimer's Disease), extending our understanding of the neural mechanisms underlying these disorders.