Aberrant striatal value representation in Huntington’s disease gene carriers 25 years before onset

Abstract Background In this study, we asked whether differences in striatal activity during a reinforcement learning (RL) task, with gain and loss domains, could be one of the earliest functional imaging features associated with carrying the Huntington’s Disease (HD) gene. Based on previous work, we hypothesised that HD gene carriers would show either a neural, or behavioural, asymmetry between gain and loss learning. Methods We recruited 35 HD gene carriers, estimated to be on average 26 years from motor onset, and 35 well matched gene negative controls. Participants completed a RL task, in an fMRI scanner, in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behaviour was modelled using a RL model and variables from this model was used to probe fMRI data. Results In comparison to well matched controls, gene carriers over 25 years from motor onset showed exaggerated striatal responses to gain as compared to loss predicting stimuli (p=0.002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p=0.0004). We found no group differences in behaviour, cognitive scores or caudate volumes. Conclusion Behaviourally, gene carriers 9 years from predicted onset have been shown to learn better from gains as compared to losses. Our data suggests a window exists in which HD-related functional neural changes are detectable long before associated behavioural change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and controls.