Akshay Nair1, Eileanoir B Johnson2, Sarah Gregory2, Katherine Osborne-Crowley2, Paul Zeun2, Rachael I Scahill2, Jessica Lowe2, Marina Papoutsi2, Stefano Palminteri3, Robb B Rutledge4, Geraint Rees5, Sarah J Tabrizi6. 1. Huntington's Disease Centre, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom; Max Planck University College London Centre for Computational Psychiatry and Ageing Research, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom. 2. Huntington's Disease Centre, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom. 3. Laboratoire de Neurosciences Cognitives et Computationnelles, Institut National de la Santé et de la Recherche Médicale, Paris, France; Département d'Etudes Cognitives, Ecole Normale Supérieure, Paris, France; Université de Paris Sciences et Lettres, Paris, France. 4. Max Planck University College London Centre for Computational Psychiatry and Ageing Research, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom; University College London Institute of Cognitive Neuroscience, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom. 5. University College London Institute of Cognitive Neuroscience, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom. 6. Huntington's Disease Centre, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom; Wellcome Centre for Human Neuroimaging, University College London Queen Square Institute of Neurology, University College London, London, United Kingdom. Electronic address: s.tabrizi@ucl.ac.uk.
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 hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning. METHODS: We recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data. RESULTS: In comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes. CONCLUSIONS: Behaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.
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 hypothesized that HD gene carriers would show either neural or behavioral asymmetry between gain and loss learning. METHODS: We recruited 35 HD gene carriers, expected to demonstrate onset of motor symptoms in an average of 26 years, and 35 well-matched gene-negative control subjects. Participants were placed in a functional magnetic resonance imaging scanner, where they completed an RL task in which they were required to learn to choose between abstract stimuli with the aim of gaining rewards and avoiding losses. Task behavior was modeled using an RL model, and variables from this model were used to probe functional magnetic resonance imaging data. RESULTS: In comparison with well-matched control subjects, gene carriers more than 25 years from motor onset showed exaggerated striatal responses to gain-predicting stimuli compared with loss-predicting stimuli (p = .002) in our RL task. Using computational analysis, we also found group differences in striatal representation of stimulus value (p = .0004). We found no group differences in behavior, cognitive scores, or caudate volumes. CONCLUSIONS: Behaviorally, gene carriers 9 years from predicted onset have been shown to learn better from gains than from losses. Our data suggest that a window exists in which HD-related functional neural changes are detectable long before associated behavioral change and 25 years before predicted motor onset. These represent the earliest functional imaging differences between HD gene carriers and control subjects.