Orbitofrontal and Thalamic Influences on Striatal Involvement in Human Reversal Learning

Cognitive flexibility is crucial for adaptation and is disrupted in neuropsychiatric disorders and psychopathology. Human studies of flexibility using reversal learning tasks typically contrast error trials before and after reversal, which provides little information about the mechanisms that support learning and expressing a new response. However, animal studies suggest a specific role in this latter process for the connections between the dorsal striatum and the centromedian parafascicular (CM-Pf) thalamus, a system which may recruit the striatal cholinergic interneurons, but which is not well understood in humans. This study investigated the role of this system in human probabilistic reversal learning, specifically with respect to learning a new response strategy, contrasting its function to that of the better understood orbitoftontal-striatal systems. Using psychophysiological interaction (PPI) analysis of functional magnetic resonance imaging (fMRI) data we show that connectivity between the striatum and both the lateral orbitofrontal cortex (lOFC) and CM-Pf pathways increased during reversal, but not initial learning. However, while the strength of lOFC-striatal connectivity was associated with the speed of the reversal, the strength of CM-Pf-striatal connectivity was associated specifically with the quality of the reversal (reduced regressive errors). These findings expand our understanding of flexibility mechanisms in the human brain, bridging the gap with animal studies of this system.