Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease

Abstract

Huntington's disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntington's disease gene (subjects with pre-manifest Huntington's disease): 16 subjects with pre-manifest Huntington's disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntington's disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntington's disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntington's disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntington's disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntington's disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntington's disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

Microcirculation of the brain: morphological assessment in degenerative diseases and restoration processes

“…HD is an autosomal-dominant inherited disease and is caused by an expansion of the CAG trinucleotide repeat in exon 1 of the Huntingtin (Htt) gene, resulting in the expansion of a polyglutamine tract in the protein (Montoya et al, 2006;Novak et al, 2012). MR imaging has identified marked gaps in the cerebral blood flow in HD.…”

Attempted and Successful Compensation in Preclinical and Early Manifest Neurodegeneration – A Review of Task fMRI Studies

“…This additional recruitment of superior and middle frontal gyrus was positively associated with CAG repeat numbers, representing another measure of disease load, rendering the interpretation of frontal recruitment as compensatory more credible (80). Interestingly, medial frontal areas also form part of the DMN, mirroring the above-mentioned interpretation of sustained performance through supporting task-negative regions by Wolf and colleagues (77).…”

Disruption of response inhibition circuits in prodromal Huntington disease

“…HD affects the whole brain, but the most prominent early effect is characterized by a loss of small to medium spiny neurons in the caudate and putamen (Vonsattel & DiFiglia, 1998). However, other neuropathology (e.g., corticostriatal gray-matter atrophy, white-matter volume loss) and subtle signs of the disease, including cognitive changes, are seen during the prodromal HD (prHD) phase, decades prior to the diagnosis of manifest HD (Duff et al, 2010; Harrington, Smith, Zhang, Carlozzi, & Paulsen, 2012; Nopoulos et al, 2010; Novak et al, 2012; Paulsen et al, 2006; Paulsen et al, 2008; Paulsen et al, 2001; Rosas et al, 2005). In conjunction with efforts to identify efficacious treatments to slow disease progression, there has been a concerted effort to identify neuroimaging biomarkers of early brain changes that could serve as outcomes in primary prevention trials of individuals in the prHD phase, when treatments are more likely to succeed.…”

“…Yet the brain mechanisms that govern different facets of cognitive decline in prHD are not well understood. Emerging functional imaging studies report different disease-related patterns of activation during working memory (Wolf et al, 2008; Wolf, Vasic, Schonfeldt-Lecuona, Landwehrmeyer, & Ecker, 2007), attention (Wolf et al, 2012), interference (Reading et al, 2004), temporal processing (Paulsen et al, 2004; Zimbelman et al, 2007), set shifting (Gray et al, 2013), and implicit emotion processing (Novak et al, 2012), typically without deficits in task performance. Some studies report changes in brain functioning in individuals far from a diagnosis (Paulsen et al, 2004; Wolf et al, 2007; Zimbelman et al, 2007), despite the absence of cognitive decline and/or striatal atrophy.…”