Supplementary Material for: Frontostriatal circuits alterations associated with cognitive flexibility deterioration in Huntington's disease

Background: Recent resting-state functional magnetic resonance imaging studies have reported abnormal functional connectivity (FC) in the prefrontal cortex (PFC)-striatum circuit in patients with premanifest Huntington's disease (HD). However, there is a lack of evidence showing persistence of abnormal frontostriatal FC and its relation to cognitive flexibility performance in patients with clinically manifest HD. Objective: To evaluate the resting state FC integrity of the frontostriatal circuit and its relation to cognitive flexibility in HD patients and Healthy Controls (HC). Method: 18 patients with early clinical HD manifestation and 18 healthy controls matched for age, sex and education participated in this study. Both groups performed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional Set-Shift (IED) task, which measures cognitive flexibility. Resting-state functional magnetic resonance images (MRI) were also acquired to examine the functional connectivity in specific frontostriatal circuits. Eight regions of interest (ROI) were pre-selected based on regions previously associated with extradimensional shifting in patients with premanifest-HD. Results: Significant negative correlations between the number of attentional set-shifting errors and the ventral striatum-ventrolateral PFC FC were found in the HD group. This group also showed negative FC correlations between the total errors and the FC between right ventral striatum-right ventrolateral PFC, left ventral striatum-left ventrolateral PFC, and right ventral striatum-left ventrolateral PFC. Negative correlations between the Extra Dimensional (ED) errors and left ventral striatum-left ventrolateral PFC and right ventral striatum-right ventrolateral PFC FC were also found. Finally, a positive correlation between the number of stages completed and left ventral striatum-left ventrolateral PFC FC was found. Conclusions: Manifest HD patients show significant cognitive flexibility deficits in attentional set-shifting that are associated with FC alterations in the frontostriatal circuit. These results show that FC abnormalities found in the prodromal stage of the disease can also be associated with cognitive flexibility deficits at a later clinical stage, making them good candidates to be explored in longitudinal studies.