FRONTO-STRIATAL CIRCUITS FOR COGNITIVE FLEXIBILITY IN FAR FROM ONSET HUNTINGTON'S DISEASE: EVIDENCE FROM THE YOUNG ADULT STUDY

Objectives

Cognitive flexibility, which is key for adaptive decision-making, engages prefrontal cortex (PFC)-striatal circuitry and is impaired in both manifest and premanifest HD (pre-HD). The aim of this study was to examine cognitive flexibility in a far from onset pre-HD cohort to determine whether an early impairment exists and if so, whether fronto-striatal circuits were associated with this deficit.

Methods

In the present study, we examined performance of 51 pre-HD participants (mean age= 29.22 (s.d= 5.71) years) from the HD Young Adult Study cohort and 53 controls matched for age, sex and IQ, on the CANTAB Intra-Extra Dimensional Set-Shift (IED) task. This cohort is unique as it is the furthest from disease onset comprehensively studied to date (mean years= 23.89 (s.d= 5.96)). The IED task measures visual discrimination learning, cognitive flexibility and specifically attentional set-shifting. We used resting-state fMRI to examine whether the functional connectivity between specific fronto-striatal circuits was dysfunctional in pre-HD, as compared to controls, and whether these circuits were associated with performance on the critical extra-dimensional shift stage.

Results

Our results demonstrated that the CANTAB IED task detects a mild early impairment in cognitive flexibility in a pre-HD group far from onset. Attentional set-shifting was significantly related to functional connectivity between the ventrolateral PFC and ventral striatum in healthy controls and to functional connectivity between the dorsolateral PFC and caudate in pre-HD participants.

Conclusion

We postulate that this incipient impairment of cognitive flexibility may be associated with intrinsically abnormal functional connectivity of fronto-striatal circuitry in pre-HD.