The role of the amygdala during emotional processing in Huntington's disease: from pre-manifest to late stage disease

Abstract

Background: Deficits in emotional processing can be detected in the pre-manifest stage of Huntington's disease and negative emotion recognition has been identified as a predictor of clinical diagnosis. The underlying neuropathological correlates of such deficits are typically established using correlative structural MRI studies. This approach does not take into consideration the impact of disruption to the complex interactions between multiple brain circuits on emotional processing. Therefore, exploration of the neural substrates of emotional processing in pre-manifest HD using fMRI connectivity analysis may be a useful way of evaluating the way brain regions interrelate in the period prior to diagnosis.

Methods: We investigated the impact of predicted time to disease onset on brain activation when participants were exposed to pictures of faces with angry and neutral expressions, in 20 pre-manifest HD gene carriers and 23 healthy controls. On the basis of the results of this initial study went on to look at amygdala dependent cognitive performance in 79 Huntington's disease patients from a cross-section of disease stages (pre-manifest to late disease) and 26 healthy controls, using a validated theory of mind task: "the Reading the Mind in the Eyes Test" which has been previously been shown to be amygdala dependent.

Results: Psychophysiological interaction analysis identified reduced connectivity between the left amygdala and right fusiform facial area in pre-manifest HD gene carriers compared to controls when viewing angry compared to neutral faces. Change in PPI connectivity scores correlated with predicted time to disease onset (r=0.45, p<0.05). Furthermore, performance on the "Reading the Mind in the Eyes Test" correlated negatively with proximity to disease onset and became progressively worse with each stage of disease.

Conclusion: Abnormalities in the neural networks underlying social cognition and emotional processing can be detected prior to clinical diagnosis in Huntington's disease. Connectivity between the amygdala and other brain regions is impacted by the disease process in pre-manifest HD and may therefore be a useful way of identifying participants who are approaching a clinical diagnosis. Furthermore, the "Reading the Mind in the Eyes Test" is a surrogate measure of amygdala function that is clinically useful across the entire cross-section of disease stages in HD.

Keywords: Amygdala; Effective connectivity; Reading the mind in the eyes; Theory of mind; fMRI.

Fig. 1

PPI GLM statistical parametrical maps. (A) Positive PPI effects originating from the amygdala during exposure to ‘angry faces’ relative to ‘neutral faces’ for all participants at a liberal threshold (p<0.001 uncorrected, cluster size 50 voxels or more). (B) Decreased PPI connectivity in PMGC's during exposure to ‘angry faces’ relative to ‘neutral faces’ (p<0.05, cluster level corrected).

Fig. 2

Correlation between PPI connectivity originating from the amygdala to the right fusiform facial area and (A) estimated years to disease onset and (B) disease burden score in PMGC's. Participants have be divided into “close” to and “far” from onset groups and further subdivided into pre-manifest, intermediate and confirmed groups to visually represent those gene carriers who have received (confirmed) or are anticipated to imminently receive a diagnosis of HD (intermediate) since scanning. Error bars show the standard errors across all healthy controls. The regression line (solid) and the 95% confidence intervals (dashed) are shown.

Fig. 3

Behavioural performance on the Reading the Mind in the Eyes task stratified by disease stage for all HD participants. ⁎ indicates a significant difference compared to controls at the p=0.05 level.

Fig. 4

Performance on the Reading the Mind in the Eyes Tasks correlated with total functional assessment score from the UHDRS.

Fig. 5

Correlation between performance on the Reading the Mind in the Eyes task and (A) the estimated number of years to disease onset and (B) the disease burden score in PMGC's.

Fig. 6

Correlation between PPI connectivity between the amygdala and the right fusiform facial area and performance on the Reading the Mind in the Eyes Task in PMGC's. The regression line (solid) and the 95% confidence intervals (dashed) are shown.