Depressive symptoms in prodromal Huntington's Disease correlate with Stroop-interference related functional connectivity in the ventromedial prefrontal cortex

Abstract

Huntington's Disease (HD) is a neurodegenerative disorder caused by a cytosine-adenine-guanine (CAG) triplet repeat-expansion in the Huntingtin (HTT) gene. Diagnosis of HD is classically defined by the presence of motor symptoms; however, cognitive and depressive symptoms frequently precede motor manifestations, and may occur early in the prodromal phase. There are sparse data so far on functional brain correlates of depressive symptoms in prodromal HD. A Stroop color-naming test was administered to 32 subjects in the prodromal phase of HD and 52 expansion-negative controls while performing functional magnetic resonance imaging at 3Tesla. Networks of functional connectivity were identified using group independent component analysis, followed by an analysis of functional network interactions. A contrast of temporal regression-based beta-weights was calculated as a reflection of Stroop-interference related activity and correlated with Center for Epidemiologic Studies Depression (CES-D) scores. For secondary analysis, patients were stratified into two subgroups by median split of CAG repeat-length. Stroop performance was independent of HTT mutation-carrier status and CES-D score. Stroop-interference-related activity of the ventromedial prefrontal cortex-node of the default-mode network, calculated by temporal-regression beta-weights, was more highly correlated with depressive symptoms in subjects in the prodromal phase of HD than in controls, differing significantly. The strength of this correlation and its difference from controls increased when a subgroup of patients with longer CAG repeat lengths was analyzed. These findings suggest that depressive symptoms in prodromal HD subjects may reflect altered functional brain network activity in the context of early HD-related brain alterations.

Figure 1

Stroop-interference is reflected by decreased accuracy and increased reaction times in the incongruent versus the congruent tasks for both controls and prodromal-HD.

Figure 2

Spatial extent of the identified components is indicated based on t-maps. ICA-timecourses indicate z-scores of component activation (solid white lines: means, dotted white lines: ± 0.2 SD) in relation to the Stroop-paradigm applied over time (TR). Green bars indicate rests between Stroop tasks, yellow: Stroop-baseline, orange: Stroop-congruent, red: Stroop-incongruent, vertical dotted green lines indicate the end of the rest-phases.

Figure 3

Linear regression analysis indicates a relationship between Stroop-interference related activity in the ventromedial prefrontal cortex (VMPFC) with CES-Depression scores in prodromal-HD but not in expansion negative controls. This effect appears stronger in the prodromal-HD subgroup with CAG repeat lengths > 42.