Frontostriatal Circuits Alterations Associated with Cognitive Flexibility Deterioration in Huntington's Disease

Area of Science:

• Neuroscience
• Neurology
• Cognitive Science

Background:

• Resting-state functional magnetic resonance imaging (fMRI) studies indicate abnormal prefrontal cortex (PFC)-striatum circuit functional connectivity (FC) in premanifest Huntington's disease (HD).
• Limited evidence exists on the persistence of frontostriatal FC abnormalities and their link to cognitive flexibility in clinically manifest HD patients.

Purpose of the Study:

• To investigate the resting-state FC integrity of the frontostriatal circuit in manifest HD patients compared to healthy controls (HCs).
• To examine the relationship between frontostriatal FC and cognitive flexibility performance in HD patients.

Main Methods:

• Eighteen early clinical manifest HD patients and 18 matched HCs underwent resting-state fMRI scans.
• Cognitive flexibility was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional (IED) set-shift task.
• FC was analyzed in preselected frontostriatal circuits known to be involved in extradimensional (ED) shifting.

Main Results:

• HD patients exhibited significant negative correlations between attentional set-shifting errors and ventral striatum-ventrolateral PFC FC.
• Specific negative FC correlations were observed between total errors and connectivity in right/left ventral striatum-ventrolateral PFC circuits.
• Positive correlation found between stages completed and left ventral striatum-left ventrolateral PFC FC.

Conclusions:

• Manifest HD patients demonstrate cognitive flexibility deficits in attentional set-shifting, associated with frontostriatal FC alterations.
• Frontostriatal FC abnormalities observed in premanifest HD may persist and correlate with cognitive deficits in later clinical stages.
• These findings highlight frontostriatal FC as a potential biomarker for tracking disease progression and cognitive decline in HD.